1Examine.comResearch Digest

Issue 4 February 2015

ERD

2Table of Contents05 Mood, dieting, and macros14 What If There Were No Dietary Guidelines?17 The iPad Hangover25 Can mice get cancer from steak?33 Sodium phosphate: a potentially underutilized ergogenic aid

39 On the whey to getting lean: one more round of whey vs. soy

45 Its (not) all in your head: how sodium intake affects headaches

51 Diets, fast and slow59 Is the glycemic index actually useful for making food choices?

66 INTERVIEW: Ivan Oransky69 INTERVIEW: Jessica Richman

3Kamal Patel, Editor-in-Chief

From the EditorLets play a little game of Choose Your Own Adventure, Health Research Edition. Itll only take a few minutes, but I hope it gets you thinking.

Youre going to be playing the role of someone scouring the web for evidence on a condition youve just been diagnosed with. The title is The Case of the Misleading Abstract. Foreshadowing? Yes.

On a random weeknight, youre supposed to be sleeping but are instead doing health research (hey, it should pay off eventually, right?). Since you havent read the February issue of ERD, you dont yet know how nighttime web-browsing is affecting your brain. Anyway, you stumble across an inter-esting abstract on pubmed. Apparently, alpha lipoic acid can help treat symptoms of a certain autoimmune disease. Not only is p less than 0.05, its less than freaking 0.001! Boom.

This is quite the useful bit of knowledge, because youve just been diagnosed with that autoimmune disease, and your doctor wants to put you on an unpleasant medication. Should you (A) go buy the supplement on Amazon, or (B) try to pull the full paper?

(A) You buy the alpha lipoic acid on Amazon It arrives in two days. You dont mention this to your doctor because hes a bit close-minded, but youre sort-of banking on the supplement helping, and hence delay starting your medication for a few weeks. A few weeks later, the pain hasnt gone away, youre still fatigued, and you have a new-found hate for alpha lipoic acid.

(B) You pull the full paper You cant actually access the full paper. Your significant other is a student, so eventually you pull the full paper and get all the details. The researchers used three different ques-tionnaires and took some blood draws, and out of all those measurements, only one was significantly better in the alpha lipoic acid group. You look up one of the references mentioned in the paper, and it actually concludes that alpha lipoic acid isnt likely to impact autoimmunity by itself. Also, the most convincing studies have been conducted on diabetic mice.

You dont buy the alpha lipoic acid. You have a little bit of nonbuyers remorse, but forget about it the next week. The $25 you saved becomes $436 by the time you retire.

Neither of these scenarios is uncommon. Most of us have bought way too many supplements based on either anec-dotes or tantalizing p-values. Granted, its really tough to face a health condition without an easy treatment, and that can make an abstract sound more promising than the full paper or body of research reveals. Money spent on ineffec-tive supplements can really add up, and sometimes it may be a better idea to focus on high-yield lifestyle habits like plenty of sleep and methods to combat stress. Dont take abstracts and their p-values as gospel, and best of luck on choosing your own adventure.

4ContributorsResearchers

Trevor KasheyPh.D(c)

Alex LeafM.S(c)

Courtney SilverthornPh.D.

Zach BohannanM.S.

Anders Nedergaard Ph.D.

Jeff Rothschild M.Sc., RD

Gregory LopezPharm.D.

Pablo Sanchez SoriaPh.D.

Kamal PatelM.B.A., M.P.H., Ph.D(c)

Editors

Arya SharmaPh.D., M.D.

Natalie MuthM.D., M.P.H., RD

Stephan GuyenetPh.D.

Sarah BallantynePh.D.

Katherine RizzoneM.D.

Spencer NadolskyD.O.

Mark KernPh.D., RD

Gillian MandichPh.D(c)

Reviewers

5Mood, dieting, and macrosTransient decrements in mood during

energy deficit are independent of dietary protein-to-carbohydrate

IntroductionWeight loss is big business. Some authorities estimate that 45 million Americans are trying to lose weight each year and spend upwards of $33 billion annually to do so. And it has been suggested that overweight and obese people experience significant improvements on a range of subjective symptoms after weight loss, regardless of diet composition.

However, dieting is also common in healthy-weight peo-ple looking to improve body composition and/or athletic performance. Consuming high-protein diets has become a popular method to aid in weight loss, as research has shown high-protein diets suppress hunger and preserve lean body

mass during energy restriction in sedentary and athletic pop-ulations. These benefits are important for dietary adherence and long-term success, but they are only a piece of the puzzle.

Dieting can be psychologically complex. The brain and ner-vous system communicate through small chemicals called neurotransmitters. Collectively, these neurotransmitters are what allow us to be aware, have emotion, remember things, move our body, regulate body temperature, sleep, and do or feel anything that our brain allows for. In fact, many dis-eases like Parkinson's, Alzheimers, depression, insomnia, ADHD, and anxiety have been linked to neurotransmitter imbalances.

6Figure 1: Select roles of mood-related neurotransmitters

There are many ways to classify neurotransmitters, but for our purposes its especially important to understand the role that amino acids play in different neurotransmitters. Some amino acids, such as glycine, taurine, and glutamate, serve directly as neurotransmitters, whereas other amino acids like tyrosine and tryptophan serve as precursors for neurotransmitter synthesis. Tyrosine is the precursor for the synthesis of the catecholamines: dopamine, adrenaline (epinephrine), and noradrenaline (norepinephrine). These neurotransmitters play a central role in attention, learning, motivation, and alertness. Tryptophan serves as the pre-cursor for serotonin, which can have an indirect effect on well-being and happiness, and plays a variety of other roles as well.

There is some controversy surrounding high-protein diets because the consumption of a lot of large neutral amino acids tyrosine, tryptophan, and the branch-chained amino

acids (BCAAs) have been shown to alter brain neuro-chemistry through basic competition. That is, these amino acids all share the same transporters that allow access into the brain, and thus they all compete for entry. Since the transporters are not specific to any one of the amino acids, the largest determinant of which enters the brain is their concentrations. Thus, if the plasma level of the BCAAs increases, then brain concentrations of tryptophan, tyro-sine, and their respective neurotransmitters is reduced. Theoretically, this may have negative consequences for mood, sleep, hunger, and overall liveliness.

On the other hand, carbohydrate intake has been observed to increase serotonin production secondary to insulin pro-moting tryptophan uptake in the brain. Theoretically, this may benefit mood. > The study under review aimed to com-pare the effects of different dietary protein-to-carbohydrate ratios on cognitive performance, mood, and sleep quality during short-term energy restriction.

Who and what was studied?The outcomes presented in this study were actually second-ary outcomes that were collected in a previous controlled trial. That trial aimed to evaluate the effects of protein intake on body composition, protein balance, and calcium homeostasis during a short-term energy deficit.

Thirty-nine volunteers (82% men) with an average age of 21 years and average BMI of 25 completed the study. Despite the technically overweight BMI, the inclusion criteria required study participants to be recreationally active (defined as three to four days a week of aerobic and/or resistance exer-cise) and physically fit (VO2peak of 4060 mL/kg/min).

The volunteers spent 31 days in a metabolic ward under constant supervision to ensure compliance to the prescribed diets and physical activity. Using a randomized block design, they were divided into three groups differing in pro-tein and carbohydrate content, but matched for total caloric intake and fat:

7 Low-protein (LP) group consuming 0.8 g/kg/day protein Moderate-protein (MP) group consuming 1.6 g/kg/day High-protein (HP) group consuming 2.4g/kg/day

The increase in protein was accommodated by an equal reduction in carbohydrates. Throughout the entire 31-day study period, protein was held constant at the assigned amount, fat was roughly 30% of total energy intake, and carbohydrates made up the remainder. Alcohol and smok-ing were forbidden, and all the subjects had lights out by 11:00 p.m. to ensure similar and adequate sleep between the groups. Nutritional sup-plements were also forbidden, with the exception of a daily multivitamin provided by the researchers.

The first ten days of the study served as the control period, with subjects practicing weight maintenance. Their energy expenditure was estimated from pre-study indirect calorimetry measurements and physical activity logs. During the subsequent 21 days, energy intake was reduced by 30% (through reductions in fat and carbohydrates) and physical activity energy expenditure was increased by 10%, for a total daily deficit of 40% com-pared to weight maintenance.

All diets were prepared by research dietitians and protein was provided as mixed, high-quality proteins (e.g. dairy, lean meats, and vegetable-based proteins). The subjects all performed regular physical activity. This included three days a week of low-volume resistance training, where the participants performed one single-joint movement per major muscle group (three sets of 15 repetitions) using workloads determined during the pre-study period, plus daily steady-state endurance activity at a low- to moderate-intensity (4060% VO2peak) pace on a treadmill or stationary bicycle.

