Examine.com Research Digest 3

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Examine.com Research Digest

Issue 3



January 2015

1

Table of Contents 05

Heart benefits of alcohol may not apply to everyone

17   21

Type 2 diabetes: a preventable disease

 33 43  51

Investigating a progression of carb and saturated fat intakes Whence the hype? Running on empty: can we chase the fat away? Fitting into your genes: do genetic testing-based testing-based dietary dietary recommendations recommendations work?

61

Combating obesity through intermittent intermittent fasting

70

How does a lifetime of marijuana use affect the brain?

79

A mouse’s microbiome microbio me may cause its brain to leak

87 

Ask the Researcher Researcher:: Stuart M. Phillips, Ph.D., FACN, FACSM FACSM

92

INTERVIEW: Ramsey Nijem

2

From the Editor “However, more research is needed ...” 

Have Have you ever seen se en that line in a journal article? O

in line or randomized trials, such as the impact o

course you have. It’s a part o almost every article that

[INSERT NUTRIENT OR DRUG HERE] on heart dis-

we review or ERD. Is more research ever not needed?

ease biomarkers in [INSERT POPULATION HERE]. reatment is unded more ofen than prevention, and

A ellow researcher and I would talk about how ubiq- multimodal prevention prevention is unded much less ofen uitous this phrase was, and whether it really meant

than interventions inves investigating tigating a single method or

anything. He eventually wrote a letter to the editor

pharmaceutical.

o an epidemiology journal, j ournal, including some analysis on how ofen the phrase was used in major journals.

Maybe that seems backwards. But it’s not easy to test

Tree years later, I still run across the phrase a dozen

the combined impact o getting regular sleep, eating

times a day. Tis may never change.

mostly unrefined oods, getting time outside in the sun, and carving out time to relax and get some per-

Why is this phrase important? Well, it ties in to one

spective. Actually, it’s pretty difficult to test even one

o the most important, important, yet least talked about issues

o those interventions. Plus there’s much less money

in health research: when are new trials justified, and

to be made on prevention, especially when it comes

what exactly should new trials test? Tere’s a field o

to ree interventions, than there is to be made by sell-

research called “ value o inormation inormation analysis analysis,” ,” which ing treatments. places a dollar amount on the public health value o each unit o new research on a given topic.

Tere’s a phrase that reers to the inherent nature o human existence, including choices and difficulties:

Tere are only so many research dollars available. Not Te Human Condition. Condition. Sometimes, I think t hink there is every topic can get unding or a large l arge randomized randomized

a counterpart in Te Research Condition. Health

trial, and many important topics go unresearched. I’d

research is complex and shifing, and somewhat

like to know whether taking vitamin D in the morn-

inherently flawed. Single trials can’t conclusively

ing causes different effects than night-time ingestion.

answer questions. questions. Subtle differences in methods and

Will we see research on this topic? Probably not.

samples lead to different results. Research doesn’t really flip flop very ofen — it’s just a much more

Major issues that have already been addressed by

iterative and grueling process than the public knows.

animal studies and observational trials ofen are next

And it’s why more research is always needed.

Kamal Patel, Editor-in-Chief  3

Contributors Researchers

Trevor Kashey Ph.D(c)

Alex Leaf  M.S(c)

Courtney Silverthorn Ph.D.

Pablo Sanchez Soria Ph.D.

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

Arya Sharma Ph.D., M.D.

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

Stephan Guyenet Ph.D.

Mark Kern Ph.D., RD

Gillian Mandich Ph.D(c)

Margaret Wertheim M.S., RD

Zach Bohannan M.S.

Sarah Ballantyne Ph.D.

Katherine Rizzone M.D.

Editors

Gregory Lopez Pharm.D.

Reviewers

4

Heart benefits of alcohol may not apply to everyone CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: The INTERGENE case-control study  Introduction With advice coming rom everyone rom physicians physicians to bartenders, a common message broadcast during the past couple decades has been that moderate consumption o alcohol is not just allowable, but beneficial or heart disease. Indeed, imbibing to the tune o one drink daily or women, or two drinks daily or men, has been associated with lower risk o cardio vascular disease. disease. Proposed mechanisms or the protective effect o alcohol on coronary coronary heart disease (CHD) include the potential benefits rom the antioxidant antioxidant effects o polyphenols in wine, and an increase in high density lipoprotein lipoprotein (HDL) levels. HDL’s most well known unction is to transport cholesterol rom arteries throughout the body back to the liver, preventing cholesterol rom being deposited in the arteries, which would cause blockages. 5

Lipid-containing Lipid-containing particles in the blood ofen gain

sequences at a given site in the DNA. Both versions

and lose different types o lipids, such as cholester-

o the DNA sequence would be considered “normal,”

ol and triglycerides. Te ability o HDL to transer

with neither likely to directly cause debilitating dis-

cholesterol cholesterol into particles like VLDL is partially reg-

ease, like a rare mutation might. However, different

ulated by cholesteryl ester transer protein (CEP).

polymorphisms may still influence susceptibility to

CEP promotes transer o HDL cholesterol into

disease.

VLDL, and in exchange HDL receives triglycerides. trig lycerides. CEP is hence thought to reduce HDL cholesterol, cholesterol,

Tis study looked at how two polymorphisms in

so less CEP in your blood means HDL particles

the CEP gene affect the odds o having CHD at

would balloon up with

 varying levels o alcohol alcohol

more cholesterol, and

intake. Te two different

more CEP would mean HDL particles would carry less cholesterol. Hold on, less HDL cholesterol … isn’t that a bad thing? Not necessarily, as HDL is more complex than just the “good cholesterol” moniker it has taken on in public par-

HDL can be anti-inlammatory or inlammatory, depending on the disease state o the body.

alleles (gene variants) o CEP are called B1 and B2. B2 is associated with decreased CEP mass and increased HDL cholesterol. Given that we have two copies each o gene, the three different genotype options in a given subject are B1B1, B1B2, or B2B2.

lance (and unortunately physician office parlance as well). HDL also has a

A previous study  showed  showed that men with B2B2 gen-

lesser known, but important role in the immune

otype who have an ethanol intake o 50 g (about

system,, perorming a variety o unctions, system  unctions, such as

three drinks) or more per day had about a 60%

binding toxic substances substances in the blood. HDL can

lower risk o heart attacks than men with lower or

be anti-inflammatory anti-inflammatory or inflammatory , depending

no alcohol intake. Tis protective effect o larger

on the disease state o the body. HDL and LDL are

amounts o alcohol was not seen in people with the

markers o disease, but they each have physiologi-

B1B1 or B1B2 genotypes. On the other hand, in a

cal unctions important to the body, and neither are

study in a Mediterran Mediterranean ean cohort, cohort, no interaction

absolute determiners o or protectors against heart

between CEP aqIB, alcohol intake, and CHD was

disease.

observed.

Back to CEP. Tere is a known polymorphism in

Why is that? One reason could be simply different

the gene that encodes CEP called CEP aqIB. A

populations. populations. As seen in Figure 1, different pop-

polymorphism is when a particular gene has two

ulations can have substantially different CEP

or more relatively common possible nucleotide

genotype requencies. Rodents such as mice have no 6

Figure 1: CETP B2B2 allele frequency in different populations

CEP gene, and also have lower risk o atherosclerosis, though many other actors may be responsible responsible

Moderate alcohol intake is ofen encouraged to

this. Complete CEP deficiency is a rare mutation

help ward off heart disease. Tis advice is largely

in humans, although it’s much more requent in one

based on HDL effects, but these effects may also

area o northern Japan. Japan . While the requency o this

be modified by your genotype.

mutation mutation is higher in people with heart disease, at least in that area o Japan, recent studies have shown that the extremely cholesterol-rich HDL in these

Who and what was studied?

people still maintains its antioxidative unction and unction  and

Population

ability to move cholesterol out cholesterol out o areas o cholesterol

Tis case-control study took place in Sweden as part

buildup. buildup. So the impact o CEP on heart disease is

o the INERGENE research program, which aims

still very much up in the air.

to assess the interaction between genetic susceptibility and chronic disease in southwest southwest Sweden. Cases

Te aim o the current c urrent study was to re-examine re-examine

with heart disease were compared against controls

the effect o alcohol intake and its interaction with

who didn’t have heart disease, to assess how alcohol

CEP aq1B polymorphism on CHD odds.

and genetic variation impacted disease prevalence. prevalence. Te CHD cases were patients under age 75, admit7

ted to three regional hospitals or acute coronary

alcohol intake or men was considered about one

syndrome and diagnosed with myocardial inarc-

drink or more daily, while low intake was about less

tion. O the CHD patients who agreed to participate,

than ½ a drink daily. For women, high alcohol intake

618 patients were included (453 men, 165 women).

was classified as about ½ a drink or more daily, while low alcohol intake was less than ¼ o a drink daily.

O those, 209 men and 86 women had a first-time

Table 1: Tertiles of Ethanol Intake

myocardial inarction, while the remaining 323 had an exacerbation o previously diagnosed CHD.

Men (g/day)

Women (g/day)

Te controls without CHD were randomly selected

Low

< 6.5

< 3.2

individuals aged 25-74 at the time o sampling, and

Medium

6.5-13.1

3.2-6.3

2,921 o them were included.

High

> 13.1

>6.3

Intervention

Te data collected or analysis in this study was CEP genotype, as well as sel-reported inormation about alcohol intake, including requency o intake

One drink is 14 grams o ethanol, which is the equivalent o about 12 ounces o beer, five ounces o wine, or 1.5 ounces o 40%-alcohol spirits.

o different types o alcohol (low-alcohol beer, medium-strong beer, strong beer, wine, dessert wine, and

Tis study examined just over 600 cases o heart

spirits) with eight response categories ranging rom

disease and almost 3,000 controls, and classified

never to three or more times a day.

how much alcohol they drank into three categories that differed based on sex.

Alcohol intake inormation reerred to intake over the previous one-year period or controls and or the one-year period prior to the most recent coronary

What were the findings?

events or study participants. Age and sex-specific

Characteristics of Case and Controls

standard serving sizes or alcoholic beverages were

For both men and women, there was a smaller per-

used to calculate the daily ethanol consumption.

centage o alcohol users in the cases compared to the control groups. For women, 80% o CHD cases and

Daily alcohol intake was divided into three levels

87% o controls reported using alcohol. For men,

(low, medium, and high), and the odds ratio (OR)

89% o cases, compared to 93% o controls, report-

was calculated or having CHD based on genotype

ing drinking alcohol. People with CHD also had

and alcohol intake. Abstainers were classified into a

lower average ethanol intake compared to controls.

ourth group, though high/intermediate intake was

Tere were no significant differences in the distri-

compared to the low group, not to the abstainers.

bution o CEP genotype (B1B1 versus B1B2 versus B2B2) between cases and controls.

All models were adjusted or age, body mass index (BMI), HDL, sex, and smoking habits. Te tertile

Te cases were older than controls (around 62 years,

cut-offs are shown in able 1. In this study, high

compared to 51) and sicker. Almost 20% o the peo8

ple with CHD had diabetes, compared to under 5% in the control group. In addition to being heavier, people with CHD were more likely to be smokers. Alcohol Intake on CHD

In the entire cohort, intermediate drinkers had a 35% lower odds o CHD, compared to low drinkers, regardless o genotype. High drinkers had a non-significant 10% lower odds compared to low drinkers. Tose who abstain rom alcohol are ofen ound in observational studies to have a higher risk o heart disease than moderate drinkers. In this study however, both low drinkers and abstainers had increased odds compared to moderate drinkers, and low drinkers did not have lower odds than abstainers. Tis suggests that the actors typically attributed to abstainers that may impact heart disease (different social habits, higher previous alcoholism, etc.) may not have had a large impact in this population. Genotype on CHD

Tere were no significant effects o genotype on CHD odds in the whole cohort, when researchers used B1B1 as a reerence. For B2B2, the 10% lower CHD odds was not statistically significant. When the same logistic regression model was not adjusted or HDL cholesterol, the B2B2 genotype was associated with a 29% lower CHD odds in the whole cohort. Te act that adjustment or HDL level reduced the effect o B2B2 on CHD odds is not surprising, as the CEP gene is known to be involved in the regulation o HDL. Alcohol Intake and Genotype on CHD

B2B2 homozygotes had a remarkable decrease in CHD odds when they were intermediate alcohol drinkers (79%) and high drinkers (52%) as compared to low drinkers. In B1 carriers (B1B1 or B1B2 genotypes), intermediate drinkers had a 20% lower odds o CHD, though it was not statistically significant. B1 carriers who were high drinkers had essentially the same odds as low drinkers.

Why “odds reduction” instead of “risk reduction”? You may have noticed the word “odds” popping up a lot in this review. The reason stems back to this study not being a randomized trial. It didn’t actively test interventions on different groups o people, and see what develops over time. Nor did it observe participants and measure variables as time progresses, like a prospective observational trial does. Rather, at one slice in time it estimated previous alcohol intake and tested or CETP alleles in a group with heart disease and a group without heart disease. Since the study was a case-control study, it can’t use the simpler and more intuitive risk terminology. Randomized trials happen over time, hence you can be sure that giving the intervention preceded the outcome, and estimate the “risk” o the outcome based on what intervention was given. That isn’t true o case-control studies such as this one, and hence you can only measure the “odds” o the outcome in one group versus another group. However, when a disease is rare, happening in around 10% or less o the population that’s studied, the odds ratio and relative risk will be approximately the same, due the mathematical ormulas or each converging.

9

B2B2 Genotype in Intermediate Drinkers

B2B2 intermediate drinkers had a substantial and significant 59% reduction in CHD odds compared to non-B2B2 intermediate drinkers. Prevented Fraction

Based on the authors’ calculation o prevented raction, this population would have had around 6% more cases o CHD i the combination o B2B2 and intermediate/high alcohol consumption had not existed.

While B1B1 and B1B2 genotypes weren’t associated with lower heart disease risk, B2B2 intermediate drinkers had 79% lower risk than low drinkers, and B2B2 high drinkers had a 52% lower risk. Tese numbers equate to an estimated 6% reduction in CHD or the overall population.

What does the study really tell us? Based on the results o the current study, intermediate to high alcohol intake does not significantly reduce CHD odds in people with B1B1 or B1B2 genotypes. In B2B2 genotypes, intermediate alcohol intake was associated with a 79% reduction in CHD odds, while high alcohol intake was associated with a 52% odds reduction. Tese results also held up to a variety o sensitivity analyses, such as measuring alcohol intake in our cutoffs rather than three, including or excluding adjustment or HDL and various other potential conounders, or when analysis was restricted to those age 60 or older or those who were enrolled at their first cardiac event. One strength o this study was that different cut-offs o alcohol intake were taken into account, rather than just comparing low and high intake. Te models were adjusted or age, BMI, HDL, sex, and smoking habits, to correct or common conounding actors. Te authors also tested additional actors, like leisure time physical activity, financial security, education levels, marital status, and diabetes status, but these had no effect on the results. It could be surmised that intermediate drinkers have more healthy behaviors than the 10

high alcohol group, but at least or the actors men-

specifically at CEP, a gene that appears to be only

tioned, this was not the case. Tus, the protective

involved in transer o cholesterol rom HDL to

effect o B2B2 at intermediate and higher alcohol

other lipoproteins. Yet it ound that the additional

intakes could not be explained by HDL cholesterol

protective effect o CEP in intermediate and high

or other liestyle and socioeconomic variables.

drinkers (on top o just the alcohol intake) was not explained by HDL levels. Tis could be due to a vari-

Tat being said, the cases and controls differed

ety o actors — perhaps a simple measurement o

widely on a variety o characteristics associated with

HDL cholesterol is less important than the number

disease, such as age, weight, and diabetic status. It is

and type o HDL particles. As was reerenced beore,

possible that there were other important conound-

HDL can be anti-inflammatory or pro-inflammatory

ers that were not controlled or.

depending on physiological context, so simply sticking HDL into a regression may not ully describe the

Te study also didn’t discuss potential mechanisms

role o HDL in the relationship between CEP gen-

that may explain the results. Previous research

otype and heart disease odds.

in Norwegians showed that HDL may not be so important or the protective effect o alcohol on heart disease. However this Swedish study looked

Te study results didn’t change when sensitivity analysis was perormed with different alcohol intake cutoffs and different conounders. However,

Earlier studies didn’t take into account CETP genotype, and likely showed a less substantial but still protective effect o alcohol intake due to a dilutional effect

the cases and controls differed in a variety o characteristics, and it’s possible that important potential conounders weren’t controlled or.

The big picture Having the B2B2 genotype didn’t have a strong protective effect on its own, and neither did drinking intermediate or high amounts o alcohol on its own. But combining these two actors was associated with a substantial reduction in the odds o heart disease. Te authors ocused mostly on intermediate intakes in their discussion, but high intakes also had a substantial reduction in odds, at 52% (compared to 79% in intermediate drinkers). Tis may be because high intakes come with much higher risks. Earlier studies didn’t take into account CEP genotype, and likely showed a less substantial but still 11

protective effect o alcohol intake due to a dilu-

large and well known previous studies, such as the

tional effect — meaning that the substantial odds

Harvard-run and U.S.-based Nurse’s Health Study 

reduction in people with B2B2 likely may have been

and Health Proessional Follow-Up Study, suggest a

diluted by the lack o CHD odds reduction in people

protective effect o the B2 allele. Te reerence group

with B1B1 or B1B2 genotypes.

in that analysis, however, was abstainers rather than those with a low alcohol intake. Women in those

Tese results confirm a previous study , which

studies were ound to have stronger benefit rom

showed that men who were B2B2 homozygotes

the B2 allele than did men, which was not ound in

with an alcohol intake o 50 grams a day or more

this Swedish study. Because study designs and pop-

had lower myocardial inarction risk, and the risk

ulations differ, it’s hard to directly compare different

reduction was the strongest when the participants

CEP studies.

drank 75 grams a day or more. In the current study, however, the greatest risk reduction was seen at an

Tis study also had some important methodologi-

alcohol intake o 6.5-13.1 grams a day, significantly

cal limitations. Subjects were queried on requency

lower daily intake than seen previously.

o alcohol intake, but were not asked about portion size. Standard portion sizes were used to calculate

It is surprisingly easy to derive different conclusions

daily alcohol intake. Tis could lead to inaccuracies

based on something as simple as cutoff points — the

in daily intake data. In addition, under-reporting

same data can be sliced into two parts with high

o alcohol intake is common during sel-reporting,

 versus low intakes, or several different intakes. And

which could skew the intermediate and high tertiles

the reerence group can also differ between studies.

o intake. Furthermore, CHD cases could also have

In this study, the reerence group was made up o

reduced their alcohol intake in response to the diag-

low alcohol drinkers, rather than those who totally

nosis or under-report intake i they think they are

abstain, as abstainers can be quite a diverse group

supposed to limit intake, but this effect is likely to be

that includes anybody rom ormer alcoholics to

same regardless o CEP genotype. Tis is a weak-

those who don’t drink or religious reasons. Some

ness o the case-control design, as a prospective study

12

With comparison groups this small, this study is just one more step in the progression o studies on the topic, rather than being the inal word on alcohol and heart disease. that collects data beore CHD develops may be less

LDL, no matter how strong the associations appear.

subject to this kind o under-reporting. It’s also pos-

While “HDL = good, CEP = bad” is a simplistic

sible that intermediate alcohol users could also have

and inaccurate way o thinking, it is surprisingly

generally healthier eating and liestyle habits that

pervasive. CEP may promote heart disease in some

were not captured in the logistic regression model.

situations, and have no effect in others.

Tis is also just one study among several on the

Tus meta-analyses o CEP’s overall effect on lip-

topic, some o which show conflicting results. Tis

ids and heart disease risk may inadvertently gloss

paper was done on a geographically limited sample

over interaction effects rom actors like alcohol

in Sweden, so the results may not apply to those in

intake levels or other variables that may moderate

another region, like East Asia or Central America.

CEP’s effects. Te topic o heart disease, alcohol,

Te small sample size also limits the conclusions

and HDL is a great example o how ocusing on a

that can be made rom this paper. Headlines read-

single article abstract without context, even i that

ing “Heart benefits unlikely rom alcohol” likely

abstract describes a well-conducted meta-analysis,

won’t mention that this study only included 13 cases

can be quite misleading. A meta-analysis is only

who had the B2 allele and were intermediate alco-

as good as the studies it contains, and the more

hol drinkers. With comparison groups this small,

complex the interactions get and the more hetero-

this study is just one more step in the progression o

geneous the study designs are, the higher the risk o

studies on the topic, rather than being the final word

a meta-analysis coming to erroneous conclusions.

on alcohol and heart disease.

A meta-analysis o seven studies ound that alcohol did not interact with the B2B2 genotype, but it com-

It’s important to remember that a variety o actors

pared current drinkers versus nondrinkers, which

could influence the effect o alcohol on heart dis-

is likely to be too crude o a comparison to uncover

ease, other than just genetics, such as age, sex, and

the more complex relationship ound in this study.

insulin resistance. Observational studies cannot attribute causation or lack o causation to HDL or

13

Context is also very important: the Tis study confirms some previous evidence while

additional effect o alcohol on heart dis-

conflicting with other evidence, likely due to

ease won’t be nearly as important or a

dividing alcohol intakes into different levels while

young person without many risk actors

using low drinkers as the reerence group rather

as it is or someone who has already

than abstainers. Te study is another part o the

had heart disease. Te combined risks

CEP and heart disease puzzle, which is yet to be

o alcohol side effects, plus potential

ully solved.

risk o alcoholism, may very well outweigh alcohol benefits or heart health

Frequently asked questions

even i one is a B2B2 carrier.

