By Paul M La Bounty¹, Bill I Campbell², Jacob Wilson³, Elfego Galvan⁴, John Berardi⁵, Susan M Kleiner⁶, Richard B Kreider⁷, Jeffrey R Stout⁸, Tim Ziegenfuss⁹, Marie Spano¹⁰, Abbie Smith¹¹ and Jose Antonio¹²

Journal of the International Society of Sports Nutrition 2011

Abstract

Position Statement: Admittedly, research to date examining the physiological effects of meal frequency in humans is somewhat limited. More specifically, data that has specifically examined the impact of meal frequency on body composition, training adaptations, and performance in physically active individuals and athletes is scant. Until more research is available in the physically active and athletic populations, definitive conclusions cannot be made. However, within the confines of the current scientific literature, we assert that:

1. Increasing meal frequency does not appear to favorably change body composition in sedentary populations.

2. If protein levels are adequate, increasing meal frequency during periods of hypoenergetic dieting may preserve lean body mass in athletic populations.

3. Increased meal frequency appears to have a positive effect on various blood markers of health, particularly LDL cholesterol, total cholesterol, and insulin.

4. Increased meal frequency does not appear to significantly enhance diet induced thermogenesis, total energy expenditure or resting metabolic rate.

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5. Increasing meal frequency appears to help decrease hunger and improve appetite control.

The following literature review has been prepared by the authors in support of the aforementioned position statement.

Introduction

Among adults 20 years or older, living in the United States, 65.1% are classified as overweight or obese [1]. Furthermore, there is no indication that this trend is improving [1]. Excess body fat has potential physical and psychological health implications as well as potential negative influences on sport performance as well. The various dietary aspects that are associated with overeating and obesity are not well understood [2]. One debated area that is often purported to play a role in body weight/composition changes is meal frequency. The amount and type of calories consumed, along with the frequency of eating, is greatly affected by sociological and cultural factors [3]. Recent evidence suggests that the frequency in which one eats may also be, at least in part, genetically influenced [4]. Infants have a natural desire to eat small meals (i.e., nibble) throughout the day [5]. However, as soon as a child reaches a certain age he/she is trained to consume meals in a generally predictable manner [5]. In the modernized world, meal frequency is affected by cultural/social norms as well as an individual's personal beliefs about his/her health or body composition. According to a study utilizing data from the 1987-1988 Nationwide Food Consumption Survey (NFCS), the average daily meal frequency for the 3,182 American adults that completed the study was 3.47 [6]. If meals that consisted of less than or equal to 70 kcals, (primarily consisting of tea, coffee, or diet beverages) were excluded from the analysis, the number decreased to 3.12 meals per day. These habits closely mirror the traditional three meals per day pattern (i.e., breakfast, lunch, and dinner) that is common throughout the industrialized world. Although it is often suggested that "nibblers" or "grazers" (i.e., defined in much of the pertinent literature as those that eat smaller meals, but more frequently throughout the day) may be at a metabolic advantage as compared to the "gorgers" (i.e., those that eat fewer, but larger meals), the evidence is inconclusive. Some scientists have theorized that consuming a small number of larger meals throughout the day may lead to increased obesity possibly due to increased fat synthesis and storage (i.e., lipogenesis) following a meal [7]. However, there remains debate within the scientific community as the available data is still somewhat equivocal.

In the last few years, studies on the effects of meal frequency have been encouraged among researchers [8]. A majority of this research is justifiably centered on the obesity epidemic. Unfortunately, there is very limited data that has examined the impact of meal frequency on body composition, training adaptations, and performance in physically active individuals and athletes. The primary purpose of this position stand is to discuss the various research findings in which meal/eating frequency has been an independent variable in human studies that assess body composition, various health markers, thermic effect of food (a.k.a. diet induced thermogenesis), energy expenditure, nitrogen retention, and satiety. Also, an attempt has been made to highlight those investigations that have included athletes and physically active individuals in interventions that varied meal frequency eating patterns.

Body Weight and Body Composition

Observational Studies

Several studies utilizing animal models have demonstrated that meal frequency can affect body composition [9-12]. Specifically, an inverse relationship between meal frequency and body composition has been reported [9-12]. Some of the earliest studies exploring the relationship between body weight and meal frequency in humans were published approximately 50 years ago. Table 1 and 2 provide a brief summary of several observational (i.e., cross-sectional, prospective, etc.) human studies that have examined the effect of meal frequency on body weight and/or body composition.

The observational studies listed in Table 1 tend to support [13-19], while investigations in Table 2 refute [2,20-29] the effectiveness of increased meal frequency on body weight and/or body composition. Some of the aforementioned studies [13-15,18,19], if taken at face value, seem to effectively suggest a compelling negative correlation between meal frequency and body composition/body weight. However, aside from obvious genetic differences between subjects, there are other potential confounding factors that could alter the interpretation of these data. Studies in humans that have compared self-reported dietary intake to measured and/or estimated total daily energy expenditure have shown that under-reporting of food is not uncommon in both obese and non-obese individuals [30]. Several investigations have demonstrated that the under-reporting may be significantly greater in overweight and obese individuals [24,30-35]. Additionally, older individuals have also been shown to underreport dietary intake [36]. Under-reporting of dietary intake may be a potential source of error in some of the previously mentioned studies [13-15,18,19] that reported positive effects of increased meal frequency. In fact, in their well written critical review of the meal frequency research from ~1964-1997, Bellisle et al. [37] point this out and suggest that classification of subjects' meal frequency and under-reporting of dietary intake can potentially complicate the interpretation of these previously mentioned studies as well as future studies that explore this relationship. Bellisle and colleagues [37] also bring up the valid point of "reverse causality" in which someone who gains weight might skip meal(s) with the hope that they will lose weight. If an individual chooses to do this during the course of a longitudinal study, where meal frequency data is collected, it could potentially alter data interpretation to make it artificially appear that decreased meal frequency actually caused the weight gain [37]. However, even taking reverse causality into account, certain studies listed in Table 1 still demonstrated a positive effect of increased meal frequency on body weight/composition even after accounting for possible under-reporters [16,17] and dieters/restrained eaters [17]. Thus, the potential problem of under-reporting cannot be generalized to all studies that have shown a benefit of increased meal frequency.

Equally important, several studies that initially found a significant inverse relationship between meal frequency and body weight/composition were no longer significant after the investigators adjusted for under-reporters [22,23], dieters/restrained eaters [24], physical activity/peak oxygen consumption [29], or other various potential confounding variables such as age, energy intake, physical activity, smoking status, etc. [21]. Nevertheless, Ruidavets et al. [17] still demonstrated a significant negative correlation between meal frequency and both BMI and waist-to-hip ratio even after adjusting for under-reporters, and dieters.

Taking all of the observational studies listed in Table 1 and 2 into account, it is difficult to make definitive conclusions about the relationship between meal/eating frequency and body weight/composition. However, when accounting for the effects of under-reporting, exercise, and other confounding variables, the preponderance of the research suggests that increased meal frequency does not play a significant role in decreasing body weight/weight composition.

Experimental Studies

The majority of experimental studies utilizing meal frequency interventions recruited overweight/obese populations [38-42]. When total daily calories were held constant (but hypocaloric) it was reported that the amount of body weight lost was not different even as meal frequency increased from a range of one meal per day up to nine meals per day [38-42]. Most recently in 2010, Cameron et al. [43] examined the effects of an eight week hypocaloric diet in both obese male and female participants. The subjects consumed either three meals per day (low meal frequency) or three meals plus three additional snacks (high meal frequency). Individuals in both the high and low meal frequency groups had the same caloric restriction (~700 kcals/day). Both groups lost ~5% of their initial weight as well as similar decreases in lean mass, fat mass and overall BMI [43]. There were no significant differences between the varying meal frequencies groups in any measure of adiposity [43].

In addition to overweight/obese populations, a few experimental investigations have been conducted in normal weight subjects [44-47]. In relation to improvements in body weight and body composition, the results were similar to those of the overweight/obese trials - no improvements with increasing meal frequencies [44-47]. Even under isocaloric conditions or when caloric intake was designed to maintain the subjects' current body weight, increasing meal frequency from one meal to five meals [47] or one meal to three meals [45] did not improve weight loss. One exception to the non-effectiveness of increasing meal frequency in bodyweight/composition was conducted by Fabry and coworkers [48]. The investigators demonstrated that increases in skinfold thickness were significantly greater when ingesting three meals per day as compared to five or seven meals per day in ~10-16 year old boys and girls. Conversely, no significant differences were observed in ~6-11 year old boys or girls [48].

Application to Nutritional Practices of Athletes: Based on the data from experimental investigations utilizing obese and normal weight participants, it would appear that increasing meal frequency would not benefit the athlete in terms of improving body composition. Interestingly, when improvements in body composition are reported as a result of increasing meal frequency, the population studied was an athletic cohort [49-51]. Thus, based on this limited information, one might speculate that an increased meal frequency in athletic populations may improve body composition. The results of these studies and their implications will be discussed later in the section entitled "Athletic Populations".

Blood Markers of Health

Reduced caloric intake, in a variety of insects, worms, rats, and fish, has been shown to have a positive impact on health and lifespan [52-54]. Similarly, reduced caloric intake has been shown to have health promoting benefits in both obese and normal-weight adults as well [55]. Some of the observed health benefits in apparently healthy humans include a reduction in the following parameters: blood pressure, C-reactive protein (CRP), fasting plasma glucose and insulin, total cholesterol, LDL cholesterol, and atherosclerotic plaque formation [55]. However, much less has been published in the scientific literature regarding the effects of varying meal frequencies on markers of health such as serum lipids, serum glucose, blood pressure, hormone levels, and cholesterol.

Gwinup and colleagues [56,57] performed some of the initial descriptive investigations examining the effects of "nibbling" versus "gorging" on serum lipids and glucose in humans. In one study [57], five hospitalized adult women and men were instructed to ingest an isocaloric amount of food for 14 days in crossover design in the following manner:

• One large meal per day

• 10 meals per day given every two hours

• Three meals per day

"Gorging" (i.e., one meal per day) led to increases in serum lipids when compared to eating three meals per day. Conversely, 14 days of "nibbling" (i.e., 10 meals per day) led to small decreases in serum lipids such as serum phospholipids, esterified fatty acids, and cholesterol [57]. It is important to point out that this study only descriptively examined changes within the individual and no statistical analyses were made between or amongst the participants [57]. Other studies using obese [58] and non-obese [59] subjects also reported significant improvements in total cholesterol when an isocaloric amount of food was ingested in eight meals vs. one meal [58] and 17 snacks vs. 3 normal meals [59]. In a cross-sectional study which included 6,890 men and 7,776 women between the ages of 45-75 years, it was reported that the mean concentrations of both total cholesterol and LDL cholesterol significantly decreased with increased meal frequency in the general population, even after adjusting for possible confounding variables such as obesity, age, physical activity, and dietary intake [25]. Specifically, after adjusting for confounding variables, the mean total and LDL cholesterol concentrations were ~5% lower in the individuals that ate more than six times a day as opposed to those only eating once or twice per day [25]. Similarly, Edelstein and colleagues [60] reported that in 2,034 men and women aged 50-89, the individuals that ate greater than or equal to four times per day had significantly lower total cholesterol than those who ate only one to two meals per day. Equally important, LDL concentrations were also lower in those who ate with greater frequency [60].

A more recent study examined the influence of meal frequency on a variety of health markers in humans [45]. Stote et al. [45] compared the effects of consuming either three traditional meals (i.e., breakfast, lunch, and dinner) or one large meal on markers of health. The study was a randomized, crossover study in which each participant was subjected to both meal frequency interventions for eight weeks with an 11 week washout period between interventions [45]. All of the study participants ingested an amount of calories needed to maintain body weight, regardless if they consumed the calories in either one or three meals per day. The individuals who consumed only one meal per day had significant increases in blood pressure, and both total and LDL cholesterol [45].

In addition to improvements with lipoproteins, there is evidence that increasing meal frequency also exerts a positive effect on glucose kinetics. Gwinup et al., [5,56] along with others [13], have reported that "nibbling" or increased meal frequency improved glucose tolerance. Specifically, when participants were administered 4 smaller meals, administered in 40 minute intervals, as opposed to one large meal of equal energy density, lower glucose and insulin secretion were observed [61]. Jenkins and colleagues [59] demonstrated no significant changes in serum glucose concentrations between diets consisting of 17 snacks compared to three isocaloric meals per day. However, those that ate 17 snacks per day significantly decreased their serum insulin levels by 27.9% [59]. Ma et al. [18] point out that the decrease in serum insulin with increased meal frequency may decrease body fat deposition by decreasing lipase enzyme activity.

Contrary to the aforementioned studies, some investigations using healthy men [62], healthy women [63], and overweight women [39] have reported no benefits in relation to cholesterol and triglycerides. Although not all research agrees regarding blood markers of health such as total cholesterol, LDL cholesterol, and glucose tolerance, it appears that increasing meal frequency may have a beneficial effect. Mann [64] concluded in his review article that there seems to be no deleterious effects in regard to plasma lipids or lipoproteins by eating a relatively large number of smaller meals. It is noted, however, that the studies where benefits have been observed with increased meal frequency have been relatively short and it is not known whether these positive adaptations would occur in longer duration studies [64].

Application to Nutritional Practices of Athletes: Although athletic and physically active populations have not been independently studied in this domain, given the beneficial outcomes that increasing meal frequency exerts on a variety of health markers in non-athletic populations, it appears as if increasing meal frequency in athletic populations is warranted in terms of improving blood markers of health.
Metabolism

Metabolism encompasses the totality of chemical reactions within a living organism. In an attempt to examine this broad subject in a categorized manner, the following sections will discuss the effects of meal frequency on:

• Diet induced thermogenesis (i.e., DIT or also known as the thermic effect of food)

• Resting metabolic rate/total energy expenditure

• Protein Metabolism

Diet Induced Thermogenesis

It is often theorized that increased eating frequency may be able to positively influence the thermic effect of food, often referred to as diet induced thermogenesis (DIT), throughout the day as compared to larger, but less frequent feedings [65]. Kinabo and Durnin [65] investigated this theory when they instructed eighteen non-obese females to consume either a high carbohydrate-low fat diet consisting of 70%, 19%, and 11% or a low carbohydrate-high fat diet consisting of 24%, 65% and 11% from carbohydrate, fat and protein, respectively [65]. Each diet was isocaloric and consisted of 1,200 kcals. In addition, on two different instances, each participant consumed their meal either in one large meal or as two smaller meals of equal size. The investigators observed no significant difference in the thermic effect of food either between meal frequencies or between the compositions of the food [65].

In two other studies utilizing normal-weight young women [66] and obese children [67] as subjects, it was reported that the ingestion of one large meal significantly increased resting energy expenditure/thermic effect of food as compared to an isocaloric food intake that was ingested in either six [66] or three [67] smaller meals. LeBlanc et al. [61] tested the thermic effect of food in six individuals after consuming four small meals as opposed to one large meal of equal caloric density. Contrary to the earlier findings of Tai et al. [66], post-prandial thermogenesis and fat utilization was greater in the group that consumed the smaller, more frequent meals [61].

Smeets and colleagues [68] conducted a very practical study comparing the differences in consuming either two or three meals a day in normal weight females in energy balance. In this randomized, crossover design in which participants consumed the same amount of calories over a traditional three meal pattern (i.e., breakfast, lunch, and dinner) compared to just two meals (breakfast and dinner) it was demonstrated that there was no significant difference on diet induced thermogenesis when measured over 36 hours in a respiration chamber [68]. However, by consuming three meals per day, fat oxidation, measured over 24 hours using deuterium labeled fatty acids was significantly greater and carbohydrate oxidation was significantly lower when compared to eating just two meals per day [68].

Resting Metabolic Rate/Total Energy Expenditure

It is argued that the best methodology to study the effects of meal frequency on metabolism utilizes a metabolic/respiratory chamber (i.e., a whole body calorimeter). While these conditions are not free living, these types of studies are able to control extraneous variables to a greater extent than other methods. Four investigations utilizing overweight/obese participants [40,41,69,70] and one investigation examining normal-weight participants [7] confined the participants to either a metabolic/respiration chamber [7,41,69,70] or a confined metabolic unit [40] and reported that there were no improvements in resting metabolic rate or 24-hour energy expenditure due to increasing the number of meals ingested. In each of these investigations, the same number of calories were ingested over the duration of a day, but the number of meals ingested to consume those calories varied from one vs. three and five feedings [40], two vs. three to five feedings [41], two vs. seven feedings [7,70], and two vs. six feedings [69]. The amount of time the participants were confined to the metabolic/respiratory chambers or metabolic unit ranged from a few hours [7] to a few days [41,69,70] to several weeks [40]. From the aforementioned studies examining the effect of meal frequency on the thermic effect of food and total energy expenditure, it appears that increasing meal frequency does not statistically elevate metabolic rate.

Protein Metabolism

Garrow et al., [40] reported that during a hypocaloric diet lasting three weeks in obese subjects, nitrogen loss was significantly less when the diet consisted of 15% protein as opposed to 10% protein. Additionally, nitrogen loss was also significantly less when five versus one meal per day were consumed and protein was kept at a constant 13% [40]. Equally important, the lowest nitrogen loss occurred when five versus one meal per day were consumed and protein content was 15% versus 10% [40]. The authors concluded that the protein content of total caloric intake is more important than the frequency of the meals in terms of preserving lean tissue and that higher protein meals are protein sparing even when consuming low energy intakes [40]. While this study was conducted in obese individuals, it may have practical implications in athletic populations. Specifically, the findings support the idea that frequent feedings with a higher protein content (15% vs. 10%) may reduce nitrogen losses during periods of hypocaloric intake.

In contrast to the Garrow et al. findings, Irwin et al. [63] compared the effects of different meal composition and frequency on nitrogen retention. In this study, healthy, young women consumed either three meals of equal size, three meals of unequal size (two small and one large), or six meals (calorie intake was equal between groups). The investigators reported that there was no significant difference in nitrogen retention between any of the different meal frequency regimens [63].

Finkelstein and Fryer [39] also reported no significant difference in nitrogen retention, measured through urinary nitrogen excretion, in young women who consumed an isocaloric diet ingested over three or six meals. The study lasted 60 days, in which the participants first consumed 1,700 kcals for 30 days and then consumed 1,400 kcals for the remaining 30 days [39]. The protein and fat content during the first 30 days was 115 and 50 grams, respectively, and during the last 30 days 106 grams of protein and 40 grams of fat was ingested. The protein content was relatively high (i.e., ~27% - 30% of the total daily calories) and may have aided in the nitrogen retention that was observed. Similarly, in a 14-week intervention, Young et al., [42] reported that consuming 1,800 kcals fed as one, three, or six meals a day did not have a significant impact on nitrogen retention in 11 moderately obese, college aged men.

It is important to emphasize that the previous studies were based on the nitrogen balance technique. Nitrogen balance is a measure of whole body protein flux, and may not be an ideal measure of skeletal muscle protein metabolism. Thus, studies concerned with skeletal muscle should analyze direct measures of skeletal muscle protein synthesis and breakdown (i.e., net protein synthesis). Based on recent research, it appears that skeletal muscle protein synthesis on a per meal basis may be optimized at approximately 20 to 30 grams of high quality protein, or 10-15 grams of essential amino acids [71-73]. In order to optimize skeletal muscle protein balance, an individual will likely need to maximize the response on a per meal basis. Research shows that a typical American diet distributes their protein intake unequally, such that the least amount of protein is consumed with breakfast (~10-14 grams), while the majority of protein is consumed with dinner (~29-42 grams) [74]. Thus, in the American diet, protein synthesis would likely only be optimized once per day with dinner. This was recently demonstrated by Wilson et al. [75] in a published abstract (utilizing a rodent model). The investigators found that equally distributing protein over three meals (16% per meal) resulted in greater overall protein synthesis and muscle mass, in comparison to providing suboptimal protein (8%) at breakfast and lunch, and greater than optimal protein (27%) with dinner [75]. In eucaloric meal frequency studies, which spread protein intake from a few (i.e., two to three meals) to several meals (i.e., greater than five meals), the bolus of protein per meal shrinks, which may provide several suboptimal, or possibly non-significant rises in protein synthesis as opposed to a few meals which may maximally stimulate protein synthesis. This is likely the case in the previously mentioned study by Irwin et al [63] who compared three ~20 gram protein containing meals, to six ~10 gram protein containing meals. Such a study design may negate any positive effects meal distribution could have on protein balance.

With this said, in order to observe the true relationship between meal frequency and protein status, studies likely need to provide designs in which protein synthesis is maximized over five-six meals as opposed to three meals. This was demonstrated by Paddon-Jones and colleagues [76] who found that mixed muscle protein synthesis was ~23% greater when consuming three large ~850-calorie meals (~23 g protein, ~127 g carbohydrate, and ~30 g fat), supplemented with an additional three small 180-calorie meals containing 15 grams of essential amino acids, as compared to just three 850-calorie meals alone. In summary, the recent findings from the Wilson study [75] combined with the results published by Paddon-Jones et al. [76] suggest that when protein synthesis is optimized, increased feeding frequency may positively impact protein status.

The inattention paid to protein intake in previously published meal frequency investigations may force us to reevaluate their utility. Nutrient timing research [77,78] has demonstrated the importance of protein ingestion before, during, and following physical activity. Therefore, future research investigating the effects of meal frequency on body composition, health markers, and metabolism should seek to discover the impact that total protein intake has on these markers and not solely focus on total caloric intake.

Application to Nutritional Practices of Athletes: Athletic and physically active populations have not been independently studied in relation to increasing meal frequency and observing the changes in resting metabolic rate/total energy expenditure. Considering the data published in overweight/obese and normal weight populations, it appears as if increasing meal frequency would not improve resting metabolic rate/total energy expenditure in physically active or athletic populations. In regards to protein metabolism, it appears as if the protein content provided in each meal may be more important than the frequency of the meals ingested, particularly during hypoenergetic intakes.

Hunger and Satiety

Research suggests that the quantity, volume, and the macronutrient composition of food may affect hunger and satiety [79-83]. However, the effect of meal frequency on hunger is less understood. Speechly and colleagues [83] examined the effect of varying meal frequencies on hunger and subsequent food intake in seven obese men. The study participants consumed 1/3 of their daily energy requirement in one single pre-load meal or evenly divided over five meals administered hourly. The meals consisted of 70% carbohydrate, 15% protein, and 15% fat. Several hours after the initial pre-load meal(s), another meal (i.e., lunch) was given to the participants ad libitum to see if there was a difference in the amount that was consumed following the initial pre-load meal(s). The scientists reported that when the single pre-load meal was given, participants consumed 27% (i.e., ~358 kcals) more energy in the ad libitum meal than those who ate the multiple pre-load meals [83]. Interestingly, this difference occurred even though there were no significant changes in subjective hunger ratings [83]. Another study with a similar design by Speechly and Buffenstein [84] demonstrated greater appetite control with increased meal frequency in lean individuals. The investigators also suggest that eating more frequent meals might not only affect insulin levels, but may affect gastric stretch and gastric hormones that contribute to satiety [84].

Stote et al. [45] reported that there were significantly greater increases in hunger in individuals eating only one meal as compared to three meals per day. In addition, Smeets and colleagues [68] demonstrated that consuming the same energy content spread over three (i.e., breakfast, lunch, and dinner) instead of two (i.e., breakfast and dinner) meals per day led to significantly greater feeling of satiety over 24 hours [68]. To the contrary, however, Cameron and coworkers [43] reported that there were no significant differences in feelings of hunger or fullness between individuals that consumed an energy restricted diet consisting of either three meals per day or three meals and three snacks. Furthermore, the investigators also determined that there were no significant differences between the groups for either total ghrelin or neuropeptide YY [43]. Both of the measured gut peptides, ghrelin and neuropeptide YY, are believed to stimulate appetite.

Although all research does not agree, it appears that the preponderance of the available research suggests that eating more frequently may decrease hunger and/or food intake at subsequent meals. Even if nothing else was directly affected by varying meal frequency other than hunger alone, this could possibly justify the need to increase meal frequency if the overall goal is to suppress the feeling of hunger.

Application to Nutritional Practices of Athletes: Athletic and physically active populations have not been independently studied in relation to increasing meal frequency and observing the changes in subjective hunger feelings or satiety. Utilizing data from non-athletic populations, increasing meal frequency would likely decrease feelings of hunger and/or food intake at subsequent meals for athletes as well. For athletes wishing to gain weight, a planned nutrition strategy should be implemented to ensure hyper-energetic eating patterns.

Athletic Populations

To date, there is a very limited research that examines the relationship of meal frequency on body composition, hunger, nitrogen retention, and other related issues in athletes. However, in many sports, including those with weight restrictions (gymnastics, wrestling, mixed martial arts, and boxing), small changes in body composition and lean muscle retention can have a significant impact upon performance. Therefore, more research in this area is warranted.

In relation to optimizing body composition, the most important variables are energy intake and energy expenditure. In most of the investigations discussed in this position stand in terms of meal frequency, energy intake and energy expenditure were evaluated in 24-hour time blocks. However, when only observing 24-hour time blocks in relation to total energy intake and energy expenditure, periods of energy imbalance that occurs within a day cannot be evaluated. Researchers from Georgia State University developed a method for simultaneously estimating energy intake and energy expenditure in one-hour units (which allows for an hourly comparison of energy balance) [50]. While this procedure is not fully validated, research has examined the relationship between energy deficits and energy surpluses and body composition in elite female athletes. In a study by Duetz et al. [50], four groups of athletes were studied: artistic and rhythmic gymnasts (anaerobic athletes), and middle-distance and long-distance runners (aerobic athletes). While this study did not directly report meal frequency, energy imbalances (energy deficits and energy surpluses), which are primarily influenced through food intake at multiple times throughout the day were assessed. When analyzing the data from all of the elite female athletes together, it was reported that there was an approximate 800 kilocalorie deficit over the 24-hour data collection period [50]. However, the main purpose of this investigation was to determine energy imbalance not as a daily total, but as 24 individual hourly energy balance estimates. It was reported that the average number of hours in which the within-day energy deficits were greater than 300 kcal was about 7.5 hours, while the average number of hours where the within-day energy surpluses were greater than 300 kcal was about three hours (which makes sense since these athletes were consuming a hypocaloric diet) [50]. When data from all the athletes were combined, energy deficits were positively correlated with body fat percentage, whereas energy surpluses were negatively correlated with body fat percentage. Similarly, the total hours with deficit kcals was positively correlated with body fat percentage, while the total hours with surplus kcals were negatively correlated with body fat percentage. It is also interesting to note that an energy surplus was (non-significantly) inversely associated with body fat percentage. In light of these findings, the authors concluded that athletes should not follow restrained or delayed eating patterns to achieve a desired body composition [50].

Iwao and colleagues [51] examined boxers who were subjected to a hypocaloric diet while either consuming two or six meals per day. The study lasted for two weeks and the participants consumed 1,200 kcals per day. At the conclusion of the study, overall weight loss was not significantly different between the groups [51]. However, individuals that consumed 6 meals per day had significantly less loss of lean body mass and urinary 3-methylhistidine/creatinine as opposed to those that only consumed two meals [51]. This would suggest that an increased meal frequency under hypocaloric conditions may have an anti-catabolic effect.

A published abstract by Benardot et al. [49] demonstrated that when a 250 calorie snack was given to 60 male and female college athletes for two weeks after breakfast, lunch, and dinner, as opposed to a non-caloric placebo, a significant amount of fat (-1.03%) was lost and lean body mass (+1.2 kg) gained. Furthermore, a significant increase in anaerobic power and energy output was observed via a 30-second Wingate test in those that consumed the 250 calorie snack [49]. Conversely, no significant changes were observed in those consuming the non-caloric placebo. Interestingly, when individuals consumed the total snacks of 750 kcals a day, they only had a non-significant increase in total daily caloric consumption of 128 kcals [49]. In other words, they concomitantly ate fewer calories at each meal. Lastly, when the 250 kcal snacks were removed, the aforementioned values moved back to baseline levels 4 weeks later [49].

In conclusion, the small body of studies that utilized athletes as study participants demonstrated that increased meal frequency had the following benefits:

• suppression of lean body mass losses during a hypocaloric diet [51]

• significant increases in lean body mass and anaerobic power [49] (abstract)

• significant increases in fat loss [49] (abstract)

These trends indicate that if meal frequency improves body composition, it is likely to occur in an athletic population as opposed to a sedentary population. While no experimental studies have investigated why athletes may benefit more from increased meal frequency as compared to sedentary individuals, it may be due to the anabolic stimulus of exercise training and how ingested nutrients are partitioned throughout the body. It is also possible that a greater energy flux (intake and expenditure) leads to increased futile cycling, and over time, this has beneficial effects on body composition.

