ERD Examine.com
Research Digest
Issue 4
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February 2015
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Table of Contents 05 14 17 25 33
Mood, dieting, and macros What If There Were No Dietary Guidelines? The iPad Hangover Can mice get cancer from steak?
Sodium phosphate: a potentially underutilized ergogenic aid
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On the whey to getting lean: one more round of whey vs. soy
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It’s (not) all in your head: how sodium intake affects headaches
51 59
Diets, fast and slow
66 69
INTERVIEW: Ivan Oransky
Is the glycemic index actually useful for making food choices?
INTERVIEW: Jessica Richman
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From the Editor Let’s play a little game of Choose Your Own Adventure,
(B) You pull the full paper
Health Research Edition. It’ll only take a few minutes, but I
You can’t actually access the full paper. Your significant
hope it gets you thinking.
other is a student, so eventually you pull the full paper and get all the details. The researchers used three different ques-
You’re going to be playing the role of someone scouring the
tionnaires and took some blood draws, and out of all those
web for evidence on a condition you’ve just been diagnosed
measurements, only one was significantly better in the
with. The title is “The Case of the Misleading Abstract.”
alpha lipoic acid group. You look up one of the references
Foreshadowing? Yes.
mentioned in the paper, and it actually concludes that alpha lipoic acid isn’t likely to impact autoimmunity by itself.
On a random weeknight, you’re supposed to be sleeping
Also, the most convincing studies have been conducted on
but are instead doing health research (hey, it should pay off
diabetic mice.
eventually, right?). Since you haven’t read the February issue of ERD, you don’t yet know how nighttime web-browsing is
You don’t buy the alpha lipoic acid. You have a little bit of
affecting your brain. Anyway, you stumble across an inter-
“nonbuyer’s remorse,” but forget about it the next week. The
esting abstract on pubmed. Apparently, alpha lipoic acid can
$25 you saved becomes $436 by the time you retire.
help treat symptoms of a certain autoimmune disease. Not only is p less than 0.05, it’s less than freaking 0.001! Boom.
Neither of these scenarios is uncommon. Most of us have bought way too many supplements based on either anec-
This is quite the useful bit of knowledge, because you’ve
dotes or tantalizing p-values. Granted, it’s really tough to
just been diagnosed with that autoimmune disease, and
face a health condition without an easy treatment, and that
your doctor wants to put you on an unpleasant medication.
can make an abstract sound more promising than the full
Should you (A) go buy the supplement on Amazon, or (B)
paper or body of research reveals. Money spent on ineffec-
try to pull the full paper?
tive supplements can really add up, and sometimes it may be a better idea to focus on high-yield lifestyle habits like
(A) You buy the alpha lipoic acid on Amazon
plenty of sleep and methods to combat stress. Don’t take
It arrives in two days. You don’t mention this to your doctor
abstracts and their p-values as gospel, and best of luck on
because he’s a bit close-minded, but you’re sort-of banking
choosing your own adventure.
on the supplement helping, and hence delay starting your medication for a few weeks. A few weeks later, the pain hasn’t gone away, you’re still fatigued, and you have a new-found hate for alpha lipoic acid.
Kamal Patel, Editor-in-Chief
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Contributors Researchers
Trevor Kashey Ph.D(c)
Alex Leaf M.S(c)
Courtney Silverthorn Zach Bohannan Ph.D. M.S.
Anders Nedergaard Ph.D.
Jeff Rothschild M.Sc., RD
Katherine Rizzone M.D.
Spencer Nadolsky D.O.
Editors
Gregory Lopez Pharm.D.
Pablo Sanchez Soria Kamal Patel Ph.D. M.B.A., M.P.H., Ph.D(c)
Reviewers
Arya Sharma Ph.D., M.D.
Natalie Muth M.D., M.P.H., RD
Mark Kern Ph.D., RD
Gillian Mandich Ph.D(c)
Stephan Guyenet Ph.D.
Sarah Ballantyne Ph.D.
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Mood, dieting, and macros Transient decrements in mood during energy deficit are independent of dietary protein-to-carbohydrate
Introduction
Weight 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 people 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 populations. 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 nervous 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 diseases like Parkinson's, Alzheimer’s, depression, insomnia, ADHD, and anxiety have been linked to neurotransmitter imbalances.
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Figure 1: Select roles of mood-related neurotransmitters
acids (BCAAs) – have been shown to alter brain neurochemistry 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, tyrosine, 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 promoting tryptophan uptake in the brain. Theoretically, this may benefit mood. > The study under review aimed to compare 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 secondThere are many ways to classify neurotransmitters, but for our purposes it’s 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 precursor for serotonin, which can have an indirect effect on well-being and happiness, and plays a variety of other roles
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 exercise) and physically fit (VO2peak of 40–60 mL/kg/min). The volunteers spent 31 days in a metabolic ward under
as well.
constant supervision to ensure compliance to the prescribed
There is some controversy surrounding high-protein diets
design, they were divided into three groups differing in pro-
because the consumption of a lot of large neutral amino acids – tyrosine, tryptophan, and the branch-chained amino
diets and physical activity. Using a randomized block tein and carbohydrate content, but matched for total caloric intake and fat:
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• 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 smoking were forbidden, and all the subjects had “lights out” by 11:00 p.m. to ensure similar and adequate sleep between the groups. Nutritional supplements 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% compared 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 (40–60% 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 selected 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 trial 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 characteristics that affect the outcome. You can statistically control for known factors, but you can’t control for factors that aren’t measurable or that you don’t 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 aren’t being studied. When randomly allocating the subjects into the experimental and control groups, the researchers first stratify them into “blocks” based on traits they wish to hold constant
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Self-reported sleep quality was assessed every morning
groups compared to the low-protein group. The diets during
upon waking using a questionnaire asking how long it
both the energy balance (first 10 days) and energy deficit
took to fall asleep, alertness at bedtime and upon waking,
phases can be seen in Figure 2.
number of awakenings during the night, restedness upon waking, and four questions used to calculate an overall
Total mood disturbances, anger, and tension significant-
index of sleep quality.
ly increased in all groups from day 11 to day 20, but were not significantly different from day 11 to day 30 and were
Finally, blood samples were collected following an overnight
not significantly different between any of the groups.
fast on days 10 and 31 to quantify plasma amino acid levels.
Additionally, confusion and vigor tended to increase during the energy deficit with no difference between groups.
In this study, 39 people were kept under observation for a month while progressively consuming fewer calories and engaging in more physical activity as the study went on. Researchers administered 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
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 performing 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 session 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
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There were also no significant differences in sleep quality
was a slight trend for the high- and moderate-protein groups
throughout the intervention in any group or between the
to retain their difference relative to the low-protein group.
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 significantly 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-
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 tyrosine levels than the low-protein group.
group differences losing their significance. However there
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.
What does the study really tell us?
The purpose of this study was to examine how the dietary protein-to-carbohydrate ratio influenced cognitive performance, 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 intervention. This suggests that it may have been the caloric deficit, not the plasma amino acid concentrations, that increased anger, tension, and total mood disturbances. 9
Similar things can be said for cognition, with all but one
levels by shuttling them into skeletal muscle and organs,
change occurring without difference between the groups.
and consequently also reduces competition for entry into
Finally, subjective sleep was mostly unaffected during the
the brain. Blood amino acid measurements were done after
entire study. The one exception was the low-protein group
an overnight fast, when insulin is minimal. Similarly, the
feeling less alert upon waking during the first ten days of
cognitive tests and mood questionnaire were completed
the dieting period only. Seeing how dopamine and nor-
roughly four hours after lunch, when insulin levels would
adrenaline play a central role in alertness, this outcome
be expected to have returned to baseline. Thus, it is possible
could be the result of the reduction of plasma tyrosine con-
that different outcomes would have been seen if the tests
centrations when the dieting period began. However, this
were administered closer to lunch when the subjects were in
would not explain why the sleep effects were not seen in the
the postprandial state.
other groups. Another limitation of the study is that it was originally So overall, what does this study tells us? It shows that a 40%
powered to detect changes in muscle protein synthesis and
caloric deficit in lean and recreationally active young adults
body composition, not cognitive outcomes. Also, without
[...] boosting protein probably won’t 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. may have a transient effect on mood regardless of the pro-
an energy-balance control group for comparison, it is not
tein-to-carbohydrate ratio. It also tells us that the dietary
possible to separate the effects of the energy deficit from the
protein-to-carbohydrate ratio does impact plasma concen-
effects of learning or the environment.
trations of BCAAs and tyrosine, but not tryptophan. This could be owed in part to the dietary supply of amino acids,
When interpreting this study, it’s important to keep certain
with all groups consuming 16 times more BCAAs and seven
caveats in mind. This study does not tell us how the dietary
times more tyrosine and phenylalanine than tryptophan.
protein-to-carbohydrate ratio would impact mood and
Nonetheless, this suggests that downstream effects of the
cognition in obese people or in individuals who diet while
dietary protein to carbohydrate ratio would be limited to
already extremely lean. Nor does this study tell us how the
the catecholamines and not serotonin.
ratio would impact performance in physique athletes such as bodybuilders or wrestlers. It also doesn’t tell us how the ratio
However, tryptophan entry into the brain is facilitated by
interacts with the absolute caloric deficit, as both groups in
insulin, which acts to reduce plasma BCAA and tyrosine
the study had an identical 40% reduction in energy intake. 10
nutritional counseling provided makes trials even harder to
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 slightly overweight young people, further research is needed to confirm whether this association holds true for other populations.
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
The big picture
This study is one of many that examine differences in cognition and mood between low- and high-carbohydrate weight-loss diets that use different durations, study populations, 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 improvements from both low-carb and low-fat diets in the first two
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
months, but after a year the low-fat group had greater improvements. Cognitive outcomes weren’t different between groups. For these types of studies, outcomes have to be taken with a grain of salt. Mood improvements may be due to weight loss rather than diet composition. Study results also differ depending on how mood was measured, and compliance with the diets as well as the type of
[...] overweight and obese people experience significant improvements on a range of subjective symptoms after weight loss, regardless of diet composition.
deprivation study mentioned earlier, sleep was also unchanged, and a previous study in overweight 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 11
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
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.
high-protein group ended up with significantly higher plasma 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 composition of the diet. Although the evidence is somewhat
Frequently Asked Questions
Would 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 reason that supplementing high doses of BCAAs would have similar if not worse effects on brain chemistry.
mixed, these studies
A recent study evaluat-
also suggest that dieting may improve mood in overweight/obese people more so than in lean people. Importantly, while these other studies had differing fat intakes, the current study controlled
Bottom line: Mood and depression issues rarely have quick fixes in the form of pills.
for fat intake so that the only dietary manipulation 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 we’re able to derive a fairly specific conclusion: boosting protein probably won’t 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. Additionally, it appears that cognition and sleep is likely to remain relatively unchanged throughout a dieting period. It’s important to keep in mind that the results were in non-obese young people, so they can’t be generalized to athletes with much greater caloric demands or to people who are pushing the boundaries of leanness.
ed the administration of a BCAA, essential amino acids (EAA), or a milk EAA mixture on brain amino acid and neurotransmitter concentrations. 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 serotonin 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 depression are more likely to experience the effect. Tryptophan supplements have been widely studied, and do
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improve mood (as well as sleep) in certain subjects. People often face choices between medicating for moderate depression 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 you’re putting in your mouth. Bottom line: Mood and depression issues rarely have quick fixes in the form of pills. Supplements that can increase serotonin can also have side effects from too much serotonin being present throughout the body. It’s 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 disturbances for the first ten or so days, which return to pre-dieting levels by the third week, regardless of the protein-to-carbohydrate 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
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.
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.
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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. 13
What If There Were No Dietary Guidelines? By Adele Hite
A recent episode of South Park lampooning America’s
stick—I have no fondness for the Food Pyramid in any ori-
epidemic of gluten anxiety features the Secretary of the
entation, nor its replacement, MyPlate. Both shapes reflect
USDA agonizing over the realization that his agency has
the advice of the Dietary Guidelines for Americans (DGA),
been recommending Americans consume large quantities
recommendations which divide the world of food up into
of this “dangerous” substance as part of a high-carbohy-
two groups: “healthy” food Americans should eat and
drate, reduced-fat diet. Determined to make amends, an
“unhealthy” food Americans should avoid. The basis for this
animated version of Tom Vilsack asserts the importance
division has little to do with beneficial nutrients food may
of the nutrition guidance his agency dispenses: “We are
or may not contain, but is instead based on the presence or
the USDA! Without us, people would be eating dirt—and
absence of components thought to impact chronic disease.
chairs.” Vilsack ultimately saves the day by turning the
For the past 35 years, DGA guidance telling Americans
Food Pyramid upside down, and while some would applaud
what to eat and not eat in order to prevent chronic disease
this transformation—everyone ends up eating butter on a
has remained remarkably consistent. 14
Problem is, it hasn’t worked very well.
political document, and they regulate a vast array of federal programs and services, influence health-related research,
During that time, rates of hypertension, high serum cho-
and direct how food manufacturers respond to consumer
lesterol, and heart disease mortality have dropped. Some
demand. Virtually no aspect of our food environment is
researchers attribute these positive changes to dietary
unaffected by the DGA. It is worth considering what impact
“improvements” in line with DGA recommendations. Other
their absence would have on these other areas.
researchers blame the fact that obesity rates have doubled and diabetes rates have tripled on our lack of adherence to
From the beginning, the DGA created clear “winners” and
DGA recommendations. It's a neat trick, giving the DGA
“losers” in our food system. Winners were processed food
credit for the good outcomes, but absolving them of the
manufacturers who could reformulate products to meet
negative ones. If Americans have indeed shifted their diets to align more closely with the DGA, the results are not what was originally intended. 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 it’s time to quit trying.
