Issue #75 January 2021

Table of Contents
Safety Spotlight: Women and creatine
The effects of creatine are quite well studied, but its sex-specific safety profile hasn't been.
Besides some non-serious side effects, creatine seems safe for women, but more work
needs to understand creatine's effects during pregnancy.

The effects of increased protein intake on overall energy intake in older adults
Boosting protein intake may help stave off the loss of muscle strength and function that can
come with age. But does increasing protein affect energy intake in older adults as well? We
cover a recent meta-analysis that explored this question.

Sugar Wars, Episode 6: The Return of the Fructose

How does fructose affect cardiometabolic risk markers calorie-for-calorie compared to
glucose or sucrose? This recent meta-analysis aimed to find out.

Deep Dive: Supplementing for senior strength and size in the context of sarcopenia
This systematic review and meta-analysis explored what supplements can stave off the loss
of muscle function that comes with aging. However, the way it categorized the studies it
used, along with the overall low quality of those studies, makes its conclusions seem a bit...
weak.

Interview: Cyriac Abby Philips, MBBS, MD, DM (Hepatology)

In this interview, we pick Dr. Philips' brain about the basics of Ayurveda, its safety, and the
story behind a recently retracted paper he was involved with detailing a case of acute liver
failure and death in a patient who was taking supplements.

Deep Dive: Comparing the efficacy of diet, exercise, and lifestyle modifications for
controlling childhood obesity
This meta-analysis looked at what lifestyle interventions work best for children with
overweight and obesity, and how much of a role parental involvement played.

Deep Dive: Do Low-Carb Diets Stoke the Metabolic Fire?

This meta-analysis concluded that longer-term low-carb dieters feel the metabolic burn, but
some methodological concerns may douse this flame a bit.

Deep Dive: Evaluating the relationship between training status and optimal protein intake
According to this recent meta-analysis, whether or not more protein is better for lean body
mass may come down to resistance training status.

2
 From the Editor
This first NERD of the new year covers health interventions that span age groups, from lifestyle
interventions for childhood obesity to protein’s effects on energy intake and muscle mass in older
people. Instead of summarizing the gamut of what we cover in this issue, I’d like to answer a
question that may pop into careful readers’ heads when reading the two articles covering protein in
older people, since there’s a hidden contradiction there that I think can be resolved.

Toward the end of our coverage of protein’s effects on energy intake, we cite three trials that
suggest increased protein intake can improve muscle mass and function in older adults. However,
we also cover a meta-analysis that tackles the specific question of how supplementation affects
muscle mass in older adults, which found that protein alone didn’t have a clear effect. Thus, we
have two competing claims in the very same issue of NERD: increasing protein both improves and
doesn’t improve muscle mass in older adults!

While these claims are contradictory on the surface, I think this can be resolved by looking at
baseline protein intakes. The people in the three studies that found a muscle-preserving effect had
average baseline protein intakes below the recommended minimum of one gram per kilogram of
bodyweight for older adults. Since they were taking in less protein than they needed, boosting
protein by 0.4–0.6 grams per kilogram of bodyweight helped improve muscle mass and function.
However, the baseline protein intake for people in the meta-analysis was above the recommended
level. Since they were already getting the protein they needed, increasing the amount didn’t help.

While I suspect that the baseline protein intake explains much of the apparent contradiction, there
are other possible explanations. A quick peek at the confidence intervals in Figure 2 from the
muscle mass meta-analysis tells me that the data are consistent with protein supplementation
leading muscle mass, so perhaps there isn’t as much of a contradiction as it initially appears. Also,
there are a few reasons to suspect that the results of the muscle mass meta-analysis may not be
reliable. Read on to find out why.

Gregory Lopez, MA, PharmD

Editor-in-chief, Nutrition Examination Research Digest

3
Safety Spotlight: Women and creatine
 Tags: Womens Health, Creatine, Safety, Meta-analysis, Supplementation

 Read this article online at Examine.com

Creatine, most often consumed in the form of creatine monohydrate, is a popular dietary
supplement used to improve strength and potentially as a therapy for certain neurodegenerative
diseases[1] and musculoskeletal disorders[2]. Creatine is a very heavily studied supplement: over
600 studies have been conducted in which creatine is the primary intervention, and over 80
reviews have reported on its performance-enhancing and therapeutic effects. That said, only 34 of
these publications reported safety data, and of these safety studies, only two were systematic
reviews. So, while creatine’s effects have been studied in depth, its safety data lags behind.
Furthermore, the research on creatine safety in women specifically has never been reviewed.
Given that as many as 65% of female athletes use ergogenic aids such as creatine, and that
women are at higher risk of having many neurodegenerative[3] and musculoskeletal[4] diseases for
which creatine may be therapeutic, understanding the sex-specific risk profile of creatine is
important.

Fortunately, just such a study has been published recently. The study[5] is a preregistered,
PRISMA-compliant systematic review and meta-analysis of 29 randomized controlled trials that
investigated the effects of creatine monohydrate supplementation in women. Sample sizes ranged
from 5 to 149 for a total of 951 participants, 18 of the studies investigated creatine’s ergogenic
effects, and 11 used creatine as a therapy for disease. Seven of the studies were conducted in
post-menopausal women, while the remaining 22 were conducted in pre-menopausal women.
None of the studies involved pregnant women. Creatine doses ranged from 1–30 grams per day for
4–365 days. The primary outcomes were deaths, serious adverse events such as disability and
hospitalization, and adverse events such as GI distress and weight gain. The secondary outcomes
were factors that could affect adverse outcome reporting, such as study design, methodology, and
dosing regimens. The researchers also assessed the heterogeneity and risk of bias of the studies.

Of the 29 studies, 18 were included in the meta-analysis, which were stratified by dosing regimen
(“maintenance”, “loading”, or “combined”). The risk of bias in the “maintenance” and “combined”
regimens was mostly low, and the risk of bias in the “loading” regimen studies were mostly unclear.
Of these 18, 10 reported no side effects or adverse events whatsoever, and a forest plot analysis
supported that there was no significant relationship between creatine supplementation and adverse
events when stratified by dosing regimen. Although gastrointestinal effects were the most
commonly reported side effect, and was even the reported reason for treatment cessation in four

4
studies, there was no statistically significant difference between creatine and placebo with regard
to gastrointestinal side effects. Furthermore, no statistically significant differences in blood urea
nitrogen (BUN), plasma urea levels, estimated glomerular filtration rate, or creatinine clearance
rates were found, and although creatinine was significantly elevated for two days in a single study,
it never exceeded biologically normal levels. Similarly, there were no statistically significant
differences in levels of liver enzymes,and no difference in mean bodyweight. Two studies reported
on cardiac side effects, having observed no instance of any cardiac effects. Finally, no deaths
occurred due to creatine supplementation.