Even though the relationship between energy intake and frequency of eating has not been systematically studied in athletes, available data demonstrates that athletes (runners, swimmers, triathletes) follow a high meal frequency (ranging from 5 to 10 eating occasions) in their daily eating practices [85-88]. Such eating practices enable athletes to ingest a culturally normalized eating pattern (breakfast, lunch, and dinner), but also enable them to adhere to the principles of nutrient timing (i.e., ingesting carbohydrate and protein nutrients in the time periods before and immediately following physical activity/competition).

Conclusion

Like many areas of nutritional science, there is no universal consensus regarding the effects of meal frequency on body composition, body weight, markers of health, markers of metabolism, nitrogen retention, or satiety. The equivocal outcomes of the studies that have examined the relationship between meal frequency and body composition may be attributed to under-reporting of food intake (especially in overweight or obese individuals), the various ages of participants, and whether or not exercise/physical activity was accounted for in the analysis. Furthermore, it has been pointed out by Ruidavets et al. [17] that the various ways a meal versus a snack is defined may lead to a different classification of study participants and ultimately influence the outcome of a study. Equally important, calculating actual meal frequency, especially in free-living studies, depends on the time between meals, referred to as "time lag", and may also influence study findings [17]. Social and cultural definitions of an actual "meal" (vs. snack) vary greatly and time between "meals" is arbitrary [17]. In other words, if the "time-lag" is very short, it may increase the number of feedings as opposed to a study with a greater "time-lag" [17]. Thus, all of these potential variables must be considered when attempting to establish an overall opinion on the effects of meal frequency on body composition, markers of health, various aspect of metabolism, and satiety. Taking all of this into account, it appears from the existing (albeit limited) body of research that increased meal frequency may not play a significant role in weight loss/gain when under-reporting, restrained eating, and exercise are accounted for in the statistical analyses. Furthermore, most, but not all of the existing research, fails to support the effectiveness of increased meal frequency on the thermic effect of food, resting metabolic rate, and total energy expenditure. However, when energy intake is limited, increased meal frequency may likely decrease hunger, decrease nitrogen loss, improve lipid oxidation, and improve blood markers such as total and LDL cholesterol, and insulin. Nonetheless, more well-designed research studies involving various meal frequencies, particularly in physically active/athletic populations are warranted.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All authors read and extensively reviewed and contributed to the final manuscript.

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© 2011 La Bounty et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Comments

by EricT

Anticaking agents, sometimes called free-flow agents, are substances added to finely powdered or crystallized food products to prevent them from caking or lumping. These are used in baking powder, salt, confectioner's sugar, chocoalte, milk, cream, and coffee powders, to name but a few. Examples are silicon dioxide, calcium silicate, sodium aluminosilicate, and dicalcium phosphate. Other natural examples include talc and potato starch.

by EricT

By Ground Up Strength

The following is a simple guide to the many different kinds of simple sugars found in prepared and processed foods. All of these sugars contain about the same carbohydrates and deliver the same amount of calories, and so are essentially equivalent, to white table sugar. To begin, the basic monosaccharides and dissaccharides important in nutrition are briefly discussed.

The Monosaccharides

Monosaccharides are the simplest form of carbohydrates. They cannot be reduced in size by hydrolosis and so are sometimes called "simple sugars". However, in common usage the term simple sugar usually also includes disaccharides, discussed below, which are two monosaccharides bonded together.

The three main monosaccharides important in human nutrition are glucose, fructose, and galactose. Glucose, a 6-carbon atom, is by far the most abundant monosaccacharide in nature and the most important nutritionally. Fructose is another monosaccharide found in fruits, flower nectar, honey, and the sap of trees. It is a good deal sweeter than glucose. The third simple sugar is galactose, which is a component of "milk sugar", a disaccharide called lactose. Glucose, fructose, and galactose are all classified as a triose, referring to the number of carbon atoms in their saccharide unit (tri- means "three" and -ose means "sugar).

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More Articles About Sugars and Added Sugar

Disaccharides

Disaccharides are the most abundant form of the ogliosaccharides, which consist of short chains of monosaccharide units joined by covalent bonds.

Sucrose, which is the disaccharide in white table sugar, is the most important nutritionally, comprising at least a third of the carbohydrate intake in an average diet. It is what most of us are thinking of when we say the word "sugar." and contains equal amounts of bonded glucose and fructose (ß-D-fructofuronasyl-α-D-glucopyronoside). Sucrose contains 5 grams of carbohydrate per teaspoon, delivering about 20 kilocalories.

Lactose, also discussed below and mentioned above is the principal carbohydrate of milk, composed of equal parts glucose and galactose. The third disaccharide is maltose. Maltose, or "malt sugar" is two glucose units linked together. It is produced anytime starch breaks down.

How Is Sugar Made?

White table sugar¹, which, as discussed, is produced from sugar cane or sugar beets. Sugar cane. which is actually a tropical grass², started being used as a source of sugar thousands of years ago in India, where it was mentioned in writings during the period of 1400-1000 B.C. Although no one knows for sure, it is generally excepted that the plant originally got its start in New Guinea. Modern sugar cane is actually a hybrid of several species of the genus Saccarum.

Sugar beets, which are white rather than red, are another viable sugar crop. They are a much more recent crop for this purpose, having only been introduced as a means for extracting sugar in 1794. Most of the world's sugar comes from sugar cane, however.

Harvested and Cut Sugar Cane
Image by Rufino Uribe via Wikimedia

How Are Sugar Cane and Sugar Beets Refined?

After the sugar cane is harvested, it is washed and then shredded by giant steel rollers, which crush and squeeze the juice from the cane. Water is then sprayed on the crushed plants to get more juice to seep out. Harvested sugar beets are washed, sliced and soaked in vats of hot water to extract the sugar.

The juice from either plant is then heated in evaporation tanks so that it is concentrated into a thick syrup called molasses. Sugar crystals are induced to form so that they can be separated from the molasses by centrifuge. After the "raw" sugar crystals are obtained, the sugar is further processed according to the end product being produced, such as white, turbinado, powdered, or brown sugar.

Harvested Sugar Beets
Image by Hans Hillewaert via Wikimedia

Types of Sugars

The sugars below may give a little less or a little more than these 20 calories but as a consumer you have know way of calculating the difference and even if you could, it would make no difference to your overall diet. Therefore, consider all of them to be the same as white granulated sugar on a teaspoon to teaspoon basis.

Although most of the sugars mentioned below are produced from sugar cane or sugar beets, there are some other sugars mentioned as well because they are sometimes used, or have been used, as ingredients in food manufacturing.

• Brown Sugar: processed white cane sugar to which molasses has been added. It contains varying amounts of sucrose, caramel, and molasses, which are impurities that are originally removed during the refinement of table sugar. Brown sugar can be anywhere from 85 to 95% pure sucrose, depending on how much molasses is added, which is what determines the difference between "light brown sugar" and "dark brown sugar" we are familiar with. Yes, it's a fair guess to say that light brown sugar contains a bit more sucrose than dark brown sugar. But not enough less to make a difference in the diet!

• Concentrated Fruit Juice: Used as a sweetener in processed foods, this is a concentrated sugar made from dehydrated and deflavored fruit juice. This sweetener is often used to sweeten products so that they can claim to be "all fruit" or "pure fruit."

• Confectioner's Sugar: Finely powdered granulated white sucrose sugar. Most confectioner's sugar for home use has some corn starch, wheat flour, or calcium phosphate added to keep it free flowing. Also known as icing sugar or frosting sugar.

• Corn Syrup: A syrup, synonymous with glucose syrup , made from maize (corn) via either acid or enzyme hydrolysis. This syrup contains glucose and varying levels of polysaccharides, maltodextrins, etc. It can be hydrolyzed to various degrees up to the point of producing pure dextrose (glucose). Corn syrup comes in various strengths (sweetness) which are determined by the amount of hydrolysis and come in "dextrose equivalents" (DE): 24, 36, and 42 DE. The higher the DE the thinner and sweeter the syrup is. The lower the DE the thicker and more starch-like. Corn syrup is one of several types of "starch hydrolysates" that are popular in the food manufacturing industry.

• High Fructose Corn Syrup (HFCS): Produced from corn syrup (glucose syrup), some of the glucose is isomerized to fructose by the enzyme glucose isomerase. Although it is possible for HFCS to be contain up to 90% fructose, the most common product used contains around 42% fructose, as this most closely resembles sucrose. HFCS is less expensive and sweeter than white sucrose sugar, and so is a popular sweetener of beverages such as soda. In other instances, such as baking, many criteria determine what type of corn syrup, or sweetener will be used.

• Honey: A sweet syrup produced from the nectar of flowers by bees as a food source for the hive. Honey is always a mixture of glucose, fructose, a small amount of sucrose, and moisture, with some other sugars and impurities. Composition will vary depending on the flowers the bees used to produce the honey. A typical batch consists of around 40% fructose and 35% glucose, and 1 to 2% sucrose. Other sugars may include isomaltose, turanose, trehalose, erlose, maltotriose, melecitose, and raffinose, but these are present in only trace amounts of less than one percent. The rest is moisture, minerals, vitamins, beeswax, ash impurities in varying amounts, some enzymes, and aromatic volatile oils, which contribute to the unique flavor. The fructose in honey is sometimes referred to as levulose by the honey industry.

• Invert Sugar: A thin liquid solution of glucose and fructose produced by adding an acid³ to a solution of sucrose (sucrose dissolved in water). The acid hydrolyzes the sucrose, causing it to break down into d-glucose and d-fructose. Sweeter than white granulated sugar, it resists crystallization, making it ideal for professional candy makers who use it to give candy a smooth, melt-in-the-mouth, texture.

• Lactose: Lactose is a natural disaccharide of glucose and galactose. It is the primary carbohydrate found in milk. Lactose is about 1/5 to 1/6 as sweet as sucrose, meaning it barely tastes sweet at all. It is highly prone to crystallization. The food industry uses lactose, separated from milk, as a browning agent in baked goods and to improve the water holding capacity of processed meats like ham. It is also used in the making of candies and frozen deserts (beside the natural lactose already found in the milk used to make ice cream, etc.). As an "added" sugar, it does not contribute much to the diet but as a natural sugar it is found abundantly.

• Maltose: Maltose occurs naturally whenever a starch molecule is broken down, whether by a plant to use it's stored starches as fuel, when seeds are germinating, or when starches are being digested in the intestinal tract. Maltose, is used in fermented beverages (beer), breakfast cereals, and some infant formulas.

The maltose used in making beer comes from malt or malt extract, which is a mix of broken down starches consisting mainly of maltose. Usually made from barley or wheat, cereal grains are allowed to sprout which causes the enzymatic breakdown (hydrolysis) of the starch to maltose.

Perhaps the most famous occurrence of maltose in a prepared food is Post's "Grape Nuts" cereal, which was made from wheat and malted barley. C.W. post is said to have mistaken the maltose for glucose (dextrose) which was commonly called "grape sugar" by manufactures at the time, hence the name Grape Nuts.

• Maple Sugar: Produced by boiling maple syrup until most of its water evaporates and the sugar crystallizes. This sugar, like maple syrup, is almost entirely sucrose with only small amounts of free glucose and fructose. It also naturally contains invert sugars. Maple sugar is not commonly used today.

• Molasses: Of all the "sugars" molasses can easily lay claim to being the most nutritious. Molasses is what is left over after the sucrose crystals are removed from the concentrated sugar cane (or beet) juice. It is boiled repeatedly in order to crystallize as much of the sugar as possible, until no more sucrose can be extracted. This repeated boiling makes the molasses become darker and darker. The darkness determines the grade, with Blackstrap molasses being the darkest and most bitter.

The amount of sucrose in molasses differs, depending on whether sugar cane or sugar beets was used. Sugar cane molasses contains about 30 to 40% sucrose, some glucose, fructose, and invert sugar. Sugar beet molasses contains about 60% sucrose. Other components are inorganic salts, organic acids including amino acids, hemicellulose and pectin fiber, waxes, and ash.

• Raw Sugar: The term "raw sugar" as for as the consumer is concerned, should be considered a marketing joke, as there is no standard definition as to what kind of sugar can be called "raw". If one wanted to be particular, the word "raw" would mean that virtually no refining of the sugar had taken place. But this also begs the question of what is "sugar" and what is simply "dried cane juice". However, most experts would tend to consider raw sugar to sugar that is extracted from sugar cane juice but not refined any further. That is, not washed or decolored. True raw sugar contains dirt, insect parts, yeast, molds, and many other contaminants. As a result, the FDA banned its sale to the public.

However, there are some products sold as "raw sugar" to consumers, such as "Sugar in the Raw". These products labelled as raw sugar could be anything but raw sugars typically are a cruder stage of the sugar production process, before "white sugar" is completely refined. In the United States, such sugar is called turbinado sugar after the centrifuge in which it is spun. In the U.K. it is called demerara sugar. This sugar has been centrifuged and some of the impurities removed but it retains a light brown, amber color due to the leftover molasses content. It is not truly "raw" however, it is simply partially refined, with larger crystal size.

Turbinado Sugar
Image by Leena via Wikipedia

Sugar Alcohols

Sugar alcohols, which are also known as polyols are used in food labelled "sugar free" and are often referred to as nutritive sweeteners. Chemically, they are saccharide derivatives in which a ketone or aldehyde group has been replaced by a hydroxyl group. These are naturally present, in small amounts, in some fruits and vegetables but they are produced commercially by hydrogenating mono, di, or polysaccharides. They have become popular as a sugar alternative because they are sweet and possess similar properties but deliver less energy, about 1 to 2.5 less calories per gram, than sugar. They are absorbed more slowly and less completely by the intestines.

However, this incomplete and slow digestion leads to sugar alcohols being fermented by the intestinal flora. If consumed in excess, they can cause gastrointestinal upset in some people, leading to flatulence, diarrhea, bloating, and other symptoms.

The advantage, in terms of calorie reduction, would appear to be small. Also, there is the problem of the tendency for people to take in more energy from foods that appear to have less calories because of "sugar free" or other reduced macronutrient labeling. Sugar alcohols do have less of an impact on dental carries (cavities) however, because bacteria in the mouth metabolize them much more slowly. This makes them particularly suited to chewing gums, breath mints, or any product that remains in the mouth for long periods.

The sugar alcohols approved for use in the U.S. include erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, and polyglycitols (hydrogenated starch hydrolysates)⁴. These products are not intensely sweet like many artificial sweeteners, the non-nutritive sweeteners like saccharin, aspartame, and sucrolose, which are also called intense sweeteners. In fact, some of the sugar alcohols are only about half as sweet as sucrose, while others are about as sweet, but no sweeter.

Demerara Sugar
Image by Glane23 via Wikimedia

Why Does Brown Sugar Become a Hard Lump?

When molasses is mixed back into white sugar, the molasses forms a film around the sugar crystals. As long as the molasses is moist, the brown sugar will be soft. But if the moisture is allowed to evaporate out of the molasses, it becomes something like a glue, causing all the sugar to stick together in a hard mass. To keep this from happening, brown sugar must be stored in an airtight container like a sealed plastic bag or tightly sealed glass jar. It may help to store it in the refrigerator.

A moist paper towel over the hard sugar will soften it back up, as the sugar draws the water in. This takes about 12 hours, however. You can also pop hardened brown sugar in the microwave for 10 to 15 seconds to soften it, but this is only temporary so the sugar must be used immediately. If your making chocolate chip cookies, make sure not to mix eggs into piping hot sugar!

What About Botulism in Honey?

The risk of botulism poisoning from honey consumption is a frequent concern. It is true that botulism spores (Clostridium botulism) may be present in honey. For this reason honey should never be given to children under the age of one year, as their intestines are not yet able to handle botulism spores, which may colonize the infants intestines and produce botulism poisoning. In healthy older children and adults, there is little risk.

One survey in 1978, which examined honey from 32 U.S. states, estimated that the maximum amount of botulism contamination in honey was around 8 to 28 spores per kilogram of honey. Other surveys in different parts of the world found no contamination in some countries but contamination with different strains in others. The level of contamination worldwide, when randomly examined, tends to be very low, as little as 1 - 10 spores per kg. and for this reason honey should absolutely not be given to children under the age of one year. However, the levels of contamination associated with infant botulism are much, much higher, on the order of 10⁴ spores per kilogram. These samples also tend to be limited to C. botulism, rather than A. or B. botulism, which may suggest that these high levels of contamination are not a random but normal incidence but the result of contamination from and outside source or the the result of botulism amplification in the beehive for some reason.

What is Molasses Used For?

Sugar cane molasses is used to make rum. Rum can actually be made by distilling fermented sugar cane juice or molasses. Cane juice is preferred in the West Indies but most Rum is distilled from molasses, which is generally considered to be the best base. To make rum, a "mash" is started using molasses that has been diluted until it contains the desired concentration of sugar. This mash is then fermented by yeast. It is possible to simply allow the yeasts that are naturally present in the environment to ferment the sugar in vats that are open to the air but most distillers prefer at least some control, understandably so, over the specific type of yeast that is allowed to ferment their mash, short of absolute laboratory precision, which would undoubtedly take some of the art out of the production of Rum. So yeast is added to the mash and the conditions are controlled to allow those yeasts to ferment, producing ethanol alcohol and carbon dioxide as by-products.

If one were making beer, which used a "wort" instead of a mash, after fermenting is done, all that would be left would be to separate the liquid "beer" from the solid precipitates (including dead yeast), carbonate, either naturally by further fermentation in the bottle, or artificially (as large production beers must use), allow the beer to age, and then it is ready to drink. So in essence, the making of beers, like Ales or Lagers, and the making of liquors such a Rum or Whiskey, starts out much the same, although using different base ingredients to start.

However, Rum is a "distillate," which means that the alcohol within the fermented mixture is extracted and collected separately by distillation. To do this, the fermented liquid is heated in a sealed vessel to around 175 degrees Fahrenheit, which evaporates the alcohols from the liquid, which are run through pipes and allowed to recondense back into a liquid state to be collected. This is a "raw spirit," which contains between 70% to 95% alcohol. It can be sold as is, and is sold this way in certain places, such as the Carribean. But most Rum is first aged and then may be blended with spices or fruits. Afterwards, the distillery blends different batches of Rum together until the taste desired is achieved. If this step was skipped, every batch of Rum a certain distillery produced would taste different. Blending the Rums allows expert tasters to reproduce the same flavors in every batch of Rum that is put into bottles. Most rum is then diluted with water so that it contains 40 to 50% alcohol by volume. Molasses can also be used to produce ethanol alcohol for fuel.

Molasses is also used to produce baker's yeast (Saccaromyces cerevisiae), or feed yeast (a high protein feed supplement). The darker molasses grades, such as Blackstrap, is used in animal feeds for livestock (Blackstrap is also available for home use). It can also be used as a crop fertilizer, for which it has advantages and disadvantages.

Molasses is used widely in baking cookies, cakes, and breads and some people like to add molasses to sweet potato or pumpkin pie. It is also used sometimes used in toffees and caramels, and included in barbeque sauces and baked beans.

What's the Difference Between Molasses, Treacle, and Golden Syrup?

There seems to be a lot of debate about the difference between molasses, treacle and a product called "golden syrup." Apparently, this debate is not new but has been going on since the 1800's. Nobody today seems to really know the difference, but many claim there is one.

Today, treacle seems to be a generic word for any syrup made in the process of refining sugar cane. However, in older texts treacle is said to refer to the waste drained from the sugar molds after the sugar was removed from the molasses, or to a more clarified molasses product.

Treacle can range from light to dark but in common parlance treacle usually refers to the light syrup that results from the first boiling, which is also called light treacle or golden syrup. However, golden syrup sometimes refers to a treacle that has been further refined by reboiling and filtration through charcoal. There is also a version of this which was "invented" and sold by a Scotsman name Lyle Abam, a product which is still sold today. This has created some confusion about the origin of golden syrup.

Much darker syrups resulting from the second boiling, are called either just treacle or dark treacle by the British, which Americans call molasses. The product of a third boiling is called Blackstrap by the British and Americans alike.

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by EricT

At present, there are about 100 elements known. The human body uses around 27 of these. The most abundant is oxygen, which makes up approximately 63% of the body's mass. Carbon comprises 18%, hydrogen 9%, and nitrogen 3%. These four are the key elements in body's most important molecules: water, proteins, lipids, carbohydrates, and nucleic acids.

Water accounts for about 55 to 65% of the body's weight. Proteins and lipids (fats) make up about 30 to 45% and minerals comprise another 5%. The remaining one percent is comprised of carbohydrates, nucleic acids, and various other organic molecules.

Except for water, each of the major molecules is made of smaller molecules. For instance, proteins are made up of amino acids and carbohydrates like the storage polymer glycogen are made of glucose molecules.

Approximate Amount of Body Mass Comprised of Each Element

• Oxygen: 63
• Carbon: 18%
• Hydrogen: 9%
• Calcium: 1.5%
• Phosphorus: 1%
• Potassium: 0.4%
• Sulfur: 0.3%
• Chloride: 0.1%

Trace Elements in the Body

Trace elements such as silicon, boron, aluminum, iron, and selenium contribute less than 0.01% to the body's mass. Some other trace elements are:

• manganese
• florine
• vanadium
• iodine
• tin
• chromium
• cobolt
• molybdenum
• zinc
• copper

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by EricT

As a continuance of my assault on the misleading ideas about "natural" food, this is yet another follow-up to a series of blog posts where I discuss chemicals in foods and the concept of natural. In the last one I talked about the difference between chemicals as nutrients and chemicals as pharmacologic agents. I explained that some chemicals in food do have a physiological affect beyond their basic biological functions. Others, such as compounds in herbals used for medicinal purposes simply have no function as a "nutrient." All of these, though, have one thing in common and that is summed up by saying that "The poison OR the remedy is in the DOSE." This is important in helping us recognize the difference between nutrition information and alternative medicine information.

There are a number of very successful "food" blogs on the internet. The majority of them seem to be of the 'concerned parent' variety. They are, to put it bluntly, a reaction, not a revelation. Oh, things are so bad! There are chemicals in our food! Oh my, and lions and tigers and bears, too!

Anybody can react. But when the public takes it's cues from reactionary viewpoints that have little or no background, the culture's view of food becomes warped. People, more and more want to know what's in their food. More and more there are complaints about how inadequate and misleading food labels are. It is actually a bit ironic when you understand why food labels are designed the way they are designed. Would you buy the folllowing food product after reading its ingredients list?

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ethonoic acid
a-D-glucopyranosyl-(1.2)-ß-D-fructofuranose
p-hydroxybenzyl and indolymethyl glucosinolates
S-propenyl and other S-alkyl cysteine sulfoxides
ß-carotene and other carotenoids
phosphatidylcholine

Most people would think that was a chemical soup with some good stuff thrown in for balance. The good stuff would be the stuff they recognized as being sold in pill form as dietary supplements. The rest is poison!

Actually, though, that's the active ingredients in coleslaw, according to Tom P. Coultate, a food biochemist and author of "Food: The Chemistry of Its Components." It's healthy. At least it is not "unhealthy". You know the saying, "never eat what you can't pronounce." Can you pronounce coleslaw?

What amazes me, though, is how easy marketing undoes the negative connotations of those big scientific sounding chemical names. You want the public to change its opinion of an organic chemical? Stick it in a bottle, claim it does this or that for the body, and put it on the natural health store shelf. These chemicals may not be bad for you per se. In fact, they may not have any action whatsoever in the human body. Yet, in pill or liquid form under the guise of "dietary supplement" they are gobbled up by a health concerned public who would run away screaming from the same chemical (name) found on a food label.

One of those chemicals is chlorophyll. Chlorophyll is used as a colorant in foods. But chlorophyll is very unstable and there are a great many complex things to be considered in the extraction and production of chlorophyll colorants. The chemical that ends up in foods is not the chemical that was originally found in the living plant materials. Most often it is Sodium Copper Chlorophyllin.

According to the FDA, sodium copper chlorophyllin is "a green to black powder prepared from chlorophyll by saponification and replacement of magnesium by copper. Chlorophyll is extracted from alfalfa (Medicago sativa ) using any one or a combination of the solvents acetone, ethanol, and hexane…Sodium copper chlorophyllin may be safely used to color citrus-based dry beverage mixes in an amount not exceeding 0.2 percent in the dry mix." 4

I have no trouble imagining some of those concerned food bloggers crying foul over this "chemical" on their food label. Many reactionaries are too busy reacting to ever have heard of chlorophyll in the first place. But they may have some cause for asking questions because it is a natural chemical that has been heated, chemicially extracted, adulterated, etc. It has to be, otherwise you would not get that great green color. Because the chemical is, as I said, too unstable. You want green, not brown.

Yet chlorophyll as a dietary supplement is proclaimed by some manufacturers to be equivalent to the snake oil remedies of old. I also have no trouble imaging some of those very same zealots drinking down their chlorophyll supplement after reading from Mercola or somebody how very bad the sodium copper chlorophyllin found in foods is but how very good his chlorophyll supplement is¹

They may be surprised to find out, then, should they bother to read the ingredients on the supplement label, that their supplement is, you guessed it, sodium copper chlorophyllin. Do you think I'm wrong about this? I don't think so. I'll bet you anything that the same chemical on a food label will cause "grave concern" when it is happily consumed in the form of a supplement. Now, a little investigation would make anyone realize that the supplement industry is subject to the same constraints as the food industry. They cannot pull stable chlorophyll out of their as..hats, after all.

So, what is this chlorophyll supposed to do for your body? That is, what does it do when you take it in a supplement? Well it "promotes cleansing" and it is an "internal deodorizer." That sounds good to me. I want my insides to be clean and I do not want them to stink. I'm in.

But it doesn't stop there. You see, chlorophyll, even though it is not seen as "anything special" by biochemists and nutritionists, is converted to BLOOD in the body! I'll bet you did not know that when you ate a nice salad the chlorophyll in the leaves was converted into blood! I must have a lot of extra blood because I like a good salad.

According to Ann Wigmore, author of the "Wheatgrass Book," chlorophyll is a "living battery." "An animal's body also stores and produces heat and energy: the difference is that plants can get their energy directly from the sun, whereas animals and humans cannot. IN essence, the same life force in nature that explodes into greenery every spring can be transferred into the human body via the consumption of wheatgrass juice. The body can then use this super-nutritious, vital energy to heal and repair itself as needed." 2

This is a great example of how to write a good book. When in doubt, make shit up! This is one of the most popular assertions about chlorophyll, that it is very similar to hemoglobin, which is the compound that carries oxygen to our blood. The idea is that the body can take chlorophyll, as it is, and turn it into hemoglobin. You know, because it's similar. It's just a bit of alchemy. Let's not bother with nutrition.

What about the science behind chlorophyll as a nutraceutical? Well there has been some research into chlorophyll's (chlorophyllin's) antimutagenic and anticarcinogenic properties. The idea is that it may protect DNA against ionizing radiation and that it may be an anti-tumor and also protect against side effects from anti-cancer drugs. The problem is that this is in vitro, meaning in a petri dish. There is no reason to think that ingesting chlorophyll will protect you from cancer and radiation.

Chlorophyll, once you ingest it, is subject to the same harsh digestive environment as everything else you eat. There is no evidence that chlorophyll has any nutritional value, in itself. It contains magnesium, so that's good. In fact, 15 to 30% of the magnesium in plants may be associated with the chlorophyll. And it may have copper if it's the stabilized kind. Beyond this, though, even if chlorophyll could do something great in your body, the stuff would never make it into your body in it's whole form. Yes, it is used as an internal "deodorant" but lots of things are used for lots of purposes that make no sense.

Another thing that the FDA says about sodium copper chlorophyllin is that it is exempt from certification. "Certification of this color additive is not necessary for the protection of the public health, and therefore batches thereof are exempt from the certification requirements of section 721(c) of the act." 4

Won't the "government is bad supplements are good" crowd be confused by all this? If the FDA says that something is not considered to be harmful to human health..that, essentially, they aren't concerned about it, it MUST be bad! Big brother, after all is in league with everything evil in order to ruin our health and get our money. But the supplement companies, they are out to help us. They wouldn't lie to us. They aren't evil like big food and big government. They want to save mankind. Shoot. Isn't this a pickle? Cognitive dissonance, oh, it hurts!

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by EricT

By Sandra Wilkins

The use of prescription drugs is often overlooked as a major factor that contributes to nutritional deficiencies. Typically, the focus is placed on diet and perhaps some lifestyle issues, but many are unaware that the medications they use are possibly creating additional health problems that may not become apparent for a long time. Drug-induced nutrient depletion is a health threat that is not acknowledged by the majority of health care practitioners and it's not because of a lack of information about the subject, because many studies have been published that document the drug-induced depletion of nutrients.