Does requency o alcohol consumption matter?

Why are studies on cardiovascular

Would 49 grams o alcohol once weekly (average o

effects o alcohol and CEP so con-

seven grams/day) be just as beneficial or CHD risk

 flicting? 

in a B2B2 homozygote as daily alcohol intake o 7

It’s not really possible to do a ran-

 grams? 

domized trial o different alcohol

It’s unclear rom these study results how requency

intakes, and see what the cardio-

o alcohol intake affects CHD risk reduction. Since

 vascular effects are. Without RCs,

binge drinking is not advised, the smaller amount

observational studies in different

would be more consistent with current health guide-

populations couple with mechanis-

lines or daily consumption. Heavy drinking increases

tic and animal studies to orm the

the risk o some types o stroke and atrial fibrillation,

evidence base.

which highlights the variety o other cardiovascular outcomes that are related to alcohol consumption.

Analyses in observational studies can use a variety o statistical

Is B2B2 protective or CHD when combined with

methods and control or different

intermediate alcohol intake in both men and women? 

possible conounders, which could

It’s unclear at this point whether the B2B2 geno-

lead to different conclusions even

type with intermediate alcohol intake is protective

using the same data. So, even

against CHD in women. Te study under review

though the largest meta-analysis

and Nurse’s Health Study may have not had a large

on CEP to date shows that the

enough number o heart disease cases to detect

B2 allele has a statistically sig-

these effects. For women who are non-drinkers or

nificant but weak protective

low drinkers, increasing alcohol intake to reduce

effect, the result is heavi-

CHD risk wouldn’t necessarily be advised, giv-

ly dependant on the

en other data that suggests a higher risk o other

methods used

chronic disease, including breast cancer, linked with

by the studies

alcohol intake.

it included. 14

Additionally, the mechanisms by which CEP may help prevent or promote heart disease are also not clear. In other words, this is a research area that is still progressing, and disagreements exist within the academic community. We will keep our collective eyes out or new studies on this topic. Does my CEP allele mean that I have higher risk o heart disease? 

Tis is the million dollar question, or which there is only a five cent answer: we don’t know. Although this particular study had compelling results due to studying a variety o alcohol intake levels and adjusting or a variety o variables, CEP study results in general are really all over the place. For example, one review ound that the effect o B2B2 differed depending on the population that was looked at. In participants with a high risk o heart disease it was protective, while in general populations it promoted heart disease! Te requency o B2B2 also differed, being much less requent among those with high risk. B2B2 sometimes could predict whether a lipid-lowering drug would prevent heart disease, and sometimes couldn’t. Can I take a drug to modiy my CEP activity and  prevent heart disease? 

Because increased CEP activity decreases HDL levels, this became a research target or new medications in the 2000s. One promising drug, torcetrapib, reliably raised HDL levels by inhibiting CEP activity, as well as lowering LDL. However, the trial was terminated early  due to torcetrapib causing a 25% increase in cardiovascular deaths alongside a 60% increase in deaths rom any cause. So to repeat: we don’t know quite how CEP affects

[...] there's only a small portion o the population or whom alcohol intake is protective against CHD, and most all o them are unaware that they have a potentially protective gene. heart disease. Te effect o your genotype may be modified by your diet, habits, medications taken (especially statins) and even other genes. HDL and LDL by themselves don’t mean that much in isolation, and neither does your CEP genotype. Some people are able to get a portion o their genomes sequences through services such as 23andme, and that may help inorm the effect o alcohol on a particular individual’s heart health. Tat being said, the evidence is nowhere near concrete, and the uncertainty about alcohol benefits on heart health is one o the major takeaways on this topic.

What should I know? 15

In short, moderate alcohol consumption may not protect everyone equally rom heart attacks. Protective effects likely depend on genetics. Te results o this study raise the question o whether the recommendations regarding alcohol intake or the prevention o CHD are too overarching. Substantial CHD odds reduction was only seen in people who were B2B2 homozygotes, with intermediate to high alcohol intake. For someone giving advice about how to prevent heart disease (like a physician, or someone advising an older parent), keep in mind that the evidence is still quite mixed on this topic. In the context o public policy, the authors estimated that 6% o heart disease was prevented by the combination o B2B2 and intermediate/high alcohol intake. Tis is not a huge amount or something that can have several important detriments like drinking alcohol does. It’s important to note that only 19% o the entire cohort in this study had the B2B2 genotype. While the requency o this genotype in the general population is unknown, the beneficial effect o alcohol intake on CHD odds would only apply to the small segment o the population who are B2B2 homozygotes with intermediate to high alcohol intake. Perhaps in the uture, genetic testing will help us determine our behaviors around alcohol. But or now it seems there’s only a small portion o the population or whom alcohol intake is protective against CHD, and most all o them are unaware that they have a potentially protective gene. ◆

We’ll discuss the potentially complex relationship between alcohol and heart disease in the private ERD readers’ Facebook group. Join us!

16

Type 2 diabetes: a preventable disease By Stephan Guyenet, Ph.D. Three thousand and ive hundred years ago, ancient Egyptian physicians reported excessive urination in some o their patients—a key diagnostic sign o diabetes. The mummy o Queen Hatshepsut, a powerul pharaoh who ruled ancient Egypt during this time period, suggests that she was obese and likely suffered rom type 2 diabetes. Throughout history, other royals have been posthumously diagnosed with probable type 2 diabetes, including the portly King Henry VIII o England. Diabetes has been a scourge o the affluent or thousands o years. Diabetes is defined as a ailure o blood glucose con-

leading to a near-total disappearance o circulating

trol, leading to excessively elevated blood glucose.

insulin. In type 2 diabetes (ormerly called adult-on-

Tis ailure o blood glucose control results rom

set diabetes), the body’s tissues lose their sensitivity

insufficient action o the pancreatic hormone insulin,

to the insulin signal. Te pancreas compensates by

which normally constrains blood glucose concen-

secreting more insulin, but eventually the beta cells

trations, both in the asting state and afer meals.

are unable to maintain this excessive level o insulin

During type 1 diabetes (ormerly called juvenile-on-

secretion, insulin levels decline, and blood glucose

set diabetes), the body’s immune system attacks and

levels rise.

destroys insulin-secreting beta cells in the pancreas,

17

Diabetes is extremely rare in cultures that maintain a liestyle similar to our (nonroyal) distant ancestors, yet more than a third o modern Americans are projected to develop diabetes at some point in lie. Tis ailure o blood glucose control, and accompa-

bled to 36 percent. Te rest o the affluent world is

nying metabolic disturbances, leads to the amiliar

ollowing closely behind. Excess body at is likely the

signs and symptoms o diabetes: excessive thirst

single largest contributor to the modern epidemic o

and urination, glucose in the urine, excessive hun-

diabetes.

ger, weight loss, atigue, slow healing, and eventually,  vascular disease, kidney ailure, as well as nerve and

Te ollowing graph illustrates the relationship

retinal damage.

between body mass index (BMI; a measure o body atness) and diabetes incidence over a five-year peri-

Te reason type 2 diabetes is no longer called

od in American men:

“adult-onset diabetes” is that it now occurs in children as well as adults. Tis trend is part o an

Diabetes Risk According to BMI

increase in global diabetes risk  that affects people o nearly all age groups in all affluent nations. Diabetes is extremely rare in cultures that maintain a liestyle similar to our (non-royal) distant ancestors, yet more than a third o modern Americans are projected to develop diabetes at some point in lie. Nearly all o these cases will be type 2 diabetes. Fortunately, the causes o diabetes are well known, so much so that we know how to prevent the large majority o cases. Let’s have a look. Obesity

Over the last century, but particularly the last three decades, Americans have bought progressively lon-

A BMI between 18.5 and 25 is considered lean, 25

ger belts. In 1971, 15 percent o Americans were

to 30 is considered overweight, and 30 or great-

obese, yet by 2009, that number had more than dou-

er is considered obese. As you can see, the risk o 18

developing diabetes increases rapidly with increas-

people gain at, lose muscle, and become more sed-

ing BMI, and the relationship is extremely strong.

entary with age.

A man with a BMI greater than 35 (obese) has a 42-old greater risk o developing diabetes than a

Physical activity

man with a BMI below 23 (lean). I we zoom in on

Muscle tissue is the single largest user o glucose

the lower end o the graph, we can see that diabetes

in the body, and when its uel needs are high, it

risk increases by 50 percent even beore we leave the

increases its sensitivity to insulin to accelerate glu-

lean BMI range, and more than doubles or people

cose uptake. Because o this, physical activity causes

who are only slightly overweight!

a rapid and proound increase in muscle insulin sensitivity , leading to an increase in whole-body insulin

Diabetes Risk According to BMI

sensitivity. Tis increase in insulin sensitivity only lasts a ew days, so regular physical activity is essential to maintain it. Not surprisingly, people who are more physically active have a lower risk o developing diabetes, and the association is substantial. People who engage in regular vigorous exercise, or even walk regularly , have just over hal the diabetes risk o people who are the most sedentary. Genetics

One o the most effective ways to avoid type 2 diabeCountless experiments show that this is more than  just an association: excess body at contributes to the metabolic disturbances that lead to type 2 diabetes. Tis appears particularly true o the visceral at that surrounds the organs underneath the abdominal wall. Age

Nearly all liestyle-related disorders are strongly linked to age, and type 2 diabetes is no exception. Among the elderly, the yearly likelihood o being diagnosed with diabetes is more than 30 times greater than among young adults. Part o this excess risk isn’t linked to age directly, but to the act that most

tes is to choose your parents wisely. All o the most common orms o diabetes, including type 2 diabetes, have a strong genetic component. Like most liestyle-related disorders, diabetes is not usually caused by a single gene variant. Rather, it’s caused by complex interactions between many different gene  variants and the environment in which a person lives. Possibly or genetic reasons, certain racial groups are at a higher risk o diabetes than others. For example, Asians, including people o Indian descent, are at a higher risk o developing type 2 diabetes at any given BMI. In other words, a modestly overweight Indian or Chinese person may have the same diabetes risk as an obese Caucasian person. 19

Te genes that influence type 2 diabetes risk tend to be involved in the development and unction o the insulin-secreting pancreas, and to a lesser extent, body atness. Some o these genes may determine how well beta cells are able to cope with the metabolic battering that accompanies obesity and insulin resistance. Preventing type 2 diabetes

Some risk actors aren’t modifiable: we simply have to live with them. We can’t change the genetic cards we’ve been dealt, nor can we roll back the years o our lives that have elapsed. Still, the risk actors we can control are so powerul that they can eliminate the large majority o type 2 diabetes risk. Several randomized controlled trials have clearly demonstrated this, including the massive Diabetes Prevention Program (DPP) trial. Tis trial reported that a combination o dietary weight loss and regular exercise reduced the risk o developing diabetes by an astounding 58 percent over a 2.8-year period in pre-diabetic volunteers. Several similar trials conducted in other countries and other racial/ethnic groups reported almost identical results. Tis is one o the greatest triumphs o modern biomedical science.

diabetes risk increases by 50 percent even beore we leave the lean BMI range, and more than doubles or people who are only slightly overweight!

Keep in mind that these trials started with people who were already nearly diabetic, and who didn’t lose much weight or adhere particularly closely to the intervention. Imagine what a lietime o healthy living could do. ◆

Stephan is an obesity researcher, neurobiologist, and author. In addition to his research, he enjoys synthesizing and communicating science or a general audience. He has a B.S. in biochemistry (University o Virginia) and a Ph.D. in neurobiology (University o Washington). His blog Whole Health Source is a ree resource or anyone who loves the science o health.

20

Investigating a progression of carb and saturated fat intakes Effects of step-wise increases in dietary carbohydrate on circulating saturated fatty acids and palmitoleic acid in adults with metabolic syndrome Introduction Saturated at reduction has long been a major target o dietary guidelines, although recent meta-analyses have ailed to show an association with heart disease. Current recommendations in the U.S. include limiting saturated at intake to less than 10% o total energy intake. However, a reduction in at intake typically leads to an increase in carbohydrate intake. A consequence o overconsumption o carbohydrates is increased de novo lipogenesis (DNL). DNL is a process which involves the synthesis o atty acids rom non-lipid sources, such as carbohydrates or amino acids. Interestingly, even energy-balanced diets, and single-meal consumption o carbohydrates above the normal oxidative capacity o the body have been shown to 21

increase DNL. Te percentage o ingested carbohydrate contributing to DNL is however quite minor in

Saturated at is commonly targeted or reduction

people who aren’t insulin resistant and overeeding

by dietary guidelines. Tis typically leads to an

on refined carbohydrate.

increase in carbohydrate intake, which at high levels may cause the body to create ats through

Te major end-product o DNL is the saturated at

de novo lipogenesis. Tis study investigated sev-

palmitic acid (denoted 16:0, reerring to 16 carbons

eral levels o saturated at and carb intake to see

and zero double bonds), which can be desaturated

how they affected plasma saturated ats and pal-

within the body to orm the monounsaturated at

mitoleic acid.

palmitoleic acid (16:1). Higher blood levels o palmitoleic acid have been associated with an increased risk  o metabolic syndrome and greater amount o

Who and what was studied?

inflammatory markers. Palmitoleic has mixed evi-

Te study was an 18-week controlled dietary

dence however, also being associated with some

intervention in which the participants were ini-

positive biomarkers such as higher HDL and greater

tially ed a low-carbohydrate diet that gradually

insulin sensitivity. Divergent impacts could be due

shifed to a high-carbohydrate diet over six con-

to the effects o different liestyle actors and differ-

secutive phases (rom lowest carb to highest carb:

ent physiological conditions (such as how much o

C1→C2→C3→C4→C5→C6).

DNL is rom adipose tissue versus rom the liver). Prior to beginning the six eeding interventions, the Tis study sought to assess how incremental chang-

participants were instructed to ollow a low-carbo-

es in dietary carbohydrate intake and decreases in

hydrate “run-in” diet or three weeks that mimicked

saturated at intake affect plasma saturated atty

the first low-carbohydrate phase, in order to initiate

acid and palmitoleic acid levels. Te study was con-

metabolic adaptations to carbohydrate restriction.

ducted in adults with metabolic syndrome under

Baseline and “run-in” nutrient intakes were deter-

hypocaloric conditions.

mined with the help o three-day ood logs.

The percentage o ingested carbohydrate contributing to DNL is however quite minor in those who aren’t insulin resistant and overeeding on reined carbohydrate. 22

All ood was provided or the subjects during the

Only very-low and non-caloric products such as

18-week intervention. Participants picked up their

coffee, tea, water, and diet soda were allowed to be

meals three to our times per week, and i the sub-

consumed by the participants in addition to the

 jects could not travel to pick up their ood, the

provided oods. Bee, eggs, and dairy were the pri-

researchers arranged or delivery in order to ensure

mary protein and at sources, with higher and lower

that every subject received their ood as planned.

at versions used depending on the study phase.

Blood testing was done at baseline, afer the run-in

Low-glycemic carbohydrates were emphasized

diet, and afer each phase (beore transition to the

throughout.

next diet) to determine atty acid composition and other blood markers.

Te subjects were 12 overweight and obese men and our women with metabolic syndrome, between 30

Over the entire 21-week period (intervention and

and 66 years old (average 44.9) with BMI ranging

run-in), the subject’s diets were designed to produce

rom 27-50 kg/m2 (average 37.9). Exclusion criteria

a 300 kcal deficit per day. Resting energy expendi-

included having diabetes, liver, kidney, or other met-

ture (REE) was estimated at baseline with indirect

abolic or endocrine dysunction. Participants who

calorimetry and multiplied by an activity actor to

were physically active were asked to maintain their

estimate the total daily energy expenditure (DEE)

activity levels while sedentary people were asked not

o the subjects. Protein was held constant at 1.8

to begin an exercise program.

grams per kilogram o ideal bodyweight. As carbohydrates were increased every three weeks over the six eeding phases, total at was decreased to maintain energy intake. Tus, across the entire study, protein and calorie intake was similar. Saturated at was also maintained, at 40% o total at intake. In comparison, Americans only derive around 34% o their calories rom any kind o at, with around 13%

Tis study investigated the effects o various carbohydrate diets on a group o overweight and obese participants. Study participants initially ate a low-carbohydrate diet that turned into a high-carbohydrate diet over 18 weeks, in six phases.

coming rom saturated at.

Indirect calorimetry

What were the findings? Energy intake (EI) across the eeding interventions averaged about 2,500 kcal per day and protein intake

Indirect calorimetry measures the production o

averaged about 125g per day (20% EI). As designed,

carbon dioxide and consumption o oxygen to esti-

protein and energy intake remained constant over

mate heat production. This is then entered into an

the 18-week intervention. As seen in Figure 1, car-

equation to estimate resting energy expenditure.

bohydrate intake started at an average o 47 grams

Although not without error, indirect calorimetry

per day (7% EI) and rose to an average o 346 grams

remains the gold standard  or measuring energy

per day (55% EI). otal at intake started at an aver-

expenditure in laboratory settings.

age o 209 grams per day (73% EI) and dropped 23

Figure 1: Carb and saturated fat intake by study period

to an average o 80 grams per day (28% EI). Te

Compared to baseline, asting glucose & insulin,

authors claim that compliance was high, based on

HOMA-IR (measure o insulin resistance), and

 verbal communication and inspection o returned

systolic and diastolic blood pressure significantly

ood containers. Tere were no dropouts.

decreased at C1, but were not significantly altered throughout the six eeding phases.

Both body weight and at mass (measured by DXA) showed a significant decline rom baseline to C1

Despite saturated at intake starting at 84 grams per

(about seven kilograms and our kilograms, respec-

day and decreasing to 32 grams per day, the propor-

tively), and continued to decline throughout the

tion o total saturated atty acids in blood lipids was

entire intervention, ultimately resulting in an aver-

not significantly affected. Palmitic acid (16:0), the

age loss o about 10 kilograms o bodyweight and

predominant saturated atty acid within blood lipids,

eight kilograms o body at. Neither weight loss nor

significantly increased rom baseline to C1 and sig-

at mass were significantly different between C4 and

nificantly decreased rom C1 to C2, C3, C4, and C5.

C6, suggesting that most o the change occurred in

C6 was not significantly different rom C1.

the first 12 weeks (run-in, C1, C2, & C3). Stearic acid (18:0, which is commonly ound in aniotal, LDL, and HDL cholesterol values were not

mal ats and cocoa) was not significantly changed

significantly altered across any o the eeding phases.

in cholesterol esters. But rom baseline to C1, it was

riglycerides levels dropped about 22% rom base-

significantly reduced in phospholipids and also

line to C1. Tese levels stayed constant through C5

decreased in triglycerides through the intervention,

and had a significant return to baseline values at C6.

ending with a significant reduction in C6 relative to C1. Phospholipid concentrations showed an oppo24

site pattern, increasing throughout the intervention and ending with a significant increase in C6 relative to C1. Tere was a significant reduction in total monounsaturated atty acid concentrations rom baseline to C1 only. Similar to 18:0, as carbohydrate increased, plasma oleic acid (18:1) decreased in triglycerides, but increased in phospholipids.

Lipoproteins and lipid ractions

Palmitoleic acid (16:1) was significantly reduced rom baseline to C1 in triglycerides and cholesterol esters, and trended or an increase in

This study looked at how much pal-

phospholipid concentrations. All these markers showed increasing

mitoleic acid was contained in three

concentrations with increasing carbohydrate intake and ended the

different locations in blood plas-

intervention with significantly greater concentrations o palmitoleic

ma: triglycerides, phospholipids,

acid at C6 relative to C1.

and cholesterol esters. Lipoproteins shuttle lipids (such as atty acids

Tere was great individual variation in palmitoleic acid concentra-

and cholesterol) around the body.

tions during each diet phase with notable outliers. For instance, one

Phospholipids orm the outer shell

subject had triglyceride concentrations o palmitoleic acid rise by

o lipoproteins, while cholesterol

nearly three-old rom C1 to C4 (2% to about 5.8%) and urther rise

esters and triglycerides make up the

rom C4 to C6 (about 5.8% to 7%). However, another subject showed

majority o the core.

no changes across the entire intervention, and another showed reductions as carbohydrate intake increased.

So the “phospholipid raction” reers to the ats that are contained in the

Study participants lost body weight and at over the 18-week intervention, with most o the changes occurring in the first 12 weeks. Te blood samples researchers analyzed suggested that carbohydrate intake can influence blood levels o compounds like palmitoleic, stearic, and palmitic acid.

phospholipids, with the same reasoning or “triglyceride raction” and “cholesterol ester raction”. Sometimes these different ractions respond the same way to diet, and sometimes they don’t . Hence it’s

important to measure all o them.