A battery of cognitive tests were administered on days 11, 20, and 30 in the afternoon, about four hours after lunch. These time points were select-ed to represent the beginning (day 11), the midpoint (day 20), and end (day 30) of the dieting period. During the control period, three practice sessions were allowed for familiarization and to help reduce the potential of a learning effect (performing better because of practice rather than the variable of interest). During the cognitive testing, self-reported mood state was also assessed, utilizing the Profile of Mood States questionnaire. This questionnaire asks the question, how are you feeling right now? and has the responder rate 65 mood-related adjectives on a zero to four point scale.

Stratified block randomization

Randomization methods are very important for avoiding potential sources of bias, yet often are not reported adequately in journal articles. When it comes to designing clinical tri-al groups, balance is key. If two groups are tested, and one of the groups is a good deal healthier than the other one, the results are likely to be biased.

Randomization solves much of this problem, by giving each subject an equal likelihood of being in different study groups. But what happens when the sample size is small (as it often is in trials, as huge intervention studies require huge amounts of money)? The smaller the sample size, the more likely it is that groups will differ in char-acteristics that affect the outcome. You can statistically control for known factors, but you cant control for fac-tors that arent measurable or that you dont know about.

As opposed to simple randomization, randomization through a stratified block design allows the researchers to statistically remove variables of the study subjects that could potentially influence the study results but arent being studied. When randomly allocat-ing the subjects into the experimental and control groups, the researchers first stratify them into blocks based on traits they wish to hold constant

8Self-reported sleep quality was assessed every morning upon waking using a questionnaire asking how long it took to fall asleep, alertness at bedtime and upon waking, number of awakenings during the night, restedness upon waking, and four questions used to calculate an overall index of sleep quality.

Finally, blood samples were collected following an overnight fast on days 10 and 31 to quantify plasma amino acid levels.

In this study, 39 people were kept under observa-tion for a month while progressively consuming fewer calories and engaging in more physical activity as the study went on. Researchers adminis-tered cognitive tests and measured plasma amino acid levels.

What were the findings?The original trial that provided data for this study assessed the impact of protein intake on body composition. All three groups lost weight during the energy deficit, but the total fat loss as a percentage of weight loss was greater and the total fat-free mass loss smaller in the moderate- and high-protein

groups compared to the low-protein group. The diets during both the energy balance (first 10 days) and energy deficit phases can be seen in Figure 2.

Total mood disturbances, anger, and tension significant-ly increased in all groups from day 11 to day 20, but were not significantly different from day 11 to day 30 and were not significantly different between any of the groups. Additionally, confusion and vigor tended to increase during the energy deficit with no difference between groups. Depression and fatigue were the only mood-states that did not differ throughout the intervention.

There was also a lack of differences between any groups on the cognitive tests throughout the intervention. Although there were nine cognitive tests administered, only one test (the Four-Choice Reaction Time test) differed in any of the group comparisons, with the high protein group perform-ing better than the moderate protein group.

While all groups tended to improve on cognitive tests during the energy deficit period, the improvements were observed in tests that also happened to improve during every practice ses-sion within the energy balance phase. This suggests that the improvements through the energy deficit period were a result of a learning effect rather than being due to the energy deficit.

Figure 2: Protein & carb intake by study period

9There were also no significant differences in sleep quality throughout the intervention in any group or between the groups, with the one exception being a significant reduction in alertness upon waking in the low-protein group from day 11 to day 20, which returned to normal at day 30.

Finally, plasma BCAA concentrations were significant-ly higher and tyrosine concentrations significantly lower in the moderate- and high-protein groups relative to the low-protein group on day 11, but the difference between the high- and moderate-protein groups was not significant. Moreover, upon entering energy deficit (days 20 and 30), all groups showed significant elevations in plasma BCAA and reductions in tyrosine concentrations, with the between-group differences losing their significance. However there

was a slight trend for the high- and moderate-protein groups to retain their difference relative to the low-protein group.

The biggest shift in mood happened after day 11. Study participants felt significantly more anger and tension, though depression and fatigue were not affected. Mood did not change much after day 20. The results were fairly consistent between groups eating different amounts of protein, though the high- and moderate-protein groups had higher BCAA concentrations and lower tyro-sine levels than the low-protein group.

What does the study really tell us?The purpose of this study was to examine how the dietary protein-to-carbohydrate ratio influenced cognitive perfor-mance, mood, and subjective sleep quality. The premise is that manipulating dietary protein and carbohydrate intake would modulate neurotransmitter synthesis (primarily serotonin and dopamine). It was indeed shown that plasma BCAA and tyrosine, but not tryptophan, concentrations were impacted by the dietary treatments in a relatively short period of time, as the differences were noticeable by the end of the ten-day control period. However, at this time there were no differences between the groups in cognition, mood, or sleep.

At the end of the dieting period, the differences in plasma BCAA and tyrosine concentrations became insignificant. However, there was a trend towards significance, suggesting that a larger sample size or longer duration may have been needed to detect the differences. Regardless, mood changes were not different between the groups and were transient, returning to pre-dieting levels by the end of the interven-tion. This suggests that it may have been the caloric deficit, not the plasma amino acid concentrations, that increased anger, tension, and total mood disturbances.

Total mood disturbances, anger, and tension [...] were not significantly different between any of the groups, suggesting that diet composition had no effect on mood changes.

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Similar things can be said for cognition, with all but one change occurring without difference between the groups. Finally, subjective sleep was mostly unaffected during the entire study. The one exception was the low-protein group feeling less alert upon waking during the first ten days of the dieting period only. Seeing how dopamine and nor-adrenaline play a central role in alertness, this outcome could be the result of the reduction of plasma tyrosine con-centrations when the dieting period began. However, this would not explain why the sleep effects were not seen in the other groups.

So overall, what does this study tells us? It shows that a 40% caloric deficit in lean and recreationally active young adults

may have a transient effect on mood regardless of the pro-tein-to-carbohydrate ratio. It also tells us that the dietary protein-to-carbohydrate ratio does impact plasma concen-trations of BCAAs and tyrosine, but not tryptophan. This could be owed in part to the dietary supply of amino acids, with all groups consuming 16 times more BCAAs and seven times more tyrosine and phenylalanine than tryptophan. Nonetheless, this suggests that downstream effects of the dietary protein to carbohydrate ratio would be limited to the catecholamines and not serotonin.

However, tryptophan entry into the brain is facilitated by insulin, which acts to reduce plasma BCAA and tyrosine

levels by shuttling them into skeletal muscle and organs, and consequently also reduces competition for entry into the brain. Blood amino acid measurements were done after an overnight fast, when insulin is minimal. Similarly, the cognitive tests and mood questionnaire were completed roughly four hours after lunch, when insulin levels would be expected to have returned to baseline. Thus, it is possible that different outcomes would have been seen if the tests were administered closer to lunch when the subjects were in the postprandial state.

Another limitation of the study is that it was originally powered to detect changes in muscle protein synthesis and body composition, not cognitive outcomes. Also, without

an energy-balance control group for comparison, it is not possible to separate the effects of the energy deficit from the effects of learning or the environment.

When interpreting this study, its important to keep certain caveats in mind. This study does not tell us how the dietary protein-to-carbohydrate ratio would impact mood and cognition in obese people or in individuals who diet while already extremely lean. Nor does this study tell us how the ratio would impact performance in physique athletes such as bodybuilders or wrestlers. It also doesnt tell us how the ratio interacts with the absolute caloric deficit, as both groups in the study had an identical 40% reduction in energy intake.

[...] boosting protein probably wont help you avoid the doldrums of starting a diet. The initial ten days of beginning a diet may be the most psychologically difficult, but that this will pass with time.

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The results of this study suggest that mood is affected during caloric restriction, regardless of the specific macronutrient breakdown. However, since the participants of this study were slight-ly overweight young people, further research is needed to confirm whether this association holds true for other populations.

The big pictureThis study is one of many that examine differences in cog-nition and mood between low- and high-carbohydrate weight-loss diets that use different durations, study popula-tions, and magnitude of energy deficit.

For instance, in an eight week study of overweight or obese subjects, nearly all cognitive outcomes showed no difference between low or high carbohydrate groups. In a separate year-long study, obese subjects had similar mood improve-ments from both low-carb and low-fat diets in the first two months, but after a year the low-fat group had greater improvements. Cognitive outcomes werent different between groups.

For these types of stud-ies, outcomes have to be taken with a grain of salt. Mood improve-ments may be due to weight loss rather than diet composition. Study results also differ depending on how mood was measured, and com-pliance with the diets as well as the type of

nutritional counseling provided makes trials even harder to compare.

