Ground Up Strength News

Portion Size: Effect on Food Intake and Possible Interventions

Thu, 02 Sep 2010 16:01:38 +0000

By Ingrid HM Steenhuis and Willemijn M Vermeer

VU University, Department of Health Sciences and EMGO and
Institute for Health and Care Research, De Boelelaan 1085,
1081 HV Amsterdam, the Netherlands

International Journal of Behavioral Nutrition and Physical Activity 2009

The prevalence of overweight and obesity has increased. A strong environmental factor contributing to the obesity epidemic is food portion size. This review of studies into the effects of portion size on energy intake shows that increased food portion sizes lead to increased energy intake levels. Important mechanisms explaining why larger portions are attractive and lead to higher intake levels are value for money and portion distortion. This review also shows that few intervention studies aiming to reverse the negative influence of portion size have been conducted thus far, and the ones that have been conducted show mixed effects. More intervention studies targeted at portion size are urgently needed. Opportunities for further interventions are identified and a framework for portion size interventions is proposed. Opportunities for intervention include those targeted at the individual as well as those targeted at the physical, economic, political and socio-cultural environment.

Introduction

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Overweight and obesity are increasing problems in western societies. Environmental factors contribute to the obesity epidemic [1] by promoting energy intake and limiting opportunities for energy expenditure [2]. A strong environmental factor influencing energy intake is food portion size [3-6]. Although research on the actual development of portion sizes is limited, it is clear that portion sizes have increased over the past decades [7-11]. Studies have been conducted in the United States [7-10] and in Denmark [11]. These studies show that, since the 1970s, portion sizes of especially high energy-dense foods, eaten inside as well as outside the home, have increased. This accounts for both amorphous foods and foods served in units [9]. Fast-food restaurants, for example, have shown a trend over the last decades to supersize their portions, and have introduced large and mega meals [9-11]. Another example is the increased package sizes of products sold in supermarkets, such as sugar-sweetened beverages [11].

Food portions in the United States tend to be larger than in Europe. However, in Europe, portion sizes have also increased [5,10,11]. Increased portion sizes may lead to increased energy intake levels. Studies on interventions that aim to reverse this trend are scarce, and urgently needed. In this article, firstly we review the effects of portion size on energy intake, followed by possible explanations for this relationship. Next, we assess the currently available interventions and their effectiveness. To conclude, we identify further opportunities for interventions aimed at portion size and propose a framework for portion size interventions.

Methods

Search strategy

For this review, firstly we asked: What is the effect of portion size on energy intake? Secondly, we assessed the effects of currently available portion size interventions on food intake. Studies were identified using the PUBMED database, the Cochrane Library and the Web of Science (ISI). The following keywords were used for the first question: 'portion size'; 'energy intake'; 'food intake'; and 'food consumption'. For the second part, the keywords 'portion size'; 'intervention'; or 'programme' were used. Furthermore, studies were also identified based on references of the found articles.

Inclusion and exclusion criteria

Only studies with adults as research population were included in this review. However, intervention studies with a mixed study sample, but consisting mainly of adults, were also included. Studies with less than 20 subjects were excluded in all cases. Food intake had to be an outcome measure of the study to be included in the review. More specifically, food intake of the product whose portion size was manipulated had to be an outcome measure (for example, instead of only the food intake of a non-manipulated subsequent meal). In addition, for the second part, intervention studies that used food selection as an outcome measure were also included.

For the first question, studies varying only the package format and not the actual portion size were excluded (for example 30 grams in a small package versus 30 grams in a large package). Regarding study design, between subjects designs were included as well as within subjects cross-over designs for the first research question. Since studies into the effectiveness of interventions aimed at portion size are very scarce, no further requirements were defined regarding research design for the second question.

Portion size and energy intake

Do increased portion sizes lead to increased energy intake levels? Thirteen studies met the inclusion criteria and investigated this relationship, mostly using a within subject's cross-over design (see Table 1) [12-24]. The larger portion sizes used in the studies varied from 125% of the control portion to up to 500% the control portion, but most studies investigated portion sizes between the control size and twice the control size. All studies showed that people's energy intake increases when offered a larger portion. This also accounts for food with an unfavourable perceived taste, i.e. stale popcorn [23].

Table 1. Studies into the effects of portion size on food intake

Hide Table 1

First author, year (reference)	Study design	Respondents	Type of food	Main outcome
Diliberti,2004 [12]	Between subjects, parallel group design, with two different portion sizes (100%a, 152%)	Cafeteria visitors at a university campus, n = 180	Baked pasta in cheese sauce (54% fat, energy density 1.7 kcal/g)	-Increased energy intake when served a larger portion, 43% more (172 kcal) -Overall extra energy intake of entire meal 25% (172 kcal)
Fisher, 2007 [13]	Within subjects cross over design, with two different portion sizes (100%a, 200%)	Low income Hispanic and African American mothers, n = 58	Macaroni & cheese (1.51 kcal/g), apple juice (0.47 kcal/g), crackers (4.62 kcal.g), chicken (1.73–2.42 kcal/g), rice (0.8 kcal/g), cereal (4.0 kcal/g)	-Increased energy intake when served a larger portion, 21% more (270 kcal), over 24 hour period
Flood, 2006 [14]	Within subjects cross over design, with two different portion sizes (100%a, 150%) (and three different beverages)	Adults, n = 33 (aged 18–45)	Beverages (regular cola (0.4 kcal/g), diet cola, water)	-Increased beverage intake when served a larger portion, 10% more for women, 26% for men (regular cola)
Kral, 2004 [15]	Within subjects cross over design, with three different portion sizes (100%a, 140%, 180%) (and three different energy densities)	Women (aged 20–45), n = 39	Italian pasta bake (25% fat, 60% carbohydrate, 15% protein, 1.25 kcal/g–1.75 kcal/g)	-Increased food intake when served a larger portion, 20% more food intake when served the largest portion compared to the smallest portion -Combined effect with energy density: 56% more energy intake when served the largest higher energy dense portion compared to the smallest lower energy dense portion (225 kcal)
Raynor, 2007 [16]	Random 2(small amount or large amount, 100%a, 200%) × 2 (small unit or large unit) between subjects design	Adults (aged 18–30), n = 28	Potato chips, cheese crackers, cookies, candy	-Increased energy intake when served a larger portion, 81% (2246 kcal), over three day period -No effect of package unit size
Rolls, 2002 [17]	Within subjects cross over design, with four different portion sizes (100%a,125%, 150%, 200%)	Adults (aged 21–40), n = 51	Macaroni & cheese (1.63 kcal/g)	-Increased energy intake when served a larger portion (resp. 12% more (64 kcal), 19% more (105 kcal), and 30% more (161 kcal)
Rolls, 2004 [18]	Within subjects cross over design, with five different portion sizes (100%a, 150%, 204%, 357%, 507%)	Adults (aged 20–45), n = 60	Potato chips (5.4 kcal/g)	-Increased energy intake when served a larger portion, 184 kcal more for women when comparing largest vs smallest portion, for men 311 kcal -No short term compensation at dinner
Rolls, 2004 [19]	Within subjects cross over design, with four different portion sizes (100%a, 134%, 167%, 200%)	Adults (aged 20–45), n = 75	Deli-style sandwich, (2.4 kcal/g)	-Increased energy intake when served a larger portion, 31% more for women when comparing largest vs smallest portion (159 kcal), for men 56% more (355 kcal)
Rolls, 2006 [20]	Within subjects cross over design, with three different portion sizes (100%a, 150%, 200%)	Adults (aged 19–45), n = 32	Complete daily menu (varying from 0.2 kcal/g (vegetable side dish) to 5.5 kcal/g (snack foods	-Increased energy intake when served larger portions, for all food categories, resp. 16% more (women 335 kcal/day, men 504 kcal/day) and 26% more (women 530 kcal/day, men 812 kcal/day) -No compensation over two day time period
Rolls, 2007 [21]	Within subjects cross over design, with two different portion sizes (100%a, 150%)	Adults (aged 20–40), n = 23	Complete daily menu, each day different	-Increased energy intake when served larger portions, for all food categories except fruit as afternoon snack and vegetables, average increase in energy intake 423 kcal/day -No compensation over 11-day time period
Wansink, 2001 [22]	2 (medium or large container, 100%a, 200%) × 2(perceived favourable vs unfavourable taste) between subjects design	Moviegoers (aged 11–89), n = 151	Popcorn	-Increased food intake when served a larger portion, for both perceived favourable and unfavourable taste, 53% more
Wansink, 2005 [23]	Random 2 (medium or large container, 100%a, 200%, × 2 (fresh or stale) between subjects design	Adult moviegoers, n = 158	Fresh and stale popcorn	-Increased food intake when served a larger portion, for both fresh and stale popcorn, resp. 45% and 34%
Wansink, 2005 [24]	Random between subjects, parallel group design (normal bowl vs self refilling bowl)	Adults (ages 18–46), n =	Soup	-Increased energy intake when served a larger portion without accurate visual cue, 73% more (113 kcal)

a smallest portion is referred to as 100%

Steenhuis and Vermeer International Journal of Behavioral Nutrition and Physical Activity 2009 6:58 doi:10.1186/1479-5868-6-58

Effects of at least 30% higher consumption levels due to portion size are reported frequently [12,16,17,19,22-24], with larger effects for larger portion sizes (see Table 1). The effects have been shown for a variety of foods, such as macaroni [17], a pre-packaged snack [18], beverages [14] or popcorn offered in a cinema setting [22]. Larger effects are found for men [18-20], compared to women. If the increase in portion size was combined with a higher energy density, even larger effects on energy intake were observed [15]. Furthermore, research showed that the effects of portion size can persist over several days, with no indication of meal-to-meal compensation [20,21]. Rolls et al [21] showed that the average increase in caloric intake owing to 50% larger portions did not decline over a period of eleven days, and resulted in a cumulative increase of, on average, more than 4600 kcal during the eleven-day research period.

Explanations: Portion distortion and value for money

Important factors found in the literature, explaining why people buy and eat larger portion sizes than they actually need, are the notions of 'value for money' and 'portion distortion'. Larger portions are made attractive by offering more value for money, i.e. having a lower price per unit. Lower unit costs also explain why larger package or portion sizes lead to a higher user volume [6,25,26]. Based on qualitative focus group interviews, it seems that consumers experience the lower price per unit in case of larger portions as a natural pattern and are used to it (March 2007; unpublished data).

Next, continuous exposure to larger food portion sizes contributes to 'portion distortion' among consumers [11,27]. People experiencing portion distortion perceive larger portion sizes as an appropriate amount to consume at a single occasion [28]. It also refers to the fact that individuals do not realize that their portion size commonly exceeds the serving size [29]. With respect to portion distortion, a number of aspects are relevant. First, larger portions have become standard and, as a consequence, consumers have difficulty selecting amounts of food that are appropriate for their weight and activity levels [30]. Second, market place portions differ increasingly from recommended standard portion sizes defined by federal agencies [30]. In fact, market place portions are often three to four times larger than the recommended portion size, while consumers perceive market place portions as standard portions [31].

Several studies have shown that people tend to select substantially larger portions than the recommended portion sizes [28,29,32,33]. Third, labels on food packaging are not always clear with respect to the serving size. Sometimes, unrealistic small serving sizes are used on food packages in order to give consumers a positive impression about the number of servings in one package and the caloric content [29]. Similarly, using the terms 'small', 'medium' and 'large' also creates confusion, as people's interpretation of these terms differs [34]. A fourth factor relevant in portion distortion is the 'unit bias' people might experience. Geier et al [35] define unit bias as 'a sense that a single entity is the appropriate amount to engage, consume or consider'. The size of the unit or package sets a consumption norm for consumers, which might not be an appropriate norm in accordance with food recommendations [35,36]. Many people interpret package size as a single serving size and are unaware of the fact that a package contains multiple servings [37]. Fifth, and finally, tableware might also contribute to portion distortion, although study results are inconclusive as yet. The vertical-horizontal illusion is well known: people only use the vertical dimension to estimate portion size [38]. Also, it seems that people serve themselves more food if using a larger bowl [39,40]. However, for plate sizes, this finding could not be replicated [41].

Once larger portions have been selected because of the value for money and portion distortion principle, passive over-consumption is likely to occur. In particular, people tend to overeat palatable, high energy-dense (e.g. high in fat) foods, without deliberate intention [42].

Interventions

Intervention studies

Is it possible to reverse the trend towards larger portions and the consequently higher energy intake levels? Despite the fact that a broad range of interventions aimed at portion size have been suggested in the literature, very few intervention studies aimed at portion size have been conducted thus far. Only five studies were found that met the inclusion criteria for the intervention studies (see Table 2) [43-47]. It must be noted that two of these intervention studies were conducted among relatively small samples [46,47], with 24 and 33 respondents respectively. Also, three of these five studies were conducted among a relatively young and healthy population; i.e. college students [43,45,46]. Few other studies describing an intervention aimed at portion size and targeted at adults were found. However, these studies did not have food intake or selection as their outcome measurement, or were not evaluated at all [27,48-52]. These interventions were developed to target the improvement of consumers' portion size estimation skills, and to educate people about appropriate portion sizes [27,48-52]. Of the five included studies, two were targeted at reducing portion sizes [45,46].

A portion size reduction of 25%, studied in a laboratory setting, was effective in decreasing energy intake. Moreover, reducing the energy density, while keeping the same portion size, led to a larger decrease in energy intake [46]. However, a study into reducing portion sizes in a college setting showed no effects on total energy intake [45]. Lieux and Manning [45] studied an intervention based on limiting portion sizes of hot entrées in a dining facility at an American university. Portion size labelling or portion size information seems to be ineffective in decreasing energy intake [44,47]. In Harnack's study [44], portion size labelling was combined with another pricing structure (i.e. standardized pricing: the same price per gram for small and large portions; instead of value size pricing: the per unit cost decreases as portion size increases), which was also ineffective in changing the caloric intake. As customers are not used to standardized pricing, it might be that repeated exposure is necessary in order to achieve an effect [44].

Suggestions for individual and environmental interventions aimed at portion size

Several suggestions for interventions aimed at portion size have been given in the literature (see Table 3). Interventions can be targeted at the individual, comprising the education of consumers. Educational interventions should address awareness and teach behavioural strategies for portion control at home as well as, for example, in restaurants [4,7,10,11,28,29,31,53,54] (see Table 1 for more details regarding the suggested interventions).

Further, environmental interventions are important as well, since increased portion sizes are part of a changed food environment. Physical, economic, political and socio-cultural aspects of the environment can be distinguished according to the ANGELO-grid (ANalysis Grid for Environments Linked to Obesity) [1]. The physical environment refers to available options to make a healthy choice; the economic environment refers to the cost of healthy choices; the political environment refers to rules and regulations that may influence healthy choices; and the socio-cultural environment refers to social and cultural norms influencing healthy choices [1,55]. Interventions aimed at portion size can be put in place in all four types of environment (see Table 1). Decreasing portion sizes, or a wider range of available portion sizes, are examples of interventions aimed at the physical environment [10,23,28,29,33,53,54,56,57]. Pricing strategies to make smaller portions more attractive aim to alter the economic environment [4,26,53,54]. Possible interventions in the political environment are portion size requirements in certain settings, such as schools, or formulating realistic serving size standards [33,48,53,58]. Finally, interventions in the socio-cultural environment could be directed at chefs in restaurants, aimed at changing their knowledge, attitudes and skills regarding portion size and thereby influencing their customers' food consumption (see Table 3 for more details regarding the suggested interventions).

Portion size intervention framework

The suggested interventions target different aspects of portion size, which contribute to a higher energy intake mentioned before (see 'Portion distortion and value for money'). Figure 1 shows a framework for portion size interventions. The underlying factors causing portion distortion can be diminished by means of environmental interventions, mainly in the physical and political environment. Alongside this, education of consumers may help them to cope with an environment filled with portion distortive factors. Furthermore, proposed pricing strategies direct the value for money principle. Most of the suggested interventions are targeted at the selection of food, which is of great value because once a larger portion is selected, over-consumption is very likely to occur. Yet, by decreasing the energy density of food products and meals, one is still able to select a larger volume, while having fewer consequences for energy intake. Since value for money, as well as portion distortion phenomena, are less important using this strategy, this might be a promising alternative and attractive to both consumers and retailers.

Figure 1. Framework for portion size interventions

Feasibility

The feasibility of interventions targeted at portion size depends on the willingness of both consumers and point-of-purchase settings to accept these interventions. A qualitative study into consumer attitudes about portion size interventions indicated that consumers had particularly favourable attitudes towards a larger variety of portion sizes and pricing strategies, followed by labelling interventions (March 2007; unpublished data). Another qualitative study using semi-structured individual interviews with representatives of point-of-purchase settings, showed that most interventions aimed at portion size can be considered as innovative. Nonetheless, offering a larger variety of portion sizes and portion-size labelling were perceived as especially feasible interventions [59]. Also, O'Dougherty et al [60] showed that a third of fast-food restaurant patrons favoured a law requiring restaurants to change their pricing strategies and offer lower prices for smaller portions, instead of more value for money for larger portions.

Conclusion

Portion sizes seem to have increased considerably over the last few decades. It is important to continue studying trends in actual portion size development, since not many studies are currently available. The same applies to studies into the long-term effects of increased portion sizes. This review summarizes the available evidence, demonstrating that increased portion sizes lead to increased energy intake levels. Important factors explaining why larger portions are attractive, and why they lead to higher intake levels, are related to value for money and portion distortion. Only few intervention studies have been conducted to target portion size. Interventions that have been tested were directed mainly towards the physical environment, namely portion size reduction and portion size labelling or information. So far, interventions have shown mixed effects. Intervention studies are urgently needed, to find out what type of interventions, targeted at portion size, are effective, in what setting, and among which target groups. These studies should focus on educational programmes, but also on interventions in the physical, economic, politic and socio-cultural environments.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

IS conceived of the study, carried out the literature review and drafted the manuscript. WV participated in the literature review and helped to draft the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors wish to thank Franca Leeuwis for her contribution to this study.

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© 2009 Steenhuis and Vermeer; licensee BioMed Central Ltd.
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by EricT

Self Control: Not all its Cracked Up To Be

Wed, 01 Sep 2010 15:44:26 +0000

This is an expanded version of a post originally published on GUStrength's blog in July, 2009.

More and more, everyone is learning that "diets" don't work. Sure, people drop weight on diets but they fail to make a lasting change. I don't need to go into this, you know all about yo-yo dieting. Despite this there are still plenty of judgmental folks (who probably wouldn't know a problem if it bit them in the tuchus) who will say stuff like, "jeez, what ever happened to old fashioned self-control".

I was reading a blog the other day that mentioned diets and how they don't work and somebody had to come on and make this comment about self-control. I was taken aback not only by the judgmental attitude but also by the fact that the commenter completely failed to see the point of the post.

Diets are ALL ABOUT SELF-CONTROL. And they don't work. Self control doesn't work. Do the math. Are you getting this. It ain't about self-control.

Self-Control is basically the same thing as impulse control. And it is also pretty much the same thing as self-denial. These are short-term solutions to a long-term problem.

Say you are waiting in line and some obnoxious person butts in front of you and then glares at you as if daring you to do something about it. You quash your impulse to smack him one. That is self-control. Good for you. You have mastered your anger. This time.

Now, lets say that by some quirk of fate this kind of thing happens on Monday and then again Tuesday, Wednesday, and every other day of the week.

Here is the thing. Even though you practiced self-control on Monday it is no guarantee that you will be better equipped to handle this situation when Friday rolls around and it happens for the fifth time. In fact, by that time you will likely be fed up and when buddinsky number five comes along you may just go off like Mentos and Diet Coke.

The Diet Coke/Mentos Theory of Fat Loss
image by Mike Murphy via wikimedia

The reason self-control works for what it is good for…controlling aggressive impulses and other unsociable or inappropriate behavior is because we are not constantly faced with situations like this. That is, in situations where we have to learn not to give in to our more primitive and greedy impulses.

But when we treat all our eating habits and exercise habits in terms of self-control we tend to become less able to regulate our behavior well over time. If your entire life becomes nothing more than controlling every "impulse" and those impulses make you feel guilty even when you don't give in to them you become MORE likely to turn to those very activities you are trying to avoid.

Self-control tends to involve a set of rules and regulations that we adhere to. Matter of fact, most experiments involving self-control (in children) have started with a "rule", in a way. Such as leaving a treat in a room and saying you can have ONE treat now but if you wait until I come back you can have TWO.

You are ALLOWED to take the treat. The only reason you must practice self-control is because the rule says if you control yourself and wait for gratification you get MORE. Sounds like the way many people end up dieting! It's a confusing message. If you adhere to the rules you get to have a reward. If you reward yourself you are "cheating" (having a cheat meal).

The key, therefore, is not self-control but self-regulation. This is a subtle but very important distinction. More and more people, of late, are expressing concern over the fat loss focus of diets. Instead, some say, we should focus on healthy practices, which have a built-in reward system and should result, in the long run, in fat loss. Meanwhile, a healthier lifestyles that is focused on health rather than loss of fat will have immediate health benefits.

Now, I don't know if this dichotomous view of fat loss is the way to go. It may be a bit naive to assume that the simple desire to live healthier will result in an obese person becoming a thin one. However, it should be a distinct improvement for some of the focus on fat to be shifted towards health. A more balanced perspective, if you will. Hyper-focused modalities tend to result in these punishment-reward systems that we see in "dieting" and this is the dieter engaging in "self-control". A more balanced approach which has as it's end goal a healthy body and mind should go much further toward self-regulatory behavior. The difference between self-regulation and self-control is that self-regulation means that you are IN CHARGE of yourself. Whereas, self-control is actually placing the locus of control externally rather than within yourself.

Self-control, according to Michael Kellerman in Enhancing Recovery is a "mode of volition in which an individual works according to an internal model of an action requested or desired by another person without necessarily integrating this model into his own system of belief."

Requested by another person and NOT integrated in his own system of belief. That is the take home point. The "other person" is the person who wrote the diet plan you happen to be using. Or, we could just replace person with plan. The point is we don't get anywhere in the long run because the behaviors we use during periods of "self-control" do not become a part of our own governing system. Kellerman says that in the long run this results in "alienation" where a person becomes unable to behave according to his or her own needs.

Self-control of this kind tends to work for a short term and then fail, followed by a reversion to previous negative behaviors or by leading directly to negative results. Each negative consequence leads to the person going further and further into a downward spiral.

Fat loss is not the only area that suffers from the misunderstanding of self-control. Most strength training ideas are built on ideas about self-control, after all. Even worse the "fitness" gimmicks such as "Fitness Boot Camps" and other such nonsense that makes it seems like fitness is about having some guy in BDU's yell at you.

There is an older thread in the GUS forum that calls attention to the idea that good strength training involves "not being a pussy" or "a slacker" and that people need someone to call attention to those times when they are slacking and give them a "kick in the pants". Basically you are supposed to 'force yourself' to train and go in and just get the job done. Be assured that you will NEVER succeed in your training if you regularly must force yourself to train and no amount of yelling will change that!

As I said in the thread many people think that self-control and self-denial is the key to success in training, fat-loss, everything. They think that these factors are synonymous with "discipline". The "just get it done" attitude of many trainers is inherent in the so popular cookie-cutter strength training programs that I am always complaining about. The ultimate result of relying too much on self-control is a loss of autonomy and this results in the chronic inability to self-regulate. In other words, the longer you engage in this sort of behavior, the more difficult it will be to come out of it and develop behaviors centered on self-direction and self-regulation. The end result is failure in every sense of the word. Autonomy means being IN CHARGE rather than 'in control'.

You may never have thought of it before but the idea of being in control means that you are otherwise bound to be out of control. So instead of focusing one's energy on reigning out of control behaviors one should focus on continual regulation of behavior in the first place. I'll see if I can describe this with an analogy:

Have you ever walked by a patch of fresh wet cement on the sidewalk and been tempted to put your hand print or foot print in it? Or sign your name. Or, in some instances, even been tempted to walk right across the thing? I have. It's a bit like the urge to jump off a high object…perverse but there nonetheless. Yet, as inviting as a nice smooth patch of wet concrete is most sidewalk surfaces are free of hand-prints and signatures. Sure it happens but not nearly as often as one would think. That is, not nearly as often as one would think if people were out of control. But people largely self-regulate themselves and the urge to deface a patch of cement is fleeting and weak. In fact, they don't place orange cones and yellow tape around fresh sidewalks patches to "control" people but mostly to warn them so they don't accidentally blunder in. So, I'm saying that maybe smooth sidewalks exist because people are able to self-regulate and they don't need barriers to keep them from stepping in wet cement.

The same type of self-regulatory behavior that keeps your hand out of cement or that keeps you from testing your theory that you could land a 30 foot drop is the type of behavior that will lead to success in fat loss, or fitness, or strength training. When you self-regulate it means that you are OKAY with your life-style. You are happy and satisfied with it. Little urges stay little urges and when you give in to them you give in to them in reasonable ways. For instance, maybe you just poke the tip of your index finger into that cement. Fun stuff. Or, instead of trying the 30 foot drop you go for 15. That keeps your life balanced and controlled without a sense of denial and restriction and you don't "go off" like Mentos and Diet Coke!

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by EricT

When Snacks Become Meals: How Hunger and Environmental Cues Bias Food Intake

Wed, 01 Sep 2010 13:30:00 +0000

International Journal of Behavioral Nutrition and Physical Activity

International Journal of Behavioral Nutrition and Physical Activity 2010

by Mitsuru Shimizu¹, Collin R Payne², and Brian Wansink³

While environmental and situational cues influence food intake, it is not always clear how they do so. We examine whether participants consume more when an eating occasion is associated with meal cues than with snack cues. We expect their perception of the type of eating occasion to mediate the amount of food they eat. In addition, we expect the effect of those cues on food intake to be strongest among those who are hungry.