What does the study really tell us? Tere are numerous studies showing associations between higher proportions o palmitoleic acid in blood and tissue, and adverse health outcomes such as metabolic syndrome in adults and adolescents, hypertriglyceridemia, type-2 diabetes, coronary heart disease, and prostate cancer. However, since none o these studies establish causality, it is possible that these conditions lead to high25

er proportions o palmitoleic acid (or example,

reductions in weight and at mass were observed,

palmitoleic acid may be the body’s attempt at a pro-

making the causative actor difficult to isolate. And

tective response to what is being eaten) rather than

there was no weight loss matched control group to

 vice-versa. With the mixed associations shown in

account or weight loss effects. Between the lower

studies, it is hard to know or sure what the exact

palmitoleic acid concentrations, the weight and at

health effects o palmitoleic acid are.

loss, and the reduction in carbohydrate intake, we cannot say which came first and which led to which.

It is also difficult to quantiy the amount o palmitoleic acid needed to increase the risk o these

On the other hand, by the end o the intervention,

endpoints, as ew studies have done so. In the

when carbohydrate intake was similar to baseline

Physicians Health Study , one standard deviation

intake (346 grams vs. 333 grams) plasma palmi-

increase in plasma phospholipid palmitoleic acid

toleic acid levels returned to levels similar to those

concentrations was

observed at baseline

associated with a

despite significantly

significant 17% higher risk o heart ailure even afer adjustment or BMI, alcohol consumption, smoking, exercise, and plasma omega-3 levels. In the study under review, baseline daily intake o car-

With the mixed associations shown in studies, it is hard to know or sure what the exact health effects o palmitoleic acid are.

bohydrate and at

lower weight and at mass, strongly suggesting that it was carbohydrate intake that influenced plasma palmitoleic acid levels. Te authors also repeated the entire experiment backwards in five additional subjects

averaged 333 grams and 130 grams, respectively.

(rom high to low carbohydrate intake) and ound

During the first phase o the intervention, carbo-

that plasma palmitoleic acid responded in the exact

hydrate intake dropped to an average o 47 grams,

opposite pattern as the main study group, which

while at intake rose to an average o 209 grams.

supports the idea that carbohydrate intake influ-

It was during this time that the most significant

ences palmitoleic acid concentrations. Even so, the

changes in blood lipid atty acid concentrations

overall diets were hypocaloric, and we cannot con-

occurred, including a major reductions in palmitole-

clude how carbohydrate intake would influence

ic acid levels. Additionally, this was when significant

palmitoleic acid levels under eucaloric or hyperca-

improvements in insulin sensitivity, blood pres-

loric contexts.

sure, and plasma triglyceride levels were obser ved. However, this was also when the most significant 26

Tis study provides evidence to suggest carbohydrate intake influences palmitoleic acid levels. Although evidence is mixed, high levels o palmitoleic acid in the blood are associated with metabolic syndrome, type 2 diabetes, coronary heart disease, and other health problems. In this study, participants experienced a drop in palmitoleic acid levels when they were eating low-carb meals in the first phase o the study.

erentiation, prolier-

The big picture With 18 ull weeks’ worth o ood provided or the participants, this study provided a well-controlled environment in which to study the effects o diet on palmitoleic acid. Yet despite the findings rom this study, the relative risk rom various palmitoleic acid concentrations in the blood remains to be determined. In the previously mentioned Physicians’ Health Study, the highest quartile had an average palmitoleic acid level o only 0.50%, whereas in the current study, even when phospholipid palmitoleic acid concentrations were at their lowest during the low carbohydrate phase, absolute concentrations averaged 0.61%, putting these participants above the  vast majority o the Physicians Health Study subjects. Other blood lipid changes add urther complexity to the implications o this study. For instance, increasing carbohydrate intake led to greater phospholipid oleic acid concentration, which in contrast to palmitoleic acid, has been shown to attenuate the pro-inflammatory and cytotoxic effects o excessive saturated atty acid incorporation. Myristic acid, which showed a reduction with carbohydrate restriction, plays a physiologically critical role in de novo ceramide synthesis (necessary or regulating cell di-

ation, and apoptosis) and has been shown to increase delta-6 desaturase activity (first step in creating long-chained polyunsaturated atty acids such as EPA, DHA, and arachidonic acid rom their shortchained precursors). Te applicability o this study to real-lie situations is uncertain. Tere were only 16 participants, with widely varying BMIs, each using a particular dietary composition or a limited period o time. Te effect o carbs on blood lipids was conounded by the weight loss that was designed into the study, without a weight loss control group that would help to isolate the effects o carbs. Also, a variety o different outcomes were measured. So while palmitoleic acid was emphasized in the title and study discussion, other important outcomes had different results. For example, outside o C1, cholesterol and blood pressure didn’t change regardless o diet. Te sub jects in this study already had metabolic syndrome, 27

so changes in things like blood pressure and triglycerides may be more important than changes in bound plasma atty acids, since some o these atty acids are linked to metabolic syndrome (which they already have) while blood pressure may have a more direct impact

A given topic [...] can be explored in a variety o different ways, and the results can be interpreted by the study authors in different ways as well.

on their health.

gram, the Egg Nutrition Center, and the Robert C. And Veronica Atkins Foundation. Te unding sources did not have a say in designing the study or writing the manuscript. However, these organizations are quite clearly interested in the research on saturated atty acids, thus the variety o stud-

Also, circulating ree atty acids, which are linked to

ies unded by them. Te primary investigators are

metabolic and heart health, were not assessed.

also noted low-carb researchers. Tis also doesn’t mean the study is biased, but it is one thing to keep

While the total proportion o plasma saturated ats

in mind when interpreting the study findings. A

didn’t differ in any o the diet phases, different indi-

given topic (here, the effect o carbohydrate intake

 vidual plasma atty acids can have different effects.

on plasma saturated atty acids), can be explored

Palmitic acid, the predominant saturated atty acid

in a variety o different ways, and the results can be

which was noted in the paper to be a predictor o

interpreted by the study authors in different ways

metabolic syndrome and heart disease, was actually

as well. It’s important to look at the broader context

lower in phospholipids (but not the other two lipid

o literature and the nitty-gritty study details rather

ractions) rom C2-C5 than it was during the low

than just take the author’s word or it.

carb C1 or high-carb C6 periods. Tis finding was not explained, nor were changes in stearic acid and oleic acid. So while a variety o atty acids were measured and reported, palmitoleic acid was the only one ocused on in the discussion. Unortunately it was also the only ocused on in many news stories with inaccurate headlines such as “Heart disease and diabetes risk linked to carbs, not at, study finds”. It must be noted that this study was unded by the

Other plasma atty acids, such as palmitic, myristic, and oleic acid, may be important or evaluating the health effects o different carbohydrate and at intakes. Although measured, these were not a ocus o the study. Nor were more direct predictors o heart and metabolic health, such as blood pressure. Te study was unded by dairy, bee, and low-carbohydrate organizations.

Dairy Research Institute, Te Bee Checkoff pro28

Frequently Asked Questions What else influences plasma palmitoleic acid levels?

Te current study lends support to the idea that palmitoleic acid concentration in the plasma is more reliant on carbohydrate intake than at intake. However, the study was conducted under hypocaloric conditions, and previous research has suggested that dietary intake o palmitoleic acid (which is rich in a ew select oods such as macadamia nuts) does significantly influence plasma concentrations during weight maintenance. Alcohol has also been suggested to reduce palmitoleic acid concentrations, with one study  reporting significantly lower levels in people consuming more than 100mL o ethanol consumption per week (seven regular 12-ounce beers) compared to people consuming less. Tis study also ound palmitoleic acid concentrations to be independent o smoking status. How do various biomarkers o atty acids in the body differ?

Biomarkers o atty acid composition differ rom dietary intake, in that biomarkers reflect both the intake and the utilization o the atty acids. Because not everyone is similar in how we absorb, transport, and metabolize nutrients, biomarkers allow us to look beyond simple dietary intake and ocus on the physiological consequences o consuming certain substances. Moreover, biomarkers can provide a long-term picture o dietary intake. Due to the essential nature o atty acids in cell structure, assessment can involve numerous body tissues in addition to blood and urine (e.g. hair, nails, skin, breath, saliva, eces). However, measuring blood plasma is the most common method. Serum triglycerides reflect dietary intakes over the past hours to days, whereas cholesterol esters and phospholipids reflect daily intakes. Only body at stores (adipose tissue) tend to reflect long-term dietary at consumption (e.g. years), and even this measure can be inaccurate in people who have experienced cycles o at loss and gain. How strongly is palmitoleic acid associated with heart disease, when compared to other biomarkers?

Although statistically significant, the strength o the relationships 29

Only body at stores tend to relect long-term dietary at consumption (e.g. years), and even this measure can be inaccurate in people who have experienced cycles o at loss and gain. between palmitoleic acid and health parameters is

a simultaneous increase in palmitic, myristic, and

low to moderate. For instance, in one study o over

stearic acid levels. Although these changes were in

3200 Chinese adults, palmitoleic acid concentrations

adipose tissue and not serum biomarkers, it rais-

could only explain about 37% o the variance in

es the question o whether the current study could

triglyceride levels and 14% o the variance in HDL-

have been influenced by seasonal changes as its six

cholesterol levels.

month duration, by necessity, spanned more than one season. Since subtle changes in plasma atty acid

It should also be kept in mind that atty acid levels

levels were tracked over increments o time, it would

in any biomarker represent a proportion and not an

be difficult to differentiate what changes were at least

absolute measure. Tus, greater integration o cer-

partly a result o the season.

tain atty acids into the biomarker can reduce the percentage o other atty acids without their absolute

What dietary sources have a lot o palmitoleic acid

amount changing. All o the aorementioned studies

in them? 

demonstrating associations between atty acids and

According to the USDA nutrient database, roasted

health outcomes were based on percentages, mak-

chicken skin rom the leg and thigh contains the

ing it difficult to draw conclusions as these are not

greatest amount o palmitoleic acid with 2.8 grams

quantifiable values. One person could have double

per 100 grams o ood. Bee at ollows with about

the amount o palmitoleic acid in serum as another

1.9 grams, then turkey skin with 1.34-1.5 grams, and

person and still have similar percentages i they also

finally butter at 0.96 grams. Poultry skins contain

have double the amount o blood lipid.

the most palmitoleic acid on average, ollowed by bee at and butter. Macadamia oil is a rich source,

Tere is also evidence o seasonal variations in at-

containing 19% palmitoleic acid.

ty acid profiles. One early study   showed greater proportions o saturated atty acids in the adipose

Keep in mind that palmitoleic acid is different than

tissue o the legs and arms during summer com-

trans-palmitoleic acid. Te latter comes rom very

pared to winter. Tis difference was attributable to

limited sources, mostly red meat and dairy rom

a reduction o palmitoleic and oleic acid levels, with

grass-ed cows, and is not synthesized by the body. 30

ranspalmitoleic acid in plasma lipids and adipose tissue has been repeatedly associated with

revolve

better metabolic outcomes, as shown in this paper

around insu-

by ERD reviewer Stephan Guyenet, Ph.D.

lin-mediated glucose disposal into both muscle and at tissue. Tis raises an interesting

 Are there benefits to palmitoleic acid rom diet? In

contradiction, with the studies demonstrating asso-

 plasma? Elsewhere? 

ciations between palmitoleic atty acid levels in the

A very recent study published in December o 2014

blood and some adverse health outcomes such as

ound that eeding mice 300 milligrams o pure

diabetes. Like certain cholesterol markers, palmitole-

palmitoleic acid per kilogram o bodyweight daily,

ic acid may be more o an indicator that something

in addition to their normal diets or ten days signifi-

might be physiologically wrong rather than a cause.

cantly increased glucose uptake in at tissue through

DNL is one possible cause o increased palmitoleic

increased expression o glucose-uptake transporter

acid levels, and very high levels may be a marker that

4 (GLU4; necessary or insulin-stimulated glucose

something is increasing DNL to dangerous amounts

uptake into tissues). Tis was despite no changes in

(such as prolonged overeating o carbohydrate, or

plasma atty acid levels.

worsening glucose tolerance rom uncontrolled diabetes, both o which can disrupt carbohydrate

Earlier studies have also ound palmitoleic acid to

metabolism). Suggesting that palmitoleic acid is

enhance glucose uptake and insulin sensitivity  o

100% detrimental does not seem accurate given the

skeletal muscle, and reduce liver at buildup. Te

complexity o evidence on the topic.

authors o this study suggest that palmitoleic acid may act as a major signaling lipid produced rom at tissue or communication with distant organs. In obese sheep, inusion o palmitoleic acid twice daily or 28 days preserved insulin sensitivity beore beginning an obesogenic diet, possibly through a reduction o intramuscular at. It appears that the benefits o palmitoleic acid

What should I know? Tis study suggests that the presence o certain atty acids in blood lipids appears to depend more on carbohydrate than at intake under hypocaloric conditions in overweight and obese people with metabolic syndrome. Tere were minor – but uniorm – changes in a ew select atty acids, such as 31

myristic acid, oleic acid, and palmitoleic acid, but no

It’s also important to know what this study does not

significant changes in total saturated and monoun-

show: it doesn’t show that DNL happens at major or

saturated atty acid concentrations.

dangerous rates when eating moderate carb levels, it doesn’t show that increasing levels o carb intake

Tere was also inter-individual variance in the pal-

increased overall plasma saturated at, and it doesn’t

mitoleic concentration response to carbohydrate

prove that low-carb diets are superior to moder-

intake, which is important given the small sample

ate carb diets or heart or metabolic health. While

size. While most subjects showed a positive asso-

weight loss decreased as carbs were added, that may

ciation, others stayed relatively unchanged and

 very well be due to increased water weight or chang-

some showed an inverse association. Moreover,

es in compliance.

there was greater variance as carbohydrate intake increased. Te absolute palmitoleic concentration

Te authors conclude that the increased propor-

 varied between about 2-4% in plasma triglycerides

tions o palmitoleic acid concentrations may signal

when carbohydrate intake was lowest during C1, but

impaired carbohydrate metabolism, yet in vitro and

 varied between about 2-7% during the high-carbo-

animal studies have suggested that palmitoleic acid

hydrate C6 phase.

is insulin-sensitizing. It seems prudent not to draw health-based conclusions rom this study. Rather,

Still, the implications o changes in plasma palmitole-

the conclusion appears to be that consumption o

ic acid levels have yet to be determined. Many studies

carbohydrates can have an impact on plasma atty

demonstrate associations between adverse health

acid proportions in overweight and obese individu-

outcomes and increased palmitoleic acid levels, but

als under hypocaloric conditions. Whatever health

reverse causality cannot be ruled out, nor differing

implications this may lead to will require urther

impacts o palmitoleic acid in different contexts. We

testing to illuminate. ◆

also do not know what influence many other dietary, liestyle, and environmental actors have. Rather than having obvious health implications or differing carb levels, this study serves as additional evidence or those eating low-carb higher saturated at diets (and losing weight) who are apprehensive about impacts on their plasma atty acids. As

Te health implications o this study are unclear. Te lack o impact o dietary saturated at on plasma saturated atty acids was already shown in previous studies. Tis study did show an effect o carbohydrate on palmitoleic acid levels, but the relative importance o that is unknown.

is the case with cholesterol, what you eat does not translate directly to what is floating around in your blood. However, the lack o correlation between

Low carb diets are nothing i not controversial. For

dietary saturated at and plasma saturated at was

some evidence-based discussion on their potential

already shown by a previous paper rom the same

health effects, check out the ERD private Facebook

research group (albeit only the triglyceride raction

group.

was studied). 32

Whence the hype? The association between ex aggeration in health related science news and academic press releases: retrospective observational study  Introduction When it comes to health news, even though we know not to “believe the hype,” hype still happens and it has an impact. Not only is the public’s use o health care services influenced by the media, but even proessionals aren’t immune. Press coverage o medical research findings is associated with those findings being cited more by other scientists. Even doctors in the ER test more or certain inections that have been getting heavy press coverage. Since the press is so influential, it’s important that the media reports medical findings accurately. But it doesn’t seem like that’s happening: past research has shown media coverage o medical and nutritional research is ofen distorted. But all o this doesn’t imply that the blame lies with the science journalists. Tey are ofen under

immense pressure to write more, ast, which encourages reliance on press releases and summaries rom news agencies, universities, and other public relations outlets. Tis is why it’s quite possible that journalists are reporting the inormation they are receiving (airly) accurately, and instead it is the inormation sources they rely upon which lead to media hype. Indeed, a previous study  o press releases rom medical centers ound that many provided exaggerated claims, while ew provided caveats and precautions about their claims. Similar results were ound in cancer genetics research, where press releases ofen exaggerated causal claims which were then repeated by the media. But the origin o the hype may go back even urther than press releases. One study  ound that exaggerated claims ofen could be traced back to the abstract o the original journal article.

33

Te purpose o the study under review was to

With all o this inormation in hand, the researchers

expand upon the research above and trace the

rigorously defined how hype was created at each o

source o the hype in health science news.

the three stages: original journal article, press release, and news report.

Hype is ubiquitous in health news reporting. But this hype may come rom places other than  journalists exaggerating findings. Health news impacts not only the general public, but also physicians and other researchers.

Tis was accomplished by creating a detailed coding system, which reviewers could use to grade each source or the kinds o claims they were making in order to compare the hype level and notice any dierences between the research, press releases, and news reports. o do this rigorously, the researchers

Who and what was studied? Te researchers began by searching or publicly-accessible press releases rom Russell Group universities (the top 20 research universities in the UK) that covered research related to human health and were based on peer-reviewed research published in scientific journals in 2011. For each press release based on published scientific research, associated print and online news stories were then located. Broadcast news wasn’t examined in this study.

ocused on three specific areas: • Advice-giving (e.g. “Eating chocolate may be beneficial or…” or “Doctors should advise patients to…”). Tis was coded at our levels depending on how implicit or explicit the advice was. • Causal statements rom correlational research (e.g. “drinking wine might increase cancer risk...” rom a study that only observed correlations between these two things). Tis was

Even doctors in the ER test more or certain inections that have been getting heavy press coverage.

coded at seven different levels, on a continuum rom statements that explicitly mentioned correlation, to those that were ambiguous (e.g. “wine linked to cancer risk”) to those that were explicitly implying causality (e.g. “drinking wine increases cancer risk”). • Conclusions phrased in human terms when research was done on animals, cells, or simulations (e.g. “a pregnant woman’s stress levels…” concerning studies that were only done in rats). Tese were also coded at different levels depending on how implicitly or explicitly the conclusions were stated.

34

When coding or advice, the entire journal article, press release, or news story was examined. Tere was a total o 213 press releases (116 o these had news reports related to them), and 360 total news stories included. Furthermore, or press releases and news stories, only the title and first two sentences were coded, since news writing is ormulaic and ofen ollows an “inverted pyramid” structure, where the main claims are stated first. A sample o 182 press releases, 95 with news, and 261 news stories were used here. Only the abstract and discussion were coded or the original journal articles. Finally, when examining human conclusions rom non-human studies, the main statements o 105 press releases (48 with news) and 115 news articles were coded, while only the abstract and discussion sections o journal articles were coded. wo other areas were also examined to get a measure o how well-justified the claims made in press releases and news articles actually were. Tis was done by noting which press releases and news articles had explicit caveats to their causal claims, advice, and inerence to humans (e.g. “Te scientists who carried out the study emphasized that they could not say or certain...”) and explicit justification or any o these three types o claims (e.g. “even afer taking into account the effect o extra body weight on blood pressure, there was still a significant link with sweetened drinks”). In addition to these two areas, some other acts about the studies being reported were collected as well, such as duration, sample size, and sources o quotes. Te researchers explicitly took the peer-reviewed journal article as the baseline or the claims being made in press releases and news stories concerning the research. Te original journal articles themselves were not act-checked or examined to see i they were over-hyping anything. Which is not surprising, given that the authors o this study aren’t likely to be experts in dozens o biomedical and health research areas. So hype was measured by whether press releases and news articles were exaggerated compared to the original journal article. I the original journal article itsel contained hype, this study would not be able to detect it. But, i hype does exist in the original peer-reviewed research (and the authors o this study think it’s likely), then any hype 35

But the origin o the hype may go back even urther than press releases. One study ound that exaggerated claims ofen could be traced back to the abstract o the original journal article. ound in this study is likely an underestimate o

33% o press releases contained more strongly-word-

overall hype, since hype originating in the peer-re-

ed claims o causation than the associated journal

 viewed scientific literature is not being taken into

article warranted, and 36% o press releases inflated

account. Te researchers were also quite careul to

relevance to humans rom non-human studies. So,

make sure that their coding scheme was reproduc-

it seems that press releases tend to add quite a bit o

ible. Tey did this by double-coding 27% o press

hype in all three areas studied.

releases and journal articles, and 21% o news stories. Tey ound that there was a 91% concordance

It was also ound that 36% o news reports contained

rate in coding. Te researchers then ran simulations

more direct or explicit advice than the corre-

to make sure that a 10% discrepancy in coding

sponding journal article. However, this does not

wouldn’t affect their main conclusions, and it didn’t.

necessarily imply that the journalists were the ones inflating the advice. Te odds o exaggerated advice

Researchers examined press releases rom the top 20 research universities in the UK to determine the origin o hype, or exaggeration, in media reports on new scientific findings. Exaggeration was determined by the presence o advice unsupported by scientific evidence and inappropriate extrapolation o evidence.

in news was 6.5 times higher when the press release contained exaggerated advice than when it didn’t. A similar pattern held or the two other areas o hype examined. While 39% o news articles were more strongly deterministic than what was warranted by the associated journal article, the odds that the news had distorted causal statements was 19.7 times higher i the press release also contained distortions.