Nutritional deficiencies do not become obvious quickly. A marginal nutrient deficiency, referred to as a "subclinical deficiency," indicates a deficiency of a particular vitamin or mineral that is not severe enough to produce a classic deficiency sign or symptom. In many instances the only clue of a subclinical nutrient deficiency may be fatigue, lethargy, difficulty in concentration, a lack of well-being, or other vague symptoms.

Deficiency-related health problems may never be diagnosed, and the patient may end up taking additional medications for complaints that are really the body's signal for nutrition therapy.

Drugs can deplete nutrients by decreasing their absorption, or by hindering the way nutrients are transformed by the body. They can also affect the storage of nutrients or the way the body excretes the end products of the metabolism of nutrients.

The key to preventing this kind of deficiency is to know what vitamin or mineral can be affected by the drug prescribed to the patient.

If the drug will be used for a lengthy period of time the patient should simply increase intakes of the specified nutrient for the duration of the use of the drug. This simple step will help prevent deficiency-related health problems and help improve the chances of achieving the desired health outcomes for patients.

Some examples of nutrient depletion are as follows:

• Antacids deplete calcium and phosphorus
• Antibiotics deplete B vitamins (all of them), intestinal flora and Vitamin K
• Antidiabetics deplete Coenzyme Q10
• Anti-inflammatories deplete Vitamin C, folic acid, potassium and iron
• Cholesterol-lowering drugs deplete Coenzyme Q10
• Cardiovascular drugs deplete calcium, folic acid and zinc
• Ace Inhibitors deplete zinc
• Beta-Blockers deplete Coenzyme Q10 and melatonin

About the Author

Sandra Wilkins, D.T. has extensive experience in natural health and clinical nutrition. As a Dietetic Technician Sandra works with hospital staff dietitians, performing patient nutrition assessments,food and drug interaction education, and patient diet education. In a different capacity she writes guide books on nutrition and wellness. Her background includes 14 years experience in natural health practices, so her combined natural health and clinical nutritional experience makes her uniquely qualified to help clients to tackle health issues. http://www.easystepsfordiabeteshealth.com

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by EricT

In my post Homeopathy Is Not a Drug and Other Babbles I had quite a rant, albeit a very informative one, about some idiotic things a NaturalHealth.com article said about homeopathy and about homeopathy quackery in general. If you read that you will be more in flow with what is to follow. Cuz I'm not done!

Much of that post concerned chemicals. The food faddist or the homeopathic zealot, when he hears the word chemical, cries "POISON!" Yet, chemicals are what our food is made of and the term toxic chemical, taken by itself is meaningless.

In my response to a reader of Jamie Hale's article Organic Food: The Real Story I had quite a lot to say about the idea of toxins. The reader tried to draw some vague distinction between "natural toxins" and "toxins developed in the last 100 years":

"There is one very important point that must be considered when speaking of ANY toxins, whether natural toxins we can expect to find in organic foods or "synthetic" toxins.

But before I bring up that point I'd like to talk about the word toxin itself. It's always a good idea to define our terms. Colloquially, we use the word toxin to describe any bad chemical that gets into your body and interacts with the body's cells in a negative way, causing damage. A poison could be thought up as a very bad toxin that does a great deal of damage very quickly or kills you outright very quickly. So lets assume by the word toxin we mean chemicals that cause slow damage.

Most people are probably not aware that in biology a toxin is a bit more specific. That is, they are damaging chemicals or poisons that are produced IN NATURE BY BIOLOGICAL MEANS.

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Even in the case of insecticides like DDT, which the article mentioned, we are still talking about organic chemicals. DDT for instance, is an organochloride. So even though we talk about these things being synthesized or isolated they are still produced via chemical reactions involving organic compounds that…happen in nature. We just ramp it up and produce chemicals in large quantities that only happen very rarely "by themselves". There are many examples of these types of toxins.

The biological toxins that plants produce to defend themselves or for whatever reason and the organic pollutants that we "produce" and then introduce into the environment artificially…they are all NATURAL."

So, what is an example of a natural chemical found in plants that we are all familiar with? Salicylic acid is a very good example. A chemical called salicin is found in abundance in the willow tree. That is used to make salycylic acid, what we all know as aspirin. 1 It is an analgesic, good for pain. It is good to fight inflammation, as a non-steroidal anti-inflammatory (NSAID). It can reduce fevers, as an antipyretic. It is a prophylactic measure against heart attack and stroke for those at risk. It is the active ingredient in many anti-acne skin-care products and an antiseptic in some toothpastes. It's a pretty useful chemical. When I was growing up, baby aspirin was a pretty regular thing for aches, pains, and headaches. That was before we were aware of how toxic aspirin is to children.

In children, aspirin is associated with Reye's syndrome. It is a condition of acute encephalopathy and fatty change in the viscera. Although the syndrome has been recognized since 1963, it took a while for it to be associated with aspirin. In 1980, 556 children with Reye's syndrome were reported. After 1987, when aspirin was identified as a culprit, very few cases have been identified. 2

If you take enough salicylic acid, it will be toxic to you as well. As I painstakingly pointed out in the first post linked here, it is all about the dose. As I also pointed out, anything, if you were able to consume enough of it, could become a poison. This was recognized as long as 500 years ago by a guy by the unwieldy name of Theophrastus Phillipus Auroleus Bombastus von Hohenheim, aka Paracelsus, who said: "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist." Yes, we have Latin in this blog. That means, basically, that everything is a poison and nothing is a poison and only the dose makes a thing a poison or a remedy. Or, like I said earlier, the word toxin, taken by itself, is meaningless. Today, we usually sum that quote up as "The dose makes the poison." Tell a homeopathic zealot, a "natural food" snake oil artist, or other assorted crank that and he may want to kill you for it, just as Paracelsus's enemies were rumored to have done to him! 3

Salicylic acid is found in varying quantities in all fruits, vegetables, herbs and spices. It plays an important role in how plants protect themselves from pathogenic infection. 4 According to Hayat, et al., it is a phenolic derivative plant hormone that is distributed in a wide variety of plant species. It is involved in plant growth, thermogenesis, flower induction, uptake of ions, ethylene biosynthesis¹, stomatal movement, reversal of ABA effect on leaf abscission, enhancement of chlorophyll and carotenoid pigments, photosynthetic rate, and more. 6

Plants make salicylic acid, in particular after exposure to a pathogen, and use it as a key regulator of SAR and expression of defense genes. In fact, as early as the 1930's a phenomenon called systemic acquired resistance (SAR) has been known whereby spraying salicylic acid on plant crops "snaps them to attention and puts their defenses on high-alert against future attacks." 7 Clearly this chemical is a bit important to plants, as are a great many other chemicals that plants produce. Lots of these chemicals could be harmful in large enough doses. And many of them could be helpful at the right dose as well.

So we understand that the plant foods we eat contain chemicals that could be toxic. But rarely does a plant food contain enough of any one chemical to be toxic. The plants that do contain such large amounts…we do not eat. For instance, we do not eat willow, we use it as a medicine. Willow then is a "herbal" rather than a food plant. Even though it contains some of the same nutrients as the plants we do eat (which may also be called herbs sometimes but let's avoid that semantic quagmire). Certain plant nutrients, therefore, when functioning in large doses as a drug can be considered pharmacologic agents. Single plants that we eat rarely, if at all, contain a large enough dose of such pharmacologic agents to have an impact on disease treatment or even prevention that falls beyond the physiologic functions of the specific nutrients.

Salicylic acid (SA) has no important nutritional role for humans. In fact, it interferes with the transport and excretion of certain nutrients, such as folate, thiamin, vitamins C and K. 8 Obviously it has a other effects. As became apparent in the earlier post, there is an interesting dose-dependent paradox involved. One medicinal use of the chemical is as an antipyretic (fever reducer). At low doses it is an effective agent for this. As I stated earlier it is highly toxic at large enough doses. In fact, one of it's effects at high doses is the opposite of it's fever reducing effect at low doses. It raises body temperature to dangerous levels, called hyperpyrexia.

There is evidence that suggests that consumption of fruit and vegetables has a protective role in the development of chronic degenerative diseases such as cardiovascular disease (CVD) and cancer. We know that aspirin therapy, with SA being the major metabolite, is used as a prophylactic in those at risk for heart attack and stroke. There is some evidence that chronic low-dose aspirin therapy may be a helpful preventative against cholorectal cancer, as well. Is it reasonable to ask, therefore, whether the SA in fruits and vegetables plays a role in the protective nature of these foods? Could it be that chronic consumption of these foods means that we take in very low does of SA but enough to raise circulating levels to the point where it contributes to this protection, similar to how aspirin therapy does? Yes. This is a reasonable question that has in fact been asked. 4

However, it is important to know the difference between what science asks and what we should take as food being medicine. If you've wondered what the point of this expansive essay on SA is, you've now encountered it. See, while there are many nutritional reasons to eat lots of fruit and vegetables, a reasonable one is not so you can get your salicylic acid! If SA plays a part in the protective nature of FV consumption, no scientist would tell you to abandon the aspirin therapy that your doctor prescribed for you. FV consumption would simply be seen as a potentially helpful adjunct to that therapy. And of course there are a great many other interesting chemicals that may be important such as ellagic acid and other phenolic phytochemicals. Right now there are still as many questions as answer about these compounds.

Certainly it is true that some nutrients, even vitamins, can have physiologic effects beyond their functional role in the body. High dose niacin (nicotinic acid), for instance is used as a cholesterol lowering agent. Using niacin this way is no longer using it for nutrition. We do not "use" or "take" nutrients, after all. Using niacin this way is using it as a drug. The doses go well beyond the amount of the vitamin needed for biological functions. The amounts used for cholesterol lowering, in fact, must far exceed the requirements of nutrition and the recommended daily amounts. This comes with clear-cut dangers and such therapy must be monitored. Yet, I can assure you that you will find many "nutrition experts" to tell you that some supplementary Niacin in your diet is "all you need to lower your cholesterol." We must be aware that a nutrient to be used as a pharmocologic agent is no longer being used as a mere dietary supplement!5

Conduct a search such as "salicylic acid in human nutrition" and you will doubtless get many "nutrition" articles telling you about all the SA in fruits and vegetables and hinting that this will have some effect on your health that makes it worth your while to eat those fruits and vegetables. A "medicinal" affect will be implied. Here we get to the gist. There is a difference between information about nutrition and information about alternative medicine, or mainstream medicine. If a certain food chemical featured in a "nutrition" article is not an actual nutrient, then you are not looking at a nutrition article. Most likely, unless you are reading a good scientific journal, you are looking at an alternative medicine article.

The problem is that, at present, most nutrition information is, in fact, actually alternative medicine information. Chemicals like SA are the fodder for these articles. This is dangerous and irresponsible, to say the least. A person who replaced his aspirin therapy with large amounts of fruit and vegetables because some silly article suggested to him that it's the same difference could be putting themselves at grave risk. The act of trying to cure disease by a careful manipulation of the foods we eat is NOT nutrition. It is fallacy, at best, and as Shwartz and Swhartz point out in "An apple a day: the myths, misconceptions, and truths about the foods we eat," we must view it with skepticism.

On the cover of that book is the picture of an apple that is labeled with some of the apples constituents. Among these are vitamin C, water, sugar, polyphenols, acetone, and formaldehyde. The book goes on to explain that one apple contains over 300 different compounds. Are we getting the idea here?

Clearly, trying to cure a disease by close manipulation of thousands of compounds, of which even the lowly apple has 300, is a bit silly. Yet a healthy diet can certainly play a role in preventing disease. However, we must go on what we know and consider the net diet, not individual compounds whose properties are just now beginning to be unraveled. Most of the quack nutrition articles I have been mentioning tend to focus on one or two "superfoods" which are miracles of prevention by virtue of one antioxidant or another. Most of these articles tend to ignore the fact that a hundred other fruits or vegetables rather than the one they focused on could have contained much higher levels of anti-oxidants. As I've pointed out in the past, picking the best food is not such a clear cut proposition.

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by EricT

By Ground Up Strength

Sea salt is often touted as a more healthful alternative to ordinary table salt. Many food products are now proclaiming the use of sea salt on their labels and health food stores have long promoted it's healthful benefits. Although some of today's food advertising concerning sea salt is in regards to it's giving a better flavor to the food products there is no doubt an additional incentive to take advantage of the public's perception of sea salt as more nutritious and health giving.

Ordinary table salt, the salt such as Morton's which we are all familiar with, is sodium chloride (NaCl) and is commonly derived from halite (rock salt). Salt has long been of great importance, not only to provide sodium in our diets and flavor to our dishes, but also for food preservation and chemical production. In fact, table salt only accounts for about one percent of all the salt used and the rest is used to produce chloride, de-ice roads in winter, agriculture, food processing, and various other manufacturing processes. A great amount of salt is used in the dairy industry, for tanning leathers, fertilizer, caustic soda and soda ash.

Salt can also be mined by the evaporation of sea water. For instance, around the coast, sea water can be pumped into shallow ponds which are allowed to evaporate so that the salt crystallizes on the floor of the pond to be collected later. Alternatively it can be taken from natural inland "brine springs" which occur where rock salt is close to the surface and water moving through the ground dissolves the salt and forms brine streams. It is also mined, as mentioned, from underground deposits as rock salt, which accounts for about one third of salt production in the United States. These halite deposits come from the seas of long ago (millions of years) which have dried up and left their salt behind in huge amounts. Besides evaporation of sea water and rock salt, lake brines, and the salt crust from dry lake beds make up the rest of salt production.

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The Uyuni Salt Flats in Bolivia
image by Ricampelo via wikimedia

All Salt is Sea Salt

When sea water evaporates a brine of sodium chloride (NaCl) forms, most of the other minerals precipitate out, and the salt crystals fall to the bottom of the solution. Although some additional trace minerals may be left in sea salt products, such as magnesium and iodide, there is no additional health benefit and the compositions of most salt sold for human consumption is close enough to identical to be called identical. As well, table salt has long been fortified with iodide so any iodide in sea salt products cannot be considered to be significant.

As you may have gathered, all salt can correctly be called "sea salt" since all salt, at one point, came from the sea. And, in fact, many of the products, sold as sea salt in your grocery store may well be the same exact salt that is sold as "salt" under another brand name. It may well have been supplied by the same company, coming from the same place. Morton salt, which most people are familiar with, comes mostly from land bound salt mining, except in California, where it is sea salt, sold as the same product. Morton does not label salt that comes from the land as sea salt, as some other brands do. But as stated, all salt is technically sea salt. 3

A 1992 article in Vegetarian Times magazine by Sally Cullen, "Salient Points About Salt", reports that a senior lab technician for Cargil, Inc., a major salt producer, supplies salt to both natural-food companies and grocery stores. The only difference in the salts supplied, according to the technician, is the type of anti-caking additive used. The "natural" salts use magnesium carbonate and the grocery store salts use silica aluminate. Each company simply put's its own brand name on the product. According to the same article, Hain brand sea salt and Safeway house brand salt are the same salt, from the same producer, evaporating pans, and bin. 3

The consumer needs to be aware that unless a sea salt product is known to come from a particular location and the salt from this location is known to possess certain attributes, such as trace minerals or other deposits, which give it a unique flavor in cooking, there is no need to pay more for a product sold as "Sea Salt".

It is frequently reported that sea salt is "less refined" than ordinary salt and while this is sometimes true it is not always the case. In the U.S. all salt sold for human consumption must contain at least 97.5 percent sodium chloride, whether labeled sea salt or not. It must be free from heavy metal contaminants as well. This, essentially, means that all salts sold in the U.S. MUST be refined to some extent. A few different trace minerals may be present, here or there, depending on the salt's origin, and these may contribute to flavor. But there is no significant nutritional difference whatsoever. Do not rely on sea salt as a way to ensure consumption of trace minerals. This would contribute nothing measurable except excess sodium, at best. Table salt contains around 21,00 to 23,00 milligrams of sodium per teaspoon, depending on the brand and degree of refinement.

The flavors and odors from a particular salt may be important to cooks, and various sea salts can make a difference in this regard. Some salts have other minerals added to them as well, such as Hawaiian sea salt which has Alaea, a volcanic red clay high in iron oxide, added to it. 4

Some other sea salts are Black salt, Kala Namak, or Sanchal, from India, which has a pink gray color and a sulfurous odor. Sel Gris from France, also called Celtic salt or Grey salt, which is gray to light purple because of it's clay content. Other salts may be more or less refined depending and have slightly different flavor depending on the region they come from. See this overview of different salts for more information.

Don't believe the claims you may read about the "healthful" benefits of sea salt versus "unnatural" table salt. These claims are imaginary and based on nothing but the typical concept that anything that sounds more natural must be better for you. Choose your salt based on it's properties for your dishes, nothing else.

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by EricT

By Ken Adams, M.D. and Scott E. Conard, M.D.

Vitamin A and the pre-vitamin, beta carotene are closely related supplements. There are definite benefits to the nutritional supplementation of both Vitamin A and beta carotene but there are also dangers to their supplementation. Many people do not realize that beta carotene is converted within our bodies to Vitamin A but supplementation of one in lieu of the other is not equivalent to the supplementation of both. There are also other members of the antioxidant carotene family include cryptoxanthine, alpha-carotene, zeaxanthin, lutein, and lycopene, most of which do not convert into significant amounts of vitamin A. These will be discussed also in this article.

Sources and Physiologic Functions

Sources: Foods that are rich in vitamin A are milk, cheese, butter, eggs, liver, and such fish as herring, sardines, and tuna. The richest sources of vitamin A are the liver oils of shark, halibut, and polar bear. Rich sources of pre-vitamin A are spinach, carrots, papaya, oranges, sweet potatoes, and cantaloupes. Poor sources of vitamin A and pre-vitamin A are vegetable oils, white lard, white corn, cereals, beef, and legumes.

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Vitamin A Food Sources

Pre-Vitamin A (b-carotene) Food Sources

Biochemistry

Vitamin A is a fat-soluble vitamin. Vitamin A is a collective term for retinal, retinol, retinoic acid, and b-carotene. The vitamin A in foods of animal origin, such as eggs, milk, butter, and liver, occurs largely in the form of retinyl esters. A retinyl ester is a molecule of retinol esterified with a molecule of a fatty acid, such as palmitic acid. The fatty acid is bound to the hydroxyl group of retinol. Plants do not contain vitamin A; however, some plants are rich sources of pre-vitamin A. Pre-vitamin A takes the form of a family of compounds called the carotenoids. More than 500 carotenoids occur in nature, though only about 50 of them can be used as precursors of vitamin A. The most important of these is all-trans-b-carotene. The prefix all-trans indicates that all of the double bonds are in the trans conformation rather than the cis conformation. Vegetables that are dark green, orange, and yellow are rich sources of the carotenoids. Other forms of pre-vitamin A are cryptoxanthine and a-carotene. Some carotenoids cannot be converted to vitamin A by mammals. These include lutein, lycopene, and canthaxanthine.

Vitamin A serves three classes of functions: support of epithelial cells (lungs and tracheal integrity), fetal growth and vitality of the testes, and utilization in the visual cycle. Dietary retinoic acid can support only the first function. Retinoic acid cannot be stored in the liver. Retinyl esters, retinol, and retinal are interconvertible. Retinal can be oxidized to form retinoic acid. All three functions of vitamin A can be supported by dietary retinyl esters, retinol, or retinal. Although these forms can be converted to retinoic acid, retinoic acid apparently cannot be reduced to form retinal. Dermatological problems like acne, psoriasis, Darier's disease, and skin aging are effectively treated with retinoic acid and topical tretinoin.

Populations at risk

In the United States, patients suffering from chronic intestinal disease, malignancy, malaria, pneumonia, and anorexia nervosa are deficient in vitamin A. Requirement for this vitamin is increased in patients with appendectomy, burns, cirrhosis, and biliary obstruction. Stress can increase excretion. Zinc and protein deficiency can decrease transport. Premature infants and those suffering from cystic fibrosis and rheumatic fever are also at risk.

Signs and Symptoms of Deficiency

Night blindness is the earliest symptom.Severe vitamin A deficiency leads to xerophthalmia, which can result in corneal ulceration, Bitot's spots, and blindness. Thickening of the bone, loss of lung elasticity, epithelial keratinization, impaired hearing, urinary calculi, and keratinization of salivary glands are also seen. In males, sperm production ceases. In females, fetuses are reabsorbed.

Safety

The hazards of excess vitamin A are well established with ingestion of excessive amounts of preformed vitamin A. Intake of 7,500-15,000 mg preformed retinal equivalents (RE) daily for periods of months to years can produce adverse effects including liver toxicity and possible birth defects. Prolonged daily consumption of <7,500 RE (<25,000 IU) is considered safe in the age group of 18-54. For the liver, it had to be taken for 6 years to become toxic. There has been one report of toxicity for doses in ranges as low as 1,500 - 3,000 mgm (5000-10,000IU), but these results were not reproducible and are contrary to the vast majority of the medical literature. There is no evidence that supplements of 3,000 mg RE (10,000 IU) are harmful to normal adults, including pregnant women and the elderly.

There is no evidence that conversion of beta-carotene to vitamin A contributes to vitamin A toxicity, even when beta-carotene is ingested in large amounts. The only consistent adverse effect of high beta-carotene intakes has been coloration of the skin related to hypercarotenemia. The possibility that beta-carotene causes lung cancer will be discussed later. A review of all published evidence on beta-carotene shows two studies, the ATBC trial and the CARET which suggest adverse effects. The rest of the evidence has shown beta-carotene to be safe.

Hypervitaminosis

Early signs of chronic hypervitaminosis are reflected in the skin, which becomes dry and pruritic, the liver, which becomes enlarged and cirrhotic, and in the nervous system, where a rise in intracranial tension mimics the symptoms of a brain tumor. Hypervitaminosis in pregnancy may cause congenital malformations like precocious skeletal growth and transient hydrocephalus. Anorexia, vomiting, loss of hair, nystagmus, gingivitis, glossitis, lymph node enlargement, and delayed clotting time are other symptoms. Isotretinoin is teratogenic and is absolutely contra-indicated in women with childbearing potential unless they have unresponsive, disfiguring acne. Hyperlipidemia occurs with prolonged use of isotretinoin. Hypervitaminosis can lead to vitamin neurotoxic effects. Closely related to the neurological symptoms of hypervitaminosis are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. A study showed that after 49 months of follow up, ingestion of retinol caused a 7% increase in alkaline phosphatase, 11% increase in triacylglycerol, 3% increase in cholesterol and 1% decrease in HDL. The participants were randomly assigned to receive retinol (7,576 retinol equivalents RE, or 25,000 IU) or a placebo daily. Because a 1% increase in cholesterol concentrations has been reported to be associated with a 2% increase in coronary artery disease risk, long term ingestion of 7,576 RE vitamin A should be considered with caution.

Consuming too much vitamin A could increase your risk of osteoporosis. Two studies showed that a daily vitamin A intake > 1.5 mg resulted in a 6% decrease in overall bone density and doubled the risk of hip fracture. Excess levels of this vitamin weaken bones by increasing its rate of resorption.

Periconceptional

Vitamin A is essential for normal reproduction and development. Doses > 10,000 IU/d as supplements have been reported to cause malformations in a single epidemiologic study. Nonhuman primate data show no teratogenicity at doses of 30,000 IU/d. Because no study reports adverse effects of 10,000 IU/d preformed vitamin A supplements, and this dose is more than the Recommended Dietary Allowance during pregnancy (2670 IU or 800 RE/d), it is recommend that women living in industrialized countries or who otherwise have nutritionally adequate diets may not need to ingest more than the RDA of preformed vitamin A as supplements. If periconceptional vitamin A exposures to levels up to 30,000 IU/d (9,000 μg RE/d) do occur unintentionally, multiple animal studies do support only very low risk. Teratogenicity nor vitamin A toxicity has been observed in multiple species exposed to high doses of beta-carotene.

Elderly subjects

Elderly people who take vitamin A may be at increased risk for vitamin A overload. Greater fasting plasma retinyl esters were associated with long-term vitamin A supplement use (>5y) and biochemical evidence of liver damage. For supplemental vitamin intakes of 5,001-10,000 IU/d, elderly people showed a 2.5 fold increase in plasma retinyl esters over non-users, while there was a 1.5 fold increase for young adults.

Alcoholics

Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. New pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. Depletion ensues with hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation is recommended. It is complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. Beta-carotene was considered innocuous until recently, when it was found to also interact with ethanol.The combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and possibly, cardiovascular complications. Thus, ethanol, while promoting a deficiency of vitamin A, also enhances its toxicity as well as that of beta-carotene. In drinkers this narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency.

Vitamin A, as retinol or retinyl esters is used to treat deficient patients. The RDA for vitamin A is 1.0 mg of retinol or its equivalent. The international unit (IU) is used to compare the biological activities of various sources of vitamin A.

Literature

James Goodwin presents the case for carotenoids and cancer. He makes the argument that the most consistent relationship between antioxidants and cancer has been made for carotenoids to lung cancer risk. Studies have found an inverse association of lung cancer risk with the frequency of consumption of dark green and yellow vegetables. One study showed a significant decrease in the risk of lung cancer (especially squamous cell carcinoma) with higher intake of total vitamin A, especially from vegetable sources. In the Western Electric Study, the protective effect of carotenoids was found in men at all levels of cigarette smoking. A seven-fold risk of developing lung cancer was observed for those in the lowest quartile of carotene intake at baseline.

Some studies have been inconsistent about smoking status and the protective effect of beta-carotene on lung cancer. A study of supplementation with antioxidants, the ATBC Cancer Prevention study, found significantly more lung cancer cases in the smoking group receiving beta-carotene supplements. This was also found to be the case in the CARET trial of asbestos workers. They were using 20 mg/day and 30 mg/day in the ATBC and CARET trials respectively. On the other hand, there was evidence in the CARET that beta-carotene may reduce the risk of lung cancer in former smokers. In contrast to these trials, no increased risk was noted in the longer term PHS trial.

The effects of alcohol or high intakes of retinal on the liver have been proposed as explanations for the adverse findings in the CARET and ATBC trials. Data suggests that heavy concurrent smoking is a necessary condition for a promotional effect of beta-carotene. Former smokers whose tissues would theoretically have been subjected to the some mutagenic and carcinogenic effects of cigarette smoke show decreased, not increased, rates of lung cancer with beta-carotene treatment.

Studies have also been done that suggest a positive role of carotenoids for breast, esophageal, cervical, pancreatic, and colorectal cancer. In another study, people with low vitamin A intake who received vitamin A had approximately a 50% reduction in their risk of breast cancer, providing evidence for a protective effect due to vitamin A itself. Carotenoid consumption also appeared to decrease risk of bladder cancer for those < 65.[28] A nutrition study conducted in Linxian, China, showed that supplementation with retinol and zinc might protect against the development of gastric neoplasia.

Two trials have looked at supplementation with Cis-retinoic acid which prevented squamous cell carcinoma of the head and neck in smokers, and beta-carotene which reversed the changes of oral leukoplakia.[28,29]Beta-carotene had an inverse relationship with the development of thyroid carcinoma.

Beta-carotene supplementation for 2 years produces neither benefit nor detriment in the prevention of cardiovascular disease or cancer in women. The authors explain that individuals with high intakes of fruits and vegetables containing beta-carotene experience lower risks of developing cancer.

Dr. Dutta reported that Barrett's esophagus patients who take beta-carotene supplements apparently experience improvements that appear to be due to a hike in a protective protein called heat shock protein (HSP-70). In earlier studies, Dr. Dutta demonstrated that beta-carotene supplementation reduced the burning sensation that these patients experienced. Beta-carotene was also shown to inhibit cancer cells in vitro.

Cataract

It was found that dietary carotenoids and long term vitamin C supplementation may decrease the risk of cataracts.

Lycopene

Lycopene occurs in tomatoes and tomato products. Protective effects of a lycopene-rich diet on some types of cancer were suggested. There are several mechanisms potentially underlying the protective effects of lycopene. Little is known about the metabolism of lycopene. Potentially biologically active oxidation products of lycopene have been identified in human plasma. Cooking is a factor in releasing the desirable antioxidants from tomatoes. Research in the field of nutrition and health has shown that monounsaturated oils such as olive oil or canola oil are most desirable in facilitating absorption of lycopene. A study showed that consumption of 70-75 mg/d of lycopene can increase plasma concentrations of lycopene necessary for enhancing human health.

Oxidative damage

It was concluded that the consumption of tomato products may reduce the susceptibility of lymphocyte DNA to oxidative damage.

Prostate Cancer

Tomato-based foods may be beneficial regarding prostate cancer risk. Intake of lycopene was inversely associated with risk of prostate cancer and advanced prostate cancers. Some observational studies found no beneficial effect of lycopene on prostate cancer risk.

Other cancers

Studies showed a pattern of protection against all cancers. The beneficial effect of raw tomatoes in this population may be due to the fact that they constitute perhaps the most specific feature of the Mediterranean diet. Other animal studies have found beneficial effects of lycopene in lung neoplasia and bladder cancer.