One-hundred and twenty-two undergraduates (75 men, 47 women; mean BMI = 22.8, SD = 3.38) were randomly assigned to two experimental conditions in which they were offered foods such as quesadillas and chicken wings in an environment that was associated with either meal cues (ceramic plates, glasses, silverware, and cloth napkins at a table), or snack cues (paper plates and napkins, plastic cups, and no utensils). After participants finished eating, they were asked to complete a questionnaire that assessed their hunger, satiety, perception of the foods, and included demographic and anthropometric questions. In addition, participants’ total food intake was recorded.

Participants who were in the presence of meal-related cues ate 27.9% more calories than those surrounded with snack cues (416 versus 532 calories). The amount participants ate was partially mediated by whether they perceived the eating occasion to be a meal or a snack. In addition, the effect of the environmental cues on intake was most pronounced among participants who were hungry.

The present study demonstrated that environmental and situational cues associated with an eating occasion could influence overall food intake. People were more likely to eat foods when they were associated with meal cues. Importantly, the present study reveals that the effect of these cues is uniquely intertwined with cognition and motivation. First, people were more likely to eat ambiguous foods when they perceived them as a meal rather than a snack. Second, the effect of the environmental cues on intake was only observed among those who were hungry.

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Background

There is considerable evidence that environmental and situational cues influence food intake [1].However, the specific psychological (cognitive and motivational) processes underlying those relationships are not often well addressed. This research illustrates how cognitive and motivational factors mediate and moderate the relationship between environmental cues and food intake. Specifically, consider whether a person views an eating occasion – such as a reception or a party – as a snack or meal. Typically, a meal involves a particular set of characteristics (such as eating while seated, with utensils, and so on) [2, 3], and they generally involve greater calorie intake than snacks [2, 4]. If people perceive the occasion as a meal, their hunger may lead them to increase their consumption – via goal fulfillment – more than if they had instead perceived it to be a snack. If environmental cues that suggest an eating occasion is either a meal or a snack can lead to an increase or decrease in consumption, then people’s perception of such should mediate the relationship between these cues and how much they eat.

Yet, there is sparse research examining the possibility of environmental cues affecting food perceptions in this context. One exception is a study conducted by Pliner and Zec [5]. In Experiment 1 they found that participants who ate foods in appetizer-main course-dessert order in a meal-like environment (seated at a dining table in a carpeted room) were more likely to describe the experimental condition using meal or lunch type words than those who ate the same foods (e.g., soup, Turkey sandwich) divided into 29 small portions in a snack-like environment (standing at a kitchen counter).

For instance, participants in the snack-like condition consumed 6 portions of soup, whereas those in the meal-like condition consumed a single portion. Although the presentation of foods differed between the two conditions, the quantity of foods consumed was almost identical (i.e., 369 kcal). In Experiment 2 they demonstrated that participants who had eaten in the meal-like environments consumed less food after a 20-minute delay than those in the snack-like condition. This suggests that simply perceiving an eating occasion to be a meal made a person less likely to eat a short time later. However, because they did not assess the difference in the perceptions in Experiment 2, it is unclear if perceptions truly drove the subsequent decrease in consumption among participants in the meal-like environment. These studies also varied both the environmental cues (being seated versus standing) and the presentation of the same foods. It would be useful to keep the presentation of the food constant and to assess psychological processes underlying behavior.

What is needed is research that provides identical but ambiguous foods to people, but manipulates the surrounding environmental cues to suggest that it is either a snack or a meal. As such, changes in consumption could be more clearly attributed to the external cues from the environment, not to the food. We expect to see participants in the meal condition not only perceive those identical foods to be a meal, but also to eat more as a result. In addition, not only do we expect that this perception will mediate their intake, but we believe that the effect of the environmental cues (i.e., increased food intake) may be moderated by their level of hunger. Consistent with previous findings that people were more likely to drink when they were subliminally primed with drinking-related words only if they were thirsty [6, 7], we expected that the meal-cue participants would eat more than the snack-cue participants, particularly if it had been a long time since they had previously eaten, using this as a proxy for hunger.

In summary, as research assessing psychological processes underlying the relationship between environmental cues and intake is sparse, we examine both a cognitive mediator—perception of identical foods cued as either a snack or meal—and a motivational moderator—hunger. We randomly assign undergraduate students to two experimental conditions in which they are instructed to eat ambiguous foods in an environment that is associated with either meal cues (ceramic plates, glasses, silverware, and cloth napkins at a table), or snack cues (paper plates and napkins, plastic cups, and no utensils). We expect meal-cue participants to consume more than snack-cue participants. We also expect the association between the environmental cues and the amount of food eaten to be mediated by the extent to which the eating occasion is perceived as a meal or a snack. Finally, we expect the strength of the association to be moderated by hunger, such that the association is particularly strong among those who are hungry.

Methods

Participants

One-hundred-twenty-two undergraduate students (75 men, 47 women), with a mean BMI of 22.8 (SD = 3.38), were recruited at a large northeastern U.S. university through sign-up sheets in seven large classes in fields outside of psychology and nutrition. In exchange for participation, students received extra credit and their name was entered into a drawing to win an iPod. The study had Institutional Review Board approval, and participants were treated in accordance with American Psychological Association guidelines.

Procedure and Materials

To determine what foods would be ambiguous enough to be considered either meal or snack foods, a focus group of 120 participants rated 36 foods regarding how they perceived them as snack versus meal foods on a 9-point scale (1 = snack; 9 = meal). We used three foods that were uniform in size, could be discretely counted, and that fell in the middle of this range: quesadillas (4.04), pizza (5.35), chicken wings (4.81). To examine what cues individuals associate with a specific type of eating occasion, a pilot survey asked the same pool of participants the extent to which they associated 20 different factors (ceramic plates, seating arrangements, paper cups, plastic silverware, cloth napkins, and so on) with meals and snacks[8].

To examine whether the presence of these meal-related cues was stronger than the influence of time, four study sessions were conducted at a time traditionally associated with meals (12:00) and one at a time typically associated with snacks (3:30). After assessing their availability, participants were allocated to either a 12:00 or 3:30 session. Participants were randomly assigned to either a meal-cue condition or to a snack-cue condition at both times. An average of 30 participants were scheduled for each session. Participants were given a nametag and told it was to promote socialization.

In the meal-cue condition, participants walked into the room where the tables were already set with place settings that included a ceramic plate, a drinking glass, and silverware wrapped in a cloth napkin. After participants were seated and had an opportunity to socialize, they were told that they could then serve themselves from the buffet at their leisure, and that they could take as much food as they would like. In addition to water and diet soft drinks, three target foods were served (quesadillas, pizza, and chicken wings). While participants selected their food, researchers unobtrusively recorded how many pieces of each food were taken. After participants finished their food, and after a sufficient amount of socializing had occurred (consistent with the cover story), they were given a questionnaire to complete. Following this, they were thanked, debriefed, and dismissed. After leaving, any of the three foods remaining were separately weighed. Participant’s total caloric intake was calculated by taking the difference in weight between what they served themselves and what remained.

The procedure in the snack-cue condition was identical except that the setting was altered to promote snack-like environmental cues. The dinnerware (plates and napkins) were paper, the utensils and glasses were plastic, and there was no place for participants to sit until after they finished eating.

In the questionnaire, participants were asked to estimate the total calories they believed they ate. They were then asked to indicate how much of each food they took on a 9-point scale, (1 = not very much; 9 = a lot). Satiety was measured by a two-item 9-point scale (“I couldn’t eat another bite of food” and “at this moment I feel full”), which were combined into a single index of satiety given high reliability (a = .73). They then indicated how meal-like or snack-like they felt the foods they ate during the experiments were (1 = more of a snack; 9 = more of a meal). Last, they were asked how long since they had eaten their last meal along with demographic and anthropometric questions (gender, age, weight, and height).

Results and Discussion

Because there were no significant main effects or interactions with gender, age, and BMI, analyses were collapsed across those variables. There was a marginally significant main effect of the time of experiment (noon versus 3 p.m.); participants who participated in the noon sessions ate directionally more than those in the 3 p.m. sessions F (1, 118) = 2.97, p = .09. However, because this main effect was only observed on their actual food intake, and because the interaction effects between this and the experimental manipulation did not reach conventional level of significance (p = .15), analyses were collapsed across the time of experiments. This factor was subsequently treated as a covariate in the analyses.

The Impact of Meal-Related Cues on Intake

As expected, an analysis of covariance (ANCOVA) in which the independent variable was the experimental condition (a dichotomous variable; meal-cue versus snack-cue) and the covariate was the time of experiment, demonstrated that participants in the meal-cue condition were more likely to report that the food they ate was a meal (M = 3.91, SD = 2.08) than those in the snack-cue condition (M = 3.13, SD = 1.73), F (1, 110) = 4.45, p = .04, .2 = .04. As indicated in Table 1, the meal-cue participants’ actual caloric intake was significantly greater (M = 531.79, SD = 246.92) than the
snack-cue participants’ (M = 416.39, SD = 192.92), F (1, 119) = 7.62, p = .007, .2 = .06, and they also reported eating more (all ps < .05). Despite eating more and reporting they ate more, there were no differences in their perceived level of satiety (p = .98).

How Meal versus Snack Perceptions Mediate Intake

To examine if these differences in food intake were mediated by participant’s perceptions of an eating occasion being a meal or a snack, a series of multiple regression analyses were conducted to determine if the strength of the association was reduced after controlling for the participants’ food perception [9]. First, we predicted each dependent variable from (a) the experimental condition (a dichotomous variable; meal-cue versus snack-cue) and (b) the time of the experiment (a dichotomous variable; noon versus 3:30 p.m.) as a controlling factor. Second, we predicted participants’ perception of the foods they ate from (a) the experimental condition and (b) the time of the experiment, as in the first step. Third, we predicted each dependent variable from (a) the experimental condition (b) the time of the experiment, and (c) their perception of the foods, to see if the experimental condition was still a significant predictor for the dependent variable.

These analyses revealed that the participants’ meal perception partially mediated the association between the environmental cues and the actual total food intake, whereas it did not mediate the associations with other variables (such as estimated total food intake). Specifically – as needed for evidence of mediation – the significant main effect of the experimental condition in the first step, ß = .243, t (119) = 2.76, p = .007, was not significant in the third step, ß = .143, t (109) = 1.58, p = .12 (see Figure 1). However, because a Sobel test indicated that the mediational role of the meal perception was marginally significant, Z = 1.756, p = .08 [10], we are reluctant to conclude that the perception accounted fully for the original association between the condition and food intake. Nevertheless, in addition to conceptually replicating Pliner and Zec’s findings [5], the present study showed tentative evidence of the mediational role of the perception between environmental cues and food intake.

The Moderating Influence of Hunger

Last, to determine if the association between the experimental condition and participants’ actual food intake was moderated by their hunger, operationally defined as the length of time since they had eaten their most recent meal, we conducted a multiple regression in which we predicted participants’ actual food intake from (a) the experimental condition, (b) their hunger (i.e., the length of time since they had eaten last meal), (c) the time of the experiment as a controlling factor, and (d) a condition x hunger interaction term. In this analysis, we mean-centered the scores that went into these terms by subtracting the appropriate mean from each predictor (i.e., each main effect) before computing the interaction terms [11]. This analysis revealed that there was a significant interaction effect between the experimental condition and their hunger, ß = .217, t (117) = 2.30, p = .02. As indicated in Figure 2, simple slopes tests demonstrated that participants who were hungry (+1 SD above the mean) consumed much more food when surrounded with meal cues, ß = .487, t (117) = 3.73, p < .001, than did those who were not hungry (-1 SD below the mean), p = .72. Thus, part of the impact that these effect of environmental and situational cues have on a person’s food intake depends on their hunger.

Thus, consistent with general findings of the relationship between cognition and deprivation-reducing behavior [6, 7], the significant impact of hunger confirms the role of motivation as a moderator. That is, the influence of environmental cues on eating behavior was observed only among participants who were hungry. This was further confirmed by an additional finding that the association between the experimental condition and participant’s satiety was also moderated by hunger, ß = .005, t (117) = 2.89, p = .005. Simple slopes tests revealed that hungry participants were more satisfied when they were in the meal-cue condition, ß = 1.296, t (117) = 2.17, p = .03, than in the snack-cue condition. This could be because hungry participants were satisfied because they could eat more. Indeed, controlling for their actual intake reduced the association, ß = 1.048, t (116) = 1.66, p = .10, suggesting that intake mediated the association between the experimental condition and their satiety. In contrast, those who were not hungry were actually less satisfied when they were in the meal-cue condition, ß = -1.244, t (117) = -2.18, p = .03, which is virtually unchanged after controlling for their actual intake, ß = -1.267, t (116) = -2.22, p = .03.

Conclusions

Evidence is accumulating to suggest that specific meal and snack patterns influence overall food consumption, nutrient intake, and diet quality [2, 12-14]. For example, Kerver et al. found that people who ate three meals per day (breakfast, lunch, and dinner) had higher intakes of micro-nutrients such as calcium, vitamins, and folic acid than those who skipped breakfast or lunch. On the other hand, breakfast or lunch skippers who ate more than two snacks had higher intakes of energy on average than those who ate three meals, suggesting that eating snacks contributes to higher consumption of energy and lower quality diets [13]. It is important to note, however, that whether a person perceives an eating occasion as a meal or a pre-dinner snack could influence what and how much they eat, and whether they decide to eat later [5]. This may be especially true for ambiguous foods such as finger foods (sandwiches, pizza, and so on) that can be perceived as either meal or snack foods.

The present study demonstrated that environmental and situational cues associated with an eating occasion could influence overall food intake. Regardless of the time of the day, people were more likely to eat ambiguous foods when they were associated with meal cues such as being seated at a table with a ceramic plate, a glass, and silverware wrapped in a napkin. Importantly, the present study reveals that the effect of these cues is intertwined with cognition and motivation. First, people were more likely to eat more of these foods by perceiving them as a meal rather than a snack. Second, the effect of the environmental cues on intake was only observed among those who were hungry. Thus, the present study not only addressed how perception of type of eating occasion mediates the association between environmental cues and food intake, but revealed that the impact of this association depended on hunger.

The first finding is particularly important in that it helps fill a research gap between the effects of environmental cues and eating behavior. Although there is substantial research evidence indicating that food intake is influenced by environmental and situational cues such as portion size [1], the role cognition plays in this relationship has not been well addressed. Although there are several potential psychological mediators between environmental cues and our food intake, the present study revealed that our perception of whether an eating occasion is a meal could play a role in the relationship.

This is not to say that people are normally aware that they eat more foods because they perceive them as meal [15]. Indeed, most evidence suggests that people are usually not aware of environmental or situational cues that influence their food intake [16, 17]. It seems that because our actual food intake is unconsciously influenced by the environmental cues surrounding an eating occasion, it is only partially mediated by our conscious perception of the eating occasion.

On the other hand, given the marginally significant Sobel test, there could be other mediators between the experimental condition and actual food intake. For example, participants in the meal-cue condition may have felt more comfortable while eating, which could also influence food intake. Future research should focus on those other mediators to more thoroughly examine the relationship between the environmental cues and food intake. More importantly, the experimental design of the present study does not exclude the potential reverse causal effect. Namely, participants may have been more likely to perceive the eating occasion as meal because they ate more. Indeed, the association between the experimental condition and participants’ perception of the foods was not significant after controlling for their actual total food intake, ß = .138, t (109) = 1.51, p = .13. However, a Sobel test indicated that the mediational role of the actual food intake was not significant, Z = 1.619, p = .11, suggesting that this reverse causality also lacked the evidence of full mediational role. Future research should also examine if the meal versus snack perception influences subsequent food intake. For instance, it may by useful to measure whether participants perceive an eating occasion as snack or meal before they start eating. If the meal perception still mediates food intake, reverse causality can be ruled out.

The general nature of these findings has practical implications. For instance, because people who are more likely to perceive an eating occasion as a snack tend to eat less, their overall calorie intake should be smaller than those who are more likely to perceive an eating occasion as a meal. This is consistent with evidence that eating several small meals is better than eating a few big meal to decrease calorie intake [18]. However, recall that breakfast or lunch skippers who ate more than two snacks had higher intakes of energy, but lower quality diets with respect to nutrient intake [13]. The present study may suggest that those types of people tend to eat less when they perceive an eating occasion with ambiguous foods as snacks rather than meals. However, they could have subsequently eaten a full meal afterwards because they believed the snack was not enough or did not “count” as a real meal, as suggested by other studies [5]. For instance, if an individual perceives the sandwich and brownie they eat at a 5:30 reception as a snack, he or she may be more likely to follow this up with a pizza for a 7:30 dinner. This pattern can lead to substantial energy intake. Based on our findings, one possible way to prevent this is to associate those ambiguous foods with meal cues. For instance, if one eats sitting down during the reception, they may perceive it to be a meal, thus pre-empting their belief that they
need to eat the 7:30 pizza.

The second finding – the moderating influence of hunger – is also important because it shows that the effect of environmental and situational cues on food intake is particularly pronounced among hungry people. In other wors, people are less likely to be influenced by environmental cues in an eating setting if they are not hungry. This is conceptually consistent with previous findings suggesting the moderating role of motivation in the relation between the priming and drinking behavior [6, 7]. After all, regardless of whether a person perceives a sandwich and a brownie as a meal or a snack, they need to have the physiological drive – the appetite – to consume it. We interpret this result with caution, because we relied on participants self-report of time since last meal as a proxy measure of hunger. However, the fact that hungry participants consumed a similar amount of food as those who were not hungry when they were in the snack-cue condition has a particularly important implication for reducing and preventing overeating. Given the fact that subtle environmental and situational cues influence how much people eat, changing those cues may lead to reduction in overall food intake [1, 19]. As suggested in the present study, asking people to eat foods while standing may reduce consumption by cutting a snack-like environment. This reduction in consumption may reduce overeating as long as people do not compensate at a later time.

Competing interests

There is no conflict of interest including financial competing interest.

Authors' contributions

MS has contributed to the analysis, interpretation, and drafting the manuscript. CRP has contributed to the design, collection, and revising the manuscript. BW has contributed to the design, collection, and interpretation of data and revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Special thanks to Julia Langer, Lenny Vartanian, Sandra Cuellar, and Kate Abowd for their contributions to this research.

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11. Aiken LS, West SG: Multiple regression: Testing and interpreting interactions. Newbury Park, Sage 1991
12. Gatenby SJ: Eating frequency: Methodological and dietary aspects. Brit J Nutr 1997, 77(Suppl 1):7-20
13. Kerver JM, Yang EJ, Obayashi S, Bianchi L Song WO: Meal and snack patterns are associated with dietary intake of energy and nutrients in US adults. J Am Diet Assoc 2006, 106:46-53
14. Longnecker MP, Harper JM, Kim S: Eating frequency in the Nationwide Food Consumption Survey (U. S. A), 1987-1988. Appetite 1997, 29:55-59
15. Nisbett R, Wilson T: Telling more than we can know: Verbal reports on mental processes. Psychol Rev 1977, 84:231-259
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17. Wansink B, Painter JE, North J: Bottomless bowls: Why visual cues of portion size may influence intake. Obes Res 2005, 13:93-100
18. Jenkins DJA, Wolever TMS, Vuksan V et al. Nibbling versus gorging: Metabolic advantages of increased meal frequency. N Engl J Med 1989, 321: 929-934.
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© 2010 Shimizu 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.

by EricT

They Are Not Smarter Than You: Facts, Knowledge, and Reasoning Skills

Wed, 18 Aug 2010 22:52:51 +0000

Never assume that your “authority figure” is smarter than you. I constantly see trainees accepting everything a certain person says because they simply feel that they are not smart enough to apply any thought to it so they must simply absorb it as gospel.

I was looking around for Mel Siff items on the internet and came across Tony Gentilcore’s “Resource Page”. After the entry on Mel Siff’s book “Facts and Fallacies of Fitness” Gentilcore wrote:

“Mel Siff is smarter than you, and here is why. This book will serve as your "ammo" for any nimrod who thinks they know what they’re talking about.”

Now, Gentilcore is just being smarmy as he is apt to do. I mean what do you expect? He’s around 18 or so. But this attitude is a very typical and very real one. Logically if Mel Siff is smarter than you then you cannot hope to understand what he says enough to use it as “ammo”. So the real message here seems to be the typical one. Memorize and regurgitate everything he says to the “nimrod” you disagree with. The “nimrod” may well be wrong but if he takes the time to frame his arguments based on his best knowledge and critical thinking while you just repeat "facts" you’ve read…guess who is smarter? I’ll give you a hint…it ain’t you.

Facts and Knowledge

So, the key words in that last paragraph are "facts" and "knowledge". They are not the same thing. There is an easy way to instantly differentiate the two. Facts don't change very often; knowledge does.

The fact is that many people who would like to frame themselves as experts read books such as Supertraining and Science of Practice of Strength Training and then water it down and regurgitate isolated bits of it without any real understanding of the material. They have the books yet they are still nimrods. These books are meant to be interpreted. Books are instruments of knowledge not knowledge itself! These people have misunderstood the difference between data, facts, "truth" and knowledge.

I'm going construct (fancy for "make up") a scenario to illustrate the difference between fact and knowledge. A big thanks to John Denker's "Truth in Contrast to Knowledge" for helping me make this up. I will start with a fact:

The biceps brachii muscle is a flexor of the elbow joint.

That, folks, is a fact. I can state without any reasonable degree of doubt the the biceps flexes the elbow joint and that this has been "true" for thousands of years. This fact did not come about when the elbow flexor discovery man found out that the biceps brachii flexed the elbow. It was a fact way before that and will continue to be a fact while the elbow flexor guy rests in eternal peace, for ever and ever, amen.

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Let's assume that lots of people have checked and rechecked, verified and re-verified the findings of the elbow flexor discovery man and that it has been observed in many different circumstances that the biceps flexes the elbow. We hold it as fact. The fact hasn't changed. When this fact was discovered, however, our knowledge changed and now most beginning strength trainees know the fact that the biceps flexes their elbow. Or they darn well should know it! But even if only I knew it it would still be fact. Fact is, after all, fact.

So being aware of certain facts is part of our knowledge. But knowledge itself is much more far-reaching than a simple awareness of isolated facts. So let's look at knowledge. We can make different statements about the biceps brachii muscle based on the given fact:

The biceps brachii is an elbow flexor

Many people have observed that the biceps brachii flexes the elbow

The biceps brachii only flexes the elbow

At least one of the functions of the biceps brachii is flexion of the elbow joint

when someone does a dumbbell curl they will use the biceps brachii to flex the elbow

We've covered the first statement. It's a pretty good statement. The second as well. The third statement though is absolutely false. It sounds good to most people because it is so darn exact. However, we cannot conclude that the the only function of the biceps brachii is elbow flexion. Our knowledge of the facts cannot lead us to that conclusion (in this scenario). The first statement we can go around saying all the time and therefore make an assertion without any fear that next year we will turn out to be wrong and so have our career go down the drain.

The fourth statement is wishy-washy. Who likes a wishy-washy statement? Well, the person who wants to make use of valid reasoning and use of data should like a wishy-washy statement when it doesn't go too far like statement three does. In fact, of all five statements, statement number four is the most "scientific".

The fifth statement must be valid though, right? Wrong. First of all, we've assumed that a dumbbell curl is elbow flexion against resistance. We don't need to argue that. However, based on the simple fact that the biceps brachii is a known flexor of the elbow joint we cannot conclude that everyone who does a dumbbell curl will use the bicpes brachii to accomplish the movement. Could it be that there are other elbow flexors? If a persons biceps were destroyed or paralyzed could they still flex the elbow and thus perform a curl exercise? We don't know because we don't have enough data. We lack the facts. So we cannot assert that statement five is "true".

So part of knowledge is recognizing the limitations of facts. Let's say we want to know about statement five. It's not so easy. In fact it is downright difficult to ascertain the validity of that statement. You've got figure out a whole lot of other things about how the muscles and movements work and how they are controlled by the nervous system.

Is there more than one flexor of the elbow? Do these muscles work together? If so, can one muscle be "left out"? Also, if one muscle is paralyzed, can another muscle "take it's place? Or, if not, can remaining muscles be "re-educated" in some way to perform the movement? In short, can we say that EVERYBODY will use their biceps brachii if they perform a dumbbell curl? We cannot. Based on the one isolated fact that the biceps is an elbow flexor we cannot hold statement five as valid. We even lack data to make it reasonably less precise and so make it more valid.

Hypothesis

However, we could hypothesize statement five. If the statement is a hypothesis we are not saying it's true, we are saying that maybe it's true. Maybe it's not. We could even say, "it's probably true", and as long as we don't get precious about it it's still a hypothesis.

We want to avoid getting attached to our ideas. So a great way to handle statement five would be to immediately go a look for something that will make it invalid. Proving it would be very difficult indeed. But invalidating it in a way that it will never be an absolute assertion is easier. We could do research to look for well documented cases, for instance, of the results of paralyzed biceps brachii (and perhaps associated muscles) and the effects this has on flexion of the elbow. We may find case studies. Even one well documented case study, no matter how exceptional it may prove to be, is enough to disprove the hypothesis. Enough to make to make us abandon the general statement as it stands. By doing this we've also countered the oft repeated assertion that 'case studies are useless'. See, science isn't so mysterious after all.

On the other hand, perhaps a friend of ours tells us a story about his cousin Bob and how Bob lost the use of his biceps brachii but was able to, after a time, bend his elbow to some useful extent and even curl a dumbbell. This is anecdotal evidence. We cannot rely on this story. However, even this anecdotal evidence may encourage us to keep looking. After all, even though anecdotal evidence is unreliable it is not always "false". We keep looking and we find several well documented cases of people with a paralyzed biceps brachii who were able to regain elbow flexion. We could be reasonably sure that our hypothesis "when someone does a dumbbell curl they will use the biceps brachii to flex the elbow" is false. If you have a whole group of hypotheses related to the role of the biceps brachii in elbow flexion you may choose to remove this particular one.

But let's say we don't go around constructing hypothesis packages. We just wanted to see if that one statement was unreasonable, as we suspected it probably was. We've still begun to use so-called scientific-method. What's more we simply used a bit of reasoning and research. We didn't set up an experiment and we wouldn't have the means or the know-how to do so if we wanted to.