Energy deficits have also been explored in several studies. One found that two days of near 100% caloric deprivation had no effect on mood in healthy young men, and a study in physically active soldiers found a 30-day energy deficit (40%) to not significantly affect mood-state in comparison with a calorie-adequate diet.

In overweight and obese men and women, a six month long 25% energy deficit was shown to improve depression scores at three and six months, but participants who followed a 67% energy deficit for three months followed by a weight maintenance diet only showed improvement at the end of the intervention. In all three of these energy deficit studies, results also showed no significant changes in cognition as a result of dieting.

Perhaps surprisingly, energy deficits have often been shown to not impact sleep. In the short-term near 100% caloric

deprivation study men-tioned earlier, sleep was also unchanged, and a previous study in over-weight premenopausal women found that four weeks of an 800kcal/day diet (energy deficit of 1460 kcal/day) did not affect sleep quality.

Increasing the dietary protein-to-carbohydrate ratio has been shown to result in some cognitive improvements in other studies, but typically for only certain selected outcomes rather than cognition or mood as

[...] overweight and obese people experience significant improvements on a range of subjective symptoms after weight loss, regardless of diet composition.

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a whole. For example, one trial compared the effects of a normal (1.5g/kg) or high (3g/kg) protein diet in healthy normal-weight young adults. For three weeks, all foods and beverages were provided by the research staff. Cognitive performance improved in both groups, but only the high protein group significantly reduced reaction time. The high-protein group ended up with significantly higher plas-ma concentrations of the BCAAs, which the authors suggest may have been the cause of the improved reaction time

Collectively, the above suggests that changes in mood are reliant on a variety of factors, such as the length of the diet, magnitude of caloric restriction, and occasionally com-position of the diet. Although the evidence is somewhat mixed, these studies also suggest that dieting may improve mood in overweight/obese peo-ple more so than in lean people.

Importantly, while these other studies had dif-fering fat intakes, the current study controlled for fat intake so that the only dietary manipula-tion was the protein to carbohydrate ratio. It was also highly controlled, with subjects being housed in a metabolic ward and given all meals and beverages. Thus were able to derive a fairly specific conclusion: boosting protein probably wont help you avoid the doldrums of starting a diet. The initial ten days of beginning a diet may be the most psychological-ly difficult, but that this will pass with time. Additionally, it appears that cognition and sleep is likely to remain relative-ly unchanged throughout a dieting period. Its important to keep in mind that the results were in non-obese young people, so they cant be generalized to athletes with much greater caloric demands or to people who are pushing the boundaries of leanness.

The results of this study support the idea that changes in mood may be influenced more by the duration and magnitude of a diet, rather than its macronutrient composition.

Frequently Asked QuestionsWould BCAA supplements impact these neurotransmitters? Since BCAAs are the problem in regard to competition for entry of neutral amino acids into the brain, it stands to rea-son that supplementing high doses of BCAAs would have similar if not worse effects on brain chemistry.

A recent study evaluat-ed the administration of a BCAA, essential amino acids (EAA), or a milk EAA mixture on brain amino acid and neurotransmitter con-centrations. It found that the BCAAs in an amount similar to many low dose BCAA supplements that are currently being marketed does indeed

blunt increases in serotonin by competitively inhibiting the uptake of tryptophan from the bloodstream.

Can I just take supplemental tryptophan to increase sero-tonin levels and improve my mood? If only it were so easy. While serotonin levels are associated with mood, many other factors are involved. In studies where people are purposely deprived of tryptophan, some show a markedly worse mood. However, this is highly dependant on who the subject is, and those who have a history of depres-sion are more likely to experience the effect.

Tryptophan supplements have been widely studied, and do

Bottom line: Mood and depression issues rarely have quick fixes in the form of pills.

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improve mood (as well as sleep) in certain subjects. People often face choices between medicating for moderate depres-sion with SSRIs, or taking a supplement such as tyrosine or 5-HTP (the precursor to serotonin). Mood is an incredibly complex phenomenon, and unfortunately studies rarely if ever compare medications to supplements. And lifestyle factors such as stress and sleep can be as or more important than what youre putting in your mouth.

Bottom line: Mood and depression issues rarely have quick fixes in the form of pills. Supplements that can increase sero-tonin can also have side effects from too much serotonin being present throughout the body. Its usually best to take a step back and consider a variety of angles rather than a singular amino acid or other supplement.

What should I know?Jumping into a 40% energy deficit may result in mood distur-bances for the first ten or so days, which return to pre-dieting levels by the third week, regardless of the protein-to-carbohy-drate ratio. This matches up quite nicely with what many refer to as the low-carb flu. The lack of differences between the groups of the current study suggests that perhaps it should be called the dieting flu, as it appears that these effects are not isolated to low-carbohydrate diets. Similarly, cognition and subjective sleep quality showed minimal changes, some of which were transient.

When considered in conjunction with the benefits of higher protein diets during times of caloric restriction for muscle preservation and satiety, it seems prudent to not worry about the hypothetical problems that a high protein to carbohydrate ratio would have on brain chemistry and neurotransmitters, as these changes do not appear to significantly impact cognitive function. Any mood or cognitive disturbances that do occur appear to be transient and may be owed to the caloric deficit itself rather than the macronutrient ratios.

In the mood for diet analysis? Join us at the Facebook ERD forum to talk about low-carb flu, low-calorie blues, and how the evidence matches experience.

Any mood or cognitive disturbances that do occur appear to be transient and may be owed to the caloric deficit itself rather than the macronutrient ratios.

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What If There Were No Dietary Guidelines?

By Adele Hite

A recent episode of South Park lampooning Americas epidemic of gluten anxiety features the Secretary of the USDA agonizing over the realization that his agency has been recommending Americans consume large quantities of this dangerous substance as part of a high-carbohy-drate, reduced-fat diet. Determined to make amends, an animated version of Tom Vilsack asserts the importance of the nutrition guidance his agency dispenses: We are the USDA! Without us, people would be eating dirtand chairs. Vilsack ultimately saves the day by turning the Food Pyramid upside down, and while some would applaud this transformationeveryone ends up eating butter on a

stickI have no fondness for the Food Pyramid in any ori-entation, nor its replacement, MyPlate. Both shapes reflect the advice of the Dietary Guidelines for Americans (DGA), recommendations which divide the world of food up into two groups: healthy food Americans should eat and unhealthy food Americans should avoid. The basis for this division has little to do with beneficial nutrients food may or may not contain, but is instead based on the presence or absence of components thought to impact chronic disease. For the past 35 years, DGA guidance telling Americans what to eat and not eat in order to prevent chronic disease has remained remarkably consistent.

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Problem is, it hasnt worked very well.

During that time, rates of hypertension, high serum cho-lesterol, and heart disease mortality have dropped. Some researchers attribute these positive changes to dietary

improvements in line with DGA recommendations. Other researchers blame the fact that obesity rates have doubled and diabetes rates have tripled on our lack of adherence to DGA recommendations. It's a neat trick, giving the DGA credit for the good outcomes, but absolving them of the negative ones.

If Americans have indeed shifted their diets to align more closely with the DGA, the results are not what was originally intend-ed. On the other hand, if the U.S. government has been unable, for the past 35 years, to convince Americans to follow its dietary advice, maybe its time to quit trying.

If there were no DGA tell-ing Americans what to eat, would heart disease mortality spike? Unlikely, since heart disease death rates had been in decline for over a decade before the DGA were created. Would rates of obesity and diabetes climb even further? Under current conditions, i.e. DGA recommendations being followed or ignored depending on who you ask, the predictions are by 2030, more than half of Americans will be obese and, by 2050, one in three Americans will have diabetes. As obesity and diabetes rates did not begin their rapid ascent until after the DGA were created, it is not likely eliminating them would make matters worse.

In fact, the DGA are far more than health prescriptions that Americans do or do not follow. They are a powerful

political document, and they regulate a vast array of federal programs and services, influence health-related research, and direct how food manufacturers respond to consumer demand. Virtually no aspect of our food environment is unaffected by the DGA. It is worth considering what impact their absence would have on these other areas.

From the beginning, the DGA created clear winners and losers in our food system. Winners were processed food manufacturers who could reformulate products to meet

DGA standards; losers were farmers who pro-duced eggs and meat, which couldnt be easily modified. When the DGA directed consumers to avoid saturated fats, man-ufacturers replaced them with trans fats. Pink slime emerged from the beef industrys efforts to produce lower fat products.

Olestra, high-fructose corn syrup, polydextrose, soybean oil, and other

products of the food science laboratory were used to make food healthier, giving food manufacturers the opportunity to plaster health claims on labels and directing consumer attention away from whole foods, which carry no labels and no such claims. The disappearance of the DGA would help level the playing field and perhaps begin to eliminate some unwanted additives from our food supply.