Age-related macular degeneration

Lycopene may be beneficial in age-related macular degeneration and cataracts

Diabetes Mellitus Type-2

Increased free radical activity and high lipid oxidation impair glucose disposal in the peripheral tissues and exacerbate diabetic complications. Because of its extended system of conjugated double bonds, beta-carotene can scavenge peroxyl radicals and exert strong antioxidant activity, suggesting a protective effect against the development of type 2 DM. Several studies show that increased intake of vegetables that are rich in carotenoids lowers risk of type 2 DM. Those assigned to a diet with more vegetables have a lower incidence of type 2 DM. It is possible that the reduction in risk with vegetables rich in carotenoids may be due not to their beta-carotene content rather than other nutrients in these foods. Supplementation with beta-carotene for an average of 12 years had no effect on the risk of type 2 DM. In a study of hemodialysis patients, risk of diabetes was inversely related to plasma beta-carotene concentration. In a study of serum beta-carotene and risk of type 2 DM, participants had a 55% lower risk of development of type 2 DM, but this association was greatly reduced after controlling for cardiovascular risk factors. Plasma levels of other carotenoids, such as lycopene and cryptoxanthin, also were found to be inversely related to glucose intolerance.

Plasma vitamin A levels in diabetics:

Patients affected by type 1 DM showed that plasma retinol is significantly decreased in younger insulin-dependent diabetic patients, while alpha-tocopherol is significantly altered in diabetic patients with nephropathy. Plasma retinal, or its ratio to cholesterol, were significantly and independently reduced in the younger subset of diabetics as compared to controls. In patients with type 2 DM showed similar results, while two other studies showed no evidence of deficiency of vitamin A in Type 2DM subjects.

Relation between dietary vitamin intake and resistance to insulin-mediated glucose disposal

A study suggests that vitamin A intake is associated with enhanced insulin-mediated glucose disposal.

Melanoma

Beta-carotene supplementation had no significant impact upon melenoma risk in a trial. An overall 17% reduction in melanoma was observed among physicians randomized to 50 mg of beta-carotene, but was not statistically significant.

Nutritional Anemia in Pregnancy

Improvement in vitamin A status may contribute to the control of anemia in pregnancy. Vitamin A and iron supplementation was studied in anemic pregnant women. Maximum hemoglobin was achieved with both vitamin A and iron supplementation with one-third of the response attributable to vitamin A and two-thirds to iron. After supplementation, the proportion of women who became non-anemic was 35% in the vitamin-A-supplemented group, 68% in the iron-supplemented group, 97% in the group supplemented with both, and 16% in the placebo group.

Infectious diseases

Trials showed that adequately supplying vitamin A, either through supplementation or adequate diet, had a major role in preventing morbidity and mortality in children in developing countries. In developed countries, vitamin A may also have a role in those with life threatening infections such as measles and those who may have a relative deficiency, such as premature infants.

Respiratory syncytial virus infection in children

High dose vitamin A therapy is effective in reducing morbidity and mortality with measles infection. Children with acute respiratory syncytial virus (RSV) infection have low serum vitamin A concentrations. A trial of high dose vitamin A therapy among children 1 month to 6 years of age found no evidence of a beneficial effect of vitamin A for the treatment of RSV infection.[65] One study showed that treatment of previously healthy respiratory syncytial virus-infected infants at doses of 12,500-25,000IU is safe and well tolerated.

Crohn's Disease

Vitamin A therapy has been claimed to be of benefit to patients with Crohn's disease. In one long-term study, vitamin A has shown no benefit to patients with Crohn's disease who are in remission.

Summary Vitamin A and Carotenoids

Vitamin A is essential for the support of the differentiation of epithelial cells and thus, maintains lung and tracheal integrity support and viability of the reproductive system and utilization in visual cycle. These three functions of vitamin A can be supported by dietary retinyl esters, retinal and retinal, but not retinoic acid. Vitamin A also stimulates immunity and is also essential for the formation of bone, protein, and growth hormone. Beta-carotene, the pre-vitamin form of vitamin A, acts as an antioxidant and also may enhance immune system functioning. Other members of the antioxidant carotene family include cryptoxanthine, a-carotene, zeaxanthin, lutein, and lycopene, most of which do not convert into significant amounts of vitamin A.

A number of claims have been made about the beneficial effects of vitamin A and the carotenoids, which includes: Night blindness; Retinopathy; Photosensitivity; Conjunctivitis and blepharitis; Macular degeneration; Cataract; Most infections; Urinary tract infection; Recurrent ear infection; Immune function; Minor injuries; Measles; HIV support; Crohn's disease; Menorrhagia; Premenstrual syndrome; Abnormal pap smear; Peptic ulcer; Acne; and Alcohol withdrawal.

Night blindness is the earliest symptom of vitamin A deficiency, and vitamin A supplementation at this stage can help prevent development of xerophalmia, corneal ulceration, and blindness. Evidence exists in support of intake of vitamin A and carotenoids and decreased risk of cataracts. Vitamin A may prevent loss of lung elasticity, epithelial keratinization, salivary gland keratinization, urinary calculi, and impaired hearing. Dermatological problems like acne, psoriasis, Darier's disease, and skin aging may also be treated effectively with retinoic acid and topical tretinoin. Improvement in vitamin A status may contribute to the control of anemia in pregnant women.

Evidence strongly suggests that higher intake of vitamin A, may significantly decrease the risk of lung cancer, especially squamous cell carcinoma. Low serum carotenoids were also found to be associated with a 200% increase risk of lung cancer. Studies suggest a positive role of carotenoids for breast, cervical, esophageal, pancreatic, and colorectal cancer. Vitamin A has shown a protective effect in the risk of breast cancer and may protect against the development of gastric neoplasia and squamous cell carcinoma of the head and neck. Carotenoid consumption has shown to decrease the risk of bladder cancer, and lycopene may reduce the susceptibility of lymphocyte DNA to oxidative damage. Supplementation with beta-carotene has shown inverse relationship with the development of thyroid cancer and also caused reversal of oral leukoplakia. Beta-carotene may also have a protective effect against the development of type 2 DM. A non-significant reduction in melanoma was observed with beta-carotene supplementation.

Populations who are prone to be deficient in this vitamin like patients with chronic intestinal diarrhea, malignancy, malaria, pneumonia, and anorexia nervosa should receive supplementation. As stress can increase the vitamin excretion, patients with appendectomy, burns, cirrhosis, and biliary obstruction may benefit from supplementation. Premature infants and those suffering from cystic fibrosis and rheumatic fever should receive vitamin A supplements.

Our recommendations for adults is 5000 IU/d of vitamin A with 100% beta-carotene. This amount can be obtained from approximately ¾ serving of boiled spinach, 2 ½ servings of raw carrots, 5 servings of raw papaya, and 1/5 serving of baked sweet potato. In general, a dose of <25000 IU is considered safe in the age group of 18-54. Beta-carotene is safe even when consumed in large amounts, and there is no evidence that conversion of beta-carotene to vitamin A contributes to vitamin A toxicity.

Vitamin A in excess is hepatotoxic and neurotoxic. In pregnant woman, it may cause congenital malformations in developing fetus, like precocious skeletal development and transient hydrocephalus. Long-term ingestion may increase cholesterol concentrations and thus, increase the risk of coronary artery disease and should be considered with caution. Risk of osteoporosis and hip fractures is also increased with excess consumption.

About the Authors

Ken Adams, M.D.
Team Physicians, USACycling
Principal
Physicians' Natural Choice

Scott E. Conard, M.D.
Principal
Physicians' Natural Choice

by EricT

By Roger B. McDonald and Rodney C. Ruhe

Department of Nutrition, University of California, One Shields Ave, Davis, CA 95616, USA
Nutrients 2010

Life expectancies after the age of 70 and the number of individuals living with age-related chronic conditions that affect daily activities continue to increase. Age-specific nutritional recommendations may help to decrease the incidence or severity of age-related debilitating chronic disorders. However, research in this area has seen limited success in identifying nutrition-related mechanisms that underlie the functional loss and chronic conditions that occur as a function of time. We believe that the limited success in establishing age-specific nutrition recommendations for the older population reflects, at least in part, research designs that fail to consider the evolutionary and biological bases of aging and longevity. Longevity has evolved as a by-product of genes selected for their contribution in helping the organism survive to the age of reproduction. As such, the principle of genetic determinism provides an appropriate underlying theory for research designs evaluating nutritional factors involved with life span. Aging is not a product of evolution and reflects stochastic and/or random events that most likely begin during the early, reproductively-active years. The genetic determinism model by which young (normal, control) are compared to old (abnormal, experimental) groups will not be effective in identifying underlying mechanisms and nutritional factors that impact aging. The purpose of this commentary is to briefly discuss the difference between aging and longevity and why knowing the difference is important to nutrition research and to establishing the most precise nutritional recommendations possible for the older population.

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Introduction

Life expectancies after the age of 70 and especially after the age of 85 have yet to reach a plateau. While life expectancy after the age of 70 continues to increase, so too do the number of individuals living with age-related chronic conditions that affect daily activities. Many believe that age-specific nutritional recommendations for the older population may help to decrease the incidence or severity of debilitating, non-disease disorders that occur with increasing age. However, research in this area has seen limited success in identifying nutrition-related mechanisms that underlie the functional loss and chronic conditions that occur as a function of time.

We suggest that lack of success in establishing age-specific nutritional recommendations for the older population reflects, at least in part, research designs that do not consider the biological differences between aging and longevity. Failure to consider these differences may also lead to difficulty in precisely defining aging or longevity, a prerequisite to efficient experimental designs. Distinguishing human biological aging from longevity can be difficult due to the fact that the rate of aging may affect the length of the life span. Moreover, the lack of predation, control of childhood diseases, and effective therapies for life-threatening disease have extended the human post-reproductive life span, making the distinction between aging and longevity even more difficult. Nonetheless, such a distinction will be necessary to develop the most effective research designs evaluating the mechanisms that underlie the impact of nutrition on aging or longevity. Although we acknowledge that there are many valid definitions for aging, we suggest that biological aging be defined as the progressive, event-dependent decline in the ability to maintain biochemical/physiological function. Longevity is the length of the life span independent of the biological aging process. This brief commentary will provide justification for these two definitions.

The ability to define aging and longevity separately has become possible only in recent years. Biogerontological research conducted during the last two decades has, to a large degree, solved the
evolutionary problem of longevity and aging. Evolutionary theorists have mathematically and empirically demonstrated that longevity is genetically determined from genes that are selected for a reproductive advantage [1,2]. As such, the principle of genetic determinism provides an appropriate underlying theory for research designs evaluating nutritional factors involved with life span. Investigations evaluating possible gene-nutrient interaction should prove valuable in the search for nutrients that affect longevity. On the other hand, aging is not a product of selective evolution. The aging process more closely reflects chance events that affect biological systems during development or during the early reproductively-active years [3]. The genetic determinism model by which young (normal, control) are compared to old (abnormal, experimental) groups will not be effective in identifying mechanisms by which nutritional factors affect aging. Aging will be best understood by evaluating biological systems during development that are most susceptible to time- or event-dependent alteration leading to functional loss and chronic conditions in old age.

Why should a nutrition researcher know the difference between aging and longevity? In the next decade and a half in economically-developed countries, the population of individuals who will be over the age of 70 years will rise from the current 13% to almost 20%. In the United States that percent increase represents an additional 35 million people. Given the disproportionate amount of health care dollars spent on this population, much of which is covered by entitlement programs, we must do all we can to insure a healthy aging population—anything less could be economically catastrophic. Dietary recommendations are a significant part of the overall strategy for improving the health of the aged population.

In an effort to improve the health of older Americans through dietary recommendations, the Committee on the Dietary Reference Intakes (CDRI) has added two age classifications, 51–70 and 70+. However, after 12 years of having these new age classifications, recommendations in the 51–70 and 70+ age groups do not, in general, differ significantly from younger adult age groups [4]. The CDRI attributes the lack of age-specific recommendations to insufficient research. While more research will be necessary, the inability to establish age-specific recommendations also reflects results from research designs that have based their hypotheses on outdated theory. We believe that precise and sustainable recommendations for the older population will come from research designs that consider the most up-to-date findings from biogerontology, including the related but distinct biological processes of aging and longevity [5–7]. Knowing the difference between aging and longevity will be fundamental to developing the strongest designs for nutrition research aimed at establishing recommendations and improving the health of the older population.

In this commentary, we discuss the difference between aging and longevity and why knowing this difference is important to nutrition research. To this end, a brief review will be presented of evolutionary and genetic findings showing that aging lacks genetic determinism whereas longevity evolved. Through this scientific evidence we will show why knowing the difference between aging and longevity is critically important to designing appropriate nutrition research that can be used for nutritional recommendations in the elderly population. A brief discussion will follow as to why establishing nutritional recommendations for the older population will be best achieved by first evaluating genetic/metabolic pathways in young populations that are most susceptible to the chance events leading to age-related functional loss. The interaction between aging and disease will not be covered here. Previous reviews have described thoroughly the differences between aging and disease and the reasons why using disease as a research model for aging may not be tenable [5,6].

Imprecise Terminology: Aging vs. Longevity

In 1952, Sir Peter Medawar delivered a lecture at the University of London focusing on the evolutionary problem of aging entitled .The Unsolved Problem of Biology. [8]. He argued that natural selection could not have worked to fix genes causing the loss in physiological function that begins as reproductive success declines. Medawar reasoned that the extrinsic hazards of the environment present throughout evolutionary history would result in an age distribution that favored a young, reproductively-active population. The younger population would have had greater fitness simply because there were more of them than the population of reproductively-active older individuals. The high rate of reproduction (fitness) in young vs. old age groups would result in traits important for survival to reproduction age being selected over alleles expressing proteins that insure the maintenance of physiological function well past reproduction age. Aging could not have evolved through natural selection.

Medawar’s suggestion that aging did not arise from natural selection came at a time when genetic determinism through natural section was universally accepted as the only explanation for evolution. Therefore, a hypothesis that could explain, in term of genetic determinism, how alleles giving rise to aging could be selected in the absence of natural selection was needed. To this end, Medawar turned to genetic drift, a population genetics theory predicting that alleles in small populations can be fixed in the general population’s genome as a matter of chance. Medawar was building on the ideas of Haldane [9] that a small population of late-life reproducers carried genes conveying the aging phenotype. This small population could contribute to the establishment of an aging phenotype because nonlethal but physiologically detrimental genes expressed only in late life could arise in a population because they would not have had any effect on reproduction. Natural selection would have selected neither for nor against these genes. Medawar named his evolutionary aging theory mutation accumulation.

Medawar’s verbal postulations on aging provided the foundation for scores of researchers investigating the evolutionary, genetic, and biological basis of aging and longevity. However, his theory on aging contained a significant flaw that has been perpetuated in research designs for over 50 years. That is, he used the terms aging and longevity interchangeably even though his theoretical models focused exclusively on longevity. Medawar’s model for aging/longevity did not consider the possibility that life span and the functional loss characterizing aging could have arisen through different evolutionary/biological processes. Subsequent work found that longevity and aging are distinct biological events.

The differences between aging and longevity became clearer with the mathematical descriptions by W.D. Hamilton [1] and later by B. Charlesworth [10]. Hamilton’s mathematics agreed with Medawar’s verbal speculation that genes did indeed affect events leading to either aging and/or longevity. However, these genes were not the type that Medawar had suggested, i.e., fixed by genetic drift and specific to the aging phenotype. Rather, Hamilton’s mathematical model predicted that longevity was determined by genes selected for reproductive success and not by genes that were expressed only late in life. His model showed that the force of natural selection on mortality was highest before the start of the reproduction phase and declined thereafter (Figure 1). Because the force of mortality was highest prior to reproduction, evolution would have worked to select genes that were necessary for combating mortality in early life, i.e., surviving to reproduction age. Mortality (life span), therefore, must be related to genes selected for survival to reproduction age. Hamilton provided the first mathematically implicit evidence that life span (longevity) had evolved and was directly related to genes that optimized survival to the age of reproduction. Importantly, his model was specific to longevity and did not include variables of age-related functional loss.

Hamilton’s mathematical theory on longevity was a monumental breakthrough in the understanding of how life span, not aging, evolved. Based on his mathematical models, several laboratories using artificial selection methods to approximate evolution have supported Hamilton’s theories on the evolution of longevity [11–13]. Populations of Drosophila selected in the laboratory for their timing of reproduction showed that late-life reproducers do indeed live significantly longer than flies having their highest rate of reproduction early in the life span (Figure 2). Genetic studies in yeast, C. elegans, and Drosophila have also shown that genes affecting life span have been selected first and foremost for their role in enhancing survival to reproduction age (see review [14]).

Figure 1. Hamilton’s calculation on the force of natural selection on mortality (s(x)) and fecundity (s’(x)). Data used are from life-tables of the United States between 2000 and 2004 (Adapted from [2]).

Figure 2. Life span of female Drosophila artificially selected for early and late life reproduction (Adapted with permission from John Wiley & Sons [12]).

Mathematical models and empirical experimentation have unequivocally established that longevity evolved from genes selected for their impact on survival to the age of reproduction. Because these investigations did not include measures of age-related degeneration, conclusions as to the genetic basis of aging cannot be made. Nonetheless, hundreds if not thousands of publications exist describing research that either directly or indirectly implicate specific genes as being involved in age-related degeneration. Not one gene has been identified that causes osteoarthritis, presbyopia, sarcopenia, or any other of the hundreds of age-related degenerative and chronic disorders observed in the aged population. The reason for this is simple-these genes do not exist.

The Disposable Nature of the Soma and the Cause of Aging

Aging arose serendipitously in evolutionary history as a result of a trade-off between the germ line and somatic cells in the distribution of resources. This trade-off has been developed into a formal
theory by Thomas Kirkwood and is known as the Disposable Soma Theory of Aging [15]. The foundation of this theory lies directly in a basic principle of natural selection, i.e., all environments have finite resources and individuals compete for these resources. Organisms that use the finite resources most efficiently will be the ones to successfully survive to reproduction age. The Disposable Soma Theory posits that the most efficient use of resources in multicellular organisms is to give highest priority to the cells that are responsible for the continuation of the species, i.e., the cells of reproduction, or the germ line. Supporting cells, those of the soma, would only need enough resources to accomplish their primary task of supporting the germ line. That is, the soma could be disposed of once reproduction had occurred.

But, where and how were those resources being spent? The Disposable Soma Theory predicts that that the distribution of resources by the early metazoans was preferentially diverted to repair mechanisms of the DNA in the germ line. This suggestion is consistent with the observation that the energetic cost for maintaining DNA fidelity is rather high. If, because of finite resources, an organism had to make an evolutionary choice between accuracy in the DNA of the germ cell or repair of a somatic cell, the germ cell would be chosen so as to provide the best chance of survival for the next generation. The immortality of the germ line has come at the cost of somatic mortality.

Chance, Aging, and Nutritional Recommendation

The evidence presented thus far leads to the conclusion that aging is a random and/or stochastic phenomenon. A substantial literature exists describing that the primary mechanism associated with the random nature of aging is entropy, a property of the Second Law of Thermodynamics (see reviews [5–7]). Briefly, biological systems defend themselves against the unceasing disorder of entropy by continuously restoring the free energy lost to chemical reactions that maintain molecular fidelity (structure, function). At its very basic level, survival to reproduction age simply reflects the selection of genes that maintain free energy states conducive to life. However, there is no reproductive advantage for an individual to sustain molecular fidelity after the age of reproduction. Genes would not have been selected for the purpose of maintaining the high cost of combating entropy throughout the life span. The age-related decline in physiological function reflects a gradual loss in the ability to defend against the Second Law of Thermodynamics, i.e., entropy. Importantly, the age-related loss in the ability to defend against entropy manifests purely as random events with respect to the physiological systems affected.

The random nature of aging suggests that chance plays a significant part in determining the physiological system or systems that experience declining function in the older population. The role of chance as a factor in the aging process has been reviewed in detail [3]. Chance precludes genetic determinism and introduces an element of uncertainty that cannot be controlled easily in population-based research, the type of research commonly used as the basis for establishing nutritional recommendations. The CDRI recognizes the problem of random variation in the aging population when stating that research investigating dietary recommendations for the older population is confounded by increased error (random variation) in the data [4]. Moreover, the error becomes greater with advancing age, suggesting that nutritional recommendations based on the current scientific rationale, i.e., genetic determinism, are even less accurate for the oldest age groups.

Chance also raises the possibility that every sample population will be unique and that no sample population can be relied upon to provide meaningful predictive results for the entire aged population. Take for example the results from studies investigating the value of nutritional antioxidants as modulators of aging. Nutritional antioxidants prevent damage to the cell in vitro and the accumulation of cellular damage has found wide acceptance as a proximal cause of organism aging. The epidemiological data suggest that the rate of aging and age-related disease may decrease in populations consuming foods high in antioxidants [16,17]. Consistent with the epidemiological data, small sample size cross-sectional supplementation investigations tend to find positive outcomes between experimental (supplemented) and control (non-supplemented). However, several large randomized clinical trials have failed to demonstrate the benefit of antioxidant supplements in the aging population (see review [18]). That is, the small cross-sectional studies have not been reliable indicators of the usefulness of antioxidant nutrition in the general older population.

The dominant role of chance in the aging process (but not longevity) leads to the inevitable conclusion that the fundamental process of biological aging cannot be modulated through interventions during old age. The nutrition researcher may find this statement difficult to accept given the overwhelming successes that nutrition interventions had on infant and childhood health. The reason that nutrition interventions improved the health of infants and children was that nutrients had targets to interact with, i.e., genes selected for survival to reproduction age. Since aging did not arise through selective evolution, nutrients may or may not alter expression of genes in the older population. Recommendations for the older population arrived at by using genetic determinism will be unreliable—without genetic determinism, it is a matter of chance.

If modulating aging by nutritional intervention during old age will not produce the desired results, how then will nutrition intervention be effective in improving the health of the older population? We suggest that the research approach should focus on possible variation in function among individuals in younger age groups that may predispose them to differential rates of functional decline during advancing age. We must focus our attention on the time in the life span in which genetic determinism has the greatest influence on random aging outcomes, i.e., the development, juvenile, and reproductively-active periods. Only after gaining a clear understanding of how chance and randomness shape the genetic pathways in younger populations that, in turn, affect the outcomes in the older population, should nutrition recommendations be considered.

Refocusing nutrition and aging research to be consistent with the current understanding of the cause
of aging may not be as difficult as it first may appear. While a personal genomic approach will ultimately be required in humans, several investigative models exist that may prove useful. The Fetal Origins Hypothesis (a.k.a Fetal Basis of Adult Disease) suggests that some diseases have their bases in utero [19]. Most research in this area has focused on the relationship between fetal/maternal nutrition and adult-onset obesity. These investigations suggest that undernutrition in utero leads to higher incidences of adult-onset obesity, hypertension, cardiovascular disease, and type II diabetes [20]. Recently, a link between Parkinson’s and Alzheimer’s Disease and a toxic gestational environment during neurodevelopment has begun to emerge [21]. For example, the amyloidogenic proteins A. and A. precursor as well as BACE1 (the A. cleavage enzyme) are elevated in non-human primates exposed to lead during infancy [22]. Although the current focus of research linking the developmental environment with aging remains on age-related disease, it would not be surprising to find that the rate of aging and the trajectory in the age-related loss of soma maintenance, independent of overt disease, may also have fetal origins.

The age-related alterations to the vascular system and the development of certain types of cancer have been used extensively as models of the aging phenotype. A substantial literature exists describing how dietary habits during childhood may induce dysfunction of various systems during aging. Some recent publications provide additional examples of specific research areas that should be given consideration [3,5,6] in this regard.

Conclusions

Evolutionary and genetic research has clearly established that longevity has evolved whereas aging is a random/stochastic process driven primarily by chance events occurring during development and the reproductive years. Knowing the difference between aging and longevity will determine, in part, the scientific approach to research questions aimed at evaluating the impact that nutrition may have on the aging population. If the primary purpose of the research is to determine the factors involved with longevity, then focusing on altering the expression of specific genes by specific nutrients will be appropriate. If, however, the aim of the research is to evaluate how nutritional interventions can modulate the aging process and improve the health of the older population, then the genetic determinism model will be inappropriate. Research designs that focus on chance events in young populations that lead to altered states of aging will be the more powerful. Effective nutritional recommendations for the aged population will most likely be ones that focus on dietary changes in the younger populations.

Acknowledgements

The author wishes to acknowledge Jon Ramsey for his critical review of the manuscript, and Jennifer Ruhe for her technical assistance.

References

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© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).

by EricT

By Krista S. Crider¹, Lynn B. Bailey² and Robert J. Berry³

Nutrients 2011

Periconceptional intake of folic acid is known to reduce a woman’s risk of having an infant affected by a neural tube birth defect (NTD). National programs to mandate fortification of food with folic acid have reduced the prevalence of NTDs worldwide. Uncertainty surrounding possible unintended consequences has led to concerns about higher folic acid intake and food fortification programs. This uncertainty emphasizes the need to continually monitor fortification programs for accurate measures of their effect and the ability to address concerns as they arise. This review highlights the history, effect, concerns, and future directions of folic acid food fortification programs.

History

Folic Acid and the Prevention of Neural Tube Defects

Folate is a water-soluble vitamin and includes endogenous food folate and its synthetic form, folic acid. In its naturally occurring form folate lacks stability in food storage and preparation [1]; however, folic acid is stable [1–3] and used for supplements and food fortification. There are many critical cellular pathways dependent on folate as a one-carbon source, including DNA, RNA, and protein methylation, as well as DNA synthesis and maintenance [4]. A number of genetic polymorphisms affect critical components of folate pathways and metabolism, and have been associated with an increased risk for NTDs [5]. However, the exact mechanism(s) by which folic acid reduces the risk of NTDs is not known and remains an active area of research.

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Neural tube defects (NTDs) occur when the neural tube fails to close early in embryonic development, resulting in damage to the exposed underlying neural tissue. These birth defects can result in significant morbidity and mortality depending on the location and severity of the lesion. The most severe.anencephaly.is incompatible with life; the lower lesions observed with spina bifida cause a range of morbidities, including urinary and fecal incontinence and paralysis of the lower limbs [6].

The relationship between apparent folate deficiency and NTD occurrence was hypothesized as early as 1965 [7]. After a number of studies suggested that folic acid might reduce the risk of NTDs [8–10], a randomized control trial (RCT) to determine the effectiveness of folic acid supplementation in the prevention of the recurrence of NTDs was undertaken by the British Medical Research Council [11]. That RCT found that women with a previous history of a pregnancy affected by an NTD reduced their recurrence risk by 70% by taking 4000 micrograms (µg) of folic acid daily. The following year, in a Hungarian RCT, a 100% reduction in risk of a first occurrence of an NTD-affected pregnancy was found among women who took a prenatal vitamin containing 800 µg of folic acid daily [12].

In 1991, the Centers for Disease Control and Prevention recommended that women with a history of a prior NTD-affected pregnancy should consume 4000 µg of folic acid daily starting at the time they begin planning a pregnancy [13]. Subsequently, in 1992, the U.S. Public Health Service recommended that all women of childbearing age consume 400 µg of folic acid daily through fortification, supplementation, and diet to prevent NTDs [14]. In 1998, the Institute of Medicine (IOM) recommended that women capable of becoming pregnant should consume 400 µg of folic acid daily from fortified foods or supplements, or both, in addition to that obtained through a normal diet [15]. In 2009, the U.S. Preventive Services Task Force published updated guidelines that reinforced these recommendations [16].

Encouraging women to consume a supplement containing 400 µg of folic acid daily has limitations as a primary public health program. In the United States, up to 50% of all pregnancies are unplanned [17]. The neural tube closes early in embryonic development (28 days after conception), therefore a woman should begin folic acid supplementation ideally prior to becoming pregnant. Education campaigns encouraging women to increase their use of supplements have not been effective at reaching every high-risk population [18]. To compound the problem, a recent UK cohort study showed that women planning a pregnancy only marginally increased their compliance with health behaviors and folic acid supplement use [19]. Other countries have recommendations to prevent NTDs by improving diet or encouraging supplement use, or both, but do not have mandatory fortification programs. An evaluation of NTD trends in such countries has revealed no significant changes since recommendations were enacted [20]. It has been suggested that well-implemented mandatory fortification programs, unlike voluntary fortification programs, might help reduce disparities [21]. Given these issues, mandatory fortification programs have been implemented in many countries to maximize their effects and reduce the high costs associated with prevention programs such as education campaigns and other interventions that require behavioral change [22].