"The" Scientific Method

Now let's move on to another very likely scenario that goes on in fitness, bodybuilding, strength training and related forums every single day. Now we have abandoned the first scenario where we knew hardly anything about the biceps. But we still remember that we were able to discount statement five as being a valid assertion. Somebody states in a thread about dumbbell curls that dumbbell curls ALWAYS use the biceps brachii. You respond and say that it is unreasonable to assume that a dumbbell curl must always use the biceps brachii and it would be more correct to say that "the large majority of the time, a dumbbell curl will use the biceps brachii", or something like that.

Of course you wouldn't really make such a nit-picking statement but in the spirit of science you decide to nitpick a little. The original poster responds to you by saying, "prove it, where are the studies?", Which is the number one "unscienfific" response you will get to anything that has any claim to being a scientific assertion on a forum.

The poster has made the classic mistake of assuming that science is about studies being done to 'prove' things. When you say that his assertion is unreasonable you've hinted that you can disprove it. OR, cast serious doubt on it's validity. You've done the research. However, you have not experimented, or designed and executed some perfect example of the 'scientific method'. Yet you have engaged in science. The idea that research is something distinct from science is one of the most destructive ideas to real science out there. Your study of the literature to find examples that would serve to disprove a statement was research. Research is gathering information. The science is the "knowledge" that is gained from research. Observing, experimenting, gathering data, analysing data and studying literature are all research. What is science?

Science is knowledge. That is science is scientific knowledge itself. It is also a method or way of going about gaining knowledge. These are not the same thing but together they fall under the umbrella of the thing which we call "science". However, those who would like to confuse and befuddle us will insist that 'science is not a thing'. They would like you to buy the notion that the "act of carrying out science" is what science is. Others just like to say that science is a "method". Which is of course a thing.

We may say that biology, for example is "a science". We may also say that science is a "method of attaining knowledge". So biology is a topic we gather knowledge about but science itself is not the same thing as the areas it covers. However, since those who argue this use words like "knowledge" and "physical world", they are hopelessly confusing everyone who would like to learn stuff. The only people who are not confused are scientists because scientists don't walk around concerning themselves with "what is science?".

Since knowledge and the physical world cannot be placed into discrete little packages the very statement that "biology is a science" but "not science itself because science is a method" is one of those have your cake and eat it too moments. It's "a science" but it is not "science". To avoid such pretentious clap-trap, how about we say that biology is a category of science and that science is way of gathering, organizing, and categorizing knowledge of the physical world.

Unfortunately it has become in vogue to invoke the so-called 'scientific method' as being the same thing as 'science' and the strict definition of it. And while modern science uses much more rigid principles than the science of ancient times, that does not mean that science can be boiled down to a static cook-book recipe and that this recipe is "the scientific method'. The purveyors of such nonsense wish simply to pretend that they own the cookbook and you do not. When in fact there are many ways of gaining knowledge…it's just that some are better than others. In other words, they are saying that science is an activity and that by extension, only those with the cookbook can do it. While this may be a perfectly acceptable way to view science, it has no claim to being the only way to view it. There are many rules as to what science is NOT but there are few hard and fast rules as to what science is. That is, the more we try to rigidly define science so that we can lay claim to it while excluding others, the more we muddy it. Everyday, as a result, discussions on those forums I mentioned devolve from the discussion of science to the discussion of what science is or is not.

Do not take discussions about "the" scientific method seriously. There is not one "method" to science so if we take the term seriously we really don't get science. Knowledge can be gained in many ways and by many paths. "The" scientific method is as literal as "the" strength training method. Which is to say there is really no such "actual" thing.

"It seems to me that there is a good deal of ballyhoo about scientific method. I venture to think that the people who talk most about it are the people who do least about it. Scientific method is what working scientists do, not what other people or even they themselves may say about it."
- Percy by Percy W. Bridgman (From: Reflections of a Physicist, 1955)

We can say that knowledge and science is not simply absorbing pieces of information and then regurgitating it to beat down some "nimrod" you suspect to be engaging in "broscience". But the constant argument over science may just be putting the cart before the horse. The average student of strength training need not be armed with prodigious and complex knowledge in order to learn about strength training and be successful in doing it. And even those with prodigious knowledge will admit that their knowledge is, and will remain, woefully incomplete.

What you must not do though is fall prey to the feeling that since "science" is too complex and since the answers provided are not always concrete, then there is no use in bothering. I guarantee that even if you don't find the answers you are looking for you will find a lot of other things! And sometimes the answer is no answer. That's okay too.

We found a pretty good answer to our dumbbell curl question. So what is it that made that whole inquiry scientific as opposed to "following the scientific method" or any of the more pretentious ways to view science? We can list a few things about it:

The hypothesis was testable or checkable in some way.

For some statement to be a valid hypothesis it MUST be testable or checkable! This is one of easiest ways to distinguish science from nonscience. If there is no hope of ever being able to test something then it is not scientific.

This doesn't mean we experimented or went out and tried to directly observe people with paralyzed biceps. It means we simply looked for cases to disprove the hypothesis. That's checking. We just were able to do a lot less checking because we already suspected the statemet was too general to be useful. It's very hard to PROVE a general statement but to disprove one can be a very simple and straightforward process

We had preconceptions going in.

People often think that it is unscientific to preconceive. That is because they confuse preconceptions with bias. How can one not preconceive? It is actually more scientific of us to use our reasoning skills to give us clues as to the direction our research should take! Without "preconception" we'd be stuck on this simple problem for a lot longer than should be necessary. It's okay to preconceive..we have to conceive of a plan. That does not mean we will invent data when are preconceptions do not match our findings. We simply must not cling to our preconceptions for too long as they lead us down blind alleys.

We didn't use a cookbook "method"

We let the problem itself and our knowledge of the interconnected details lead us in the right direction. It would have been "unscientific" to simply take the statement at face value and scour Pubmed looking for "proof" of it!

We had a question and we LOOKED FOR AN ANSWER.

That is science. There are plenty of people that will try to tell you that it's not science, it's research. So it is!

The point is that science is the business of looking for the answers to questions. Endless discussions about what science is are not helpful because science is not like a horses mouth. That is, you can engage in endless debate about how many teeth a horse has, as scholastic monks of legend were once said to do, but the best way to find out is to go up to a horse, open up his mouth, and count his teeth. At no point will we be able to look science in the mouth. We used logical thinking. Or, better yet, we used what is nowadays called 'critical thinking'.

Arguments versus Assertions

How was what we did, in our scenario "logic" as opposed to many of the shenanigans people get up to on the net these days. Such as "drinking a gallon of milk a day will get you jacked"?

Well, that statement about milk is an assertion. Much like our assertion that the biceps brachii is a flexor of the elbow. The difference is that the milk drinking assertion will make you look like an idiot and the biceps assertion will serve you very well, with no decoration or qualification unless asked for. Assertions are different from arguments. Many pseudo authoritarian types go around making a whole lot of assertions but make very few arguments.

I used the word argument at the beginning of this post: "Logically if Mel Siff is smarter than you then you cannot hope to understand what he says enough to use it as “ammo”. So the real message here seems to be the typical one. Memorize and regurgitate everything he says to the “nimrod” you disagree with. The “nimrod” may well be wrong but if he takes the time to frame his arguments based on his best knowledge and critical thinking while you just repeat "facts" you’ve read…guess who is smarter? I’ll give you a hint…it ain’t you."

Going around quoting Mel Siff is simply making assertions of a type. That does not make you smarter than someone else. I am ASSERTING then, that taking the time to frame good arguments is smarter than just reading and regurgitating books. So what in the world is the difference between and argument and an assertion? An argument is a series of statements all connected up together so that you can come to a valid conclusion.

We can rest assured that nobody has ever constructed a logical argument around the proposition that "a gallon of milk a day makes you jacked". While deciding how to research our hypothesis about dumbbell curls and the biceps muscle, we used arguments without even having to think them out or write them down. Making arguments is part of logical reasoning. And we used logical reasoning to direct our inquiry. To be more specific, I'll construct an argument after the fact (yep, you can do that to, it's allowed). But first I have to explain the process.

An argument consists of propositions. These propositions are declarations or assertions and are called premises. The premises are used to come up with a conclusion. I am only concerned here with deductive arguments. In a deductive argument the conclusion is logically entailed by the premises. That is, the conclusion logically follows from the premises and if the premises are true then the conclusion must be true. However, and this is a big however, arguments do not have to be 'true', so when I say, "if the premises are true" I mean that should we assume that the premises are true. In this way, arguments are not said to be true or false but to be valid or invalid. All the premises can be untrue and the conclusion can be untrue but as long as the conclusion follows logically from the premises the argument is valid. So an argument is a form of reasoning.

Inductive Arguments

Before I go on, in the interest of thoroughness, the other type of argument that I hinted at above is an inductive argument. Inductive arguments are not a great way of making a point but we use inductive thinking all the time. It is not as useful as deductive reasoning but it is not entirely useless for every day decision making. But for critical thinking it is much more difficult to pin down just what a good inductive argument is and whether it is useful at all. A great example of an inductive argument comes from Bill Philips and Michael D'Orso in "Body for Life":

"Dumbbell training is inherently safe. I've never observed a torn muscle or any other serious injury resulting from the proper use of dumbbells."1

It so happens that that inductive argument is an absurd statement but it's still an inductive argument. Maybe a better one:

"When I deadlift I pay the utmost attention to quality. I constantly check my form. I have performed the deadlift thousands of times and I have very precise ways with which to progress the lift, warm up to the lift, and cycle the lift. Out of hundreds and hundreds of deadlift sessions I have only been injured once and this was due to a pre-existing back injury and not directly caused by the deadlift. I think it is improbable, therefore, that I will be injured when I deadlift today."

That is an inductive argument. I haven't even tried to say that it is "true" only that I am reasonably sure that it is probably true. One feature that makes inductive arguments much different from dedutive arguments is that inductive arguments can be improved by more premises. If I were to add that I was only using half my one repetition maximum and that I was sticking to sets of 3 with that weight I could state with even more confidence that I probably will not be injured. I'd also be wasting my time but you get the point…

Deductive Arguments

So inductive reasoning is not useless and if you are not willing to accept the need for some inductive reasoning then you may as well not train. Because when it comes to things like injuries and safety, most all arguments are inductive! Get used to it or don't bother. It would be nice if the practice of resistance training was so pat and neat that safety could consist solely of this type of argument:

1. Dropping heavy things on your foot will injure your foot

2. Forty Five pound weight plates are heavy.

Therefore, if you drop a 45'r on your foot you will injure your foot

That is a deductive argument. It does not even need to be for sure true that if you drop a heavy thing on your foot it will get injured. It is only necessary that the conclusion is necessitated by the premises and in this case it is. Therefore this is a valid argument. And it's probably a true one as well! You could use the scientific method to test it out. Let me know.

I said before that we used deductive arguments to help direct our inquiry into the dumbbell curl biceps question. Remember, this is just a scenario that I have made up, therefore I am making up the arguments as the type of reasoning that might have occurred. This does not mean you are confined to certain arguments. We may have used different reasoning and therefore different arguments had we both been trying to solve the same problem.

We started with a hypothesis, or statement, or whatever you want to call it, that we wanted to be able to discard because we suspected it was an unreasonable statement: "When someone does a dumbbell curl they will use the biceps brachii to flex the elbow."

The reason we thought the statement was unreasonable was because we found it to be too general. The reason we found it to be too general is because of our knowledge that elbow flexion, like most movements, is not confined to only one muscle. Therefore we used deductive reasoning to lead us to the conclusion that the statement was too general. Although we didn't think them out or write them down, we can think about the form those deductive arguments might have taken, as a thinking exercise. Then the conclusions themselves become the premises that lead us to our conclusion about the original statement. One such argument may be something like this:

1. If biceps brachii is but one flexor of the elbow joint, and

2. There are several other muscles which flex the elbow such as the brachialis and brachioradialisis muscles and

3. Muscles that serve the same function around a joint can substitute for other muscles which serve that function then

The statement that a dumbbell curl always uses the biceps brachii cannot be said to be certain.

Remember that our premises need not be true. In this argument the first two premises are true and the third one is "maybe true" but would need a whole other investigation to determine. But based on the three premises, the conclusion MUST follow. That is exactly the kind of thinking that would lead us to question the statement about curls and then go actively look for instances that support our proposition that it is an unreasonable statement because it is too general and absolute.

I chose the third premise for a reason, as it represents the kind of red herring that many of the people you will encounter use to play at science and logic without really understanding it. There is a very good chance that if you presented the above argument to a person to explain how you decided to disprove the dumbbell curl statement, your subsequent disproof would be ignored and instead you will be asked to "prove" statement three. When, in fact, statement three has nothing to do with your disproof of the original statement but is only part of a set of premises you used to bring you to conceive that the dumbbell curl statement was a little dumb.

Red Herrings and Raising the Bar

Upon explaining this, painstakingly, to your respondent, you are told, "how can you ignore muscle substitution? Are you saying it's unimportant? How can you call yourself a strength trainer when you don't even think it's important to discuss muscle substitution?" This very common argumentative fallacy, which is called a red herring, a grown up version of the thing you used to do to your teacher when you distracted her with irrelevant questions until the bell rung.

Red Herrings often give way to "raising the bar" which I usually call "moving the goal posts". This is especially juicy because of the differences between and argument and an explanation. The reason you told about the argument you used to direct your inquiry was not to make an argument but to offer an explanation. While an argument is a set of statements used as evidence to support the (logical) conclusion, an explanation is an attempt to make something comprehensible. It is about the why's and wherefore's. In this instance I described the argument that I used in order to show the operation or circumstances that led me to my investigation. Often times when we make explanations we are treated as if we are making arguments.

Arguments versus Explanations

There can be much overlap between argument and explanation. Both are rationales. We are attempting to describe the logic behind the things we reason out. The main difference between an argument and an explanation is that while an argument uses premises to support a conclusion in an explanation the conclusion is treated as already accepted and we are trying to explain why or how the "fact" of the conclusion exists. Arguments can be a part of an explanation, of course.

These things are much easier in subjects such as physics when there are very well established physical "laws" or principles. In training for muscular strength and performance, however, there are very few such easily applicable and dependable rules! Good "theories" for strength training would be "risky" theories. As we shall see, most of the grandaddy laws involve very little risk and there is no "case" which cannot be interpreted to fit them.

This has turned out to be such a long post I will have to save the rest for another part. The next part will be about rules, laws, and principles and I will say some stuff about the so-called seven laws of resistance training.

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Bibliography

1. "Deduction and Induction." Philosophy 103: Introduction to Logic. Web. 18 Aug. 2010. <http://philosophy.lander.edu/logic/ded_ind.html>. : full source reference

by EricT

The Impact of Zinc on Human Health: The Essential Toxin

Fri, 13 Aug 2010 22:29:13 +0000

By Laura M. Plum, Lothar Rink and Hajo Haase

Institute of Immunology, Medical Faculty,
RWTH Aachen University, Pauwelstrasse 30,
52074 Aachen, Germany

International Journal of Environmental Research and Public Health 2010

Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.

Introduction

In the periodic table of the elements, zinc can be found in group IIb, together with the two toxic metals cadmium and mercury. Nevertheless, zinc is considered to be relatively non-toxic to humans [1]. This is reflected by a comparison of the LD50 of the sulfate salts in rats. According to the Toxnet database of the U.S. National Library of Medicine, the oral LD50 for zinc is close to 3 g/kg body weight, more than 10-fold higher than cadmium and 50-fold higher than mercury [2]. An important factor seems to be zinc homeostasis, allowing the efficient handling of an excess of orally ingested zinc, because after intraperitoneal injection into mice, the LD50 for zinc was only approximately four-fold higher than for cadmium and mercury [3]. In contrast to the other two metals, for which no role in human physiology is known, zinc is an essential trace element not only for humans, but for all organisms. It is a component of more than 300 enzymes and an even greater number of other proteins, which emphasizes its indispensable role for human health. Optimal nucleic acid and protein metabolism, as well as cell growth, division, and function, require sufficient availability of zinc [4].

In this review, we will give a brief summary of zinc homeostasis, followed by a description of the effects of acute zinc intoxication and the consequences of long-term exposure to elevated amounts of zinc. Besides systemic intoxication, there exists evidence for a physiological involvement of endogenous zinc in toxicity on the cellular level, e.g., regulating apoptosis in many different cell types, and having a prominent role in neuronal death. In the end, we will also briefly discuss the detrimental effects of zinc deficiency, because, unless they are exposed to zinc in the workplace or by accident, healthy individuals are at far greater risk of suffering from the adverse effects associated with zinc deficiency than from those associated with intoxication.

Zinc Homeostasis

The human body contains 2–3 g zinc, and nearly 90% is found in muscle and bone [5]. Other organs containing estimable concentrations of zinc include prostate, liver, the gastrointestinal tract, kidney, skin, lung, brain, heart, and pancreas [6-8]. Oral uptake of zinc leads to absorption throughout the small intestine and distribution subsequently occurs via the serum, where it predominately exists bound to several proteins such as albumin, a-microglobulin, and transferrin [9].

On the cellular level, 30–40% of zinc is localized in the nucleus, 50% in the cytosol and the remaining part is associated with membranes [4]. Cellular zinc underlies an efficient homeostatic control that avoids accumulation of zinc in excess (see also Figure 1a). The cellular homeostasis of zinc is mediated by two protein families; the zinc-importer (Zip; Zrt-, Irt-like proteins) family, containing 14 proteins that transport zinc into the cytosol, and the zinc transporter (ZnT) family, comprising 10 proteins transporting zinc out of the cytosol [10].

The same transporter families also regulate the intracellular distribution of zinc into the endoplasmic reticulum, mitochondria, and Golgi. In addition, many mammalian cell types also contain membrane-bound vesicular structures, so-called zincosomes. These vesicles sequester high amounts of zinc and release it upon stimulation, e.g., with growth factors [11,12].

Figure 1. Cellular zinc homeostasis and its impact on cytotoxicity (A) Cellular zinc homeostasis is mediated by three main mechanisms. First, by transport through the plasma membrane by importers from the Zip-family, and export proteins from the ZnT-family. Second, by zinc-binding proteins such as metallothionein. Third, by transporter-mediated sequestration into intracellular organelles, including endoplasmic reticulum, Golgi, and lysosomes. Tight control of zinc homeostasis is required for maintenance of cellular viability, whereas deregulation leads to cell death. (B) A particular role in intracellular zinc homeostasis is played by the metallothionein/thionein-system. Free and loosely bound zinc ions are bound by the apo-protein thionein (Tred), to form metallothionein (MT). Elevated levels of free zinc ions can bind to zinc finger structures of the metal-regulatory transcription factor (MTF)-1, thus inducing the expression of thionein. Additionally, oxidation of thiols by reactive oxygen (ROS) or nitrogen (RNS) species triggers the formation of the oxidized protein thionin (Tox) with concomitant release of zinc.

Finally, metallothioneins (MTs) play a significant role in zinc homeostasis by complexing up to 20% of intracellular zinc (Figure 1b) [13,14]. MTs are ubiquitous proteins, characterized by a low-molecular weight of 6–7 kDa, high cysteine content, and their ability to complex metal ions. One MT molecule can bind up to seven zinc ions. Through different affinities of the metal ion binding sites, it can act as a cellular zinc buffer over several orders of magnitude [15]. Dynamic regulation of cellular zinc by MT results from the synthesis of the apo-form thionein (T) in response to elevated intracellular zinc levels by triggering the metal response element-binding transcription factor (MTF)-1 [16]. In addition, oxidation of cysteine residues can alter the number of metal binding thiols, connecting redox and zinc metabolism. An in-depth discussion of this complex subject can be found in a recent review [17].

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Exposure to Zinc

There are three major routes of entry for zinc into the human body; by inhalation, through the skin, or by ingestion [18]. Each exposure type affects specific parts of the body (Figure 2) and allows the uptake of different amounts of zinc.

Exposure by Inhalation

Inhalation of zinc-containing smoke generally originates from industrial processes like galvanization, primarily affecting manufacture workers. In addition, military smoke bombs contain zinc oxide or zinc chloride, making soldiers a group in which several cases of inhalation of zinc-containing fumes were described. For example, Homma and colleagues reported a case of two soldiers who developed adult respiratory distress syndrome (ARDS) upon exposure to a zinc chloride-containing smoke bomb [19]. The two men died 25 and 32 days after the accident, respectively. Another soldier was exposed to concentrated zinc chloride for several minutes during military training [20]. He also developed ARDS 48 h after exposure. After tracheal intubation and mechanical ventilation for eight days, he left the hospital, and four months after the incident he returned to work without any respiratory disorder [20]. There are a few additional reports of related incidents with smoke bombs having similar effects on the respiratory tract [21,22].

However, in none of the incidents there was unequivocal evidence that zinc was the main cause for the respiratory symptoms. Not only was no information about the concentrations available, but also the inhaled smoke contained several other ingredients besides zinc chloride. In addition, zinc chloride is generally caustic, so the effects could have risen from the specific properties of the compound, rather than being a direct effect of zinc intoxication.

The most widely known effect of inhaling zinc-containing smoke is the so-called metal fume fever (MFF), which is mainly caused by inhalation of zinc oxide. This acute syndrome is an industrial disease which mostly occurs by inhalation of fresh metal fumes with a particle size <1 µm in occupational situations such as zinc smelting or welding [23]. Symptoms of this reversible syndrome begin generally a few hours after acute exposure and include fever, muscle soreness, nausea, fatigue, and respiratory effects like chest pain, cough, and dyspnea [24]. The respiratory symptoms have been shown to be accompanied by an increase in bronchiolar leukocytes [23]. In general, MFF is not life-threatening and the respiratory effects disappear within one to four days [25].

Development of MFF is connected to the exposure level, but very little data is available concerning the zinc concentrations that trigger this syndrome [26]. Two volunteers developed MFF as a consequence of acute inhalation (10–12 minutes) of 600 mg zinc/m3 as zinc oxide [27]. Hammond and colleagues reported about workers who had shortness of breath and chest pain 2–12 hours following exposure to 320–580 mg zinc/m3 as zinc oxide [28]. Only small changes in forced expiratory flow were observed after exposure to 77 mg zinc/m3 (15–30 minutes) as zinc oxide [29]. Several reports of exposures to lower concentrations of zinc oxide (14 mg/m3 for eight hours, 8–12 mg zinc/m3 for up to three hours and 0.034 mg zinc/m3 for six to eight hours) did not result in symptoms of metal fume fever [28,30,31]. Today, the permissible exposure limit according to the Occupational Safety and Health Administration (OSHA) is 5 mg/m3 for zinc oxide (dusts and fumes) in workplace air during an 8-hour workday, 40-hour work week [32].

Figure 2. Comparison of the effects of zinc intoxication versus deficiency. Intoxication by excessive exposure to, or intake of, zinc (left hand side), and deprivation of zinc by malnutrition or medical conditions (right hand side), have detrimental effects on different organ systems. Effects that could not be attributed to a certain organ system or affect several organs are classified as systemic symptoms.

Dermal Exposure

Dermal absorption of zinc occurs, but the number of studies is limited and the mechanism is still not clearly defined. Agren and colleagues pointed out that the pH of the skin, the amount of zinc applied, and its chemical speciation influence the absorption of zinc [33,34].

In a study in which a 25% zinc oxide patch (2.9 mg/cm2) was placed on human skin for 48 hours, there was no evidence of dermal irritation [33]. In another study comparing the dermal effect of different zinc compounds in mice, rabbits, and guinea pigs, zinc chloride was clearly the strongest irritant, followed by zinc acetate, causing moderate, and zinc sulfate, causing low irritations. Consistent with the study by Agren, zinc oxide did not show any irritant effect on skin [35].

As mentioned above, zinc chloride is caustic, and the irritation does not necessarily indicate a toxic effect of zinc. In contrast to a potentially harmful effect of zinc on skin, it should be noted that zinc is a well-known supplement for topical treatment of wounds and several dermatological conditions [34,36-38]. Based on the existing data, it can be concluded that dermal exposure to zinc does not constitute a noteworthy toxicological risk.

Oral Exposure

Due to its nature as an essential trace element, oral uptake of small amounts of zinc is essential for survival. The recommended dietary allowance (RDA) for zinc is 11 mg/day for men and 8 mg/day for women [39]. Lower zinc intake is recommended for infants (2–3 mg/day) and children (5–9 mg/day) because of their lower average body weights [39]. This is significantly below the LD50 value, which has been estimated to be 27 g zinc/day humans based on comparison with equivalent studies in rats and mice [18]. In general, uptake of such an amount is unlikely, because approximately 225–400 mg zinc have been determined to be an emetic dose [40]. However, there is one published report of a woman who died after oral intake of 28 g zinc sulfate. After ingestion, she started vomiting and developed tachycardia as well as hyperglycemia. She died five days later of hemorrhagic pancreatitis and renal failure [41].

Immediate symptoms after uptake of toxic amounts of zinc include abdominal pain, nausea, and vomiting. Additional effects include lethargy, anemia, and dizziness [42]. Particular effects of excessive oral zinc exposure are discussed in detail below.

Gastrointestinal Effects

The gastrointestinal tract is directly affected by ingested zinc, before it is distributed through the body. Therefore, multiple gastrointestinal symptoms after oral uptake of zinc have been reported. Brown et al. described several cases in which high zinc ingestion resulted from storage of food or drink in galvanized containers. Ingestion was caused by the moderately acidic nature of the food or drink, enabling the removal of sufficient zinc from the galvanized coating. The resulting symptoms included nausea and vomiting, epigastric pain, abdominal cramps, and diarrhea [40].

In a study by Samman and Roberts, symptoms such as abdominal cramps, vomiting and nausea occurred in 26 of 47 healthy volunteers following ingestion of zinc sulfate tablets, containing 150 mg elemental zinc, for six weeks [43]. However, similar doses have been used in several other zinc supplementation studies without comparable side effects [44].

In addition to zinc sulfate, other zinc compounds like zinc oxide and zinc gluconate also have a similar impact on the gastrointestinal system [45-47]. A 39-year-old man showed nausea, vomiting, and abdominal pain six hours after ingesting 150 g of a 10% zinc oxide lotion, but without signs of systemic toxicity. Furthermore, he developed gastroduodenal corrosive injury. The symptoms persisted for three days and on the fifth day of admission, the corrosive injury showed regression without cicatrization [47].