Because the DGA influence research agendas, they have imposed their shape on emerging science; its outcomes reflect the policy in whose image it is made. Without the DGA, government-funded nutrition science would operate without the ideological constraints created by govern-ment-backed dietary advice. Without the DGA, a diabetes

It's a neat trick, giving the DGA credit for the good outcomes, but absolving them of the negative ones.

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prevention trial using a reduced-carbohydrate diet might not just be an idle fantasy, but an NIH-funded reality.

Without the DGA, federal nutrition programs could tailor their programs and practices to the needs of the individuals and com-munities that they serve, instead of being directed by remote, one-size-fits-all, top-down dietary guidance.

Finally, the DGA assert that science has unquestionably estab-lished links between diet and chronic disease. It hasnt, but the DGAs list of good and bad foods implies chronic disease is entirely under the control of the consumer. This assumption places the burden for prevention and cost of care on individuals, relieving the government and other institutions of the responsi-bility to improve economic, environmental, and social conditions related to health. Eliminating the DGA would open up the possi-bility for rethinking this approach to public health.

In many ways, the DGA were a big fat mistake. It is time we acknowledge that and move on, not by turning the current DGA

upside down, but by throwing them out altogether. Would Americans starting eating dirtor chairs? I dont think so. Maybe, they might just start eatingbetter.

Adele Hite is director and co-founder of Healthy Nation Coalition, a non-profit health advocacy organization dedicated to promoting critical nutrition literacy, individualized and community-based approaches to food and essential nutrition, and an understanding of food-health rela-tionships that goes beyond nutritional and caloric content of food. She is also a registered dietitian and PhD student in communication, rheto-ric, and digital media at North Carolina State University. She has masters degrees in English education and public health nutrition and has pur-sued graduate studies in nutrition epidemiology.

Prior to her graduate studies, she worked as the patient educator at Duke Lifestyle Medicine Clinic. Her current research involves a critical examination of the U.S. Dietary Guidelines for Americans, par-ticularly their history, their scientific underpinnings, their effects on the food-health environment, and the implications of these recommendations as a structure of power in the sociopolitics of food production and consumption.

Would Americans starting eating dirtor chairs? I dont think so. Maybe, they might just start eatingbetter.

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The iPad HangoverEvening use of light-emitting eReaders negatively affects sleep, circadian timing, and

next-morning alertness

IntroductionWithin the last few decades there have been massive developments in portable technol-ogy. High-powered devices have now become lightweight, convenient, and affordable. Many activities, like book reading, have been digitized. With the development of this technology, what once had been a common pastime to help get us to sleep may now actually be doing the opposite by causing a shift in our circadian rhythm for sleep.

A circadian rhythm is essentially an organism's daily internal clock. In humans it accounts for many of our physiological fluctuations throughout the day. A major mol-ecule that affects our sleep biorhythms is melatonin. Many have heard of melatonin used as a sleep aid, and for good reason. Melatonin is a hormone that is released by the pineal gland in the brain and is involved with sleepiness and sleep regulation.

Melatonin production is heavily influenced by sunlight interacting with retinal pig-ments. When light hits the retina, arylalkylamine N-acetyltransferase production is

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depressed. Arylalkylamine N-acetyltransferase is an enzyme that catalyzes a crucial step in melatonin biosynthesis. Therefore, when light is absent, melatonin concentration builds and sleepiness ensues.

What happens when the retina is exposed to light during sleepy time hours? Research has shown that exposure to artificial light at night suppresses mel-atonin levels and increases alertness. When melatonin is suppressed, the body is tricked into thinking it is still daytime and the circadian rhythm can shift, especially when this happens repeatedly. This shift makes it difficult to fall asleep. When a person cant sleep due to (light-induced) melatonin suppression, that signals there has been a shift in the biological clock, rel-ative to the normal 24-hour circadian cycle. As seen in Figure 1, levels of hormones in the body such as melatonin and cortisol fluctuate throughout the day. If the time course of one hormone is thrown out of whack, sleep and other physiological outcomes may be shifted as well.

Figure 1: Variation in melatonin and cortisol throughout the day

But why is this a problem? There is no definitive explanation as to why we need sleep, but we know that chronic deprivation is detrimental to our immune system, ability to perform, memory, and a laundry list of other things in regard to general health.

The International Agency for Research on Cancer, an agency directly related the World Health Organization, has classified shift-working as a probable carcinogen.

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Without question, sleep is important. In fact, chronic sup-pression of melatonin via evening light exposure has serious implicated health risks, such as cancer. Such conditions are frequently seen in shift-workers, like nurses and fire fighters. The International Agency for Research on Cancer, an agency directly related the World Health Organization, has classified shift-working as a probable carcinogen. Shift work represents an extreme of altered sleep patterns, but the mechanisms behind cancer incidence due to altered melatonin secretion and circadian rhythm shifts have been widely researched.

Cancer risk aside, there are other legitimate reasons to study this phenomena, as it directly relates to performance (both mental and physical) and general health. The aim of this study is to quantify the effects of light-induced melatonin suppression, caused by iPad use before sleep, on sleep quali-ty and feelings of lingering sleepiness after waking up.

Who and what was studied?The title of this paper includes light-emitting eReaders, but it is important to note that the experimental arm of this study was conducted exclusively with Apple iPads.

This was an inpatient randomized crossover study that included twelve healthy individuals who had all abstained from stimulants (which was lab-verified), and were oth-erwise free of any disorders that affected sleep quality and sleep patterns. Three weeks before the study began, the participants adhered to a strict sleep schedule of 10:00 p.m to 6:00 a.m, which was verified by logs, call-ins, and wrist actigraphy (which measures movement patterns).

The study participants lived on the premises for the duration of the study. Sleep schedules were fixed at 10:00 p.m to 6:00 a.m.

For five days in a row, four hours before lights out, but in otherwise dim light, the study participants either:

1. Used an Apple iPad on maximum brightness2. Read a print book

Lighting conditions were kept tightly controlled through-out the duration of the study. The iPad was at a fixed angle and distance (about 1.5 feet away) from the participants face to ensure equal light exposure between participants. Study participants were able to pick whatever literature they wanted, with the exception of comic books (possibly due to different light reflections with colorful comics) and techni-cal reading (possibly sleep inducing). Participants remained in their beds at a fixed angle for the entirety of their reading period, except for a 15 minute break at the 2.75 hour mark.

The research group measured:

1. How long it took the participants to fall asleep and sleep activity. a. Polysomnography (PSG) was performed on nights four and five. PSG records all biophysical activity and patterns during sleep. b. Electroencephalography (EEG) concurrently measured brain activity.

2. Melatonin levels a. On the fifth night, blood was drawn hourly and suppression was measured by comparison to starting measurements.

3. Alertness and sleepiness a. Self reported: participants completed a dimly-lit computer generated survey both one hour before sleep and approximately six times during their first waking hour. b. Physical measurements: EEG was taken upon waking under reproducible conditions. Study participants were asked to be still and stare at a black dot for 3 minutes. Riveting.

4. The group measured the spectral output of several commercial e-reader devices at the same distance the face was placed from the e-reader during the time of

the experiment.

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Study participants adhered to a strict waking and sleeping schedule during the study. Before bed, each participant read for several hours, using either an iPad or a print book.

What were the findings?iPad use consistently suppressed night-time levels of mel-atonin, which were significantly lower than when paper books were used. In fact, reading paper books resulted in no suppression. Once the lights were dimmed, the melatonin onset peak was shifted to a later time period with iPad use when compared to paper book use. Effectively, the iPad artificially inflated the length of the day perceived by the brain, by about an hour and a half! This shift in circadian rhythm for iPad users happened even though the room lights were dimmed.

These changes in melatonin were associated with changes in sleep patterns of the participants. On average, the iPad users took about 10 minutes longer to fall asleep when compared to paper book readers (at around 25 minutes, compared to 15 in the paper book group).

Coincidentally, there was also a decrease of Rapid Eye Movement (REM), or dream-inducing sleep, by about the same amount of time. However, the total amount of time spent sleeping, the efficiency of that sleep (defined as the percentage of time in bed spent actually asleep), and time spent in non-REM sleep were not significantly different between groups. While the exact function of REM sleep is not fully known, one theory is that its involved in memo-ry consolidation. As an analogy, computer hard drives can accumulate fragmented segments of memory after long periods of usage, and defragmenting the hard drive is a function of the Windows operating system to remedy that (or at least it was in the 2000s). A reduction in REM could have a multitude of impacts, including potential disruption of the blood brain barrier, which is theorized to be involved

in a variety of conditions such as multiple sclerosis and Alzheimers disease.