What were the findings? Te researchers ound that 40% o press releases contain more direct or explicit advice than the journal articles upon which they were based did. Similarly,

Similarly, 47% o news articles reporting on non-human studies contained exaggerations, with the odds o these exaggerations being 56% higher i the press releases contained similar distortions. As seen in

36

Figure 1: How press release hype correlates with news hype

Figure 1, hype occurs in both press releases and news articles, and it’s much more likely to be present in news articles i the press releases also contain hype. So there is hype… but why the hype? Te authors hypothesized that one possible motivation or exaggerating claims in press releases could be to increase the chance that the press release will be picked up and reported by the news. But when the researchers looked at the data, they ound that there was no statistically significant association between the percentage o press releases that had at least one news story published on their topic and whether or not the press release was hyped in any o the three ways this study examined. Also, the average number o news stories per press release did not vary between any o the three types o hype. So, whatever the motivation, hype in press releases is not actually correlated with more press coverage. Finally, the researchers ound that caveats about and justifications or the claims being made were quite rare in both press releases and news stories, with at most only 17% o these claims having some sort o caveat or justification (depending on the type o claim and source). Tere was no association observed between caveats and  justification in press releases and news uptake, however. But there was a strong association between press releases having caveats and justifications about their claims and news sources having them as well.

Te results o this study show that about 40% o press releases generated by the scientists contain the seeds o hype: exaggeration. Moreover, news reports based on hyped-up press releases tended to contain more hype and exaggeration than news reports based on press releases with cautionary statements. 37

What does the study really tell us?

Why correlation doesn’t necessarily equal causation

Te study tells us that both biomedical press releases and news reports contain exagger-

Correlation just means that when you see one thing occur a lot,

ations that go beyond the peer-reviewed

another thing occurs a lot along with it. For instance, in this study,

 journal articles upon which they are based.

there is a strong correlation between news reports that have hype

Specifically, this study looked at exaggera-

and press releases that have hype. Assuming the observed correla-

tions o three kinds. Tey ound that 33%

tion is actually true, then there are generally three explanations or

to 40% o press releases and 36% to 47% o

why it could occur:

news reports contain stronger inerences than were warranted by peer-reviewed

• A causes B: For example, it could be that press releases con-

 journal articles, depending on the type o

taining exaggerations are indeed picked up by the media

exaggeration.

and repeated.

Tis study also tells us that news reports

• B causes A: This would be that exaggerated news stories

were much more likely to contain these

about a piece o research lead to exaggerated press releases.

types o exaggerations i the associated press

Assuming that press releases are written beore the news

releases also had them. Te odds o that

stories, though, this possibility is unlikely here, since causes

news reports would contain exaggerations

don’t work backward in time.

was 6.5 to 56 times higher i the associated press release also had such exaggerations.

• Some third actor causes both A and B: perhaps journalists are ignoring the press releases and working directly rom

While the population under scrutiny was

the journal articles and interviews with the researchers. And

press releases rom Russell Group univer-

perhaps the press releases are doing the same. Thus, the

sities in the UK, the authors explicitly state

source o the hype in this case would be the the original

that they have no reason to suspect that

researchers.

this group o universities differs rom other sources o press releases in any significant

There is no way to differentiate between these three possibili-

way, although this claim was not supported

ties rom a correlation alone. However, one can narrow down the

or argued or in the paper. I the authors are

possibilities through independent reasoning, as we did by using

correct, these results should be generalizable

temporal reasoning above. However, i possible, the best way to

to press reports outside o Russell Group

establish causation is not through observational studies like this

universities and the news based on those

one but through careully controlled experiments where research-

reports.

ers actively intervene by changing only one variable and then seeing what happens when compared to a control group. This is

Overall, these results are at least consistent

part o the reason why randomized double-blinded, placebo con-

with the hypothesis that a lot o the hype

trolled trials are the gold standard in the biomedical sciences. 38

ound in medical reporting originates not with the

ound in news stories were also ound in the press

 journalists reporting reporting the news, but with the press press

release, which also points to the media’s reliance on

releases written by universities. But beore jumping

press releases. Finally, study details such as sample

to conclusions about causality ourselves, an import-

size and study duration were very rarely reported in

ant caveat caveat must be mentioned, one with which the

the news i the press release did not include similar

authors o this study were also well-aware: this

details, but was usually reported in the majority o

study was observational in

news articles only i the

nature, which means that

associated press release

although it can provide inormation on correlations, causality cannot be directly inerred. However, there are several lines o reasoning to suggest that press releases are indeed a major reerence or news articles. First, other retrospective retrospective and  and prospective studies prospective  studies have ound that press releases influence news. Second, the researchers o this study took a look at the dates, quotes, and areas o ocus in press releases and news reports, and ound that these three areas seem

72%

o quotes ound in news stories were also ound in the press release, release, which also points to the media’s reliance on press releases.

to point to reliance on

had similar details. So, while causation cannot be definitively definitively established in this kind o obser vational study study,, there is additional evidence that at least points in the direction that exaggeration in press releases leads to exaggeration in associated news articles. Finally, the authors ound no statistically significant correlation between whether press releases had any o the three types o hype examined and whether and how much they were picked up by the

press releases by the media. Specifically, Specifically, news stories

media. Tey also ound that press releases including

were only selected i they were published within 30

caveats and justifications didn’t seem to affect news

days o the press release date.

coverage. So, cautious, careully-crafed press releases do not seem to be correlated with lower press

Furthermore, the authors ound that 87% o news

coverage, and over-hyped press releases don’t seem

articles selected were released within one day o the

to get more press, either.

publication publication o the associated press release, leaving  very little time or the journalists journalists to do any addiadditional independent research. Also, 72% o quotes 39

and scientists themselves can take responsibility responsibility Tough the study was observational in nature

or more accurate biomedical reporting by crafing

and did not attempt to determine i the original

more careul press releases.

 journal article contained contained hype, hype, it provides provides evidence to suggest press releases can significantly

Journalists could in theory take more time to

influence the way news is presented to the public.

independently independently check acts and read the pertinent per tinent

Te research also suggests that hyped-up press

background literature, but the current journalis-

releases get the same amount o coverage as press

tic culture has culture has put a lot o pressure on journalists

releases with cautionary statements, due to the

to produce more material in less time than ever,

news media’s reliance on press releases.

and so journalists may be orced to rely on easier and quicker sources o inormation, such as press

The big picture

releases and inormation rom news agencies. And an entire journalistic culture can be very hard to

Media is ofen blamed or blamed or hyping medical findings,

change, particularly when it’s encouraged by a

but this study adds to a growing body o research

changing industry.

which suggests that the ault does not lie solely with  journalists. Many Many o the exaggerations exaggerations ound ound in the

It may seem that there are a lot o troubling find-

news were also ound in the press releases on the

ings in this study. But because the authors ound no

same topic which preceded the news reports. Since

incentive to hype up press releases (since more hype

press releases are ofen crafed in collaboration with

doesn’t lead to more press), they end with a hopeul

scientists,, both non-scientist scientists non-scientist writers at universities

message: a relatively relatively small handul o people in uni-

the current journalistic culture has put a lot o pressure on journalists to produce produce more material in less time than ever, and so journalists may be orced to rely on easier and quicker sources o inormation, such as press releases and inormation rom news agencies. 40

 versities can help create create better health inormation inormation

was ound, that doesn’t mean that everything is

or everyone by crafing more accurate press releases

exaggerated — that, itsel, would be an exaggera-

at little cost to themselves. t hemselves.

tion! In this study, a large minority o news reports had exaggerations exaggerations o some sort, but it was still the

Frequently Fr equently asked questions q uestions Do scientists hype up their results in peer-reviewed  journal articles? 

Tis study didn’t examine hype in the original journal articles, instead using the peer-reviewed articles as a baseline. However, the authors o this study were clear that they thought it was quite possible that hype occurs in peer-reviewed literature, too. However, since assessing spin and hype in the scientific literature takes some expertise in specialized fields, this is a much harder question to assess. Although one study did find that spin o a certain sort could be traced back to journal article abstracts, which is a good reason to read more than just the abstracts!  Just how how pervasive is “the hype”?  hype”? 

It’s important to emphasize that just because hype

minority. One o the exaggerations these authors looked at was extrapolating results rom non-human studies to humans. Why is this a bad thing? 

Because less than 10% o animal findings can be used clinically in human humanss. Tere are lots o reasons or this, rom  rom physiological differences and dierences between how an induced disease model behaves in an animal when compared to naturally-occurring human diseases, to systematic biases and methodological flaws in animal studies, but overall, there are many unknowns. Animal experiments are very important important to point out promising leads or scientists to test down the road clinically, and also help our understanding o basic biomedical science. However, it’s pretty poor reasoning to think that i something worked once or twice in a petri dish or a rat, it’d definitely work in a human. A therapy may even be wildly successul in rats, but cause terrible headaches and suicidal ideation. Rats don’t really report those side effects as effectively as humans do. So, i the press gave me accurate inormation, I’d be able to make accurate decisions, right? 

Not necessarily. Te idea that

41

It’s important to emphasize that just because hype was ound, that doesn’t mean that everything is exaggerated — that, itsel, would be an exaggeration!

to contradict itsel constantly, but that’s largely because individual studies are conducted differently and some may have had errors. Te overall weight o the evidence is much less affected by these individual studies, and that ofen isn’t reflected in the evening news.

What should I know? Hype in news coverage o biomedical research is correlated with hype ound in press releases rom universities. Tis strongly implies (but, since this was an observational study, does not definitely establish) that hype mostly starts not with journalists, but with the university press releases that summarize the biomedical research. Journalists simply report on the hype that already exists in the press releases. Furthermore,

all people need is good inormation to draw good

hyped up press releases don’t seem to draw more

conclusions is called the “deficit model” o the public

news coverage, so there’s little real incentive or uni-

understanding o science. I people don’t have a defi-

 versities to hype up biomedical research.

cit o knowledge, they’d make good choices and have a greater respect or science. Te cold hard acts are

Keep in mind that every link in the research and

all that’s needed. But this model suffers rom some

reporting chain can have an incentive to exaggerate.

serious flaws.

While researchers do have a degree o accountability due to peer review, the system is imperect. Funders

Knowing the acts doesn’t mean you’ll act on

can also indirectly influence research by selectively

them. Plus good reasoning skills, understanding o

unding certain studies, which researchers are well

extra-scientific culture and methods, and much more

aware o when attempting to attain grants. And this

is ofen needed. One o the motivations behind the

study shows that exaggeration or inaccuracies can

Examine Research Digest is to give you, the reader,

be amplified urther at the reporting level. So to tru-

at least one more piece o the puzzle o supplement

ly understand a research topic ofen requires not just

science. We’re not just trying to spooneed you

knowledge o the specific topic at hand, but a deep

“acts,” but also hope to help you learn how to reason

and broad knowledge o how research works. ◆

through research a little better, a little bit at a time. Also, science is an iterative process, and the popu-

o discuss recent examples o exaggeration in the

lar press is not a great tool or reflecting that. I you

media and press releases, join us at the private ERD

only read about studies in the media, science seems

readers’ Facebook group. 42

Running on empty: can we chase the fat away? Body composition changes associated with fasted versus non-fasted aerobic exercise Introduction Te idea o asted cardio to accelerate at loss has been, or the most part, based on a key assumption: with no ood in our system, our at stores are the go-to energy source, assuming low- to moderate-intensity cardio training. Te use o at is acilitated by the low levels o liver glycogen and insulin, and short-term studies suggest that asted cardio does increase at oxidation over 24 hours. It stands to reason that i done on a sustained basis, then there might be a greater amount o at loss compared to i the training was done afer eating breakast or in the afernoon. But is this assumption correct?

43

Who and what was studied? Tis is the first study to investigate the chronic effects o asted and ed cardio training on body composition during a diet, which is likely a common situation in dieters. Previous research was done on isocaloric or hypercaloric diets. wenty university-going emales (average age o 22.4 years) were recruited to participate in one hour o treadmill running, three days per week, while ollowing a hypocaloric diet or our weeks. All the women reported habitual aerobic exercise several days per week (some were off-season collegiate track and field athletes), but none were involved in any resistance training programs. Te exclusion criteria included injuries and medical complications in an attempt to ensure the women were otherwise “healthy.” As seen in Figure 1, the treadmill running consisted o a five minute warm-up and cool-down at 50% o the age-determined maximal heart rate (MHR), separated by a 50 minute bout at 70% MHR. Heart rate monitors were used to ensure

exercise was at the appropriate intensity. Te hypocaloric diet consisted o customized dietary plans that induced a 500 kcal daily deficit. Food was not provided by the investigators. Te Mifflin-St. Jeor Equation multiplied by the ‘moderately active’ activity actor was used to estimate total daily energy expenditure (DEE), and 500 kcal was cut rom this value. Protein was set at 1.8 grams per kilogram o bodyweight and at

Figure 1: Outline of cardio training protocol and diet

at 25-30% total kcal. Adherence to the diet was monitored through the participants sel-reporting, using MyFitnessPal. Te women were pairmatched based on initial body weight and divided into two groups: FED and FASED. Te number o athletes and non-athletes were evenly distributed between the groups. All the women completed the exact same our-week diet and exercise program, with the only difference being the timing o a meal replacement shake (250 kcal; 20 grams protein; 0.5 grams at; 40 grams carb). Te FASED group consumed it immediately afer the 44

Mifflin St. Jeor Equation  Men: TEE = (10W + 6.25H - 5A - 5)*AF W = weight (kg) H = height (cm)

Women: TEE = (10W + 6.25H - 5A - 161)*AF A = age (years) AF = activity actor

Sedentary:

little or no exercise

x 1.2

Lightly active: Moderately active: Very active:

light exercise/sports 1-3 days/week moderate exercise/sports 3-5 days/week hard exercise/sports 6-7 days/week

x1.375 x1.55 x1.725

Extra active:

very hard exercise/sports and physical job

x1.9

training session, while the FED group consumed it

with trends or reductions in body at percentage

immediately beore. Te protein was rom whey and

and waist circumerence, all while preserving their

the carbohydrates rom maltodextrin.

lean body mass. But between the groups there were no significant differences.

Body composition was assessed with the BodPod, which has been shown to be reliable when used by

Specifically, the average weight lost in the FASED

young athletic women. At baseline, the only signifi-

and FED groups was 1.6 vs. 1.0 kilograms, respec-

cant difference between the groups was in age, with

tively, while the average at lost was 1.1 vs 0.7

the FED group being, on average, almost three years

kilograms, respectively. On the surace this may

younger (21 vs 23.8). Te average baseline BMI was

suggest a small advantage or the FASED group,

23.3 kilograms/m2, and the average baseline body

with the relatively small sample size or short study

at percentage was 26.3% in the FASED and 24.8%

duration limiting the statistical power to detect sig-

in the FED group.

nificant differences. However, these differences were not trending towards significance.

Tis study investigated the effects o asted cardiovascular exercise on young women ollowing a hypocaloric diet. Study participants reported their ood intake through MyFitnessPal. Researchers conducted the one-hour treadmill run test three times a week, or the duration o the study.

In act, the p-values averaged 0.8-0.9 or the various body composition measurements (these p-values were ound through correspondence with a study author), indicating that the difference between the groups had at least an 80% probability o being due to chance. Finally, the FASED group started with a slightly greater body at percentage and at mass,

What were the results? Afer the our-week intervention, there was no significant difference between the groups in any measure o body composition. Both groups had significant reductions in weight, BMI, and at mass,

providing greater opportunity or at loss rom the beginning. Still, it’s possible that a larger sample size or longer duration may have changed the results. Te study also suggests that there was a dietary disconnect in the young women during the study. Te 45

How does the BodPod work? The BodPod is actually the name o one o two commercially available models or body composition testing (the other being the PeaPod that is used with inants). The BodPod works through a method called Air Displacement Plethysmography . The volume o the body is measured indirectly by determining the volume o air that is displaced within an enclosed chamber (the BodPod). Once volume is known, density o the body can be calculated using this value with the person’s weight. The density is then entered into one o several population-speciic conversion ormulas to estimate the percent body at. The way that it works is similar as the body-at estimating “dunk tank” (ormerly the gold standard beore DXA), except it uses air instead o water.

DEE was around 2150 kcal, which would make the

mate weight loss or different situations, whether

dietary plans based on 1650 kcal a day. At this 500

rom research or real lie.

kcal per day deficit, average at loss should happen at around one pound per week, i we assume one pound o at is 3500 kcal (a rule o thumb that is not always accurate). However, average at loss was only 40-60% this amount and total weight loss was only 50-90%, which suggests that either the women may

Both the ed and asted groups had lost weight by the end o the study, with the asted group having lost slightly more. However, these results were not significantly different.

have consumed more kcal than they were told, or that the DEE overshot actual requirements. Either way, the women reported consuming an average o around 1240-1280 kcal/day, which is around 400 kcal less than they were told to eat. Similarly, they only consumed about 1.2 grams per kilogram o bodyweight in protein per day, compared to the planned 1.8 grams per kilogram. Whether the women were under-reporting, under-eating, or a combination o both remains unknown. However, under-reporting is somewhat likely given its prevalence in previous weight loss studies. You can plug weight, calorie intakes, and calorie expenditure into Dr. Kevin Hall’s NIH body weight simulator to esti-

What does the study really tell us? Tis study clearly shows that a caloric deficit coupled with moderate-intensity aerobic exercise results in weight loss. It is novel in that it also shows that there is no difference in weight or at loss when the cardio is perormed in a ed or asting state, at least over the our weeks tested. Tis may seem counter-intuitive based on simple biological reasoning, but makes more sense when we take into account how adaptive and complex the human body really is. For instance, it has been previously demonstrated 46

that consumption o a light Mediterranean breakast

We cannot necessarily extrapolate these results to

beore 36 minutes o moderate-intensity treadmill

other populations. Light-intensity asted cardio is a

running results in a significantly greater utilization

common tactic or physique sports, such as body-

o at 12 and 24 hours afer the training session

building when dieting or extreme leanness, and

when compared to the same exercise session done

it would be a long-shot to generalize these results

asted. It may be prudent to view body composition goals and at loss over the course o days rather than hours, since the body uses readily available uel but then stores lefover uel over time. It is also worth considering the effect o the pre-cardio meal. Te meal replacement shake used in the current study contained 40 grams o carbohydrate in combination with 20 grams o protein. It has been shown that carbohydrate ingestion beore and during moderate-intensity cardio exercise reduces the expression o genes involved in at metabolism. However, it has also been shown that although carbohydrate ingestion suppressed at breakdown, the rate o at breakdown can still be in excess o the amount o at needed or energy production, and thus the carbohydrates may not limit at oxidation.

The big picture Is it air to say that this study has put a nail in the coffin or asted cardio? Well, not really. For young women at a healthy weight who are truly eating under maintenance, it is very applicable. But the duration was airly short at our weeks and the sample size small. Even with the highly insignificant p-values, we cannot entirely rule out the possibility that subtle changes between the asting and ed groups would have taken more time or more people to become apparent. Another conounding variable is the uncontrolled dietary intakes: even though ood logs were collected daily, inaccurate measurements and misreporting could have influenced outcomes.

[...] evidence suggests that premenopausal women derive a greater proportion o energy rom at during exercise when compared to men, but that males have a greater basal at oxidation rate. to those individuals without similar longer-term studies perormed to compare asted and ed exercise conditions. Tat said, there is some evidence to suggest that at oxidation during exercise is independent o body at percent and relies more on cardiorespiratory fitness.

47

As or gender, evidence suggests that premenopausal

that over the course o the day at oxidation may be

women derive a greater proportion o energy rom

somewhat similar between the age groups. How age

at during exercise when compared to men, but

ultimately influences outcomes would require yet

that males have a greater basal at oxidation rate.

another study.

Tis may be due to differences in sex hormones and sympathetic nervous system responsiveness, but we

Tese results are part o a growing picture o how

would need another study like this conducted in

asted cardio impacts weight loss. Studies have

men to say or sure i asted cardio would be superi-

shown that different populations, diets, and types o

or to ed cardio.

cardio can impact results. As seen in Figure 2, pre vious research has been done on young men eating

Finally, older men demonstrate a higher basal

hypercaloric and isocaloric diets, and overweight/

respiratory quotient relative to younger men, sug-

obese women eating their normal diet, with varying

gesting less basal at oxidation, but they also show

results depending on the study.

less change in response to ood intake, suggesting

Figure 2: Other research on fasted vs fed cardio

48

long-term study compares the modalities (HII Tough this study provides some evidence to sug-

 vs moderate steady state) in diverse populations.

gest asted cardiovascular exercise is not more

Research shows that while the ofen cited post-ex-

effective or improving the rate o weight loss than

ercise calorie burn rom HII isn’t that large, HII

ed cardio or young women, the limited nature o

may still have hormonal and appetite benefits that

the study means more research is needed beore

impact at loss.

these results can be applied to other populations.  Are there other reasons to perorm asted cardio? 