Zinc-Induced Copper Deficiency

Taking up large doses of supplemental zinc over extended periods of time is frequently associated with copper deficiency [48-50]. This correlation seems to be caused by the competitive absorption relationship of zinc and copper within enterocytes, mediated by MT. The expression of MT is upregulated by high dietary zinc content, and MT binds copper with a higher affinity than zinc. Consequently, available copper ions are bound by MT and the resulting complex is subsequently excreted [51,52]. Oestreicher and Cousins stated that the dietary intake of different doses of copper and zinc did not significantly alter the absorption of the other metal, as long as they were given at the same ratio, irrespective if 1 mg/kg copper and 5 mg/kg zinc, or up to 36 mg/kg copper together with 180 mg/kg zinc were given [53]. Nevertheless, copper absorption is depressed when zinc is given in high excess over copper [54].

Frequent symptoms of copper deficiency include hypocupremia, impaired iron mobilization, anemia, leukopenia, neutropenia, decreased superoxide dismutase (SOD) (particularly erythrocyte SOD (ESOD)), ceruloplasmin as well as cytochrome-c oxidase, but increased plasma cholesterol and LDL:HDL cholesterol and abnormal cardiac function [55-57].

Furthermore, Irving and colleagues reported the case of a 19-year old woman who was supplemented with two doses of 50 mg zinc per day as part of a treatment of Hallervorden–Spatz syndrome, leading to a total daily intake of about 121.25 mg of zinc for more than 5 years, corresponding to approximately 15 times the RDA. Her daily intake of copper was 2 mg, which was approximately twice the RDA. As a result, she was markedly anemic and had severe neutropenia. Zinc-induced copper deficiency was confirmed by elevated serum zinc and low copper and ceruloplasmin serum levels. Four weeks after zinc therapy was stopped, all hematological and trace-metal parameters showed strong trends toward normalization and were normal after eight months [58].

Prasad and colleagues reported several cases of patients with sickle cell anemia who received 150 mg zinc/day and consequently showed low plasma copper, low ceruloplasmin, leukopenia, and anemia [59]. Another case report described a 31-year-old schizophrenic man who had been ingesting coins for 10 years [60]. He entered the hospital with symptoms including nausea, vomiting, and abdominal pain. Furthermore, profound anemia, neutropenia, and virtually absent serum copper and ceruloplasmin levels together with elevated zinc levels were diagnosed. Upon X-ray examination a large number of coins (totaling $22.50) were identified and surgically removed. Following the surgery, anemia and copper deficiency rapidly resolved. His copper deficiency was attributed to the ingestion of pennies, which since 1982 are composed of 98% zinc and 2% copper [60]. Several additional reports of zinc-induced copper deficiency leading to anemia and several other cytopenias were reviewed by Fiske and colleagues [55].

The mechanism by which copper deficiency induces anemia is based on the requirement of copper for several enzymes involved in iron transport and utilization and, therefore, in heme synthesis. For example, ceruloplasmin is a ferroxidase that binds copper and converts ferrous to ferric iron, allowing it to bind to transferrin and be transported. Cytochrome-c oxidase is also dependent on copper, and is required for the reduction of ferric iron to be incorporated into the heme molecule [61-63]. In addition to interference with heme synthesis, copper deficiency causes approximately 85% reduction of ESOD in the red blood cell (RBC) membrane, decreasing RBC survival time [64].

Whereas a recent meta-analysis found no general effect of zinc supplementation on serum lipoproteins [65], it may occur as a consequence of disturbed copper homeostasis. Copper deficiency is related to alterations of serum cholesterol levels [57]. In healthy men, a daily intake of 160 mg zinc/day decreased HDL cholesterol significantly [66,67]. Also, young women who ingested 100 mg zinc/day showed a reduction in HDL cholesterol [68]. A study with 24 men who were fed omnivorous diets that were deficient in copper (0.89 mg) and high in zinc (21.4 mg), i.e., a Zn:Cu ratio of 23.5, showed low plasma copper, ESOD and HDL cholesterol, while LDL cholesterol was elevated [69]. This study was stopped after 11 weeks because four participants experienced cardiac abnormalities. Klevay and colleagues fed one man an omnivorous diet providing a Zn to copper ratio = 16 for 105 days. Plasma copper and ceruloplasmin decreased, whereas total cholesterol and LDL cholesterol increased [70]. This experiment was ended when arrhythmia was detected. Taking into account several additional studies, Sandstead suggested that cardiac abnormalities were associated with Zn to copper ratios =16 [57].

Zinc Supplementation and Cancer

Whereas several other metals are well-known carcinogens, zinc is not generally considered to be a causative agent for cancer development. In contrast, displacement of zinc from zinc-binding structures, e.g., finger structures in DNA repair enzymes, may even be a major mechanism for carcinogenicity of other metals such as cadmium, cobalt, nickel, and arsenic [71].

One well investigated example in which an involvement of zinc in cancer development was suggested is prostate cancer. Notably, zinc levels in prostate adenocarcinoma are significantly lower than in the surrounding normal prostate tissues, suggesting an implication of zinc in the pathogenesis and progression of prostate malignancy [72-74]. This is based on a down regulation of the zinc transporter Zip1, which is responsible for zinc uptake and accumulation in prostate cells [75,76].

Men with moderate to higher zinc intake may have a lower risk for prostate cancer, but the opposite may be true at extremely high doses and long-term supplementation [77]. A study by Leitzmann and colleagues examined the association between supplemental zinc intake and prostate cancer risk among 46,974 U.S. men. During 14 years, 2901 new cases of prostate cancer were observed, of which 434 were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day did not cause a higher prostate cancer risk, whereas long-term supplementation with higher doses increased the relative risk 2.9-fold [78]. This increased risk may not be due to direct carcinogenicity of zinc, because it is known that immunosuppression significantly increases the incidence of cancer, and, as discussed in the following paragraph, high doses of zinc can be immunosuppressive.

Immunological Effects of Zinc

Sufficient availability of zinc is of particular importance to the immune system. Thereby, it plays a key role in multisided cellular and molecular mechanisms [79,80]. For instance, zinc influences the lymphocyte response to mitogens and cytokines, serves as a co-factor for the thymic hormone thymulin, and is involved in leukocyte signal transduction [81-83]. An influence of zinc excess on T cell function was observed in several in vitro studies. In cell culture, very high zinc concentrations (above 100 µM) in a serum-free culture medium stimulate monocytes to secrete pro-inflammatory cytokines [84], but actually inhibit T cell functions. In general, T cells have a lower intracellular zinc concentration and are more susceptible to increasing zinc levels than monocytes [85,86]. Also, in vitro alloreactivity was inhibited in the mixed lymphocyte reaction (MLC) after treatment with more than 50 µM zinc [87]. A similar inhibition was observed when the MLC was done ex vivo with cells from individuals that had been supplemented with 80 mg zinc per day for one week, inicating that zinc supplementation has the potential to suppress the allogeneic immune response at relatively low doses [88].

An in vivo study supported the finding that zinc excess can affect lymphocyte function. 83 healthy volunteers ingested 330 mg zinc/ day in three doses for a month. The treatment had a small but significant influence on the lymphocyte response to the mitogens phytohemagglutinin (PHA) and Concanavalin A (Con A). Interestingly, it was observed that zinc had an immuno-regulatory influence, i.e., it decreased the lymphocyte response in high responders and had an enhancing effect on low responders [89].

The Role of Zinc in Cell Death

In addition to the systemic toxic effects of zinc, this metal is also involved in the regulation of live and death decisions on the cellular level. First, we will discuss its role in apoptosis. Second, we will focus on an organ where zinc toxicity has been investigated in great detail, the brain.

Impact of Zinc on Apoptosis

The exact role of zinc in the regulation of apoptosis is ambiguous. A variety of studies indicate that, depending on its concentration, zinc can either be pro- or anti-apoptotic, and both, zinc deprivation and excess, can induce apoptosis in the same cell line [90-93].

The induction of apoptosis by high levels of intracellular zinc has been shown in different tissues and cell types [93-95]. Reports indicate that accumulation of intracellular zinc, either as a consequence of exogenous administration or release from intracellular stores by reactive oxygen species or nitrosation, activates pro-apoptotic molecules like p38 and potassium channels, leading to cell death [93,96-98]. Increased intracellular zinc levels may also induce cell death by inhibition of the energy metabolism [99,100].

Sensitive targets of zinc toxicity are the anti-apoptotic Bcl-2-like and pro-apoptotic Bax-like mitochondrial membrane proteins. In context of its apoptosis-inducing properties, zinc has been shown to increase the expression of Bax, leading to a decrease in the Bcl-2/Bax ratio [101]. As a consequence, dissipation of the mitochondrial membrane potential leads to the release of cytochrome-c from mitochondria into the cytosol [96,102-105].

The anti-apoptotic properties of zinc likely comprise two main mechanisms. First, zinc limits the extent of damage induced during oxidative stress, thereby suppressing signaling pathways resulting in apoptosis. Second, zinc directly affects several proteins and pathways that regulate apoptosis.

Consistent with the first issue, zinc deficiency has been shown to induce oxidative stress [106-108]. Mechanisms by which the redox-inert zinc protects cells against oxidative damage seem to include its property to protect sulfhydryl groups in proteins from oxidation [109]. Furthermore, by stabilizing lipids and proteins, zinc can preserve cellular membranes and macromolecules from oxidative damage. On the other hand, it has to be noted that elevated availability of zinc may also induce oxidative stress, and its impact on redox homeostasis may either be protective or promoting, depending on its availability [17].

With regard to the second mechanism, interaction of zinc with several apoptosis-regulating molecules has been reported. Zinc is a potent caspase-3 inhibitor [110] with an IC50 below 10 nM [111]. Furthermore, inhibition of caspases-6, -7, and -8 at low zinc concentrations was also shown, with caspase-6 being the most sensitive of the three [112].

Zinc deficiency can also induce apoptosis by disrupting growth factor signaling molecules such as ERK and Akt [113]. Other molecular targets for zinc are the anti-apoptotic Bcl-2-like and pro-apoptotic Bax-like mitochondrial membrane proteins. Zinc has been shown to increase the Bcl-2/Bax ratio, thereby increasing the resistance of the cells to apoptosis [114]. Consistent with this, in a study by Zalewski and colleagues apoptosis was induced in premonocytic cells by treatment with hydrogen peroxide. Supplementation with 1 mM zinc increased the ratio of Bcl-2 to Bax resulting in the inhibition of active caspase-3 and reduction of apoptosis [115]. Zinc-mediated apoptosis is abrogated by chelation with TPEN [116]. This is not undisputed, because it has also been shown in another study that zinc can increase the expression of Bax, leading to an decreased Bcl-2/Bax ratio and the release of cytochrome-c from mitochondria [101].

The influence of zinc on apoptosis is very complex and data are in part even contradictory. Amongst others, variables in this complex network are tissue and cell type, zinc concentration, expression of zinc transporters and zinc-binding proteins, other environmental circumstances like oxidative or nitrosative stress, and the involvement of multiple molecular targets with opposing functions.

Role of Zinc in Neuronal Death

A prominent and well investigated example for the control that zinc exerts on survival on the cellular level is the brain. This will now be discussed in more detail as an example of the mechanisms by which zinc can influence cellular survival.

Normally, homeostatic mechanisms should prevent zinc from accumulating in the brain to reach toxic concentrations as a result of excessive oral ingestion. However, there are reports of neurological symptoms following zinc intoxication, e.g., of a boy who showed lethargy and focal neurological deficits three days after he ingested 12 g of metallic zinc [117].

Many studies indicate that zinc acts as a neuromodulator [118-121]. On the other hand, experimental evidence indicates that endogenous zinc might be a relatively potent, rapidly acting neurotoxin, and, to a lesser extent, also a gliotoxin [122-126].

Zinc is stored in and released from vesicles in presynaptic terminals of a specific subset of neurons that also releases glutamate. Therefore, these neurons are defined as ”gluzinergic” neurons [119, 127]. Zinc can be released from presynaptic terminals during synaptic transmission, enabling it to enter postsynaptic somata and dendrites of cells via zinc-permeable ion channels [105]. These channels include NMDA (N-methyl-D-aspartate)-gated channels [128], voltage-gated calcium channels [129,130] and the calcium-permeable AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate channel [131,132].

In addition to being sequestered in vesicles of presynaptic terminals in the gluzinergic neurons, zinc can also be bound to MT, especially MT-III, in perikarya as well as being taken up by mitochondria [133]. The MT-III isoform is found only in the brain and it is abundant in the gluzinergic neurons [134,135].

Exposure to 300–600 µM zinc for 15 minutes results in extensive neuronal death in cortical cell culture [136]. Considering that neurons store high amounts of free zinc in their terminals [137] that are released upon depolarization [138,139], zinc may play an active role in neuronal injury. Furthermore, membrane depolarization, which is associated with acute brain injury [140], greatly increases the potency of zinc to act as a neurotoxin [141]. Weiss et al. confirmed this by showing that depolarization
with high concentrations (25 mM) of potassium media requires just a five minute-exposure to 100 µM zinc to kill all neurons in cortical cell culture [131].

Zinc has been described as a critical component of the excitotoxic cascade occurring after ischemia, seizures, and head trauma [141-143]. The first study providing evidence that zinc accumulation may play a role in the selective death of dentate hilar neurons after global ischemia in rats was done by Tonder and colleagues [144]. In the meantime, zinc accumulation in dying or dead neurons has not only been shown in the hippocampal hilar region, but also in all brain regions damaged in global ischemia such as hippocampal CA1, neocortex, thalamus, and striatum [145]. Consistent with the hypothesis that zinc-accumulation may lead to neuronal cell death, this event was prevented by the intraventricular injection of the zinc-chelating agent CaEDTA [145].

Zinc release and accumulation of zinc ions was also observed in a rat model of traumatic brain injury, where Suh and colleagues showed that trauma is associated with loss of zinc from presynaptic boutons and appearance of zinc in injured neurons. Again, neuroprotection occurred by intraventricular administration of a zinc chelator [146].

For some time, vesicular zinc was thought to be the only releasable pool of zinc in the brain [127]. This led to the assumption that the zinc ions accumulating in injured neurons must be entirely of presynaptic origin [127], but when ZnT-3 knock-out mice were investigated, which lack histochemically reactive zinc in synaptic vesicles, they still showed zinc accumulation in degenerating neurons, pointing toward sources other than synaptic vesicular zinc [147]. Alternative dynamic zinc sources might be MT-III as well as mitochondrial stores in the postsynaptic neurons [148,149].

Although zinc is redox-inactive in biological systems and exists only as a bivalent cation, there is evidence that zinc toxicity in neurons is mediated mainly by oxidative stress [141]. Zinc-induced cell death is associated with increased levels of reactive oxygen species in neurons [150,151]. In addition, free-radical-generating enzymes like NADPH oxidase are induced and activated by exposure to zinc [152]. Finally, zinc-induced cell death has been shown to be attenuated by various antioxidant interventions [96,153].

Besides oxidative stress, nitrosative stress can also affect zinc-induced neuronal injury. Nitric monoxide plays a crucial role in zinc toxicity by releasing zinc ions from MT [154], and inhibition of nitric oxide synthase significantly reduces zinc release from brain slices during oxygen and glucose deprivation [155]. Consistent with this, Frederickson and colleagues observed that nitric oxide also rapidly releases zinc from presynaptic terminals [156].

In addition to the impact of zinc on apoptosis discussed above, zinc-induced apoptosis in neurons might be based on two additional mechanisms. First, zinc-exposed neurons show an induction of the neutrophin receptor p75NTR and p75NTR-associated death executor (NADE) [157], a combination that can trigger caspase activation and apoptosis [158]. Second, high intracellular zinc concentrations trigger dysfunction of neuronal mitochondria, resulting in the release of pro-apoptotic proteins such as cytochrome-c and apoptosis-inducing factor (AIF) [148].

Although the release of intracellular zinc triggers neuronal apoptosis [96,159,160], indicators of necrosis such as cell body swelling and destruction of intracellular organelles have also been observed [96,150], indicating that zinc-induced neuronal cell death might encompass both apoptotic and necrotic mechanisms [143]. Taken together, alterations of neuronal zinc homeostasis have a profound influence on cellular survival during acute insults, and zinc chelators are discussed as potential therapeutic agents for the treatment of stroke [161].

It seems likely that zinc is also involved in neurodegenerative diseases, e.g., zinc and a deregulated zinc homeostasis could be important to onset and progression of Alzheimer’s disease [162]. Here, the use of metal chelators such as clioquinol to restore normal neuronal zinc homeostasis has shown promising results in vivo [163].

Zinc Deficiency

As discussed above, systemic zinc toxicity is not a major health problem. On the other hand, due to its essentiality, a lack of this trace element leads to far more severe and widespread problems. Both, nutritional and inherited zinc deficiency generate similar symptoms [164], and clinical zinc deficiency causes a spectrum from mild and marginal effects up to symptoms of severe nature (Figure 2) [165].

Human zinc deficiency was first reported in 1961, when Iranian males were diagnosed with symptoms including growth retardation, hypogonadism, skin abnormalities, and mental lethargy, attributed to nutritional zinc deficiency [166]. Later studies with some Egyptian patients showed remarkably similar clinical features [167]. Additional studies in the ongoing years manifested zinc deficiency as a potentially widespread problem in developing as well as in industrialized nations [168].

Severe zinc deficiency can be either inherited or acquired. The most severe of the inherited forms is acrodermatitis enteropathica, a rare autosomal recessive metabolic disorder resulting from a mutation in the intestinal Zip4 transporter [169]. Symptoms of this condition include skin lesions, alopecia, diarrhea, neuropsychological disturbances, weight loss, reduced immune function, as well as hypogonadism in men, and can be lethal in the absence of treatment [170].

Acquired severe zinc deficiency has been observed in patients receiving total parental nutrition without supplementation of zinc, following excessive alcohol ingestion, severe malabsorption, and iatrogenic causes such as treatment with histidine or penicillamine [165]. The symptoms are mostly similar to those arising during acrodermatitis enteropathica.

Some reports indicate the existence of another group of inherited disorders of zinc metabolism. They lead to baseline zinc plasma levels above 300 µg/100 mL, more than three times the physiological level, while iron and copper levels stay normal [171-173]. Even though this exceeds the amount normally found in serum after zinc intoxication, symptoms range from none to severe anemia, growth failure, and systemic inflammation, and resemble zinc deficiency rather than chronic or acute intoxication [172-175]. The elevated zinc levels have been attributed to excessive binding to serum proteins, e.g., by albumin [171,173], or to overexpression of the zinc-binding S100 protein calprotectin [172,174]. Hence, the large amounts of zinc in the serum of these patients are sequestered by proteins, potentially even depleting biologically available zinc [175].

Clinical manifestations of moderate zinc deficiency are mainly found in patients with low dietary zinc intake, alcohol abuse, malabsorption, chronic renal disease, and chronic debilitation. Symptoms include growth retardation (in growing children and adolescents), hypogonadism in men, skin changes, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, abnormal dark adaptation,
and anergy [165].

Moderate zinc deficiency can also occur as a consequence of sickle cell disease [176].
Hyperzincuria and a high protein turnover due to increased hemolysis lead to moderate zinc deficiency in these patients, which causes clinical manifestations typical for zinc deficiency, such as growth retardation, hypogonadism in males, hyperammonemia, abnormal dark adaptation, and cell-mediated immune disorder [177] connected with thymic atrophy [178].

In mild cases of zinc deficiency, slight weight loss, oligospermia and hyperammonemia were observed [165]. One population in which mild zinc deficiency occurs with high prevalence, even in industrialized countries, are the elderly. Here, a significant proportion has reduced serum zinc levels, and zinc supplementation studies indicate that this deficiency contributes significantly to increased susceptibility to infectious diseases [44].

The overall frequency of zinc deficiency worldwide is expected to be higher than 20% [179]. In developing countries, it may affect more than 2 billion people 166,180-182]. Furthermore, it has been estimated that only 42.5% of the elderly (=71 years) in the Unites States have adequate zinc intake [183]. This widespread occurrence combined with the variety of clinical manifestations makes zinc deficiency a serious nutritional problem, which has a far greater impact on human health than the
relatively infrequent intoxication with zinc.

Conclusions

Zinc is an essential trace element, and the human body has efficient mechanisms, both on systemic and cellular levels, to maintain homeostasis over a broad exposure range. Consequently, zinc has a rather low toxicity, and a severe impact on human health by intoxication with zinc is a relatively rare event.

Nevertheless, on the cellular level zinc impacts survival and may be a crucial regulator of apoptosis as well as neuronal death following brain injury. Although these effects seem to be unresponsive to nutritional supplementation with zinc, future research may allow influencing these processes via substances that alter zinc homeostasis, instead of directly giving zinc.

Whereas there are only anecdotal reports of severe zinc intoxication, zinc deficiency is a condition with broad occurrence and potentially profound impact. Here, the application of “negative zinc”, i.e., substances or conditions that deplete the body of zinc, constitute a major health risk. The impact ranges from mild zinc deficiency, which can aggravate infections by impairing the immune defense, up to severe cases, in which the symptoms are obvious and cause reduced life expectancy.

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152. Noh, K.M.; Koh, J.Y. Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J. Neurosci. 2000, 20, RC111.

153. Seo, S.R.; Chong, S.A.; Lee, S.I.; Sung, J.Y.; Ahn, Y.S.; Chung, K.C.; Seo, J.T. Zn2+-induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells. J. Neurochem. 2001, 78, 600-610.

154. Aizenman, E.; Stout, A.K.; Hartnett, K.A.; Dineley, K.E.; McLaughlin, B.; Reynolds, I.J. Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J. Neurochem. 2000, 75, 1878-1888.

155. Wei, G.; Hough, C.J.; Li, Y.; Sarvey, J.M. Characterization of extracellular accumulation of Zn2+ during ischemia and reperfusion of hippocampus slices in rat. Neuroscience 2004, 125, 867-877.

156. Frederickson, C.J.; Cuajungco, M.P.; LaBuda, C.J.; Suh, S.W. Nitric oxide causes apparent release of zinc from presynaptic boutons. Neuroscience 2002, 115, 471-474.

157. Park, J.A.; Lee, J.Y.; Sato, T.A.; Koh, J.Y. Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. J. Neurosci. 2000, 20, 9096-9103.

158. Mukai, J.; Hachiya, T.; Shoji-Hoshino, S.; Kimura, M.T.; Nadano, D.; Suvanto, P.; Hanaoka, T.; Li, Y.; Irie, S.; Greene, L.A.; Sato, T.A. NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR. J. Biol. Chem. 2000, 275, 17566-17570.

159. Lobner, D.; Canzoniero, L.M.; Manzerra, P.; Gottron, F.; Ying, H.; Knudson, M.; Tian, M.; Dugan, L.L.; Kerchner, G.A.; Sheline, C.T.; Korsmeyer, S.J.; Choi, D.W. Zinc-induced neuronal death in cortical neurons. Cell. Mol. Biol. 2000, 46, 797-806.

160. Manev, H.; Kharlamov, E.; Uz, T.; Mason, R.P.; Cagnoli, C.M. Characterization of zinc-induced neuronal death in primary cultures of rat cerebellar granule cells. Exp. Neurol. 1997, 146, 171-178.

161. Barkalifa, R.; Hershfinkel, M.; Friedman, J.E.; Kozak, A.; Sekler, I. The lipophilic zinc chelator DP-b99 prevents zinc induced neuronal death. Eur. J. Pharmacol. 2009, 618, 15-21.

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163. Sensi, S.L.; Paoletti, P.; Bush, A.I.; Sekler, I. Zinc in the physiology and pathology of the CNS. Nat. Rev. Neurosci. 2009, 10, 780-791.

164. Ackland, M.L.; Michalczyk, A. Zinc deficiency and its inherited disorders: a review. Genes. Nutr. 2006, 1, 41-49.

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hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am. J. Med. 1961, 31, 532-546.

167. Prasad, A.S.; Miale, A.J.; Farid, Z.; Sandstead, H.H.; Schulert, A.R. Zinc metabolism in patients with the symptoms of iron deficiency, anaemia, hepatosplenomegaly, dwarfism and hypogonadism. J. Lab. Clin. Med. 1963, 61, 537-549.

168. Sandstead, H.H. Zinc deficiency. A public health problem? Am. J. Dis. Child 1991, 145, 853-859.

169. Wang, K.; Zhou, B.; Kuo, Y.M.; Zemansky, J.; Gitschier, J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet. 2002, 71, 66-73.

170. Aggett, P.J. Acrodermatitis enteropathica. J. Inherit. Metab. Dis. 1983, 6, 39-43.

171. Failla, M.L.; van de Veerdonk, M.; Morgan, W.T.; Smith, J.C., Jr. Characterization of zinc-binding proteins of plasma in familial hyperzincemia. J. Lab. Clin. Med. 1982, 100, 943-952.

172. Fessatou, S.; Fagerhol, M.K.; Roth, J.; Stamoulakatou, A.; Kitra, V.; Hadarean, M.; Paleologos, G.; Chandrinou, H.; Sampson, B.; Papassotiriou, I. Severe anemia and neutropenia associated with hyperzincemia and hypercalprotectinemia. J. Pediatr. Hematol. Oncol. 2005, 27, 477-480.

173. Smith, J.C.; Zeller, J.A.; Brown, E.D.; Ong, S.C. Elevated plasmz zinc: a heritable anomaly. Science 1976, 193, 496-498.

174. Saito, Y.; Saito, K.; Hirano, Y.; Ikeya, K.; Suzuki, H.; Shishikura, K.; Manno, S.; Takakuwa, Y.; Nakagawa, K.; Iwasa, A.; Fujikawa, S.; Moriya, M.; Mizoguchi, N.; Golden, B.E.; Osawa, M. Hyperzincemia with systemic inflammation: a heritable disorder of calprotectin metabolism with rheumatic manifestations? J. Pediatr. 2002, 140, 267-269.