Keeping in mind the suppressed melatonin levels and decreas-es in REM sleep, iPad users reported lower levels of sleepiness in the evening. EEG readings confirmed this by showing less power in the delta/theta frequency ranges (associated with sleep and drowsiness) when compared with print book read-ers. The following morning, iPad users were much sleepier than print readers. It took iPad users on the order of hours to fully recover from their sleep episode and gain full alertness after waking in the morning. Chronic use of these devices before bed may impair wakefulness, to the point where iPad users might not feel truly awake until late morning.

Data for the print book readers was essentially the oppo-site, with greater feelings of tiredness in the evening and increased wakefulness in the morning. This increase of tiredness in the morning experienced by iPad users is likely related to decrease in REM sleep, and might be explained by the circadian phase shift. Since the wake times were set between the groups, and the phase was shifted to a later time, the study participants who used iPads essentially woke up when their body thought they should still be sleeping. If

Effectively, the iPad artificially inflated the length of the day perceived by the brain, by about an hour and a half!

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sleep and wake times were not regulated, its possible that this may not have been observed. However, since most people must wake at a particular time (but not go to bed at a particular time) its easy to see how these issues quickly compound.

The iPads peak light output is in the blue range of the visible spectrum at 452 nm. The physiological effects from this blue light makes sense given the light output of humans original light source: sunlight also peaks under 500 nm, and melanopsin pigment in the human eye absorbs in a peak range of about 480 nm. Its not unre-alistic to posit an artificial sun response when exposed to these higher energy photons. Even though this wavelength may not seem as bright to humans when exposed to an equal power of white light (which peaks at 612 nm), what mostly matters to the brain is the excitation of the correct eye pigments to depress the production of the arylalkylamine N-acetyltransferase, which in turn decreases circulating melatonin.

In the short term, a person may get acute sleep onset insomnia due to a shift in circadian rhythm. However, using electronic devices that emit blue light may have biological ramifications in the long term, especially since chronic melatonin suppression had been linked to an increased risk of various types of cancers. Unlike in this study, though, most people self-select their bedtimes (and to a lesser extent wake times). If a self-selected bedtime and wake time are not aligned with the bodys natural circadian rhythm, this, combined with blue-light expo-sure, may further exacerbate the phase-shift phenomenon and lead to chronic issues associated with sleep deprivation.

Lastly, a four-hour read time was established in this study, when many people may spend even longer times in front of a screen (either TV, computer, tablet, or phone) from afternoon to bedtime. The effects of longer exposure times are unknown, while tablet and phone displays continue to get brighter each year.

Study participants using iPads before bed took about ten minutes longer to fall asleep, experienced less REM sleep, and found it much harder to feel fully awake in the morning than people that read print books before bed.

The big pictureThe findings are somewhat scary for the average person who loves the Internet, which houses a vast collection of research on nutrition and health issues (and cat pictures) that can easily keep you up for hours. Back-lit tablets suppress and delay

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melatonin, affect EEG, negatively affect sleep quality, and hinder the ability to wake up in the morning. But do the findings of this rigorously controlled study apply to free-liv-ing humans?

At first glance, it may seem difficult to translate the data to the typical person not staying in such controlled con-ditions. But this is not the case. On the one hand, study participants remained in a bed (in a reclined position) for almost the entire duration of the study with an IV insert-ed and electrodes stuck to their heads. On the other hand, this may actually be a decent model system for the typical inactive adult.

Assuming a person works for eight hours per day at a desk (staring at a light emitting screen), sleeps for eight hours per day (but probably less) and then spends four plus hours per day using electronic devices for entertainment rather than work, its probably not much different than the lab setting.

The study participants also had to adhere to regular eating and sleeping times. Taking these things into account, it is likely that the negative effects of this study may even be understated. This study only had people in a phase shift-ed state for five days, where a person may be chronically phase shifting for years. This may lead to chronic infections, general malaise, premature fatigue/overtraining, and even precursors to metabolic syndrome.

The use of blue-light emitting devices is growing at a consis-tent rate. The use of these devices near bed time is likely to interfere with the bodys natural sleep patterns. Continued interference may lead to chronic sleep issues, which are linked to a host of negative conditions listed above. The study is not clear about how quickly this phase shifting takes place and how quickly it can be corrected. Since there are quantifiable differences between the two experimental groups, and both groups went through each condition, it is safe to say that these phase transitions can be altered over the course of days.

Take note that there is nothing uniquely bad about iPads or even tablets in general. Phones, laptops, and televisions are all devices that emit blue light at substantial levels.

Frequently asked questions: If I wanted to time my iPad use to avoid a phase shift, what is recommended? If a four hour exposure (from 6:00 p.m. to 10:00 p.m.) leads to a 1.5 hour phase shift, then presumably a substantially shorter exposure time ending much earlier in the evening would lead to less phase shifting and more appropriately timed melatonin secretion. But further research would be needed to know specifics. Keep in mind that if the four hour exposure occurred much earlier, in the daytime hours, mel-atonin would already be suppressed by sun/light exposure and you wouldnt have to worry.

If you have to use a tablet/laptop/phone at night, it may be helpful to dim the screen as low as possible, while still being able to read. One way to get around this is using blue-

If you have to use a tablet/laptop/phone at night, it may be helpful to dim the screen as low as possible, while still being able to read.

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light blocking glasses, which have amber lenses and hence make you look quite silly (but also smart and innovative compared to friends/mates that may mock you.) As seen in Figure 2 these have been shown to allow for melatonin production, and hence improve sleep quality and potentially even mood. If you cant or wont use these glasses, but still want to use your device at night, consider free programs such as f.lux for laptops or other alternatives for mobile devices. These automatically make the screen dimmer and more red as the sun sets. Some apps can even lower screen brightness more than a device allows on its own.

Can supplementing melatonin help to restore altered sleep rhythm? If melatonin is used as a sleep aid in order to fall asleep during the time of maximum sleep propensity, this is plausi-ble. Examine.com has a very extensive article on melatonin and its proper supplementation protocol. Melatonin may be an option for artificially attenuating the down-shifted mel-atonin peak if an iPad is used before bed. That being said,

melatonin isnt the only determinant of circadian rhythm, so artificially restoring melatonin levels probably wont eliminate all the negative effects of bright electronic devices.

So while the specific efficacy of melatonin for phase shift caused by iPads hasnt been researched, there is a cheaper and simpler solution. Occams razor dictates that the sim-plest answer is often correct -- rather than putting a bandaid on the problem of shifted sleep, you could work on enforcing a habit of natural light exposure. Some sunlight during the day, and no bright light in the hour or more before bed. It sounds tough, but starting slow (for example, shifting device use a bit earlier each week) can make the transition easier.

The study authors noted that the relatively easier time print-ed-book readers had in falling asleep is actually similar to the effect size of the popular insomnia medication Lunesta. Simply constraining bright light to earlier hours could be an effective and side effect free treatment option for those with sleep issues.

Figure 2: Effect of light and blue-light blocking glasses on melatonin

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Should I have any issues with my e-ink device? No, the spectrum of the e-ink device is comparable to a regular paperback book. However, some e-ink devices now have front-lit capacity, where light is directed on to the screen, rather than projected through it. There is no peer reviewed data on spectral emission from those devices in this study, but anecdotally some of these devices appear to have somewhat bluish hues (as opposed to the yellow of cer-tain lightbulbs). Reading these devices on a dim brightness setting with room lights turned off may be comparable or even better than reading a print book with dim room light-ing, since less of your field of vision will be lit. This has not been formally studied though.

Bulbs that can change color and brightness automatically, such as the Philips Hue, are increasingly popular. While you dont have to go out and buy fancy smartphone-controlled light bulbs (although they are kind of cool), at least dim-ming your room lights at night can greatly help melatonin secretion. What about the lucky people who can sleep with lights on, maybe falling asleep to the TV or while your part-ner is awake? Theyre not so lucky after all -- sleeping with the lights on causes sleep to be shallow with more likely arousals in the middle of the night.

Even being exposed to low intensity blue light, like those blue LEDs on power cords, can make you more drowsy the next morning. So it can pay dividends to be more aware of what kind of light surrounds you throughout the evening all the way into slumber time.

Will using a blue-light emitting device during the day inter-fere with my sleep patterns? This is unlikely, as the mechanism of this phenomena is associated with delayed melatonin accumulation. Melatonin is at imperceptible levels during the day, so there would be no quantifiable effect of inhibiting its synthesis with blue light. The sun emits the very same wavelengths in apprecia-ble amount.