Note that the risk ratio 95% confidence intervals, which describe the range of values the risk ratio is
likely to be, varies from 0.51 to 2.98. There’s a considerable difference between something
increasing the risk of an event by 50% and almost 300%. The fact that this confidence interval is so
large, and that the upper value is so high, suggests that there’s still room for a lot more data before
any firm conclusions can be drawn. Also keep in mind that only four of the included studies actually
tried to establish a causal link between creatine and potential side effects. These studies reported
gastrointestinal upset, muscle cramps, and headache. If creatine supplementation results in any
side effects, these are likely candidates.

To summarize: based on the reported data, there do not seem to be any safety concerns regarding
creatine supplementation by women who are not pregnant. This is consistent with previous[6]
studies[7] conducted[8] on the topic[9]. While not much is known about creatine’s effects during
pregnancy, at least one study[10] is underway to explore the question. Some studies tried to
determine causality and found gastrointestinal upset, muscle cramps, and headaches may occur
due to creatine supplementation, but it’s too early to draw any firm conclusions.

^ Go back to table of contents

5
 References
1. ^ Herminia D Rosas, et al. PRECREST: a phase II prevention and biomarker trial of
creatine in at-risk Huntington disease. Neurology. (2014)
2. ^ Tarnopolsky MA, et al. Creatine monohydrate enhances strength and body
composition in Duchenne muscular dystrophy. Neurology. (2004)
3. ^ Steven K Malin, Nancy Cotugna, Cheng-Shun Fang. Effect of creatine
supplementation on muscle capacity in individuals with multiple sclerosis. J Diet
Suppl. (2008)
4. ^ Thomas J Wilkinson, et al. Can Creatine Supplementation Improve Body
Composition and Objective Physical Function in Rheumatoid Arthritis Patients? A
Randomized Controlled Trial. Arthritis Care Res (Hoboken). (2016)
5. ^ Deborah L de Guingand, et al. Risk of Adverse Outcomes in Females Taking Oral
Creatine Monohydrate: A Systematic Review and Meta-Analysis. Nutrients. (2020)
6. ^ Poortmans JR, Francaux M. Adverse effects of creatine supplementation: fact or
fiction?. Sports Med. (2000)
7. ^ E Bizzarini, L De Angelis. Is the use of oral creatine supplementation safe?. J
Sports Med Phys Fitness. (2004)
8. ^ R L Terjung, et al. American College of Sports Medicine roundtable. The
physiological and health effects of oral creatine supplementation. Med Sci Sports
Exerc. (2000)
9. ^ Francaux M, Poortmans JR. Side effects of creatine supplementation in athletes.
Int J Sports Physiol Perform. (2006)
10. ^ Deborah L De Guingand, et al. Creatine and pregnancy outcomes, a prospective
cohort study in low-risk pregnant women: study protocol. BMJ Open. (2019)

6
The effects of increased protein intake on
overall energy intake in older adults
 Tags: Protein, Appetite, Meta-analysis, Supplementation, Older Adults

 Study under review: The Impact of Protein Supplementation on Appetite and Energy
Intake in Healthy Older Adults: A Systematic Review with Meta-Analysis

 Read this article online at Examine.com

Quick Takes
• What was the question? What are the effects of increasing
protein intake on energy intake in older adults both via a
single protein dose and over the course of several weeks?
• How was it answered? Researchers conducted a meta-
analysis of randomized controlled trials.
• Who was studied? Participants were at least 60 years old
with no known medical conditions.
• What was the intervention? Participants increased their
protein intake through supplementation or dietary changes
intended to increase protein consumption.
• What's the main takeaway? While single-dose acute protein
supplementation increased total caloric intake shortly
afterward, it made no clear difference on energy intake in the
longer term.
• Any caveats? Many of the included studies had an unclear

7
 risk of bias. Also, longer-term trials tended to rely upon self-
reporting, which may have introduced error when calculating
caloric intake. Finally, the increase in protein intake in the
longer-term studies may have been too small to affect
appetite or improve muscle mass and function, which could
explain the lack of effect on energy intake. Future longer-term
protein studies using higher doses would be useful to
examine this question.

What was the question?

What is the effect of protein supplementation on energy intake in healthy older adults?

Why was the question worth asking?

Muscle mass and function decreases with age. This process is called sarcopenia[1], and is
associated[2] with an increased risk of disability, loss of independence, reduced quality of life, and
increased risk of mortality. One of the possible causes of sarcopenia may be decreased protein
intake and utilization during aging for various reasons, summarized in Figure 1.

Figure 1: Dietary protein’s connection to loss of muscle

mass and function with aging

8
Reference: Bauer et al. J Am Med Dir Assoc. 2013 Aug.[3]

In addition to engaging in aerobic and resistance training, getting enough calories and protein is
recommended[4] for preventing the loss of muscle mass associated with aging. However, many
older adults fail[5] to meet the dietary protein intake recommendations[6] of 1–1.5 grams per
kilogram of bodyweight per day. This is why protein supplementation may play an important role in
addressing these suboptimal intakes.

Although protein supplementation among older adults can increase total protein intake, it may also
suppress[7] appetite and, consequently, compromise energy intake. While several trials have
examined these potential effects, their results have not yet been pooled to quantify the overall
findings of the literature. As such, the goal of the study under review was to conduct a meta-
analysis of the effects (both acute and chronic) of protein supplementation on energy intake in
older adults.

Sarcopenia, the age-related loss of muscle mass and function, is

associated with several negative health outcomes. Getting enough
calories and protein is necessary to fight sarcopenia. Although

9
 protein supplementation can increase protein intake, it may also
reduce energy intake by suppressing appetite. The study under
review is a meta-analysis that investigated the effects (both acute
and chronic) of protein supplementation on energy intake in older
adults.

How was the question answered?

The authors conducted meta-analyses of randomized controlled trials that looked at the acute and
chronic effects of protein supplementation on energy intake in healthy older adults over 60. The
researchers included studies that used either protein supplements or specific foods targeting an
increase in protein intake in participants, and a control group of either placebo or no treatment.

Ultimately, seven trials (and 22 comparisons) were included in the meta-analyses of the acute
effects of protein supplementation on ad libitum energy intake (i.e., energy intake at a test meal
alongside/following protein supplementation) and total energy intake (i.e., energy intake at the test
meal plus the energy content of the supplement). Moreover, 11 trials (and 12 comparisons) were
included in the meta-analysis of the chronic effects of protein supplementation on energy intake.
The seven acute trials involved 116 participants (61 men and 55 women) with an average age of
71 years and BMI of 25. The 11 longitudinal trials involved 687 participants (236 men and 451
women) with an average age of 70 years and BMI of 26.

The researchers also conducted subgroup analyses for acute trials based on supplemental protein
quantity (no more than 30 grams vs. more than 30 grams), protein type (whey protein vs. other),
protein timing (alongside a meal vs. at least 60 minutes before a meal), protein form (solid/semi-
solid vs. liquid), and type of control (flavored water/water, saline, or nothing). For longitudinal trials,
subgroup analyses were conducted based on study duration (no more than 12 weeks vs. more
than 12 weeks), intervention type (protein supplementation alone vs. protein supplementation
combined with exercise intervention) and protein type. Subgroup analyses based on sex (female,
male, or mixed) were conducted in both acute and longitudinal trials.