175. Sampson, B.; Kovar, I.Z.; Rauscher, A.; Fairweather-Tait, S.; Beattie, J.; McArdle, H.J.; Ahmed, R.; Green, C. A case of hyperzincemia with functional zinc depletion: a new disorder? Pediatr. Res. 1997, 42, 219-225.

176. Prasad, A.S. Zinc deficiency and effects of zinc supplementation on sickle cell anemia subjects. Prog. Clin. Biol. Res. 1981, 55, 99-122.

177. Prasad, A.S. Zinc deficiency in patients with sickle cell disease. Am. J. Clin. Nutr. 2002, 75, 181-182.

178. Dardenne, M.; Savino, W.; Wade, S.; Kaiserlian, D.; Lemonnier, D.; Bach, J.F. In vivo and in vitro studies of thymulin in marginally zinc-deficient mice. Eur. J. Immunol. 1984, 14, 454-458.

179. Wuehler, S.E.; Peerson, J.M.; Brown, K.H. Use of national food balance data to estimate the adequacy of zinc in national food supplies: methodology and regional estimates. Public Halth Nutr. 2005, 8, 812-819.

180. Cavdar, A.O.; Arcasoy, A.; Cin, S.; Babacan, E.; Gozdasoglu, S. Geophagia in Turkey: iron and zinc deficiency, iron and zinc absorption studies and response to treatment with zinc in geophagia cases. Prog. Clin. Biol. Res. 1983, 129, 71-97.

181. Cavdar, O.A. Zinc deficiency and geophagia. J. Pediatr. 1982, 100, 1003-1004.

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183. Briefel, R.R.; Bialostosky, K.; Kennedy-Stephenson, J.; McDowell, M.A.; Ervin, R.B.; Wright, J.D. Zinc intake of the U.S. population: findings from the third National Health and Nutrition Examination Survey, 1988–1994. J. Nutr. 2000, 130, 1367S-1373S.

© 2010 by the authors; licensee Molecular Diversity Preservation International, 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

Amplitude Of Movement, Law of Repetitive Motion, and Plyometrics

Fri, 13 Aug 2010 00:02:08 +0000

You may have heard trainers and coaches talk about movement amplitude. I often talk about amplitude as being one of those performance characteristics that determine the outcome of a training regimen and one of the factors indicating reductions or improvement in performance.

Amplitude is also part of the "law of repetitive motion" equation developed by Dr. Michael P. Leahy, who is the founder of Active Release Techniques (ART). This "law" is an equation describing the interaction between various parameters of human motion: I=NF/AR where:

I = Insult or injury to the tissues
N = Number of reps
F = Force (as a percentage of maximum strength)
A = Amplitude
R = Relaxation period (lets just say rest)¹

I doubt that Leahy was thinking of 400 pound back squats when he came up with that and I will not attest to it's right of title as "universal law" since it will break down depending on the type of movement (I'll get into that a bit later). For resistance training it also ignores interset rest which also greatly influences tissue recovery. Most trainees keep a fairly constant rate of repetition. That is the "rest between reps" is held fairly constant. Even small deviations in rate (or frequency) will tend to even out over time.

The equation translates: Tissue injury or insult is equal to the number of reps times the force applied divided by amplitude times relaxation period. This means that the greater the reps and force the greater the insult to the tissues. The greater the amplitude and rest the lower the insult to the tissues. Most trainees will get most of that. Except for amplitude. What the heck is that?

You might know a physics definition or even several different ways of looking at wave amplitudes. The best way to describe what amplitude is, to me, is to invoke a guitar string. Think of the resting position of the string as the "zero point". Now you pluck the string by pulling on it a certain distance and letting go. The string vibrates back and forth in a wave. The peak of that wave goes back to the point which is the distance you originally pulled it, but never beyond that point. The distance between that peak and the original zero point is the amplitude. This is the most common and basic way (I think) of looking at amplitude.²

The definition of amplitude changes depending on the system (e.g. sound wave, spring, pendulum, etc.) and what to measure is a personal choice but usually the distance is measured from the middle to the extremes. And the unit of measurement could change depending on the conditions. This is important in human movement since some movements would be more correctly measured as an angle rather than a distance.

image via wikimedia

In the above image of a wave diagram γ is the amplitude. See that it fits, more or less, my description. By the way, λ is the wavelength. The important thing to see is that amplitude is basically a distance measurement. It is important not to take this thinking to far because if you try to relate human movement to wave amplitude things get messy. The time it takes for one repetition becomes a "period" and a repetition itself becomes a cycle. We don't want that although there are a number of "strength scientists" around who would have no problem applying this type of jargon to strength training.

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So amplitude is, for human movement, range of motion or change in position, or even displacement of the implement in a resistance exercise. All three could work. The important thing to know is that it is most useful to measure amplitude as the extent of movement or displacement from a mean to the extreme range of a repetitive movement. A little imagination and you'll see that this leaves a lot open for interpretation. It gets tricky and that is why such pat little equations, although superficially useful, can never be universally applied. There are different types of amplitude where movement is concerned.

There is "external amplitude" which is the range of movement of the entire body relative to some external benchmark such as the ground or an apparatus such as a gymnastic apparatus. Then there is "internal amplitude" which is the range of motion of individual body segments or joints or their movement relative to each other.1

A very typical scenario during the progression of the squat, whether back squat, front squat, etc. is that while the load on the bar increases relatively quickly for a period of time the amplitude decreases. Amplitude is a very easy concept to understand in this case. The mean is the upright, standing or ready position. The amplitude is the total distance the bar moves from that starting point. The deeper the squat the greater the amplitude. This is only external amplitude though and ignores the movement of individual joints and body segements. Which means that even if external amplitude remains apparently constant, the range of motion may be borrowed from inappropriate joints. So it not only matters "how deep" one goes, but what point is measured. Even a squat with good and constant amplitude could be very stressful to certain tissues. For instance, only the bar travel is measured, and the apparent depth is actually lumbar flexion rather than a deep "knee bend" using full range of motion in the hips, knees, and ankles. So amplitude is NOT just one measurement and what we measure matters.

Amplitude of course is not the only consideration. It's one among many..but this post is supposed to be about describing amplitude so I'll attempt to contain myself.

Since the distance the bar travels in our scenario does not remain constant (assuming internal amplitude does) the amplitude does not remain constant. Since amplitude is part of performance then performance does not remain constant. Simple but largely ignored by most trainers.

Applying the "law of repetitive motion" to this works fairly well as a general guideline as we can see that the force applied is going up and the amplitude is going down. So the tissue stress theoretcially goes up (again, internal amp being contstant) And despite the very large forces involved the law should predict that resistance training, when performed with full range of motion and sensible volume, is less injurious to tissues than acitivities such as running. It does not make sense, in fact, to group resistance training under the same "law" as high impact activities. Plyometrics, for instance can involve forces even greater than strength training. Even simple jumping movements, such as jumping jacks, can impart ground reaction forces (GRF's) of 3 to 5 times body weight.2 Depth jumps must surely impart the greatest GRF's of any plyometric drill. How does amplitude affect these forces?

Looking at the amplitude of a depth jump, however, would yield different conclusions. A depth jump is a plyometric exercise where the trainee stands on a box of certain height and performs a vertical jump with a controlled landing while flexing the hips, knees, and ankles but controlling the torso, followed by an immediate vertical jump from the floor as high as possible.

The height of the box would be one possible measure of amplitude. The distance the shoulders move may be another. A higher box during plyometric depth jump increases the load on the body (which is extreme to begin with) and thus the potential for injury. The extra force must be attenuated during landing by increasing the amplitude of flexion involved. This increase in amplitude would by no means lessen the injury impact to skeletal tissues. During a plyometric movement there is only a certain range of amplitude that is useful because to much amplitude increases the force the athlete must overcome in order to reverse the movement. Too much force and the amortization phase is increased which may defeat the purpose of the exercise since the phase between the eccentric and the concentric must be kept short to take advantage of the stretch-shortening cycle. Suddenly the law of repetitive motion isn't looking so good. All movement isn't the same. Human movement is too complex to apply a simple little equation to.

However, we can still say that the amplitude of joint movement must be kept high or maintained in order to 1.) perform the movement correctly and with skill and 2.) decrease the chances of injury. Knowing this we can also keep in mind a few other parameters which influence movement amplitude:

Mobility and Flexibility

Mobility must be constantly maintained to ensure that movements can be performed fluidly and with full range of motion of the various joints. While there is some question as to this, for resistance training it is probably useful to posses a degree of mobility that is slightly greater than that which is required by the movement or lift. In other words, what Bompa referred to as a "flexibility reserve".3 However, I emphasize the word "slight" here. There is no need for hyper-mobility and for most this takes the form of an over-indulgence in either flexibility training such as static stretching or the prolonged indulgence in various contortions that have no relation to human peformance such as in some yoga practices.

Time of Day

Range of motion can vary depending on the time of day. This is especially true of lumbar range of motion with this effect being more marked in flexion range of motion than extension. The lumbar flexion range of motion increases throughout the day from morning to afternoon.4 And, in general, most people are more flexibile in the afternoon than in the morning.

The most oft cited data are observations by Osolin in 1971 which reported that range of motion was lowest in the morning and greatest between 10 and 11 Am and 4 and 5 PM, however subsequent observations have amplitude being greatest at different periods and most tests were done on specific body regions. The peak "suppleness" of your lumbar region may occur at a different time of day than your hamstrings. It would be extremely difficult to find good data but it is safe to say that your range of motion will increase throughout the day and begin to dip again after about 4 PM, which some wiggles in between and that the stiffness we all feel in the morning is not just a feeling but indicates much less range of motion than occurs slowly throughout the rest of the day. Diurnal variations in movement amplitude lend credence to the advice that one should train always at the same time of day, when possible. And this of course would apply to training specifically for mobility as well.

Law of Repetitive Motion and Resistance Training

A number of writers have attempted to meld the law of repetitive motion with resistance training. What the law brings to the student of strength training is the understanding that training injuries are more likely to result from cumulative trauma brought about by high volume weight training with low amplitude. This is a valuable lesson since many trainers and trainees alike tend to assign heavy weight low volume resistance training to a higher risk category than high volume, moderate intensity training. While the acute risk of very heavy loads is greater the chronic risk of high volume training, as exemplified by the bodybuilding body part split, is much greater and most injuries are the result of chronic tissue overload.

However such a formula can be nothing more than a basic guideline when it comes to resistance training. Such a formula taken as "law" could lull a trainee into a false sense of security. It is much more applicable to continuous cyclic movements such as running than to the repetitive movements of resistance training. It is also important to realize that the bodies tissues do not only adapt to movement but also to static postures and positions held habitually for long periods of time.

Comments

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Bibliography

1. Alter, Michael J. "Ch. 19: Functional Aspects of Stretching and Flexibility." Science of Flexibility. Champaign, IL: Human Kinetics, 2004. 257. Print.

2. McKay H, Tsang G, Heinonen A, MacKelvie K, Sanderson D, Khan KM 2005 Ground reaction forces associated with an effective elementary school based jumping intervention. Br J Sports Med 39:10–14

3. Bompa, Tudor O., and Tudor O. Bompa. "Ch. 13: Speed Flexibility and Coordination Training." Periodization: Theory and Methodology of Training. Champaign, IL: Human Kinetics, 1999. 375. Print.

4. Ensink FB, Saur PM, Frese K, Seeger D, Hildebrandt J: Lumbar range of motion: influence of time of day and individual factors on measurements. Spine 1996 , 21:1339-1343

by EricT

Footnotes

Nutrition is Not a Top Ten Proposition

Mon, 09 Aug 2010 02:28:31 +0000

I'm going to give you three vegetables. You pick the best one.

Tomatoes
Green (Bell) Peppers
Spinach

Now I'm going to give you three more. Pick the best one again.

Green (Bell) Peppers
Spinach
Tomatoes

Would you like to do it again? I guess not.

The best vegetable in the first list is green peppers. Surprise! The best vegetable in the second list is spinach. If I had put okra in that list okra would have won. I loves me some okra. Fried okra. Okra inn soup. Gumbo. Yes sir. I even love the sort of slimy thing it's got going on.

I wasn't really trying to trick you. I was making a point. In the first food list I was aiming for total antioxidant content. Any antioxidant. Would you have guessed that if I had placed RED bell peppers in that list green peppers still would have won? Despite the colorful carotenes. That's right. If I was going for carotene and writing a list about "how to improve your eyesight" the red peppers would have been way at the top of the list! If I were to make a list like that, which I wouldn't.

In the second list I was aiming for calcium and magnesium content. So spinach wins the day. So which is more nutritious? It simply depends on your parameters and it is exactly why there does not yet exist a way to systematically rate food in terms of health and nutrition. Oh, believe me people are working on it. But it ain't easy. Foods are not magic health bullets. Green peppers, spinach, and tomatoes are all great vegetables. It would have been easy to make tomatoes win one too, wouldn't it?

The Humble Green Pepper
image by byrdiegyrl via Flickr

The point then is that top ten (or twenty) lists of the "best" vegetables or any other foods are not useful EXCEPT for the people who write them. And they write them because they know that "lists" are big hits on the webernet. It's web marketing 101. Make a list and they will come. And talk. Nutrition is not a top ten proposition. Eat your vegetables. Eat the ones you love. Hey..good news, romaine lettuce has more beta carotene than spinach. I heard you hate spinach but love the romaine!

Comments

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by EricT

Programs and Methods Versus Principles: Wave Loading and Interval Training

Sun, 08 Aug 2010 20:46:48 +0000

When is a program a program and when is it programming methodology? Easy. A program is a program when you are doing it exactly as it has been written or planned. And it is "programming methodology" when somebody spins it into one.

The question to ask about "principles" versus programs which which came first. We can use our experience with training to make many observations. While making those observations we may be using programs, or "routines". We can then take these observations and derive philosophies and principles. If the observations are sound and the conclusions we make from them are sound they will apply regardless of the programming methodology. In other words they will have a good chance of being generally true rather than just true if we use a particular way of programming.

Most such "theories", however, involve no risk because they simply cannot be refuted. Any instance can easily be "interpreted" to fit someone's philosophy or experience. In fact, this is a central problem with those who think that experience trumps knowledge. Each new experience is explained in light of the previous experience so that it doesn't matter if the experience base if five or three thousand. A narrow and prejudiced knowledge base informs each interpretation. But since the theories based on this experience cannot be refuted by any means, the theories are worthless. Theories must be testable. Therefore there must be an inherent risk!

It does not matter, though, once we have derived sound principles and philosophies, where they came from. Let me put that a different way. When you flip a light switch you know that an electrical current is coursing through the wire and making the bulb light up. It doesn't really "matter" to you whether Benjamin Franklin really stood out in a storm with a key tied to a kite. The electric light is the application and how the principles that govern that application were derived does not change anything. If on the other hand, electricity only 'worked' with lightning, then the Franklin with the kite story would be a lot more important. If we wanted power for our light bulbs we'd somehow have to harness lightning. If this were at all possible and practical.

Lightning in a bottle is exactly what you get with many training programs that claim to be in themselves part of a larger programming methodology.

We know that to gain strength we need a certain amount of stimulus. We then need to recover from that stimulus in a reasonable period of time. This is a generalizable concept. How much stimulus at any given time and therefore how much recovery is not contained within the concept. As soon as we define the amount of stimulus to apply and how to vary that stimulus, etc..we have moved away from principle into method. As soon as we put enough methods into a more or less comprehensive plan of training we have moved into programming. For the trainee doing that program to be able to derive some original principle from the program itself would be a feat of reverse engineering.

The thing about principles of training is that they point to many different possible directions. They are generalizable and fundamental rules that we use to help us make choices, among many possible solutions, for our training. Once we have made a choice we have an application or method. Something cannot be both a principle and an application! Even specific methods themselves can be based on more conceptual "methodologies".

So no matter how someone "spins" it for you, do not believe that programs are the same thing as "programming". They cannot be because they denote applied principles rather than principles themselves. The same thing applies to isolated "methods".

You can envision a principle and all the possible choices of methodologies and then methods as a branching tree with the principle being the trunk. This is a useful way of viewing it as we can then think of the impact of removing or cutting off branches or offshoots of branches. The closer you get to the trunk, the worse off the tree! In this way, we cannot cut the trunk without destroying the tree. Likewise, if we cut off a major branch close to the trunk we do a lot more damage than if we cut off a smaller branch along that trunk. This is of course assuming that the underlying principle, the trunk, is correct in the first place and this is just a simple visual model to apply to single principles.

A Word on Method and Principle

Before I move on I should point out that my use of the words "method" and "principle" are purposeful and deliberately used with specific connotations for this post. The words method and principle do not always have to have such distinct meanings and in fact the word method can be used to mean much the same thing as principle. For instance the term "scientific method" is more idiomatic and the method part of scientific method does not actually denote one specific rote or step by step process. Method in this case has more in common with an over-riding principle. Misunderstanding of this term, in fact, causes a huge misunderstanding as to what is science and what is not science. Here, however, the two words are used specifically and I hope without ambiguity.

Wave Loading and Potentiation

The perfect example is Poliquan's 1/6 Principle. Although Charles Poliquan tends to call most things he comes up with "principles", his method of doing waved sets is a more blatant example of confusing method with principle.

All ways of using waved sets rely on the phenomenom of post-activation potentiation. The following explanation of potentiation (or facilitation) is a cut and paste from the most recent GUS newsletter:

…For the layman's version it means that after lifting a heavy load your strength is "potentiated" a bit. The effect is residual so that right after you lift a heavy load you get this enhanced strength effect and repeated exposure makes this potentiation a semi-permanent state. Now we have one more reason why I PREACH about heavy loads.

Here is the more precise and complete explanation that I have taken from "The Singles Scene" by myself and Joe Weir (no point in rewriting it all):

"A nerve impulse arrives from at the NMJ (neuro-muscular junction). Ach (acetylcholine) is released into the synaptic cleft. This is excitation. Some stuff happens and what results is an action potential which travels the fiber to the muscle.

When Ach is released it excites the post-synaptic membrane of the connecting neuron, thus changing membrane permeability. If threshold for excitation is reached, the change in membrane potential between the two motor neurons increases the flow of positive charges into the cell and this is called the EPSP (excitatory post-synaptic potential). This EPSP must be at threshold for the neuron to discharge. But even if it is not the resting membrane potential is temporarily lowered and its tendency to fire is increased.

Basically the neuron’s potential to fire and thus stimulate its motor unit(s) is on more of a “hair-trigger”. It is less “inhibited” than it was prior to the beginning of a training session.

This results in both temporary changes during a workout and repeated exposure to very heavy lifting results in more permanent changes. This is part of the explanation for neural changes accounting for strength gains, especially early on."

The long-term effects of facilitation we need not concern ourselves with except to realize it is one of the ways in which the nervous system adapts to heavy lifting and thus how we grow stronger.

The short term and more immediate effects are what many so called "advanced" methods try to take advantage of. Waved sets or "wave loading" is the most famous "method" of taking advantage of this phenomenon.

So, PAP is the underlying principle and wave loading is one methodology that can be used to take advantage of this. And the wave loading methodology is used in many different ways, or specific methods. Poliquan's method is most similar to the 5/1 method except the single is performed first. Although I consider performing the single first, as in the 1/6 method, an improvement over performing the higher rep sets first, it is beyond me what is supposed to be magical about six reps as opposed to five and in fact it hardly matters if you do 4 or 5 or 6 or simple leave it open. It is simply simpler and 'cleaner' and therefore easier to implement for most trainees. The underlying rationale for WHY we use wave loading can change our expectations and utilization, though. This is another problem with principles as opposed to application. The principles point the way to something but the way to what? But I digress.

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Looking at our tree model, PAP (post-activation potentiation) is the trunk. Waved sets is one of several possible major branches (boughs). Poliquan's 1/6 principle is one of the lesser branches on the wave loading branch. It's a twig. I think if you have my tree visual firmly in mind you will have a hard time thinking of a twig as a principle! You will also see that hacking off the twig hardly makes a difference to the tree. It will stand strong and proud.

The kind of thinking behind this “principle” could lead a trainee to think that in order to take advantage of PAP 5 or 6 reps must be used and these must be preceded by singles using a certain intensity, etc. A basic understanding of of facilitation, however, and some critical thought, would lead the trainee to understand that this is not a predictable phenomenon and any wave loading technique is simply a way of organizing one's training to try to make the most of the facilitation effect of heavy loads, thus allowing the trainee to make the necessary logical leap that there must be many other ways by which this phenomenon could be addressed in one's training. The experimentation that could result would make for a much smarter and more successful trainee than one who simply follows rote methods without any thought as to their origins.

Interval Training

Here is a simple way to look at the underlying principle of interval training as given in "Exercise Physiology" by McArdle et al. Although you probably cannot run a "4 minute mile" it is very likely that you can run a mile in four minutes. To explain that, I'm saying that you cannot maintain the very high exercise intensity continuously for four minutes as only a few "world class" runners can do so. However, given intervals of recovery in between high intensity bouts of running, you may be able to complete a mile in four minutes of actual run time. If you tried to do it continuously you'd fail and would be unable to sufficiently recover from the attempt make any reasonable effort to try again. But if you space out your all out running with some "relief intervals" or cool down periods…suddenly a four minute mile is within grasp. That is, you've "run" for four minutes and gone a mile. You just haven't "run" continuously. You have done MUCH more high intensity work than you would have otherwise been able to do.1

This is the underlying rationale, or principle behind interval training. Specifically, you are relying on high energy phosphates as the primary source of energy during brief periods of high intensity. There is no appreciable build up of lactic acid and recovery is very quick during the relief or cool down periods. This rationale, again, is what underlies interval training but interval training itself is a method or class of training. There are of course many variables such as the actual intensity of the exercise, the duration, the length of relief intervals, and repetitions. The specific activity and conditions dictate how those variables are used. For example, you would not use the same interval lengths for uphill sprints as you would for running on the level. For interval training to make sense there must be a fairly narrow range of work to rest ratios. Otherwise sufficient recovery could not occur within intervals and the whole point of interval training would be lost.

As should be apparent from the theme of this post, rationales and principles are not popularized and are therefore not common knowledge. Specific methods and programs are. High Intensity Interval Training (HIIT) is a popularized method of interval training which involves short periods of high (at or above 80% V02 Max) or very high (above V02 max) followed by recovery periods appropriate to the intensity. There is nothing new about this idea and could be compared to any sprint interval but instead of being used to improve anaerobic or aerobic capacity this style of interval training has been hyped to the fat loss or bodybuilding crowd as "cardio" which has become synonymous with fat loss exercise.

Although HIIT proponents seem to have discounted any performance improvement from intervals and instead focus exclusively on the (much exaggerated) EPOC effect and and it's effect on energy substrate use (fat burning) during the post training period HITT does preserve the basic tenants of interval training. However, since the exercising public at large only understand interval training in terms of HITT and have no conception of the underlying principles of intervals in general, the door has been opened for the marketing of interval training methods that simply ignore these principles and thus the true benefits of intervals. A recent example is ShaunT's "Max Interval Training" which "turns interval training on it's head" by using long five minute periods of "high intensity" followed by very brief one minute relief intervals. If you have understood the rationale for intervals thus far, then you will understand that this "method" is nonsense. The cool down periods are much too short to allow sufficient recovery so that any true semblance of "high" intensity could not be maintained throughout the session.

Max Interval Training is an example of a common phenomenon when methods or programs are "improved" upon by individuals who lack a basic understanding of the difference between method and principle. Usually this results in simply "making it harder" rather than making it more efficient or effective for the goals at hand. Since the method is simply a brainless “tweak” of an existing exercise craze, any attempt to rationalize it would have to be based on the circumstance of training rather than any principle or rationale that came before. This is called a “spin”. It is inventing a set of rationales after the fact to explain the proposed results of the training and the reasons therefore for doing it.

Comments

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Bibliography

1. McArdle, William D., Frank I. Katch, and Victor L. Katch. "Ch. 21: Training for Anaerobic and Aerobic Power." Exercise Physiology: Energy, Nutrition, and Human Performance. Baltimore: Williams & Wilkins, 1996. 409-11. Print. : full source reference

by EricT

Is Excess Calcium Harmful to Health?

Sun, 01 Aug 2010 22:01:24 +0000

by Robin M. Daly and Peter R. Ebeling

Department of Medicine (RMH/WH), The University of Melbourne, Western Hospital, Melbourne 3011, Australia

Nutrients 2010

Most current guidelines recommend that older adults and the elderly strive for a total calcium intake (diet and supplements) of 1,000 to 1,300 mg/day to prevent osteoporosis and fractures. Traditionally, calcium supplements have been considered safe, effective and well tolerated, but their safety has recently been questioned due to potential adverse effects on vascular disease which may increase mortality. For example, the findings from a meta-analysis of randomized controlled trials (currently published in abstract form only)¹ revealed that the use of calcium supplements was associated with an ~30% increased risk of myocardial infarction. If high levels of calcium are harmful to health, this may alter current public health recommendations with regard to the use of calcium supplements for preventing osteoporosis. In this review, we provide an overview of the latest information from human observational and prospective studies, randomized controlled trials and meta-analyses related to the effects of calcium supplementation on vascular disease and related risk factors, including blood pressure, lipid and lipoprotein levels and vascular calcification.

Introduction

Maintaining an adequate calcium intake through dietary sources or supplements is widely regarded as a safe and effective strategy for the prevention and treatment of osteoporosis. In both postmenopausal women and older men calcium supplementation or increased dietary calcium through fortified milk has been shown to slow or prevent bone loss at common fracture sites such as the hip and spine [1-5]. It is likely that these positive effects on bone density translate into anti-fracture efficacy, as the findings from a recent meta-analysis of randomized controlled trials (RCTs) in adults aged 50 years and older reported that calcium supplementation or combined calcium and vitamin D supplementation reduced the relative risk of fractures by 12% [6].

