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 inormation inormation 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 reers 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 transer
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 transer protein (CEP).
polymorphisms may still influence susceptibility to
CEP promotes transer o HDL cholesterol into
disease.
VLDL, and in exchange HDL receives triglycerides. trig lycerides. CEP is hence thought to reduce HDL cholesterol, cholesterol,
Tis study looked at how two polymorphisms in
so less CEP in your blood means HDL particles
the CEP 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 CEP 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-inlammatory or inlammatory, depending on the disease state o the body.
alleles (gene variants) o CEP are called B1 and B2. B2 is associated with decreased CEP 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 unortunately 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,, perorming 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 CEP aqIB, alcohol intake, and CHD was
disease.
observed.
Back to CEP. Tere is a known polymorphism in
Why is that? One reason could be simply different
the gene that encodes CEP called CEP aqIB. A
populations. populations. As seen in Figure 1, different pop-
polymorphism is when a particular gene has two
ulations can have substantially different CEP
or more relatively common possible nucleotide
genotype requencies. Rodents such as mice have no 6
Figure 1: CETP B2B2 allele frequency in different populations
CEP 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 CEP 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 CEP on heart disease is
o the INERGENE 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
CEP 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 inarc-
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 inarction, 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 CEP genotype, as well as sel-reported inormation 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 inormation reerred 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 CEP 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 reerence. 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 CEP 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 conounders, 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 conounding 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 CEP, a gene that appears to be only
tioned, this was not the case. Tus, the protective
involved in transer 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 CEP in intermediate and high
or other liestyle 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 reerenced beore,
possible that there were other important conound-
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 CEP 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 perormed with different alcohol intake cutoffs and different conounders. 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 conounders 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 CEP 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 Proessional Follow-Up Study, suggest a
diluted by the lack o CHD odds reduction in people
protective effect o the B2 allele. Te reerence 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 inarction risk, and the risk
ulations differ, it’s hard to directly compare different
reduction was the strongest when the participants
CEP 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 reerence group can also differ between studies.
o intake. Furthermore, CHD cases could also have
In this study, the reerence 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 CEP 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 beore 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, CEP = bad” is a simplistic
sible that intermediate alcohol users could also have
and inaccurate way o thinking, it is surprisingly
generally healthier eating and liestyle habits that
pervasive. CEP 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 CEP’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.
CEP’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 reerence 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
CEP 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 CEP 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 RCs,
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 conounders, 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 CEP 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 CEP 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 CEP 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, CEP 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 modiy my CEP activity and prevent heart disease?
Because increased CEP 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 CEP 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 CEP 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 CEP genotype. Some people are able to get a portion o their genomes sequences through services such as 23andme, and that may help inorm 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 powerul 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 liestyle similar to our (nonroyal) distant ancestors, yet more than a third o modern Americans are projected to develop diabetes at some point in lie. 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 liestyle similar to our (non-royal) distant ancestors, yet more than a third o modern Americans are projected to develop diabetes at some point in lie. 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 beore 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 proound 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 liestyle-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 liestyle-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 powerul 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 beore 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 lietime 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 overeeding
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, reerring 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 liestyle 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 overeeding on reined 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 (beore 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 dysunction. 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 aniotal, 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” reers 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 quantiy 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, prolier-
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-lie 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 conounded 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. Unortunately 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 relect 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 aorementioned 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 (GLU4; 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, inusion o palmitoleic acid twice daily or 28 days preserved insulin sensitivity beore 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 uniorm – 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, liestyle, 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 proessionals 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 inections 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 inormation they are receiving (airly) accurately, and instead it is the inormation 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 inormation 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 dierences 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 inections 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 inerence 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 careul 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 inerences 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 beore 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 careully 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 beore 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 inormation on correlations, causality cannot be directly inerred. However, there are several lines o reasoning to suggest that press releases are indeed a major reerence 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, careully-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 careul 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 inormation, such as press
The big picture
releases and inormation 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 hopeul
scientists,, both non-scientist scientists non-scientist writers at universities
message: a relatively relatively small handul 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 inormation, such as press releases and inormation rom news agencies. 40
versities can help create create better health inormation inormation
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 dierences 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 successul 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 inormation, 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 inormation 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 imperect. 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 spooneed 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 breakast 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 FASED. 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 FASED 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 beore. Te protein was rom whey and
and waist circumerence, 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 FASED
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 surace this may
younger (21 vs 23.8). Te average baseline BMI was
suggest a small advantage or the FASED 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 FASED 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 FASED 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 inants). 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-speciic 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 beore 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 lie.