DGA standards; losers
It's a neat trick, giving the DGA credit for the good outcomes, but absolving them of the negative ones.
were farmers who produced eggs and meat, which couldn’t be easily modified. When the DGA directed consumers to avoid saturated fats, manufacturers replaced them with trans fats. “Pink slime” emerged from the beef industry’s efforts to produce lower fat products. Olestra, high-fructose
If there were no DGA tell-
corn syrup, polydextrose,
ing Americans what to eat,
soybean oil, and other
would heart disease mortality spike? Unlikely, since heart
products of the food science laboratory were used to make
disease death rates had been in decline for over a decade
food “healthier,” giving food manufacturers the opportunity
before the DGA were created. Would rates of obesity and
to plaster health claims on labels and directing consumer
diabetes climb even further? Under current conditions,
attention away from whole foods, which carry no labels and
i.e. DGA recommendations being followed or ignored
no such claims. The disappearance of the DGA would help
depending on who you ask, the predictions are by 2030,
level the playing field and perhaps begin to eliminate some
more than half of Americans will be obese and, by 2050,
unwanted additives from our food supply.
one in three Americans will have diabetes. As obesity and diabetes rates did not begin their rapid ascent until after
Because the DGA influence research agendas, they have
the DGA were created, it is not likely eliminating them
imposed their shape on emerging science; its outcomes
would make matters worse.
reflect the policy in whose image it is made. Without the DGA, government-funded nutrition science would operate
In fact, the DGA are far more than health prescriptions
without the ideological constraints created by govern-
that Americans do or do not follow. They are a powerful
ment-backed dietary advice. Without the DGA, a diabetes 15
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 communities 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 established links between diet and chronic disease. It hasn’t, but the DGA’s 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 responsibility to improve economic, environmental, and social conditions related to health. Eliminating the DGA would open up the possibility 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
Would Americans starting eating dirt—or chairs? I don’t think so. Maybe, they might just start eating—better.
“upside down,” but by throwing them out altogether. Would Americans starting eating dirt—or chairs? I don’t think so. Maybe, they might just start eating—better.
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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 relationships that goes beyond nutritional and caloric content of food. She is also a registered dietitian and PhD student in communication, rhetoric, and digital media at North Carolina State University. She has masters degrees in English education and public health nutrition and has pursued 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, particularly 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. 16
The iPad Hangover Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness
Introduction
Within the last few decades there have been massive developments in portable technology. 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 molecule 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 pigments. 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 melatonin 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 can’t sleep due to (light-induced) melatonin suppression, that signals there has been a shift in the biological clock, relative 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
The International Agency for Research on Cancer, an agency directly related the World Health Organization, has classified shift-working as a probable carcinogen.
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.
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Without question, sleep is important. In fact, chronic sup-
1. Used an Apple iPad on maximum brightness
pression of melatonin via evening light exposure has serious
2. Read a print book
implicated health risks, such as cancer. Such conditions are frequently seen in shift-workers, like nurses and fire fighters.
Lighting conditions were kept tightly controlled through-
The International Agency for Research on Cancer, an agency
out the duration of the study. The iPad was at a fixed angle
directly related the World Health Organization, has classified
and distance (about 1.5 feet away) from the participants
shift-working as a probable carcinogen. Shift work represents
face to ensure equal light exposure between participants.
an extreme of altered sleep patterns, but the mechanisms
Study participants were able to pick whatever literature they
behind cancer incidence due to altered melatonin secretion
wanted, with the exception of comic books (possibly due to
and circadian rhythm shifts have been widely researched.
different light reflections with colorful comics) and technical reading (possibly sleep inducing). Participants remained
Cancer risk aside, there are other legitimate reasons to study
in their beds at a fixed angle for the entirety of their reading
this phenomena, as it directly relates to performance (both
period, except for a 15 minute break at the 2.75 hour mark.
mental and physical) and general health. The aim of this study is to quantify the effects of light-induced melatonin
The research group measured:
suppression, caused by iPad use before sleep, on sleep quality and feelings of lingering sleepiness after waking up.
1. How long it took the participants to fall asleep and sleep activity.
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 otherwise 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:
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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in a variety of conditions such as multiple sclerosis and
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.
Alzheimer’s disease. Keeping in mind the suppressed melatonin levels and decreases 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
What were the findings?
iPad use consistently suppressed night-time levels of melatonin, 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 it’s involved in memory 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
sleep and drowsiness) when compared with print book readers. 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 opposite, 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! 20
sleep and wake times were not regulated, it’s 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) it’s easy to see how these issues quickly compound. The iPad’s 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 human’s 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. It’s not unrealistic 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 body’s natural circadian rhythm, this, combined with blue-light exposure, 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 picture
The 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 21
melatonin, affect EEG, negatively affect sleep quality, and
The study participants also had to adhere to regular eating
hinder the ability to wake up in the morning. But do the
and sleeping times. Taking these things into account, it is
findings of this rigorously controlled study apply to free-liv-
likely that the negative effects of this study may even be
ing humans?
understated. This study only had people in a phase shifted state for five days, where a person may be chronically
At first glance, it may seem difficult to translate the data
phase shifting for years. This may lead to chronic infections,
to the typical person not staying in such controlled con-
general malaise, premature fatigue/overtraining, and even
ditions. But this is not the case. On the one hand, study
precursors to metabolic syndrome.
participants remained in a bed (in a reclined position) for almost the entire duration of the study with an IV insert-
The use of blue-light emitting devices is growing at a consis-
ed and electrodes stuck to their heads. On the other hand,
tent rate. The use of these devices near bed time is likely to
this may actually be a decent model system for the typical
interfere with the body’s natural sleep patterns. Continued
inactive adult.
interference may lead to chronic sleep issues, which are linked to a host of negative conditions listed above. The
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.
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-
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, it’s probably not much different than the lab setting.
atonin would already be suppressed by sun/light exposure and you wouldn’t 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 blue22
light blocking glasses, which have amber lenses and hence
melatonin isn’t the only determinant of circadian rhythm,
make you look quite silly (but also smart and innovative
so artificially restoring melatonin levels probably won’t
compared to friends/mates that may mock you.) As seen
eliminate all the negative effects of bright electronic devices.
in Figure 2 these have been shown to allow for melatonin production, and hence improve sleep quality and potentially
So while the specific efficacy of melatonin for phase shift
even mood. If you can’t or won’t use these glasses, but still
caused by iPads hasn’t been researched, there is a cheaper
want to use your device at night, consider free programs
and simpler solution. Occam’s razor dictates that the sim-
such as “f.lux” for laptops or other alternatives for mobile
plest answer is often correct -- rather than putting a bandaid
devices. These automatically make the screen dimmer and
on the problem of shifted sleep, you could work on enforcing
more red as the sun sets. Some apps can even lower screen
a habit of natural light exposure. Some sunlight during the
brightness more than a device allows on its own.
day, and no bright light in the hour or more before bed. It sounds tough, but starting slow (for example, shifting device
Can supplementing melatonin help to restore altered sleep
use a bit earlier each week) can make the transition easier.
rhythm? If melatonin is used as a sleep aid in order to fall asleep
The study authors noted that the relatively easier time print-
during the time of maximum sleep propensity, this is plausi-
ed-book readers had in falling asleep is actually similar to
ble. Examine.com has a very extensive article on melatonin
the effect size of the popular insomnia medication Lunesta.
and its proper supplementation protocol. Melatonin may be
Simply constraining bright light to earlier hours could be an
an option for artificially attenuating the down-shifted mel-
effective and side effect free treatment option for those with
atonin peak if an iPad is used before bed. That being said,
sleep issues.
Figure 2: Effect of light and blue-light blocking glasses on melatonin
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Even being exposed to low intensity blue light, like those blue LEDs on power cords, can make you more drowsy the next morning. Should I have any issues with my e-ink device?
Will using a blue-light emitting device during the day inter-
No, the “spectrum” of the e-ink device is comparable to a
fere with my sleep patterns?
regular paperback book. However, some e-ink devices now
This is unlikely, as the mechanism of this phenomena is
have front-lit capacity, where light is directed on to the
associated with delayed melatonin accumulation. Melatonin
screen, rather than projected through it. There is no peer
is at imperceptible levels during the day, so there would be
reviewed data on spectral emission from those devices in
no quantifiable effect of inhibiting its synthesis with blue
this study, but anecdotally some of these devices appear to
light. The sun emits the very same wavelengths in apprecia-
have somewhat bluish hues (as opposed to the yellow of cer-
ble amount.
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 lighting, 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 don’t have to go out and buy fancy smartphone-controlled light bulbs (although they are kind of cool), at least dimming 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 partner is awake? They’re 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.
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 deficiency. Chronic sleep deficiency and consistently impaired melatonin production may increase the risk of many inconveniences, 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 important but undercovered health issues may be the downstream effects of poor sleep caused by using these devices at night.
◆
Even being exposed to low intensity blue light, like those blue LEDs on power cords, can make you more drowsy the
Don’t you dare read this past 10pm. But if you choose to
next morning. So it can pay dividends to be more aware of
anyway, head over to the ERD private Facebook group to
what kind of light surrounds you throughout the evening all
talk about how to improve your light-related sleep habits.
the way into slumber time. 24
Can mice get cancer from steak? A red meat-derived glycan promotes inflammation and cancer progression
Introduction
Red meat is one of the foods the media loves to hate, perhaps 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 haven’t 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 hypotheses 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 isn’t 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 probably will never be a human RCT with red meat as a variable and colorectal cancer as an outcome, we’re 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 molecules 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. 25
The two sialic acids of interest were n-acetylneuraminic acid
would have provided a resistance advantage for these dis-
(denoted Neu5Ac) and n-glycolylneuraminic acid (denoted
eases many millennia ago.
Neu5Gc), which are seen in Figure 1. Structurally, these two molecules are identical except for an additional hydroxyl
Despite this genetic change, Neu5Gc is still found in low
(-OH) group on Neu5Gc. These molecules are found in a lot
levels in normal human tissue - so any molecules would
of animal-based dietary sources in different levels, with beef
have to come from dietary sources and then be incorporat-
and caviar having the highest levels of Neu5Gc.
ed into our own cell membranes. It’s also found in higher levels in malignant tissue. The researchers speculated
Neu5Gc is interesting, because it’s not something that
that because this molecule is “foreign” to our bodies, our
humans can synthesize from Neu5Ac - the gene that codes
immune systems would react to it by producing antibodies
for the enzyme needed to add on the hydroxyl group had
to attack it. Indeed, it has been shown that 85% of people
a sequence deletion several million years ago and thus is
tested had antibodies against Neu5Gc. It is not known why
nonfunctional. This likely conferred several evolutionary
15% of the people tested did not possess the antibodies.
advantages. First, it may have been a factor in our ability to increase our brain development beyond that available to our
An immune system that is constantly turned “on” results in
primate cousins. Second, certain pathogens such as select
inflammation. Markers of inflammation increase when the
strains of malaria as well as an E. coli toxin bind to Neu5Gc,
immune system is fighting off a foreign pathogen. In acute
so lacking the enzyme necessary to synthesize Neu5Gc
situations, inflammation is beneficial! However, we’re learn-
Figure 1: Humans and Neu5Gc
26
ing that chronic inflammation does not do a body good. Chronic inflammation has been linked to heart disease,
Figure 2: Neu5Gc in common foods
various bowel syndromes such as irritable bowel syndrome (IBS) and Crohn’s, 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 foreign 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 consumption 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 consumption results in systemic inflammation due to the presence of foreign, meat-derived molecules. phospho-N-acetylneuraminic acid hydroxylase (CMAH)
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-
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.
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 model 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-
Keeping the notations straight: All gene symbols are italicized (ex. Cmah) while all protein abbreviations 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. 27
[...] 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. Male mice were fed a normal diet, or a normal diet supple-
animals to mount their own immune response against the
mented with porcine submaxillary mucin (PSM). Translation:
Neu5Gc.
pig salivary gland excretions, yum. PSM has a high concentration of Neu5Gc and was meant to simulate the con-
Two additional experiments created the anti-Neu5Gc
sumption of red meat in humans. The PSM-supplemented
immune response prior to feeding and looked at HCC
mouse diet contained 0.25mg of Neu5Gc per gram of feed,
tumor formation. One tested the specificity of the immune
which is similar to the highest concentrations seen in red
response by feeding the mice the PMC enhanced diet,
meat. After being fed this diet for several weeks, the levels
which created elevated levels of Neu5Gc, or a diet enhanced
of Neu5Gc in the mouse were similar to levels observed in
with the unhydroxylated precursor molecule Neu5Ac. A
humans adhering to a red meat rich diet for several years.
second experiment compared pre-immunized wild-type mice that had a functional Cmah gene to the genetically
It’s important to note that most epidemiological data in
modified mice without the Cmah gene.
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, PSMand 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
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 PSMenhanced 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.
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HCCs (9% and 7% respectively) but 47% of the genetically
Scientists crack why red meat is linked with cancer - and SUGAR may be to blame. - Headline on the Daily Mail, 12/30/14 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)
modified mice exposed to the Neu5Gc immunogen had developed HCCs.