Mandatory Food Fortification Programs

Regulations for mandatory fortification of wheat flour with folic acid are currently in place in 53 countries although in many cases these regulations have not been implemented [23]. In 2006, the World Health Organization and the Food and Agricultural Organization of the United Nations published guidelines to help countries to set the Target Fortification Level, the Minimum Fortification Level, the Maximum Fortification Level and the Legal Minimum Level of folic acid to be used to fortify flour with folic acid [24]. In the United States, mandatory fortification of enriched cereal grain products with folic acid was authorized in 1996 and fully implemented in 1998 [25]. The U.S. program adds 140 µg of folic acid per 100 g of enriched cereal grain product and has been estimated to provide 100–200 µg of folic acid per day to women of childbearing age [26–28]. Although mandatory flour fortification programs increase folic acid intake, research has shown that they do not reach all women of reproductive age adequately [29,30]. For maximum benefit, folic acid fortification of additional food products might be needed to reach all population groups effectively [31]. The mandatory folic acid fortification level in select countries including the US is illustrated in Table 1 [32].

Table 1. Levels of folic acid fortification in countries with mandatory fortification programs.

Effect of Mandatory Fortification of Food with Folic Acid on NTD Prevention

NTDs

The original impetus for folic acid food fortification programs was to reduce the occurrence of NTDs and associated morbidity and mortality, although a number of other health effects have been postulated. For the purposes of this review, we have limited this discussion to NTD risk reduction. Folic acid fortification to reduce NTDs is considered one of the most successful public health initiatives in the past 50–75 years [32]. Studies in the United States, using various methodologies, have shown decreases of 19%–32% in the prevalence of NTDs overall since the implementation of folic acid fortification in 1998 [37–40]. Larger decreases have been found in programs that were able to capture NTD cases using prenatal information, including elective terminations [37]. Recent reports have suggested that anencephaly and spina bifida have seen similar declines, although it took additional years of fortification for the declines in anencephaly to match those of spina bifida [23,40].

Canada, South Africa, Costa Rica, Chile, Argentina, and Brazil also have reported declines in NTDs (19%–55%) since the initiation of folic acid food fortification [33–36,41–46]. The magnitude of the decrease in NTD prevalence observed in each country has been dependent on a number of factors. The greatest decline in NTD prevalence has been observed in those countries with the highest background prevalence. Other variables that have influenced the decline in NTD prevalence after fortification include the folate status of the population before fortification, the number of people consuming fortified foods, and the ability of birth defects surveillance systems to effectively ascertain the decline in prevalence of NTDs as a result of folic acid fortification. Although there were variations in the rates of NTDs among countries before fortification (10.6–17.0 cases per 10,000 live births), since folic acid fortification the decreased rates have been less variable (6.3–10.0 cases per 10,000 live births), as previously reviewed [32]. These data suggest that a prevalence of 5–6 cases per 10,000 pregnancies represents the lowest prevalence that is achievable through current folic acid fortification practices and that a proportion of the remaining NTDs are not sensitive to folic acid [23,32]. Recent evidence indicates that low maternal vitamin B12 is a significant predictor (independent of folate) of NTD risk [47].

Blood Folate Concentrations and the Prevention of NTDs

One way to evaluate the effect of food fortification programs is to measure blood folate concentrations among the population. Folate deficiency is defined as a serum folate concentration <7 nmol/L (~3 ng/mL) or a red blood cell folate concentration <315 nmol/L (~140 ng/mL) [15]. Homocysteine concentration may be considered a .functional. indicator of folate status in conjunction with blood folate concentrations [48]. Although the blood folate concentration needed to achieve a maximal reduction in the risk for folate-sensitive NTDs is unknown, among an Irish cohort, Daly et al. found that the greatest reduction in NTDs was observed at blood folate concentrations much higher than those set for folate deficiency [49]. This suggests that for NTD prevention elimination of folate deficiency is insufficient. Folic acid from multiple sources might be needed to achieve a blood folate concentration high enough for optimal NTD risk reduction [31].

Higher Folic Acid Intake Relative to Sources

In the United States, folic acid intake can come from multiple sources, including supplements, enriched cereal grain products, ready-to-eat breakfast cereals as well as other types of fortified food. A variety of foods can be fortified with folic acid under different U.S. Food and Drug Administration rules.such as ready-to-eat breakfast cereals and energy bars and drinks.as well as from the mandatory fortification of enriched cereal grain products [50]. Supplements and ready-to-eat cereals provide up to 400 µg of folic acid in pill form or per serving, respectively.

Since the implementation of mandatory folic acid fortification in the United States, the types of population-based studies examining the potential beneficial or adverse effects of such fortification have been limited. Available studies.such as cross-sectional, ecological, and case reports.cannot be used to establish causation. Most of the concern surrounding folic acid fortification comes from studies of higher intakes of folic acid or higher blood folate concentrations, or both. Pills used in RCTs testing the effectiveness of folic acid intake on other health outcomes commonly contain 800–2500 µg of folic acid [51], and higher blood folate concentrations are associated with excess use of supplements containing folic acid [50,52].

The tolerable upper intake level (UL) (1000 µg/day) was established by the IOM in 1998 as one-fifth of the lowest observed adverse effect level (5000 µg/day) associated with a potential adverse outcome in early case reports (the masking of vitamin B12 deficiency anemia) [15]. Even at dosages of 15,000–100,000 µg of folic acid daily, the IOM found limited evidence of direct toxicity from folic acid [53–58]. Recent studies have shed light on the means by which the intake would exceed the UL for most individuals. In a nationally representative study from the United States, Yang et al. found that food fortification supplied a steady low level of folic acid intake (~138 µg/day) and only 2.7% of the adult population had folic acid intakes that exceeded the UL [50]. Moreover, the only adults with usual intakes above the UL were those who consumed more than 400 µg of folic acid daily through supplements [50,59]. Among children whose usual intake of folic acid was limited to that from enriched cereal grain products, no one’s usual intake exceeded the UL [60].

Concerns about Potential Adverse Effects

With any public health intervention, there are concerns about potential adverse consequences. Continued monitoring of fortification programs is critical to be able to address emerging concerns as new hypotheses are generated. Monitoring could include regulatory oversight of the flour fortification industry, surveillance of NTDs if possible, surveys of blood folate concentrations in the population, and surveillance for potential adverse effects. Assessing the sources and amounts of folic acid consumed is critical to studies because we know that fortification is a relatively small contributor to higher levels of daily folic acid intake. Folic acid has been used successfully for more than 40 years and throughout its use there have been concerns about its safety. In this review, we address some of the old and newly emerging concerns.

Masking of B12 Deficiency Anemia

Historically, concerns surrounding folic acid use have focused on the possibility that folic acid could mask the anemia caused by vitamin B12 deficiency. Early case reports (1940–1960) suggested =5000 µg of folic acid daily could mask a vitamin B12 deficiency by preventing the development of anemia. In turn, this could delay the diagnosis of an underlying vitamin B12 deficiency and thereby allow vitamin B12 deficiency-associated neuropathies to progress [15]. It is recognized that the diagnosis of a vitamin B12 deficiency and/or response to treatment should be dependent on a series of vitamin B12 blood status indicators and not solely on hematological indices which may not be reliable [15]. The IOM concluded in 1998 that there was .no clear evidence of folate-induced neurotoxicity in humans. [15]. Several studies both before and after fortification have examined this issue and concluded that, at current recommended intakes, there is little evidence of masking or exacerbation of neuropathies [61–64].

Cancer and Epigenetic Changes

Many studies, as reviewed, have shown that a diet high in folate (from fruits and leafy green vegetables) is associated with lower risks of many types of cancer [65]. Recently, focus has shifted to the possibility that folic acid intake might lead to changes in epigenetic patterns. Epigenetics is the study of heritable changes that do not involve changes in DNA sequence. Folate is used by two different metabolic pathways.DNA synthesis and DNA methylation (an epigenetic modification).as a source of one-carbon methyl groups [4]. Epigenetics has been hypothesized to play a key role at the interface of gene–environment interactions and might help to explain different health outcomes (e.g., birth defects, cancer, and mental health) occurring among those with similar genetic backgrounds [66–68].

As a result of the fact that folate is a source of the methyl group for DNA methylation and that DNA methylation is a ubiquitous regulator, there are countless biologically plausible hypotheses of how folic acid might affect any disease of interest, either positively or negatively. Most of the concern has surrounded cancer, most likely because the field of epigenetics has been studied largely in the context of tumorogenesis [69–74]. There are clear DNA methylation pattern changes in tumors [73–75]. It has been suggested in a recent review that folic acid might prevent some cancers and might promote other neoplasias [76]. It has been hypothesized that early exposure to folic acid might prevent tumors through the provision of enough methyl groups to maintain proper methylation patterns and repair of DNA. In contrast, after the development of tumors, higher intake of folic acid might promote growth of existing tumors [76]. However, a very recent meta-analysis of the RCTs of the effects of B vitamins on 37,485 individuals with existing cardiovascular disease showed no increased risk of cancer incidence (relative risk (RR) 1.05, 95% confidence interval (CI) 0.98–1.13), cancer mortality (RR 1.00, 95% CI 0.85–1.18) or all-cause mortality (RR 1.02, 95% CI 0.97–1.08) [51]. Since the implementation of mandatory folic acid fortification in the United States in 1998, both incidence and mortality of colorectal cancer have continued to decline [77].

In 2008, the European Food Safety Authority (EFSA) convened a working group to consider whether there was enough evidence to recommend a full risk assessment to determine whether folic acid was causing cancer, especially colorectal cancer. The EFSA concluded that, .there are currently insufficient data to justify such an assessment and that current evidence does not show an association between high folic acid intakes and cancer risk but neither do they confidently exclude a risk. [78].

There are a number of knowledge gaps that need to be filled before we know if folic acid affects disease risk through DNA methylation in humans. The normal patterns of DNA methylation across the genome are unknown, as are the .normal. levels of variation among and between individuals and populations. The National Institutes of Health has an initiative to map the epigenome that is modeled on the Genome Project to begin to describe DNA methylation. It also is unknown if DNA methylation patterns among humans can be altered by folic acid or other micronutrients, or both, or if the patterns change by the timing of exposure (e.g., different response among adults vs. among children or fetuses). Animal models have shown that it is possible to alter the prenatal exposures to one-carbon sources (folic acid, choline, betaine, etc.) and affect DNA methylation at a specific locus and that this can affect the phenotype of the offspring regardless of the adult animal’s diet [79]. Currently, there is no evidence of this effect among humans. The interaction of folic acid and epigenetics will continue to produce hypotheses that will need to be tested carefully.

Unmetabolized Folic Acid

Folic acid normally is reduced to tetrahydrofolate following uptake by the liver [80]. If the body’s
ability to reduce folic acid is exceeded, unmetabolized folic acid will be found circulating in the blood.
One experimental study suggested that unmetabolized folic acid would be found after consuming a bolus of >200 µg of folic acid [81]. Intakes exceeding this threshold would be common through the use of supplements or fortified foods such as breakfast cereals [82], but unlikely would be reached through intake of folic acid from mandatory U.S. fortification levels alone [81,83–87]. Because folic acid has been a long-standing component of over-the-counter supplements and prenatal vitamins, if looked for, unmetabolized folic acid would have been found among a large proportion of the U.S. population for decades. Only recently has the laboratory equipment needed to measure circulating unmetabolized folic acid become available. Unmetabolized folic acid has been found among many groups examined.from older U.S. adults [87] to the cord blood from newly delivered infants [88]. It has been hypothesized that unmetabolized folic acid is related to cognitive impairment among seniors [89], although the findings might have been confounded by patients with pernicious anemia. Currently, there are no definitive studies that have found health effects from exposure to unmetabolized folic acid.

Systematic Reviews of Potential Beneficial and Adverse Effects Prior to the Implementation of Folic Acid Fortification Programs

The food safety agencies in a number of countries considering mandatory folic acid fortification have considered the potential that folic acid may have both beneficial and adverse effects. Among these agencies are the UK Food Standards Agency (FSA) [90], the Food Safety Authority of Ireland (FSAI) [91], Food Standards Australia New Zealand (FSANZ) [92], and the Health Council of the Netherlands [93]. The recommendation to approve folic acid fortification has been the consensus decision presented in final reports from these countries. However, for a variety of reasons, to date only Australia has completed implementation of its program.

Experiences in the United Kingdom

In 2006, the Scientific Advisory Committee on Nutrition (SACN) of the UK FSA recommended that mandatory fortification with folic acid should proceed, together with controls on the intake of folic acid from voluntarily fortified foods [90]. Then in 2007, the SACN was convened at the request of the UK FSA to review potential adverse effects of folic acid on colorectal cancer risk because of two papers published earlier that year. In 2009, after an extensive review, the panel concluded that there currently were insufficient data to support the concerns that folic acid fortification promoted cancer and announced its decision to support its previous recommendation for mandatory folic acid fortification [94].

Experiences in Ireland

In 2006, the FSAI recommended that mandatory fortification with 120 µg of folic acid per 100 g of bread should begin without changing the existing practice of voluntarily fortifying foods with folic acid [91–95]. However, in 2008, the FSAI implementation group reported to the Department of Health and Children that mean intake of folate in Ireland had increased to 90 µg daily, primarily from the intake of folic acid from voluntarily fortified foods, of which the FSAI documented more than 200 individual kinds of foods [96]. In 2009, the FSAI announced that because (1) women of childbearing age were receiving 30% more folate in their diet than they were 3 years earlier (the source of which was mostly from voluntary fortification) and (2) the incidence of NTDs in Ireland had been reduced to 9.3 per 10,000 livebirths, there would be limited benefit to public health to require mandatory folic acid fortification at that time [97]. This decision will be open to reconsideration as additional information becomes available on potential adverse outcomes [97]. Additionally, because previous studies have shown that voluntary fortification likely does not reach all subpopulations of women of childbearing age who are at risk [21] and given that NTD prevalences of 5–6 per 10,000 livebirths have been achieved among other populations [98], there might be room for further reductions in folic acid-preventable NTDs in Ireland.

Experiences in New Zealand and Australia

In 2007, FSANZ recommended that Australia and New Zealand implement mandatory programs to fortify bread with folic acid. Both governments agreed to implement this plan by September 2009 [92]. However, in June 2009, bakers in New Zealand began a campaign to stop the plan [99]. The media campaign funded by the Baking Industry Association of New Zealand raised many concerns in the public’s mind as to the safety of folic acid fortification. As a result, the plan for mandatory fortification of bread in New Zealand was put on hold for 3 years [100]; Australia, however, implemented mandatory fortification as scheduled in September 2009.

Future

Existing folic acid food fortification programs have reduced significantly the number of pregnancies affected by NTDs and the associated morbidity and mortality. In the future, new hypotheses will be generated that will need exploration and testing, such as concerns over the possibility of epigenetic changes. Careful monitoring of existing and proposed programs will enable the scientific community to evaluate blood folate concentrations needed for NTD prevention, evaluate and respond appropriately to concerns as they arise, and document the benefit of these public health programs. As with any public health program, it is important to revisit recommendations regularly as additional information becomes available. A significant portion of the estimated 300,000 NTDs worldwide that occur yearly are preventable by the consumption of folic acid and continue to be a great public health burden globally [32].

Declare

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).

by EricT

There has been a lot of support for Michal Pollan's books for the last few years (he was on Colbert ) and his books "In Defense of Food" as well as his earlier book "The Omnivore's Dilemma" are both very popular. I even saw Mike Boyle singing the praises of Pollan while imagining he knew more about nutrition than "nutritionists" by virtue of having read Pollan's books. Even though, strictly speaking, Pollan is not a nutritionist but a journalist. But hey, I've also seen Mike Boyle and others sing the praises of Mercola, so go figure. I would hesitate to get my nutrition information from a strength coach or a journalist. That is not to say that I would not take their advice, but only that I would hesitate to consider that advice as seriously as I would consider the advice of someone who is a nutrition specialist.

Many people blame processed foods and, by extension, so called "unnatural foods" for the obesity epidemic, a rise in heart disease, and pretty much every other health problem known to man. In a general sense it's a classic case of confusing correlation with causation. You can certainly blame the processed food industry (in all it's definitions) for a lot of things and make arguments about it's impact on the environment, etc..

But I find Pollan's books a bit sensationalistic for my taste and his pretense to "science" is particularly annoying to me. Attacking science while trying to sound scientific is just plain silly.

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I have often used "American cheese" as an example of a not so valid assumption about processed foods. Not all American cheese products are the same but let's assume I'm talking about Kraft American cheese…the original.

The automatic assumption is that American cheese is "bad" just because it is processed. But from a purely nutritional standpoint and if you know how it is made…it can be considered pretty sound. It has a better protein to fat ratio and it DOES start with cheddar cheese to which whey and such is added. There are some additional preservatives that many foodies would scream about but they haven't been linked to any health effects. "Real" cheese has mold inhibitors added.

But here is the biggest fallacy. CHEESE is as PROCESSED as you can GET! The whole reason cheese was invented was to PRESERVE milk. That is, it is a way of processing milk in order to preserve it.

Yet, Michael Pollan, on Colbert, mentioned American cheese and how terrible it is. But said how he supported regular "natural" cheese.

As is typical he made a statement that he obviously hadn't researched much. Offhandedly, he mentioned that American cheese has like 40 ingredients! I would have advised him to check a label before making such a statement on national television. It depends of course on what particular product we're talking about but in truth, it has about a quarter that number.

There may be some "processed cheese foods" out there that have that many ingredients but there are actual legal definitions as to what can be named American cheese, etc..

• Pasteurized process cheese (100% cheese which includes "American Cheese" and "Pasteurized process American cheese"), (e.g., "Kraft Deli Deluxe American Cheese", "Land o Lakes American Cheese", "Laughing Cow").
• Pasteurized process cheese food, which contains at least 51% cheese.
• Pasteurized process cheese product which contain less than 51% cheese and cannot be advertised as cheese under FDA regulations (e.g. "Velveeta, "Kraft Singles")
• Pasteurized process cheese spread

Pollan, I would suppose, does not like waste. Well, regular cheese making produces a lot of scraps and leftovers that would be WASTED unless they were used in making the "processed cheese". And look at whey, which is added to American cheese. That is a byproduct of the cheese industry!

Cheese is simply a processed food and American cheese is further processed cheese to give it certain advantages. None of which should be automatically assumed to be unhealthy as compared to regular cheese. But 'regular' cheese is "natural". Right?

I am not saying that Pollan has not done his research when it comes to big food in general. He obviously has. But like many sensationalist journalists, he tends to steer away from the type of research that would not support his assumptions and beliefs. If you were to visit a puppy mill you might be left with a very bad impression of dog breeding, for instance. But not all dog breeding is evil.

Nutritionism, according to Pollan, is the idea that it is the individual nutrients in food, as discovered by science, which determines their dietary value. He say's that through this kind of thinking we have become separated from the natural food chain (there's that natural word again) and have lost our eating instincts. For instance, our instincts governing food intake. We have become increasingly reliant on nutrition experts and since nutrition science cannot completely understand how food affects the body, relying on nutrition science is a fallacy.

Pollan says this is the downfall of food and of our health. Nutritionism, according to Pollan, is what nutritionists do. I am seeing more and more nutrition bloggers pick up this term as if it is meaningful and use it as an umbrella attack against any nutrition concept they disagree with. Arguments against "nutritionism" are so vague and indistinct I don't see how any mindful blogger can take them seriously.

The argument against so-called nutritionism is that we can't know the full, synergistic effect that "whole foods" have and not looking at the whole picture creates unhealthy dietary trends based on food "parts" rather than food as a whole. In fact more often than not, I see people who think like Pollan doing the opposite while nutritionists are looking at the big picture. Probably because the "foodies" are so busy attacking rather than coming up with solutions they are blind to their own contradictions.

The Rule of Falsifiability

Funny, that relying on science should be a fallacy…but relying on a vague concept like "nutritionism is bad" is not. It's funny because the entire argument represents a scientific and logical fallacy. That is because it violates the rule of falsifiability.

Examine the above explanations. There does not exist a set of arguments that you could possibly find that could ever counter them. Try it. Try to come up with a valid counterargument. You can't do it, because it is a claim that cannot be falsified. Oh, you say, well then it must be true! You know better than that.

For something to be valid then a logical counter argument or set of arguments that would make it invalid MUST be conceivable. Otherwise it is meaningless. According to James Lett:

"The rule of falsifiability is essential for this reason: If nothing conceivable could ever disprove the claim, then the evidence that does exist would not matter; it would be pointless to even examine the evidence, because the conclusion is already known — the claim is invulnerable to any possible evidence. This would not mean, however, that the claim is true; instead it would mean that the claim is meaningless."

You can read more on that in A Field Guide to Critical Thinking.

Emotive Statements, What Ought to Be, and Worldview

See, Pollan's statements are not scientific ones, or even logical ones, at all. They are instead his emotional declarations about how things "ought to be". They make no claims which can be examined evidentially or which can be disproven. So, in effect, what Pollan says are his own personal value statements. For the critical thinker, it is essential to learn to recognize the difference between a factual statement, which is one that can possibly be falsified, and a value statement. In this blog, I have written about value statements many times.

He says that being separated from our 'hunter gatherer' origins and thus the natural food chain, which led us to eat by our instincts, is what has made us unhealthy. This statement falls under what Lett describes as the undeclared claim which is "a statement that is so broad or vague that it lacks any propositional content". The undeclared claim is basically unintelligible and consequently meaningless."

Since there is no one definition for the term instinct and certainly no real scientific understanding of how our instincts affect our eating or any of the other vague allusions in Pollan's arguments then there is nothing with which to counter them. I cannot use nutritionism to defend against an attack such as this on nutritionism itself. Therefore the attack itself is completely pointless. What does it mean to be 'separated from the food chain'? What does it mean to 'eat by our instincts'? How would we be able to tell when we are doing this? When we are not? Can a lack of instinctual eating somehow be observed in the body? The fact is, these claims are so vague that anything that happens to human health can be used to defend it. Everything fits, thus nothing fits.

There may be something, somewhere, to what Pollan is saying about nutritionism but to my way of thinking there is not much to be gained in vague philosophical arguments about the food chain and instinct.

That is, there is not much to be gained that informs us about our health. There is much to be gained in terms of the damage the global food market does to our environment. And it is certainly true that this contributes to our cultural eating habits in unhealthy ways. But knowing that will not miraculously result in some kind of idealized eating culture and thus idealized health.

The ad-hominem attacks on nutritionists, as a whole, are unfounded and show a profound lack of understanding about what nutritionists do as opposed to what biochemists and the like do. Attacking the other side without a clear understanding of what the other side is up to not only shows your arguments to be invalid but displays your lack of depth when addressing your chosen subject. However, the wide-spread use of the credential "nutrionists" by dodgy quacks certainly creates a problem. It is a title that can be used by anyone, anywhere. But this does not mean that you can trust information from someone just because they attack nutritionists!

For instance, when plant extracts in supplement form have been given in clinical trials, such as the antioxidant polyphenols in pomegranates and blueberries, there is very little result. Many nutritionists are quick to note that if there is any protection against disease from the the compounds found in foods, that this protection probably comes from a great many compounds working together. Probably thousands of compounds. Their conclusion? Eat whole foods, mostly colorful vegetables. The same conclusion as Pollan but coming from a different direction. Except that nutritionists would never tell you that simply eating by your "instincts" is a magical ticket to health and if they did they would probably be a "Naruropath" or some other kind of wanna-be doctor.

I think that many people confuse the "health, nutrition, and well-being" industry with nutrition science. And I think many people confuse "nutritionists" with nutrition science. There are some individuals who call themselves nutritionists who are very good and use science with a high degree of expertise. And there are others that fit the bill of Dara O Braian's quib "Dietitian is to nutritionist as dentist is to toothiologist". But to lump all of this group into the dietary supplement and "natural health" caegory is an unfair assumption. These industries inflate, misinterpret, and outright lie, about the results of nutrition research to sell their products. They make conclusions that the researchers themselves disagree with, and quite often. Did nutrition science help to create these industries, by giving them a perfect marketing resource? You bet.

But it is naive to think that savvy business people would not be able to take advantage of ANY and ALL trends in food culture to create hugely profitable industries. History shows that they can and will. Where do you think granola came from? Or Quaker Oats.

Funny as it may seem, I would recommend the book, In Defense of Food, for it's first chapter. I just don't think it is anywhere near a complete treatment of the subject.

One very important message that Pollan relates is that "organic" does NOT mean "sustainable". And even when we are making healthy choices we can still, by many people's view, be making wrong ones because of the stranglehold that multi-national corporations have on the food market.

For a more varied perspectives on food culture I urge you to check out the Food, Culture, & Society Journal. You can view a sample issue at the website. Check out The French Paradox, the Healthy Drinker, and the Medicalization of Virtue by Jessica Mudry while it is still available. I cannot link it directly as the journal uses session ID's which would expire. In this paper Mudry explains how wine drinking has become "scientized" and the drinker has become a patient, concerned with the relationship between illness and health. The paper is a good example of the kind of thing that Pollan tries to do but is unable to due to lack of objectiveness. This is much in line with my recent statements concerning "scientific" viewpoints about strength training in which strength training has become "corrective exercise" and the trainee has become a patient.

Also check out the work of Jack Kloppenburg, JR. and the book, Food and the Mid-Level Farm: Renewing an Agriculture of the Middle

To finish up this very long and rambling post, here is Pollan on Colbert back in 2009. Keep your ears opened for another unscientific statement from Pollan about high fructose corn syrup.

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by EricT

By Ken Adams, M.D. and Scott E. Conard, M.D.

Sources and Physiologic Functions

Sources

Liver, kidney, muscle meats, eggs, cheese, milk, and fish are excellent sources of vitamin B12. It is not found in plant foods or in yeast. Fermented foods such as soy sauce, tempeh, and miso, and fortified foods such as soymilk are also good sources of this vitamin.

Biochemistry

Vitamin B12 is water-soluble. Cobalamine contains the element cobalt surrounded by a porphyrin like ring. The coenzyme forms of cobalamine are 5'deoxyadenosylcobalamine and methylcobalamine. Four types of cobalamin play a role in human metabolism, including cyanocobalamin (the form known as B12), methylcobalamin (the main form in the serum), and adenosylcobalamin (the main storage form in the liver). Cobalamin acts as coenzyme in two known pathways of human metabolism: demethylation of the folate derivative needed for the thymidylate synthesis, and conjugation of folic acid into the active polymer forms of folate. Cobalamin deficiency may produce a functional folate deficiency by trapping folate in these pathways and limiting its regeneration. Cobalamin is essential for the regeneration of tetrahydrofolate needed in purine and thymidine synthesis. Vitamin B12 is essential for growth, blood cell formation, nutrient metabolism, thyroid functioning, and myelin formation. It prevents accumulation of methyl melonoic acid, and thus, prevents production and incorporation of abnormal fatty acids into the nerve cell membrane. This may account for some of the neurological manifestations associated with deficiency. It may have a role in homocysteine metabolism and thus, control of atherosclerosis.

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Populations at risk

Vitamin B12 deficiency is commonly caused by pernicious anemia (PA). The major defect in PA is gastric atrophy and absence of intrinsic factor, which is essential for B12 absorption. Disorders of gastric mucosa, intestinal infections, malabsorption secondary to gastrectomy, total ileal disease, or resection and genetic defects in the absorption and transport mechanisms may result in development of deficiency state. Strict vegetarianism over an extended period of time and tapeworm infestation are the other risk factors. A study showed that the vegans had B12 intakes below the RNI; and 35% of the long-term vegetarians and vegans had serum vitamin B12 concentrations below the reference range. Cigarette smoking also affects vitamin B12 status. A univariate analysis showed significantly lower plasma, red blood cell (RBC), and buccal mucosa of vitamin B12 concentrations in cigarette smokers compared to non-cigarette smokers.

Signs and Symptoms of Deficiency

The major defect of B­12deficiency is an impairment of growth, particularly of rapidly dividing cells such as immature RBC. Infants with severe deficiency present with anemia and neurological problems, such as flaccidity, poor muscular control, twitching, and abnormal electroencephalogram. In adults, it is characterized by megaloblastic anemia and later development of neuropsychiatric symptoms. Neurological symptoms include numbness of the hands and feet, parasthesias, decreased vibration sense, and ataxia. CNS symptoms may occur without anemia and are irreversible. Poor growth, sore, smooth tongue, spleenomegaly, thrombocytopenia, and leucopenia are also seen.

Vitamin B12 toxicity

There are no signs of vitamin B12 toxicity, per se. There are a few rarely reported side effects that might be attributable to the vitamin, but such side effects are not necessarily related to the dose. These possible side effects include: diarrhea, blood clots in the legs, feelings of swelling over the entire body. These are the signs of an allergic reaction: hives or a rash, itching, swelling of the lips, mouth, or throat, wheezing or other difficulty breathing.