Frequently Asked Questions

Circumstances will mediate the answer to this question. For instance, asted cardio exercise has been

What about High-Intensity Interval raining (HII)

shown to attenuate weight gain, enhance glucose

 or at loss? 

tolerance and insulin sensitivity, and increase gene

HII is an entirely different beast than moderate

expression o enzymes involved in at oxidation

intensity cardio exercise. It requires more careul

in healthy males ed a at-rich hypercaloric diet,

programming in the routine to ensure adequate

whereas the same exercise protocol perormed afer

recovery and isn’t typically done on a daily basis. In

consuming breakast showed weight gain with no

Aside rom actual health beneits, some people don’t enjoy exercise with ood in their stomach, and others have more energy in the morning when asted training is commonly perormed. terms o actual at loss, the breakdown and utiliza-

detectable improvements in glucose metabolism.

tion o at or energy is blunted at higher intensities

Aside rom actual health benefits, some people don’t

in avor o glucose, as higher intensities rely more

enjoy exercise with ood in their stomach, and oth-

heavily on the anaerobic energy system.

ers have more energy in the morning when asted training is commonly perormed.

Tus, between the reduced requency, shorter duration, and greater reliance on glucose or energy, HII may not be superior to steady-state cardio or at loss. But we won’t know or certain until a

What should I know? Tere are two main takeaways rom this study. Tis

49

is the first study to address the effects o asted or ed cardio under hypocaloric conditions, and it was shown that there were no significant differences between asted and ed cardio in any body composition measurements. Te greatest limitation is likely the study population o young healthy women, which makes generalizing the results to men and people o different fitness levels difficult. o make the results o such trials even more certain or any given population, longer trial lengths, larger sample sizes, and finding a way to standardize the diet more would help. All o these actors can make trials much more expensive, however. Second, this study lends urther support to the idea that we should remain skeptical o drawing longterm conclusions off short-term interventions. For example: last February it was shown that measures o muscle protein synthesis did not correlate with actual muscle growth ollowing a resistance training routine in untrained males. Again, it would be difficult to generalize these results to experienced lifers, but when taken in combination with the current study it seems prudent to be critical o claims based only on acute responses. Not every study applies well to real-lie health and fitness situations.



Have you done asted cardio and lost a bunch o weight? Burned out? Somewhere in between? Let us know your n=1 experience, and what you think o this study in the Facebook ERD private orum.

50

Fitting into your genes: do genetic testing-based dietary recommendations work? Disclosure of genetic information and change in dietary intake: A randomized controlled trial Introduction Science fiction is ull o stories o genetic testing and its potential to revolutionize medicine and human perormance. However, it’s not clear i the uturist hopes match scientific reality. Now that consumer genetic testing is both cheap and accessible, researchers have begun to study whether or not these services can actually help assess and manage health risks.

Because it’s such a new field, most o the research on the role o genetic testing or health management has been ocused on diseases with known genetic risk actors, such as BRCA mutations, which greatly increase breast cancer risk. As research progresses, more and more genes and gene variants are being identified as risk actors or disease. However, as consumer genetic tests become more common, they’ve been used or a variety o lesser known exposure-disease associations based on more common gene variations. 51

Genetic testing will likely become more prevalent as it becomes cheaper, and consumers without much knowledge o genetics or disease will have access to inormation that they may not know how to handle. Genes can affect a variety o nutrition-related areas — everything rom how we metabolize different uel sources to how we absorb different nutrients. But does it actually help people to have access to this inormation? Do people who receive advice based on genetic tests change their habits? Te researchers in this study assessed whether or not genetic testing and subsequent dietary recommendations had an actual effect on diet, not just in the first days or

Genes can affect [...] everything rom how we metabolize different uel sources to how we absorb different nutrients.

weeks afer being tested, but up to a year aferward. consumer genetic testing, which meant they were Te most established associations in genetics are or mutations that increase susceptibility to major diseases, such as BRCA or breast cancer. With the advent o direct-to-consumer genetic testing, a variety o lesser known genes have been tested, some o which can impact nutrients.

mostly young, emale, Caucasian or Asian, and had at least an undergraduate degree. Tis is obviously not a typical cohort or representative o the Canadian population as a whole. Because this study specifically assessed intake o our specific substances (caffeine, vitamin C, added sugar, and sodium), the inclusion criteria included

Who and what was studied? Tis study was a ollow-up to a previous study  assessing whether or not people thought genetic testing and nutrition advice based on that testing was useul. Because the participants o that previous study thought that personalized nutritional advice based on genetics was better and more understandable than general nutrition advice, the researchers perormed this study to assess whether or not the participants actually used the advice they were given. Both studies used the same large cohort o Canadian participants, who represented the “typical” users o

people who consumed at least 100 mg o caffeine a day, at least 10% o calories rom added sugars, at least 1500 mg o sodium per day, and no vitamin C-containing supplements. Tese measures were assessed using a ood requency questionnaire that was emailed to all o the participants at the start o the study. Because o these requirements, only 157 out o 1639 participants in the cohort were eligible or this trial. Eligible participants were then randomized to receive monthly dietary inormation that was either based on their genetic risk actors (the intervention group) or general recommendations (the controls). 52

Dietary recommendations or the intervention group

min C deficiency when consuming lower than

were based on whether or not the participants had

recommended amounts. Tese genes code or

known variations o our genes, as seen in Figure 1:

glutathione S-transerases, which detoxiy environmental chemicals. Glutathione and vitamin

• CYP1A2: increased risk o heart attack and

C can protect each other rom oxidation, and

high blood pressure when consuming >= 200

serum vitamin C levels differ depending on

mg o caffeine. Tis gene encodes proteins in

GS genotypes.

the cytochrome p450 amily, which includes enzymes that metabolize nutrients and drugs.

• AS1R2: increased risk o consuming excess

One variant makes you a “slow” caffeine metab-

sugars. Tis gene codes or a taste receptor sub-

olizer (and hence more stimulated by caffeine)

unit that can influence your sweet tooth.

and another makes you a “ast” metabolizer. Many different medications can impact this

• ACE: increased risk o high blood pressure

enzyme, and potentially urther slow down the

when consuming excess sodium. Some people

breakdown o caffeine.

are more sensitive to salt than others, when it comes to blood pressure. Te ACE gene plays a

• GSM1 and GS1: increased risk o vita-

major role in determining salt sensitivity.

Figure 1: Frequency of risk alleles in intervention group

53

A reduction o sodium to 400 mg/ day has been estimated to prevent up to 28,000 deaths and be more effective than using common medications to manage high blood pressure o assess the effects o the emailed dietary recommendations, the participants were sent additional ood requency questionnaires at three and 12 months afer the initial enrollment in the study. Food requency questionnaires are notoriously inaccurate, but they are regarded as the most cost- and time-effective way o generally assessing the dietary habits o a population. Te subjects were also sent monthly email reminders o their dietary recommendations, which are likely not the most effective way to modiy a person’s behavior unless that person gets very ew emails and has lots o ree time. However, it does mirror the real-lie situation o ordering a genetic test rom a testing service, and getting email as the main orm o communication, rather than the more hands-on personal communication typical o many clinical trials.

What were the findings? For most measures, the monthly recommendations based on participant genotypes did not significantly affect dietary intakes at three or 12 months, compared to the control group. Te only exception to this was sodium intake, and in that case, the difference was only seen at 12 months. However, despite the difference between the inter vention and control groups or sodium intake at 12 months, the intervention group with the ACE gene  variation still ailed to meet the recommendations they were provided, with only 34% meeting the lower recommended intake at 12 months versus 24% in the control group. However, the roughly 300 mg/day reduction in sodium by the intervention group is still likely clinically relevant, as recent evidence by the Institute o

Tis study used email to remind study partic-

Medicine has pointed to sharp reductions in sodi-

ipants o their nutritional recommendations,

um being less beneficial than previously thought. A

which were based off o genetic testing. Email was

reduction o sodium to 400 mg/day has been esti-

also used to track what the study participants

mated to prevent up to 28,000 deaths and be more

ingested during the study, specifically caffeine,

effective than using common medications to man-

 vitamin C, added sugar, and sodium.

age high blood pressure, which shows that smaller changes than sometimes deemed optimal can have major impacts on a population-wide level. 54

Tese findings are likely related to the act that most

Tis high variance results in what statisticians reer

o the participants had daily consumption values

to as “noisy” data: measurements in which the varied

that were within recommendations at baseline (91%

initial values make it difficult to make strong statis-

or caffeine, 86% or vitamin C, 76% or added sug-

tical conclusions. For instance, i one person drinks

ars, and 61% or sodium). Te act that sodium

no coffee and another person regularly drinks our

intake significantly changed may also be related to

cups a day, that’s a relatively large spread. I that first

the act that 80% o participants with high-risk ACE

person starts drinking one cup a day because they

 variants consumed beyond the recommended sodi-

took a stressul job, and the second cuts down to

um level at baseline. For comparison, only 38% o

two cups a day because o the advice they received,

participants with the CYP1A2 variation consumed

those are both still within the initial range o zero to

more than the recommended amounts o caffeine

our cups per day, so it makes it hard to determine i

at baseline. Blood pressure may also have seemed

those changes in consumption are normal or i they

a more critical health issue or some o the partic-

were caused by the dietary advice.

ipants than something like vitamin C deficiency, since or better or or worse the ormer is typically

Te large amounts o variability at baseline make it

associated with heart disease, while the latter brings

hard to generate meaningul conclusions later.

to mind scurvy, pirates, and colds. Furthermore, as one might expect rom a study conducted via emailed ood requency questionnaires to a population with highly varied baseline data, the estimated intakes  varied greatly among participants, which ofen resulted in standard errors larger than the mean values themselves (or example, at 12

Te majority o study participants did not significantly change their dietary habits over the course o the study. Sodium intake was affected most, though only 34% o the group met their recommended sodium intake by the end o the 12-month study. Te mean reduction o the group, while not as large as intended, would still likely be enough to make an important impact on a population-wide level.

months, the change in the control group’s caffeine consumption was -0.3 +/- 17.8 mg/day).

55

What does the study really tell us?

On the other hand, one-on-one consultations with

Tis study intended to clariy the real-lie impact

the difference between these two methods has not

o genetic testing based dietary recommendations,

been compared.

genetic counselors or other experts could have a greater effect than monthly email reminders, but

and ended up showing that it had little to no effect when it comes to behavioral modification, compared

Based on the findings o this trial, the answer to the

to traditional advice on its own. Like many studies,

question, “Does nutrition-related genetic testing

this is one in which the applicability o the results

affect liestyle behaviors?” is “Maybe or some select

is difficult to interpret,

nutrients, but likely not in

and it could be that the

a consistent and reliable

significant change noted in sodium intake at 12 months is not applicable to most other nutrients (i sodium and blood pressure is deemed a more important issue to act on than other nutrients), or the results may be due to the vagaries o statistical variation (the control group used or comparison had increased sodium intake

reviews [...] have ound inorming people o their genetic risk actors does little to actually change behavior.

at 12 months, making the difference between the groups larger). Tis is especially true because there was no effect on sodium intake at three months, and the decrease in sodium intake at six months still didn’t lead to the participants meeting the recommended intakes. However, it’s also just generally difficult to extrapolate the findings o trials like this, which use samples that are not representative o the general public. I someone is highly motivated and dedicated to minimizing their liestyle-associated risk actors, the results o a genetic test may be more useul.

ashion.”

The Big Picture Te findings o this study are generally in line with other studies and reviews that have ound inorming people o their genetic risk actors does little to actually change behavior. It should also be noted that this is still a very new field, and there is a lack o data on how genetic

inormation can best be used or behavioral modification. It’s not necessarily clear how to best deliver genetic inormation to people, and this is a major conounder or any study at the moment. It could be that genetic inormation can be an effective agent o behavioral change, but we simply don’t know how to effectively deliver it or pair it with existing interventional strategies. We don’t even know who will be responsible or providing personalized recommendations — will physicians work with genetic testing companies? Will consumers mostly be interpreting results on their own?

56

Tese difficulties apply to many biometric-based

motivation or a person to pay attention to advice,

intervention trials (meaning those that use a phys-

and then there has to be even more motivation to

iological measurement, such as blood pressure or

ollow that advice in the ace o lie’s daily stress.

blood glucose), which are actually scientifically ar

Because this study didn’t specifically ask the partici-

more complicated than they seem. It seems easy to

pants i they wanted to change their habits based on

ask whether or not biometric test results affect behav-

their genetic test results, that actor wasn’t controlled

ior in a meaningul way, but there are many other

or at all. Te results might have been very different

aspects to that question that may introduce scientific

had the surveyed population been more (or less)

uncertainty into those types o studies. For example,

concerned with optimizing their health. Furthermore,

The results might have been very different had the surveyed population been more (or less) concerned with optimizing their health. researchers have to assess the reliability o their tests,

a similar study on highly motivated populations, like

assess the effectiveness o how they report the results

athletes or people recently hospitalized or health

o those tests to participants, decide how to measure

issues, might have very different results.

that effectiveness, and then determine whether the effects they see are real or somehow related to the

Despite these issues, consumer genetic testing is still

nature o the study cohort or statistical anomalies.

a promising field because it offers a way to actually

Each o these points could be enough to write a the-

act on all o the genetic inormation that has accu-

sis, so the field needs to grow substantially beore

mulated over the years. Without a cost-effective

anything can be said with much scientific certainty.

way o sequencing individuals, all o the genetic  variations that have previously been associated with

In this study, these uncertainties were urther com-

disease are relatively useless. For example, even i

pounded by the way the researchers interacted with

we know that CYP1A2 variation is related to ca-

the study participants, which was almost entirely

eine-associated hypertension, it does little good

through email. Most peoples’ inboxes are constant-

unless we have a cost-effective way o testing what

ly spammed by a variety o newsletters and other

 variant a person has. Consumer genetic testing may

inormation, and it’s very easy or a monthly email

provide this “outlet” to make gene association stud-

to become a monthly auto-delete or spam older

ies more useul by inorming large populations o

denizen. Tere usually has to be some sort o major

their genetic variants. 57

However, it’s not clear how actionable this disclosure is. And i it is actionable, it’s not clear i people actually care enough to change. Te impact o research on genetics (or epigenetics or microbiomics or any other “-ic”) is difficult topic to assess, and despite the modern advances in sequencing and genetics, human behavior may be the limiting step in applying findings. Te more biometric data we’re able to find out about any given person, the more that an age-old question applies: “How would you live i you knew how you were going to die?” Te study doesn’t address possible negative aspects o genetic testing. Nutrient-related tests may be less susceptible to major negative aspects, but it’s quite possible that consumers could misinterpret a test, and ocus on a result when the true source o their health issues lies elsewhere (in other words, a red herring). It’s even possible that someone might pin their hopes on a nutrition-related intervention, and stop taking a medication when they haven’t cleared it with their doctor. Tis is a case o “knowing just enough to hurt yoursel.” Just because you know what the MHFR gene does (a gene that regulates homocysteine, involves B vitamins, and is a topic o much contention) doesn’t mean that it’s the source o all your health problems.

Frequently Asked Questions Is genetic testing useul or general liestyle recommendations?

Genetic testing may help guide liestyle choices, but many o the tested genes (such as the ones in this study) only show effects with intakes beyond recommendations. So i you adhere to general recommendations, it may be less useul. It seems obvious that adjusting your liestyle to address certain genetic risk actors would help reduce risk, but that has yet to be definitively proven.

  How would you live i you knew how you were going to die? Who most benefits rom genetic testing? 

Tis study was limited by the population it investi-

People with amily histories o diseases may find

gated. Even the best advice is ignored i there is no

benefit rom genetic testing, but it’s also a dou-

internal motivation or change. Additional stud-

ble-edged sword. Tere aren’t always preventative

ies on multiple populations such as those that are

strategies available or all o the diseases with high-

interested in optimizing their health, or one that

risk mutations, so it may just uel a sense o atalism.

is more reflective o the general population, can

Similarly, researchers have yet to develop reliable

shed light on the best way to deliver the results o

risk assessment models based on genetic screening.

genetic testing and how to best structure liestyle

Genetic counselors are specifically trained to help

changes based on those results.

people interpret and address the results o genetic testing and amilial risk actors. 58

People with amily histories o diseases may ind beneit rom genetic testing, but it’s also a double-edged sword. There aren’t always preventative strategies available or all o the diseases with high-risk mutations, so it may just uel a sense o atalism. Although we know that genetics has a proound

ics to ully understand a test result, and it’s easy to

impact on chronic disease risk (especially rom twin

 jump to conclusions that aren’t truly evidence-based.

studies), we don’t know much about which specific genes are involved. Not to mention that genes can

Te real-lie implications o different genetic tests is

have complex interactions with other genes, diet, and

still uncertain, which is part o the reason popular

environment. In the case o most chronic diseases,

testing company 23andme was reprimanded in 2013.

we don’t have the ability to look or specific polymor-

Te FDA orced 23andme to stop marketing their

phisms and give meaningul advice on that basis.

direct-to-consumer genetic testing service, as the health reports provided by the company were seen

I a client brings me a genetic test and wants to train

as being too close to disease diagnosis, and 23andme

or eat a certain way, what should I tell him or her?

was preparing to market the tests quite heavily to the

Tis is a balancing act between your proessional

public. Tus 23andme now mostly provides raw data

opinion and your client’s opinions. And different

without as much interpretation as they did previously.

states vary with regards to what credentials are needed to give different types o advice, so make

Tis crackdown illustrated the many uncertainties

sure to look into what you are and aren’t allowed to

associated with genetic testing. Someone without

do. Te personalization offered by a plan that caters

much knowledge o genetic epidemiology (which

to a client’s test results may enhance adherence, and

is … most everybody) might have a hard time

it’s unlikely to be harmul i it encourages intake o

interpreting test results. It may not be optimal or

healthy oods, but you should always thoroughly

consumers to mostly receive raw inormation rath-

research a given topic beore offering advice to any

er than health reports, but it’s also important not to

clients. Most trainers lack the background in genet-

“lead on” consumers with test result interpretation

59

that may not be accurate. So it’s always a good idea

tle to no change in intake or the other items studied

to get an expert opinion, such as rom a genetic

(caffeine, vitamin C, and added sugar intake).

counselor, or important health issues that may be impacted by genetic tests.

While genetic testing results may enhance adherence to diet and supplementation plans, this study only

How are the findings o this study comparable to

provides some evidence that it might be possible to a

other biometric testing services such as microbiome

small degree. It’s also unclear i this is actually spe-

analysis?

cific to genetic inormation, or applies to any type o

Personalized biometrics is a rapidly growing field,

personalization.

but it’s not necessarily clear how all that extra data can most effectively influence behavior or risk ac-

Furthermore, effects may depend on the specific

tors. Inormation can change everything, and even

compound studied. For example, based on the inor-

save lives. For some people, collecting tons o data

mation ound in this study, it may be much easier

and tracking everything you do distracts rom bigger

or most people to reduce sodium intake than it is

issues that impact health. People somehow managed

or people to reduce caffeine consumption. Future

to stay healthy long beore “Quantified Sel ” became

research testing other personalized recommenda-

a buzzword.

tions or other dietary components, perhaps using different controls, will help in developing this very

Genetic test results rom this study are quite di-

new research area. ◆

erent than microbiome analysis. Metrics like microbiome composition can change relatively rapidly in response to behavioral changes. For example, dietary changes, or even moving to a new home, can change gut microbiome compositions. But since not

Have you made changes based on genetic tests or microbiome testing? Discuss genes and nutrition over at the ERD private orum on Facebook.

much is known about optimal microbiome composition, microbiome analysis may serve a more inormational role at this point, rather that to spur direct and specific action (outside o a generally progut health liestyle). Tat being said, much o this is speculation, as it’s a young field with a constantly evolving research base.

What should I know? Tis study tested how dietary recommendations based on genetic testing results affected dietary intakes. Te effects were relatively minor and were only seen in one o our measures, sodium intake. Tere was lit-

60

Combating obesity through intermittent fasting Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges Introduction Short-term asting due to religious belies has been practiced or thousands o years. More recently, intermittent asting (IF) has been becoming more popular. Tere are different kinds o IF, including randomly skipping a meal/meals, alternate day asting, and using time-restricted eeding (RF) windows.

61

A RF protocol has participants consuming all o their daily energy intake within a set window o time (our hours, six hours, etc), inducing a 12-22 hour daily asted window. While human trials are limited, an increasing number o animal studies are showing that RF appears to be beneficial or improving many chronic disease risk actors, even while consuming a diet that should otherwise make the animal obese and diabetic. Prior to this new study, however, it was not known i the benefits o RF extended beyond protection against high-at diets, or i RF could be protective against excessive sugar or ructose intake. Questions also remained about RF’s effect on pre-existing obesity, as well as its lasting effects.

Who and what was studied? Tis is a very thorough animal study that looked at the effectiveness o RF against a variety o nutritional challenges. Te researchers studied high-at, high-ructose, and high-sucrose diets consumed within nine hour, 12 hour, and 15 hour eeding windows. In rodent studies the term “high-at diet” doesn’t just mean a diet high in at. No avocados, no cheese, no macadamia nuts. It means a purified high-at diet based on refined ingredients. It’s calorie-dense and not very healthy. Te study also had groups alternating between five days o RF (simulating weekdays) and two days o ree-access to ood (weekends). In addition, they looked at both the immediate effects, as well as the legacy effects, when the RF routines were changed

ime-restricted eeding (RF) has been a part

to allow long periods o unrestricted ood access.

o religious practices or thousands o years.