Mice fed diets high in a cell surface sugar molecule found in red meat had higher levels of inflammation markers. The inflammatory response was specific to Neu5Gc and not the similar Neu5Ac precursor molecule. The combination of consuming that sugar molecule and manipulating the mouse immune system to make antibodies against that sugar molecule caused mice to develop more liver tumors than control groups.
The big picture
“Scientists crack why red meat is linked with cancer - and
through injections of red blood cell (RBC) ghosts. The mice
SUGAR may be to blame” - Headline on the Daily Mail,
were then fed either PSM-enhanced diets, or diets rich in
12/30/14
Neu5Ac through supplementation with edible bird’s nest (EBN). Translation: the salivary secretions of the swiftlet
Contrary to media assertions claiming that scientists now
bird, highly prized as a culinary delicacy. Yum?
know why red meat causes cancer, this study actually had some limitations. First off - there is no human data present-
Because the mice lacked the Cmah gene, they were unable
ed. There is an interesting mechanism proposed and a very
to convert the dietary Neu5Ac to Neu5Gc. Here, elevated
carefully designed model created to ask a specific mecha-
interleukin-6 levels were seen only in the PSM-fed mice
nistic question, but this may just be the first baby step on
and not in the EBN-fed mice. Additionally, 2 out of 7 mice
a long journey to “knowing” the true cause, if a single one
(29%) in the PSM feed group developed HCCs over the
even exists, for the increased incidence of cancer seen in
course of 55 weeks, whereas none of the mice in the EBN
consumers of red meat in large quantities. Mice models are
feed group developed tumors.
almost always the first starting point for asking a question about biological cause and effect, but results should nev-
The final experiment compared the genetically modified
er be taken as conclusive or directly applicable to humans
mice with their wild counterparts. Mice were pre-ex-
at this stage. Cancer has been caused and cured in mouse
posed to either chimpanzee RBC ghosts with cell surface
models a dozen times over, in ways that have turned out to
Neu5Gc immunogens, or human RBC ghosts with cell
be completely inapplicable in humans.
surface Neu5Ac immunogens. All mice then received the PSM-enhanced food. After 85 weeks, a comparable num-
The study design itself, aside from being only conducted in
ber of wild type and genetically modified mice that had
mice, had its own limitations. Studies in genetically similar
been exposed to the Neu5Ac immunogen had developed
mice provide nowhere near the applicability of data that a
29
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 system 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 incidence 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 it’s difficult to draw direct comparisons between a tumor that forms in the liver in one species versus one that forms in the colon in another 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 company that is investigating targeted antibodies as a potential cancer therapeutic. It’s 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. 30
no other related factors such as other dietary patterns and
This study provides evidence to support a molecular 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.
exercise were evaluated. And then there’s the question of the differing effects of a sudden immune trigger by introducing 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 comparisons at this point is challenging.
Frequently asked questions
How 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 study’s aims. The quantity of the food exposure is at least
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
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. somewhat similar to human intakes, unlike some studies that show that a particular chemical or food is carcinogenic 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,
a slight but consistent correlation between red meat consumption 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 everybody, and if this line of research does bear out it may be more useful for people with either a previous personal history of cancer, or a family history of cancer.
31
Should I be concerned about inflammation? What can I do about it? Possibly - a lot of studies have shown that chronic inflammation 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, improving sleep, consuming more plant-based foods, increasing exercise and utilizing stress reduction techniques, promote
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 broader 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 isn’t 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.
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general health outside of any inflammation concerns as well. To discuss mouse models, in vivo experiments, and recipes with and without red meat, visit the ERD Private Forum on Facebook.
32
Sodium phosphate: a potentially underutilized ergogenic aid Effect of sodium phosphate supplementation on repeated high-intensity cycling efforts Introduction
Phosphate doesn’t get much attention in the nutrition and supplement world, but it performs many important functions 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 production as a part of the basic structure of phosphocreatine and adenosine triphosphate (ATP). Phosphocreatine serves as an energy store that is available immediately during exercise, and can release energy without the need for oxygen. ATP contains three phosphate groups and is often referred to as the body’s 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
33
research setting that's a more realistic reflection of real-life cycling conditions (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 performance 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.
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 determine if there is an effect from the supplement trial. For example, studies can test participants using a time-trial (covering 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 distance 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 participants are recreational athletes or trained professionals, etc.
This was a double-blind placebo-controlled study. Participants were given 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
Underlying all of these variables are gender differences, as men and women can differ significantly when it comes to fuel sources, metabolism, and specific adaptations to exercise. And most studies, including this one, have been in males only.
testing took place at the same time of day (within an hour) to control for 34
circadian variation. Participants also kept a 24-hour diary
as overall power output during sprints (5%) and time trials
of all food and drink intake prior to the initial test and were
(4%) in the sodium phosphate group. Supplementation had
required to replicate that energy intake as closely as possible.
no impact on performance during the first set, but it led to performance improvements in the second, fourth and fifth
The test protocol was modified from cycling race simula-
set, effectively reducing the fatigue seen in the later sets
tions used in previous research, and attempted to emulate
of sprints. No differences were seen in the placebo group
the constant up and down effort of actual racing. This test
during any set of sprints.
took 43 minutes to complete, which is substantially shorter than cycling road races. The test was, however, similar to
Similarly, supplementation led to an improvement of 9%
criterium and certain track cycling races.
compared to baseline during the second time trial, which was set six. It is hard to say why the power output in set six
The protocol itself was a mix of four sets of 6 × 15 second
was higher than set three, but it may be due to psychologi-
maximal sprints (with 45 or 15 seconds recovery in between
cal factors related to the final section of the test. Again, no
sprints) and two sets of five minute time-trials. Active
differences were seen in the placebo group during either of
recovery for three minutes (pedaling at 100 W) separated
the time trial sets.
each set. Another important aspect of this study is that no differences
Seventeen competitive male cyclists supplemented 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
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 supplementation 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 isn’t 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 statistical model, researchers can establish the smallest change that would still be beneficial (or harmful) and use the confidence limits to make a qualitative statement about the real-world significance of the changes. This study also classified outcomes for the smallest worthwhile change as beneficial, trivial, or harmful. 35
[...] 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. actually decreased in the sodium phosphate group on day
endurance athletes. Six days of supplementation resulted in
one and day four, while serum phosphate concentrations in
improved performance (greater work and power outputs)
the placebo group remained unchanged.
during a simulated cycling road race, which included a mix of repeated short-duration sprints and five-minute maximal
Total work (measured in kilojoules) increased in the sodium
efforts. Impressively, the benefits still existed four days after
phosphate group on day four, while the increases seen on
supplementation had stopped.
day one were not statistically significant. However, analysis for the smallest worthwhile change indicated that improve-
Since the test used in this study took 43 minutes to com-
ments in overall power output and overall sprint power
plete, it is unclear how these benefits would translate to
output (but not time trial power output) would likely still
a road cycling race lasting three to seven hours. However,
be of benefit in competition. No changes were seen in the
because of the lingering effects of the supplementation, it
placebo group.
is reasonable to think that sodium phosphate would benefit endurance athletes competing in events lasting not only
Cyclists supplementing sodium phosphate experienced 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
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 creatine phosphate synthesis, phosphate-stimulated glycolysis, and enhanced oxidative metabolism (even with no changes in serum phosphate levels). • Enhanced red blood cell 2,3-diphosphoglycerate
36
(2,3-DPG) synthesis, promoting a decreased affinity
road cycling protocol incorporating repeated-sprints and
of hemoglobin for oxygen and resulting in great-
short duration time-trial efforts. These benefits were still
er unloading of oxygen to the peripheral tissues.
evident four days after supplementation had finished, with
Previous research has shown that it took approxi-
no performance differences found between day four and
mately two weeks for RBC 2,3-DPG concentration to
day one post-loading.”
return to baseline following only three days of sodium phosphate loading. • Improved myocardial efficiency, providing a great-
The differences here were small (about 5% improvements) but highly significant in the world of competitive sports,
er stroke volume (and cardiac output), leading to
where fractions of a second can make the difference
increased and more efficient oxygenation of the mus-
between winning and losing. Sodium phosphate appears to
cles during exercise.
be an effective supplement for trained endurance cycling
• Improved hydrogen ion buffering capacity, which is
athletes looking for improvements.
important for repeated sprint ability. There are still many unknowns in regard to sodium phosAll of these factors may have played a role in this study, con-
phate supplementation, such as how long the optimal
sidering this protocol would have engaged multiple energy
dosing period is, how long the effects will last upon stop-
systems (creatine phosphate, anaerobic glycolysis, aerobic
ping the supplement, effects of repeated loading periods,
glycolysis) during the course of the test.
whether gender differences exist, and precise mechanisms of action.
This study adds to the growing body of evidence that supports the use of sodium phosphate as an ergogenic aid for endurance athletes.
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.
The big picture
“Six days of sodium phosphate supplementation resulted in enhanced performance during a simulated high-intensity
Frequently Asked Questions
What type of sodium phosphate did the study use?
This study (and many others) used tribasic dodecahydrate
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. 37
sodium phosphate. Previous research using dicalcium phosphate or calcium phosphate has failed to find performance improvements. It is possible that the lack of performance enhancements were due to using a different loading protocol (in some cases only giving a single dose), or possibly lower bioavailability. However, further research is needed to confirm this hypothesis. How much sodium phosphate should I supplement? Studies have generally used three to five grams or 50 milligrams per kilogram of fat-free mass, per day. However, different dosages haven’t been compared much against each other. And as mentioned previously, studies tend to be in males only. Along with the limited sample size of many studies, and their inclusion of highly-trained endurance athletes, the results may not apply as well to a typical active individual. Will sodium phosphate supplementation cause GI distress? It is possible that high doses of sodium phosphate can cause gastrointestinal distress. To minimize this side-effect, sodium phosphate is best ingested in smaller doses spread in three to four doses throughout the day, with food. What about the association between serum phosphorous and cardiovascular disease? There is an association between serum phosphate and cardiovascular disease, however this study showed that supplementation does not raise serum levels and paradoxically may even decrease them.
What I should know?
Sodium phosphate may be an effective supplement to
improve cycling performance in highly trained athletes, but exact dosing strategies, performance benefits, and mechanisms of action remain to be elucidated.
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Cyclists, endurance athletes, and sodium phosphate aficionados (do they exist? maybe they should) can check out the private Facebook ERD forum for more discussion on this paper. 38
On the whey to getting lean: one more round of whey vs. soy
Whey Protein Supplementation Preserves Postprandial Myofibrillar Protein Synthesis during Short-Term Energy Restriction in Overweight and Obese Adults Introduction
Stuart Phillips’ group at McMaster University has been conducting research on all things protein for close to two decades, with particular emphasis on how
protein feeding affects protein synthesis at the whole-body level, as well as specifically in the muscle tissue (obtained from muscle biopsy specimens). Measuring protein synthesis (or degradation) in muscle is the best biomarker of ongoing muscle anabolism or catabolism that exists. Protein synthesis during weight loss is important since keeping muscle on helps regulate blood sugar and keeps metabolism higher. Obtaining information about fat or protein turnover at a particular point in time can tell us how well the body is conserving lean mass during weight loss, which is what this study intended to do.
39
Who and what was studied?
The purpose of this study was to examine the effects of whey and soy supplementation on protein synthesis and biomarkers of lipolysis during weight loss, with carbohydrate supplementation as the control. Even though body compo-
which is the major factor protein’s ability to stimulate protein synthesis.