The researchers assessed the risk of bias of the included trials with the Cochrane Collaboration’s
risk of bias assessment tool for RCTs. Bias was assessed as high, low, or unclear over six
domains: selection (random sequence generation and allocation concealment), performance

10
(blinding of participants and personnel), detection (blinding of outcome assessment), attrition
(incomplete outcome data), reporting (selective reporting), and other. Publication bias was
assessed using funnel plots. The meta analysis was preregistered and followed PRISMA
guidelines. Outcome data were summarized in a random-effects model, and heterogeneity was
tested using the I2 statistic.

In this study, researchers conducted meta-analyses to assess the

effects of protein supplementation (through either protein
supplements or specific foods targeting an increase in protein
intake) on energy intake in healthy older adults. Three meta-
analyses were performed to assess the effects of protein
supplementation on: acute ad libitum energy intake (i.e., energy
intake at a test meal alongside/following protein supplementation);
acute total energy intake (i.e., energy intake at the test meal plus
the energy content of the supplement); and chronic energy intake.
Researchers also conducted subgroup analyses to explore the
potential sources of heterogeneity.

What was the answer?

According to the meta-analyses of the acute trials, consuming protein prior to a meal reduced ad
libitum energy intake at that meal (-39 kcal; no heterogeneity). However, when the energy content
of the supplement was accounted for, total energy intake was greater with protein supplementation
(+155 kcal; moderate heterogeneity). In the meta-analysis of the longer-term studies, there were no
differences in daily energy intake between protein and control (low heterogeneity), despite protein
supplementation successfully increasing total daily protein intake by around 0.3 grams per kilogram
of bodyweight per day.

In the subgroup analyses, no significant differences were found for the ad libitum energy intake.
For the acute effects of protein on total energy intake (i.e., energy intake at the test meal plus the
energy content of the protein supplement), there were significant differences for protein timing,
control type, and sex, shown in Figure 2. Specifically, energy intake was higher when the the

11
protein supplement was served at least 60 minutes prior to the meal, when water/flavored water
was used as the control, and in men-only and mixed-sex trials. There were no differences between
groups in any of the subgroup analyses of longitudinal trials.

Figure 2: Statistically significant acute subgroup

differences (with 95% confidence intervals)

According to the risk of bias assessment, about 80% of the trials had an unclear risk of bias for
selective reporting, about 50% of the trials had an unclear risk of bias for allocation concealment
(which is admittedly a tough thing to conceal in many nutrition trials), and about 25–35% of the
trials had a high risk of bias for blinding of outcomes assessors, personnel, and participants. The
researchers did not detect any publication bias.

The findings of the study under review indicate that protein

supplementation increases total energy intake acutely, especially
when the protein supplement is taken at least 60 minutes prior to
the test meal, and when water/flavored water is used as a control.
Moreover, protein supplementation does not affect overall energy
intake in the long term, despite it increasing total daily protein
intake by around 0.3 grams per kilogram of bodyweight per day.

12
How much should you trust the answer?
Overall, this was a relatively well-conducted study. Its strengths include that it was preregistered
and PRISMA-compliant, and that the researchers assessed risk of bias with the Cochrane
Collaboration’s risk of bias assessment tool. Moreover, the authors used a random-effects model
(which is a more appropriate choice for the analysis, as it does not assume that the included trials
are homogeneous) to summarize the data, even in analyses in which no heterogeneity[8] was
detected. There are, however, also some limitations worth addressing.

First, in the risk of bias assessment, more than 50% of the trials were of an unclear risk of bias for
the domains of selective reporting and allocation concealment. Moreover, about 25–35% of the
trials had a high risk of bias for blinding of outcomes, assessors, personnel, and participants.
These reduce confidence in the results of the meta-analyses.

Second, in the February 2020 version of the preregistration records, the researchers stated that
subgroup analyses would be based only on protein quantity (in acute trials) and intervention
duration (in longitudinal trials). However, in the published paper, a large number of subgroup
analyses were conducted to examine potential sources of heterogeneity. This discrepancy between
the preregistration records and published paper reduces confidence in the results of the subgroup
analyses, and suggests that they should be considered exploratory.

Third, in longitudinal trials, energy intake was assessed using 24-hour dietary recalls or food
diaries. Since misreporting[9] of energy intake is typical when dietary intake is self-reported, and as
protein may have appetite-suppressing[10] effects, it’s possible that energy intake may have been
over-reported by participants supplementing with protein, or under-reported to a greater degree by
participants in the control groups. However, this is highly speculative. Moreover, the fact that none
of the eight trials that reported bodyweight changes found that protein supplementation decreased
bodyweight suggests that there was, indeed, no decrease in energy intake.

A more likely explanation for the lack of differences in energy intake between groups in longitudinal
trials is that the increase in protein intake of around 0.3 grams per kilogram of bodyweight per day
may have been too small to suppress appetite. That said, it’s also worth pointing out that this
increase in protein intake may also be too small to improve muscle mass and function, as the
results from[11] other[12] trials[13] suggest that, in elderly populations, protein increases of around
0.4–0.6 grams per kilogram of bodyweight per day may be needed to achieve these beneficial
effects.

The issue of the generalizability of the results is also important to consider: the trials included in the
meta-analyses involved healthy older adults. Considering there may be differences[14] in the
magnitude of appetite suppression with protein supplementation between younger and older men,

13
with younger men experiencing greater appetite suppression, and that both physiological and
psychological health issues may affect appetite[15], the results of the study under review can’t be
generalized to younger populations or populations with medical issues.

The results of this meta-analysis suggest that, in healthy older

adults, protein supplementation increases energy intake acutely,
but does not affect energy intake in the long term. While, overall,
these findings are trustworthy, it should be noted that the increase
in total protein intake was around 0.3 grams per kilogram of
bodyweight per day. The results of the subgroup analyses, which
suggest greater increases in energy intake acutely when the
protein supplement is taken at least 60 minutes prior to the test
meal, and when water/flavored water is used as a control, should
be considered exploratory.

What’s the take-home?

This meta-analysis suggests that, in healthy older adults, protein supplementation increases total
energy intake acutely, and results in a small increase in total protein intake in the long term without
affecting overall energy intake. While these results support the use of protein supplementation in
healthy older adults without compromising energy intake, keep in mind that the increase in total
protein intake may have been too small to have appetite suppressing effects, or to improve muscle
mass and function.

Did you expect the results to show counterproductive effects of

protein in older adults? Share your thoughts in the private NERD
Facebook forum!