What should I know? Most all modern back-lit portable electronic devices emit high-energy blue light. The human eye is sensitive to blue light exposure, leading to suppressed melatonin production. This suppression of melatonin production causes a shift in sleep patterns. Hence, sleeping out of line with your natural endogenous sleep patterns may lead to chronic sleep defi-ciency. Chronic sleep deficiency and consistently impaired melatonin production may increase the risk of many incon-veniences, disorders and diseases.

While other health topics (such as low carb vs high carb) may be subject to many more studies, one of the most import-ant but undercovered health issues may be the downstream effects of poor sleep caused by using these devices at night.

Dont you dare read this past 10pm. But if you choose to anyway, head over to the ERD private Facebook group to talk about how to improve your light-related sleep habits.

Even being exposed to low intensity blue light, like those blue LEDs on power cords, can make you more drowsy the next morning.

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Can mice get cancer from

steak?A red meat-derived

glycan promotes inflammation and cancer progression

IntroductionRed meat is one of the foods the media loves to hate, per-haps while still secretly loving it. Any time new research is published that deals with red meat consumption and X (where X might be cancer, heart disease, diabetes, etc.) the major news outlets pick it up, running scary headlines to attract clicks. The science, however, is typically a bit more nuanced than the bold claims of news headlines would lead the average reader to believe. So is there actually anything to worry about when eating red meat?

There is a modest but consistent correlation between diets high in red meat and cancer risk in human epidemiological studies. Scientists havent been able to figure out why this link exists yet, or if the risk is increased by red meat directly or through some other related factor. A number of hypothe-ses have been proposed: grilling red meat creates dangerous compounds, the iron in red meat generates free radicals, or people that eat more red meat are more likely to engage in other diet and health behaviors that promote cancer, such as a high fat or low vegetable diet (which is largely based on correlational findings). So far, there isnt enough substantive

proof to hold any of these reasons up as the definitive cause of the increased cancer risk.

Although there is no definitive proof, the collection of mechanisms, human biomarker RCTs, animal studies, and observational studies do see to support the hypothesis that red meat increases digestive cancer risk. Since there proba-bly will never be a human RCT with red meat as a variable and colorectal cancer as an outcome, were unlikely to be able to assess causality in humans.

This particular paper attempted to explain one possible mechanism involved in the meat-cancer correlation from an immune response standpoint. Our simplified images of a cell typically depict a roundish circle denoting the cell membrane, with a bunch of stuff inside the cell. In reality, cell surfaces are covered with different kinds of mole-cules sticking out from the cell membrane. Many of these molecules are long sugar chains made up of units called monosaccharides. The researchers looked at a particular group of monosaccharides called sialic acids, which are linked into larger structures known as glycans.

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The two sialic acids of interest were n-acetylneuraminic acid (denoted Neu5Ac) and n-glycolylneuraminic acid (denoted Neu5Gc), which are seen in Figure 1. Structurally, these two molecules are identical except for an additional hydroxyl (-OH) group on Neu5Gc. These molecules are found in a lot of animal-based dietary sources in different levels, with beef and caviar having the highest levels of Neu5Gc.

Neu5Gc is interesting, because its not something that humans can synthesize from Neu5Ac - the gene that codes for the enzyme needed to add on the hydroxyl group had a sequence deletion several million years ago and thus is nonfunctional. This likely conferred several evolutionary advantages. First, it may have been a factor in our ability to increase our brain development beyond that available to our primate cousins. Second, certain pathogens such as select strains of malaria as well as an E. coli toxin bind to Neu5Gc, so lacking the enzyme necessary to synthesize Neu5Gc

would have provided a resistance advantage for these dis-eases many millennia ago.

Despite this genetic change, Neu5Gc is still found in low levels in normal human tissue - so any molecules would have to come from dietary sources and then be incorporat-ed into our own cell membranes. Its also found in higher levels in malignant tissue. The researchers speculated that because this molecule is foreign to our bodies, our immune systems would react to it by producing antibodies to attack it. Indeed, it has been shown that 85% of people tested had antibodies against Neu5Gc. It is not known why 15% of the people tested did not possess the antibodies.

An immune system that is constantly turned on results in inflammation. Markers of inflammation increase when the immune system is fighting off a foreign pathogen. In acute situations, inflammation is beneficial! However, were learn-

Figure 1: Humans and Neu5Gc

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ing that chronic inflammation does not do a body good. Chronic inflammation has been linked to heart disease, various bowel syndromes such as irritable bowel syndrome (IBS) and Crohns, and yes, cancer.

So, we finally have a hypothesis: A) red meat consumption leads to B) incorporation of a foreign molecule into our bodies, which leads to C) an immune response to the for-eign molecule, which leads to D) systemic inflammation, which leads to E) an increased incidence of cancer. The researchers used simulations of A and C, and evaluated their hypothesis in mice.

Though the media often links red meat consump-tion to an increased risk of cancer, scientists are still trying to determine what aspect of red meat results in cancer, or if this link exists at all. Researchers in this study tried to determine if red meat consump-tion results in systemic inflammation due to the presence of foreign, meat-derived molecules.

Who and what was studied?To confirm and quantify previous findings, the research-ers used a new analytic method to determine the amount of Neu5Gc in different foods. The results are summarized in Figure 2. Neu5Gc was absent in fruits and vegetables, most seafood, poultry, and butter. It was found in low lev-els in milk and cheeses, bison, lamb, and pork. In beef, the Neu5Gc content was approximately 2-30 times higher than in other red meats and ranged from 0.025-.231mg/g, the highest of any of the tested foods other than caviar. The Neu5Gc content of beef varied greatly however, and the lower range was more in line with other foods. By contrast, poultry, dairy, and seafood were all high in Neu5Ac.

The researchers used a genetically modified mouse mod-el for their experiments, as is often done in initial in vivo studies. This particular mouse had the Cmah gene removed, meaning that they could not produce the cytidine mono-

phospho-N-acetylneuraminic acid hydroxylase (CMAH) enzyme needed to convert Neu5Ac to Neu5Gc. Unlike most of our mammalian friends, including primates that are still very genetically similar to us in other ways, humans do not produce a functional CMAH enzyme due to a deletion in the gene sequence for the enzyme. So like in humans, any Neu5Gc in these genetically modified mice would have to come from dietary sources.

Keeping the notations straight: All gene symbols are italicized (ex. Cmah) while all protein abbrevi-ations are all caps and non-italicized (ex. CMAH). Human gene symbols are written in all caps, while mouse and rat gene symbols capitalize only the first letter. So the full length mouse Cmah DNA sequence produces the CMAH enzyme, while the truncated human CMAH DNA sequence would produce no functional enzyme.

Figure 2: Neu5Gc in common foods

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Male mice were fed a normal diet, or a normal diet supple-mented with porcine submaxillary mucin (PSM). Translation: pig salivary gland excretions, yum. PSM has a high concentration of Neu5Gc and was meant to simulate the con-sumption of red meat in humans. The PSM-supplemented mouse diet contained 0.25mg of Neu5Gc per gram of feed, which is similar to the highest concentrations seen in red meat. After being fed this diet for several weeks, the levels of Neu5Gc in the mouse were similar to levels observed in humans adhering to a red meat rich diet for several years.

Its important to note that most epidemiological data in humans has linked diets high in red meat to an increased risk of colon and colorectal cancer. In this particular mouse model, however, the organ of interest for spontaneous tumor formation was the liver (hepatocellular carcinoma, or HCC). The researchers used liver cancer as an outcome because this mouse strain is naturally susceptible to spontaneous liver tumors. So the choice of liver cancer was somewhat arbitrary -- if the strain had been susceptible to pancreatic cancer, they may have used that as the outcome instead.

To create models of inflammation similar to humans, PSM- and control-fed mice were immunized against Neu5Gc by injecting red blood cell ghosts (which are empty red blood cells) that did or did not contain Neu5Gc. This caused the

animals to mount their own immune response against the Neu5Gc.

Two additional experiments created the anti-Neu5Gc immune response prior to feeding and looked at HCC tumor formation. One tested the specificity of the immune response by feeding the mice the PMC enhanced diet, which created elevated levels of Neu5Gc, or a diet enhanced with the unhydroxylated precursor molecule Neu5Ac. A second experiment compared pre-immunized wild-type mice that had a functional Cmah gene to the genetically modified mice without the Cmah gene.

What were the findings?The first experiment showed that elevated markers of inflammation were only seen in the mice that were fed PSM-enhanced food for 12 weeks prior to receiving an injection of Neu5Gc antigen. Compared to mice that were fed standard food for the same time period, or fed PSM-enhanced food but received a control injection, levels of interleukin-6, serum amyloid A protein, and haptoglobin were all elevated at highly statistically significant levels. This was also confirmed to happen in a dose-dependent manner; as the injected antigen concentration increased, so did the levels of inflammation markers.