Figure 1: Grams of amino acids per 100 grams of whey isolate or soy isolate
sition was measured during this study, the effect of whey or soy protein supplementation on body composition was not a major endpoint of the study. This was likely due to the relatively short duration of the study, as small body composition changes would not be detectable even with DXA (Dual X-ray Absorptiometry) measurements, which the study uses and is considered the gold standard for body fat measurement. Previous research has shown the error from DXA to be around 1.2%, which would eclipse the relatively minor body composition changes from this study. There have been many studies comparing the effects of soy and whey protein in stimulating protein synthesis and affecting body composition in a range of conditions, but few that have looked specifically into the effect on protein synthesis and lipolysis during weight loss. The studies that have previously compared whey to soy in their ability to stimu-
Essential Amino Acid
Whey Protein Isolate
Soy Protein Isolate
Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine Total BCAAs Total EAAs
6.1 12.2 10.2 3.3 3.0 6.8 1.8 5.9 24.2 49.2
4.9 8.2 6.3 1.3 5.2 3.8 1.3 5.0 18.1 36.0
In order to examine the effects of soy or whey on protein synthesis during weight loss, 40 healthy, overweight and obese participants (19 males and 21 females) were included and randomized to to receive either a twice daily whey supplement (27 grams per supplement), soy protein supplement (26 grams per supplement) or carbohydrate (CHO) controls (25 grams per supplement), resulting in a total daily protein intake
late protein synthesis and stimulate gross muscle hypertrophy in other contexts have generally found whey to be superior to soy. As seen in Figure 1, this is probably due to whey having a more complete amino acid profile (most soy is very low in two of the essential amino acids, methionine and lysine) and especially due to whey’s higher leucine content,
[...] research has shown the error from DXA to be around 1.2%, which would eclipse the relatively minor body composition changes from this study.
of 1.3 grams per kilogram of bodyweight in the protein-supplemented groups and 0.7 grams per kilogram of bodyweight in the CHO group. All food was provided by the research team in the form of prepackaged meals, to increase compliance. During the study, all participants were first put on a three-day 40
maintenance diet (given maintenance calories and 1 gram
significantly higher after ingestion of whey protein than
per kilogram of body weight of protein), subjected to the
after soy. Soy still outperformed the CHO control supple-
first test day, and then put on 14 days of a hypocaloric diet,
ment. In fact, the plasma leucine release (measured by the
followed by the second test day. The purpose of the main-
area under the curve [AUC]) from whey was almost three
tenance diet was to equilibrate the subjects and put them
times higher than that for soy, whereas the essential and
on even ground, metabolically speaking. The hypocaloric
total amino acid AUC’s were approximately twice as high.
diet was calculated to provide an energy deficit of 750 kcals per day, which should result in a weight loss of one to three
Not surprisingly, there were also differences in insulin and
kilograms over the course of 14 days. On both of the test
glucose concentrations following ingestion of the supple-
days, the subjects received stable isotope infusions with
ment between protein groups and the CHO control group,
isotope-labelled phenylalanine and glycerol, were DXA
both before and after the dietary intervention. Ingesting the
scanned, and had blood and muscle samples taken.
glucose control supplement resulted in higher glucose and insulin levels than ingesting either protein supplement, with
Body composition (total, fat and lean mass) was obtained
no difference between soy and whey protein supplementa-
from DXA scans. Muscle protein synthesis was calculated
tion groups. As amino acids are absorbed more rapidly into
from tissue enrichment of stable isotope labelled phenyl-
the bloodstream from whey protein than soy protein, it is
alanine in muscle samples. Lipolysis (fat burning) was
plausible to expect higher blood glucose and insulin levels
calculated using the appearance of the isotope-labelled glyc-
after whey supplementation.
erol in the blood. Glucose and insulin levels were obtained from blood samples.
There was also a significant difference between the amount of circulating glycerol between the protein groups and the
Overweight and obese participants were randomized to receive either soy or whey protein, or a carbohydrate control, and put on a hypocaloric diet. Body composition measurements and muscle protein synthesis were measured and compared between groups.
What were the findings?
The researchers found no significant difference in body composition between the groups. This was actually the expectation for a study of this duration and diet composition.
CHO control group. Glycerol was lower in the CHO group than in either protein group. This indicates that lipolysis is suppressed following CHO ingestion relative to both of the protein groups. In the post-prandial condition, the amount of glycerol in the blood is a measure of the rate of ongoing lipolysis. Fat is stored as triglycerides, and when fat stores receive neuroendocrine signals to mobilize fat, tri-
It has been shown numerous times that whey is a so-called “fast” protein, which means that the amino acids in it are absorbed faster than other proteins with a similar amino acid content. In this study we see this yet again, as release of leucine, essential amino acids and total amino acids were 41
[...] this study actually does not prove that whey is superior for maintaining lean mass during weight loss. [...] whey probably is better, but that cannot be determined from these results because this study lacks statistical power to find such differences. glycerides are hydrolyzed into fatty acids and glycerol, both of which are released to the circulation. The fatty acids are metabolized in most of the body, whereas most of the glycerol is used for gluconeogenesis. The most likely explanation for the lower glycerol levels observed following CHO ingestion is probably that insulin strongly inhibits lipolysis. Since it was shown that the CHO supplement resulted in higher insulin, this further reinforces this hypothesis. The main finding of the study was the effect of the protein supplements on protein synthesis in the myofibrillar protein fraction of muscle (the so-called Fractional Protein Synthesis, FPS), before and after the dietary intervention. The researchers measured FPS before and after protein ingestion, as well as before and after the dietary intervention. The baseline FPS was around 0.02-0.03%/hour, but upon stimulation it increased to 0.06-0.07%/hour for whey and 0.03-0.04% for soy. When the FPS was expressed as the change in FPS from before to after supplement ingestion, soy scored higher than the CHO control supplement and whey scored higher than both. This means that whey stimulates the protein synthesis in muscle more efficiently than soy protein does.
Whey protein was absorbed more quickly than soy protein, and stimulated muscle protein synthesis by roughly two times the amount that soy supplementation did. However, no differences in overall body composition was observed between the groups.
The big picture
The results regarding amino acid, glucose, insulin, and glycerol concentrations were in line with numerous previous observations.
When it comes to the findings for body composition, this study actually does not prove that whey is superior for maintaining lean mass during weight loss. There’s a fair chance that whey probably is better, but that cannot be determined from these results because this study lacks statistical power to find such differences. In order for differences between groups to manifest as statistically significant, a sufficient number of subjects must 42
be enrolled. If the between-group difference we are looking
degradation is just as important as modulation of protein
at is small relative to the variation in the observations, this
synthesis. This is supported by the results of some studies,
calls for more subjects. The study duration was short (14
which have shown that different protein sources may have
days) and therefore the changes in lean and fat mass are
different influences on protein synthesis and degradation.
small compared to the margin of error using a DXA scanner, meaning that if any difference did exist between groups,
The reason that protein synthesis is more frequently report-
it would have taken more participants or a longer study
ed is that the technology for measuring protein synthesis
duration for significant changes to manifest.
is much better than the technology available for measuring protein degradation. All of these factors make it difficult
If you know the variation in the measurement you are doing,
to conclusively state whey’s superiority over soy based on
you can actually calculate
this study. The protein
the number of subjects
synthesis measurement
needed to detect a group difference of a given size. This is called a power analysis. The researchers actually describe that they knew they had inadequate power to detect between-group differences, which was acceptable as this was not part of the primary objective for the study. Alternatively, this may be a real and
[...] whey stimulates protein synthesis in myofibrillar proteins much more efficiently than soy protein supplementation.
valid finding. It is possi-
used in this study is a surrogate for the effect on muscle mass. But changes in muscle mass can be measured directly with something like DXA, albeit this requires a more challenging study setup, meaning more subjects for longer time and a higher study cost. Of course, studies can always be better or
ble that although one protein source may be more effective
more detailed, so maybe this study will be the springboard
than another in a short window of time for measuring FPS,
for the next, more detailed study.
overall dietary intake may be most important for producing long-term adaptations in body composition.
Lastly, funding for this study was provided by the Dairy Research Institute through the Whey Protein Research
What the study did show, however, was that whey stimu-
Consortium. However, the reported findings are in
lates protein synthesis in myofibrillar proteins much more
agreement with the literature and with other studies not
efficiently than soy protein supplementation. How this
supported by dairy farmer’s associations.
translates into lean mass sparing during weight loss is very hard to derive for numerous reasons. FPS is normally used as a surrogate biomarker for a snapshot of hypertrophy processes. However, hypertrophy or atrophy is the result of net protein synthesis or degradation, which is again the product of gross protein synthesis and net protein degradation. Therefore, it should be apparent that modulation of protein
Frequently asked questions
How much daily protein synthesis and degradation happens normally, and under weight loss or muscle gain conditions? Baseline fasted FPS in this study was around 0.02-0.03%/ hour, whereas the fed FPS was two to three times higher. Based upon these numbers, and MPS and FPS data record43
ed elsewhere in the literature, we can assume an average total protein synthesis of 1.0-1.5%/day. This means that 1.0-1.5% of the protein of the muscle protein is built up and broken down per day at muscle mass equilibrium. The amount of muscle made out of protein is constant, at around 20% of the wet weight of muscle. As a normal adult (60-80 kilograms / 130-175 pounds) carries 30-40% of his or her body weight as muscle mass, this corresponds to 200-400 grams of muscle (or 40-80 grams of muscle protein) that is built up and broken down, daily. In the context of changes in muscle mass during sustained weight loss or resistance training, the net changes in muscle mass are generally on the order of 10-50 grams per day. These can be bigger at the onset of weight loss or weight gain, but it still underscores that much more protein is being built up and broken down on a daily basis, than that
protein synthesis measurements and several molecular biology biomarkers, such as insulin signaling through the
which is ultimately gained or lost as hypertrophy or atrophy.
Akt/mTOR signaling cascade or FOXO transcription factor
Has there been research connecting muscle protein synthesis
by the poor reliability of the molecular biology biomarkers,
to the end result of muscle hypertrophy? A previous paper from Phillips’ research lab compared the protein synthesis measured following a resistance exercise bout in a part of a chronic resistance training study with the gross hypertrophy measured after 16 weeks of the resistance exercise program. The researchers found no correlation between the two measures. Even though that was in a training study, the result underscores that maybe using protein synthesis is not as good of a biomarker as we sometimes would like to think. What about molecular biology markers of muscle gain and loss -- do they have similar findings as muscle protein synthesis?
expression. In this case, however, this is more likely caused as they can display anabolic signaling even in grossly catabolic cachectic subjects.
What should I know?
Ingestion of whey protein stimulates myofibrillar protein synthesis during weight loss more efficiently than soy protein and naturally better than carbohydrate. This indicates that protein obtained from whey may more efficiently spare muscle mass than protein from soy, but the actual impact is outside the capabilities of this study to assess.
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To dig into the science of protein synthesis a bit more, head over to the Facebook ERD forum.
It is also worth noting that there is a disconnect between 44
It’s (not) all in your head: how sodium intake affects headaches
Effects of dietary sodium and the DASH diet on the occurrence of headaches: results from randomised multicentre DASHSodium clinical trial
Introduction
Though headaches are very common, very little is known about what causes them. Obviously, certain dietary choices (namely too much alcohol or not enough water) can cause headaches, so it makes sense that other foods could also cause headaches. However, the evidence for this claim is spotty at best.
For example, it was once believed that monosodium glutamate (MSG) could cause headaches. This belief was largely the result of a doctor who wrote a letter to the New England Journal of Medicine on “Chinese restaurant syndrome,” his term for the physical effects of his own overindulgences. The link between MSG and headache has not been proven in rigorous studies, and the evidence is covered on Examine. com. Yet that single letter was enough to make MSG the most researched dietary factor related to headaches. 45
Headaches have been linked to other health and lifestyle
needs and compliance with the study protocol.
factors too. One of the most common factors is hypertension. Because hypertension is associated with headaches,
Compliance is critical for a detailed trial like this, so par-
and blood pressure levels have a well-known dietary com-
ticipants were required to eat at least one meal at the study
ponent, it is reasonable to believe that dietary factors that
site, five days per week. All of their other food was provid-
influence hypertension may also influence the occurrence
ed when they came for their on-site meal. The participants
of headaches. Therefore, the authors of this study set out to
were asked to record any uneaten food as well.
examine the links between headache occurrence and two dietary factors known to reduce hypertension: the Dietary
After the run-in period, participants were randomized to
Approaches to Stop Hypertension (DASH) diet and reduc-
either the DASH diet or a “typical American diet.” Each
ing sodium intake.
participant stayed on the same diet during the entire study. They were then further randomized to one of three different
Who and what was studied
This study on headaches was part of a much larger study of the DASH diet and reduced sodium intake in hypertensive or prehypertensive individuals. The original goal of that study was to analyze whether the DASH diet and reduced sodium levels have synergistic effects on blood pressure. This study is a secondary analysis of 390 participants from the original trial, being the roughly 95% of participants who completed side-effect questionnaires. Since the original study was a major trial designed to test interactions between multiple dietary interventions, it was extremely well controlled, and that feature carried over into this study. Participants had three separate baseline visits separated by at least seven days, and during that time (about two weeks), they were fed a run-in diet to assess caloric
sodium levels (low, medium, or high), with the highest level being equivalent to the “typical” American sodium intake. Every 30 days, each participant was switched to a different sodium level after a seven-day “washout” period, until each participant had received all three sodium levels. During the last week on each sodium intake level (at the end of every month), the participants were tested for blood pressure, body weight, and via urinalysis, and were surveyed for a variety of adverse events such as headaches and fatigue. The urinalysis served a dual purpose of both assessing metabolic factors and ensuring compliance (by measuring sodium secretion). This study design is a great example of a well-designed randomized crossover study because it has strict adherence policies, multiple assessments of compliance, and blinded data collection staff.
Are secondary analyses second-class citizens in the research world? Secondary analyses are often treated the same as analyses from the original study, at least in the media. But they probably shouldn’t be. The original study that this was based on wasn't designed to examine the headache issue, so it's not quite as convincing as a study that was. The reason has to do with statistics. When you state a primary hypothesis before launching the study, conclusions are more statistically reliable than doing post hoc hypothesis testing. This is because you can fish around for significant results and make a paper out of whatever you find (which may or may not be due to chance, despite a significant p-value), as opposed to being forced to focus on your main hypothesis no matter what the outcome was when you state it a priori. 46
Study participants were split into two groups: eating a diet designed to reduce hypertension, or a typical American diet. Then, each participant spent a month eating at each of three different sodium levels: low, medium, or high. Researchers measured blood pressure and body weight, as well as tracked when headaches occurred.
Figure 1: Incidence of severe headaches by diet and sodium intake
What were the findings?