At present, most dietary guidelines recommend that older adults and the elderly aim for a habitual total calcium intake (diet and supplements) of 1,000 to 1,300 mg per day. These requirements are based largely on data from calcium balance studies and the determination of the ‘maximal calcium retention’ or the threshold value at which balance does not further improve as intake increases [7]. However, recent data based on calcium intakes around predicted zero balance suggests that calcium requirements should be in the range of 741 to 1035 mg/d for healthy adults, regardless of age or sex [8]. While it is beyond the scope of this review to debate the specific merits associated with the determination of calcium requirements for adults, it is important to highlight that many elderly people do not obtain sufficient calcium through dietary sources alone. As a result, calcium supplements are widely recommended and have traditionally been considered a safe alternative to meeting calcium requirements. The most common side effects relate to bloating, constipation and more uncommonly, a slightly increased risk of kidney stones [9].

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Over the past two decades there has been a growing body of evidence to suggest that the use of calcium [13-19] or calcium-vitamin D supplements [10-12] may lead to a number of non-skeletal health benefits, including beneficial effects on cardiovascular disease (CVD) and related risk factors, type 2 diabetes, certain cancers and even mortality. For instance, several clinical trials and metaanalyses have reported that calcium supplementation may improve serum lipids concentrations [15-17] and blood pressure [18,19]. Based on these findings, one might expect that increased calcium would have protective effects on various cardiovascular endpoints, such myocardial infarction (MI), coronary heart disease (CHD) or stroke. However, there is emerging data from various studies (observational, an RCT and a meta-analysis) that long-term use of calcium supplements in healthy older adults, particularly women, may not be safe because it could have an adverse effect on cardiovascular outcomes [20-22]. Because ageing is also associated with an increased incidence of CVD, even a slight increase in adverse vascular events would be clinically important because it might counterbalance any beneficial effects of calcium supplements in preventing osteoporosis and fractures.

This review provides an overview of the latest evidence relating to the effects of calcium supplementation on vascular disease and related risk factors and associated mortality in the elderly. Several reviews have recently evaluated the impact of dairy foods on cardiovascular disease risk [23,24], and thus we will not focus on their potential effects. However, the general consensus from these reviews is that dairy food consumption is not associated with a higher risk of CVD.

Calcium Supplementation, Cardiovascular Disease and Mortality

There have been a number of large observational epidemiological and prospective studies which have investigated the association between calcium intake and calcium supplement use, and cardiovascular disease risk and related mortality in older women and men. Typically, the findings from these studies indicate either a neutral effect [25-27] or a modest protective effect of a high total calcium intake against vascular disease and even mortality [10,14,28]. With regard to the specific effects of calcium supplements however, most studies to date have reported a non-significant effect. For example, in a prospective study of 34,486 postmenopausal Iowa women aged 55–69 years followed for 8 years, the relative risk of ischemic heart disease (IHD) mortality was 0.67 (95% CI, 0.47–0.94) for women in the highest compared to lowest quartile for total calcium intake (diet + supplements) [14].

In contrast, for women (n = 56) taking >500 mg/d of calcium supplements there was no significant risk reduction [multivariate relative risk (RR) 0.88 (95% CI, 0.64, 1.23)] [14]. Similar non-significant findings with regard to calcium supplement use were reported in a 12 year prospective study in 39,800 men aged 40–75 years enrolled in the Health Professionals Follow Study [25]. In this study, the multivariate RR for developing IHD in the highest quintile of calcium supplement use (median 1000 mg/d) compared with non-users was 0.87 (95% CI, 0.64, 1.19); the RR for nonfatal MI and IHD were 1.02 (95% CI, 0.71, 1.46) and 0.61 (95% CI, 0.34, 1.10), respectively [25]. Two other large studies also reported that the RR of stroke was no different in men or women who received 400 mg/d or more of supplemental calcium compared with non-users [26,27].

Data from a small study of acute hip fracture patients showed that the use of prescribed calcium and vitamin D supplements post-fracture was associated with a 36% and 43% reduction in death in women and men, respectively, after 3 years [28]. Contrary to all these findings, a recent prospective study in 10,555 Finnish women aged 52-62 years who were free of coronary heart disease (CHD) at baseline and followed for a mean of 6.55 years, reported that women using calcium supplements (or calcium plus vitamin D) had a 24% increased risk of CHD compared to non-users [1.24 (95% CI, 1.02, 1.52)] [21]. It is somewhat difficult to explain these findings given that the average age of the women was 57 years, and those taking supplements had a lower BMI, were more often non-smokers or former smokers and had less diabetes and hypertension mortality than non-users.

Although there are no RCTs that have specifically evaluated the effect of calcium supplement use on CVD events or related mortality, a number of studies have pre-specified or performed secondary analyses to assess the effect of calcium supplementation on various cardiovascular endpoints, including MI, stroke, CHD, sudden death or their combination (Table 1). Of these, the findings from a recent preplanned secondary analysis of a 5-year RCT of 1471 healthy, elderly postmenopausal women who received calcium citrate (1,000 mg/d) or placebo has received the most attention because it has raised concerns about the cardiac safety for supplemental calcium [20].

However, an accompanying editorial highlighted that data from this study were not totally consistent, and thus must be interpreted cautiously [29]. In the analysis based on self-report and then adjudication by physicians (verified), those receiving calcium supplementation had a increased risk of MI (RR self report 2.24, p < 0.001; RR verified 2.12, p < 0.05) and the composite endpoint of MI, stroke or sudden death (RR self report 1.66, p < 0.01; RR verified 1.47, p = 0.08) [30] (Figure 1: omitted). When the authors then searched the New Zealand hospital database of hospital admissions to identify additional vascular events that might have been missed, no statistically significant differences were detected between the calcium and placebo groups for either MI [RR 1.49 (95% CI, 0.86. 2.57)] or the composite endpoint [RR 1.21 (95% CI, 0.84, 1.74)] [30] (Figure 1: omitted). However, rate ratio analysis revealed a trend for an increased risk of MI (1.67, p = 0.058) and the composite endpoint (1.43, p = 0.043).

These findings do not provide conclusive evidence, although surprisingly the authors maintain that ‘…there are reasonable grounds for doubting the safety of calcium supplements…’ and suggest ‘… there should be a reappraisal of their role in the management of osteoporosis…’ [31]. This view is not universally shared. Other investigators have raised concerns about various aspects of this study, including the relatively small number of vascular events and the wide confidence intervals, the borderline significance of many of the findings, and the failure to consider other important confounders, including serum 25-hydroxyvitamin D [32,33]. It is therefore critical that the results from other similar calcium supplementation studies be considered when evaluating the clinical and public health significance of these findings.

A summary of the key findings from the various RCTs that have evaluated the effects of calcium supplementation or combined calcium-vitamin D supplementation on cardiovascular related endpoints is presented in Table 1. In all these previous RCTs (with the exception of the Auckland study) there were no statistically significant adverse (nor beneficial) effects of calcium supplementation on CVD risk. For example, in an Australian study of 1460 postmenopausal women aged =70 years who were randomized to take calcium carbonate (1,200 mg/d) or placebo for 5 years, Prince et al. [3] reported that incident IHD was no different between the supplemented and placebo group [HR 1.12 (95% CI, 0.77,1.64)]. Similarly, secondary analysis of a 4-year RCT in 1179 postmenopausal women aged >55 years in the United States found no excess occurrence of MI or other vascular events in the calcium treated (1,400–1,500 mg/d calcium citrate or carbonate) compared to placebo group [34].

However, the participants in this study were ~10 years younger than the Auckland women. Despite this, it is intriguing that both these trials were similar to the Auckland study in terms of their design, study duration, number of participants and baseline calcium intakes (~850–1,000 mg/d), but failed to observe any significant adverse effects. In addition, the dose of calcium was less in the Auckland study (1,000 mg/d versus 1,200–1,500 mg/d). However, one possible explanation for the contrasting results may relate to the type of calcium supplements used. Women in the Auckland trial consumed calcium citrate, whereas calcium carbonate was used in the Australian study and carbonate or citrate in the US trial.

Calcium citrate has been reported to have superior bioavailability compared with calcium carbonate [35], and leads to a greater acute rise in ionized calcium concentration [36]. These findings, together with the fact that calcium carbonate must be taken with meals, may be one explanation for the contrasting results. Differences in serum 25-hydroxyvitamin D [25OHD] levels may also be a contributing factor given that low vitamin D has been associated with an adverse cardiovascular risk profile and increased risk of CV events [37,38]. Serum 25OHD levels were not reported in the Auckland study, but in the Australian and US trials levels ranged from a mean of 67 to 72 nmol/L. When evaluating the potential adverse effects of calcium supplement use on vascular events and related mortality, it is also worth considering data from two of the largest trials [RECORD study and the Women’s Health Initiative (WHI)] that were designed to examine the effects of calcium carbonate and/or vitamin D on fracture incidence [39,41]. In both these studies, no significant overall effect of supplement use on cardiovascular event rates or mortality was observed [10,39,41].

The RECORD Study did not report vascular events, but there were no differences in death rates between calcium supplement users and non-users (17.7% vs. 16.2%) [39]. In the WHI trial involving over 36,000 postmenopausal women, the HR was 1.04 (95% CI, 0.92–1.18) for MI or CHD death [41] and 0.91 (95% CI, 0.83, 1.01) for total mortality [10]. There was a trend for an increase in a composite endpoint of MI, death from CHD, coronary artery bypass graft or percutaneous coronary intervention [HR 1.08 (95%CI 0.99–1.18)] [41]. A major limitation of this study is that over 50% of the women were using non-study calcium supplements. Interestingly, when the analysis was restricted to women not self administering calcium, there was a 17% significant increased risk of MI or coronary revascularization [HR 1.17 (95% CI, 1.01, 1.36)] [22]. However, in a subsequent study the authors reported that in women younger than 70 years of age, there was a trend toward a reduction in the risk of total, cardiovascular and cancer mortality in those receiving calcium plus vitamin D supplementation [10]. When interpreting these findings and those from the RECORD study, it is important to consider the use of vitamin D given the evidence that supplemental vitamin D may reduce cardiovascular disease risk and all-cause mortality [43]. Other potential important confounding factors must also be considered when evaluating the results of the WHI study, including non-compliance and the use of HRT.

Table 1. (forthcoming)

In light of the emerging concern that a high supplemental calcium intake may be associated with an increased risk for cardiovascular events, two recent studies have reviewed the available calcium supplementation RCTs that included cardiovascular endpoints [22,44]. Wang et al. [44] conducted a systematic review of prospective studies and RCTs that examined calcium supplementation, vitamin D supplementation or both on subsequent cardiovascular events. When the data from the RCTs were combined, the RR for CVD was 1.14 (95% CI, 0.92, 1.41) for calcium supplements versus placebo, and 1.04 (95% CI, 0.92, 1.18) for combined calcium plus vitamin D versus double placebo. There was also no significant effect of vitamin D supplementation on CVD [RR 0.90 (95% CI, 0.77, 1.05)] [44]. Based on these findings, the authors concluded that calcium supplements seem to have minimal cardiovascular effects, but a limitation of this study is that only a small number of trials were included in the meta-analysis.

A more recent and comprehensive meta-analysis included a larger number of trials (n = 15), with patient-level data available for five studies (n = 8151), and trial-level data for 11 studies (n = 11,921) with a mean follow-up of 4 years [22]. The inclusion criteria for this study were placebo controlled trials >12 months in duration with a calcium supplement dose >500 mg/d and at least 100 participants [22]. For participants allocated to calcium supplements, the HRs for MI were 1.31 (95% CI, 1.02, 1.67) and 1.27 (95% CI, 1.01, 1.59) for the patient- and trial- level data, respectively. This indicates that the use of calcium supplements was associated with an ~30% increase in cardiovascular disease risk. However, since these results are currently only available in abstract form, it is difficult to provide a more comprehensive evaluation of the methodology and study findings.

Calcium Supplementation, Lipids and Blood Pressure

If the use of calcium supplements is associated with an increased risk of cardiovascular disease, one might expect that other common cardiovascular risk factors, such as cholesterol, lipids and blood pressure, would also be adversely affected. Contrary to this hypothesis, the findings from a number of clinical trials have shown that calcium supplementation was associated with improvements in serum lipids concentrations, particularly in women [15-17]. This effect is reported to be due to the binding of calcium to fatty acids and bile acids in the intestines, which leads to a reduction in fat absorption [16,45]. It has also been proposed that a reduction in parathyroid hormone (PTH) and/or 1,25-dihydroxyvitamin D following calcium supplementation may lead to a decrease in intracellular calcium which reduces calcium flux into adipocytes [46].

This may then inhibit lipogenesis and promote lipolysis [46], leading to lower adiposity and thus favorable effects of lipid and lipoprotein levels. This proposed effect of calcium on adipocyte lipid metabolism, along with the reported pressor effects of calcium on vascular smooth muscle cells [47], may also explain the findings that calcium supplementation can lower the risk of hypertension. Results of several meta-analyses of RCTs indicate that calcium supplementation can lead to small but significant reductions in both systolic and diastolic blood pressure [18,19], with the greatest blood-pressuring lowering effects observed in those with the lowest baseline calcium intakes ( < 600–800 mg/d) before supplementation [19,48] and/or those who are hypertensive [49]. Based on these findings, it would appear that any potential adverse effects of calcium on cardiovascular endpoints are unlikely to be secondary to changes in either lipids or blood pressure.

Calcium Supplementation and Vascular Calcification

Vascular calcification is a marker of sub-clinical atherosclerotic disease, and an independent predictor of subsequent vascular morbidity and mortality in men and women, including CHD, CVD and mortality [50]. In patients with kidney disease, there is evidence from clinical trials showing that the use of calcium supplements is associated with increased vascular calcification [51]. For example, the results from a 12 month trial in 200 hemodialysis patients comparing calcium acetate or carbonate with a non-calcium based binder (sevelamer) showed that calcium supplementation lead to a more rapid increase in both coronary and aortic calcification [52]. In the Auckland Calcium Study, the authors speculated that the upward trends in cardiovascular event rates could be related to the age of the participants and their associated reduction in renal function [20]. The mean glomerular filtration rate (GRF) of the women in this study was 61 (SD 11) mL/min [31], which indicates that a portion of women had impaired renal function. In 90 pre-dialysis patients with a mean GRF of ~30 mL/min, supplementation with calcium carbonate for an average of 2 years resulted in a significant increase in coronary artery calcification (CAC), but these changes in total calcium scores (TCS) were not significantly different from controls (178 vs. 205) [53]. Therefore, it is questionable whether impaired renal function is a likely reason for the increased vascular risk in the postmenopausal women receiving calcium in the Auckland trial.

In apparently healthy older men and women, there are few studies which have investigated the effects of increased calcium on the progression of vascular calcification. Bhakta et al. [54] conducted a retrospective analysis in a subgroup of participants (n = 257) enrolled in the prospective Epidemiology of Coronary Artery Calcification study in Minnesota who were aged >60 years and had complete 4-year follow-up on aortic value calcification (AVC) as assessed by electron beam computed tomography (EBCT). In women, the progression of AVC or CAC over a mean of 3.7 years was no different between those who reported using calcium supplements (n = 25) and those who did not (n = 114); no men in the study reported using calcium supplements. Similarly, the findings from a 2year RCT involving 163 healthy men aged 57 ± 10 years who had taken 1200 mg/d of supplemental calcium or placebo revealed that supplementation was not associated with an increase in coronary calcification assessed by computed tomography (CT) [55].

In contrast, in a retrospective analysis of a 2-year RCT, we reported that supplementing the diet with calcium and vitamin D3 fortified milk (1,000 mg/d and 800 IU/d) may accelerate abdominal aortic calcification (AAC) measured by CT in older men, but only in those who presented with AAC prior to the commencement of the study [56]. In this subgroup of men, who had a mean dietary calcium intake at study entry of ~900 mg/d, the mean AAC scores increased significantly in the milk relative to control group [mean change (95%CI); 24 (7, 42); controls 6 (-5, 18), P < 0.05], independent of age, BMI, anti-hypertensive or lipid-lowering medication use, smoking, exercise or blood pressure [56]. It is difficult to explain these results given that there were no differences between the fortified milk and control groups for changes in weight, fat mass, blood pressure, lipids, serum calcium, GFR, fat or saturated fat intake. In addition, baseline serum 25OHD levels were ~75 nmol/L, and increased further following supplementation which might be expected to have a protective effect.

The development of vascular calcification is a complex process that is not only dependent on the physio-chemical effects of calcium and phosphate, but also on factors that can regulate the differentiation of smooth muscle cells to osteoblast-like cells; similar to those in osteogenesis. Potential mediators include both inhibitors [pyrophosphate; osteoprotegerin (OPG); osteopontin, matrix Gla protein (MGP), fetuin A, parathyroid hormone-related protein (PTHrP); fibroblast growth factor 23 (FGF 23)] and activators [phosphorus, calcium, alkaline phosphatase; bone morphogenetic protein 2, 1,25(OH)2D; osteocalcin; osteonectin; oxidized low density lipoprotein (LDL), advanced glycation end products (AGEs)] that regulate this process [51]. Previous research has shown that serum OPG, which inhibits osteoclast differentiation and activity and stimulates osteoclast apoptosis, is related to cardiovascular events [57], and the presence and/or severity of aortic calcification in patients undergoing haemodialysis [58] or those with peripheral vascular disease [59]. However, in 80 healthy older women from the Auckland Calcium Study, no differences were observed for the changes in serum OPG and MGP in women treated with calcium or placebo for 5 years [31].

Calcium Supplementation and Cerebrovascular Disease Risk

Some of the early work examining the relationship between calcium and cerebrovascular disease suggests that there may be a protective effect of calcium. For example, in an ecologic study of elderly people from the southwest of France, a high level of calcium in drinking water was associated with a lower risk of noncerebrovascular (10%) and cerebrovascular (14%) related death [60]. Calcification of vascular smooth muscle has also been associated with brain lesions, which are a marker of cerebrovascular disease.

In the elderly, there is some evidence that a high calcium intake is associated with brain lesions. Payne et al. [61] examined the relationship between dietary calcium and vitamin D intakes and brain lesions, measured by MRI scans, in 232 elderly men and women (95 with current or prior depression, 137 without depression). They found that both calcium and vitamin D were positively associated with a higher total volume of brain lesions, even after controlling for potential confounders, including age, hypertension, diabetes, heart disease, kilocalories, group (depression or no depression), and lesion load (high or low). Furthermore, the authors’ earlier work found that individuals consuming high-fat dairy products (1.8 serves per day) had 1.5 times greater brain lesion volume than those consuming 0.3 serves per day [62]. Although cause-and-effect cannot be established from these cross-sectional studies, the apparent link between calcium and brain lesions warrants further research given that brain lesions have also been linked to an increased risk of cognitive impairment, dementia, and depression.

Calcium Supplementation and Kidney Stones

Kidney stones have been linked to a high calcium intake, but this appears to depend on the source of calcium. Several prospective studies reported that a diet high in calcium is associated with a reduced risk of kidney stones, possibly by reducing gut absorption of oxalate which is one of the main components of kidney stones [63,64]. In contrast, the use of calcium supplements has been associated with an increased risk, although these finding are not consistent. For instance, data from the 7-year Women’s Health Initiative (WHI) trial revealed that the risk of kidney stones (renal calculi) was increased by 17% in those receiving calcium and vitamin D supplements [HR 1.17 (95% CI, 1.02, 1.34) [9]. In contrast, a systematic review of calcium supplementation trials in postmenopausal women revealed that most studies show no increase in stone risk with a high calcium intake (diet or supplements), and in fact several trials reported an inverse association between calcium intake and stone risk [65].

Serum Calcium and Cardiovascular Disease Risk

It has been suggested that the increased risk of vascular disease with calcium supplementation may be related to serum calcium concentrations [31]. There is indirect evidence to support this hypothesis. A number of observational and prospective studies in men and women have reported that serum calcium levels were related to the risk of MI [66,67] and even death [67]. Data from 40,538 hemodialysis patients showed serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (RR, 1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus at 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and =9.0 mg/dL) [68]. Importantly, higher adjusted serum calcium concentrations were also associated with an increased risk of death, independent of serum phosphorus. In the same study, only moderate to severe hyperparathyroidism (PTH concentrations =600 pg/mL), but not more modest increases in PTH, was associated with an increase in the relative risk of death. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization in dialysis patients.

A recent post-hoc data analysis from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial of raloxifene treatment in 7259 postmenopausal women with osteoporosis examined the associations between higher baseline calcium and phosphorus levels and incident cardiovascular events over 4 years [69]. After adjustment for multiple covariates, including 25(OH)D, parathyroid hormone, and phosphorus, adjusted hazard ratios (95% confidence interval) per SD of calcium were significantly increased for combined cardiovascular outcomes [AHR 1.17 (95% CI, 1.01-1.35), p = 0.03], but were either marginal for cerebrovascular events [1.22 (95% CI, 0.99-1.49), p = 0.06], or not significant for coronary heart disease [1.12 (95% CI, 0.92-1.37), p = 0.25], and death [1.18 (95% CI, 0.94-1.48), p = 0.16]. Associations between serum phosphorus and cardiovascular events did not persist after adjustment for additional confounders. Thus, there was an independent association between higher serum calcium levels, but not higher serum phosphorus levels, and higher rates of cardiovascular events in postmenopausal women with osteoporosis. It is interesting to speculate that greater increases in serum calcium resulting from calcium citrate than calcium carbonate may be responsible for the findings in the Auckland study of postmenopausal women.

Conclusion

In conclusion, the findings from this review that evaluated the results from observational and prospective studies, RCTs and meta-analyses, highlight the heterogeneity of findings regarding whether the use of calcium supplements has any adverse effects of health, including kidney stones, vascular disease and mortality. In terms of CVD and its related risk factors, the vast majority of studies have failed to observe any significant adverse effect of calcium supplement use. However, the findings from a recent meta-analysis of published RCTs (currently published in abstract form only) that included most of the key calcium supplementation trials having cardiovascular events as secondary outcomes, provide the most compelling data to support the notion that the use of calcium supplements may increase the risk of MI in postmenopausal women [22]. While these findings are of concern, the clinical and public health implications need to be carefully considered. What is the key message for physicians, health care professionals and patients? We believe that it would be unwise at this point to recommend that older women avoid or stop taking their calcium supplements. Unfortunately, this may well be the key message conveyed when the findings from this meta-analysis are published.

When evaluating whether calcium supplements adversely affect vascular disease, it is important to consider that total calcium intakes may exceed 2,000 to 2,500 mg per day (1,000–1,200 mg/d supplemental calcium plus 800–1,000 mg/d dietary calcium). At these levels, there may well be some cause for concern, but several important questions still remain. Is the level of risk the same for all women or is it greatest in those already at high risk of CVD? Does the level of risk vary by the type of calcium supplement used, particularly those that led to greater elevations of serum calcium concentrations, and does the addition of vitamin D counteract this increased risk? Is there a threshold level of calcium above which intakes become detrimental to health? Although there is currently no evidence to support such a threshold, a recent study in healthy adult men and women aged 19 to 75 years which was designed to determine the level of dietary calcium to maintain neutral calcium balance, reported that the calcium requirements (or recommended dietary allowance) for men and women should be approximately 1035 mg/d [8]. While some have questioned the balance-based approach used to estimate the average calcium requirements in this study [70], these findings provide some evidence that daily calcium requirements may be lower than previously estimated.

It is evident from the above discussion that there are still many important unanswered questions that need to be addressed before women are advised to stop taking their calcium supplements. Unfortunately it is unlikely that there will ever be a long-term RCTs conducted to address whether the use of calcium supplements is associated with increased vascular disease because the primary hypothesis would be one of harm [31]. Therefore, large cohort prospective studies comparing groups with habitually high versus low calcium intakes (or those regularly taking calcium supplements) will be important to gain an insight into the long-term effects of high calcium intakes on vascular disease and related mortality. Until then, we recommend that healthy older women adhere to the current guidelines which typically recommend a total calcium intake of 1,000 to 1,300 mg/d, which can be readily achieved through both dietary sources and the addition of calcium supplements, when required.

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Acknowledgements

Robin M. Daly is supported by a National Health and Medical Research Council (NHMRC) Career Development Award (ID 425849).

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by EricT

The Effects of Alcohol on Athletic Performance and Recovery

Sat, 31 Jul 2010 19:48:25 +0000

by Luke D. Vella and David Cameron-Smith

Molecular Nutrition Unit, School of Exercise and Nutrition Sciences, Deakin University, Burwood,

Nutrients 2010

Alcohol consumption within elite sport has been continually reported both anecdotally within the media and quantitatively in the literature. The detrimental effects of alcohol on human physiology have been well documented, adversely influencing neural function, metabolism, cardiovascular physiology, thermoregulation and skeletal muscle myopathy. Remarkably, the downstream effects of alcohol consumption on exercise performance and recovery, has received less attention and as such is not well understood. The focus of this review is to identify the acute effects of alcohol on exercise performance and give a brief insight into explanatory factors.

Introduction

Athletes, like the rest of the population, consume alcohol. Sporting clubs and associations are frequently reported in the media to place bans or restrictions on the availability and consumption of alcohol by contracted athletes. Yet the same media organizations also report on alcohol-fuelled violence or misdemeanors perpetrated by these same athletes, suggesting anecdotally that athletes consume alcohol, occasionally to excess. This is quantitatively supported by dietary surveys of athletic populations that demonstrate self-reported alcohol intake constitutes up to 5% of the total daily energy intake in elite athletes [1]. However this is far from universal, as survey data reports either greater [2,3], or reduced [4,5] alcohol ingestion in athletic populations than the general community. This high variability in reported alcohol intake within athletic groups may in part be due to the characteristics of each sporting discipline. Alcohol intake appears to be positively associated with team sports where alcohol consumption is often encouraged as a component of team/group bonding and can be related to stress relief [6].

The detrimental effects of alcohol on human physiology have been well documented with acute alcohol ingestion affecting many aspects of metabolism, neural function, cardiovascular physiology, thermoregulation and skeletal muscle myopathy [7-9]. Yet the impact that alcohol ingestion has on exercise performance and more critically recovery has received less detailed scrutiny. This review aims to provide insights into the current knowledge around how alcohol acts to impair both exercise performance and the critical mechanisms by which alcohol acts at the cellular level to retard recovery following strenuous activity.