While many o our human readers may ollow a

Recently it has captured the attention o biomedi-

high-at diet with no ill-effects, it should be noted

cal research due to promising research or disease

that unrestricted (ad libitum) access to a high-at

prevention, mostly in animal studies.

diet in mice causes obesity, insulin resistance, as well as associated problems like dyslipidemia, hepatic steatosis (atty liver), and elevated cholesterol.

[...] it was not known i the beneits o TRF extended beyond protection against high-at diets, or i TRF could be protective against excessive sugar or ructose intake. 62

Intervention

(bolded below) all ell into one o these six groups

A total o 392 12-week-old male mice were subject-

(bolded and italicized):

ed to a variety o eeding regimens and divided into six main cohorts, all maintained on a 12-hour:12hour light:dark cycle, and ed during the dark-phase

1. High-fructose: ed a high-ructose diet or 11 weeks either ad lib (FrA) or RF (Fr).

when time-restricted. Feeding during the darkphase is optimal or mice, who are nocturnal. Tis

2. High-fat high-sucrose: ed a high-at high-su-

is opposite to humans, who (should) consume the

crose diet or 12 weeks either ad lib (FSA) or

majority o their daily energy intake during the light

RF (FS).

phase. 3. High-fat TRF and 5T2A : ed a high-at diet As seen in Figure 1, there were A LO o variables

or 12 weeks. With respect to eeding windows,

manipulated in this trial, producing many differ-

there were our different groups: either ad libi-

ent diets. Reer to the figure or list to match up the

tum (FA), in a nine hour RF window (9hF),

alphabet soup o different interventions to speci-

12 hour RF window (12hF), or alternated

ic diet descriptions. Te different individual diets

between five days o nine hours RF (week-

Figure 1: The many, many different diets variables tested in the study diets

63

days) and two days o ad lib (weekends) or 12

as mice given unlimited access, but gained hal as

weeks (52A).

much weight. Interestingly, weight gain was similar when mice were given a high-ructose or normal

4. High-fat and normal chow : ed a high-at diet ad lib (FA) or in a 15 hour RF window

diet either ad lib or RF — suggesting that ructose isn’t especially attening in rodents.

(15hF), or a normal chow diet either ad lib (NA) or in a 15 hour RF window (15hN) or nine weeks. 5. Short-term crossover (13:12): ed a high-at diet or 25 weeks with the eeding regimen switched or some mice (to or rom RF) midway through the experiment (the FAA, F, FA, and FA groups).

6. Long-term crossover (26:12) : ed a high-at diet or a normal chow diet or 38 weeks with the eeding regimen switched or some mice afer 26 weeks and then maintained another 12 weeks (FAA, F, FA, FA eeding groups on a high at diet and NAA, N, NA, NA eeding groups on normal chow).

What were the findings?

The results o this study provides some additional evidence that a calorie is not always a calorie, at least in mice.

Te study authors provided a succinct summary o its results: “TRF protects against excessive body weight gain without affecting caloric intake irrespective of diet, time schedule, or initial body weight.”  What exactly does that mean? Bodyweight:

Te results o this study provide some additional evidence that a calorie is not always a calorie, at least in mice. Mice ed a high-at, high-sugar diet within a nine hour window consumed equivalent calories

When comparing a high at diet using nine, 12, and 15 hour RF, ood consumption was equivalent, but longer eeding times resulted in greater increases in body weight. Te 9 hour group had a 26% weight gain, while the 15 hour group gained 43%, and the group with unlimited access gained 65%. It is important to remember that all our groups were consuming the same number o calories per day. Te authors didn’t give much detail about how calorie intake was measured, as ar as specific methods used. Rodent calorie intake can be difficult to measure, depending on experimental conditions, and 64

TRF appears to be very effective in protecting against weight gain during a range o challenges, including highat and high-sucrose diets, as well as promoting weight loss and stabilization in preexisting diet-induced obesity. measurement technique is important or a trial such

on RF or 26 weeks and then switched to unrestrict-

as this.

ed access. As expected, mice gained weight upon switching to ad lib eeding though their weights

o urther test the effects o RF, the researchers

stabilized at a much lower increase in body weight

set up three crossover experiments. When mice

(106%) than mice never on RF (157% increase in

were alternated between five days o nine hour RF

body weight). Again, it needs to be noted that equiv-

(weekdays) and two days o ad lib (weekends) or 12

alent calories were consumed among all groups.

weeks, they only had a 29% gain in body weight, as opposed to a 61% weight gain or the FA (ad lib ed)

o determine i RF could have benefits or mice

mice. As with the previous cohorts, ood consump-

with pre-existing obesity, both the short and long-

tion was the same between groups.

term crossover studies included a group which were switched rom ad lib to RF eeding. During

Another portion o the study was to determine the

the 25-week study, these mice had a small drop in

longer term and lasting effects o RF. Mice were

body weight and maintained this weight, which

ed a high-at diet or 25 weeks, with the eeding

was not different rom the mice that were always

regimen switched or some mice midway through

on RF. Switching mice rom ad lib high-at diet to

the experiment. Te mice who were started on RF

RF led to a 5% loss in body weight rom the time

displayed rapid weight gain upon switching to ad

they changed, which is impressive compared to a

lib eeding, and in the end weighed as much as mice

25% weight gain in mice who were always allowed

who were always consuming ad lib (111% body-

ad lib access to ood. In the longer (38-week) study,

weight gain). In contrast, the group who stayed on

switching mice rom ad lib high-at diet to RF led

RF or the entire 25 weeks only had a 51% increase

to a 12% loss in body weight rom the time they

in body weight.

changed, compared to an 11% weight gain in mice who were always allowed ad lib access to ood.

In the longer-term crossover study, mice were kept 65

RF appears to be very effective in protecting

to ad lib and RF had asting insulin in between

against weight gain during a range o challenges,

those two groups.

including high-at and high-sucrose diets, as well as promoting weight loss and stabilization in preexist-

A glucose tolerance test was also perormed and

ing diet-induced obesity.

all o the mice, except the mice eating normal ood, showed improved glucose tolerance compared to

Body fat and inflammation:

their ad lib counterparts. Te crossover studies also

While each experimental group had comparable

revealed that RF can reverse prior glucose intoler-

lean mass, it was the differences in at mass that

ance as a result o diet-induced obesity.

made up the differences seen in total body weight. Compared to ad lib ed, mice on RF had reduc-

Lipids:

tions in body at o 62% (high-at, high-sucrose)

Tis study suggests RF is protective or a lot o

and 26% (high-ructose). Increasing the length o

things, and blood lipids were no exception. Liver

the RF windows (rom nine hour to 12 hour to

triglyceride levels were reduced in all mice on a RF

15 hour) led to an increase in percentage o body

high-at, high-sugar diet compared with their ad-lib

at, but even the 15 hour window was protective

ed counterparts. In addition, switching mice to RF

compared to ad lib consumption. Mice in the

prevented urther hepatic triglyceride accumulation

5:2 group were also protected rom excessive at

in ad lib ed mice, suggesting RF as a possible clin-

accumulation (48% less body at than ad lib eed-

ical tool against atty liver disease. Likewise, serum

ing). Mice on a normal diet that were ed ad lib

triglycerides were also normalized when mice were

but transerred to RF has 55% less at than mice

switched rom ad lib high-at to RF. On a lower at

maintained on ad lib diets.

diet however, serum triglycerides were unchanged between RF and ad lib.

Reduced inflammation was also seen in mice on RF (by looking at mRNA levels o pro-inflamma-

Cholesterol levels, both absolute levels as well as the

tory cytokines NF-a, IL-1b, and pro-inflammatory

daily rhythmic variation, can also improve on RF.

chemokine Ccl8/Mcp2).

Mice ed either high-at or high-sugar diets on RF had significantly lower serum cholesterol levels than

Blood glucose regulation:

those on ad lib eeding. It should be noted that there

When mice were ed a ‘normal’ diet, RF did not

are substantial differences in cholesterol metab-

offer any extra advantage over ad lib when looking

olism between humans and mice. For example,

at asting glucose levels. However, on a high-at or

rodents have very low LDL compared to humans

high-sugar diet, RF reduced asting glucose lev-

due to more rapid clearance by LDL receptors. Most

els compared with ALF. Fasting insulin levels were

serum cholesterol is carried by HDL, and they are

reduced in all RF groups ed a high-at diet. In

extremely resistant to atherosclerosis because o that.

the crossover studies, insulin levels were nearly 5

In experiments knocking out their LDL receptors,

times lower in mice maintained on RF compared

their lipids become more human-like and then they

with ad lib, while groups who had some exposure

become more likely to develop atherosclerosis. Tis 66

would suggest that changes in serum cholesterol in

Tis study confirms that, in animals, RF can be

mice may be caused by different mechanisms than

an effective treatment or a variety o disease states

could occur in humans.

such as obesity, diabetes, high cholesterol, atty liver, and circadian dysunction, in the absence o a cal-

Additional benefits: Mice on RF showed better

orie deficit. While the ‘bad’ diets showed the more

coordination skills and improvements in physical

dramatic effects o RF, mice ed normal-chow still

endurance tests (nearly double the endurance per-

showed better body composition.

ormance o the ad lib group), which were not the result o greater muscle strength, fiber type or glycogen storage, but likely rom improved metabolic responses to mobilizing energy stores. Enzymes that regulate glycogen synthesis and gluconeogenesis (creation o glucose rom non-carbohydrate sources) were affected by RF, as was the anabolic insulin/ Akt and catabolic AMPK pathways, and a variety o cycling amino acid metabolites resulting in more avorable daily patterns.

Mice that were subjected to a restricted eeding window gained less at and had better blood lipid profiles than mice that were allowed to as much as they wanted, even though all the mice consumed the same amount o calories.

What does the study really tell us?

Although we are not mice, these models can be extremely valuable or understanding the mechanisms behind metabolic health and disease states.

Although we are not mice, these models can be

Keep in mind that these mice were always ed during

extremely valuable or understanding the mecha-

the dark phase. It has been previously shown in

nisms behind metabolic health and disease states.

rodents that the ood timing relative to the light:dark

Tis study offers a great deal more inormation than

cycle is very important (even in RF). Some mice

previous RF studies, because they used not only a

have experienced an 18-19% increases in body weight

high-at diet, but also high-sucrose, high-ructose,

when eating the same number o calories during the

 various RF windows (nine, 12, and 15 hour), five

“wrong” (light) phase, compared to the dark phase

day RF, two day ad lib eeding, and longer term (25

(normal eating times). o extrapolate this to humans

and 38 week) crossover studies to determine lasting

we need to think o the opposite, and pick our nine to

effects o RF.

12 hour windows during the daytime. 67

The big picture RF could promote wider adherence than conventional dieting methods, because the emphasis is on the timing o ood intake and not on calorie counting. Tere will certainly be uture studies which can investigate the mechanisms o action, as well as a large-scale randomized control trial (RC) in humans. Until uture studies are done, we can only guess at how much o these results will translate to humans. Tere are a ew existing human studies which use RF, but nothing on the scale that is needed. Tere is a great deal o research on Ramadan, which eatures a month-long RF window. However, these meals aren’t aligned to circadian rhythms, occurring at night, instead o during the day. Tere are a ew other recent studies which show reduced daily energy intake, and either improved or no-change in insulin action. rying a RF window or yoursel could offer benefits with very little downside. However, i you are prone to hypoglycemia, consult your doctor beore trying this. Please see the FAQ or additional precautions. ime will tell i a RC can show similar results to what this study has shown, but it is indeed  very promising rom a number o angles and or a diverse population.

FAQs

light:dark cycle would be basically impossible. However, while rodent studies can control more actors between groups, randomization in humans could help to minimize variation between groups. Costs o testing so many interventions over a long study may be prohibitive. In addition, all o the animals were sacrificed in order to be ully studied, which doesn’t go over very well with human participants or the institutional review boards who approve the study. Tere are a ew more aspects o the study that would differ in humans. Humans normally consume ood in a time-restricted manner. I you have breakast at 7:00 a.m. and dinner at 6:00 p.m., that is an 11 or 12 hour eeding window. Most people don’t eat in the middle o the night, but when mice are ed high at diets, they ofen do eat in the middle o the night (much more ofen than when they’re ed healthy chow). Also, in this study, the major effects o RF only maniested when animals were ed unhealthy, purified diets. RF didn’t have as much o an effect when mice were eating a healthy diet. Humans typically aren’t ed purified oils and refined oods in high amounts over the course o months in studies. Lastly, in humans, as ar as we currently know, a calorie really is a calorie (as long as it’s absorbed into circulation). Tere is no other ood property or diet characteristic known to substantially impact adiposity in humans. Mice are not like that — many studies have shown calorie-independent effects o

Tis is great! Could a similar study be done in

diet characteristics on adiposity. Mice are able to

humans?

modiy energy expenditure more readily and to a

Not the whole study with all the measurements,

larger extent than humans.

but some parts could be done and have been done. o have complete control o the amount and type

Does it matter when my window is? 

o ood eaten or 38 weeks while controlling the

It’s hard to say with certainty, but rom the existing 68

literature the best answer would be to keep most

those who want to bulk up or are still growing (high

o your ood intake in the light phase, since animal

school and college athletes), or people in very high

data seems to suggest that eating in the “wrong”

 volume and high intensity training phases, such as

(sleep) phase leads to greater weight gain. Tis

cyclists or triathletes. People with advanced liver

would change with the seasons, during the summer

disease should speak to their doctor beore practic-

the times can be more flexible, but during winter it

ing RF. While RF may be protective against atty

may be best to keep the window earlier in the day.

liver, a bedtime snack is typically recommended or

Remember, our body’s clock is the light:dark cycle,

people with advanced liver disease.

and not the time displayed on your watch. Do I have to skip breakast?

No! A growing body  o research suggests a high-protein breakast may have avorable effects on appetite control. Additionally, glucose tolerance is better in the morning, compared with later in the day due to circadian variation. Tis impaired evening glucose tolerance is likely due to decreases in both insulin secretion and insulin sensitivity . When considering the circadian variation in glucose tolerance, a roughly 9:00 a.m. - 6:00 p.m. window may work well, although a variety o individual actors play into exact timing. Can my window change rom day to day?

Tis study showed benefits rom five days o RF, ollowed by two days o ad lib, suggesting that there is some flexibility or the eating phase, and you do not necessarily need to ollow a rigid daily time window. Keeping most o your ood intake to the light phase, but moving it up or back by a ew hours

What I should know? Tis animal study suggests that keeping ood intake within a nine to 12 hour daily eeding window can be beneficial in a number o different ways. Tese results become more apparent when consuming a poor diet that would otherwise lead to obesity and metabolic dysunction, but benefits also extend to animals eating an otherwise ‘normal’ diet. Te natural question that arises is: Should I try time restricted eeding? We don’t know how well the benefits shown in this study applies to humans, given the physiological and environmental differences rom rodents, but restricting ood to moderate daily eeding windows is unlikely to do harm or most people. Access to ood at all times o the day, during all times o the year is not necessary or most humans, and trying a different eating pattern may produce quite beneficial results without having to micromanage different parts o your diet.◆

depending on the day could probably still be okay. o discuss all the different possible types o intermitIs there anyone who should NO try this?

tent asting protocols, and their impacts on humans,

Yes, extended asting windows can be a stress on the

check out our private Facebook group or ERD

body. Ofen a ‘good’ stress, but someone who is deal-

readers.

ing with a lot o other stressors in their lie should approach this diet conservatively. Also, athletes should probably not get too ambitious, particularly 69

How does a lifetime of marijuana use affect the brain? Long-term effects of marijuana on the brain Introduction Marijuana use is popular due to the psychoactive effects o gamma-9-tetrahydrocannabinol (HC). It’s known that marijuana has a multitude o effects on the brain, as seen in Figure 1, but understanding the exact effects can be a complicated scientific process. Within the brain, there are two major types o cells: neurons and glial cells, pictured in Figure 2. Neurons are the cells that respond to and carry electrical signals, while glial cells provide support and protection to the neurons. Networks o cells orm either gray matter or white matter tissue. Gray matter and white matter both are made up o neurons (and glia), but the gray matter is the cell bodies that contain the nucleus and most o the cellular machinery, while the white matter are the thin “telephone lines” between neurons, wrapped in a myelin sheath (which is a structure that is part o a specialized class o glial cells).

70

FIGURE 1: Brain areas affected by marijuana

Gray matter is involved in everything the brain does — such as processing and cognition activities, including decision making and sel-control. It’s grey due to the lack o myelin, the insulating sheath around the outside o some brain cells. White matter physically connects and coordinates communication between different regions o the brain by carrying electrical impulses rom neuron to neuron. Te myelin is white in color, which distinguishes it visually rom the gray matter. Tis particular study investigated several specific regions o the brain, in addition to types o brain tissue. Te orceps major and orceps minor are two regions o white matter in

Figure 2: Brain terminology

the brain. Te orceps major connects the occipital lobes within the cerebral cortex and the orceps minor connects the rontal lobes o the cerebral cortex. Within the rontal lobes, there is a region o the brain called the orbitorontal network. Tis network is made up or our lobes: the lef and right orbitorontal cortex (OFC) and the lef and right temporal lobes. Te primary unction o this region o the brain is decision-making, specifically the analysis o the possible rewards o a decision. Tis region o the brain displays high levels o activation during addiction-seeking behaviors like heavy drug use. Specifically or marijuana 71

use, the OFC also has a high concentration o cannabinoid 1 (CB1) receptors, the receptor that binds HC. Previous studies looking at the effects o marijuana have conflicting results. Some studies showed increases in tissue volumes in certain regions o the brain, others have showed decreases in the same areas o the brain, and still others have shown no effects. Tis could be due to differences in the study populations, either in regard to

Who and what was studied? Tis was an observational (non-interventional) study that compared 48 regular cannabis users with 62 non-users o similar age and sex. A regular user was defined as someone who sel-reported using marijuana at least our times a week and took a drug test (via a urine sample) that was positive or HC at enrollment. A non-user was defined as someone who

Research on marijuana impacts on brain unction has had conlicting results.

the participant characteristics, or in the level o marijuana use. Other potential conounding variables include only investigating a particular age range or duration o marijuana use, the enrollment o subjects who used other substances along with marijuana, or designing the study to only look at a single region o the brain. Tis study attempted to overcome those limitations by looking at a broad range o participant ages, evaluating a subset o participants who exclusively used marijuana, and using several different types o MRI scans to evaluate a number o actors in the brain globally.

sel-reported no marijuana use and had a negative drug test at enrollment. All study partic-

ipants took an IQ test at the beginning o the study. Marijuana users were also assessed or behavioral issues related to possible marijuana dependency through the Marijuana Problem Survey (MPS). Te MPS asks participants to identiy and rate problem areas such as missing work, conflicts with amily and significant others, or legal issues as a result o their marijuana use. Once enrolled, study participants underwent three different MRI scans to assess different structural and unctional aspects o the brain: • a high resolution visual MRI scan to quantiy the

Marijuana affects a variety o brain regions,

amount o gray matter in the participant’s brain

including a region called the orbitorontal cortex (OFC) involved in decision-making. Research on

• a unctional MRI (MRI) scan to determine

marijuana impacts on brain unction has had con-

unctional connectivity, or how much blood

flicting results.

flow occurred in different brain regions • a diffusion tensor imaging (DI) scan to deter72

mine structural connectivity, or how much white matter exists between different regions o the brain, and how organized the white matter is Because marijuana is ofen used along with other substances, the researchers separated out a subset o the cannabis users into “exclusively cannabis users,” who had no sel-reported use o alcohol or tobacco. Tis allowed the researchers to determine i any o the structural and unctional changes seen in the MRI scans were due to cannabis use alone.

Tree different MRI scans were used to assess gray matter, white matter, and connectivity between brain regions. Users o marijuana only, rather than users o marijuana and other substances, were also tested separately.

What were the findings? Te researchers noted a statistically significant difference in the IQ scores o the cannabis users, compared to the non-users. Mean IQ scores were approximately five points lower among cannabis users, even though the educational levels between the two groups were similar. However, urther statistical analysis did not indicate a direct causal link rom marijuana use, to neural abnormalities that may arise rom its use, to lowered IQ. A number o alternative actors, such as genetics and environment, could be involved in this causal pathway, or even explain the difference between the groups themselves. Tough untested, it’s also possible that a lower IQ could increase the likelihood that someone will become a regular marijuana user, rather than lowered IQ being an effect o heavy marijuana use.

Te average IQ score in the cannabis users group was approximately five points lower than in the non-users group, though statistical analysis could not confirm i this was a cause or an effect o marijuana use, or due to other actors.