The high sodium diets (whether “typical” or DASH) had a significantly greater incidence of headaches compared to the low sodium diets. Going from low to intermediate to high sodium levels steadily increased headache odds in both the DASH diet (36% to 38% to 43%) and control diets (39% to 41% to 47%). However, the difference in headache risk between the intermediate sodium intake group and the lowest and highest sodium intake groups was not statistically significant. This may be related to the fact that this is a secondary analysis of a study not specifically designed to analyze headache occurrence. Headaches were were only measured once in each study period, and the study didn’t collect data on previous headache prevalence, among other design limitations. Interestingly, the association between headache occurrence and sodium intake persisted regardless of hypertension status or blood pressure. As one might expect in a trial of hypertensive individuals who were fed the DASH diet, some participants experienced a decrease in blood pressure below hypertensive levels. However, even in these individuals, the correlation between headache risk and sodium intake remained. Perhaps most surprisingly, there was no overall difference in headache occurrence between the “healthy” DASH diet and the “typical” American diet. There was however a difference between DASH dieters eating low sodium (36% had headaches) and control dieters eating high sodium (47% had headaches). The study participants also classified their headaches as mild, moderate, or severe. Most headaches were classified as mild, and higher sodium intakes generally were associated with a bit higher (although not statistically significant) mild-to-moderate headache rates. Despite the small number of severe headaches, Figure 1 shows that high sodium seemed to have an association with severe headache incidence. This association trended toward significance in both diet groups.
47
What does this tell us?
The Big Picture
hypertension affects headaches, and this study indicates
well-established. Similarly, the correlation between dietary
that sodium affects headaches in hypertensive individuals.
factors and hypertension is well-known, in part thanks to the
However, diet and hypertension status did not play a role
“grandfather” of this and many other dietary trials: the DASH
in the interaction between sodium intake headaches, which
study. On the opposite side of these famous and well-de-
suggests that sodium intake and headache risk may be
signed studies is the largest body of “evidence” for dietary
linked even in people who are not hypertensive.
factors that contribute to headache: a bunch of studies that
It is well-known that sodium affects hypertension and that
The correlation between hypertension and headaches is
refute anecdotal evidence linking headache to MSG conThis is supported by the data that show that hyperten-
sumption. Some believe that diets high in fruits and veggies
sion status was not correlated with the effects of sodium
are a panacea of sorts, and can curb pretty much any malady
on headache risk, but it is also worth mentioning that the
including headache. This study doesn’t support that notion.
hypertensive participants had significantly more headaches than the people with normal blood pressure. So there may
This study does show that sodium intake and headache
be more to the interactions between hypertension, sodi-
are probably correlated, but it’s still not known how. The
um, and headaches than can be revealed by the design of
simplest theory is that headaches are related to sodium’s
this study. It’s possible that sodium may impact headaches
effect on blood pressure. This study provides relatively weak
through mechanisms unrelated to blood pressure.
evidence, since it shows that sodium intake and headache correlate regardless of blood pressure levels, diet, or hyper-
It is important to remember that this trial, no matter how
tensive status. We’re left with a situation that’s as promising
well-designed, was not originally intended to study the
as it is frustrating. It’s relatively certain that sodium intake
effects of sodium intake on headache. Therefore, these analy-
(or intake of sodium-rich foods) affects headache occur-
ses are based only on reports of headaches while on the study
rence, but there’s no good explanation as to how that
protocol. Headache frequency was not assessed at baseline,
happens. Regardless, this study still makes the case for lower
which may be one of the reasons that this study’s findings are
sodium consumption than is typical in modern diets, if one
only significant for the high and low sodium intake groups.
is trying to reduce headaches.
This is an important factor to consider when comparing these data to other studies on headache occurrence.
However, other merits of reducing sodium intake have been heavily debated recently. A recent study in the Journal of the
Perhaps most surprisingly, there was no overall difference in headache occurrence between the “healthy” DASH diet and the “typical” American diet. 48
American Medical Association (JAMA) that found no associ-
Heart Association recommends <2.4 grams sodium and
ation between sodium intake and mortality or cardiovascular
says 1.5 is even better. The US Centers for Disease Control
disease. Though headaches are not the same as death, the
recommendations are similar to those of the AHA.
differences between the studies are still worth mentioning. Notably, the JAMA study analyzed data from a much longer
Generally speaking, if you have cardiovascular disease or
time frame in a much larger cohort of patients, but it did so
hypertension, less than 1.5 grams of sodium per day is a
using self-reported data. In contrast, this study followed a smaller group of patients (but still sizeable by trial standards) with much more rigorous requirements and assessments. The World Health Organization (WHO) and other groups already recommend a diet with significantly lower sodium than the average American consumes, due to the interaction between sodium and hypertension. A reduction of headache occurrence may be an added benefit. The typical American consumes ~182.7 mmol sodium per day, which is similar to the 150 mmol received by the high sodium intake group in this study. The current WHO recommendation is 87 mmol/ day. However, it should be noted that the WHO recommendation is still higher than the intake of the low sodium group in this study (50 mmol). So although there may be a general consensus of “eat less sodium,” there is not nearly enough evidence to offer a firm recommendation beyond a general upper limit. And that is besides the recent controversy about whether sodium reduction actually has benefits, which could turn decades-old diet advice on its head. For headache sufferers, this study provides a tantalizing bit of well-controlled evidence, especially since effective prevention for some people can seem quite elusive. But don’t equate the results with causation -- it’s still possible that high-sodium foods eaten in the study could cause headache independent of their sodium content. The data on headaches resulting from foods and nutrients is unfortunately
It’s relatively certain that sodium intake (or intake of sodium-rich foods) affects headache occurrence, but there’s no good explanation as to how that happens.
quite sparse.
Frequently Asked Questions There are many different recommendations for sodium intake (WHO, AHA, etc). Which should I follow? That’s hard to answer definitively. The WHO recommends
good goal. If you’re otherwise healthy, you can probably get away with eating up to 2.4 grams, but that is based on governmental and organizational guidelines, which may change as evidence is changing.
<2 grams sodium (so <5 grams/day salt). The American 49
It’s important to note, however, that none of these recom-
MSG has sodium in it. Could that possibly explain the
mendations are based on headaches at all. They are strictly
effects observed in some individuals consuming MSG?
related to the research on interactions between hyperten-
Most MSG health effect reports are anecdotal. The effects of
sion and sodium.
MSG may be overstated, as blinded trials haven’t identified any adverse events associated with MSG consumption, even
Is this study sufficient to recommend or adopt a reduced
in individuals who self-identify as “sensitive” to MSG.
sodium diet for people who suffer headaches? It’s impossible to make a definitive statement about recom-
In fact, in one study, individuals who claimed to be sensitive
mendations based on one or even a few studies, no matter
to MSG were repeatedly randomized in four separate trials,
how well-designed. However, if you struggle with head-
and only two out of 130 responded appropriately to their
aches, reducing sodium consumption may be worth a try
treatment in all four trials. Furthermore, regularly con-
because it’s a relatively easy intervention without any known
suming enough MSG to notably affect sodium intake levels
side effects and multiple potential benefits.
would be a substantial feat because a gram of pure MSG equates to only 150 mg of sodium. It would take over 13
Is there any good reason to increase sodium intake?
grams of MSG to reach the maximum intake recommended
It is often recommended that individuals engaged in very
by the WHO (2 grams).
strenuous activity (for example, ultramarathon runners) should consume something with added sodium to prevent hyponatremia, but there isn’t that much evidence to support this assertion, and it may be more important to limit excessive fluid intake. Oral rehydration therapy (for people with major GI illnesses or severely dehydrated individuals who need to recover electrolyte levels) has sodium as one of its major components, but the effects of that therapy are related to the interplay between glucose, sodium, and water absorption in the small intestine rather than sodium alone. Furthermore, if a person experiences a GI illness that severe, they are likely already receiving medical care that includes a comprehensive rehydration protocol. Individuals who engage in extreme weight cuts for sport performance may consume
What should I know?
This study was very well-designed and had a rather strong conclusion. It showed that sodium intake likely influences the prevalence of headaches irrespective of other dietary or demographic parameters. However, it’s important to note that the effect size was not large, which implies that reduced sodium consumption may reduce the frequency of headaches, but it’s rarely the sole cause and unlikely to be the sole solution. However, most people can stand to reduce intake of junk foods that are often high in salt, and it’s unlikely to cause any negative effects, except possibly reducing your consumption of delicious and addictive snacks you ate as a child.
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extra sodium to rehydrate, but it is likely more effective when combined with glucose.
If all this analysis is giving you a headache, take a load off on the Facebook ERD forum.
Lastly, those with low blood pressure can also find salt to be useful when facing hypotensive episodes.
50
Diets, fast and slow
The effect of rate of weight loss on long-term weight management: a randomised controlled trial Introduction
Many people say that dieting is hard, and that keeping the lost weight off is even harder. But
we don’t need to take their word for it, the science of weight loss backs up their claims. One review, containing evidence gathered during most of the 20th century, found that only about 15% of obese people were successful in keeping a significant amount of weight off long-term through dieting! Why is dieting so hard? Maybe it’s because the way we go about dieting isn’t quite right. Government agencies in the U.S., U.K., and Australia all recommend an initial, gradual weight loss strategy of one to two pounds a week. Gradual weight loss is recommended for several reasons. It allows more time for people to form the habit of eating fewer calories. Also, crash diets with very low daily caloric intake can sometimes lead to nutritional deficiencies. Plus, it’s claimed that crash diets lead to larger rebounds after the diet is over, which makes sense considering that very low calorie diets have been seen to lower basal metabolic rate. 51
But is this true? There is certainly some evidence to suggest
the relative lack of evidence comparing rapid and gradual
that it is. For instance, one study found that counselling
weight loss. By randomizing rapid versus slow weight loss,
overweight and obese women to make small changes in
the researchers hoped to answer whether or not the speed of
their diet with the goal of 1800 calories per day succeeded
initial weight loss actually affects keeping the weight off.
in slow, steady and sustainable weight loss that persisted even after a year. A control group that provided counselling encouraging a 1200 calorie/day diet ended up with regaining weight after a year. However, there is disagreement about whether or not slow weight loss actually leads to better outcomes. One review of
Guidelines currently suggest that slow weight loss is preferred to rapid weight loss, since rapid weight loss may not lead to sustainable results over time. The evidence, however, is not clear-cut on this matter.
the literature suggests that faster initial weight loss was associated with better long-term weight maintenance, as long as proper support is provided. A recent trial, which encouraged older, obese women to decrease daily caloric intake to 1200 while increasing physical activity, found that the people who achieved more rapid weight loss both lost more weight and kept more weight off. However, this trial was not randomized, so it’s hard to say whether the rapid weight loss caused the increased success in weight maintenance or not. Sustained rapid weight loss is a bit more common in clinical settings. Protein-sparing modified fasts (PSMFs) are sometimes prescribed to very obese patients, and have calorie intakes of 500-600 kcal per day. For these patients, PSMFs can have better long-term weight loss than other approaches. While there is a rebound, as with any diet, adherence is fairly high and people remain motivated because they can see the scale moving. These patients, as they tend to be very heavy, also tend to face substantial and often immediate health risks if weight is not lost. The purpose of this study was to address
Who and what was studied? Participants were recruited via advertisements in
Melbourne, Australia. To be included in the trial, the participants had to be obese (defined as a BMI between 30 and 45) but otherwise healthy adults between 18 and 70 years old. People who smoked, were on medications that could affect weight, had any clinically significant disease (such as diabetes), or who used weight-loss drugs or adhered to a very low calorie diet three months prior to recruitment were all excluded. The 204 participants were studied in two different phases. The goal of the first phase was to have participants lose 15%
[...] only about 15% of obese people were successful in keeping a significant amount of weight off long-term through dieting!
of their weight, either quickly or slowly. The second phase took only people who met this goal, so they could be observed to determine how well their weight loss could be maintained. The first phase was performed by randomly assigning participants to either a fast or slow weight loss program. 52
Both programs had the aim of a 15% loss in weight using an overall caloric deficit of 105,000 calories, but over different time frames and using different methods. The fast program consisted of replacing three meals a day with Optifast, a commercial meal replacement. The total caloric intake for this group varied between 450 - 800 calories a day, depending on the individual’s needs to reach their 15% weight loss goal over 12 weeks. This rate of weight loss is about equal to 1.5 kilograms or 3.3 pounds per week. The slow group’s diet consisted of a 400 - 500 calorie deficit achieved by using one or two Optifast meal replacements, alongside a diet concordant with the Australian Guide to Healthy Eating from 1998 (which has since been updated to allow for more protein), which suggests that 15% of daily calories come from protein, 25–30% from fat, and 55–60% from carbohydrates. The aim of the slow diet was for each participant to lose 15% of their weight over 36 weeks, which would average out to about 0.5 kilograms or 1.1 pounds per week. Both groups were given the same educational material and assigned to biweekly meetings with a dietician, who provided feedback on their progress. Both groups were also encouraged to exercise at a mild or moderate intensity for at least 30 minutes a day. Study participants who succeeded in losing at least 12.5% of their weight in both groups moved on to the second phase of the study. The purpose of the second phase was to determine whether the rate of weight loss affected the ability to maintain the losses. Each participant received an individualized plan, which again adhered to Australian Guide to Healthy Eating. Each participant’s goal was to maintain their weight. They met with a dietician four and 12 weeks into phase 2, and every 12 weeks thereafter, for 144 weeks. Their adherence to the diet was monitored via self-reported food intake logs. If a participant was gaining weight, they were advised to change their diet to create a 400 - 500 calorie deficit. In addition to weight, fasting ghrelin (a hormone that induces
Random samples, random assignment This study was a randomized trial. But what exactly was randomized, and why does randomness matter in the first place? There are two types of randomness that pertain to trials like this: random sampling and random assignment. Random sampling is when each member of a population has an equal chance of being selected for a study. It allows you generalize the result of a study from the subset included in the study to the entire population. Why can’t you do this without a random sample? Because there may be bias otherwise. For instance, if we put a poll up on Examine.com to ask people “Do you care about the evidence behind abstracts?” we’d probably get a large number of “yes” responses. You Examine.com readers exceptionally curious, and definitely not a random and representative sample. This study did not use a random sample of people, but instead enrolled people who answered an ad or heard about the study through word of mouth. Since this sample could be biased (for instance, perhaps those who answered the ad were very motivated to lose weight), it would be hard to generalize the results of this study to all people. However, this study used another kind of randomness that is also important: they randomly assigned participants to groups. This helps to infer causality in a study because it helps to get rid of confounding factors.
hunger) and leptin (a hormone that induces satiety) blood levels 53
One of the biggest findings from this study is that the rate of weight loss does not affect weight regain in the tested population
What were the findings?