14
^ Go back to table of contents

15
 References
1. ^ Alfonso J Cruz-Jentoft, Avan A Sayer. Sarcopenia. Lancet. (2019)
2. ^ Beaudart C, et al. Sarcopenia: burden and challenges for public health. Arch Public
Health. (2014)
3. ^ Bauer J, et al. Evidence-based recommendations for optimal dietary protein intake
in older people: a position paper from the PROT-AGE Study Group. J Am Med Dir
Assoc. (2013)
4. ^ Morley JE, et al. Nutritional recommendations for the management of sarcopenia. J
Am Med Dir Assoc. (2010)
5. ^ J L Krok-Schoen, et al. Low Dietary Protein Intakes and Associated Dietary
Patterns and Functional Limitations in an Aging Population: A NHANES analysis. J
Nutr Health Aging. (2019)
6. ^ Deutz NE, et al. Protein intake and exercise for optimal muscle function with aging:
recommendations from the ESPEN Expert Group. Clin Nutr. (2014)
7. ^ Veldhorst M, et al. Protein-induced satiety: effects and mechanisms of different
proteins. Physiol Behav. (2008)
8. ^ DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. (1986)
9. ^ Poslusna K, et al. Misreporting of energy and micronutrient intake estimated by
food records and 24 hour recalls, control and adjustment methods in practice. Br J
Nutr. (2009)
10. ^ A M Johnstone, R J Stubbs, C G Harbron. Effect of overfeeding macronutrients on
day-to-day food intake in man. Eur J Clin Nutr. (1996)
11. ^ Ten Haaf DSM, et al. Protein supplementation improves lean body mass in
physically active older adults: a randomized placebo-controlled trial. J Cachexia
Sarcopenia Muscle. (2019)
12. ^ Mitchell CJ, et al. The effects of dietary protein intake on appendicular lean mass
and muscle function in elderly men: a 10-wk randomized controlled trial. Am J Clin
Nutr. (2017)
13. ^ Doyeon Kim, Yongsoon Park. Amount of Protein Required to Improve Muscle Mass
in Older Adults. Nutrients. (2020)
14. ^ Caroline Giezenaar, et al. Lesser suppression of energy intake by orally ingested
whey protein in healthy older men compared with young controls. Am J Physiol Regul
Integr Comp Physiol. (2015)

16
15. ^ Pilgrim AL, et al. An overview of appetite decline in older people. Nurs Older
People. (2015)

17
Sugar Wars, Episode 6: The Return of the
Fructose
 Tags: Fructose, Meta-analysis, Cardiovascular Disease, Glucose, Metabolic Syndrome

 Study under review: Effect of fructose instead of glucose or sucrose on cardiometabolic

markers: a systematic review and meta-analysis of isoenergetic intervention trials

 Read this article online at Examine.com

Quick Takes
• What was the question? How does fructose intake affect
cardiometabolic disease risk markers compared to glucose or
sucrose?
• How was it answered? Researchers conducted a meta-
analysis of randomized and nonrandomized clinical trials.
• Who was studied? The trials included almost 2,000
participants, ages 13–62. Most studies involved people
without a diagnosed disease, although some studies involved
participants with glucose dysregulation or non-alcoholic fatty
liver disease. Average BMI categories ranged from normal to
obese.
• What was the intervention? Participants followed diets
containing a set amount of calories as fructose compared to
similar diets containing the same amount of energy as
glucose or sucrose in interventions lasting at least one week.

18
 • What's the main takeaway? There were no clear
differences between the effects of fructose compared to the
same amount of calories from glucose or sucrose, with two
exceptions: researchers observed a small diastolic blood
pressure drop when fructose was substituted for glucose, and
a bump in apolipoprotein B levels when high-fructose corn
syrup was substituted for sucrose.
• Any caveats? Poor or unclear study quality and differences
between the included studies warrant some caution when
interpreting these results.

What was the question?

What is the effect of fructose consumption on markers of cardiometabolic disease, in comparison to
glucose or sucrose?

Why was the question worth asking?

It’s often been argued that fructose is the primary driver of all cardiometabolic disease, but the
evidence for this hypothesis is mixed at best.

Cardiometabolic diseases are a group of related metabolic disorders, including non-alcoholic fatty
liver disease (NAFLD), type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease (CVD),
and metabolic syndrome. Each of these is linked to excess calorie intake, but preclinical studies[1],
observational studies[2], and some clinical trials[3] do suggest that fructose consumption might play
a role in these conditions, even independently of calorie intake.

However, reviews looking at fructose in comparison to other common sugars like glucose, sucrose
(a disaccharide of glucose and fructose, also called table sugar), and high fructose corn syrup
(HFCS; a liquid sweetener typically containing 42–55% fructose) have provided mixed results. The

19
main conclusions of these past studies are summarized in Figure 1. These previous meta-analyses
do not converge on a clearly unified answer.

Figure 1: The sometimes contradictory takeaways from

past meta-analyses on fructose
Insulin resistance[4] Isocaloric fructose may increase insulin resistance in the liver.

Metabolic syndrome Fructose consumption (not necessarily isocaloric) raised fasting

components[5] blood sugar, blood pressure, and triglycerides.

Bodyweight[6] Isocaloric fructose had no influence on body weight.

Lipids[7] Isocaloric fructose had no influence on any blood lipid

measurement.

Glycemic response[8] Isocaloric fructose lowered after-meal blood glucose and insulin
compared to sucrose or glucose.

Glycemic and Isocaloric fructose lowered fasting blood sugar, HbA1c, and
cardiometabolic bodyweight to small degrees.
markers[9]

How fructose compares to isocaloric amounts of other sugars in terms of cardiometabolic impact is
an important question to address, since it takes calories out of the picture and determines how
fructose compares toe-to-toe against other sugars. The present review provides the most up-to-
date look at how the effects of fructose stack up against those of other sugars.

Dozens of studies and several meta-analyses have attempted to

clarify the metabolic effects fructose might have relative to
glucose. Although they are consistent with one another in some
respects, areas of uncertainty remain.

20
How was the question answered?
The authors searched databases for human randomized and nonrandomized controlled trials that
looked at interventions with a duration of more than one week in which researchers kept total
calories the same while replacing fructose or high fructose corn syrup with sucrose or glucose.
Included cardiometabolic outcomes were total cholesterol, low-density lipoprotein cholesterol (LDL-
C), high-density lipoprotein cholesterol (HDL-C), circulating triglycerides (TGs), apolipoprotein A1
(ApoA1; a major protein component of HDL-C), apolipoprotein B (ApoB; a major protein component
of LDL-C species), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood
glucose, and bodyweight. This systematic review was preregistered and reported in accordance
with PRISMA guidelines[10].