[...] most epidemiological data in humans has linked diets high in red meat to an increased risk of colon and colorectal cancer. [...] the organ of interest for spontaneous tumor formation was the liver.

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In the second experiment, the test mice were first exposed to Neu5Gc immunogens (which are able to induce an immune response in addition to an antibody response) through injections of red blood cell (RBC) ghosts. The mice were then fed either PSM-enhanced diets, or diets rich in Neu5Ac through supplementation with edible birds nest (EBN). Translation: the salivary secretions of the swiftlet bird, highly prized as a culinary delicacy. Yum?

Because the mice lacked the Cmah gene, they were unable to convert the dietary Neu5Ac to Neu5Gc. Here, elevated interleukin-6 levels were seen only in the PSM-fed mice and not in the EBN-fed mice. Additionally, 2 out of 7 mice (29%) in the PSM feed group developed HCCs over the course of 55 weeks, whereas none of the mice in the EBN feed group developed tumors.

The final experiment compared the genetically modified mice with their wild counterparts. Mice were pre-ex-posed to either chimpanzee RBC ghosts with cell surface Neu5Gc immunogens, or human RBC ghosts with cell surface Neu5Ac immunogens. All mice then received the PSM-enhanced food. After 85 weeks, a comparable num-ber of wild type and genetically modified mice that had been exposed to the Neu5Ac immunogen had developed

HCCs (9% and 7% respectively) but 47% of the genetically modified mice exposed to the Neu5Gc immunogen had developed HCCs.

Mice fed diets high in a cell surface sugar mol-ecule found in red meat had higher levels of inflammation markers. The inflammatory response was specific to Neu5Gc and not the simi-lar Neu5Ac precursor molecule. The combination of consuming that sugar molecule and manipulat-ing the mouse immune system to make antibodies against that sugar molecule caused mice to devel-op more liver tumors than control groups.

The big pictureScientists crack why red meat is linked with cancer - and SUGAR may be to blame - Headline on the Daily Mail, 12/30/14

Contrary to media assertions claiming that scientists now know why red meat causes cancer, this study actually had some limitations. First off - there is no human data present-ed. There is an interesting mechanism proposed and a very carefully designed model created to ask a specific mecha-nistic question, but this may just be the first baby step on a long journey to knowing the true cause, if a single one even exists, for the increased incidence of cancer seen in consumers of red meat in large quantities. Mice models are almost always the first starting point for asking a question about biological cause and effect, but results should nev-er be taken as conclusive or directly applicable to humans at this stage. Cancer has been caused and cured in mouse models a dozen times over, in ways that have turned out to be completely inapplicable in humans.

The study design itself, aside from being only conducted in mice, had its own limitations. Studies in genetically similar mice provide nowhere near the applicability of data that a

Scientists crack why red meat is linked with cancer - and SUGAR may be to blame. - Headline on the Daily Mail, 12/30/14

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large scale human study that includes a wide variety of population factors (age, sex, race, weight) would. Also, the PSM-enhanced food intervention was meant to simulate only red meat consumption, not to simulate a typical human diet that is usually full of varied food products other than red meat. For example, a recent small study in humans suggested that consumption of a certain type of starch may counteract some of the cancer risk effects of red meat consumption. And the immune exposure to the Neu5Gc immunogen in the final experiment introduced an external factor at a single point in time, instead of a lifetime of immune system exposure that likely has varied and currently unknown effects. The immune sys-tem is incredibly complex, and there are examples of immune system responses having both pro- and anti-cancer effects.

As the study authors note, there is currently no published research that examines the correlation of anti-Neu5Gc antibodies in humans with cancer risk. So it will be important for future research to examine the mechanism found in this study in a human sample. Finally, there is the question of organ system relevance. This particular mouse model was used because there is a low level background inci-dence of spontaneous tumor formation in the liver over time, which more closely resembles the spontaneous formation of tumors in older humans rather than tumors that are artificially implanted in mouse organs for research purposes.

However, red meat consumption has not been correlated with increased liver cancers. Some of the primary non-genetic risk factors for that disease are certain viral infections and alcohol consumption, both of which may also involve some aspect of chronic inflammation, but have never been linked to Neu5Gc. Cancer is a complex disorder, so its difficult to draw direct comparisons between a tumor that forms in the liver in one species versus one that forms in the colon in anoth-er species. The tumors in the mouse did show incorporation of Neu5Gc into the tissue, but Neu5Gc has been found in a number of different malignant tissues in humans (as well as in healthy tissue), so there may be non-specific incorporation of the molecule into tumors in general.

The results of this study suggest a possibly novel explanation for the correlation between red meat consumption and cancer, and might be able to explain some of the contradictions with previously proposed explanations. The jury is still out on whether this is relevant to humans. The research team believes in the importance of this study, however. The last two authors listed on the paper have licensed anti-Neu5Gc antibody technology from their institution and co-founded a com-pany that is investigating targeted antibodies as a potential cancer therapeutic. Its possible that regardless of any mechanistic explanations, Neu5Gc still might be an interesting new target for cancer drugs, or perhaps a biomarker that can be used in additional research.

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This study provides evidence to support a molec-ular link between meat consumption and cancer caused by inflammation, but since no human evidence was gathered in this trial, much more research is needed before these results can be applied to people.

Frequently asked questionsHow applicable are these results to humans? The fact that the genetically modified mice lacked the gene that is also non-functioning in humans did make this mouse model more human-like for the purposes of this studys aims. The quantity of the food exposure is at least

somewhat similar to human intakes, unlike some studies that show that a particular chemical or food is carcino-genic when fed to rats in 100 or 1000 times the quantity a human could ever possibly consume. That being said, it would be nearly impossible for a human to consume a 100% beef diet consisting of the highest-Neu5Gc beef, except for the small number of people who eat only red meat and no plant products.

There are several reasons why the results may not apply to humans. Mice were consuming only the enriched feed in the experiments, whereas humans typically have a much more varied diet that does not include only red meat. Also,

no other related factors such as other dietary patterns and exercise were evaluated. And then theres the question of the differing effects of a sudden immune trigger by introduc-ing exposure to an antigen or immunogen, compared to a lifelong antibody exposure in humans that likely begins as soon as a child begins eating solid foods. Finally, the organ of interest in the mice was completely different than the organ of interest in humans, so drawing any direct compari-sons at this point is challenging.

Should I change my diet? Probably not solely as a result of this study. While there are some interesting mechanistic correlations in the data, there is too little evidence to be able to draw conclusions from these experiments alone. This particular study was not attempting to add to the body of knowledge that shows

a slight but consistent correlation between red meat con-sumption and elevated cancer risk in humans, but rather attempting to tease out a possible molecular cause for the effects seen, given that previous theories such as mutagens created by grilling and generation of free radicals may not explain the whole story.

Even one of the study authors commented in an interview that dietary changes are probably not necessary for every-body, and if this line of research does bear out it may be more useful for people with either a previous personal his-tory of cancer, or a family history of cancer.

Cancer has been caused and cured in mouse models a dozen times over, in ways that have turned out to be completely inapplicable in humans.

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Should I be concerned about inflammation? What can I do about it? Possibly - a lot of studies have shown that chronic inflam-mation in general has a lot of negative health effects. As mentioned previously, even low levels of inflammation have previously been correlated with a number of negative health effects. Regardless of any specific connections that may come from further inquiry of this data, making efforts to reduce systemic inflammation is likely a healthy long term choice.

Quite a few supplements have been touted as reducing inflammation, but here too much more research is needed. A number of diet and lifestyle changes can be easily made though. Many of the things that reduce inflammation, such as reducing tobacco and excessive alcohol use, improv-ing sleep, consuming more plant-based foods, increasing exercise and utilizing stress reduction techniques, promote general health outside of any inflammation concerns as well.

What should I know?In a very carefully designed and controlled experiment, genetically modified mice were fed a diet meant to simulate consumption of red meat (and only consumption of red meat, rather than red meat in the context of a much broad-er and varied diet). After being exposed to an immune challenge against a cell surface molecule found in red meat, the mice had increased markers of inflammation and an increased occurrence of liver tumors.

More research is warranted into this possible mechanism, as there isnt yet human data, so applying these results directly to humans is more speculative at this time. In terms of red meat and protein in general, Examine.com has looked at the human science behind the observed increase in cancer risk multiple times, most recently here and here.

To discuss mouse models, in vivo experiments, and recipes with and without red meat, visit the ERD Private Forum on Facebook.