Vitamin B12 is usually considered a non-toxic substance. Even taking it by injection at high doses does not seem to increase the risk for toxicity

Elevated levels of Vitamin B12 can occur in polycythemia vera. Polycythemia vera is a disease state in which the proportion of blood volume that is occupied by red blood cells increases. Diagnosis is characterized by an absolute increase in red blood cells and in the total blood volume, although it is not unusual to also have increases in white blood cells and platelets. A bone marrow examination may be done. However, it is not functional in determining a definitive diagnosis. Laboratory studies confirm the diagnosis by showing increased RBC mass and normal arterial oxygen saturation in association with splenomegaly (spleen enlargement) or two of the following: thrombocytosis, leukocytosis, elevated leukocyte alkaline phosphatase level, or elevated serum vitamin B12 or unbound B12-binding capacity.

Vitamin B12 Recommendations: RDA in μg (mcg)

• Infants birth to 6 mos - 0.3mcg
• Infants 6 mos to 1 yr - 0.5mcg
• Children 1 yr to 3 yr - 0.7mcg
• Children 4 yr to 6 yr - 1.0mcg
• Children 7 yr to 10 yr - 1.4mcg
• Adolescent males 11yr to 14 yr - 2.0mcg
• Adolescent females 11 yr to 14 yr - 2.0mcg
• Adolescent males 15 yr to 18 yr - 2.0mcg
• Adolescent females 15 yr to 18 yr - 2.0mcg
• Adult males 19 yr to 50 yr - 2.0mcg
• Adult females 19 yr to 50 yr - 2.0mcg
• Adult males 51 yr plus - 2.0mcg
• Adult females 51 yr plus - 2.0mcg
• Pregnant Women - 2.2mcg
• Lactating Mothers (1st 6 months) - 2.6mcg
• Lactating Mothers (2nd 6 months) - 2.6mg

Cyanocobalamin Vitamin B12 Food Sources

The Literature

Homocysteine:

The total homocysteine (tHcy) level in the serum is related to pregnancy complications, neural tube defects, mental disorder, and cognitive impairment in the elderly. In addition, over 80 clinical and epidemiological studies provide ample evidence that an elevated tHcy level is a common cardiovascular risk factor. The effect of vitamin B12 on the tHcy level is modest with a maximum of a 10 - 15% reduction. However, a low serum B12 level may prevent an optimal response to folic acid. There also exists the concern that folic acid supplementation alone may correct the hematological findings associated with B12 deficiency, but may precipitate the neurological sequelae of B12 deficiency.

Cobalamin deficiency in the elderly

Vitamin B12 deficiency is present in up to 15% of the elderly population. This is documented by elevated methylmalonic acid with or without elevated total homocysteine concentrations in combination with low or low-normal vitamin B12concentrations. Clinical signs and symptoms of vitamin B12deficiency are insensitive in elderly subjects, and comorbidity in these subjects makes responses to therapy difficult to interpret. Clear-cut megaloblastic anemia and myelopathy or neuropathy are rare in elderly vitamin B12deficient subjects. Many elderly subjects with hyperhomocysteinemia have undiagnosed vitamin B12deficiency with elevated serum methylmalonic acid concentrations. Therefore, such elderly subjects should not receive folic acid supplementation before their vitamin B12status is diagnosed. Results of a study showed potential usefulness of serum MMA and Hcys in identifying subclinical or tissue deficiency of vitamin B12. Clinicians should be aware of the risk of vitamin B12 deficiency in older people and of current screening algorithms using serum metabolites. Large amounts of oral vitamin B12supplementation may be effective in lowering serum methylmalonic acid values in the elderly. However, the dose of vitamin B12in most common multivitamin preparations is too low for this purpose. The traditional treatment of pernicious anemia in the United States is injections of vitamin B12. However, several studies in subjects with pernicious anemia showed that oral doses of 300-1000 mg are effective in raising serum vitamin B12concentrations and preventing clinical abnormalities. It is likely that similar doses of vitamin B12(100-1000 mg) would be effective in elderly subjects with less complete malabsorption.

Undiagnosed pernicious anemia is a common finding in the elderly, especially among black and white women. Findings from a study by Carmel show that almost 800,000 elderly people in the United States have undiagnosed and untreated pernicious anemia and, thus, would be at possible risk for masked cobalamin deficiency if exposed to large amounts of folate. This number does not include those elderly with cobalamin deficiency caused by other disorders or the still unknown number of younger people with unrecognized pernicious anemia and other causes of deficiency.

Low cobalamin concentrations are common in the elderly. Although only a minority of such persons displays clinically obvious symptoms or signs, metabolic data clearly show cellular deficiency of cobalamin in most cases. The evidence suggests that this is not a normal physiologic expression of the aging process. Rather, the elderly seem at increased risk for mild, preclinical cobalamin deficiency. Classical disorders such as pernicious anemia are the cause of this deficiency in only a small proportion of the elderly. A more frequent problem is food-cobalamin malabsorption, which usually arises from atrophic gastritis and hypochlorhydria, but other mechanisms seem to be involved in some patients. One study demonstrated no significant difference in either free or protein-bound cobalamin absorption between healthy middle-aged and older adults, and no alteration in cobalamin absorption in subjects identified as having mild to moderate atrophic gastritis. Thus, the high prevalence of low cobalamin levels in older people cannot be explained by either the aging process or mild to moderate atrophic gastritis. The diminished absorption should not be viewed as a natural consequence of aging. According to the American Journal of Clinical Nutrition, the partial nature of this form of malabsorption produces a more slowly progressive depletion of cobalamin than does the more complete malabsorption engendered by disruption of intrinsic factor-mediated absorption. The decreased progression of depletion is the most likely cause and this explains why mild pre-clinical low levels are connected most frequently with food-cobalamin malabsorption rather than with pernicious anemia.

The effects of hypochlorhydria and acidic drink ingestion on protein-bound vitamin B12 absorption was investigated in elderly subjects. Omeprazole causes hypochlorhydria and thus, protein-bound vitamin B12 malabsorption, and ingestion of an acidic drink improves protein-bound vitamin B12 absorption. Omeprazole therapy acutely decreased cyanocobalamin absorption in a dose-dependent manner. Patients taking cimetidine should also take vitamin B12 supplements. About 10-20% of elderly are deficient in cobalamine. There was a high (14.5%) prevalence of cobalamin deficiency as demonstrated by elevations in serum methylmalonic acid and homocysteine in addition to low or low normal serum cobalamin levels in elderly outpatients. The serum cobalamin level was insensitive for screening since similar numbers of patients with low normal serum cobalamin levels of 201-300 pg/mL compared with patients with low cobalamin levels (< or = 200 pg/mL) had markedly elevated metabolites which fell with cobalamin treatment. The latter study suggested that the lower limit of the normal range for Cbl level should be increased to 300 pg/mL.

Hearing impairment is one of the four most prevalent chronic conditions in the elderly. Houston et. al., in their recent article, suggested that poor vitamin B12and folate status might be associated with age-related auditory dysfunction.

Data suggest that serum cobalamin levels decrease in normal aging. This association is present only in the non-demented group, but not the demented group. In one study, a lower cobalamin concentration was observed in Alzheimer's disease sufferers still living in their own homes compared with institutionalized persons with AD, which may be related to, but not fully explained, by eating habits. Patients with AD living in their own homes are at risk of developing cobalamin deficiency, and monitoring of serum cobalamin concentrations might be useful in this group. One small study in 22 elderly patients with low serum cobalamin, showed that vitamin B12 may be beneficial in the treatment of Alzheimers. A study in 50 Chinese subjects suggested that cobalamin deficiency did not invariably cause cognitive impairment in older people. In another study, vitamin B12 replacement did not result in the slowing of the progression of dementia.

As it becomes clear that most low cobalamin concentrations in the elderly are neither artifacts nor normal expressions of aging, but represent a mild clinical deficiency state (and occasionally a clinically overt one), and as it has become clearer that in one half of the cases absorption of cobalamin is impaired in one way or another, the usual dismissal of patients with low cobalamin concentrations should be reexamined. A broad spectrum of options can be formulated, though none of these alter the common consensus that symptomatic deficiency must always be treated promptly. The options include the following:

1. Do nothing about cobalamin concentrations unless they become clinically noticeable. The arguments in support of this include the sheer number of patients involved, the costs, skepticism about medical intervention for biochemical changes, the fact that only a small minority of affected patients are symptomatic, the likelihood that whatever progression exists is very slow, and the fact that studies have shown no ill effects, even after many years of withholding treatment. The counter arguments are that absence of overt symptoms do not necessarily equal a state of well-being, that the underlying gastric disturbance is one half of the affected people which suggests that the cobalamin deficiency will persist and probably progress, that prevention has at least as much merit as cure, and that preclinical cobalamin deficiency may be a sentinel of serious underlying diseases, such as pernicious anemia in premyelopathic stage or celiac disease.

2. Automatically treat all patients with low cobalamin concentrations. The arguments in support of this hypothesis are that it is a cheap efficient way to ensure that no one who might benefit goes untreated, that a detailed work-up may be neither practical nor effective in view of its expense and the limited availability of many of the newer tests, and that cobalamin is not toxic and will not harm those who might receive it unnecessarily. The arguments against this approach are the resulting failure to identify serious underlying diseases that may have caused the deficiency in some of the patients, the failure to identify in some a need for more complex treatment or attention to complications, and the possibility that the amount and presumably the oral route of cobalamin therapy that such an approach dictates may prove inadequate to some patients. It is worth noting that cobalamin deficiency, even though less frequent than in nonsupplemented individuals, was still found in elderly patients who were taking cobalamin supplements. Thus, although cobalamin supplements are likely to work satisfactorily in people with food-cobalamin malabsorption, this has never been established and may be more complex than assumed. One can ask whether cobalamin pills taken with meals bind to the food proteins and fail to be absorbed by someone with food-cobalamin malabsorption. Moreover, it is not certain that all patients with unsuspected pernicious anemia (estimated to occur in 2% of all elderly and 10-20% of those with low cobalamin concentrations) will absorb enough cobalamin from a pill, especially if doses < 100 mg are taken, or if it is taken haphazardly, as routine supplements often are.

3. Give cobalamin supplements to all elderly people, regardless of their cobalamin concentrations. The arguments in favor of this, beyond those already stated in the preceding option, are that a problem of such proportions may benefit from equally broad solutions, that it saves the cost of widespread cobalamin testing (which in any case may provide falsely normal and falsely abnormal results), and that it may have potential benefits for patients with very early stages of negative balance. The counterarguments are that supplements recommended population-wide tend to lead to high intakes by those who are more affluent, health conscious, and functionally intact, and tend to be ignored by the poor and the impaired.

4. Continue the traditional medical approach of individual evaluation and therapy. The arguments for this approach are based on its laudable goal of making the specific diagnosis; identifying possibly treatable underlying diseases; addressing prognostic issues; treating those who need it with specific, tailored therapeutic approaches; and avoiding treatment of those who do not need it. The arguments against it are the cost in time and money of evaluating millions of people, and the uncertainty of what constitutes optimal diagnostic evaluation, given that currently standard, clinical tests such as blood counts and Schilling tests give negative results in most cases.

The choice to be made among these options and their variations can reflect only personal philosophies and biases at this time. To the concerns already mentioned, could be added uncertainty about the possible adverse effects created by changes in folate status and other changes. Unprotected exposure to nitrous oxide, a widely used inhalant during surgery may constitute another common and under-appreciated source of clinical risk for the elderly with marginal cobalamin status. All these issues must be carefully weighed when devising an optimal approach to the common problem of mild, preclinical cobalamin deficiency in the elderly.

HIV disease progression

In a study conducted in HIV positive men, participants with low serum vitamin B12 concentrations (< 120 pmol/L) had significantly shorter AIDS-free time than those with adequate vitamin B12 concentrations (median AIDS-free time = 4 vs. 8 y, respectively, P = 0.004). In a cross sectionals study, Remacha et. al. found that HIV-1 infected patients that had lower serum vitamin B12 concentrations had lower hemoglobin, leukocytes, CD4+ lymphocytes, and CD4+/CD8+ lymphocytes than HIV-1 infected patients with normal serum vitamin B12 concentrations. Ninety percent of the patients with low serum vitamin B12 concentrations had AIDS compared with only 66% of patients with adequate vitamin B12 concentrations. Similar results were noted in other studies. Another study showed that subjects with low CD4 lymphocyte counts, low serum vitamin B12 levels, anemia, or low neutrophil counts were more likely to have hematologic toxic effects when treated with AZT. Low serum concentrations of vitamin B6 and folate were not associated with either progression to AIDS or decline in CD4+ lymphocyte count. Therefore, Serum vitamin B12 concentrations seem to be an early and independent marker of HIV-1 disease progression. The effectiveness of vitamin B12 replacement therapy in slowing disease progression, however, is still unknown and should be the focus of further research.

Breast Cancer

Menopausal women with lower median B12 concentrations were found to have a higher risk for the development of breast cancer when compared to controls. In the same study, an increased risk of breast cancer was observed among women in the lowest fifth of the distribution of vitamin B12 as compared to women in the other four higher fifths, suggesting a threshold effect for B12. However, the possibility cannot be excluded that an unidentified protective factor for breast cancer associated with higher B12 concentrations might have led to the protective association between vitamin B12 and breast cancer. The mechanisms underlying the association between B12 and breast cancer might be explained by the role of B12 as a co-substrate in the synthesis of methionine, for which a methyl group is transferred from methyl tetrahydrofolate to homocysteine. Thus, lower concentrations of B12 might result in reduced synthesis of de novo methyl groups, leading to DNA hypomethylation, which may play a role in carcinogenesis. Through diminished availability of unsubstituted tetrahydrofolate, which is involved in reactions generating thymidilate and purines, lower B12 concentrations might also lead to reduced DNA synthesis and, thus, impaired DNA repair mechanisms.

Male Infertility

Vitamin B12 deficiencies can lead to reduced sperm counts and lowered sperm motility. Thus, it is suggested that B12 supplements might improve fertility in men who are truly deficient in this vitamin.

Diabetic Neuropathy

In a double-blind study, patients with diabetic neuropathy who received methylcobalamin showed statistical improvement in the somatic and autonomic symptoms with regression of signs of diabetic neuropathy. Motor and sensory nerve conduction studies showed no statistical improvement after 4 months. The drug was easily tolerated by the patients and no side effects were encountered. In another study, intrathecal injection of methylcobalamine (2,500 micrograms in 10 ml of saline) in patients with symptomatic diabetic neuropathy showed improvement in paresthesia, burning pains, and heaviness. The mean peroneal motor-nerve conduction velocity did not change significantly. Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. Thus, these findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.

Multiple Sclerosis

A massive dose of methyl vitamin B12 (60 mg every day for 6 months) was administered to 6 patients with chronic progressive MS, a disease which usually had a morbid prognosis and widespread demyelination in the central nervous system. Although the motor disability did not improve clinically, the abnormalities in both the visual and brainstem auditory evoked potentials improved more frequently during the therapy than in the pre-treatment period. Thus, it is suggested that a massive dose methyl vitamin B12 therapy may be useful as an adjunct to immunosuppressive treatment for chronic progressive MS. Another study showed that serum cobalamin deficiency is uncommon in multiple sclerosis.

Summary

Vitamin B12 is essential for purine and thymidine synthesis. It is also essential for growth, blood cell formation, nutrient metabolism, thyroid functioning, and myelin formation. It helps in maintaining the integrity of nerve cell membrane and is also needed in the production of the mood affecting substance called SAM (S-adenosyl methionine). Cobalamin deficiency may produce a functional folate deficiency by trapping folate in metabolic pathways and limiting its regeneration, and also functions with folate in lowering plasma homocysteine levels, which is an independent risk factor for coronary artery disease.

A number of claims have been made about the conditions in which Vitamin B12 may be supportive: pernicious anemia, Crohn's disease, Vitiligo, Tinnitus, Atherosclerosis, High Cholesterol, Diabetes, Osteoporosis, Retinopathy, HIV support, Shingles (herpes zoster/postherpetic neuralgia, Hepatitis, asthma, and infertility in males.

Evidence strongly supports that Vitamin B12 has a modest effect in lowering the tHcy and optimizes the response to folic acid. There also exists the concern that folic acid supplementation alone may correct the hematological findings associated with B12 deficiency, but may precipitate the neurological sequelae of B12 deficiency. The total homocysteine (tHcy) level in the serum is related to pregnancy complications, neural tube defects, mental disorder, and cognitive impairment in the elderly. Vitamin B12 may have a protective effect in the risk of breast cancer. Low B12 concentrations are shown to be associated with increased risk of breast cancer, which may be because lower concentrations of B12 might result in reduced synthesis of de novo methyl groups leading to DNA hypomethylation, which may play a role in carcinogenesis. Serum vitamin B12 concentrations seem to be an early and independent marker of HIV-1 disease progression, although the effectiveness of vitamin B12 replacement therapy in slowing disease progression is still unknown. Further role of B12 in homocysteine lowering is discussed in Homocysteine section. Clinicians should be vigilant to the possibility of cobalamin deficiency in the context of neuropsychiatric illnesses.

Vitamin B12 deficiency is common in elderly population, most of whom are undiagnosed with elevated serum methyl malonoic acid concentrations. Although the high prevalence of low cobalamin levels in older people cannot be explained by either ageing process or mild to moderate atropic gastritis, undiagnosed pernicious anemia and food-cobalamin malabsorption are very common in the elderly. Patients with Alzheimer's disease living in their own homes are also at increased risk of developing a cobalamin deficiency. Poor vitamin B12 and folate status might be associated with age-related auditory dysfunction. Thus, it appears that in one half of the cases, absorption of cobalamin is impaired in one way or the other, and the usual dismissal of patients with low cobalamin concentrations should be re-examined.

In general populations who are prone to be deficient, like patients with pernicious anemia and those with disorders of gastric mucosa, intestinal infections, gastrectomy, ileal disease, or resection, and genetic defects in absorption and transport mechanisms, should receive supplementation. Strict vegetarians and cigarette smokers should consume adequate amounts in their diet to prevent development of hematological and neurological symptoms of B12 deficiency. Delay in diagnosing and treating vitamin B12 deficiency may result in permanent neurological damage.

Our recommendations for adults is 800 μg/d. This amount can be obtained from approximately 1.4 boiled eggs, 1 serving of cheddar cheese, 8 fl oz of milk with 2% fat and 1/100 servings of liver (beef braised). Patients with pernicious anemia are traditionally treated with vitamin B12 injections, while oral doses of 300-1000 μg/d are shown to be equally effective in raising serum vitamin B12 concentrations and preventing clinical abnormalities. Doses of 100-1000 μg/d may be effective in the elderly patients. Anyone supplemented with more than a 1000 μg/d of folic acid may be initially evaluated to prevent potential problems.

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by EricT

By Ken Adams, M.D.

Vitamin B1 (Thiamine) Sources and Physiologic Functions

Sources

Pork, whole grains, and legumes are the richest sources of thiamine. Outer layers of seeds are particularly rich in this vitamin.

Populations at Risk

The populations most at risk of developing a thiamine deficiency are chronic alcoholics in Western countries and those with an over dependence on polished rice as a staple in undeveloped nations. In alcoholics it may be caused by decreased intake, reduced absorption, and impaired ability to use the absorbed vitamin. Thiamine is spared by fat, protein, sorbitol, and Vitamin C. High carbohydrate intake, parenteral glucose, pregnancy, lactation, high basal metabolic rate, and antibiotics will increase needs. Also, it is readily lost in persons consuming raw fish, tea, coffee, blueberries, red cabbage, and cooking with excess water and baking soda. Breast fed infants of thiamine deficient mothers are particularly at risk, as death from cardiac failure can result within a few hours, even though the mother appears healthy. Other risk factors include chronic colitis, fever, malignant disease, sprue, and thyrotoxicosis. Intestinal absorption of thiamine appears to be controlled and limited, and modest increases in the serum concentration were accompanied by active renal clearance.

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Signs and Symptoms of Deficiency

Children present with aphonia, cardiomyopathy, and polyneuritis. Symptoms involving the heart include tachycardia, cardiomegaly, and cardiac failure. Neurological symptoms include mental confusion, anorexia, ataxia, nystagmus, and weakness of hands, calves, and feet as a result of degeneration of sensory and motor nerves. Thiamine deficiency in adults is called Beri-beri and is characterized by dry skin, irritability, disorderly thinking, and progressive paralysis. In chronic alcoholics, a syndrome of Wernicke's - Korsakoff"s Psychosis develops. Ataxia and Nystagmus (Wernicke's ) develop early and, if left untreated progresses to amnesia, confusion, and polyneuropathy ( Korsakoff's ). Complete recovery at this stage is seen in only 25% of the patients. Vomiting, diarrhea, edema, and weight loss are other non-specific symptoms.

Safety

Due to relative increase in sympathetic activity, nervousness, sweating, tachycardia and tremors can be seen with excess thiamine. Edema and vascular hypotension occur as a result of capillary leakage. Allergies, fatty liver and herpes are common. Folates and thiamine cause seizures and excitation when administered in high dosage directly into the brain or cerebrospinal fluid (CSF) of experimental animals, but have rarely been reported to cause human neurotoxicity, although fatal reactions to i.v. thiamine are well known.

Biochemistry

The biologically active form of thiamine is TPP (thiamine pyrophosphate). It acts as a coenzyme in the oxidative decarboxylation at the pyruvate and the alfa-ketoglutarate steps in the energy producing Kreb's cycle and is particularly important in the tissues of the nervous system. It also acts as a coenzyme in the oxidative decarboxylation ( of alfa-keto acids and in the formation or degeneration of ketols ) by transketolase in the Pentose phosphate pathway, the intermediary products of which are used in the synthesis of ribonucleotides such as ATP & GTP, deoxyribonucleotides such as dATP & dGTP, and nucleic acids DNA & RNA. Thiamine is also essential for protein catabolism, acetyl choline synthesis, normal muscle tone in cardiac and GI tissues, and for normal growth and appetite.

In human the storage of thiamine is is in greatest concentrations in skeletal muscle, heart, brain, liver, and kidneys. The human stores about 25 to 30mg of thiamine. ThMP and free (unphosphorylated) thiamine is present in plasma, milk, cerebrospinal fluid, and just about all extracellular fluids. Unlike the highly phosphorylated forms of thiamine, ThMP and free thiamine are capable of crossing cell membranes.

Thiamine Recommendations: RDA in mg

• Infants birth to 6 mos - 0.3mg
• Infants 6 mos to 1 yr - 0.4mg
• Children 1 yr to 3 yr - 0.7mg
• Children 4 yr to 6 yr - 0.9mg
• Children 7 yr to 10 yr - 1mg
• Adolescent males 11yr to 14 yr - 1.3mg
• Adolescent females 11 yr to 14 yr - 1.1mg
• Adolescent males 15 yr to 18 yr - 1.5mg
• Adolescent females 15 yr to 18 yr - 1.1mg
• Adult males 19 yr to 50 yr - 1.5mg
• Adult females 19 yr to 50 yr - 1.1mg
• Adult males 51 yr plus - 1.2mg
• Adult females 51 yr plus - 1.0mg
• Pregnant Women - 1.5mg
• Lactating Mothers - 1.6mg

Thiamine hydrochloride is the common supplemental form. Thiamine therapy for alcoholics may involve a single injection of 10-mg thiamine or 50 mg of oral fat-soluble thiamine propyl disulfide that permits efficient absorption in alcoholics. Erythrocyte transketolase activity is considered the most reliable index of the functional state of thiamine.

Vitamin B1 Food Sources

Literature

A cross-sectional investigation of patients with congestive heart failure being treated with loop diuretic therapy showed that thiamine deficiency may occur in a substantial proportion of patients with congestive heart failure (CHF) and dietary inadequacy may contribute to increased risk. Men and nonwhite patients with CHF appeared most likely to have evidence of thiamine deficiency, although this reflects, in part, the gender composition of the patients recruited for the study. Patients with more severe CHF (as indicated by lower percentages of left ventricular ejection fractions) had greater biochemical evidence of thiamine deficiency. Another study found left ventricular ejection fraction to be adversely affected by thiamine deficiency and described that, when these patients were supplemented with thiamine intravenously, the ejection fraction improved significantly. Thus, nutritional assessment of thiamine status, including dietary intake, may be an important component of care for patients with CHF who are being treated with loop diuretic therapy.

Cognitive functioning

A study by Benton et. al demonstrated the association between improved thiamine status and improved performance on a range of measures of cognitive functioning in females. No such association was found in males. Although it was not possible to establish the reason for a beneficial response in females rather than males, there is evidence that females respond differently to dietary factors.

Alzheimer's disease

Results of one study suggest that probable Alzheimer's Disease (pAD) is associated with a decrease in plasma thiamine levels. In another study, a 40-50% decrease of thiamine diphosphate (TDP) was found in patients with frontal lobe degeneration of the non-Alzheimer's type (FNAD). As TDP is an essential co-factor for oxidative metabolism and neurotransmitter synthesis, and because low thiamine status (compared with other species) is a constant feature in humans, a nearly 50% decrease in cortical TDP content may contribute significantly to the clinical symptoms observed in FNAD. This study also provides a basis for a trial of thiamine to improve the cognitive status of the patients. A mild beneficial effect in patients with Alzheimer's disease was observed on supplementation with Fursultiamine (TTFD), a derivative of thiamine, at an oral dose of 100 mg/day in a 12-week open trial. Similar benefits were observed in another trial with high dose thiamine (3-8 g/d), while a 12 month study with 3 g/d of thiamine showed no apparent benefit in slowing the progression of dementia of the Alzheimer's type. Thus, weak and contradictory evidence suggests that vitamin B1 may be helpful for Alzheimer's disease.

Assessment of thiamine status

In several human studies during the past 10 years, thiamine status was assessed either by measuring thiamine pyrophosphate response alone or by using TPP response measures in conjunction of calculated estimates of thiamine intake from diet histories. Some investigators have combined estimates of thiamine intake with measures of thiamine status other than TPP response, such as erythrocyte TPP [18] or plasma TPP In several of these reports, poor thiamine status, as defined by TPP response, could not be related to less-than-adequate thiamine intake. Several authors have noted that valid TPP response measures depend on a kinetically normal enzyme. Hence, disease states, such as alcoholic encephalopathy, may affect enzyme-cofactor binding, and thus, TPP response. Rigorous statistical analysis of relationship between urinary thiamine excretion and TPP response seems to be lacking in the report generally cited as evidence of the validity of TPP response measures. In the ICNND report, categories of thiamine status appear to relate superficially to urinary thiamine excretion, but when there is no clear break-point in the curve for thiamine intake plotted against urinary excretion, it is difficult, in contrast to the case with urinary riboflavin excretion, to define deficiency. One author has demonstrated that in non-human species, pyruvate dehydrogenase appears to be a more sensitive indicator of tissue thiamine deficiency than is transketolase. A study by Gans et. al. raises questions about the usefulness of the TPP response as the sole indicator of marginal thiamine status. Thiamine status was measured in 137 incarcerated and 42 nonincarcerated adolescent males by use of both dietary intake data and a standard biochemical assay, thiamin pyrophosphate (TPP) response. Although average daily thiamine intake of nonincarcerated subjects was significantly higher than that of incarcerated subjects, both groups appeared to be at minimal risk for marginal thiamine status. Comparison of TPP response values indicated that there was no significant difference between groups. However, approximately 24% of the total population appeared to have less than adequate RBC thiamine on the basis of current standards for TPP response. Neither dietary intake nor reported previous alcohol intake was correlated with TPP response. Thus, clinical standards of thiamine deficiency seem to lack firm definition. Perhaps a better, more valid metabolic measure, such as thiamine or TPP in plasma, should be investigated and adopted. Also, intake data as well as some appropriate measure of enzyme activity or function may be important values to assess to describe the thiamine status of a group more correctly.

Summary

Thiamine is essential in the metabolism of proteins, carbohydrates, and fats. It is also needed in the synthesis of ATP and GTP and nucleic acids DNA and RNA. It acts as a coenzyme in the energy producing Kreb's cycle and is particularly important in the tissues of the nervous system. Thiamine is also essential for acetylcholine synthesis, maintenance of normal tone of muscle in cardiac and GI tissues, and for normal growth and appetite.

A number of claims have been made about the beneficial effects of thiamine on numerous conditions. (Fibromyalgia, HIV Support, Pregnancy and postpartum support, Canker sores - mouth ulcers, and Minor injuries)

Evidence strongly suggests that patients with CHF may benefit from thiamine supplementation. Patients with CHF who are on loop diuretics are shown to have thiamine deficiency and patients with more severe CHF showed greater biochemical evidence of thiamine deficiency. Thiamine supplementation is shown to improve the left ventricular ejection fraction significantly.

Thiamine supplementation may improve cognitive functioning and has been shown to improve performance on a range of cognitive tests in females.