Almost 90% of participants completed phase 1 (the weight loss phase) of the study, with significantly more people dropping out of the slow weight loss group (18% vs. 3%). The biggest reason cited for dropout was difficulty of sticking to the diet. As seen in Figure 1, more people in the fast weight loss group achieved their goal of reducing their weight by 12.5%, and the result held up whether all subjects were considered or just those that completed phase 1. There was no significant difference in changes in fat-free mass in either group.
Figure 1: Rate of weight loss
and subjective hunger assessments were also measured at the start of the study, the end of phase 1, and weeks 44 and 144 of phase 2. A subgroup of participants also had their 3-beta-hydroxybutyrate levels drawn, which is a measure of ketosis. Activity was measured with a pedometer.
This trial was implemented in two phases. In phase 1, obese adults were randomized into two diets designed to reduce their weight by 15% over either 12 weeks (the fast group) or 36 weeks (the slow group). In phase 2, participants who succeeded in losing at least 12.5% of their weight were put on a maintenance diet designed to maintain the weight loss. Researchers intended to determine if rapid weight loss leads to rebound weight gain, and what role hunger plays in the rebound process.
There were some biochemical differences between the groups in phase 1 as well. The fast weight loss group had significantly higher levels of 3-beta-hydroxybutyrate (indicating ketosis) partway through phase 1, but there was no difference between groups at the end. Leptin (which promotes satiety) decreased throughout phase 1 for both 54
groups, but decreased significantly more in the fast weight loss group. Ghrelin (a hormone that induces hunger) rose equally for both groups throughout phase 1. Both groups
Figure 2: Success rate during weight loss phase (12.5% or more weight loss)
reported an increase in subjective hunger, although there was no difference between the groups. The fast weight loss group tended to walk about a thousand steps more per day than the slow weight loss group, even though they were both given the same exercise advice. However, the amount of steps taken did not differ between groups when only participants who succeeded in losing 12.5% of their weight were examined. People who walked more were not more likely to meet their goal, as there was no significant difference in number of steps taken per day between people who met the weight loss goal and people who didn’t. Overall, 51 participants from the slow weight loss group and 76 from the rapid group moved on to phase 2 of the study in order to determine if the weight loss could be maintained. There was no significant difference in the dropout rate between groups in phase 2 of the study. All but six people
Leptin rose at a similar rate in both groups in phase 2, but
(one from the slow group and five from the fast group)
participants who regained less than 25% of the weight lost
started regaining weight, and so were put on a 400 - 500
in phase 1 had much lower leptin levels than those who
calorie per day deficit, as per the experimental protocol. As
gained more than 75% of it back. Ghrelin levels decreased
seen in Figure 2, during phase 2, no significant difference
a little during phase 2, but still remained elevated, with no
in weight gain was seen between groups; both regained
significant difference between groups. However, subjective
over 75% of the weight they originally lost on average. This
hunger was higher in the group that lost weight quickly
put both groups at a total of about 5% weight loss over the
than in those who lost it slowly.
course of the study. The pedometer measurements also didn’t differ between groups.
There were also some differences in adverse events between the groups. During phase 1, one person developed acute
Also, crash diets with very low daily caloric intake can sometimes lead to nutritional deficiencies. 55
cholecystitis, a condition known to occur with rapid weight changes, where the bile duct of the gallbladder is blocked, which leads to inflammation. The authors of the study considered this to likely be caused by the rapid weight loss. Two other serious adverse events occurred in the rapid weight loss group (cancer) that the authors do not think was caused by the rapid weight loss. One person in the rapid weight loss group also withdrew due to worsening depression, on which the authors did not comment. There were no adverse events in the slower weight loss group.
It’s quite apparent that the body fights losing weight and keeping it off.
The fast weight loss group had an easier time sticking to the diet than the slow weight loss group. The fast weight loss group was also more successful in losing at least 12.5% of their weight in phase 1 of the study. Both groups gained back about 30 pounds during phase 2 while trying to maintain their weight loss, with no significant difference between the two groups. Hormonal and subjective measures of hunger rose throughout phase 1, and only dipped slightly in phase 2.
What does the study really tell us?
One of the biggest findings from this study is that the rate of weight loss does not affect weight regain in the tested population: obese nonsmokers, who don’t take any weight loss drugs and who don’t have diabetes. This puts a dent in the idea
that rapid weight loss leads to greater weight gain down the road. It also tells us that rapid weight loss can be even more successful than gradual weight loss, since more people were able to stick to the rapid weight loss plan than the gradual one, while also meeting their weight loss goal. It also tells us something many of us already know: dieting is hard. The total weight loss for both groups ended up being about 5%. Most of the weight lost during the dieting phase of the study was regained during the maintenance phase, although that phase was an incredible 144 weeks long, so it’s not like the weight was regained right away. It’s also important to note that results reflect averages for the sample -- some may have been wildly successful, while for others life events may have gotten in the way, as they often do. In other words, there can be quite a bit of human variation when trying rapid vs gradual weight loss. It’s quite apparent that the body fights losing weight and keeping it off. Hunger was observed to increase and persist in both groups throughout both phases, boosted by a rise in ghrelin (a “hunger hormone”) that persisted for at least three years (the length of this study), and which doesn’t level off much, even as weight is regained. Leptin levels (a “satiety hormone”) also remained low in people who 56
kept weight off, but rose in people who put significant weight back on, suggesting that the body is attempting to get its weight back to where it started. Keep in mind, the people in this study had access to nutritional counseling and were under medical supervision throughout the course of the study. The authors note that because of this, the results of this study may actually be better than what could be expected in the real world, where people are not under such strict supervision. This was also one conclusion of a systematic review of weight loss studies, and suggests that the methodology of rigorous clinical trials like this may make their results less generalizable outside of the context of a controlled study environment. The fact that the study’s participants did not have diabetes and did not smoke, and that a specific brand of meal replacement was used, may further limit the generalizability of these results. But, since this was a randomized trial, a pretty strong conclusion can be drawn: fast weight loss does not necessarily cause fast regain, and can be a relatively effective method for weight loss for some people.
This study found that losing weight quickly does not lead to any more weight gain than losing weight more slowly, and in fact can be more effective. However, it may be difficult to generalize these results to different populations outside of a clinical setting.
Making more choices drains willpower, which has been shown to affect food choice. meal replacements that use high-quality protein and are fortified with nutrients have a better safety record when used under medical supervision. Early PSMF diets employed for rapid weight loss used fairly incomplete proteins like collagen, along with very few micronutrients, and thus do not apply to modern PSMFs. There are some aspects of the rapid weight loss plan that may have helped the participants of this study be more successful. First, participants in the fast group in this study didn’t have to measure portions, as they completely relied on meal replacements to lose weight, whereas people in the slow group still ate some conventional meals. Measuring portions to count calories isn’t always accurate and can be hard to learn, which may explain some of the fast group’s success. Also, the use of meal replacements eliminates
The big picture
Despite the fact that some government agencies and “common sense” dictates that losing weight more slowly is more sustainable, this study showed that rapid weight loss can be a more effective method of losing weight, and doesn’t necessarily lead to more weight gain. Very low calorie diets have had a history of safety concerns, primarily caused by poor nutrition. At such a low calorie intake, you’re unlikely to get the nutrients you need to be healthy. However, modern
variety in the diet, which helps satiety and leads to less food eaten, and has been seen to increase diet compliance and weight loss in another study. The psychological phenomenon of decision fatigue may also play a role here. Making more choices drains willpower, which has been shown to affect food choice. While caution in extrapolating the results of this study to other populations is warranted, this study is an important
57
contribution to the science of dieting. According to the
5% drop in weight can help significantly lower the risks of
authors, there were no randomized, controlled trials specifi-
developing many of the chronic diseases associated with
cally studying the effects of the rate of weight loss on weight
obesity.
maintenance. Due to the relative lack of evidence for the widespread belief that rapid weight loss can lead to stron-
Keep in mind that the study participants regained weight
ger rebound weight gain, this belief has been questioned in
over three years. After one year, they had still retained more
some recent papers. The current study adds to the evidence
than half of their initial weight loss. Maybe if the study
supporting that, at least for some people, some of the time,
implemented a one-year anniversary kick-in-the-butt to
slow and steady does not always win the race.
get participants back on track, the results might have been different. But as it stands, the study protocol was the same
This study suggests that while very low calorie diets have been shown to be be potentially harmful in the past, they may be a viable weight loss option for obese people if done under proper nutritional and medical supervision. There are several behavioral reasons why modern meal replacements may have contributed to the success of the fast weight loss group in this study.
throughout the three years of maintenance, and that didn’t really work out. Can crash diets be harmful? Yes, in some circumstances they can be. In this study, one person suffered from an inflamed gallbladder, which was attributed to the diet. The American Association of Clinical Endocrinologists mention several other dangers, such as uric acid buildup in the blood from very low calorie diets, which can lead to severe complications, including kidney damage. These kinds of diets, with calories under 1000 kcal
Frequently asked questions
How much of the weight loss came from muscle in this study?
per day, should be done under medical supervision.
What should I know?
Fat-free mass was measured at the end of both phases
This study found that medically-supervised, rapid weight
using bioelectrical impedance, and it did not significantly
loss in obese individuals leads to no more weight gain after-
decrease in either group. While bioelectrical impedance
ward than slower weight loss. This method also had a higher
is often considered a worthless, garbage, waste-of-time
success and compliance rate. This runs counter to current
measurement among those who are really into fitness, it’s
recommendations, which suggest that rapid weight loss is
actually not a bad way to measure changes in a single indi-
harder to achieve, and can lead to greater weight gain down
vidual over time.
the road.
However, it is important to point out that muscle loss was not measured throughout the weight loss phase. But while we can’t really say too much about muscle loss from this
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Hungry for more? Whet your appetite for discussion in the private ERD readers’ Facebook group.
study, a large change in muscle loss would have likely shown up in the group means. The people in this study only lost 5% of their bodyweight by the end of the study. That’s not much, right? Modest weight loss can still have several benefits. Even a 58
Is the glycemic index actually useful for making food choices?
Effects of High vs Low Glycemic Index of Dietary Carbohydrate on Cardiovascular Disease Risk Factors and Insulin Sensitivity Introduction
Foods that contain similar amounts of carbohydrates may differ in the amount and speed at which they raise blood glucose levels. This quality is referred to as the “glycemic index” (GI), and is based upon the blood glucose response (total area under the glucose curve) over two hours to 50 grams of its carbohydrate content, as compared with 50 grams of glucose. The higher a GI value is, the more the food raises blood sugar in a way similar to pure glucose. Lower GI carbs are those that digest more slowly and don’t raise raise blood glucose to the same degree. However, GI can also be a function of insulin response, and not just a function of carbohydrate digestion or meal composition. It has become common practice among healthcare professionals to suggest an individual consume “low glycemic index” carbohydrates. However the effects of GI on diabetes and cardiovascular disease (CVD) risk factors have been equivocal in trials, as well as meta-analysis of observational studies.
59
Further complicating matters is the fact that carbohydrates
Over half (52%) of the participants were women and
are not eaten in isolation, but generally as part of mixed
51% were black. The authors oversampled black partici-
meals containing fat, fiber, potassium, polyphenols, and
pants because of their “disproportionate burden of insulin
other nutrients that can affect health measures. It is still
resistance and other risk factors that result in high rates
uncertain what (if any) practical significance there is for
of diabetes and cardiovascular disease.” Signs of metabol-
manipulating GI in the context of an otherwise healthy diet.
ic dysfunction were present in many of the participants, including hypertension (26%), obesity (BMI ≥30) (56%),
The DASH diet, or Dietary Approaches to Stop
LDL cholesterol at or above 130 mg/dL (68%), triglycerides
Hypertension, is an eating plan recommended for people
at or above 150 mg/dL (17%), and elevated (≥100 mg/dL)
with hypertension or prehypertension. The DASH diet has
fasting blood glucose (30%).
been shown to reduce blood pressure, lower risk of coronary heart disease, and improve bone mineral status. The
Four possible diets were provided based on the DASH-diet
diet puts a big emphasis on increasing fruit and vegetable
guidelines. Participants were provided all of their meals,
consumption, controlling sodium intake, and reducing pro-
snacks, and calorie-containing beverages throughout the
cessed food.
study. The intake of key factors such as total carbohydrates, fiber, fatty acids, potassium, and sodium was controlled for.