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Sodium phosphate: a potentially underutilized

ergogenic aidEffect of sodium phosphate supplementation

on repeated high-intensity cycling efforts

IntroductionPhosphate doesnt get much attention in the nutrition and supplement world, but it performs many important func-tions during exercise and everyday life. These include acting as an intracellular buffer and enabling the release of oxygen from hemoglobin. It also plays a critical role in energy pro-duction as a part of the basic structure of phosphocreatine and adenosine triphosphate (ATP). Phosphocreatine serves as an energy store that is available immediately during exer-cise, and can release energy without the need for oxygen. ATP contains three phosphate groups and is often referred to as the bodys energy currency.

Sodium phosphate has shown promise as an ergogenic aid for endurance athletes thanks to a growing body of research, though it is relatively unknown whether supplementation improves performance outside of a lab, in the context of the ever-changing demands of athletic competitions. Previous research has found improvements in maximal aerobic capacity (VO2 max) after supplementation, though mixed results have been found for lower intensity endurance performance.

The purpose of the study under review was to investigate the effects of sodium phosphate supplementation in a

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research setting that's a more realistic reflection of real-life cycling condi-tions (repeated maximal sprint and short time-trial efforts), after six days of sodium phosphate supplementation, as well as four days after stopping supplementation, to determine any lasting effects.

Who and what was studied?Seventeen competitive male cyclists with an average age of 34.7 completed this study. As seen in Figure 1, these are elite level athletes who ride about 200 miles per week, with an average of 5.4 years of racing experience and VO2 max of 71 ml/kg/min.

Figure 1: Elite male competitive cyclists in the study

After an initial familiarization session and assessment, baseline perfor-mance was measured, followed by six days of supplementation with either sodium phosphate or a placebo. The performance testing was then repeated on day one and day four after stopping the supplementation.

This was a double-blind placebo-controlled study. Participants were giv-en either 50 milligrams per kilogram of fat-free mass per day (about 3.3 grams) of sodium phosphate or placebo (mix of glucose and table salt), divided into four doses and taken with meals (every four to five hours) for six days.

Great care was taken to replicate the potential confounding variables before each test. Participants did not exercise for 24 hours before each trial, and testing took place at the same time of day (within an hour) to control for

Why do study results differ for a given ergogenic

supplement?

One reason that sports supplements can show benefit in some studies but not others is because there are many different testing procedures that researchers can use to deter-mine if there is an effect from the supplement trial.

For example, studies can test participants using a time-trial (cov-ering a pre-set distance as quickly as possible), time to exhaustion (maintaining a pre-set pace for as long as possible), or repeated sprint tests (generating as much power as possible each time). Within these different protocols there is a lot of potential variability, like the dis-tance of the time trials, the intensity for the time to exhaustion tests, or the number of repeated sprints to be measured, as well as rest time between efforts, whether the partic-ipants are recreational athletes or trained professionals, etc.

Underlying all of these variables are gender differences, as men and women can differ significantly when it comes to fuel sources, metabo-lism, and specific adaptations to exercise. And most studies, including this one, have been in males only.

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circadian variation. Participants also kept a 24-hour diary of all food and drink intake prior to the initial test and were required to replicate that energy intake as closely as possible.

The test protocol was modified from cycling race simula-tions used in previous research, and attempted to emulate the constant up and down effort of actual racing. This test took 43 minutes to complete, which is substantially shorter than cycling road races. The test was, however, similar to criterium and certain track cycling races.

The protocol itself was a mix of four sets of 6 15 second maximal sprints (with 45 or 15 seconds recovery in between sprints) and two sets of five minute time-trials. Active recovery for three minutes (pedaling at 100 W) separated each set.

Seventeen competitive male cyclists supplement-ed sodium phosphate or a placebo for six days. Performance tests were done on the first and fourth day after supplementation stopped.

What were the findings?Increases were seen for overall power output (5%), as well

as overall power output during sprints (5%) and time trials (4%) in the sodium phosphate group. Supplementation had no impact on performance during the first set, but it led to performance improvements in the second, fourth and fifth set, effectively reducing the fatigue seen in the later sets of sprints. No differences were seen in the placebo group during any set of sprints.

Similarly, supplementation led to an improvement of 9% compared to baseline during the second time trial, which was set six. It is hard to say why the power output in set six was higher than set three, but it may be due to psychologi-cal factors related to the final section of the test. Again, no differences were seen in the placebo group during either of the time trial sets.

Another important aspect of this study is that no differences in power output were found between day one and day four in the sodium phosphate group, meaning the effects of the supplementation were still present four days after supple-mentation had ceased. No changes in power output were observed in the placebo group throughout the testing.

No differences in serum phosphate concentrations were reported between the groups at baseline, day one, or day four. However, compared with baseline, serum phosphate

What the heck is the smallest worthwhile change?P-values are used in research in order to establish statistical significance, i.e. the probability of whether or not a relationship between two variables has occurred by chance and how strong the relationship is. But often there isnt a way to make inferences about the clinical or real-world significance of the effect.

Sometimes, useful effects may not be statistically significant, while statistically significant effects may not always be actually useful. Using an alternative sta-tistical model, researchers can establish the smallest change that would still be beneficial (or harmful) and use the confidence limits to make a qualitative state-ment about the real-world significance of the changes. This study also classified outcomes for the smallest worthwhile change as beneficial, trivial, or harmful.

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actually decreased in the sodium phosphate group on day one and day four, while serum phosphate concentrations in the placebo group remained unchanged.

Total work (measured in kilojoules) increased in the sodium phosphate group on day four, while the increases seen on day one were not statistically significant. However, analysis for the smallest worthwhile change indicated that improve-ments in overall power output and overall sprint power output (but not time trial power output) would likely still be of benefit in competition. No changes were seen in the placebo group.

Cyclists supplementing sodium phosphate expe-rienced a 5% boost to power output during the performance test. Most of the benefits were observed later in the tests, suggesting sodium phosphate can reduce fatigue.

What does the study really tell us?This study adds to the growing evidence that suggests sodium phosphate may be an effective ergogenic aid for

endurance athletes. Six days of supplementation resulted in improved performance (greater work and power outputs) during a simulated cycling road race, which included a mix of repeated short-duration sprints and five-minute maximal efforts. Impressively, the benefits still existed four days after supplementation had stopped.

Since the test used in this study took 43 minutes to com-plete, it is unclear how these benefits would translate to a road cycling race lasting three to seven hours. However, because of the lingering effects of the supplementation, it is reasonable to think that sodium phosphate would bene-fit endurance athletes competing in events lasting not only from 15 minutes to one hour, but likely into the four to seven hour window of elite road races.

There are a number of proposed mechanisms behind these improvements, which the study did not specifically explore. These include:

Increased phosphate availability contributing to cre-atine phosphate synthesis, phosphate-stimulated glycolysis, and enhanced oxidative metabolism (even with no changes in serum phosphate levels).

Enhanced red blood cell 2,3-diphosphoglycerate

[...] it is reasonable to think that sodium phosphate would benefit endurance athletes competing in events lasting not only from 15 minutes to one hour, but likely into the four to seven hour window of elite road races.

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(2,3-DPG) synthesis, promoting a decreased affinity of hemoglobin for oxygen and resulting in great-er unloading of oxygen to the peripheral tissues. Previous research has shown that it took approxi-mately two weeks for RBC 2,3-DPG concentration to return to baseline following only three days of sodium phosphate loading.

Improved myocardial efficiency, providing a great-er stroke volume (and cardiac output), leading to increased and more efficient oxygenation of the mus-cles during exercise.

Improved hydrogen ion buffering capacity, which is important for repeated sprint ability.

All of these factors may have played a role in this study, con-sidering this protocol would have engaged multiple energy systems (creatine phosphate, anaerobic glycolysis, aerobic glycolysis) during the course of the test.

This study adds to the growing body of evidence that supports the use of sodium phosphate as an ergogenic aid for endurance athletes.

The big pictureSix days of sodium phosphate supplementation resulted in enhanced performance during a simulated high-intensity

road cycling protocol incorporating repeated-sprints and short duration time-trial efforts. These benefits were still evident four days after supplementation had finished, with no performance differences found between day four and day one post-loading.

The differences here were small (about 5% improvements) but highly significant in the world of competitive sports, where fractions of a second can make the difference between winning and losing. Sodium phosphate appears to be an effective supplement for trained endurance cycling athletes looking for improvements.

There are still many unknowns in regard to sodium phos-phate supplementation, such as how long the optimal dosing period is, how long the effects will last upon stop-ping the supplement, effects of repeated loading periods, whether gender differences exist, and precise mechanisms of action.

Keep in mind that energy demands differ between sports, and sodium phosphate supplementation may affect athletes in various non-cycling endurance sports, such as running and swimming, differently.

Frequently Asked QuestionsWhat type of sodium phosphate did the study use? This study (and many others) used tribasic dodecahydrate

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