Populations who are prone to be deficient in this vitamin, like chronic alcoholics, patients with malabsorption syndromes, and those who consume high carbohydrates should receive supplementation. Pregnancy, lactation, high basal metabolic rate, and parenteral glucose therapy will increase the requirements of thiamine. Breast-fed infants of thiamine deficient mothers should receive adequate supplementation, as death from cardiac failure can result within hours, even though the mother appears normal.

Our recommendation for adults is 25 mg/d. This amount can be obtained from approximately 41 servings of Pork (lean arm braised), 28 servings of Pork (bacon cured/pan fried), and 80 servings of Pinto Beans (boiled). The RDA for adults is 1.5 mg/d, although a range of doses from 1-25 mg/d is usually consumed. Thiamine therapy for alcoholics may involve a single injection of 10-mg thiamine or 50 mg of oral fat-soluble thiamine propyl disulfide that permits efficient absorption in alcoholics. Wernicke's syndrome, which involves ataxia and nystagmus, develops early and, if left untreated, may progresses to Korsakoff's psychosis, the neurological manifestations of which are irreversible in 75% of the patients. Fatal reactions to high doses of I.V. thiamine have been reported.

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by EricT

By Ken Adams, M.D.

Pyridoxine (B6) Sources and Physiologic Functions Sources

Poultry, fish, liver, and eggs are good sources of this vitamin; meat and milk contain lesser amounts. Pyridoxine in animal sources is 96% bioavailable. Vitamin B6 can be made by intestinal bacteria in healthy persons. Plant foods such as legumes, peanuts, potatoes, yeast, bananas, corn, cabbage, yams, prunes, watermelon, and avocados also contain this vitamin.

Populations at risk

As this vitamin is widely distributed, deficiency is rare except in chronic alcoholics and among women taking oral contraceptives. Elderly persons and infants of preeclamptic mothers or mothers deficient in B6 are at risk. Patients on Cycloserine, hydantoin, hydralazine, isoniazid, and penicillamine should be given B6 supplementation. High protein diet increases the needs of this vitamin.

Severe deficiencies of vitamin B6 are rare, but mild deficiencies are extremely common. Dietary data from Second National Health and Nutrition Examination Survey (NHANES II) in 11,658 adults aged 19-74 y showed that 71% of males and 90% of females consumed less than the 1980 recommended dietary allowance (RDA) of vitamin B6. Vitamin B6 is the most common deficient water soluble vitamin in elderly. Single drug and drug combinations taken by elderly individuals may impose nutritional risk. Unwanted outcomes of drug-food and drug-nutrient interactions can be minimized by instructing elderly men and women and their caregivers to avoid timing errors in drug-taking behavior and toxic reactions due to food incompatibility. In addition, drug-induced nutritional deficiencies can be avoided by advising drug-taking elderly on the appropriate levels of nutrient intake. In a study which compared the nutrient intakes of American children aged 2 to 10 years, vitamin B6 was found to be below the RDA in more than 50% of the population.

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Birth control pill usage and occupational exposure to carbon disulfide induce vitamin B6 deficiency and/or enhance vitamin B6 requirement. Both compounds cause adverse psychological/neurological disorders such as extreme irritability, manic depressive tendencies, headaches, and other variables, but related disorders presumably by disrupting normal vitamin B6 metabolism and vitamin B6 administration has been found to alleviate their adverse psychological symptoms. Further studies are needed to experimentally evaluate this interrelation. Conjoined exposure to OCs and CS2 may result in an enhanced disruption of tryptophan metabolism which may in turn cause exaggerated psychological sequelae associated with CS2 exposure.

Signs and Symptoms of Deficiency

In infants, convulsive seizures and hyperactivity are the usual presenting symptoms. Diarrhea is also common. Anemia and peripheral neuritis are seen in tuberculosis patients on isoniazid who develop pyridoxine deficiency. 20-30% of homocystinuric patients with dislocation of the lens of the eye, osteoporosis (brittle spine), mental retardation, and a tendency for spontaneous blood clots that can lead to heart attacks and death, respond to vitamin B6 therapy.

Biochemistry

Vitamin B6 isa collective term for pyridoxine, pyridoxal, and pyridoxamine, all of which serve as precursors of the biologically active coenzyme, pyridoxal phosphate. Pyridoxal phosphate functions as a coenzyme that catalyze reactions in protein metabolism, conversion of tryptophan to niacin, fat metabolism, carbohydrate metabolism, folic acid synthesis, glandular and endocrine functions, and for the nerve and brain energy. Vitamin B6 has a clear benefit in lessening the severity of homocystinuria, a rare disease that usually results from a defect in an enzyme used for degrading homocysteine.

Safety

Deficient and excess intakes of pyridoxine can produce neurologic disturbances. Most cases of sensory neuropathy have resulted from intakes of over 600 mg/day, but some evidence suggests that it may result from doses as low as 300-500 mg/d and that the total exposure over time is the determinant of toxicity. There is one report that a daily intake of 117 mg/day (on average) for 2.9 years may be related to some toxicity. In the same study however, the control group that did not get any neuropathy had an average intake of 116 mg/day for an average of 1.6 years, and some women in both groups had been taking as little as 50 mg/day, questioning the accuracy of the telephone survey method used to determine neuropathy.

Vitamin B6 is toxic at doses that are 1000 times the RDA. Daily doses of 2 to 5 g of pyridoxine can produce difficulty in walking and tingling sensations in the legs and soles of the feet. Continued consumption of the toxic dose results in further unsteadiness of walking, difficulty in handling small objects, and numbness and clumsiness of the hands. Where vitamin B6 supplementation is stopped, recovery begins after 2 months. Complete recovery may occur after 2 to 3 years of discontinuing consumption of the vitamin B6 supplements. One study showed development of pure central-peripheral distal axonopathy with pyridoxine abuse. Pyridoxine dose was 0.2 to 5 g/d, and duration of consumption before symptoms was inversely proportional to the daily intake. In all patients with adequate follow-up, improvement followed discontinuation of pyridoxine.

Is pyridoxine safe for long-term use in large segments of the population, including children? It would appear from retrospective analysis of several studies that pyridoxine is safe at doses of 100mg/day or less in adults. In children, there is not enough data to make any sort of suggestion. Because the major neurologic complication is a peripheral neuropathy, and the causes of this condition are myriad, pyridoxine may cause neuropathy only in patients with a pre-existing susceptibility to this condition. Family histories, drugs, alcohol, nutritional status, and toxic exposure at home or in the work place may all be predisposing factors which, in combination with pyridoxine, produce the peripheral neuropathy that is not seen in other patients taking the same dosages. The duration of exposure that causes neuropathy is still a major question. Extremely high doses cause neurologic injury within a few days, and chronic low doses seem relatively safe.

Deterioration of acne vulgaris or eruption of an acneiform exanthema was demonstrated during treatment with vitamin B6 and/or vitamin B12 in 14 patients. Females were, by far, the more frequently affected. The appearance of skin symptoms, even outside the age groups typically affected by acne vulgaris, is characteristic. The clinical appearance of acneiform exanthema occurring during treatment with vitamin B6 or B12 consists of loosely disseminated small papules or papulopustules on the face (especially on the forehead and chin), on the upper parts of the back and chest, and spreading to the upper arm. The pathogensis of the change is not yet certain. The acneiform rash generally fades within a short time after vitamin B6 or vitamin B12 treatment has been stopped.

Vitamin B6 Recommendations: RDA in mg.

• Infants birth to 6 mos - 0.3mg
• Infants 6 mos to 1 yr - 0.6mg
• Children 1 yr to 3 yr - 1.0mg
• Children 4 yr to 6 yr - 1.1mg
• Children 7 yr to 10 yr - 1.4mg
• Adolescent males 11yr to 14 yr - 1.7mg
• Adolescent females 11 yr to 14 yr - 1.4 mg
• Adolescent males 15 yr to 18 yr - 2.0mg
• Adolescent females 15 yr to 18 yr - 1.5mg
• Adult males 19 yr to 50 yr - 2.0mg
• Adult females 19 yr to 50 yr - 1.6mg
• Adult males 51 yr plus - 2.0mg
• Adult females 51 yr plus - 1.6mg
• Pregnant Women - 2.2mg
• Lactating Mothers (1st 6 months) - 2.1mg
• Lactating Mothers (2nd 6 months) - 2.1mg

Pyridoxine Vitamin B6 Food Sources

The Literature: Heart disease Prevention

Homocysteine

Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with deficiencies of vitamin B6, folate, and cobalamin. Patients who were given vitamin B6 for carpal tunnel syndrome and other degenerative diseases were found to have 27% of the risk of developing acute cardiac chest pain or myocardial infarction, compared with patients who had not taken vitamin B6. Dr. Ellis found that among his elderly patients expiring at home, the average age at death from myocardial infarction was 8 years later in those who had taken vitamin B6, compared with those who had not taken vitamin B6. The preventive effect of vitamin B6 on progression of coronary heart disease may be related to increased formation of pyridoxal phosphate, the coenzyme that is required for catabolism of the atherogenic amino acid, homocysteine.

The total homocysteine (tHcy) level in the serum is related to pregnancy complications, neural tube defects, mental disorder, and cognitive impairment in the elderly. In addition, over 80 clinical and epidemiological studies provide ample evidence that an elevated tHcy level is a common cardiovascular risk factor. Oral treatment with pyridoxine up to 300mg/d does not lower the fasting tHcy level in healthy subjects or vascular patients. However, pyridoxine (10 - 250 mg/d) lowers an abnormal postmethionine load tHcy level in most patients and, when combined with folic acid, nearly all obtain a normal postmethionine tHcy level.

Platelet aggregation:

In a randomized trial, Pyridoxine inhibited ADP- or epinephrine-induced aggregation by 48% and 41% (p < 0.001), respectively. It also prolonged both bleeding and coagulation time. Pyridoxine significantly reduced total plasma lipid and cholesterol levels, whereas it enhanced HDL-cholesterol level. Thus, it is suggested that oral vitamin B6 inhibits platelet aggregation in normal subjects.

Essential Hypertension:

In a study, treatment of hypertensive patients with pyridoxine significantly reduced systolic (p < 0.01) and diastolic blood pressure (p < 0.005), plasma NE (p < 0.005), and E (p < 0.05) within 4 weeks. The dose of pyridoxine used in these patients was 5 mg/kg body weight/d. Thus, pyridoxine may be beneficial in the treatment of hypertension.

Neurotransmitter Production

Pyridoxine has been known as an essential cofactor in the production of neurotransmitters. For this reason, it has been considered a therapeutic adjunct in a variety of conditions with known or suspected neurotransmitter abnormalities. Among these conditions are seizures, Parkinson's disease, depression, chronic pain, headache, behavior abnormalities of adults and children, and peripheral neuropathy. Other clinical uses for pyridoxine include treatment of premenstrual syndrome and carpal tunnel syndrome. The potential neurotoxicity of pyridoxine makes it essential that vitamin intake be included as part of medical history.

Diabetic neuropathy:

Vitamin B6 has been recommended in the treatment of diabetic neuropathy. Vitamin B6 deficiency was thought to be the causative factor for neuropathy in diabetes. However, several studies show that vitamin B6 supplements may not be beneficial in these patients. In one of these studies, 18 patients with symptomatic diabetic neuropathy were treated with placebo or pyridoxine. After 4 months of follow-up, there was no difference between the two groups with regard to fasting plasma glucose, motor nerve conduction velocity, or ophthalmologic examination at the beginning or at the conclusion of the study. These results suggest that vitamin B6 deficiency is not a factor in the etiology of diabetic peripheral neuropathy.

Gestational diabetes:

In a study of 14 pregnant women with gestational diabetes, a relative pyridoxine deficiency was thought to exist. After treatment with vitamin B6 (pyridoxine) 100 mg/day for 14 days, the oral glucose tolerance improved considerably. It was hypothesized that increased xanthurenic-acid synthesis during pregnancy may cause gestational diabetes. Treatment with vitamin B6 makes the production of xanthurenic-acid normal by restoring tryptophan metabolism and improves the oral glucose tolerance in patients with gestational diabetes.

Kidney Stones:

Weak evidence suggests that pyridoxine may be useful in the therapy of kidney stones. Twelve recurrent stone formers with hyperoxaluria were administered pyridoxine-HCl (10 mg/day) daily for a period of 180 days. Urinary oxalate decreased significantly (p less than 0.05) by the 90th day of pyridoxine therapy, and thus, pyridoxine in low doses (10 mg/day) is of therapeutic value for hyperoxaluric stone formers.

Autism:

A review of four therapeutic crossed-sequential double-blind trials with 60 autistic children examined the effects of vitamin B6 alone, magnesium alone, and in combination on behavioral improvement. Modest behavioral improvement was observed among children taking both magnesium and B6, but not when either one of those taken alone.

Cognitive Development

Vitamin B6 is an essential cofactor in the developing central nervous system and may influence brain development and cognitive function. Recent work in animal models suggests that vitamin B6 deficiency during gestation and lactation alters the function of receptors thought to play an important role in learning and memory. A deficiency of vitamin B6 during brain development has been shown to result in neurochemical and morphological changes that are expressed behaviorally as tremors, irritability, abnormalities in motor function, and spontaneous seizures, although the specific mechanism is still not understood. Numerous studies have suggested that pregnant and lactating women may have dietary intakes of vitamin B6 that are well below the recommended dietary allowance, which may affect the vitamin B6 status of their offspring. Reports indicate that unsupplemented lactating mothers have a milk vitamin B6 level that, in some cases, is lower than 100 μg/L, a concentration that places infants at risk of development of seizures. Although this level of vitamin B6 in milk does not always result in clinical signs of frank vitamin B6 deficiency, it may influence the normal development of the child. Evidence for such an effect was noted in an Egyptian study where abnormalities in behavior were observed in infants whose mothers had vitamin B6 levels in milk below 85 mg/L.

Thus, many conditions in clinical neurology may be responsive to pyridoxine as a therapeutic agent. The observations that serotonin deficiency is a common thread in patients with headache, chronic pain, and depression, and that pyridoxine can raise serotonin levels open a wide range of therapeutic options. Comparison with amitriptyline in the treatment of headache appears to show about equal efficacy, although side effects would be expected to be more of a problem with the amitriptyline. Some medical authorities have taken this so far as to suggest that many of the behavioral disorder problems are caused by "toxic" exposures to chemicals that are pyridoxine antagonists and that supplementation at early stages may reduce the incidence of hyperactivity and aggressive behavior.

Interaction with Medications

Vitamin B6 (pyridoxine) supplementation during isoniazid (INH) therapy is necessary in some patients to prevent the development of peripheral neuropathy. In vivo pyridoxine is converted into coenzymes which play an essential role in the metabolism of protein, carbohydrates, fatty acids, and several other substances, including brain amines. INH apparently competitively inhibits the action of pyridoxine in these metabolic functions. The routine use of pyridoxine supplementation to prevent peripheral neuropathy in high risk populations is recommended.

Carpal Tunnel Syndrome

Vitamin B6 is effective in the treatment of carpal tunnel syndrome and related disorders in patients with vitamin B6 deficiency. A study found that higher plasma pyridoxal 5'-phosphate (PLP) concentrations, particularly in unsupplemented males, appeared to be associated with less frequent pain/discomfort, tingling and nocturnal awakening. In contrast, higher vitamin C concentrations or a relative deficit of plasma PLP in comparison to the plasma vitamin C (higher ASC/PLP ratio) were, in some analyses, associated with greater sensory latencies or with more prevalent and frequent symptoms. This raises the possibility that vitamin C supplementation in the presence of vitamin B6 deficit might be injurious to the median nerve and thus promote the development of the hand/wrist symptoms of CTS. Thus, there are significant relationships between plasma vitamin levels and both components of CTS (specific symptoms and median nerve slowing). The interaction between plasma PLP and ASC appears to be particularly important with respect to symptoms. Hence, vitamin B6 is commonly recommended for carpal tunnel syndrome.

Premenstrual Syndrome

A review of 12 controlled trials on vitamin B6 in the treatment of the premenstrual syndrome showed a weak evidence of positive effects of vitamin B6. A major drawback of the trials is the limited number of patients included. In a more recent well designed study, 120 women were randomized to receive active drug or placebo. Pyridoxine at 300 mg/d showed no greater benefit compared to placebo in symptom reduction.

Vitamin B6 and Exercise

Vitamin B6 may play an important role in exercise response. Vitamin B6 is essential to the production of energy during exercise. If vitamin B6 status is poor, exercise performance may be impaired. Vitamin B6 supplementation may increase the levels of plasma growth hormone during exercise and immediately following exercise. The physiologic significance of these changes has not been explored but are thought to increase muscle mass and reduce body fat. Female athletes and those who participate in sports which emphasize low body weights (e.g., dancers, wrestlers, gymnasts and runners) may be prone to low dietary vitamin B6 intakes.

Asthma

Weak evidence suggests that vitamin B6 may be useful in asthma. A double-blind study with 76 asthmatic children followed for five months indicated significant improvement in asthma following pyridoxine therapy (200 mg daily) and reduction in dosage of bronchodilators and cortisone. The data suggest that these children with severe bronchial asthma had a metabolic block in tryptophan metabolism, which was benefitted by long-term treatment with large doses of pyridoxine. In another double-blind placebo-controlled trial, 31 patients requiring steroids (oral or inhaled) for the treatment of their asthma received pyridoxine 300 mg per day or placebo. After a 9 week follow-up, treatment with oral pyridoxine failed to improve the outcome variables in patients requiring steroids for the treatment of their asthma.

Depression

Weak evidence suggests that vitamin B6 may be beneficial in the treatment of depression. The augmentation effect of 10 mg each of vitamins B1, B2, and B6 in 14 geriatric inpatients with depression who were treated with tricyclic antidepressant treatment was assessed in a well-designed study. The vitamin treated group showed trends toward greater improvement in scores on ratings of depression and cognitive function, as well as in serum nortriptyline levels compared with placebo-treated subjects. Thus, B complex vitamin augmentation in the treatment of geriatric depression should be considered.

Summary

Pyridoxine is essential for protein, fat and carbohydrate metabolism, folic acid synthesis, glandular and endocrine function. It is also essential for the formation of serotonin, and dopamine, and aids in the formation of several neurotransmitters and is therefore, an essential nutrient in the regulation of mental processes and the mood.

A number of claims have been made about the beneficial effects of vitamin B6 on numerous conditions: atherosclerosis, attention deficit disorder, autism, alcohol withdrawal syndrome, diabetes, fibrocystic breast disease, carpal tunnel syndrome, chemotherapy, HIV patients, nephrolithiasis, osteoporosis, photosensitivity, retinopathy, and canker sores.

Evidence strongly suggests that vitamin B6 has a preventive effect in the progression of coronary artery disease. Although it did not show any effect in lowering the fasting plasma homocysteine level, vitamin B6 supplementation is shown to lower postmethionine load tHcy, which might be the reason for its cardioprotective effect.

In well done studies it has shown efficacy on par with amitriptyline in the treatment of chronic headaches. Many clinical conditions like chronic pain and depression, which are caused by serotonin deficiency, might benefit from vitamin B6 therapy. As it functions as an essential cofactor in the production of several neurotransmitters, it may be considered a therapeutic adjunct in the treatment of several conditions like seizures, Parkinson's disease, behavioral abnormalities of adults and children, and peripheral neuropathy. Vitamin B6 is also found to be effective in the treatment of carpal tunnel syndrome in patients with vitamin B6 deficiency. Exercise performance is improved with vitamin B6 supplementation.

Populations who are prone to be deficient in this vitamin such as chronic alcoholics, women on oral contraceptives, patients on Isoniazid, and athletes should receive supplementation. Pregnant and lactating women should consume adequate amounts of vitamin B6 in their diets for the normal development of central nervous system and cognitive function and for the prevention of abnormal behavioral development.

Our recommendations for adults is 40 mg/d, as there is weak evidence of some toxicity at 50 mg/d. Vitamin B6 is usually safe and can be consumed in amounts of 10-300 mg/d. Although side effects are rare, doses over 300 mg/d may result in adverse neurological outcomes. Pregnant and lactating women should not consume more than 100 mg/d. Vitamin B6 supplementation should be stopped immediately when sensory neuropathy with numbness in the hands and feet and/or difficulty in walking develops while on therapy.

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by EricT

By Ken Adams, M.D. and Scott E. Conard, M.D.

Sources and Physiologic Functions

Sources: Liver is an excellent source of riboflavin. Milk, cheese, egg whites, legumes, peanuts, fish, meats, broccoli, spinach, and fortified grains are good sources. The UV component of sunlight destroys Riboflavin. Hence, milk should be protected in opaque cartons from bright light during storage. Proteins, dextrins, and starch decrease the need for this vitamin.

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Populations at risk

Alcoholics and poorer populations of the United States may be deficient in Riboflavin, among other nutrients. Deficiency is widespread in under-developed countries. As it is mainly absorbed in the ileum, total/subtotal gastrectomised patients develop a deficiency. Chronic infection, malignancy, pregnancy, lactation, and consumption of broad-spectrum antibiotics and chloramphenicol are other risk factors. A dietary interview conducted in 403 elderly people showed that the majority had sufficient amounts of riboflavin from the diet, but the margin towards deficiency was small. Hence, elderly people should be considered a vulnerable group with respect to the intakes of vitamins and minerals.

An adolescent population ranging in age from 13 to 19 years and of a low socioeconomic status in New York City, was surveyed for riboflavin deficiency. Deficiency was determined from estimation of erythrocyte glutathione reductase activity, an accurate reflector of riboflavin nutritional status. The overall prevalence of deficiency among those not on vitamin supplements was 26.6%. The prevalence did not depend on sex or age. There was a correlation between milk consumption and riboflavin nutritional status. The prevalence was highest among those consuming less than 1 cup/week and least among those taking 3 or more cups a day. The latter group was comparable in this respect to those receiving daily vitamin supplements. Adolescents are at a high risk for nutritional deficiencies because of their notoriously poor dietary habits, and the estimation of riboflavin deficiency may be an indicator of overall nutritional status.

Signs and Symptoms of Deficiency

Lesions of the mouth like Cheilitis, angular stomatitis, and glossitis occur. Cheilitic lesions are painful and may result in bleeding. Purplish discoloration of the tongue - magenta tongue, is seen. Skin lesions include seborrheic dermatitis and rash on the scrotum and vulva. Ocular burning, dim vision, and photophobia are other symptoms.

Safety

Riboflavin is essentially non-toxic. After absorption from the gut, it binds loosely to serum albumin and rarely accumulates in the cell. When absorbed in excess, it is promptly excreted in the urine.

Biochemistry

The two biologically active forms of Riboflavin are Flavin mononucleotide (FMN) and Flavin adenine dinucleotide (FAD) and are called Flavins. Flavins are used as a cofactor in the energy producing Kreb's cycle at the pyruvate dehydrogenase step. FMN and FAD are each capable of accepting two hydrogen atoms forming FMNH2 and FADH2. Bound to flavoenzymes, they catalyze the oxidation or reduction of a substrate. Flavins are lost from the body as intact Riboflavin, rather than breakdown products. Vitamin status may be assessed by measuring the level of urinary Riboflavin or glutathione reductase assay.

Recommendations: RDA in mg

• Infants birth to 6 mos - 0.4mg
• Infants 6 mos to 1 yr - 0.5mg
• Children 1 yr to 3 yr - 0.8mg
• Children 4 yr to 6 yr - 1.1mg
• Children 7 yr to 10 yr - 1.2mg
• Adolescent males 11yr to 14 yr - 1.5mg
• Adolescent females 11 yr to 14 yr - 1.3mg
• Adolescent males 15 yr to 18 yr - 1.8mg
• Adolescent females 15 yr to 18 yr - 1.3mg
• Adult males 19 yr to 50 yr - 1.7mg
• Adult females 19 yr to 50 yr - 1.3mg
• Adult males 51 yr plus - 1.4mg
• Adult females 51 yr plus - 1.2mg
• Pregnant Women - 1.6mg
• Lactating Mothers (1st 6 months) - 1.8mg
• Lactating Mothers (2nd 6 months) - 1.7mg

Riboflavin - B2 Food Sources

Literature

Erythropoiesis

Riboflavin enhances erythropoiesis and may have a beneficial effect in improving hematologic status in certain conditions like sickle cell disease. The effect of riboflavin supplementation (5mg twice daily for 8 weeks) on reduced blood glutathione (GSH) and iron status was assessed in 18 patients with sickle cell disease (SCD-HbSS). Twelve SCD patients and 13 normal (Hb-AA) subjects served as the control. The total iron binding capacity (TIBC) and serum ferritin (SF) were significantly higher (p < 0.01), but GSH level, hemoglobin and transferring saturation (TS) were significantly lower (p < 0.001) in SCD patients than in normal subjects. The administration of riboflavin elicited a significant increase (p < 0.01) in serum iron and TS, but a non significant increase in SF and circulating Hb. The GSH level varied little in riboflavin supplemented but decreased significantly in unsupplemented SCD. The disparity in GSH concentration might reflect availability of FAD for regeneration of GSH from glutathione. Likewise, the hematological improvement in the supplemented group supports the assertion that riboflavin enhances erythropoiesis. For an effective management of SCD in Africa, a closer attention should be directed to the riboflavin status in hemolytic disorders. In another study, riboflavin deficiency caused a significantly lower glutathione reductase activity and higher methhemoglobin concentrations.

Migraine

In migraine prophylaxis, a significant breakthrough came from riboflavin 400 mg, which has an outstanding efficacy side-effect profile. A deficit of mitochondrial energy metabolism may play a role in migraine pathogenesis. Riboflavin (400 mg) was compared to placebo in 55 patients with migraine in a randomized trial of 3 months duration. Riboflavin was found to be superior to placebo in reducing attack frequency and headache days. Regarding the latter, the proportion of patients who improved by at least 50%, i.e. "responders," was 15% for placebo and 59% for riboflavin (p = 0.002) and the number-needed-to-treat for effectiveness was 2.3. Three minor adverse events occurred; two in the riboflavin group (diarrhea and polyuria), and one in the placebo group (abdominal cramps). None was serious. Because of its high efficacy, excellent tolerability, and low cost, riboflavin is an interesting option for migraine prophylaxis and a candidate for a comparative trial with an established prophylactic drug.

Aphthous ulcers

In an evaluation of the thiamine, riboflavin, and pyridoxine (vitamin B1, B2 and B6) status of 60 patients with recurrent mouth ulcers, 17 patients (28.2%) were found to be deficient in one or more of these vitamins. Replacement therapy of these vitamins was given to a study group of deficient patients and a non-deficient group for one month. At the end of therapy and after a follow-up period of 3 months, only those patients who had a B complex deficiency had a significant sustained clinical improvement in their mouth ulcers. Vitamin B1, B2, and B6 deficiencies should, therefore, be considered as another possible precipitating factor in recurrent aphthous ulceration.

Summary

Riboflavin is essentially non-toxic. Deficits in Riboflavin are rare but do occur in malnourished individuals and alcoholics as well as people who have received gastric bypass surgery. Deficiencies mostly manifest as skin and tongue lesions include seborrheic dermatitis and rashes on the scrotum and vulva. Ocular burning, dim vision, and photophobia are other symptoms.

People with sickle cell anemia, migraines, and aphthous ulcers have noted improvement in their conditions with supplementation.

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by EricT

By Ken Adams, M.D. and Scott E. Conard, M.D.

Niacin (Vitamin B-3):

Sources and Physiologic Functions Sources: Niacin is found in unrefined and enriched grain and cereal, milk, and lean meats, especially liver. Yeast, poultry, salt water fish, nuts, legumes, coffee, tea, dairy products, and potatoes are good sources of Niacin.

Populations at risk

In alcoholics, deficiency may be caused by decreased intake, reduced absorption, or impaired ability to use the absorbed vitamin. Chronic diarrhea, cirrhosis of the liver, diabetes mellitus, and malignant disease can result in niacin deficiency. Niacin deficiencies are rare in developed countries, as the body can make niacin from the aminiacid tryptophan. However, the antituberculosis drug isoniazid impairs the conversion of tryptophan to niacin and may produce symptoms of niacin deficiency. Patients with Tuberculosis receiving INH therapy should be supplemented with niacin.

Signs and Symptoms of Deficiency

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Severe niacin deficiency can result in a disease called Pellagra. This disease is characterized by severe dermatitis and fissured scabs, diarrhea, and mental depression. The disease is associated with "the four Ds": dermatitis, diarrhea, dementia, and eventually, death. Another sign of Pellagra is Casal's collar, which is a rough red dermatitis. Achlorhydria, retarded growth and pigmentation of the tongue, are other symptoms.