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 perormed 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 breakast
We cannot necessarily extrapolate these results to
beore 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 beore 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 conounding 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 perormed 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 beore
impact at loss.
these results can be applied to other populations. Are there other reasons to perorm 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 careul
in healthy males ed a at-rich hypercaloric diet,
programming in the routine to ensure adequate
whereas the same exercise protocol perormed afer
recovery and isn’t typically done on a daily basis. In
consuming breakast showed weight gain with no
Aside rom actual health beneits, some people don’t enjoy exercise with ood in their stomach, and others have more energy in the morning when asted training is commonly perormed. 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 perormed.
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-lie 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 perormance. 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 inormation 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 inormation? 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 useul. 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 perormed 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 inormation 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-transerases, which detoxiy 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
• GSM1 and GS1: 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 modiy a person’s behavior unless that person gets very ew emails and has lots o ree time. However, it does mirror the real-lie 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 reer
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 stressul 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 meaningul 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 clariy the real-lie 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 liestyle 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 inorming 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 liestyle-associated risk actors, the results o a genetic test may be more useul.
ashion.”
The Big Picture Te findings o this study are generally in line with other studies and reviews that have ound inorming 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
inormation can best be used or behavioral modification. It’s not necessarily clear how to best deliver genetic inormation to people, and this is a major conounder or any study at the moment. It could be that genetic inormation 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 lie’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 meaningul 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 inormation that has accu-
sis, so the field needs to grow substantially beore
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
inormation, 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 useul by inorming 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 MHFR 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 useul or general liestyle recommendations?
Genetic testing may help guide liestyle 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 useul. It seems obvious that adjusting your liestyle 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 liestyle
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 beneit 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 proound
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-lie 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 meaningul 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 proessional
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 harmul 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 inormation rath-
research a given topic beore 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 inormation, 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. Inormation can change everything, and even
compound studied. For example, based on the inor-
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 beore “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 inormational role at this point, rather that to spur direct and specific action (outside o a generally progut health liestyle). 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 belies 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 beneits 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. Reer 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 (52A).
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, FA, 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, FA, FA eeding groups on a high at diet and NAA, N, NA, 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 highat 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 perormed 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 transerred 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 dysunction, 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 inormation 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 beore 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 breakast 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 maniested 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?
modiy 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 beore 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 breakast?
No! A growing body o research suggests a high-protein breakast 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 dysunction, 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 lie 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 orbitorontal network. Tis network is made up or our lobes: the lef and right orbitorontal 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 conlicting results.
the participant characteristics, or in the level o marijuana use. Other potential conounding 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 identiy 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 quantiy the
Marijuana affects a variety o brain regions,
amount o gray matter in the participant’s brain
including a region called the orbitorontal 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 (DI) 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 orbitorontal and lef superior orbitorontal 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 DI 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 DI
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 DI scan is radial diffusiv-
o the brain, providing inormation 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 DI 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 DI 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 DI scan indicators and lietime 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 lie 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 speciically 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.
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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 inection, the BBB will hopeully stop the inection 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. Germree 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 beore
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 pathogenree 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 inerences 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 perormance 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 inants 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 inancy, 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 inants 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, inluence 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 inormation 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 Proessor in the Department o Kinesiology and an Adjunct Proessor 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 inluence o all o the aorementioned 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 scientiic 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 successul 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 Wole’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 lie 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 wie and even perhaps the best ather to my kids (I’ve been trying to make amends beore 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 proessions,
[...] 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 wie 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 transerred 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 lieblood 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 liespan. 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 handul 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” Schaeer, 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
perorm 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 perorm
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 perormance and I am now working toward
his eating. Whether it’s a slump in perormance, a
my Doctorate degree in human and sport peror-
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 perorm
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 perorm 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 perorms?
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 inections that invariably run through teams
provide enough o a stimulus to keep them strong,
each year. Tese types o inections 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 Conerence 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 preerring to have players
It’s hard to tell until you stand next to them, but
perorm 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 skinolds 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 liestyle 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-perorming 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
breakast 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 beore 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 meaningul 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 beneicial.
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 perorm 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 proessional 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 inormation
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 conerence, 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 unortunate 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.
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