The systematic review ultimately yielded 25 trials that looked at the effect of replacing fructose or
HFCS with the same number of calories of sucrose or glucose over the course of one week or
longer in humans and reported data for accompanying physiological effects. A total of 1,744
participants (47% female) ages 13–62 were included in the analysis. Eighteen studies compared
fructose with glucose, 5 compared HFCS with glucose, 10 compared fructose with sucrose, and 5
compared HFCS with sucrose. The study duration ranged from 1–12 weeks (median of 3 weeks).
The fructose dose ranged from 33–250 grams, representing 6–48% of the total daily calories
provided by the diets. Nine of the 25 studies recruited participants with obesity or type 2 diabetes.
Seven studies were classified as having low risk of bias, 6 as having high risk of bias, and 12 as
having uncertain risk of bias.

The researchers estimated the percentage of the total variation due to heterogeneity, rather than to
chance. Risk of publication bias and quality of evidence were also evaluated. Seven studies were
supported exclusively by public institutions, while the others were entirely or partially supported by
commercial funds. In fact, this meta-analysis was also supported by funds from a candy
manufacturing and research organization in Italy.

This systematic review and meta-analysis pooled data from 25

controlled trials to determine the effects of fructose on fasting
glucose, blood lipids, blood pressure and weight, compared to
glucose.

21
What was the answer?
When glucose was replaced with fructose, no significant differences were found for fasting blood
glucose, bodyweight, systolic blood pressure, ApoA1, ApoB, TGs, HDL-C, or LDL-C. The one
significant effect found was diastolic blood pressure (the bottom number in a blood pressure
reading, the blood pressure between heart beats) decreased by 2.44 mmHg when glucose was
replaced by fructose. This effect lost statistical significance when non-randomized trials were
removed from the analysis, when studies with highest risk of bias were removed, and also when
either of the two studies with the greatest effect sizes were removed.

Replacing HFCS with glucose did not change any cardiometabolic parameters in any meaningful
way, nor did replacing fructose with sucrose.

Replacing HFCS with sucrose was not associated with a meaningful effect on total cholesterol,
LDL-C, HDL-C, or TGs, but was associated with a significant decrease in apoB by a WMD of 11.29
mg/dL. For reference, physicians commonly recommend that ApoB should be lower than 130 mg/
dL to prevent cardiovascular disease, and the participants from the sole study that reported on
apoB changes had baseline levels of around 85–100 mg/dL. Little confidence can be placed on this
latter result because it was based on a single study[11] and it contradicts the null effects seen when
replacing pure fructose with sucrose.

As an aside, note that the numbers pulled from the above study that reported on apoB don’t agree
with what the authors of the study under review reported in their meta-analysis. There are also
some other discrepancies in their references.

Other than these findings, there were no other differences found. The only differences that were
found are summarized in Figure 2.

Figure 2: The only significant differences found in this

study

22
 This systematic review and meta-analysis shows that, by and
large, there does not appear to be much difference in the
metabolic effect of fructose as compared to glucose. Replacing
glucose with fructose might lower diastolic blood pressure by a
small amount, and replacing high fructose corn syrup with sucrose
might decrease apolipoprotein B, though confidence in these
results is low.

How much should you trust the answer?

If you are a long-time NERD reader, these results probably don’t surprise you. NERD has covered
recent systematic reviews about the differential effects, or lack thereof, of types of sugar for some

23
time. Check out two previous NERD deep dives on fructose, Sugar Wars, Episode 4: A New Hope
for Fructose, on the acute and chronic glycemic effect of fructose, and Sugar Wars, Episode 2:
Fructose Strikes Back, on fructose and blood lipid levels for a more in-depth take.

Previous human research points to the lack of a consistent effect of fructose above and beyond
that of other sugars when it comes to bodyweight and other cardiometabolic measures, but results
from previous meta-analyses still differ. In this study, the authors add authority to their analysis by
paying attention to details like excluding non-isocaloric comparisons in the first place, employing
rigorous sensitivity and heterogeneity analyses, and adjusting for effect-modifiers. That said, it’s
unclear why there are discrepancies between data reported in this meta-analysis and some of the
data from the original studies. Overall, this meta-analysis appears to be one of the most thorough
investigations on the subject, but review confidence is reduced because some inconsistencies in
the findings for apoB and FBG cannot be reconciled.

Even if these results are mostly in-line with other research, they lie in contrast to the conclusions of
some outspoken clinician-researchers, such as Dr. Robert Lustig’s “unifying hypothesis of
metabolic syndrome[12],” which proposes that fructose may be uniquely metabolically damaging,
particularly to the liver[13]. Though this meta-analysis does not specifically focus on the liver, it
suggests that commonly-measured markers of cardiovascular and metabolic health respond
similarly to fructose and glucose, challenging the importance of distinguishing between these two
sugars[14].

Some look to fructose’s effect of elevating uric acid (not measured in this meta-analysis) as the
primary driver of its adverse metabolic effects[15]. This theory may explain why fructose could
indirectly lead to gout, as evidenced in[16] observational[17] studies[18], and hyperuricemia, as seen
in clinical trials[19]. However, if fructose was the primary driver of NAFLD and other cardiometabolic
diseases, then this would be indicated by increased markers of hepatic de novo lipogenesis, LDL-
C, ApoB, and TGs, which are only inconsistently suggested by the evidence. To cast further doubt
on this theory, one isotopic tracer label study showed that 29–54% of ingested fructose is
converted to glucose[20] and 28% is converted to lactate, whereas less than 1% of dietary fructose
is converted to plasma triglycerides.

The fact that so many previous meta-analyses have come up with slightly divergent results can be
explained by a few factors. The first explanation is “statistical noise”—even if there’s no effect,
results will be expected to come up with positive results on occasion (1 out of 20 times, assuming
standard statistical analyses). Since different meta-analyses often include different sets of trials,
the results that show up by chance can differ between studies.

Another explanation involves the possibility of substandard statistical analyses. The present meta-
analysis looked at a number of sources of bias, including heterogeneity among studies, effect

24
modification of certain variables, publication bias, and presence of individual studies that skew the
agglomerated results. Once these were accounted for, all of the statistically significant results were
washed out. Some of the other research studies found similarly bias-confounded[21] results[5], while
others only found significant results when looking at studies in which calories were added on top of
usual[6] intake[7]. These explanations also account for the reason why the same team’s previous
meta-analysis[19] suggested a modest effect on FBG, which was not found in this analysis: having
more data allowed them to attribute the effect to heterogeneity between studies.

Another key point is that many of these studies used very large fructose exposures. The fact that
these excessive doses produced few, if any, significantly different results means that typical intakes
are even less likely to produce differences over the time scales investigated. A median of 9% of an
American’s calorie intake consists of fructose[22], equating to about 192 kilocalories or 48 grams of
fructose per day. To put this into perspective, 29 of the 35 comparison arms used to determine the
results of this meta-analysis included doses of fructose higher than the median intake, and 8 of the
comparison arms were in excess of 99% of American adult’s fructose intakes. These
supraphysiological doses are used often in preclinical animal studies[23], but they can’t provide a
realistic effect of a more relevant dose of fructose.