The objective of this randomized controlled crossover feed-
While GI values do not take mixed meals into account, the
ing study was to determine the effects of GI and amount of
meals used in the study for high– and low– glycemic index
total dietary carbohydrate in the context of a DASH-type
were put together using similar types of foods according to
diet, on various risk factors for diabetes and CVD.
their values (for instance, white bread versus whole wheat bread). The four diets were:
Who and what was studied?
A total of 163 overweight adults with above-normal blood
pressure completed this trial, which was performed at Johns Hopkins Medical Institution (Baltimore, MD) and Brigham and Women’s Hospital (Boston, MA). Participants were at least 30 years old, had elevated blood pressure (120-159 mmHg systolic and 70-99 mmHg diastolic), and were classified as overweight or obese by having a BMI of 25 or higher.
1. High–glycemic index (65% on the glucose scale), high-carbohydrate (58% of total energy) 2. Low–glycemic index (40% on the glucose scale), high-carbohydrate 3. High–glycemic index, low-carbohydrate (40% of total energy) 4. Low–glycemic index, low-carbohydrate
A sample guide to the DASH diet Type of Food Grains Fruits Vegetables Low fat dairy Lean meats/seafood Nuts/seeds/legumes Fats/sweets
Examples Whole wheat bread, rice, quinoa Apples, bananas, oranges Spinach, tomatoes, carrots Milk, yogurt, cheese Beef, chicken, salmon Almonds, cashews, beans Avocado, olive oil
Number of Servings/day 6-12 4-6 4-6 2-4 1.5-2.5 3-6/week 2-4 60
It is still uncertain what (if any) practical significance there is for manipulating GI in the context of an otherwise healthy diet. Each participant completed at least two of the study diets for five weeks each, with a two-week break consuming self-selected foods separating the diet interventions. Body weight was maintained by adjusting calorie intake, and participants recorded any additional foods as well as foods they did not eat. Maintaining body weight was important because simply losing weight can independently improve CVD risk factors.
What were the findings?
Figure 1 shows the primary outcomes at baseline and after each diet.
Figure 1: Primary Outcomes at Baseline and at the End of Feeding on Each Diet
Despite these efforts, participants still lost an average of 1 kg from baseline until the end of each diet period. However there were no differences between groups. The main outcome measures were insulin sensitivity, LDL-cholesterol, HDL-cholesterol, triglycerides, and systolic blood pressure. Daily intakes
Low carb, high GI
Low carb, low GI
High carb, high GI
High carb, low GI
Kcal
2011
1993
2011
1998
Protein (%)
23
23
16
16
Carbs (%)
41
40
58
57
Fat (%)
37
37
27
27
Fiber (g)
29
33
32
37
Potassium (mg)
3949
4026
39663
4103
Glycemic Load
112
64
172
104
Area under the glucose curve (AUC) – this is a way to measure how much and for how long a person’s blood sugar is
Study participants consumed at least two of the four available diets during the course of the study. The different diets contained either low or high carbohydrate meals, using either high or low glycemic index foods. Researchers measured insulin sensitivity, LDL-cholesterol, HDL-cholesterol, triglycerides, and systolic blood pressure.
elevated. On the high-carb diet, eating ‘low GI’ reduced the 12-hour AUC by 17% compared with high GI. However, on a low-carb diet there was no difference in glucose AUC between high or low GI diets. The low-carb, high GI diet reduced AUC by 19% compared with high-carb, high GI, but there were no differences between high or low-carbs diets with low GI. Finally, the AUC was reduced by 20% in low-carb, low GI compared 61
with high-carb, high GI. To summarize, either low-carb or
lowered with both low-carb diets, and increased on both
low GI will lower blood glucose through a 12-hour period,
high-carb diets.
but choosing both will not provide additional benefits. To summarize: Insulin sensitivity - On the high-carb diet, the low GI diet unexpectedly reduced insulin sensitivity by 20% compared with the high GI diet. There was no difference in insulin sensitivity on the low-carb diet between high and low GI, but another unexpected result was that the low GI diet increased fasting glucose levels compared with high GI. Insulin sensitivity was not different between high and lowcarb diets (at either high or low GI). Lipids and Blood pressure – LDL-cholesterol increased by 6% on a high-carb, low GI diet compared with high-carb, high GI. Glycemic index had no effect on HDL cholesterol level, systolic blood pressure, or diastolic blood pressure. However, a low-carb compared with high-carb diet increased HDL-cholesterol by 4% at high GI level. Regardless of GI value, low-carb decreased diastolic blood pressure by 1 mm HG compared with high-carb diets. On the low-carb diet, plasma triglycerides decreased by 5% with low GI compared with high GI. When comparing the low-carb diet to high-carb, plasma triglycerides were lower by 18% and 20% with high and low GI, respectively. Consuming the low GI, low-carb diet lowered triglycerides by 23% compared to the high GI, high-carb diet, but did not affect insulin sensitivity, systolic blood pressure, LDLcholesterol, or HDL-cholesterol. There were no additive effects (of carb level and GI) on any of the outcome measures. Additional analysis showed the effects of the diets were in the same among men/women, race (black and nonblack), presence of metabolic syndrome, and BMI. Changes From Baseline. All diets were successful in lowering blood pressure (systolic by 7-9 mm Hg and diastolic by 4-6 mm Hg). LDL-cholesterol was lowered with the highcarb, high GI diet and both low-carb diets by 9-10% and with the high-carb, low GI diet by 6%. Triglycerides were
Low-GI, low-carb diet vs High-GI, high-carb diet Triglyceride levels decreased by 23%
Low-GI, high-carb diet vs High-GI, high-carb diet Insulin sensitivity decreased by 20% LDL-cholesterol increased by 6%
Low-GI, low-carb diet vs High-GI, low-carb diet Triglyceride levels decreased by 5%
What does the study really tell us?
In line with the prevailing opinion in the medical community, the authors of this study expected that consuming foods with a lower GI would lead to improvements in insulin sensitivity and CVD risk factors. Unexpectedly, the low GI, high-carb diet compared with the high GI, high-carb diet actually decreased insulin sensitivity and increased LDL-cholesterol and LDL apo-B levels. It has been well established that a DASH-type diet can successfully lower blood pressure, and the same authors have previously shown that a lower-carb DASH diet can reduce plasma triglycerides, VLDL levels, and diastolic blood pressure. Varying the glycemic index of the carbohydrates in the DASH-type of diet had yet to be studied. This study suggests that in the context of a DASH diet, low GI foods do not improve CVD risk factors and may actually have some detrimental effects compared with higher GI foods. On a high-carb diet (58% of daily energy intake), choosing foods with a lower GI had no effect on levels of HDL cholesterol, triglycerides, or blood pressure, and led to small but unfavorable changes in LDL-cholesterol and insulin sensitivity. On a low-carb diet (40% of daily energy intake), choosing foods with a lower GI had no effect on levels of HDL-cholesterol, LDL-cholesterol, insulin sensitivity or
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blood pressure, but did lead to a small (5%) but favorable
Both a lower GI value and a lower carb content were able
decrease in plasma triglycerides. When compared to a high-
to lower the AUC compared to a high GI, high-carb diet.
carb, high GI diet, a low-carb, low GI diet had no effect on
Interestingly, there were no additional benefits on blood
insulin sensitivity, systolic blood pressure, LDL-cholesterol,
glucose from lowering both the GI and the carb content.
or HDL-cholesterol but did lower triglycerides by 23%.
This can be referred to as a plateau effect.
It is important to remember that this study was composed
Insulin index is another part of this equation, which refers
of overweight and obese people with elevated blood pres-
to the insulin response a particular food generates. While
sure (prehypertension or stage I hypertension), who were
this is highly correlated with carbohydrate content, Figure 2
consuming variations on a very healthy diet that included
shows that some types of foods have either lower or higher
a large number of fruits and vegetables. This study did not
insulin responses than would be predicted from their glyce-
address the effects of glycemic index on a typical western
mic responses. Specifically, foods that are high in protein, as
diet, or in normal weight people.
well as refined bakery products, may cause a disproportionately high insulin response.
While it is obvious that the GI values of foods will change when combined into meals, this study’s diets produced the expected differences in blood glucose AUC over 12 hours.
Focusing dietary recommendations simply on the glycemic index appears to be an oversimplification of the multifactorial process involved in healthy blood sugar control.
Figure 2: Mean insulin index vs glycemic index of different food types
Additional research has suggested that glycemic index values may be related as much to clearance of glucose as they are to entry of glucose into the bloodstream. Focusing dietary recommendations simply on the glycemic index appears to be an oversimplification of the multifactorial process involved in healthy blood sugar control. Although LDL-cholesterol was higher in the high-carb, low GI group, the researchers did not measure LDL-particle
63
Furthermore, high GI foods may even be favorable to low
In the context of a diet rich in fruit and vegetables and low in processed foods, glycemic index may not matter a whole lot. size or LDL-particle number. It is possible that these changes in LDL-cholesterol could be benign or even favorable. Additionally, the low carb diets contained higher amounts of protein than the high carb diets (23 vs 16% daily kcals), and the high carb, low GI diet had the greatest amount of fiber (37 g/day vs 29-33 g/day for the others). It is certainly plausible that these factors could affect results, though one might expect the effect of high fiber to be the opposite of what was observed.
The big picture
GI for certain outcomes when eating a DASH-type diet. It remains to be seen whether or not using glycemic index to select foods in the context of a typical western diet (and in a well controlled study such as this) would improve CVD risk factors.
Frequently asked questions
Protein and fiber levels were different between groups. Does that change interpretation of the results? It is possible, however the study was designed to make comparisons between high and low GI, within the context of either a high or low-carb diet. Because the protein was the same within low-carb or high-carb groups, this should not affect the outcomes. Fiber was highest in the high-carb, low GI group, which was inevitable to some degree as fiber content is a contributor to lower GI values. How does this relate to “glycemic load”? Glycemic load is glycemic index that has been adjusted to reflect typical serving size. This is useful because we rarely consume 50 grams of every food. Some foods (like grains, for many people) are consumed in greater amounts, while something like a carrot will have a high glycemic index but low glycemic load. Here is a thorough resource for glycemic load values. How was the participant adherence to the protocols? The researchers reported very high adherence, as all of the food was provided to the participants and they were instructed to write down any additional foods they may
“In the context of an overall DASH-type diet, using glycemic
have consumed and any of the food given to them that they
index to select specific foods may not improve cardiovascu-
did not eat.
lar risk factors or insulin resistance.” All food was consumed and no additional foods were eaten This quote from the study sums the findings up nicely.
on 96% of person-days on each diet. Although this was not
However, the importance of the first part of that sentence
intended as a weight-loss study, participants lost about one
should not be underestimated. In the context of a diet rich
kilogram of body weight from baseline, with no differences
in fruit and vegetables and low in processed foods, glycemic
in weight loss between any of the groups.
index may not matter a whole lot.
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I’ve [got a history of diabetes in my family] [am prediabetic] [am diabetic]. Should I eat low glycemic? Should I try the DASH diet? There are arguments on both sides. On the one hand, the DASH diet has been shown in meta-analysis to improve certain markers of blood sugar control. While evidence is mixed, long term observational data suggests that a lower GI diet can reduce the risk of some chronic diseases, with trials also showing a reduction in inflammatory markers. However, the randomized trial under review suggests that theorized benefits may be overblown. Observational data may not mean much, as people who eat lower GI could have a variety of other characteristics that help them with disease prevention. Also, micromanaging every meal based on glycemic index of specific foods is likely to be more annoying than helpful. Fat and fiber are typically present in meals consisting of minimally processed foods, and can blunt high blood sugar responses. The glycemic load of a mixed meal can be hard to estimate. If you are diabetic and on medication, listen to your physician and other health professionals, and don’t rely solely on your own research. But following a named diet isn’t a prerequisite for controlling your blood sugar.
micromanaging every meal based on glycemic index of specific foods is likely to be more annoying than helpful.
What I should know?
In the context of an overall healthy diet that is rich in fruits and vegetables, the glycemic index of foods is not something to be very concerned about. This results of this study even suggest that in the context of a higher-carb diet, high-GI foods may be preferable to low GI foods from the standpoint of their effects on insulin sensitivity and LDLcholesterol levels.
◆
Got some thoughts on this study, or the glycemic index in general? DASH over to the ERD Facebook group and let us know what you think.