73

Te subgroup o participants who were exclusively cannabis users had similar MRI results as the cannabis users group as a whole. Tis indicated that any changes in brain structure and unction were correlated with cannabis use and not the use o other substances. Te study compared the high-resolution MRI scans o the cannabis users with the non-users. A significantly lower volume o gray matter was seen in the right middle orbitorontal and lef superior orbitorontal regions o the brains o cannabis users. Tis structural difference, however, cannot be determined to be a result o cannabis use, since this is a correlational finding, thus suggesting it is also possible that subjects with lower volume o gray matter are more likely to become chronic users. When the researchers looked at MRI scans to detect brain unction in the gray matter, they ound that the cannabis users group had more

[...] the tissue that was there showed increased unctional connectivity at rest when compared to the non-users brains.

unctional connectivity in the our nodes o the OFC regions o the brain, as measured by blood

structure and level o organization o the axons in

flow in the gray matter. Even though there was less

the brain tissue.

gray matter in the cannabis users’ brains, the tissue that was there showed increased unctional con-

One indicator in the DI scan is ractional anisot-

nectivity at rest when compared to the non-users

ropy (FA). FA reflects the density and myelination

brains. Te researchers believe this to be a compen-

o the axons, and is measured on a scale rom 0 to 1.

satory mechanism to maintain brain unction even

A higher FA means that water diffusion is restricted

as brain volume decreased.

to a single direction, implying that the local water is inside long thin fibers (axons) as opposed to lit-

Next, the researchers looked at the structural con-

tle lumps (cell bodies). Tis is indicative o a more

nectivity o the same regions o the brain, measuring

fibrous and organized region. A lower FA means that

white matter in the orceps minor region that inter-

water diffusion is less restricted and indicates a less

connects the different areas o the OFC. Te DI

organized and axonally-dense region o the brain.

scan uses magnetic resonance to measure the diffusion, or passive movement o water through regions

Another indicator in the DI scan is radial diffusiv-

o the brain, providing inormation about the micro-

ity (RD). Tis is a measurement o diffusion along 74

two axes, which is decreased in more mature white matter brain tissue and increased when cells in white matter become demyelinated. Te DI scan showed that cannabis users as a group had higher FA measurements in the orceps minor, but not in the orceps major region. Tis effect was localized to the orceps minor region, as no statistically significant effects were seen in the orceps major region within the occipital lobes. In summary, this region looked more organized and more myelinated in cannabis users. A more organized neuronal network with more myelination can result in more efficient transmission o electrical signals in the existing brain tissue. Since this increased organization was seen in the orceps minor, which connects the rontal lobes, this could possibly translate to compensatory improvements in short-term memory, attention, and motivation. Te MRI scans were correlated with the intake data, and some interesting patterns emerged. While the cannabis-using group as a whole had higher FA and lower RD indicators in the DI scans, when the researchers looked at how long each individual participant had been a cannabis user, they ound that there were highly significant correlations between the DI scan indicators and lietime duration o cannabis use. Tis makes the causal, rather than just correlational explanation a bit more likely. Tere was an initial improvement in these scores (increased FA and decreased RD) over the first several years o cannabis use, ollowed by an overall decline in these indicators as usage became more long term. Te participants who had been using cannabis the longest had indications that their white matter was less organized and more demyelinated than participants who had only been using cannabis or a ew years. Additionally, the researchers ound that the unctional connectivity measured in the MRI scans showed strong correlations with a participant’s score on the MPS. Te less unctional connectivity seen on the MRI scan, particularly in the lef temporal cortex region o the brain, the more likely a participant was to have behavioral and social problems related to their cannabis use, as indicated by higher MPS scores. Within the exclusive cannabis use group, there was also a statistically significant correlation between gray matter volume in the OFC and scores on 75

There used to be misconceptions that the brain was a relatively unplastic organ afer adulthood, but more and more research is inding that both positive and negative changes can take place [...] the MPS: as the amount o gray matter in the brain

Since this study (and many others) only looks at a

decreased, the MPS scores increased.

single point in time using MRI scans, it’s not possible to determine which variable is the cause and

Te MRI also showed that activity in the OFC cor-

which is the effect. Te researchers who conducted

related with the age that the participant began using

this study noted that longitudinal studies would be

marijuana - the earlier the participant had become a

needed to ully understand this. However, since peo-

regular user, the greater unctional connectivity was

ple who had used marijuana or a longer period o

measured.

time had stronger associations with brain structure and unction, that does boost the likelihood o the

Participants who had only been using cannabis or several years showed higher indicators o axonal organization and brain tissue maturation, but these measurements declined as cannabis usage became more long-term.

causal explanation. Some mechanistic plausibility also exists, as both animal and human studies have ound potentially neurotoxic effects o marijuana. Whether the reductions in gray matter are a cause or effect o cannabis use, the brain is a complicated organ, and appears to attempt to compensate or

The big picture Te biggest challenge when interpreting this study is attempting to determine cause and effect out o all the correlations in the data. Are people who have higher IQs or more gray matter less likely to become a chronic marijuana user, or is the marijuana use causing that physical change? At least one study  has suggests that children who had smaller OFC volumes were more likely to become marijuana users in their teens.

reduced tissue volume by increasing the unctional connectivity o the present tissue. Tis may be why the new marijuana users had more organized white matter and higher resting activity on the MRI. Over time, however, these indicators declined as additional structural changes took place in response to cannabis use. Tis is really the most interesting, and perhaps slightly unexpected, part o the study. Tere used to

76

be misconceptions that

levels o HC might have

the brain was a relative-

greater long term effects

ly unplastic organ afer adulthood, but more and more research is finding that both positive and negative changes can take place due to a number o different external effects. Te initial effects o marijuana on the brain

[...] the balance o positive and negative impacts rom marijuana is hard to evaluate.

seem to be the brain’s way

on this region o the brain. Other constituents o marijuana have effects on the brain as well (although they are much less psychoactive or not at all), and strains vary in the ratio o HC to these other constituents.

o attempting to maintain regular unction in the ace o tissue loss. Te earlier a subject began using

How significant are the differences in IQ seen

marijuana, the more pronounced these initial com-

between the two groups?

pensatory effects were, since the brain still is more

Te five-point difference between the marijuana users

neuroplastic (building and wiring connections)

and non-users is within one standard deviation. Both

through adolescence and into the early 20s. Starting

groups actually scored ‘above average’ (106 and 111,

to use marijuana later in lie would not be as efficient

respectively). Tis is comparable to the difference

at taking advantage o this increased neuroplastic

seen between adults with some college education but

stage.

no degree, and adults with a college degree. Keep in mind though, the actual education levels were basi-

Te correlation between gray matter volume and

cally the same between the two groups.

scores on the MPS is unsurprising, given that the unction o gray matter is decision making and

Do randomized trials on marijuana show impacts

sel-control. A person with a lowered capacity to

on cognition?

make decisions and exercise sel-control is more likely

Tere have been a variety o cognition-related ran-

to have issues with social and psychological activities.

domized trials done on chronic marijuana users, with results typically showing some impairment.

Frequently asked questions Could different strains o marijuana have different effects on the brain?

It’s definitely possible. It’s not known i HC speciically is the cause o any structural and unctional changes in the brain, but the OFC is a region o the brain that has a high level o cannabinoid 1 receptors, which bind HC. Strains that have higher

For example, one trial ound that marijuana acutely decreased blood flow in attention-related areas o the brain. Prospective observational studies have also ound potential brain-related harm rom marijuana use. One ound that persistent marijuana use over the course o years was associated with increased cognitive problems and general decline in neuropsychological unctioning.

77

On the flip side, there has been an increasing amount o research on potential pain-related and other benefits o marijuana use, which involves other parts o the nervous system and brain. Systematic reviews o randomized trials have ound benefit or neuropathic pain, and potential or helping with other kinds o pain such as that rom fibromyalgia and rheumatoid arthritis. Given that ew i any randomized trials test chronic effects over a period o years, the balance o positive and negative impacts rom marijuana is hard to evaluate.

What should I know? Several different types o MRI scans ound differences between the brains o long-term marijuana users and non-users. Regular marijuana users had lower volumes o gray matter, but also had indicators o increased connectivity and unctional connectivity in several regions o the brain. People who had only used marijuana or several years had more connectivity in their brain’s white matter tracts, but these actors declined as use became more long term. Marijuana users also had slightly lower IQs, but it was not clear i this was due to marijuana use or other actors. Examine.com has compiled a wealth o scientific knowledge on the effects o cannabis “supplementation” on their Marijuana page. ◆

o discuss the impact o marijuana on brain unction, but without the generalities and annoyances that ofen come with debating such a topic on the web, visit the ERD private orum on Facebook.

78

A mouse’s microbiome may cause its brain to leak The gut microbiota influences blood-brain barrier permeability in mice Introduction Your gut has much more to do with your brain than just the influence it has when you’re passing by the donut shop. Since our guts take in all the uel we need rom the outside world, and our brains are necessary or navigating the outside world, the two need some way to communicate with each other. Tis method o communication between the gut and brain is called the “gut-brain axis.” In the 1970s, the molecular mechanism through which the gut and brain communicated was beginning to be understood. Several proteins and peptides (which are made out o the same building blocks 79

Figure 1: What is the blood-brain barrier?

as protein, but are smaller) were discovered, that

check out the details in Figure 1. Tere, you can see

were both produced by and affected the gut and

that the BBB keeps out large molecules, while being a

brain. But a problem arose: communication between

little more loose about certain types o smaller mole-

the brain and gut largely involved big molecules like

cules, while also selectively letting other molecules in.

proteins and peptides. How could such large molecules get across the blood-brain barrier (BBB)?

Te BBB is mainly made up o endothelial cells (the kind o cells that line the inside o blood vessels) that

In order to answer this question, we first need to

are tightly knit together by “tight junctions,” which

understand what the BBB is and what its unction

are composed o several types o proteins. Te pur-

is. Te BBB exists to make sure that compounds in

pose o tight junctions is to make sure substances

the blood don’t necessarily enter the brain, and that

don’t accidently slip in between cells. wo o the pro-

your brain keeps whatever nutrients it needs. You can

teins which make up tight junctions are claudin and 80

occludin, which are discussed later in the review.

help us) may play a role in this training. Te gut microbiome is known to contribute to other areas o

Since the BBB is made up o cells that are tightly-wo-

mammalian development, such as gut development

 ven together, it is very hard or larger molecules to

(including aspects o how it unctions as a barrier)

pass rom the bloodstream into the brain. I they do

and even other aspects o brain development. So it’s

get through, they do so either selectively through

not a ar leap to suspect that the gut microbiome

transporters or because the BBB is damaged, leaky, or

may influence the BBB as well. Te authors o this

otherwise compromised in some way.

paper set out to test exactly this hypothesis in mice.

Why does the BBB exist? Well, the brain is a pretty important organ, and so it’s wise to be selective about what gets into and out o the brain. For instance, i you get an inection, the BBB will hopeully stop the inection rom reaching the brain. But the BBB also plays a major role in the developing brain as well. One way it does so is by helping to

Gut bacteria have been observed to influence brain development, as well as influencing gut integrity. Tis inspired researchers to examine whether or not gut bacteria can also influence the integrity o the blood-brain barrier (BBB), which selectively allows molecules in and out o the brain.

regulate the environment o the growing brain to create an optimum environment or development. It also helps protect the growing brain rom toxic outside influences, such as bacteria colonizing the gut o newborns, during the so-called critical period o brain development. In summary, i your brain is a club, the BBB is like the bouncer: it does its best to stick to the list o approved molecules, and doesn’t hesitate to bar entry to the less desirable clubgoers. Like bouncers, the BBB also has to be trained. Te authors o this study hypothesized that gut microbiota (the bacteria that normally live in our gut and usually don’t cause any problems, and in act can

Who and what was studied? wo types o mice were looked at in this study: pathogen-ree and germ-ree. Pathogen-ree mice had normal gut microbiota and lacked any kind o bacteria that normally causes disease in mice. Germree mice, however, had no bacteria in the gut at all. Several questions were addressed in this study: • Does the gut microbiota o the mother affect the BBB o the developing mouse etus? Tis was addressed by comparing how well an anti-

[...] the brain is a pretty important organ, and so it’s wise to be selective about what gets into and out o the brain. 81

body could cross the BBB o etuses in mothers

normal gut flora). Tis difference in permeabili-

who were either pathogen- or germ-ree.

ty was observed toward the later part o gestation. Te increase in permeability was associated with

• Do gut microbiota affect the permeability o the BBB in adult mice? o address this ques-

decreased expression o occludin, one o the main proteins which make up tight junctions.

tion, both germ- and pathogen-ree mice were compared and the permeability o the BBB

How could microbes living in the mother’s gut affect

was tested.

the permeability o the etus’ BBB? Te authors did not determine a specific mechanism, but speculate

• What do the tight junctions o these mice look

that lower BBB permeability would be beneficial or

like? Te composition and appearance o tight

etuses whose mothers have normal gut flora. Te

 junctions were examined to see i there were di-

reason is that maternal gut microbes may require

erences between germ- and pathogen-ree mice.

higher nutritional demands in late pregnancy, which would require tighter BBB permeability so that these

• Can changing the microbiota change the permeability o the BBB? Germ-ree mice were

metabolic demands don’t impose a cost on the growing brain o the etus.

colonized by normal gut flora to become pathogen-ree mice. Te permeability o the BBB as

But what about in adult mice? Do the gut micro-

well as tight junctions were examined beore

biota affect the permeability o the BBB in them?

and afer colonization to see i changing the gut

Again, the answer is yes. Te permeability o the

microbiome could actually change the BBB.

BBB in adult mice was greater in germ-ree mice than in pathogen-ree mice in three separate tests

Tis study compared the permeability o the BBB in germ-ree mice (mice who had no gut bacteria at all) to pathogen-ree mice (who had normal gut bacteria, but none that normally cause disease in mice).

o BBB permeability. Te researchers made sure that this difference was not due to increased blood vessel penetration o the brain, since a higher density o blood vessels would mean there are is a higher chance that something would penetrate randomly,  just like how buying several lottery tickets increases your chance o winning.

What were the findings? Te researchers ound that the gut microbiota o the mother mouse can affect the BBB permeability o the developing mouse etus. Specifically, BBB permeability o etuses with germ-ree mothers (who had no significant levels o bacteria in their gut) was greater than the BBB permeability o mice whose mothers were merely pathogen-ree (and so had

Te differences in permeability could be accounted or by the differences in tight junctions ound in adult germ-ree versus just pathogen-ree mice. Te tight junctions o germ-ree mice had lower levels o two major tight junction proteins, occludin and claudin-5, as compared to pathogen-ree mice. Also, the more leaky tight junctions o germ-ree mice looked more diffuse and disorganized under 82

the microscope when compared to those o patho-

which produces acetate and propionate), and also by

gen-ree mice.

 just eeding an SCFA (butyrate) to germ-ree mice, and then measuring the effects on the BBB. Tey

Finally, would taking germ-ree mice with no gut

ound decreased BBB permeability in mice colo-

flora and colonizing them with normal flora change

nized by either kind o bacterium, as well as in mice

their leaky BBB? It turns out that, again, the answer

who were ed butyrate. In act, the BBB became just

is yes. Colonizing the gut o germ-ree mice led to a

as impermeable in these mice as in mice who were

less permeable BBB, along with increased expression

pathogen-ree.

o occludin and claudin-5. But how do the gut bacteria “talk” to the BBB and affect its permeability? One possible mechanism is  via short-chain atty acids (SCFAs) which are synthesized specifically by bacteria. SCFAs are known to affect the permeability o the gut, so perhaps they affect the permeability o the BBB too. Te researchers tested this hypothesis in two ways: by colonizing germ-ree mice with single strains o bacteria that produce SCFAs (Clostridium tyrobutyricum, which produces butyrate, and Bacteroides thetaiotaomicron,

Te researchers ound that the BBB was less leaky when mice had normal gut flora. Completely germ-ree mice had a more permeable BBB. Also, germ-ree mice subsequently colonized with normal flora experienced decreased BBB permeability. Interestingly, the BBB o mouse etuses was also leakier i their mother was germ-ree, than i she was just pathogen-ree. Te permeability o the BBB may be in part affected by short-chain atty acids produced by normal gut bacteria, which travel through the bloodstream and ultimately help make the BBB less permeable.

The permeability o the BBB in adult mice was greater in germ-ree mice than in pathogenree mice in three separate tests o BBB permeability.

What does the study really tell us? Tis study tells us that having healthy gut microbes in mice makes their BBB less permeable. Specifically, having normal gut flora in mother mice helps their etal mice develop a more impermeable BBB. Also, adult mice with normal flora have a less permeable BBB, which is associated with lower expression o certain tight junction proteins and more disorganized and diffuse-looking tight junctions. Finally, these effects o normal gut microbes on the BBB seem to be causal, since colonizing germ-ree mice with normal flora seems to decrease BBB per83

The science o our gut microbiota is still young, and we can say little or certain, but it’s starting to look like the microbes in our gut could play many roles in maintaining a healthy body. meability. Te mechanism or these changes are not known, but may have something to do with SCFA production o normal gut flora, as both monocolonizing germ-ree mice with SCFA-producing bacterial strains and just eeding germ-ree mice an SCFA decreases BBB permeability. Let’s also briefly mention what this study does not tell us. It does not tell us anything about humans taking probiotics. It does not say much about the consequences o BBB permeability and whether it’s “good” or “bad.” It also doesn’t spell out the mechanism through which gut microbiota influence the BBB’s permeability, although it does contribute evidence or a possible answer. Any inerences beyond the main point o this paper (that healthy gut microbes in mice makes their BBB less permeable compared to having no gut flora at all) would be unreliable guesswork.

The big picture Te science o our gut microbiota is still young, and we can say little or certain, but it’s starting to look like the microbes in our gut could play many roles in maintaining a healthy body. Te gut microbiota may affect cognition, and could possibly play a role in obesity . Te impact o probiotics on athletic perormance has also been examined. Fecal transplants to re-establish healthy gut flora are also starting to be tested as treatments or disease, as a recent study on ulcerative colitis in children demonstrates. Tis study adds one more piece to this puzzle by showing that gut microbiota play a role in creating a less leaky blood-brain barrier in mice, and perhaps more surprisingly, that the gut microbiome o a mother can, at least in mice, influence the BBB o the etus. Gut microbiota influence goes ar! However, the results o animal studies don’t nec-

Tis study tells us that germ-ree mice have more

essarily hold or humans. It is worth noting that

permeable BBBs than pathogen-ree mice. Any

independent research has been done on the micro-

additional extrapolation is speculation.

biome o prenatal and neonatal humans. For instance, the gut microbiome is markedly different in babies that were born via natural methods, as compared to babies born by c-section. Te gut 84

microbiome o c-section inants was much less diverse, or up to six months afer birth. Tis is the typical time period where the human diet begins to vary, naturally contributing to microbiome diversity. Te immune system goes through a lot o development during inancy, and research shows that microbe changes via birth method may influence the immune system in the long term. Tus, there is emerging evidence that the gut microbiome o inants can vary, and that this may have long-term effects. Tis work also demonstrates the importance o animal research. Animal studies can be quite important because work that is impractical, cost-prohibitive, or unethical on humans may not be deemed so or animals. For instance, this study could not have been done on humans. Te work that would go into maintaining a sterile or monocolonized human GI tract is neither practical or ethical.

Te science o how gut microbes affect health is still young. Tis study adds one more piece to the puzzle by suggesting the possibility that gut microbes can affect distant organs, like the brain, in unintuitive ways.

Frequently asked questions What about the brain itsel — does a sterile environment or an extended period o time impair neurogenesis?

Tis study did not reveal any differences in neurons themselves between germ- and pathogen-ree mice, and the long term effects o gut sterility on the brain itsel were not studied. However, there is emerging research that shows the gut may influence local neuronal development, so an impact on neurogenesis is at least theoretically possible. Also, one study  in mice ound that impaired neurogenesis due to stress could be

[...] gut microbiota play a role in creating a less leaky bloodbrain barrier in mice, and perhaps more surprisingly, that the gut microbiome o a mother can, at least in mice, inluence the BBB o the etus.

improved by administering a probiotic.

85

What else influences BBB permeability?

blood-brain barrier (BBB) than mice with complete-

While a lack o gut microbes is related to increased

ly sterile guts, containing no bacteria o any kind.

permeability, there are many other actors that can

Interestingly, the gut microbiome o pregnant mice

dictate BBB permeability. o list just a couple o

affected the BBB o their unborn etuses. Mice with

examples, increased ammonia content in the blood

healthy gut flora had etuses whose BBB was less

during liver ailure and high levels o c-reactive pro-

permeable than those who were germ-ree.

tein are associated with BBB permeability. Also, some rodent data shows downregulation in tight junction

Finally, colonizing a germ-ree mouse with a healthy

protein expression in mice that consume ethanol.

microbiome induces changes in their BBB, making it less permeable. One mechanism by which gut

What is a good way to keep my gut microbiome

microbiota may influence the BBB is through pro-

diverse?

ducing o short-chain atty acids, which enter the

Check out ERD # 2’s article “O Mice and Guts” or

bloodstream and eventually impact the BBB, making

more inormation on microbiome diversity.

it less permeable. ◆

What should I know?