Fructose and glucose are calorically the same, gram for gram. In terms of weight gain (positive
energy balance) and weight loss (negative energy balance), there is no clear a priori reason to
think that fructose would drive weight gain differently than other sugars. Even when it comes to
fullness and hunger hormones, fructose appears to be at least as filling as glucose[24], if not more
so 30 minutes after[25] ingestion[26].

Even if the observed differences between glucose and fructose metabolism in previous meta-
analyses are real and not due to chance or confounding, you would have to consume an unusually
large amount of sugar to feel those fructose-specific effects. By then, however, you would be
consuming a damaging amount of highly refined carbohydrate anyway. For example, imagine
drinking two different extra-large soft drinks, one sweetened with fructose and the other sweetened
with the same amount of glucose. It will be drinking that much soda in the first place that causes a
calorie surplus and harmful cardiometabolic effects, not a unique feature of the type of sugar being
consumed. With many of the measured cardiometabolic markers being responsive to energy
balance, and considering the mere fact that a molecule of fructose does not contribute any more to
weight status than a molecule of glucose, it’s no surprise that the effect of fructose on
cardiovascular and metabolic health parameters does not stand out from other refined
carbohydrates.

This meta-analysis confirms what other high quality reviews have

25
 already suggested: the adverse metabolic effect of fructose is
comparable to that of glucose.

What’s the take-home?

This meta-analysis found that fructose consumption is no better or worse, cardiometabolically, than
consuming glucose or other fructose-glucose combinations like sucrose and high fructose corn
syrup. The metabolic effects seen in previous meta-analyses were not observed in this latest meta-
analysis (e.g. increased TGs at high fructose doses[27], decreased SBP[19], increased[19] weight[8])
may have more to do with statistical noise or with other variables not fully accounted for.

The negative metabolic effects of excess fructose consumption are most likely tied to excess
energy consumption and the relative absence of fiber, phytochemicals, and essential
micronutrients in highly refined carbohydrates, rather than any unique effect of fructose itself.

Are these the results you would have expected? Get fired up about
fructose at the NERD private Facebook forum.

^ Go back to table of contents

26
 References
1. ^ Kim-Anne Lê, Luc Tappy. Metabolic effects of fructose. Curr Opin Clin Nutr Metab
Care. (2006)
2. ^ Richard J Johnson, et al. Potential role of sugar (fructose) in the epidemic of
hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and
cardiovascular disease. Am J Clin Nutr. (2007)
3. ^ Kimber L Stanhope, et al. Consuming fructose-sweetened, not glucose-sweetened,
beverages increases visceral adiposity and lipids and decreases insulin sensitivity in
overweight/obese humans. J Clin Invest. (2009)
4. ^ Ter Horst KW, et al. Effect of fructose consumption on insulin sensitivity in
nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials.
Am J Clin Nutr. (2016)
5. ^ a b Roya Kelishadi, Marjan Mansourian, Motahar Heidari-Beni. Association of
fructose consumption and components of metabolic syndrome in human studies: a
systematic review and meta-analysis. Nutrition. (2014)
6. ^ a b Sievenpiper JL, et al. Effect of fructose on body weight in controlled feeding
trials: a systematic review and meta-analysis. Ann Intern Med. (2012)
7. ^ a b Laura Chiavaroli, et al. Effect of Fructose on Established Lipid Targets: A
Systematic Review and Meta-Analysis of Controlled Feeding Trials. J Am Heart
Assoc. (2015)
8. ^ a b Rebecca A Evans, et al. Fructose replacement of glucose or sucrose in food or
beverages lowers postprandial glucose and insulin without raising triglycerides: a
systematic review and meta-analysis. Am J Clin Nutr. (2017)
9. ^ Evans RA, et al. Chronic fructose substitution for glucose or sucrose in food or
beverages has little effect on fasting blood glucose, insulin, or triglycerides: a
systematic review and meta-analysis. Am J Clin Nutr. (2017)
10. ^ Liberati A, et al. The PRISMA statement for reporting systematic reviews and meta-
analyses of studies that evaluate healthcare interventions: explanation and
elaboration. BMJ. (2009)
11. ^ Joshua Lowndes, et al. The effect of normally consumed amounts of sucrose or
high fructose corn syrup on lipid profiles, body composition and related parameters in
overweight/obese subjects. Nutrients. (2014)
12. ^ Andrew A Bremer, Michele Mietus-Snyder, Robert H Lustig. Toward a Unifying
Hypothesis of Metabolic Syndrome. Pediatrics. (2012)

27
13. ^ Thomas Jensen, et al. Fructose and sugar: A major mediator of non-alcoholic fatty
liver disease. J Hepatol. (2018)
14. ^ John S White. Challenging the Fructose Hypothesis: New Perspectives on
Fructose Consumption and Metabolism. Adv Nutr. (2013)
15. ^ Lukas Schwingshackl, et al. Dietary sugars and cardiometabolic risk factors: a
network meta-analysis on isocaloric substitution interventions. Am J Clin Nutr. (2020)
16. ^ S Ebrahimpour-Koujan, et al. Consumption of sugar-sweetened beverages and
serum uric acid concentrations: a systematic review and meta-analysis. J Hum Nutr
Diet. (2020)
17. ^ Sabrina Ayoub-Charette, et al. Important food sources of fructose-containing
sugars and incident gout: a systematic review and meta-analysis of prospective
cohort studies. BMJ Open. (2019)
18. ^ Soraiya Ebrahimpour-Koujan, et al. Consumption of sugar sweetened beverages
and dietary fructose in relation to risk of gout and hyperuricemia: a systematic review
and meta-analysis. Crit Rev Food Sci Nutr. (2020)
19. ^ a b c d John L Sievenpiper, et al. Fructose vs. glucose and metabolism: do the
metabolic differences matter?. Curr Opin Lipidol. (2014)
20. ^ Sam Z Sun, Mark W Empie. Fructose Metabolism in Humans - What Isotopic
Tracer Studies Tell Us. Nutr Metab (Lond). (2012)
21. ^ Elena Fattore, et al. Effects of free sugars on blood pressure and lipids: a
systematic review and meta-analysis of nutritional isoenergetic intervention trials. Am
J Clin Nutr. (2017)
22. ^ Sam Z Sun, et al. Fructose and non-fructose sugar intakes in the US population
and their associations with indicators of metabolic syndrome. Food Chem Toxicol.
(2011)
23. ^ John L Sievenpiper, et al. Is fructose a story of mice but not men?. J Am Diet
Assoc. (2011)
24. ^ Timothy H Moran. Fructose and satiety. J Nutr. (2009)
25. ^ J L Guss, H R Kissileff, F X Pi-Sunyer. Effects of glucose and fructose solutions on
food intake and gastric emptying in nonobese women. Am J Physiol. (1994)
26. ^ J Rodin. Comparative effects of fructose, aspartame, glucose, and water preloads
on calorie and macronutrient intake. Am J Clin Nutr. (1990)
27. ^ Livesey G, Taylor R. Fructose consumption and consequences for glycation,
plasma triacylglycerol, and body weight: meta-analyses and meta-regression models
of intervention studies. Am J Clin Nutr. (2008)