Safety

Many clinicians have extensive experience with the use of niacin for the treatment of hyperlipidemias. The adverse events associated with niacin can be divided into the side effects: flushing, diarrhea, indigestion, nausea, and vomiting. The more severe adverse events are hepatotoxicity, exacerbation of gout, and possible worsening of glucose intolerance. There are three available forms of niacin: the short acting or crystalline, the intermediate acting, and the long acting forms. In general, the flushing and gastrointestinal side effects tend to occur with the short or intermediate acting forms at doses as low as 50 to 100mgs, and usually resolve with continued use of the drugs. The more severe toxicity is usually seen with the longer acting forms in doses of 2-6 gm/day. From the clinical trial data it would appear that an intake of less than 500mg is associated with no identifiable risk.

Toxicity is usually seen in patients treated with high doses for hypercholesterolemia. Hypotension and dermatitis are the most common symptoms. Other symptoms of toxicity include increased pulse and respiratory rate, increased cerebral blood flow, and central nervous system stimulation. Peripheral vasodilation, fatty liver, and decreased serum cholesterol, may also be seen.

Biochemistry

The term niacin refers to both nicotinic acid and niacinamide. The biologically active coenzyme forms are niacinamide adenine dinucleotide (NAD+) and its phosphorylated derivative, niacinamide adenine dinucleotide phosphate (NADP+). NAD and NADP are used in the catalysis of oxidation and reduction reactions. The coenzyme functions to accept and donate electrons. NAD is used in energy-producing reactions involving the degradation of carbohydrates, fatty acids, ketone bodies, amino acids, and alcohol. NADP tends to be involved in biosynthetic reactions like the pentose phosphate pathway, fatty acid biosynthesis, cholesterol synthesis, and by ribonucleotide reductase. Niacin is also essential for growth, convertion of vitamin A to retinal, and prevention of Pellagra. Nicotinic acid is often used as a vasodilator.

Recommendations: RDA in mg

• Infants birth to 6 mos - 5 mg
• Infants 6 mos to 1 yr - 9 mg
• Children 1 yr to 3 yr - 9 mg
• Children 4 yr to 6 yr - 12 mg
• Children 7 yr to 10 yr - 13 mg
• Adolescent males 11yr to 14 yr - 17 mg
• Adolescent females 11 yr to 14 yr - 15 mg
• Adolescent males 15 yr to 18 yr - 20 mg
• Adolescent females 15 yr to 18 yr - 15 mg
• Adult males 19 yr to 50 yr - 19 mg
• Adult females 19 yr to 50 yr - 15 mg
• Adult males 51 yr plus - 15 mg
• Adult females 51 yr plus - 13 mg
• Pregnant Women - 17 mg
• Lactating Mothers (1st 6 months) - 20 mg
• Lactating Mothers (2nd 6 months) - 20 mg

Niacin (Vitamin B3) Food Sources

Literature

Cholesterol:

Niacin is used in the treatment of hypercholesterolemia. The efficacy and safety of lovastatin and niacin were compared in a controlled, randomized, open-label study of a 26 week duration in 136 patients with primary hypercholesterolemia. Lovastatin and niacin both exerted favorable dose-dependent changes on the concentrations of plasma lipids and lipoproteins. Lovastatin was more effective in reducing LDL cholesterol concentrations, whereas niacin was more effective in increasing high-density lipoprotein cholesterol concentrations and reducing the Lp(a) lipoprotein level. Lovastatin was better tolerated than niacin, in large part because of the common cutaneous side effects of niacin. The dosages used were lovastatin 20mg/d and niacin 1.5 g/d for 10 weeks. Similar results were seen in another study where the two drugs reduced low-density lipoprotein-high-density lipoprotein ratios to a similar level, although these effects were obtained in different ways. In this study 27 out of 37 patients finished the trial with a dose of 4.5 g/d of nicotinic acid. In another study in renal transplant patients, nicotinic acid significantly reduced the total cholesterol and the low-density lipoprotein cholesterol and significantly increased the high-density lipoprotein cholesterol. The triglyceride level was reduced by about 100 but was not significant (P = 0.09). There were no significant changes in the triglyceride and high-density lipoprotein cholesterol levels in the lovastatin treated group. Flushing developed in 67%, but there were no dropouts because of side effects.

The long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia was determined. Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients.

In one study conducted in 110 patients seen in a private medical clinic during a 5-year period, 43% of individuals given regular nicotinic acid and 42% of those given sustained-release nicotinic acid were forced to discontinue the medication because of side effects. However, some of these side effects necessitating discontinuing nicotinic acid did not occur until the patient had been taking the drug for 1 or 2 years.

In the Coronary Drug Project, Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

Lipoprotein(a)

Seman et. al. discussed the importance of treatment of elevated levels of Lipoprotein (a) levels. Recent data have supported Lp(a) as an independent risk factor for coronary heart disease (CHD). In vitro studies suggest that Lp(a) contributes to atherogenesis directly by cholesterol uptake and indirectly by the inhibition of fibrinolysis. A study by the Mayo Clinic demonstrated the association between electrophoretic detection of Lp(a) from fresh plasma and CHD in both men and women, resulting in relative risks for men and women of 1.9 and 1.6, respectively. This is further supported by Framingham Heart Study. In some studies, Lp(a) is proven to be a risk facor for CHD in men but not in women. In both studies, less than half as many new cases of CHD occurred in women as in men, which may have affected these results. The Scandinavian Simvastatin Survival Study demonstrated that Lp(a) predicted major coronary events and death in secondary prevention in both simvastatin and in controls. This somewhat contrasts with other studies that suggest that Lp(a) attributes risk only when the LDL cholesterol is high. Angiographic studies also suggest that Lp(a) can predict lumen diameter, but only in the setting of either high LDL cholesterol or low HDL cholesterol. Cross-sectional data on Lp(a) and CHD have provided some insight into the relationship between high Lp(a) levels and vascular disease in blacks versus whites, with a positive correlation between Lp(a) and CHD in some black population.

Lp(a) levels, however did not seem to be useful in predicting post-procedure outcomes. Lp(a) did not predict occlusion over 6 months in high pressure coronary artery stenting or percutaneous transluminal coronary angioplasty, or over 5 years following coronary artery bypass grafting. Furthermore, a role for accelerating atherogenesis in patients with type 2 diabetes has not been successfully linked to Lp(a).

Mechanisms that are thought to be involved in Lp(a) and CHD include the uptake of Lp(a) by foam cells, selective trapping of Lp(a) by artery wall proteoglycans, and aggregation of LDL with Lp(a). Accelerated atherogenesis involves the inhibition of plasmin formation on the endothelial surface: hence, reducing the activation of transforming growth factor bmay result in migration and proliferation of smooth muscle cells into the vascular intima. Plasmin suppression may be caused in part by the transcription regulation of plasminogen activator inhibitor-1 by the uptake of Lp(a) and very low density lipoprotein (VLDL) in the endothelial cells. In addition, Lp(a) induced endothelial dysfunction may promote vascular occlusion.

In patients with CHD or a significant risk for CHD, one should consider measuring Lp(a) and treating with either niacin or estrogen if the patient has Lp(a) cholesterol levels of more than 10 mg/dL or an Lp(a) mass of more than 30 mg/dL.

Diabetes

Treatment with nicotinamide may prevent or delay the onset of insulin dependent diabetes mellitus. In a population based diabetes prevention trial, 20,195 school children were screened for islet cell antibodies. Risk can be determined by measuring the ratio of antibodies to islet cells (ICA antibody test). Of these, 185 had islet cell antibodies and met the criteria for treatment with nicotinamide. 173 received this treatment. The study population has an average follow up time of 7.1 years. The incidence of diabetes in children who tested positive for ICA antibodies, and who were given niacinamide, was reduced by about 60%. Nicotinamide has a protective effect against the development of insulin dependent diabetes in this setting, but the size of the effect has a wide confidence interval. In recent onset type 1 diabetes, niacinamide may prolong the "honeymoon period". Another study showed that nicotinamide improves insulin secretion and metabolic control in lean type 2 diabetic patients with secondary failure to sulphonylureas. Nicotinamide improves C-peptide release in type 2 diabetic patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin.

Peripheral vascular disease

Several double-blind studies showed that inositol hexaniacinate can improve walking distance in patients with intermittent claudication. In one of the studies, 120 patients received either placebo or 2 g of inositol hexaniacinate daily. Over a period of 3 months, the inositol hexaniacinate treated group showed a significant improvement in walking distance.

Raynaud's disease

The effects of 4 g/day of Hexopal (Hexanicotinate inositol) or placebo was examined in 23 patients with primary Raynaud's disease during cold weather. The Hexopal group felt subjectively better and had demonstratively shorter and fewer attacks of vasospasm during the trial period. Serum biochemistry and rheology was not significantly different between the two groups. Although the mechanism of action remains unclear, Hexopal is safe and is effective in reducing the vasospasm of primary Raynaud's disease during the winter months.

Osteoarthritis

In a double-blind placebo controlled study, 72 patients with osteoarthritis were randomized for treatment with niacinamide or an identical placebo for 12 weeks. Niacinamide improved the global impact of osteoarthritis, improved joint flexibility, reduced inflammation, and allowed for reduction in standard anti-inflammatory medications when compared to placebo. This study indicates that niacinamide may have a role in the treatment of osteoarthritis.

Summary

Vitamin B3 (Niacin) is found in unrefined and enriched grain and cereal, milk, and lean meats, especially liver.Yeast, poultry, salt water fish, nuts, legumes, coffee, tea, dairy products, and potatoes are good sources of Niacin. Chronic diarrhea, alcoholism, cirrhosis of the liver, diabetes mellitus, and malignant disease can result in niacin deficiency. Niacin deficiencies are rare in developed countries, as the body can make niacin. Significant research shows that Niacin can increase HDL levels and reduce LP(a) which improves one's cardiac risk profile. Research shows the benefit of Niacin supplementation has a protective effect against the development of insulin dependent diabetes (Type I) and in Type II diabetics improves C-peptide release in patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin. Additional research shows potential benefit in the treatment of Raynaud's disease, peripheral vascular disease and osteoarthritis.

Hypotension and dermatitis are the most common symptoms of hypervitaminosis. Other symptoms of toxicity include increased pulse and respiratory rate, increased cerebral blood flow, and central nervous system stimulation. Peripheral vasodilation, fatty liver, and decreased serum cholesterol, may also be seen.

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by EricT

By Shanthi Johnson¹ and Krista Leck²

Abstract

Background:The study examined the effects of dietary fasting on physical balance among young healthy women.

Methods:This study undertaken involving 22 young healthy women (age = 22 ± 1.5) using a within subject counterbalanced 2-week crossover study design. Participants were asked to refrain from consuming any food or beverage for 12 hours prior to the fasting trial and to maintain their regular diet for the non-fasting trial. Measures included: a background questionnaire, 24-hour dietary recall, and functional reach and timed single-limb stances.

Results: Fasting resulted in significant declines in functional reach (p < 0.01), and ability to balance in a single limb stance with eyes open, on both the dominant and non-dominant legs (p < 0.01 and p < 0.01, respectively), and with eyes closed on the dominant leg (p < 0.01).

Conclusions: The findings have implications for athletic performance in younger individuals as well as emphasizing the need for health education for young women to avoid skipping meals.

Background: Importance of Balance

The importance of balance can be seen in every aspect of daily living: walking up stairs, bending over to tie shoes or standing still. While the human body must be able to adapt to its environment and movements in order to maintain this balance, the loss or impairment of balance influences quality of living, decreases athletic performance, and can lead to injury [1,2]. Balance refers to an individual's ability to maintain the body in mechanical equilibrium and relies on specific postural mechanisms and sensory inputs (e.g., visual, somatosensory, vestibular) the purpose of which is to promote an appropriate alignment of body posture to maintain an upright stance against the force of gravity [3,4]. The two main aspects of balance that have been critically assessed are static and dynamic balance. Static balance is balance while the body is at rest, while dynamic balance refers to the ability to maintain balance during movement [1,5-7].

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Balance is a complex and multifaceted fitness parameter and is assessed in a number of different ways. In young and old individuals, balance is generally assessed using functional performance tasks that evaluate everyday living skills (e.g., obstacle courses, timed up and go tests or functional reach tests) as well as more challenging situations (e.g., modifying a sensory input and the use of firm and compliant surfaces). Measures such as functional reach have also been used to quantify dynamic balance in all age groups [8]. Similarly, static balance can be assessed using a timed single limb stance procedure (e.g., eyes closed or open or a maximum timed duration), or by using a force plate to measure and quantify postural sway [9-12]. With minimal disturbances in balance, the ankle strategy is used to regain postural stability. However, as the difficulty increases, the ankle is no longer able to maintain control and the body shifts to using other postural mechanisms such as the hip strategy and/or upper limb movement [6]. Failure to recover balance through a combination of these mechanisms will ultimately result in a fall.

Studies suggest that there are many conditions or situations which can disrupt the control of balance. Age-related physiological changes, the presence of injury, disease, and medication, can alter the ability to maintain balance. Additionally, some research has reported sex differences in the ability to maintain balance [13,14]. This difference has been attributed to womens' lower centre of gravity, which in turn improves their ability to balance [13,14]. Research has also shown that physically active individuals have an increased balancing ability over sedentary individuals of a similar stature [15]. However, over the short-term, fatiguing exercise has been shown to reduce balance [16]. While physical activity and nutrition are important parts of overall health, limited research, to date, has examined the specific relationship between nutrition and balance. The few studies that do exist have used balance tests as a secondary measurement within an overall study of nutrition and performance among elite male athletes, and show that a decrease in dietary intake negatively affects one's ability to maintain balance [17-20].

Dietary Fasting

Fasting is a state of nutritional imbalance, which is generally characterized by an absence or interruption of caloric intake over a period of time [21]. Physiologically, the body shifts into a state of early fasting, also known as a post-absorptive state, 3 to 12 hours after eating. After 12 hours of fasting, the post-absorptive state shifts to that of a fasting state, which is characterized by hypoglycemia or low blood sugar levels and the associated increase in gluconeogenic activity, with amino acids being the primary source of substrate [21-23]. Although nutrition imbalance has not been identified as a direct risk factor related to falls, the symptoms of hypoglycemia include a lack of coordination, staggering gait, fatigue, disorientation, dizziness, and vertigo. These symptoms are well-known risk factors for impaired balance and falls in the elderly population [24-26]. It is not uncommon for younger and older individuals to practice partial fasting [27]. People may skip meals and not eat for extended periods of time due to a self-imposed weight loss strategy, delayed eating due to the administration of medication or medical testing (e.g., fasting blood tests), or because of adherence to religious practices. The interruption of caloric intake places additional stress on the body, and could undermine the body's ability to perform daily living tasks.

The potential implication of fasting on functional capacity has not been well examined. Studies investigating the effects of fasting on functional performance, as determined by various fitness indicators such as endurance and balance, have used a wide variety of fast durations, ranging from 14 hours to 3.5 days [19,20]. A limited number of studies show that fasting contributes to decreased endurance capacity and reaction time, as well as reduced static and dynamic balance performance, along with increased heart rate and blood lactate levels during exercise, all of which are detrimental to performance [17,18]. Studies have shown that the ability to maintain balance is affected after fatiguing exercise [16]. Researchers have found that compensatory mechanisms exist to help maintain balance and these mechanisms are more active after fatiguing exercise [1,19,20]. The majority of these studies, however, have involved functionally elite men such as athletes or soldiers [17-20]. None of the studies involved individuals from the general population or women. As indicated earlier sex differences in the ability to maintain balance have been reported [13,14]. In addition, young women are more likely to skip meals and not eat for extended periods of time due to a self-imposed weight loss strategy. Studies have examined the role of skipping breakfast on cognition but not physical function in general and balance in particular with young women [27]. Thus, the purpose of this study was to examine the effects of dietary fasting on physical balance among young women.

Methods

Participant selection and study design

A sample of 22 Caucasian women was recruited for this study. Given the lack of research in this area involving young healthy women, power analysis was not performed. Participants were included only if they had no health conditions that could be worsened by fasting or that could affect their ability to balance (diabetes, recent/chronic head injuries and/or lower extremity disabilities, low blood pressure, vestibular and/or inner ear problems). Participant recruitment was completed through advertisement in the University bulletin after the study design and protocol were approved by the authors' institutional Research Ethics Board. The participants provided signed informed consent prior to participation.

The present study adopted a within subject counterbalanced crossover design, given the many advantages inherent in this design—all subjects served as their own controls and therefore reduced possible error variance, while reducing the needed sample size. Each participant was tested under fasting and non-fasting conditions, with half of the participants randomly assigned to start under the non-fasted condition and the remaining half completed the fasted trial first. The conditions were reversed during the second trial and the two trials were separated by a two week duration time span to avoid learning effects. All participants completed the same set of tests at each trial, in the same order. Standardized testing procedures and equipment were used throughout the study. The testing took place in the investigator's research laboratory. Snack bars and juice boxes were available for the participants to consume after study testing. No other incentives were provided to the participants.

Fasting and non-fasting protocol

Participants were provided with the fasting/non-fasting protocol prior to each test period. Thus, it was not possible to blind study participants to the testing condition. All laboratory tests took place between 9 and 11 am in order for all participants to avoid time of day variations. For the fasting trial, participants were asked to refrain from consuming food or beverages for a minimum of 12 hours prior to testing. Specifically, all participants were instructed to consume an evening meal before 8 pm prior to the day of testing and to refrain from any food or beverages until the time of testing in the laboratory. Fasting protocol was planned to mimic the scenario of skipping breakfast which is common among young women, or overnight fasting necessary for certain blood tests (e.g., fasting blood glucose). For non-fasting tests, participants were instructed to maintain normal eating habits on both the day prior to and the day of testing. In both test conditions, participants were asked to refrain from strenuous physical activity to minimize the role of carry-over effects such as fatigue, muscle damage, or physiological potentiation. Prior to each testing period, a pre-trial checklist was completed to provide information on each participant's past 24 hours of activity (e.g., timing of last meal, exercise performed, and injuries/health episodes since the previous contact).

Measures

The measures included: a background questionnaire, nutritional intake, balance tests, and a pre-trial checklist.

Background questionnaire

This questionnaire was used to elicit information related to the participants' demographic characteristics (age, education, ethnicity, employment, and financial status) and health status (perceived health, tobacco use, and physical activity level). The questionnaire was completed by the participants once, prior to the first testing period.

Nutritional intake

A 24-hour food recall was used to collect data on average caloric intake of the participants. The recalls were conducted by the student investigator trained in the protocol, using a standard form and adopting strategies to avoid recall bias by asking the participants to record food intake for 24 hours prior to the food recall interview [28]. Recalls were collected once during the study period and at mid-point between the two trials.

Physical testing

Physical testing included: 1) dynamic balance and 2) static balance. These measures were completed twice, once in the fasted condition and again in a non-fasted condition.
Dynamic balance

The functional reach (FR) test was used to assess dynamic balance [8]. For this test, the difference in centimetres between the participant's standing arm length and maximal forward reach was recorded. While standing with feet flat on the floor, the standing arm length was measured using a metric measuring tape fixed to the wall. Participants were then asked to reach as far forward as possible, without taking a step, without their heels leaving the ground or without losing balance. Three trials were performed with the farthest reach identified as the final score.

Static balance

The single limb stance was used to assess static balance [1]. This test can be performed in various time durations (e.g., 10, 25, 45 seconds or maximum time to exhaustion or termination) as well as with and without the use of a force platform. In the present study, the test was conducted on the gym floor and the maximum duration the participant could maintain a single limb stance was recorded in seconds on both the dominant and non-dominant legs, as well as in eyes open and eyes closed conditions [29], to avoid ceiling effect, given the involvement of healthy young women in this study. The dominant leg was determined by assessing which foot took the first step when participants were asked to initiate gait. Participants stood on the dominant leg, raising their non-dominant leg to a 90 degree angle at the hip and the knee joints while keeping their hands down by their sides. In this study, the test was terminated if the participant voluntarily asked to stop for any reason (e.g., sore leg), if the knee dropped below 90 degrees, if one placed the foot on the floor, or began to use arms to maintain balance. The reasons for the termination of the test were recorded for each of the four static balance testing conditions. The same set of termination criteria were used in both the fasting and non-fasting trials. Trials were conducted using the same protocol for both legs and under both conditions—eyes open and eyes closed. A practice trial was provided to each participant to ensure proper form was used during the actual trial. One test trial was completed for each condition to prevent fatigue and practice effects.

Pre-trial checklist

During each test session, participants completed a pre-trial checklist. This checklist gathered information related to fasting duration, level of physical activity prior to testing, and any change in health since recruitment or first testing.

Data analysis

Data from the two trials were numerically coded and entered into a Statistical Package for the Social Science database [30] for analyses. Descriptive statistics (means and frequencies) were used to describe the demographic and health characteristics as well as balance measures. Subsequently, paired t-test was conducted to examine the changes in balance performance scores for the two trial conditions. Completed dietary recalls were entered into a dietary analysis program, Food Processor SQL [31], and were used to calculate an average nutrient intake for a 24-hour period. Similarly, foods consumed for breakfast (in the same 24-hour period) were analyzed using Food Processor SQL to calculate the average nutrient intake. Based on the difference of nutrient intake for the whole day versus breakfast, an average "caloric loss" for fasted trials was calculated. The significance level was set at (p ≤ 0.05) for all statistical procedures.

Results

A total of 22 female, Caucasian university students participated in this study without any attrition between trials. Descriptive statistics on the demographic characteristics and health status are presented in Table 1. The age of study participants ranged from 18 to 23 years with a mean of 21.8 years (SD = 1.5). Of the study participants, 95.4% rated their perceived health status as excellent to good and all the participants were non-smokers. Over 90% of the study participants consumed alcohol on a regular basis. The majority of the participants reported performing regular physical activity (90.9%) with a range of four to six days a week (63.6%) for a duration of 30 minutes or longer (90.9%) each time. The perceived health and physical activity status was self report and no definitions were provided. None of the participants reported any injuries or medical conditions that could affect their balance.

Table 1. Descriptive statistics on the demographic and health characteristics of the participants

Data from the pre-trial checklist showed that a minimum 12-hour fast was followed by the participants during the fasted trial, with a mean fast of 15 hours. As expected, there was a statistically significant difference in the time of last meal for the fasted and non-fasted trials (p = 0.011). The average daily caloric intake was 2062 kcals with 15.2% of these calories coming from protein, 60.2% from carbohydrates and 28% from fat. When analyzing the breakfast meal individually, the average total calories from breakfast alone was 465.8 kcals or 22.6% of the day's total calories. The breakfast meal consisted primarily of carbohydrate calories (74.6%) and interruption of the consumption of breakfast contributed to an average caloric deficit of 465.8 kcals during the fasted trial.

Table 2 presents the mean scores for each of the balance measures assessed, based on the trial condition (fasted or non-fasted). For the single limb stance test, there was a decrease in duration (seconds) of the participants' ability to maintain balance as the level of difficulty increased, from eyes open, dominant leg to eyes closed, non-dominant leg in both fasted and non-fasted trials, albeit the fasted trial had consistently lower scores compared to non-fasted trial. Similarly, for the functional reach test, the participants' score was lower in the fasted trial compared to non-fasted trial. Paired comparison t-test showed that fasting resulted in statistically significant declines in functional reach (p < 0.01), the ability to balance in a single limb stance with eyes open, on both the dominant and non-dominant leg (p < 0.01 for both) and with eyes closed trial on the dominant leg (p < 0.01) among healthy young adults. No statistically significant change was observed for the static balance test in the eyes closed condition on the non-dominant leg (p = 0.13).

Table 2. Comparison of scores of physical measures between non-fasted and fasted trials

Along with the decline in balance performance between trials, an increased postural response (e.g., stumble, use of arms, knee lowered) was recorded as the reason for test termination as the degree of difficulty progressed in the single limb stance (from eyes open dominant leg to eyes closed non-dominant leg) and from the non-fasted to fasted trial (see Table 3). Specifically, in non-fasted conditions, the frequency of stumbling as the reason for termination increased with the increase in the level of difficulty in the four trials (from eyes open, dominant leg trial to the eyes closed non-dominant leg trial). However, under fasted conditions, participants showed an increase in postural responses, mainly stumbling, leading to termination in both the eyes open and closed conditions in the dominant leg but the trend was not true for non-dominant leg. In each of the trials, those in the fasted condition reported higher frequency of stumble compared to those in non-fasted condition except for the trial with the highest level of difficulty (eyes closed, non-dominant leg) in which the scores in seconds were similar (as shown in Table 2).

Table 3. Reasons for Termination of Single Limb Balance Trial (Percentage reporting Postural Response)

Discussion

The present study provided insights into the relationship between dietary fasting on static and dynamic balance. Specifically, in a sample of physically active and healthy young women, dietary fasting of a 12-hour period affected the individuals' ability to maintain dynamic and static balance as measured using the functional reach and single limb stance tests, respectively. As indicated earlier, there is a paucity of research examining this issue among young women who are more likely to skip meals and not eat for extended periods of time to lose weight. No other study was found in the literature which examined static and dynamic balance in fasting condition in women, although decline in balance has been reported in studies which involved functionally elite men such as athletes or soldiers [17-20].

In addition to the decreased duration of balance ability between fasted and non-fasted trials, increased postural control mechanism responses were noted which resulted in the termination of the test. In the present study, at the easier stages of the single limb stance test (eyes open), the majority of the participants stopped due to sore leg. However, as the difficulty increased (eyes closed) more of the body was required to maintain postural control resulting in more stumbling and use of arms to aid balance. Under fasting conditions, during both the eyes open and eyes closed trials, the majority of the stances were terminated due to a stumble. This is consistent with previous studies which suggest that individuals use various postural strategies for the maintenance of balance after fatiguing exercise [1,19,20]. The fasting condition placed additional stress on the body's ability to balance and therefore, required a larger postural response in order to maintain balance.

In the present study, a minimum fasting duration of 12 hours was adopted. Although this is slightly lower than the range of 14 hours to 3.5 days of fasting duration reported in existing studies, it is similar to the standard fasting protocols required for certain blood tests and sufficiently long for the body to switch from a post-absorptive state into a fasting state [17-21]. By using a fast duration that mimicked a skipped breakfast scenario or fasting blood test, the study protocol reflected a common fasting situation in the general population. The results can therefore be applied to everyday situations, instead of what happens under extreme fasting situations (e.g., 3.5 days of fasting). In the present study, it was estimated that fasting could have contributed to a 465.8 kcals deficit or approximately 25% of daily intake when compared to the non-fasted condition. Although there are no comparable data, studies have used a standard breakfast of 595 kcals for male participants [17]. Further research is needed to examine the physiological mechanisms underlying the relationship between fasting and balance including the role of energy regulating hormones (insulin, leptin, adiponectin, ghrelin) as well as the resulting metabolic and biochemical changes (e.g., hypoglycemia). Association between nutrition and falls should be examined further in the population of older adults [26].

While the results of the present study have furthered our understanding of the relationship between dietary fasting and its effect on physical balance among healthy, young women, it is not without limitations. The study recruited participants through a non-random sampling approach. As such, self selection bias would be inherent in the sampling approach. Also, with the lack of research in this area, it was not possible to calculate an appropriate sample size. However, based on the changes observed in the present study in the functional reach test, which is an indicator of dynamic balance, it can be estimated that 20 participants are required for each group to study whether there is a gender difference in the observed effects of fasting. Additionally, it was not possible to gather dietary data in fasting and non-fasting states. Future studies should calculate the actual caloric deficit between the two conditions.

The present study also had several strengths. The use of a within subject counterbalanced crossover design was a major strength of this study. This set-up allowed many advantages; all participants performed the tests in fasted and non-fasted conditions, served as their own controls and therefore reduced possible error variance, while reducing the needed sample size. This is the first study to date that has examined the relationship between dietary fasting and physical balance as its primary focus within the general population, with the use of a common fasting duration (e.g., skipping breakfast). Standardized testing procedures and protocols were used to minimize variance errors and ensure reproducible data.

The findings raise issues to be addressed in future research. For example, while a small decline in balance may not translate into difficulties in performing activities of daily living in younger individuals or have serious clinical significance in the day to day functioning given the higher levels of functional threshold in young individuals, these small changes in balance may affect athletic performance if the young women are also actively competing in sport in which balance is integral to performance (gymnastics, skating). Also, changes in balance could limit elderly individuals from performing basic activities as well as predispose them to high risk for falls. Future studies are needed to test the sport performance and fall risk prepositions. Falling is a complex problem influenced by a multiplicity of risk factors, yet the inability to maintain balance (i.e., postural instability) is one of the best predictors of falls among the elderly individuals [24,32]. Given the high incidence of falls and the debilitating consequences such as hip fracture among the older population [25], future studies are needed to demonstrate the effects of aging on the relationship between fasting and balance. In these studies, the appropriateness of measure such as a single limb stance with increasingly difficulty conditions (eyes closed) for frail older adults and the related safety concerns should be considered.

Competing interests

The authors declare that they have no competing interests.
Authors' contributions

CSJ contributed to the conceptualization and design, as well as to the analysis, interpretati