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Effect of Alcohol on Human Physiology

Alcohol consumption has a deleterious effect on a multitude of systems within the body and an in-depth analysis of each is beyond the scope of this review. However a brief insight into common symptoms linked to acute alcohol misuse will guide the following discussion on how alcohol influences human performance and recovery.

Effect of Alcohol in Skeletal Muscle

Multiple detrimental actions of lcohol within skeletal muscle are likely. Firstly, alcohol inhibits Ca2+ transients into the myocyte by inhibiting sarcolemmal Ca2+ channel actions. This action is reported in isolated human myotubes and rodent muscle tubes in-vitro [10-12]. Consequently this will impair excitation-contraction coupling, decreasing strength output. Yet human clinical data fails to support this in-vitro evidence [13]. Secondly, alcohol consumption may compromise sarcolemmal integrity, with evidence of greater plasma rises in the intracellular enzyme creatine kinase (CK), following alcohol ingestion and exercise [14]. Indeed, in rodents a supraphysiological dose of alcohol markedly increased plasma CK. Furthermore, in both electrically stimulated rodent muscles [15] and in human subjected to eccentric loading this not evident [13,16-18]. Thus clear mechanisms remain elusive, with a need for supporting clinical data. It is well understood that muscle cramps, pain and a loss of proprioception are common symptoms of alcohol misuse [19]; however the underlying mechanisms remain speculative.

Effect of Alchohol on Thermoregulation and Hydration

The effects of alcohol on hydration and its diuretic function are historically well recognised. The identification of alcohol as a potent diuretic date back to 1948, where a 10 mL excess urine production was evident following each gram of ethanol consumed [5]. The mechanism subsequently identified is the inhibition of anti-diuretic hormone (ADH) by ethanol [21], although this relationship is evident only in beverages containing greater than 4% (w/v) ethanol [21].

Alcohol has further been shown to act as a peripheral vasodilator. This presents several complications. Primarily this increases fluid loss through evaporation which further exacerbates the dehydration that is potentially already present. There is further an interference of central thermoregulatory mechanisms consequently resulting in a reduction in core body temperature [5,22]. Thus, not surprisingly, alcohol consumption has been repeatedly shown to decrease work tolerance in both high and low ambient temperatures [22-24].

Effect of Alcohol on Metabolism

In additional to being a readily accessible source of energy (29kJ per gram) [5], alcohol has a number of effects that bear ramifications for human metabolism. Alcohol-induced hypoglycemia has been proposed as a possible cause of symptoms common to alcohol misuse. The intake of high alcohol doses has been demonstrated to impair hepatic gluconeogenesis and subsequent glucose output [25,26], decrease the uptake of gluconeogenic precursors lactate and glycerol [27], and reduce muscle glycogen uptake and storage [27]. Alcohol has also been shown to induce a reactive hypoglycemia by exacerbating insulin secretion in the presence of a high carbohydrate meal [28]. While the detrimental effect of alcohol on glucose metabolism is strongly documented, some authors maintain that this can be negated if glycogen stores are maintained at homeostatic levels [25,29]. Specifically to exercise, acute alcohol intoxication inhibited the exercise induced rise in serum glucose concentration and caused a mild decrease in serum glucose during recovery from anaerobic exercise [25]. Further acute alcohol intoxication has been implicated in attenuating post exercise increases in serum fatty acid concentration [25]. These findings bear considerable ramifications for exercise performance and recovery. It is well documented in the literature that glucose availability plays a pivotal role in endurance performance [30,31] and further readily available stores of energy are necessary to fuel protein synthesis during muscle recovery from exercise [32].

Neurological Effects of Alchohol

Alcohol is a well-known depressant and thus acts to reduce central nervous system (CNS) excitability and cerebral activity [33], as demonstrated by a slowed encephalographic rhythm [34]. Functionally alcohol has been repeatedly shown to exhibit a dose-dependent impairment of balance, reaction time, visual search, recognition, memory and accuracy of fine motor skills [1,9]. Variances in neurological activity have also been intricately linked to a disturbance in sleep length and quality with some authors observing a loss in sleep depth with a shorter time of rapid eye movement (REM) sleep and an increase in sleep at stage 1 [35,36].

The effect of alcohol on neurological function is likely to be caused by a myriad of factors. The aforementioned effect of alcohol on glucose metabolism could affect cerebral functioning leading to symptoms of alcohol intoxication [25]. Alternatively, the accumulation of acetaldehyde, a bi-product of alcohol metabolism, has been theorized as a potential cause of the aversive neurological symptoms associated with alcohol misuse [37]; however this prospect remains speculative [19]. Further the toxic effect of a group of substances collectively termed congeners often produced during the fermentation of alcohol, are likely to contribute to the reduction in CNS activity. Methanol, histamine and polyphenols are amongst the congeners best studied [38]. Serotonin regulation provides a further prospective mechanism as this hormone has both been shown to be increased in the presence of alcohol [38] and performs various cognitive functions including memory and learning.

Alcohol and Exercise Performance

Given the numerous and complex mechanisms by which ethanol impacts on physiological systems it can be strongly hypothesized that elevated blood alcohol concentrations at the time of exercise will impair performance. Remarkably there are relatively few clinical trials that address this question.

Aerobic Performance

Earlier studies found no significant consequence of alcohol on a sub-maximal endurance performance and a 5-mile treadmill time trial respectively [39,40]. Contrastingly and not surprisingly, there is also literature that demonstrates that alcohol is detrimental to endurance performance [41-45]. What is apparent is that a threshold exists at which point alcohol becomes detriment to aerobic performance. Cofan and colleagues describe an alcohol intoxication threshold of 20mmol/L of ethanol in both animal [12] and human [10] studies, beyond which did performance decrements become significant. Further research has elaborated that this cause-effect relationship may exist in a dose dependent manner [43].

Anaerobic Performance

Despite the long list of skeletal muscle and neurological symptomatology associated with alcohol consumption, the majority of literature has been unable to establish a significant cause-effect relationship between alcohol and anaerobic performance. To the reviewers knowledge McNaughton and Pierce [43] have conducted the only research that has identified an effect of alcohol on sprint performance. This research examined five sprinters using sprint time as a measure of performance and established a detrimental, albeit inconsistent, association between alcohol dosage and sprint performance. Alcohol was ingested immediately prior to exercise testing so this data is limited to the acute effects of alcohol intoxication and does not apply to more chronic hangover symptoms. Recent research has been unable to validate these findings, and have consistently seen no change in strength or power characteristics following acute alcohol ingestion [13,16,42]. Contrasting to McNaughton and Pierce, these studies have examined force output using an isokinetic dynamometer as their outcome measure of anaerobic performance. Comparatively time trial sprint performance incorporates a high degree of motor control and coordination and may provide insight as to why these findings cannot be replicated.

Alcohol and Exercise Recovery

Most of the studies examining alcohol and athlete recovery have focused predominately on functional measures of muscle performance and blood borne markers of cellular tissue damage. To date, these studies have produced inconclusive results that fail to demonstrate a dose-dependency or critical threshold above which muscular recovery is compromised. Creatine kinase (CK) is an intra-muscular enzyme which when present in the peripheral circulation is widely used as a measure of muscle damage. Despite the clinical association between chronic alcohol abuse and skeletal muscle myopathy, acute ingestion appears to have little impact on exercise-mediated muscular damage [13,16,18].

The lack of results may be attributable to the parameters measured within these above mentioned trials. CK is highly variable and may not provide the best measure of muscle damage [45,48]. More recently, circulating levels of pro-inflammatory cytokines, released from the musculature may provide alternative measures of muscular stress and damage [47]. Inflammatory processes appear to be variably modulated by chronic and acute alcohol use. Prolonged alcoholism is associated with high circulating levels of pro-inflammatory mediators [49], whilst conversely acute consumption has been shown to decrease production of TNF-a and (IL-1) in rodent studies [50-52] It has yet to be established if cytokine concentrations are altered by acute alcohol ingestion during or immediately following intense exercise.

Similarly to the analysis of markers of muscle damage, the intra-muscular consequences of acute alcohol ingestion on aspects metabolic pathways of recovery are also ambiguous in humans. Alcohol ingestion immediately following prolonged cycling exercise has a modest impact to impair glycogen re-synthesis [48]. This action is dependent in part on alcohol replacing carbohydrates in energy-matched meals. Although acute suppression of glycogen synthesis may have been evident, examination of glycogen repletion over 24 hours demonstrated no long term detrimental impact of alcohol ingestion on muscle glycogen stores. Of particular relevance to the recovery of strength athletes is the enhanced protein synthesis that occurs post-exercise to facilitate repair and adaptive hypertrophy [53].

Acute alcohol ingestion decreases muscle protein synthesis in a dose- and time-dependent manner, in the absence of an exercise stimulus. Alcohol facilitates this firstly by suppressing the phosphorylation and activation of the mTOR pathways, the critical kinase cascade regulating translation initiation [54]. Complementing the decreased activation of the protein synthetic pathway, alcohol increases the expression of muscle specific E3 ligases; atrogin-1 and Muscle-specific RING finger 1 (MuRF1) [55]. These proteins are up regulated by conditions that promote skeletal muscle atrophy. Interestingly this was not associated with increased proteolysis, suggesting alcohol primarily impairs protein synthesis. It remains to be confirmed in rodents subjected either to muscle loading or resistance exercise that alcohol impairs protein synthesis. Subsequent clinical data is also lacking and this remains a critical absence in the scientific literature.

Functionally, the consumption of moderate amounts of alcohol augments the loss of force associated strenuous eccentric exercise [18,56]. To the researchers knowledge Barnes, Mündel and Stannard have produced the only research that has used functional measures of muscle performance to identify an interaction between post-exercise muscle damage and alcohol [18,56]. This research established a significant decrease in average peak isometric, concentric and eccentric torques at 36 hours post-exercise. This decrement appeared to be exacerbated across all three variables in the group that consumed 1g per kg of body weight immediately post-exercise. Whilst this research provides new insights into the effect of alcohol consumption on post-exercise muscle recovery, further research is required to ascertain how this relationship exists and establish the physiological mechanisms governing this response.

Conclusion

Both the affects of alcohol on human physiology and the parameters that determine athletic performance are multi-factorial and extremely complicated. A significant body of literature has established an array of adverse symptoms caused by acute alcohol ingestion. However the notion that alcohol consumption effects performance has not received enough consistent validation to advance beyond being anecdotal. Nevertheless, just because alcohol is not yet comprehensively shown to have a negative influence on performance, does not imply this review advocates its use prior to, or following competition. Indeed, the data demonstrates a severe lack of analysis on the possible detrimental action of alcohol in the recovering athlete. However, based on the available experimental evidence in cellular and rodent-models, athletes should remain wary of ingesting alcohol following intense exercise, focusing instead on effective dietary strategies proven to enhance recovery.

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by EricT

The Antioxidant Role of Glutathione and N-Acetyl-Cysteine Supplements and Exercise-Induced Oxidative Stress

Fri, 30 Jul 2010 01:49:42 +0000

by Chad Kerksick¹ and Darryn Willoughby²

Journal of the International Society of Sports Nutrition, 2005

An increase in exercise intensity is one of the many ways in which oxidative stress and free radical production has been shown to increase inside our cells. Effective regulation of the cellular balance between oxidation and antioxidation is important when considering cellular function and DNA integrity as well as the signal transduction of gene expression. Many pathological states, such as cancer, Parkinson's disease, and Alzheimer's disease have been shown to be related to the redox state of cells. In an attempt to minimize the onset of oxidative stress, supplementation with various known antioxidants has been suggested. Glutathione and N-acetyl-cysteine (NAC) are antioxidants which are quite popular for their ability to minimize oxidative stress and the downstream negative effects thought to be associated with oxidative stress.

Glutathione is largely known to minimize the lipid peroxidation of cellular membranes and other such targets that is known to occur with oxidative stress. N-acetyl-cysteine is a by-product of glutathione and is popular due to its cysteine residues and the role it has on glutathione maintenance and metabolism. The process of oxidative stress is a complicated, inter-twined series of events which quite possibly is related to many other cellular processes. Exercise enthusiasts and researchers have become interested in recent years to identify any means to help minimize the detrimental effects of oxidative stress that are commonly associated with intense and unaccustomed exercise. It is possible that a decrease in the amount of oxidative stress a cell is exposed to could increase health and performance.

Reactive Oxygen Species and Oxidative Stress

The presence of oxygen is a fundamental component of cellular metabolism. However, any situation which results in a sudden or chronic overconsumption of oxygen can lead to the production of free radicals, which are more appropriately termed 'reactive oxygen species' (ROS). Production of these reactive oxygen species is known to occur as a result of a few different mechanisms: 1) mitochondrial origin in which free radicals either escape scavenging enzymes or develop due to an error in oxidative processes, 2) inside the capillary endothelium where a hypoxic and reoxygenation process is created during intense exercise as well as during various types of cardiovascular disease, and 3) an oxidative burst from inflammatory cells which are commonly mobilized as a result of the muscle or tissue damage which is well-documented with extended or eccentric-based exercise[1]. Aerobic energy metabolism, or oxidative phosphorylation, is a critical metabolic pathway within cells to provide the energy necessary to complete our daily tasks.

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In a resting state these processes work slowly while during times of intense exercise, these metabolic processes are increased as much as 100-fold. Inside the mitochondria, the electron transport is responsible for a series of redox reactions which result in the resynthesis of ATP. In this system, O2 is reduced by cytochrome-c oxidase, which is the terminal enzymatic component of this mitochondrial enzymatic complex. As the demand and subsequent flux for this process increases so does the chance that redox uncoupling will occur and increase the accumulation of free radicals throughout the cell. A free radical is a molecule that contains at least one unpaired electron in its outer spin orbits. Characterized by their unpaired electron(s), superoxide radicals, hydroxyl radicals, hydrogen peroxide, nitric oxide, lipid alkoxyl and peroxyl radicals are the most common reactive oxygen species in living, aerobic systems[2]. It is estimated that 2–5% of the oxygen that is passed through the electron transport system inside the mitochondria results in superoxide[3]. The complete reduction of oxygen can be seen from the steps outlined below[4].

O2 + e- ? O2- Superoxide radical

O2- + H2O ? HO2 + OH- Hydroperoxyl radical

HO2 + e- + H ? H2O2 Hydrogen Peroxide

H2O2 + e- ? OH + OH- Hydroxyl Radical

Superoxide is the most well-known of the free radicals as it is commonly produced during the natural pathway of oxidative phosphorylation. Superoxide is readily dismutated by intracellular superoxide dismutase enzymes (e.g. copper superoxide dismutase [CuSOD], magnesium superoxide dismutase [MgSOD]). Consequently, these antioxidant enzymes can have many different origins (e.g. endothelial, plasma, tissue) and are commonly used in the literature to assess the amount of oxidative stress that is occurring.

Superoxide is converted primarily into hydrogen peroxide; however, from a chemical structure standpoint, hydrogen peroxide is not a free radical. It is considered to be a free radical due to its ability to readily result in the hydroxyl radical. Hydrogen peroxide, unlike other free radicals, is able to be transported across cellular membranes. The enzyme, catalase, has been shown to effectively dismantle much of the hydrogen peroxide found in our cells with water as a by-product. The hydroxyl radical is the most reactive of the free radicals and in the presence of various transition metals (e.g. Fe3+, Cu2+) it is known to directly target cellular lipids, proteins, nucleic bases, causing DNA base modification or fragmentation[5]. The ability of the hydroxyl radical to remove or add hydrogen molecules to unsaturated aspects of cellular membranes (e.g. lipid peroxidation) makes it one of the most potent free radicals in existence. Its extremely short half-life restricts its diffusion capability to other parts of the cells while also enhancing its potency[4].

To protect against the deleterious effects of ROS, our bodies have a complex system of endogenous antioxidant protection in the form of enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Under normal, resting conditions reactive oxygen species are removed from the cell preventing any subsequent damage. However, under more extreme conditions such as: 1) inadequate intake of foodstuffs containing the antioxidants, 2) excessive intake of pro-oxidants, 3) exposure to noxious chemicals or ultraviolet light, 4) injury/wounds, and/or 5) intense exercise, especially eccentric exercise, the body's endogenous antioxidant system is not able to effectively remove excessive ROS production[2]. In situations such as the ones listed above in which the production of pro-oxidant molecules increase to a point where the antioxidant system cannot effectively remove them is when oxidative stress is known to occur. Oxidative stress has been implicated in a number of diseases which include atherosclerosis, pulmonary fibrosis, cancer, Parkinson's disease, multiple sclerosis, and aging[6]. Research on oxidative stress during exercise has begun to indicate that regular training enhances the ability of these mechanisms to effective respond to the increase of oxidative product.

As mentioned before, free radicals have been found to react with macromolecules (lipids, proteins, DNA) within the cell, with one of the most frequent targets being the polyunsaturated fatty acids that largely comprise the cell membranes. The systematic oxidation of these polyunsaturated fatty acids is called lipid peroxidation. Lipid peroxidation has been found to limit different aspects of muscle or cell function by decreasing the fluidity of the membrane, making it more difficult for proteins/nutrients to pass through. Further, lipid peroxidation has been found to decrease the membrane's ability to uptake glucose as well as respond to varying levels of immune challenges[7].

Lipid peroxidation is commonly quantified in research studies by measuring the accumulation of the by-products that result from this process. One of these by-products is malondialdehyde (MDA). In response to various forms of exercise many studies have reported significant increases of malondialdehyde [7-9]. Evidence of lipid peroxidation by increased levels of malondialdehyde and other such substances such as 8-isoprostane and thiobarbarbituric acid-reactive substance levels is one of the primary means by which researchers have associated oxidative processes with an overall decrease of cellular function.

Supplementation with antioxidants, either through an increased consumption in the diet or from supplementation, has become extremely popular as a means to improve one's health or increase physical performance. It has been suggested that increasing the circulating levels of certain antioxidants (e.g. glutathione, n-acetyl-cysteine, a-lipoid acid, vitamin A, vitamin E, vitamin C, etc.) will help to prevent the accumulation of free radicals inside our cells thus reducing oxidative stress[4,10,11] while other studies have suggested the possibly of little to no effect[12]. By decreasing oxidative stress, researchers have suggested that the risk of cancer, parkinson's disease, alzheimer's disease, etc. may all be decreased. Additionally, research has also begun to link excessive oxidative stress with an up-regulation of various proteolytic pathways (e.g. calcium-activated calpains and ubiquitin-proteolytic pathway) as well as apoptosis.

Glutathione's Role as an Antioxidant

Glutathione is currently one of the most studied antioxidants. This is likely due to it being endogenously synthesized all throughout the body and it is basically found in all cells, sometimes in rather high concentrations. Investigations have highlighted many roles in which it is used including antioxidant defense, detoxification of electrophilic xenobiotics, modulation of redox regulated signal transduction, storage and transport of cysteine, regulation of cell proliferation, synthesis of deoxyribonucleotide synthesis, regulation of immune responses, and regulation of leukotriene and prostaglandin metabolism[13]. Many of these areas are highlighted below in the figure adopted from Sen and Packer to illustrate these roles of glutathione and to emphasize the importance of maintaining the redox state of the cell[11].

Glutathione Response to Exercise

Due to its large role in countering increases in lipid peroxidation which occurs during oxidative stress, especially during intense exercise, the response of glutathione has been frequently studied. Trained men who exercised to exhaustion on a treadmill had increased blood amounts of oxidized glutathione immediately after exercise, suggesting an increase in oxidative stress, but returned to rest after 1 h. A decreased level of glutathione in the plasma is the result of an increased utilization of it inside the muscle, presumably to fight or "quench" any circulating free radicals.

Other endurance-based exercise studies have reported similar results with Gohil et al. reporting an increase in oxidized glutathione after prolonged submaximal exercise with a concomitant decrease in reduced glutathione. Other studies have reported upon the changes seen in serum glutathione reductase, which is the enzyme responsible for restoring reduced glutathione from oxidized glutathione through the use of nicotinamide adenine dinucleotide (NADH)[14,15]. In these studies, an increase in glutathione reductase activity was thought to suggest an increase of oxidative stress induced by exercise.

The potential for glutathione to minimize or reduce free radicals is apparent from the reported changes in glutathione status after exercise. In response to bouts of exercise, circulating levels of reduced glutathione are found to decrease while levels of oxidized glutathione increase. When considering the changes in redox chemistry occurring as a result of an increase in exercise, the ability of the body to maintain a proper balance of glutathione is quite important. Fortunately, in response to regular exercise training, resting levels of glutathione increase as an adaptation by the body to effectively deal with the increase in free radicals that commonly results secondary to the exercise training. While many of these studies utilized endurance-based exercise, much of the same response is expected when using resistance-based exercise.

To date, few studies have been completed which utilized a typical resistance training program, but some studies using primarily eccentric contractions have been conducted. A study by Clarkson et al. had subjects complete 50 maximal contractions of the elbow flexors while having their blood taken prior to exercise, as well as immediately post-exercise and 24, 48, 72, 96 and 120 h post-exercise. They illustrated that increases in total glutathione in the plasma were found in those individuals who already had higher circulating levels, which they suggested was a greater adaptive response to the damaging exercise bout[16].

Another study which investigated the changes in glutathione status after exercise used 20–30 y men who cycled for 40 min at 60% of their maximal oxygen consumption in an attempt to determine the role of glutathione as determinants of lipid peroxidation. Upon completion of the exercise bout oxidized glutathione levels increased by about 50% in response to the exercise bout suggesting a substantial onset of oxidative stress. Additionally reduced glutathione levels decreased by 13% after the exercise bout providing evidence that the intracellular glutathione was being utilized inside the muscle or associated tissues leading to a decrease in serum levels. The authors also concluded that resting lipid peroxidation levels were also able to predict the exercise induced changes in blood total glutathione in addition to resting oxidized glutathione levels being strongly related to their post-exercise values. The results from this study highlight the critical role that glutathione homeostasis has on modulating exercise induced oxidative stress, and conversely, the effect of oxidative stress at rest on exercise induced changes in glutathione redox status[17].

Supplementation studies which have utilized exogenous forms of glutathione are not that common due to the poor ability of glutathione to stay intact throughout the cell with most of it being found to be degraded in the extracellular compartment[18]. Degradation of glutathione leads primarily to its constituent amino acids (e.g., cysteine, glycine), which can subsequently be used for glutathione synthesis inside the cell. One of the few studies that utilized exogenous glutathione used a combination of 1 g glutathione with 2 g vitamin C (another well-established antioxidant) daily for 7 days in trained athletes to test the possible effect on exercise-induced glutathione oxidation. As expected, progressive increases in exercise intensity resulted in an increase in oxidized glutathione of 34–320% compared to pre-exercise levels.

Research involving glutathione suggests strongly that it has an important role in preventing oxidative stress-associated lipid peroxidation which subsequently makes maintaining an optimal balance of glutathione necessary for it to effectively quench peroxidation of the lipid membranes. Supplementation with glutathione has been met with little success as the bioavailability of glutathione is low due its transient transport throughout the cellular network. At the current time, the bioavailability of glutathione is thought to be extremely poor due to the hydrolytic enzymes that break down the glutathione upon ingestion. Nevertheless, popularity for glutathione administration and supplementation is high due to its primary role to minimize the oxidative stress seen with exercise. Glutathione and Signal Transduction

Another important role for glutathione relates to its impact over signal transduction of gene expression inside cells. Briefly, glutathione status has been favorably linked to two well-established redox sensitive transcription factors, nuclear factor ?B (NK-?B) and activator protein-1[19,20]. Activation of NF-?B appears from these studies to be critically regulated by intracellular thiol redox status. Extremely high or extremely low levels of oxidized glutathione results in less than optimal activation of these transcription factors making it important for optimal levels of intracellular oxidized glutathione to be maintained throughout the cell[19,20]. Tumor necrosis factor-a is a cytokine of various monocytes and macrophages and is also known to potently activate NF-?B. Tumor necrosis factor-a is highly related to muscle wasting conditions such as cancer cachexia as well as AIDS and other muscle inflammatory conditions. Exhaustive exercise with athletes has been shown to increase levels of tumor necrosis factor-a in the serum creating a link between the muscle damage commonly seen with intense exercise and signal transduction of redox control parameters of the cell. Additionally, glutathione status has been investigated for its role in tumor necrosis factor-a induced activation of NF-?B, which demonstrated that NF-?B activation is related to cellular glutathione levels[21]. Consequently, these studies provide continued support that maintaining optimal cellular levels of glutathione is important for effective cellular function.

N-Acetyl-Cysteine

N-acetyl-cysteine (NAC) is an acetylated cysteine residue. An optimal thiol redox state has been demonstrated to be of primary importance if attempting to optimize the protective ability of the cell to oxidative stress. Relative to glutathione availability, one of the most important considerations has been to properly maintain the availability of cysteine in the blood as that is known to be the rate-limiting substrate for glutathione resynthesis[3]. Subsequently, identifying ways in which optimal availability of cysteine is achieved has been a primary approach in an effort to maintain the biosynthesis of reduced glutathione. Among the most widely used agents to maintain the cysteine pool is NAC in addition to a-lipoic acid, which will not be discussed in detail. While other agents have been used, NAC and a-lipoic acid are the most commonly utilized and discussed as a result of their proven safety and efficacy. In addition to the role glutathione and other thiols have on maintaining the cellular redox state, many studies have begun to explore if NAC supplementation can actually improve performance due to its ability to promote a more favorable cellular environment to achieve higher levels of performance.

One of the first studies to utilize NAC to determine its role in improving muscle performance was conducted by Reid and colleagues. They pretreated subjects with n-acetyl-cysteine infusion (150 mg·kg-1) or a 5% dextrose placebo while undergoing an extended fatiguing bout of electrical stimulation of the ankle dorsiflexors. N-acetyl-cysteine was found to have no impact over the nonfatigued muscle, but a significantly increased force output of approximately 15% was found after 3 minutes of repetitive contractions which persisted throughout the 30 minute protocol[22]. The authors concluded that NAC resulted in improved performance suggestive of oxidative stress having a causal role in the fatigue process.