28
Deep Dive: Supplementing for senior
strength and size in the context of
sarcopenia
 Tags: Sarcopenia, Meta-analysis, Supplementation, Muscle Mass, Older Adults

 Study under review: Factors influencing the efficacy of nutritional interventions on

muscle mass in older adults: a systematic review and meta-analysis

 Read this article online at Examine.com

Quick Takes
• What was the question? How do various nutritional
supplements affect muscle mass in older adults?
• How was it answered? Researchers conducted a meta-
analysis of randomized controlled trials.
• Who was studied? Participants included mostly community-
dwelling people with an average age of 78.
• What was the intervention? A variety of supplements,
including amino acids, protein, creatine,
hydroxymethylbutyrate (HMB), and polyunsaturated fatty
acids were provided to participants.
• What's the main takeaway? Neither polyunsaturated fatty
acids nor protein alone had a clear effect on muscle mass,
but amino acids combined with protein did (although both had
wide errors in their effect estimates). Amino acids on their

29
 own, creatine, and HMB also improved muscle mass.
• Any caveats? The authors attributed the effects of some
multi-supplements studies to a specific supplement in the
bunch without citing a specific reason, raising some serious
questions about how the meta-analyzed studies were
categorized. Also, many of the included studies were of low
quality. Finally, the data were often compatible with a wide
range of effect sizes with wide ranges of uncertainty in their
effect estimates, making it unclear which of these
supplements may work best.

Introduction
Loss of muscle mass during old age, also called sarcopenia, is associated with all-cause
mortality[1], fall and fracture risk[2], and some disease states, like nonalcoholic fatty liver disease[3].
It is one of the most important[1] modifiable risk factors of all-cause mortality and disease.
Sarcopenia is multifactorial[4], but is greatly affected by malnutrition, amount and type of physical
activity, and prolonged immobilization. All of these factors, combined, accentuate the loss of
muscle mass and function, reducing the quality of life for elderly people.

One of the ways in which researchers are trying to combat sarcopenia is by using[5] nutritional
interventions that either prevent the loss of, or even increase, muscle mass. Whereas the
molecular pathways that are involved are not completely understood, muscle mass is maintained
by the balance between muscle protein synthesis (the creation of new muscle proteins) and
breakdown (the degradation of muscle proteins). Resistance exercise is the most potent way of
stimulating muscle growth, but supplementing dietary protein (and amino acids) can also help.
Hence, supplementation with amino acids and/or protein might help combat sarcopenia. In
addition, some other popular supplements that can theoretically modulate this balance may offer
benefits. The way in which these supplements are consumed, including the type of supplement,
dose, frequency, timing, duration and adherence, may be key to obtaining the desired effects.

30
The authors of the current systematic review and meta-analysis evaluated the effects of these
parameters on muscle mass in older adults.

Sarcopenia, the loss of muscle mass during old age, is an

important risk factor for all-cause mortality and disease in elderly
people. In addition to resistance exercise, nutrition plays an
important role, as it can modulate the muscle protein balance.
However, the efficacy of nutritional supplements that could provide
benefits in the context of sarcopenia depend on factors like type,
dose, frequency, timing, duration and adherence.

What was studied?

This was a preregistered systematic review and meta-analysis of randomized controlled trials
(RCTs) that evaluated the effects of nutritional interventions (defined as the “provision of nutrients
separately from the diet”) on muscle mass measures in older adults. Studies were included if
participants were older than 65 years old and reported at least one muscle mass measurement
(lean mass, appendicular lean mass, skeletal muscle mass or fat-free mass).

Studies were classified according to the type of intervention: amino acids (AAs, including both
essential and nonessential), creatine (CR), hydroxymethylbutyrate (HMB), polyunsaturated fatty
acids (PUFAs) and protein supplementation (PRO). PRO studies were further divided into protein
supplementation alone, protein with AAs or protein in combination with other supplements (CR,
HMB and PUFAs). PRO studies in which there was a description of the amino acid composition
were considered as PRO plus AAs. The control group included the ingestion of placebo or the
same supplement as the intervention group without the ingredient of interest.

The quality of the studies was determined using the Cochrane risk of bias tool. The meta-analysis
was performed using a random-effects model using the change in muscle mass between baseline
and post-intervention.

A total of 29 studies were included, including 2,255 participants with a mean age of 78 years (55%
women). In studies investigating CR, all participants were men. Most studies were done in
community-based populations (n=20) and used dual-energy X-ray absorptiometry (DXA) (n=16) for

31
measuring muscle mass.

Most studies used a multinutrient supplement (n=25). Five studies used AAs, 3 studies used CR, 3
studies used HMB, 3 studies used PUFAs, and 15 used PRO. In general, in studies using protein
supplementation (alone or combined), baseline protein intake was more than 1 gram of protein per
kilogram of bodyweight.

The key study characteristics are summarized in Figure 1.

Figure 1: Key characteristics of the meta-analyzed

studies

32
Researchers included 29 randomized-controlled trials assessing
the effects of nutritional interventions on muscle mass in this meta-
analysis. The included studies involved a total of 2,255 participants
with a mean age of 78 years (55% women). Supplementation
types included amino acids, creatine, hydroxymethylbutyrate
(HMB), polyunsaturated fatty acids, and protein supplementation
(alone or in combination with other ingredients).

33
What were the findings?
Nine studies were graded as being of high quality, 6 of moderate quality, and 14 of low quality.
Overall, all nutritional interventions combined had a statistically significant, positive effect on
muscle mass (standardized mean difference (SMD) 0.324, 95% CI 0.186–0.463; equivalent to a
small effect). How each intervention on their own fared is broken down in Figure 2. As shown in
Figure 2, no significant effect was observed for PRO alone or combined with other ingredients, or
for PUFAs. There was low heterogeneity for CR, HMB and PRO plus other ingredients, whereas
high heterogeneity was observed for AAs, PRO, PRO plus AAs and PUFAs.

Figure 2: Effects on muscle mass with 95% confidence

intervals

There was no clear interaction between dose, duration, frequency or timing of supplementation, but
those studies that reported treatment adherence, with the exception of one, all found positive

34
effects of supplementation on muscle mass.

There was an overall positive effect of nutritional interventions on

muscle mass, which was derived from a significant effect of amino
acids, creatine, hydroxymethylbutyrate (HMB), and protein plus
amino acids. There was no effect from protein alone or
combinations with other ingredients or for PUFAs. There was no
significant effect of the dose, duration, frequency or timing of
supplementation, but positive results were found for all but one
study which reported adherence.

The bigger picture

In the study under review, only AAs, CR, HMB and PRO plus AAs had a significant positive effect
on muscle mass, while supplementation with PRO or PUFAs alone didn’t result in any benefit.