What’s your gut instinct about all this? Let us

Tis journal article was published in Science

know your thoughts on the ERD private orum on

ranslational Medicine, a well-regarded interdisci-

Facebook.

plinary journal whose purpose is to help connect basic science research with eventual clinical applications. Te study results may not be directly applicable in terms o directing human interventions, but it connects two massively important areas — the microbiome and the gut-brain axis. Te blood-brain barrier can both be be damaged by disease and a cause o disease, and getting certain potentially important medications through the blood-brain barrier is an active area o research. From this study we’ve learned that the microbiome may impact the blood-brain barrier, and human studies on the topic are likely to ollow. In short, this is a research area that could pay dividends or human health in the near uture. Specifically, this article showed that mice with normal, healthy gut microbiomes had a less leaky

86

s

e esearc e Stuart M. Phillips, Ph.D., FACN, FACSM

Stuart graduated with a Ph.D. rom the University o Waterloo in Human Physiology in 1995. He joined McMaster in 1999 and is now a Proessor in the Department o Kinesiology and an Adjunct Proessor in the School o Medicine at McMaster University. Stuart is a ellow o the American College o Sports Medicine (ACSM) and the American College o Nutrition (ACN). His research is ocused on the impact o nutrition and exercise on human skeletal muscle protein turnover. As well he is keenly interested in diet and exercise-induced changes in body composition and the inluence o all o the aorementioned in aging persons. An enthusiastic and energetic group o graduate students and research ellows are the true heart o Dr. Phillips’ more than 180 publications, 120 public scientiic presentations, and continuing enthusiasm or science and research. You just published a review of protein for weight

applicability in humans – see this study  or a good

loss. Te somewhat new and mildly controversial

review and meta-regression o sorts. In short, I think

“protein leverage” hypothesis is mentioned. What’s

the whole protein-seeking behaviour espoused by

 your take on that?

these two researchers and their teams is viable, but it seems that most people’s ‘natural setpoint’ or pro-

Te Simpson and Raubenheimer leverage hypothe-

tein intake is around 15-17% o total energy intake

sis is an interesting one, and one that may have some

… you have to consciously move toward higher 87

intakes and it does appear that leverages energy

I don’t think I’d have done another macronutrient

rom other macronutrients – at and carbs – and can

– at or carbohydrate – because that has so much to

control energy intake.

do with obesity and diabetes, which, or whatever reason, didn’t interest me. With protein, there’s less

Tat was a pretty complex topic or an opening ques-

people who study it and we’re a smaller group. I’m

tion. aking a step back — what originally brought

happy to have chosen protein, it still intrigues me

 you into protein research? 

and I think it’s been a good career ‘decision’ (I’ll pre-

Ha ha, yup deep end question to begin! I did an

tend I chose to study protein … I think it chose me).

undergraduate degree at McMaster in Biochemistry

But change anything? No, not likely … I am ocused

and had an epiphany o sorts when I took a nutri-

more now on some paradigm-changing work, which

tional biochemistry course in my ourth year. It

I always think is important. I’ve still got a ew more

changed the way I thought about things! I signed

years lef and my ocus will likely gradually change

up or a master’s and studied protein and endur-

in the next ew years.

ance athletes - my first paper - rom then on I was

When you ind something you’re passionate about and enjoy what you’re doing, it’s rarer to actually call it ‘work’. hooked! I loved learning, I loved school, I loved

 Although you’ve been extremely successul in

nutrition, and I liked (yes only liked) research … it

research, the struggle o climbing the ivory tower is

wasn’t until the last stages o my Ph.D. that I truly

tough. What’s your view o the “publish or perish”

grew to love research. It just evolved rom there.

environment o academia? 

Tere are many types o ‘ivory towers’, just as there My passion or protein was honed while I was a

are many types o occupations that people with a

postdoc in Bob Wole’s lab rom 1995 to 1998. I

Ph.D. pursue. In act, most people (i.e., more than

learned so much there and had a ton o un at the

80%) with a Ph.D. don’t go into academia. Within

same time! When you find something you’re pas-

academia there are ivory towers that value teaching

sionate about and enjoy what you’re doing, it’s rarer

more than research, but at McMaster the climb is

to actually call it ‘work’. So I ‘work’ at what I love

based on research first, and teaching second. So it

doing and so ar it’s been a lot o un!

does orce a publish or don’t do well atmosphere, though you can still publish and perish in my view!

I you could go back in time, is there something else

With that pressure it does create a stress, since so

 you might have ocused on?

much o your work is evaluated by nameless and 88

aceless people who figuratively ‘hold the cards’ and

commodities, which some automatically assume

can turn you one way or another. It has also lead

means you’re an industry shill and have no morals

to olks doing some pretty weird things, and even

and are bound to speak the industry/commodity

twisting or making up data, which really casts a

‘party line’. It’s hard to live within that shadow, but

shadow on everyone in science.

we’ve managed to blend basic science with, I think,

But, like most jobs, perseverance and patience tend to win out. Having good mentorship meant I learned early how to write and craf decent grants, which really helped early in my career. I think (hope) I’ve passed some o that on to others who have trained with me! Te trainees rom my lab are now installed in a ew institutions around the world and I hope they taken the good (and not so much o the bad, ha ha) with them. Has the publish or perish atmosphere had impacts on your lie and how you do research? 

Sure, early in my career I was very absorbed in my work and was not, at times, the best partner to my wie and even perhaps the best ather to my kids (I’ve been trying to make amends beore my oldest boy – now 15 – begins to see me as nobody other than the jerk who holds the car keys!!). It pays to have an understanding and supportive spouse. I do, however, think it’s true that those that tend to rise in academia have to spend a disproportionate amount o time in their work environment to succeed. I doubt whether that’s untrue in other proessions,

[...] we’ve managed to blend basic science with, I think, good science rom industry money too. I don’t eel like I’ve sold my soul and I sleep well at nights.

however, and like most things that are a passion it never really eels like work. I do have the greatest wie on the planet, however, who I might mention

good science rom industry money too. I don’t eel

is also an academic in exercise physiology, but defi-

like I’ve sold my soul and I sleep well at night. I’ve

nitely keeps our lives and the household show on the

been asked by some people why I just don’t do more

road!

basic work and get more government money.

From a research perspective, the pressure to publish

Honestly, it’s not like I haven’t tried, but unding is

has also meant doing research with industry and

tight, very tight, in Canada and everywhere. And 89

[...] so much o your work is evaluated by nameless and aceless people who iguratively ‘hold the cards’ and can turn you one way or another. It has also lead to olks doing some pretty weird things, and even twisting or making up data while we’ve done well, relatively speaking (I’d rate

inated (the nitrogen is taken off and transerred to

my grant success rate at just above 20%), the sums

another compound) and urea gets made.

o money and budget restrictions are a big hurdle or Canadian researchers to be ‘competitive’ inter-

So when people recommend two grams o protein

nationally. Still, blessings counted, fingers crossed,

per pound (i.e., 4.4 grams per kilogram) they lack

we’ve done and continue to do better than average.

a basic understanding o how and or why higher

O course all o this is due to the students, who are

protein might even possibly be used by the body

the true lieblood o our success as a group.

at that kind o level! Now, people can twist studies and show whole body protein turnover measures

Some lifers and athletes go well beyond recom-

that ‘support’ this estimate, but that’s not muscle!

mended protein intakes, and approach two grams

It’s time or a serious reality check or anybody who

 per pound o bodyweight a day. Would you expect

spouts those numbers or recommends huge doses o

nitrogenous waste rom this approach to have side

supplements like BCAAs (which have next to zero

effects over time? 

evidence or their effectiveness or building muscle,

I think the point everybody has orgotten, or

but that’s another story …).

perhaps were never taught, is that nitrogen (the essential nuclide o amino acids) is metabolically

Back to the question, does this kind o intake cause

toxic in mammals. In act, most species have evolved

‘harm’? Te biggest bugaboos or the higher pro-

a mechanism to get rid o nitrogen – ammonia in

tein diet are clearly bone loss and kidney disease.

fish, uric acid in birds – because there’s no place to

Te ‘teaching’ on both, old school teaching, is that

store ‘extra’ amino acids. Amino acids are used or

higher protein lowers blood pH, which causes bone

protein-requiring processes or they are not. You

resorption. Calcium is ‘leached’ rom your bones.

can’t ‘store’ them, you can’t magically make them

Tis results in your bones getting brittle as you

into something to be used later, so they are deam-

progress toward osteopenia and osteoporosis. Tis 90

I loved learning, I loved school, I loved nutrition, and I liked (yes only liked) research…it wasn’t until the last stages o my Ph.D. that I truly grew to love research. theory is known as the acid ash hypothesis – acid

the book’ on some o the claptrap that some olks

rom protein in blood and ‘ash’, or calcium rom

spout about higher protein and bone. Renal disease

your bones. Te take home on this theory can be

is a little more granular and harder to nail down,

neatly summarized in a series o nice meta-anal-

but I think I’ll go with the quotes rom the WHO

yses – thus an evidence-based answer: “Evidence

report on Protein and Amino Acid Requirements in

suggests a linear association between changes in cal-

Human Nutrition that states, “…the suggestion that

cium excretion in response to experimental changes

the decline o glomerular filtration rate that occurs

in net acid excretion. However, this finding is not

with advancing age in healthy subjects can be atten-

evidence that the source o the excreted calcium is

uated by reducing the protein in the diet appears to

bone or that this calciuria contributes to the devel-

have no oundation.”

opment o osteoporosis.” In addition, in the most recent revision o the DRI Furthermore, “Tere is no evidence rom superior

by the Institute o Medicine that section on protein

quality balance studies that increasing the diet acid

requirements also states that there is no relationship

load promotes skeletal bone mineral loss or osteo-

between increasing protein intakes and decline in

porosis … Promotion o the ‘alkaline diet’ to prevent

renal unction in people with normal renal unction.

calcium loss is not justified.” And finally , “All o the

Now, i you have a diseased kidney, then it’s perhaps

findings rom this meta-analysis were contrary to

not a good idea to be eating lots o protein, there

the acid ash hypothesis … Tis meta-analysis did

is pretty clear evidence that a low(er) protein diet

not find evidence that phosphate intake contrib-

(exact level not known) does extend liespan. My

utes to demineralization o bone or to bone calcium

take: it’s hard to find evidence that intakes higher

excretion in the urine.

than 1.6-1.8 grams o protein per kilogram o bodyweight are able to substantially augment gains in

Dietary advice that dairy products, meats, and

muscle mass, as reviewed here, here, here, and here.

grains are detrimental to bone health due to “acidic” phosphate content needs reassessment. Tere is no

We need to get you back on here sometime Stu.

evidence that higher phosphate intakes are detri-

 Always something new to learn. Tanks so much or

mental to bone health.” I think those analyses ‘close

taking time to talk with us!  ◆

91

INTERVIEW: Ramsey Nijem

First, I would like to thank the Examine.com team

sulted or this interview as he oversees everything,

or the interview. I am honored and will do my best

including nutrition or our team, and has seen it all

to not bore the highly educated audience.

in his over 20 year NBA career. As an aside, Chip is one o only a handul o people that can claim

Second, I would like to thank the other members

to have worked with both Michael Jordan and

o our sport science staff who seamlessly combine

Kobe Bryant or all o their championship rings (11

over 60 years o experience in the NBA with an evi-

combined).

dence-based approach. My role is split, and shared with Chip, between Lastly, I am obliged to say that the responses

traditional strength and conditioning responsibil-

below are on my behal and do not represent the

ities and sport science. We continually collect data

Sacramento Kings or the NBA.

and use the objective numbers to influence our treatment and training decisions. Everything rom

What do you do or the Sacramento Kings? How did

movement screening and joint range o motions to

 you get into strength and conditioning, and when

power characteristics and on-court player loads are

did sports nutrition come into the picture? 

collected regularly. We don’t claim to be the first to

I am the assistant strength and conditioning coach

do this, nor do we pretend to have all the answers,

or the Sacramento Kings. We do not have a “head”

rather we pride ourselves on our interdisciplinary

strength and conditioning coach. Our Director o

approach, as our ultimate goal as a sport science

Sport Science, Robert “Chip” Schaeer, was con-

staff is to keep our guys healthy. 92

My desire to become an NBA strength and condi-

in their nutrition and are able to stay healthy and

tioning coach came the day I realized I wasn’t going

perorm well, it’s my opinion that they are not opti-

to make it as a player. I figured i I couldn’t play in

mizing their potential to train, recover, and perorm

the NBA, then I’d do everything I could to train the

every night. I have observed that it ofen takes

guys that do. So I went on to earn a Master’s degree

something to trigger a player to proactively change

in sport perormance and I am now working toward

his eating. Whether it’s a slump in perormance, a

my Doctorate degree in human and sport peror-

cold, an injury, the grind o the season, or relative

mance. Sports nutrition is obviously relevant when

old age, most these guys need an experience to wake

studying and applying sports science to maximize

them up a bit. Perhaps that’s just human nature.

an athlete’s potential. Te NBA season is looooooooong. How do players

When considering the demands placed on a

cope with the grind o training, competition, stress,

high-level athlete’s

and injury?

body, one is remiss

Looong indeed.

i nutrition is not considered every bit as important as training and recovery. Indeed, what an athlete puts into their body will influence their

[...] i I couldn’t play in the NBA, then I’d do everything I could to train the guys that do.

ability to perorm

Tis is the essence o what we are trying to figure out with all o our data. How are guys adapting to the stress that the NBA season brings and how can we help them combat

over the course o the season. In a world where even

the stress that undoubtedly wears them down? Te

the slightest advantage counts, nutrition and sup-

short answer is they keep up with treatment, train-

plementation offer an opportunity to train harder,

ing, and get as much rest as they can. But how we

recover quicker, and ultimately perorm better than

go about managing loads on the court and in the

the competition.

weight room is the complexity that brings us sport science nerds to the drawing board. As a sport sci-

Do you find any correlation between what a given

ence staff we are able to watch the loads accumulate

 player eats and how well he perorms? 

over time and see how their body is reacting. We

Guys who eat a nutrient dense diet, especially diets

can use that data, in an ideal world, to structure

high in vegetable consumption, seem to resist the

training and treatment to allow or recovery, yet

 viral inections that invariably run through teams

provide enough o a stimulus to keep them strong,

each year. Tese types o inections can affect a

explosive, and injury ree. I say ‘ideal world’ because

player or weeks, so avoiding them can have a tre-

the most influential stressor to the NBA player is the

mendous impact. Although I am not naïve to the

 volume o games, and that is unchangeable. An NBA

act that some players may not take much stock

team can have our games in five nights, and in an 93

[...] i I could orce these guys to take my advice, then they would take the principles we have set in place and ully commit to them year-round. That’s not to say they don’t do a good job already, but there is always room or improvement. average month a team will play 15 games. It’s a war

 vide any ried oods or sodas and some may prohibit

o attrition.

“junk ood” on the plane, while other teams have a more hands-off approach and allow the players to

Te Western Conerence has eight teams that could

make their own decisions.

 potentially compete or the championship. Crazy! Oh yeah, this is supposed to be about nutrition ...

I’m not here to say what the best training and nutri-

what are some interesting things about how other

tion practices are, but I’m confident enough to

teams eat and train? Does it differ much rom team

know a ew things to be true. A training approach

to team?

that emphasizes the SAID and progressive overload

Te nature o the game day schedule doesn’t allow

principles while appreciating the value o injury

or time to sit down and talk shop at a philosophical

risk reduction and movement quality is going to

level, and most interactions are mid-court banter

provide a great return on investment. In a similar

during pre-game warm-up. Tus it is hard to com-

even-keeled ashion, a nutritional approach that

ment on the degree o difference between teams,

emphasizes lean protein options, ruits and veg-

although I’m sure training and nutrition practic-

gies, and complex carbohydrates will provide a

es can vary greatly. I’ve seen videos o ellow NBA

great nutrient return on caloric investment. Tese

strength coaches having players hex-bar rack pull

approaches don’t sell DVDs and t-shirts, but they

over 400 pounds rom a mid-shin height (quite

produce avorable results and are consistent with the

impressive when considering limb lengths and

evidence-base.

the amount o work being done), while I’ve heard stories o other coaches preerring to have players

It’s hard to tell until you stand next to them, but

perorm banded glute and core work all session long.

 NBA players can be quite massive. How much does

On the nutrition side, I know some teams don’t pro-

a big orward or center, like DeMarcus Cousins, eat? 94

I’d imagine they need quite a bit o uel to run up

I you could orce players to take your advice on

and down the court, plus practice and gym work.

strength, conditioning, and nutrition, what are some

I couldn’t tell you exactly how much our guys are

important gems that they should keep in mind? 

eating, but suffice to say it is a lot. A typical NBA

I I could orce these guys to take my advice on

big is likely burning between 4,000 and 5,000 calo-

strength, conditioning, and nutrition, it would be to

ries (numbers approximated using Harris Benedict

 view these things as ways to optimize their potential.

ormula or DeMarcus Cousins). oss in an over-

When a guy is making millions playing basketball,

time or two or a big minute guy and you can

it is hard to get them to see the value in some o

imagine that number can climb pretty high. We

these things. Tey figure, “Hey, I made it here doing

take weights and skinolds regularly (two to three

what I’m doing, so why do I need to change?” Tis

times per month, depending on our schedule) and

attitude is short-sighted, in my opinion. I they can

most guys are able

begin to appreciate

to remain calorically

the value o training

neutral (neither surplus or deficit) over time on their own, with little weight changes between measurements. Tis liestyle offers no shortage o calories or the guys to uel up on. In addition to catered meals at

An NBA team can have our games in ive nights, and in an average month a team will play 15 games. It’s a war o attrition.

the practice acility,

(strength and conditioning), recovery, and how nutrition is involved in all o it, they may see the potential to play at a higher level or longer. Undoubtedly a stronger, better-conditioned, better-recovered athlete is a better-perorming athlete. Not

hotels, plane rides, and arenas, we carry around a

to mention, all o these things can prolong careers

nutrition trunk stocked with snack options or the

(which o course means more money or them). I

guys. Not eating can be more o an issue with our

I could change their perspective on this stuff, my

schedule. When you get into a city at 2:00 a.m. and

 job would be much easier. ime ofen changes their

have shoot-around at 10:00 a.m., guys will sacrifice

perspective, as our veterans are willing to dedicate

breakast or an extra 30 minutes o sleep. Although

more time to these things. But i young guys bought

they are encouraged to make the right choices, like

in sooner, the results would speak or themselves.

calling or room service beore going to practice on an empty stomach, they do not always listen. In

When it comes to eating, I would orce players to

these instances, we’ll provide them with something

take a more conscious approach to their nutrition

rom the trunk.

habits. Tings like increasing lean protein consumption and limiting sugar consumption (should not 95

be read as an anti-sugar suggestion) to make room or more nutrient-dense options like vegetables, whole grains, and healthy ats. As ar as training goes, I would orce players to dedicate off-season time to the weight room. Te NBA schedule makes it nearly impossible to make any meaningul training adaptations during season, which makes the off-season an important time or improving strength and power, adding muscle, and improve movement quality and groove movement patterns to reduce injury risk. o summarize, i I could orce these guys to take my advice, then they would take the principles we have set in place and ully commit to them year-round. Tat’s not to say they don’t do a good job already, but there is always room or improvement.  Are supplements common in the NBA? I so, which ones? 

Supplements are absolutely common in the NBA. Although, similar to nutrition practices, supplementation varies rom team to team. Te most common supplements are whey protein, creatine, a multi vitamin, fish oil, and vitamin D. Other common supplements are high glycemic energy chews or gels and caffeine. For guys with sleep issues, we provide ZMA, and or chronic pain problems we provide glu-

[...] the dedication that they have is a habit that could be adapted by anyone in any line o work and would be beneicial.

cosamine chondroitin. Although we acknowledge some supplements are largely anecdotally supported (e.g. ZMA), while others may be limited to specific conditions (e.g. glucosamine and osteoarthritis), the  value o anecdotal evidence and placebo effect cannot be discounted at this level. I a glucosamine chondroitin supplement rids a guy o knee pain even one game sooner than i he had not taken it, then its use is justified in my opinion. A potential or benefit with little to no risk is a win or us.

96

In a world where even the slightest advantage counts, nutrition and supplementation offer an opportunity to train harder, recover quicker, and ultimately perorm better than the competition. Being surrounded by world-class athletes, have you

Tank you to the Examine.com team or their

noticed any particular habits that readers might

high quality work. Your website and products are

want to know about? Even though Charles Barkley

influential in my nutrition and supplementation

says he’s not a role model, I know that many people

approaches and I can’t thank you enough or doing

look up to proessional athletes.

my homework.

Te amount o time these guys put in should be applauded. Most guys are at practice early or treat-

Tanks so much or taking some time out or us

ment, weight room work, and shooting, yet stay afer

Ramsey! Tis is really, really cool inside inormation

or the same things. Surely they get compensated

to learn. Sacramento is an intriguing team in an

well or what they do, but the dedication that they

extremely tough conerence, so it’s good they have a

have is a habit that could be adapted by anyone in

smart nutrition and conditioning team supporting

any line o work and would be beneficial. With that

them. We look orward to watching the rest o the

said, they also have habits that should be avoided.

season, and best o luck to you.

Not prioritizing their nutrition, strength, and conditioning can have a huge impact on their health and longevity. Te offseason is not only a time or them to refine their game, but an opportunity to become a better, less injury prone athlete. Most guys are only ocused on playing and not the off court work. Tis is unortunate and can backfire, as the NBA is only becoming more and more athletic.

Ramsey Nijem is the Assistant Strength and Conditioning Coach or the Sacramento Kings. He has an M.S. in Kinesiology and is currently in a doctorate program.

97

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