Another fatigue model using laboratory rats, NAC infusion (150 mg·kg-1) and respiratory processes was conducted by Supinski et al.[23]. In this study they exposed the animals to an increased inspiratory load which was set up to induce fatigue of the respiratory muscle and ultimately end with respiratory arrest. N-acetyl-cysteine infusion was found to better tolerate the respiratory loading by increasing the time to respiratory arrest. Additionally, diaphragm samples of both the n-acetyl-cysteine and placebo groups demonstrated an attenuated decrease of reduced glutathione with those animals infused with NAC. This study provides evidence that NAC, a free radical scavenger, slows the rate of respiratory failure development during inspiratory resistive loading[23].

A recently published study out of Michael Reid's laboratory sought to determine the impact of NAC on fatiguing handgrip exercise. Participants were either infused with saline or NAC at a dosage of 150 mg·kg-1. While NAC was found to have no impact on force production during sustained maximal contractions, it was found to help reduce and inhibit glutathione oxidation during repetitive submaximal contractions. The authors concluded that NAC may be helpful at delaying fatigue as well as the building of oxidative stress, but more systemic, translational research on humans needs to be conducted. [24]Furthermore, a study by Medved et al. used eight male subjects who were infused with either a placebo or NAC before and while cycling for 45 minutes at 71% peak VO2 and then to fatigue at 92% peak VO2 to determine any possible antioxidant or ergogenic effect[25].

N-acetyl-cysteine infusion resulted in a 26.3% increase in time to exhaustion at 92% peak VO2. Additionally, NAC infusion also resulted in increased total and reduced NAC levels in skeletal muscle at 45 minutes of exercise and at fatigue. The exercise protocol decreased the reduced glutathione levels with no impact on overall level of total glutathione[25]. Another study by the same authors used a similar infusion but this time with three higher intensity 45 s sprints with a fourth sprint at 130% peak oxygen consumption[26]. While no change was illustrated in the time to fatigue at this higher level of intensity, NAC infusion did attenuate the reduction of reduced glutathione as well as the increase in oxidized glutathione suggesting that even with short bouts of high-intensity exercise, NAC is effective at promoting a positive redox balance within the cell[26].

It has been well-reported that infusion of NAC can be effective at attenuating or minimizing muscle fatigue as well as enhance the overall redox status inside the cell. Several areas, however, still remain to be determined when it comes with NAC administration. The studies reported thus far have used exhaustion models of endurance-based exercise leaving the area of resistance exercise, specifically damaging eccentric exercise a major area of research to be conducted. It has been widely reported that an exercise bout consisting of eccentric muscle contractions can result in substantial damage to the contractile unit, which often results in inflammation, loss of Ca2+ homeostasis and possibly induction apoptosis as a result. A study by Childs et al. used eccentric contractions of elbow flexors to initiate a muscle damage response. Subjects were supplemented with either a placebo or a combination of the antioxidants vitamin C and NAC.

In response to the muscle damage and supplementation, circulating levels of free iron (that could possibly react to form hydroxyl radicals) were increased, lactate dehydrogenase and creatine kinase, markers of protein breakdown and damage, were elevated in the supplemented group as well as an increase in markers for oxidative stress. Acute administration of the antioxidants vitamin C and NAC appear to facilitate the inflammatory and oxidative stress seen associated with muscle damage. It is possible that the amount of muscle damage and inflammation was so great during this study that administration of antioxidants had no possible benefit or as noted could possibly have had enhanced the response[27]. Currently, the relationship between muscle damage, oxidative stress and other systems of proteolysis such as apoptosis are poorly understood.

A recent study by Quadrilatero and Hoffman-Goetz sought to determine the impact of NAC infusion on the development of apoptosis in rats that were infused with either saline or NAC and ran to exhaustion. The authors reported that the 90 minute exercise protocol increased intestinal lymphocytes phosphatidylserine concentration, mitochondrial membrane depolarization, and decreased intracellular glutathione concentration (p < 0.05)[28]. Additionally, the rats that were infused with NAC better maintained their intracellular glutathione levels, prevented (p < 0.05) the externalization of phosphatidylserine, mitochondrial membrane depolarization and also prevented the loss of intestinal lymphocytes immediately and 24 h after exercise[28]. A follow-up publication from the same study found that protein levels of caspase-3 and cytochrome c (pro-apoptotic markers) and bcl-2 (an anti-apoptotic marker) were significantly (p < 0.05) elevated after exercise compared to the non-exercised controls[29]. The authors concluded from this study that oxidative stress acting through a mitochondrial pathway may play a role in intestinal lymphocyte apoptosis after strenuous exercise.

N-acetyl-cysteine is an effective scavenger of free radicals as well as a major contributor to maintenance of the cellular glutathione status in muscle cells. Studies have demonstrated some possible roles for NAC to minimize fatigue or extend the time it takes for it to accumulate as well as prevent the onset of apoptosis secondary to exhaustive exercise. It is still not known if the combination of vitamin C and NAC may be detrimental after damaging exercise as well as NAC's other possible roles during muscle damage and extensive muscle proteolysis.

Summary

In conclusion, the development of free radicals and oxidative stress during exercise is an important consideration for optimal performance, recovery, and health. Currently, the relationship between oxidative stress and prolonged, unaccustomed, high-intensity exercise is not fully determined. Even further, research exists which illustrates a possible relationship between free radicals and oxidative stress to other diseases and pathways of cellular destruction. Systems of proteolysis and apoptosis are two of the primary pathways in which oxidative stress appears to play a substantial role in the extent to which they are active in skeletal muscle. A commonly sought-after approach to oxidative stress is the exogenous administration of compounds that are thought to have antioxidant properties. Much more research at this time needs to be conducted to determine the changes seen inside skeletal muscle cells after exposure to intense, unaccustomed damaging exercise. From these studies, researchers will be able to more effectively determine what signals or environments are responsible for causing oxidative stress, proteolysis as well as apoptosis. Additionally, future research should also target on the signal transduction pathways in skeletal muscle upon exposure to oxidative stress in an attempt to identify areas of cross-communication as possible areas for effective intervention.

Figure 1: Thiol redox status and its many accompanying roles.

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by EricT

Dietary Protein and Kidney Function

Thu, 29 Jul 2010 19:11:53 +0000

by William F Martin¹, Lawrence E Armstrong² and Nancy R Rodriguez³

Nutrition & Metabolism, 2005

Recent trends in weight loss diets have led to a substantial increase in protein intake by individuals. As a result, the safety of habitually consuming dietary protein in excess of recommended intakes has been questioned. In particular, there is concern that high protein intake may promote renal damage by chronically increasing glomerular pressure and hyperfiltration. There is, however, a serious question as to whether there is significant evidence to support this relationship in healthy individuals. In fact, some studies suggest that hyperfiltration, the purported mechanism for renal damage, is a normal adaptative mechanism that occurs in response to several physiological conditions. This paper reviews the available evidence that increased dietary protein intake is a health concern in terms of the potential to initiate or promote renal disease. While protein restriction may be appropriate for treatment of existing kidney disease, we find no significant evidence for a detrimental effect of high protein intakes on kidney function in healthy persons after centuries of a high protein Western diet.

Dietary protein Intake and Kidney Function

Dietary protein intake can modulate renal function [1] and its role in renal disease has spawned an ongoing debate in the literature. At the center of the controversy is the concern that habitual consumption of dietary protein in excess of recommended amounts promotes chronic renal disease through increased glomerular pressure and hyperfiltration [2,3]. Media releases often conclude that, "too much protein stresses the kidney" [4]. The real question, however, is whether research in healthy individuals supports this notion. In fact, studies suggest that hyperfiltration in response to various physiological stimuli is a normal adaptative mechanism [5-10].

The purpose of this paper is to review the available evidence regarding the effects of protein intake on renal function with particular emphasis on renal disease. This review will consider research regarding the role of dietary protein in chronic kidney disease, normal renal function and kidney stone formation and evaluate the collective body of literature to ascertain whether habitual consumption of dietary protein in excess of what is recommended warrants a health concern in terms of the initiation and promotion of renal disease. In the following review, high protein (HP) diets will be defined as a daily consumption of greater than or equal to 1.5 g/kg/day, which is almost twice the current Recommended Dietary Allowance but within the range of current Dietary Reference Intakes (DRIs) for protein [11]. The Institute of Medicine DRI report concluded that there was insufficient scientific evidence for recommendations of an upper limit of protein intake but suggested an acceptable macronutrient distribution range of 10–35% of total energy for protein intake [11].

While the optimal ratio of macronutrient intake for adults has typically focused on fat and carbohydrate [12], contemporary discussions include the role of dietary protein [13-15]. This is particularly true given the recent popularity of high protein diets in weight management [16]. Although the efficacy of these diets with regard to weight loss is still subject to debate, several studies have demonstrated favorable physiological effects [12,16-24]. This has led to a substantial increase in protein intake by individuals adhering to contemporary weight loss plans. As a result, the safety of habitually consuming dietary protein in excess of the Recommended Daily Allowance (RDA) has been questioned.

An Overview of Chronic Kidney Disease

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Chronic Kidney Disease (CKD) is defined as either kidney damage or a decline in renal function as determined by decreased glomerular filtration rate (GFR) for three or more months [25]. It is estimated that 1 in 9 adults in the United States meet this criteria, while an additional 1 in 9 adults are at increased risk for CKD [26]. In the general population, a decline in renal function is considered an independent risk factor for both cardiovascular disease and all-cause mortality [27]. However, the extent to which a mild diminution in renal function influences this risk is not known [28].

According to the National Kidney Foundation guidelines, CKD is classified into five stages, each of which directly correlates with the severity of the disease [25]. As one progresses from stage 1 to 5 there is a concomitant decline in GFR and thus renal function. The final stage, known as end stage renal disease, represents the most severe manifestation of CKD [29]. This classification system provides a universal standard for application of clinical treatment guidelines.

Hypertension is the second leading cause of CKD and accounts for approximately 30% of all cases in the U.S. [30,31]. In one study, hypertension was associated with a premature decline in renal function in men with normal kidney function [32]. Although, initial estimates of CKD prevalence in hypertensive individuals were about 2%, recent evidence suggests that prevalence rates may be significantly higher [33]. Blood pressure control is of particular importance in hypertensive individuals with CKD. This point has been demonstrated in several trials in which antihypertensive therapy slowed the progression of CKD [34-36].

Race, gender, age and family history are four risk factors for CKD [37-40]. Recent findings suggest that modifiable lifestyle risk factors (i.e., physical inactivity, smoking, obesity) are also associated with CKD. Limited data exist regarding the role of dietary protein intake as an independent risk factor for either the initiation or progression of renal disease but population studies have consistently demonstrated an inverse relationship between dietary protein intake and systemic blood pressure [41,42]. In a randomized control trial [43], dietary protein and fiber had additive effects in lowering 24-hour and awake systolic blood pressure in a group of 36 hypertensives. While these findings suggest that high protein diets may be beneficial to hypertensive individuals, additional research is warranted since increased protein intakes often result in increased consumption of certain micronutrients known to impact blood pressure (e.g., potassium, magnesium, calcium) [44].
Dietary protein and renal function

The relationship between dietary protein and renal function has been studied for over half a century [1]. In 1923, Addis and Drury [45] were among the first to observe a relationship between level of dietary protein and rates of urea excretion. Soon after, it was established that increased protein intake elevated rates of creatinine and urea excretion in the dog model [46]. The common mechanism underlying increased excretion rates was eventually attributed to changes in GFR [47,48] and Van Slyke et al. [49] demonstrated that renal blood flow was the basis for GFR mediated changes in clearance rates in response to increased protein intake. Clearly dietary protein effects GFR [50], with both acute and chronic increases in protein consumption elevating GFR [50,51].

Dietary Protein and the Progression of renal disease

Observational data from epidemiological studies provide evidence that dietary protein intake may be related to the progression of renal disease [52]. In the Nurses' Health Study, protein intake, assessed with a semi-quantitative food frequency questionnaire, was compared to the change in estimated GFR over an 11-year span in individuals with pre-existing renal disease [53]. Regression analysis showed an association between increased consumption of animal protein and a decline in kidney function suggesting that high total protein intake may accelerate renal disease leading to a progressive loss of renal capacity. However, no association between protein intake and change in GFR was found in a different cohort of 1,135 women with normal renal function (Figure 1.). The latter finding led the authors to conclude that there were no adverse effects of high protein intakes on kidney function in healthy women with normal renal status.

Figure 1: This figure is a plot of multivariate linear regression for change in estimated GFR according to quintile of total protein intake* in participants with normal renal function (n = 1135). Data are taken from Knight et al., Ann Intern Med 2003 Mar 18;138(6):460-7 [53].

Research by Johnson et al. [54], showed protein intake as a possible risk factor for progressive loss of remaining renal function in dialysis patients. Indeed, dietary protein restriction is a common treatment modality for patients with renal disease [55,56] and practice guidelines exist regarding reduced dietary protein intakes for individuals with chronic renal disease in which proteinuria is present [57]. The National Kidney Foundation (NKF) has extensive recommendations with regard to protein intake, which are a byproduct of the Dialysis Outcome Quality Initiative [58]. Again, it is important to note that these recommendations are not indicated for individuals with normal renal function nor are they intended to serve as a prevention strategy to avoid developing CKD. Despite the clarity of these guidelines, their mere existence has resulted in concern regarding the role of dietary protein in the onset or progression of renal disease in the general population [59].
Dietary protein and renal disease

Allen and Cope's observation that increased dietary protein induced renal hypertrophy in dogs [60] led to speculation that dietary protein intake may have deleterious effects on the kidney. Later research in the rat model produced evidence supporting earlier observations from canine research [61-63]. Recently, Hammond and Janes [64] demonstrated an independent effect of increased protein intake on renal hypertrophy in mice. In this study, changes in renal function (i.e., increased glomerular filtration rate and renal hypertrophy) were observed.

Currently, a combination of hormonal interactions and renal processes are thought to explain protein-induced hyperfiltration [65]. Increased glucagon secretion in response to protein administration induced hyperfiltration [66] subsequent to a cascade of events referred to as the"pancreato-hepatorenal cascade" [67]. It has been hypothesized that cAMP works in concert with glucagon to mediate GFR [68]. To date, however, this hypothesis has not been tested and other competing hypotheses suggest other novel mechanisms of protein-induced hyperfiltration [69].

While the effect of hyperfiltration on renal function in those individuals with pre-existing renal disease is well documented [52], the application of these observations to healthy persons with normal renal function is not appropriate. To date, scientific data linking protein-induced renal hypertrophy or hyperfiltration to the initiation or progression of renal disease in healthy individuals is lacking. The possibility that protein-induced changes in renal function are a normal physiological adaptation to nitrogen load and increased demands for renal clearance is supported by changes noted in renal structure and function during pregnancy [70]. GFR increases by as much as 65% in healthy women [8] during pregnancy, typically returning to nonpregnant levels by three months postpartum [7]. Despite these changes in renal function, pregnancy is not a risk factor for developing CKD [6].

The renal hypertrophy and accompanying improvements in renal function in the contralateral kidney that occur subsequent to unilateral nephrectomy also suggest these processes are an adaptive, and possibly beneficial, response [5]. Studies show, despite prolonged hyperfiltration, remnant kidney function remained normal and did not deteriorate during long-term (> 20 yrs) follow-up in nephrectomized patients [9,10]. Thus, compensatory hyperfiltration appears to be a biological adaptation to a variety of renal challenges that is not associated with increased risk of chronic kidney disease in healthy individuals.
The Brenner Hypothesis

Perhaps the most consistently cited reference with regard to the potentially harmful effects of dietary protein intake on renal function is that of Brenner et al. [3]. In brief, the Brenner Hypothesis states that situations associated with increased glomerular filtration and glomerular pressure cause renal injury, ultimately compromise renal function, and potentially increase the risk for or progression of renal disease. Brenner proposed that habitual consumption of excessive dietary protein negatively impacted kidney function by a sustained increased in glomerular pressure and renal hyperfiltration [3]. Since the majority of scientific evidence cited by the authors was generated from animal models and patients with co-existing renal disease, extension of this relationship to healthy individuals with normal renal function is inappropriate. Indeed, a relationship between increased glomerular pressure or hyperfiltration and the onset or progression of renal disease in healthy individuals has not been clearly documented in the scientific literature. Rather, findings from individuals with compensatory hyperfiltration during pregnancy and following unilateral nephrectomy suggest otherwise [9].

The Modification of Diet in Renal Disease (MDRD) study was the largest randomized multicenter, controlled trial undertaken to evaluate the effect of dietary protein restriction on the progression of renal disease [71]. Several variables, including GFR, were measured in patients with chronic renal disease at baseline and throughout the approximately 2 year follow-up period. Patients with renal disease randomized to the very low-protein diet group had slightly slower decline in GFR decline compared with patients randomized to the low-protein diet group. Further data analyses showed patients with lower total protein intake would have a longer time to renal failure and suggested that a lower protein intake postponed the progression of advanced renal disease. Using meta-analysis to assess the efficacy of dietary protein restriction in previously published studies of diabetic and nondiabetic renal diseases, including the MDRD Study, Pedrini et al. concluded that the progression of both nondiabetic and diabetic renal disease could be effectively delayed with restriction of dietary protein [56]. Indeed, current clinical guidelines for the management of patients with renal disease continue to be based on the premise that protein intake greater than that recommended or which results in a renal solute load in excess of the kidney's excretory capabilities will contribute to progressive renal failure in persons with compromised renal function. However, of significance to this review, is the fact that imposing these guidelines on healthy individuals with normal renal function is overzealous given the current status of the scientific literature in this area.
Dietary protein and renal strain

Concerns about level of dietary protein and renal function are often presented in public health guidelines [59]. In addition to the claims that high protein intake causes renal disease, some studies have suggested that renal function may be negatively affected by routine consumption of high protein diets [72-75]. Although high protein diets cause changes in renal function (i.e., increased GFR) and several related endocrine factors [1,76,77] that may be harmful to individuals with renal disease [52,53], there is not sufficient research to extend these findings to healthy individuals with normal renal function at this time.

The lay public is often told that high protein diets "overwork" the kidney and may negatively impact renal function over time [78]. In addition, a number of highly regarded organizations appear to support this line of reasoning [79] given the physiological processes required for excretion of protein-related metabolic waste products to maintain homeostasis following consumption of protein at levels in excess of recommended amounts. Increased consumption of dietary protein is linearly related to the production of urea [80] and urea excretion is controlled by the kidney. These processes are of significant energetic cost to the kidney and represent the physiological "strain" associated with increased protein intake [81].

The word "strain" is misleading given its negative connotation. In a press release [82], one group asserted that increased dietary protein "strains" the kidney via increased urea production, and causes dehydration and accumulation of blood urea nitrogen. This press release also suggested that these events synergistically overwork the kidney and predispose humans to CKD. Scientific research is often misrepresented in this context. Research from our laboratory [83] which is cited in the press release, does not support these contentions. Rather, we found that habitual consumption of a high protein diet minimally affected hydration indices. Changes in total body water and renal function were not measured.

The concept that increased dietary protein leads to dehydration may have originated from an unsubstantiated extension of a 1954 review of the nitrogen balance literature [84]. This review focused on the design of survival rations for military operations in the desert or at sea, when water supply and energy intake are limited. Since the excretion of 1 gram of urea nitrogen requires 40 – 60 mL of additional water, increased protein intakes in the study translated into an increased water requirement (i.e., +250 mL water per 6 grams of dietary nitrogen in a 500 Kcal diet) for excretion of urea nitrogen. This increased fluid requirement is situation specific and is not necessarily applicable to individuals whose calorie and water intakes are adequate. Presently, we know of no studies executed in healthy individuals with normal renal function which demonstrate a clear relation between increased dietary protein intake and dehydration or a detrimental "strain" on the kidney. Therefore, claims that a high protein diet promotes dehydration or adversely "strains" the kidney remain speculative.

Evidence in Healthy Individuals

Although the efficacy of high protein diets for weight loss has been evaluated, there have been no reports of protein-induced diminutions in renal function despite subject populations that are generally at risk for kidney disease (e.g., dyslipidemia, obesity, hypertension) [14,15,22,85-87]. A randomized comparison of the effects of high and low protein diets on renal function in obese individuals suggested that high protein diets did not present a health concern with regard to renal function their study population [65]. In this study, 65 overweight, but otherwise healthy, subjects adhered to a low or high protein diet for six months. In the high protein group, both kidney size and GFR were significantly increased from that measured at baseline. No changes in albumin excretion were noted for either group and the authors concluded that, despite acute changes in renal function and size, high protein intake did not have detrimental effects on renal function in healthy individuals. Similar findings were recently reported by Boden et al. [88] in a study of 10 subjects who consumed their typical diet for 7 days followed by strict adherence to a high protein diet for 14 days. No significant changes were noted in serum or urinary creatinine and albumin excretion, suggesting no ill-effects of a high protein diet on renal function.

Athletes, particularly in sports requiring strength and power, consume high levels of dietary protein [89,90]. In fact, many athletes habitually consume protein in excess of 2.0 g/kg/day [91]. Supplementation with amino acids will further increase dietary protein levels in these individuals [92]. Yet there is no evidence that this population is at greater risk for kidney disease or losses in renal function [90]. Poortsmans and Dellalieux [93] found that protein intakes in the range of ~1.4–1.9 g/kg/day or 170–243% of the recommended dietary allowance did not impair renal function in a group of 37 athletes. We found no data in the scientific literature to link high protein intakes to increased risk for impaired kidney function in healthy, physically active men and women.

Dietary Protein and Kidney function in Animal Models

Although there is limited research regarding the long-term effects of high protein intakes on renal function in humans, animal models have provided insight into this quandary. Mammals fed acute and chronic high protein diets exhibit increases in GFR and renal blood flow [94]. These changes, which are comparable to those observed in humans, led to the hypothesis that high protein intakes are associated with progressive glomerulosclerosis in the rat. Recently, Lacroix et al. [95] studied the effects of a diet containing 50% protein on renal function in Wistar rats and noted no abnormalities in renal function or pathology. Collins et al. [96] also reported no adverse effects of long-term consumption of high protein diets on renal function when two years of a diet containing 60% protein failed to evoke changes in the percentage of sclerotic glomeruli in rats. Robertson et al., [97] studied the effect of increased protein intake on hyperperfusion and the progression of glomerulosclerosis in dogs that were 75% nephrectomized. After four years of feeding diets that were either 56, 27 or 19% protein, no association between diet and structural changes in the kidney were observed.

To the best of our knowledge, there has been only one report of a potentially toxic effect of excessive protein intake on renal function in the rat. Stonard et al. [98] found a diet containing 33% protein produced tubular damage in a specific strain of female rats. However, findings from this study are limited by the fact that damage was induced by a bacterial single-cell protein (Pruteen).

In summary, studies documenting high protein intake as a cause of renal disease in any animal model have not been done. Rather, studies have typically focused on the interaction between protein intake and renal function in the diseased state. As a result, findings from these investigations should not be used as a basis for dietary recommendations for humans. Studies designed to characterize the effects of dietary protein intake on renal function in healthy subjects are warranted.
Dietary protein and kidney stones

The role of high protein diets in kidney stone formation has received considerable attention. Excessive protein intake increases excretion of potentially lithogenic substances such as calcium and uric acid [99,100]. Reddy et al. [101] noted that consumption of a high protein diet for six weeks was associated aciduria and urinary calcium and claimed that this constituted increased risk of stone formation in ten healthy subjects although none of the ten subjects developed renal stones. The severe carbohydrate restriction imposed in this study may have increased keto-acid production thereby contributing acid formation. Since consumption of fruits and vegetables usually produces a marked base load [102], restriction of these foods subsequent to the diet intervention may have also contributed to the net acid load.

Studies that claim an increased propensity for stone formation as a result of increased protein intake should be taken at face value because propensity is a surrogate marker and does not represent actual stone formation. Further, randomized control trials have not been done to test whether an increased tendency for stone formation is enhanced with consumption of a high protein diet.

Epidemiological studies provide conflicting evidence with regard to the association between protein intake and the predisposition for kidney stone formation. In a prospective study of over 45,000 men, researchers found a direct correlation between animal protein intake and risk of stone formation [103]. However, findings in women are difficult to interpret due to conflicting reports in the literature. While some studies have shown a direct relationship between animal protein intake and risk of stone formation in women [104,105], other work suggests an inverse relationship exists [106].

Conflicting findings regarding the role of dietary protein in kidney stone formation limit the development of universal guidelines with regard to a recommended protein intake for individuals at increased risk for stone formation [107]. It is not likely that diet alone causes kidney stone formation [108]. Rather, metabolic abnormalities are typically the underlying cause [109]. For example, Nguyen et al. [110] found that high intakes of animal protein adversely affected markers of stone formation in those afflicted with a stone causing disorder, while no changes were observed in healthy individuals. It has been suggested that one must have a preexisting metabolic dysfunction before dietary protein can exert an effect relative to stone formation [108]. This notion has been coined the "powderkeg and tinderbox" theory of renal stone disease by Jaeger [111]. This theory asserts that dietary excesses, such as high protein intake, serve as a tinderbox which, only in tandem with a metabolic abnormality (the powderkeg), can bring about stone formation. At the present time, however, evidence showing that a high protein intake is an inherent cause of this renal abnormality or is consistently associated with increased kidney stone formation does not exist.

Conclusion

Although excessive protein intake remains a health concern in individuals with pre-existing kidney disease, the literature lacks significant research demonstrating a link between protein intake and the initiation or progression of kidney disease in healthy individuals. More importantly, evidence suggests that protein-induced changes in renal function are likely a normal adaptative mechanism well within the functional limits of a healthy kidney. Without question, long-term studies are needed to clarify the scant evidence currently available regarding this relationship. At present, there is not sufficient proof to warrant public health directives aimed at restricting dietary protein intake in healthy adults for the purpose of preserving renal function.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

WFM conducted literature search, prepared the manuscript and assisted in presentation of final draft, LEA and NRR conceived the idea, organized contents and participated in preparation of final manuscript.

© 2005 Martin 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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