65
INTERVIEW: Ivan Oransky Ivan Oransky, MD, is the vice president and global editorial director of MedPage Today, co-founder of the MacArthur Foundation-funded Retraction Watch, and founder of Embargo Watch. He previously was executive editor of Reuters Health and held editorial positions at Scientific American and The Scientist. A 2012 TEDMED speaker, he was awarded the 2015 John P. McGovern Award for excellence in biomedical communication from the Southwest Chapter of the American Medical Writers Association. He has authored or co-authored four books and written for numerous publications, including Nature, The New Republic, and The New York Times. I believe Retraction Watch is turning five later on this year. Considering the massive number of retractions you've reported on, what are a couple of your favorite ones? Like ones that might make for a good made-forTV movie (with "good" loosely defined). Retraction Watch does indeed turn five in August. Good memory! My favorite stories often change over time, but right now those that involve fake peer review – often reviewed by the very authors who wrote the papers – are still at the top of my list. It might be difficult to turn those stories into a made-for-TV movie, but we’ve turned them into a longer feature for Nature. They’re a perfect mix of pressure to publish and ingenuity, in the same way someone might construct a perfect crime – but then get caught. For a more typical made-for-TV movie script, though, I’d go with the story of Karel Bezouska, who broke into a lab one night to tamper with an investigation into his work, or Jatinder Ahluwalia, who sabotaged his colleagues and later turned out to have been dismissed from an earlier PhD program for the same reasons he eventually had to leave a second university. Why do you think the number of retractions has been going up over time? You’d expect to see more retractions as there are more papers published, but as Nature pointed out in 2011, the rise in the rate of retractions from 2001 to 2010 far outstripped the growth in papers. Part of that was definitely due to the advent of plagiarism detection software, and the fact that there are more eyeballs on 66
papers now that journals are all online. There’s also at least
I'm not sure how often meta-analyses account for included
circumstantial evidence that the amount of misconduct is
studies that have been retracted. Do you have any sense
going up, too. That’s less clear, though.
of how that issue is dealt with? After all, there isn't a duty for meta-analysis authors to follow-up on included studies,
Examine.com was plagiarized last year, and the authors
especially if they are numerous.
became extremely defensive. Have you interacted much
That’s a critical issue, but I’m not aware of anyone looking
with authors of retracted articles? What are these interac-
at it systematically, so to speak. It came up in meta-analyses
tions like?
performed after anesthesiology researcher Joachim Boldt’s
We always try to contact the authors of retracted papers.
fakery came to light. Most Cochrane meta-analyses are
Some get back to us. When they’re retracting for hon-
regularly updated, so perhaps there should be a mechanism
est error, those conversations show the best of science’s
that alerts meta-analysis authors to retractions and helps
self-correcting nature. We often add them to our “doing the
them figure out whether they need to follow up. In fact, we
right thing” category. Among those authors retracting for
were just awarded a $400,000 grant from the MacArthur
misconduct, or what sounds like misconduct, some don’t
Foundation to build a retraction database that we hope will
respond to our requests, while others don’t have much to
be linked to personal libraries authors use for referenc-
add, or give us a few details that flesh out the story. Most
es. That would make it impossible to cite a retracted paper
of the time with those kinds of retractions, we have to rely
without first knowing that it had been retracted.
on other sources for information. And then there are the handful of authors who try to keep themselves out of the
If you were magically given authority over retraction poli-
limelight by threatening to sue us. It’s never worked – quite
cies for all journals, what changes would you implement?
the opposite. Just Google “Streisand Effect.”
This seems unlikely, but since you’ve invoked magic, I’ll
Karel Bezouska, who broke into a lab one night to tamper with an investigation into his work, or Jatinder Ahluwalia, who sabotaged his colleagues and later turned out to have been dismissed from an earlier Ph.D. program for the same reasons he eventually had to leave a second university. 67
make pretend: First, I’d insist on clear notices that detailed
but in the long run it’s going to erode trust. Better to be
why exactly a paper had been retracted. No more opaque
forthright about cases of fraud, which are still uncommon,
“This paper has been withdrawn by the authors.” Of course,
then pretend they don’t exist and then have to defend sci-
that would probably require hiring different lawyers than
ence when news breaks.
the ones many publishers seem to employ today when they cave to legal threats from fraudsters. I’d also do away with
We've lightly touched on journals and information dis-
the mulligan of retractions, the unexplained “withdrawal”
semination in previous issues, talking about predatory
of papers that are published online but not in print yet. The
publishing and exaggeration in press releases. What's on
idea that such a paper doesn’t exist enough to warrant a
your mind these days concerning information dissemina-
full retraction notice is a quaint but ridiculously outdated
tion from journal articles? For example, I've read some of
notion some publishers insist on.
your writings on embargoes and the Ingelfinger Rule. I’ve more or less said my piece on how to use embargoes, if
Do high-impact journals deal with retraction in a more
journals must, but I remain concerned that the Ingelfinger
transparent manner? Are there any journals that do an
Rule prevents journalists from telling the real stories of
exemplary job of it?
science. I’ve said more about this elsewhere, but basical-
High-impact journals generally provide more informa-
ly it keeps researchers from talking to reporters for fear
tion than others in retraction notices, but they also have
of having their work rejected by top journals. You’d think
more retractions per thousand papers published. I’d say the
the rough-and-tumble world of online journalism would
Rockefeller University Press journals such as the Journal of
have eroded some of Ingelfinger’s power, but if anything
Cellular Biology do a consistently above-average job. Keep
it’s strengthened it as reporters look for the next minute’s
in mind, though, that how well a given journal investigates
“scoop.” Still, I’ve seen some chinks in the Ingelfinger armor,
allegations is usually a black box, unless we happen to learn
and that makes me happy.
of it from a source, and we’ve seen lots of journals stubborn-
◆
ly refuse to correct the record, so it’s hard not to think that the notices we see are just a tip of the iceberg phenomenon. Back to the human angle: I can't imagine being the author of a particularly egregious retracted article, and then attempting to procure more grant money and get more articles published. For academics who live and die by their CV, how can they continue in academia? That’s an excellent question, and we have to say we’re always surprised by a vocal minority of our readers who object strenuously when we ask it by following up on cases of fraud. In fact, more than half of researchers found to have committed misconduct by the Office of Research Integrity are still in the positions they had when they did the deed. That strikes us as strange, given how competitive grants are. It is a reminder, however, of how reluctant many researchers are to blow the whistle or air science’s dirty laundry. They
Dr. Oransky earned his BA at Harvard and his MD at the New York University School of Medicine. While a student, he served as executive editor of The Harvard Crimson and as co-editor-in-chief of the medical student section of the Journal of American Medical Association. In addition to his work as a medical writer and editor, Dr. Oransky teaches medical journalism at New York University’s Science, Health, and Environmental Reporting Program, and he is a clinical assistant professor of medicine at New York University School of Medicine. Dr. Oransky currently serves on the board of directors and as vice president treasurer of the Association of Health Care Journalists.
may think that’s a good way to minimize the effects of fraud, 68
INTERVIEW: Jessica Richman Jessica Richman started and sold her first company after high school. At Stanford University she earned degrees in Economics and Science, Technology and Society (with a computer science focus). Along the way, she worked for Google, McKinsey, Lehman Brothers, the Grameen Bank, and top-tier Silicon Valley venture firms. Jessica arrived at Oxford University as a Clarendon Scholar and completed an MSc at the Oxford Internet Institute. She is currently a DPhil student at Oxford with a focus on innovation, social networks, and collective intelligence. In layman's terms, how does uBiome go about testing for bacteria? What can you detect and what can't you detect? And also...is the testing technology changing from year to year? Great question, and a warm hello to all inquiring Examine.com readers. uBiome offers kits for people to sample the bacterial populations anywhere on the body and do personal experiments to learn about themselves. Sampling is done from the comfort and privacy of your own home, with a simple and non-intrusive procedure. For the gut sample, all we need is a swab of your toilet paper; for the skin sample, it’s just a swab behind your ear. We also sell kits for nose, genitals, and mouth. Each site has a unique microbiome that is home to a specific balance of flora. With the samples from each of these body sites we can tell you about the bacteria that inhabit that microbiome. You also get access to our ever-expanding database of bacteria, to see the role those bacteria play in keeping your microbiome balanced. You can track the results of probiotic usage, diet and supplement experiments, and antibiotic treatments, so you can see how they affect your microbiome over time. You can also compare your results to other participants, to see how you compare to users who have made similar dietary or lifestyle choices.
69
This is an exciting, emerging field. Our team keeps up to
For people who are new to this area, we want to help them
date on the many studies that are published about the
understand that the microbiome is influenced by both
microbiome and constantly works on ways to make this
health and lifestyle choices. What you eat impacts not only
data accessible to our participants - regardless of their sci-
your gut flora but your microbiome at other sites too.
entific background. We want to help people engage with their data in the most meaningful way possible.
More than 1.4 billion adults worldwide are overweight, with more than 500 million clinically obese. Over the past two
We've covered a couple rodent studies looking at microbi-
decades, there has been a marked rise in allergies, autoim-
ome effects on health and performance. Conclusions from
mune, and neurological disorders. Autoimmune disorders
human research are a bit more limited, due to complexity
now affect 23 million Americans alone; Asthma in western-
and inability to control as many
ized societies has risen steadily,
parameters. Where does uBiome
doubling in the last 20 years.
fit into the research picture? uBiome is the largest citizen science research study looking at the microbiome. We aim to contribute significant findings to this relatively nascent frontier of scientific research. While our test is not diagnostic, we do want to empower our community of knowledge-seekers with detailed information and personalized visualizations that will help them understand how their microbial
What you eat impacts not only your gut flora but your microbiome at other sites too.
There is overwhelming scientific evidence that the human microbiome has profound consequences for our health, and is implicated in diseases ranging from obesity, diabetes, and IBD to heart health, anxiety, and depression. uBiome is designed to help explore the scientific ramifications of the microbiome and to better understand this landscape for the novice and expert alike,
balance relates to other data sets.
but we can’t give people specific recommendations on what One of the most exciting ways uBiome fits into the micro-
to eat based on your microbiome.
biome research picture is by equipping people with tools to create their own scientific studies so they can explore
What can people currently learn by having their various
the issues most important to them. We want to see people
microbiomes sampled? What might they be able to learn
engaging with their microbiome in ways that might not
five years down the road (especially with continued testing)?
have been possible before. We want to learn what they learn.
With uBiome sampling, people can learn:
The microbiome is much more complex than most people can fathom. Some bacteria can be "bad" in one context
• What proportions of different bacteria are in their microbiome
and not so bad in another. So recommendations are likely
• How they compare to the microbiomes of other rel-
to be more complicated than for things like vitamins and
evant groups, such as healthy omnivores, vegans,
minerals. What advice do you give to gut novices about gut
smokers, and people who exercise regularly.
health? What about people who are already somewhat educated on the subject?
• How their data compares to peer-reviewed studies of the microbiome 70
Papers show that antibiotics or a drastic change in diet can alter a person’s microbiome in as little as three days. Testing provides participants with a snapshot of their micro-
are currently examining the role of bacteria such as
biome at a single point in time. However, we so want to
Streptococcus mutans in tooth decay. A healthy mouth
keep our community informed about the studies that scien-
microbiome can help fight off the bacteria that cause cavi-
tists are only now beginning to develop. Sampling now and
ties or gum disease.
at regular intervals will allow people to have early access to emerging studies, and give them the means to understand
The vaginal microbiome is also a rich area of research, with
how lifestyle or dietary choices may have changed their
new insights being generated frequently.
microbiome over time. The FDA cracked down on 23andme last year. What sort of How quickly can people change their gut microbiomes? For
regulatory issues does uBiome face, if any?
example, after a couple courses of antibiotics. Have you
uBiome is a research study, and we do not give any diagnos-
seen any particularly interesting success stories?
tic information to consumers.
Studies are just beginning to explore how susceptible the microbiome is to change. Papers show that antibiotics or a
One of the most frequently asked questions we receive is
drastic change in diet can alter a person’s microbiome in as
if we are IRB approved. For anyone not familiar with the
little as three days.
term, an Institutional Review Board is a committee that approves, oversees and reviews biomedical and behavioural
Our participants are not just simply learning about their
research involving humans. They conduct analysis to deter-
bacterial balance - many are setting out to explore the
mine whether or not research should be done. Their priority
extent to which they can hack their own microbiome. We
is to advocate for the individual participant.
are doing some internal studies on this -- stay tuned! And definitely let us know if any of you would like to join in, by
To answer that question here: uBiome has received research
writing to us at
[email protected].
study approval from E&I Review Services. To be completely sure that we had our participants’ privacy, security and
Most people focus on the gut, but uBiome samples five sites
well-being in mind, we have in fact consulted with our IRB
on the body. What are some things people should know
every step of the way. Under their advice, we completed the
about these other microbiomes?
final stages of their analysis and received approval immedi-
The important thing to realize is that your microbiome
ately after we had reached our initial funding goals.
functions differently at each of these sites. Readers of ERD are often scientists or wannabe scientists. For example, scientists who study the oral microbiome
Lots of information junkies. With so many different sourc-
71
es of information, and so many things that can be tracked, what are some of the most interesting developing microbiome topics that we should keep in mind? Any must-read gut-centered websites or blogs? There is a wealth of information available for people who want to learn more about the human microbiome. With websites such as Google Scholar becoming increasingly popular, it is becoming easier for people to access that information all the time. Institutions like MIT also offer excellent courses online for free. People who are interested in learning more about human biology, before they dive into their microbiome, might be interested to take their courses here. The National Institutes of Health is a great source for gut-centered material. For a lighter read, check out MindBodyGreen.com. And Paleo Magazine has some interesting articles and podcasts. We’re also firing up the uBiome blog, and would love to end with a question to your readers: what are the most burning microbiome-related questions on your mind, or what’s the number one thing you’d want to learn from looking at your microbiome? Thanks so much for this opportunity to share our project with the ERD community.
◆
[...] question to your readers: what are the most burning microbiomerelated questions on your mind, or what’s the number one thing you’d want to learn from looking at your microbiome?
Jessica is a co-founder of uBiome, the world's largest successful citizen science project. UBiome has been featured in Wired, MIT Technology Review, Scientific American, NPR, FoxNews, ABC News, and dozens of other media outlets. Jessica is also founder of Sciencecitizen.org, an organization that helps researchers incorporate the public into their work.
72
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Join the Discussion Online
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