It is interesting to note that protein supplementation, which is widely recommended for muscle
mass gain and maintenance, produced significant effects only when combined with AAs. At first
glance, this appears counterintuitive. After all, protein is composed of amino acids. However,
protein sources vary in their amino acid composition, so the effects of higher levels of individual
amino acids alone might show distinct physiological effects than consuming protein. From the
studies included in the AAs group, three of five studies found a significant effect on muscle mass:
two[6] were[7] performed in older participants with chronic obstructive pulmonary disease (COPD)
using essential amino acids (EAA) and one[8] was done with L-carnitine supplementation in
centenarians (the other two studies used only leucine, a key EAA). In addition, three of the four
studies using protein plus amino acids found a significant effect on muscle mass. Two[9] of them[10]
included leucine and vitamin D in addition to whey protein, and one[11] combined protein
supplementation with whole body electrical stimulation. This latter study also included a protein
only group, which showed less benefit than the combined protein plus electrical stimulation group.

Overall, these data suggest that protein intake alone, particularly when combined with an adequate
dietary protein intake (more than 1 gram per kilogram of bodyweight), has limited effects. The
addition of either electrical stimulation (which should work by the same mechanism as resistance

35
exercise) or specific ingredients like EAA or leucine appear to be needed to elicit a significant
response. As old age has been associated with “anabolic resistance[12],” particular nutrients that
modify relevant cellular processes may be more effective in preventing the loss of muscle mass.
However, these suggestions are speculative. Given the large 95% confidence intervals of the
interventions, a simpler explanation could be that the data are roughly compatible with all of these
interventions having small effects.

It is relevant to emphasize that most studies included in the meta-analysis didn’t find any significant
effect on muscle mass. This highlights the fact that nutritional interventions themselves only play a
permissive role on muscle mass growth and maintenance; this means that the stimuli necessary for
muscle maintenance and/or growth include factors that go beyond nutrition—with a specific
emphasis on resistance exercise and activity.

In addition, the fact that adherence reporting, which presumably reflects an increased adherence to
the intervention, was correlated with better outcomes, which suggests that supplementation trials
may fail in part because participants do not consume the supplement, rather than because of a
lack of effects of the supplement itself. Careful assessment of adherence must be done when
evaluating the results of such studies.

One of the major limitations of this meta-analysis is that the way in which the authors categorized
the studies might not be ideal. For example, the only study[13] which found statistically significant
effects for creatine supplementation compared a supplement containing coenzyme Q10 and
creatine to placebo (not described) in participants with COPD. However, the authors interpret this
study as evidence for creatine, and not for coenzyme Q10. The same happens with the study[14]
that showed significant results with HMB. In that study, researchers compared HMB plus arginine
and lysine, to placebo. Therefore, careful consideration and individual evaluation of the studies
must be done before attempting to extrapolate the results from this meta-analysis. Moreover, most
studies were judged as low quality and the effect sizes had a very wide confidence interval, making
the effect sizes unclear. Another limitation is that the authors don’t appear to analyze the data by
type of comparator group. That is, whether the placebo group received an energy-matched control
or a non-caloric placebo. This could be important since some elderly people consume insufficient
calories. In addition, they mixed different types of participants (healthy and unhealthy). There might
be a benefit for some supplements in unhealthy subpopulations. This specifically, however, was
not addressed by proper subgroup analyses. Finally, the meta-analysis only determined the effects
on muscle mass but not strength, which might be a more valuable marker for the decline in health
during old age and more clinically relevant[15].

Overall, nutritional interventions appeared to increase muscle

36
 mass to a small but statistically significant degree. However, this
effect came from only a handful of studies, particularly those
containing amino acids, and most of them included a supplement
with more than one ingredient. The lack of effect in most studies
may be attributed to the limited effect that nutrition per se has on
muscle mass, compared to exercise. Nevertheless, there are
problems with the categorization of supplements, as well as with
the neglected heterogeneity in the health status of participants that
preclude making a specific practical recommendation from this
study.

Frequently asked questions

Q. What causes sarcopenia?

While multi-factorial, sarcopenia appears to be driven by physiological processes at very distinct

levels[16]: from hormonal dysregulation and inflammation, to neuromuscular alterations. The
change related to the aging process is referred to as “primary sarcopenia.” There is also
“secondary sarcopenia,” arising from lifestyle factors such as lack of physical activity or
malnutrition. However, all factors interact to promote or slow sarcopenia, and thus, are modifiable
to some extent.

What should I know?

The loss of muscle mass and strength during old age, termed sarcopenia, is a major public health
problem that greatly reduces the quality of life of elderly people and increases the risk for falls,
injuries, and is associated with increased all-cause mortality. One of the ways in which sarcopenia
can be attenuated involves the use of nutritional supplements that modulate muscle mass balance.
However, factors such as the type of supplement, dose, frequency, timing, duration, and
adherence might play a key role in their efficacy.

37
This systematic review and meta-analysis of randomized controlled trials found that only a handful
of nutritional interventions involving mainly amino acids (with and without protein) and including a
combination of ingredients had a significant effect on muscle mass in generally well protein-
nourished participants. It is also worth pointing out that reporting adherence was the only factor
that predicted finding a positive result in the included studies.

The results suggest that nutritional interventions, in the absence of other treatments, have a limited
effect, but more specific data on types of populations, categories, and dosages of supplements are
needed. To be able to make reliable practical recommendations, it would also be important to know
more about the interaction with resistance training or other physical activity interventions.

Don’t let your knowledge about nutritional interventions for

sarcopenia atrophy! Head on over to the NERD Facebook group to
share your two cents about this research.

^ Go back to table of contents

38
 References
1. ^ a b Ping Liu, et al. Sarcopenia as a predictor of all-cause mortality among
community-dwelling older people: A systematic review and meta-analysis. Maturitas.
(2017)
2. ^ Suey S Y Yeung, et al. Sarcopenia and its association with falls and fractures in
older adults: A systematic review and meta-analysis. J Cachexia Sarcopenia Muscle.
(2019)
3. ^ Changzhou Cai, et al. Relationship between relative skeletal muscle mass and
nonalcoholic fatty liver disease: a systematic review and meta-analysis. Hepatol Int.
(2020)
4. ^ John E Morley, et al. Sarcopenia with limited mobility: an international consensus. J
Am Med Dir Assoc. (2011)
5. ^ Morley JE, et al. Nutritional recommendations for the management of sarcopenia. J
Am Med Dir Assoc. (2010)
6. ^ R W Dal Negro, et al. Comprehensive effects of supplemented essential amino
acids in patients with severe COPD and sarcopenia. Monaldi Arch Chest Dis. (2010)
7. ^ R W Dal Negro, et al. Essential amino acid supplementation in patients with severe
COPD: a step towards home rehabilitation. Monaldi Arch Chest Dis. (2012)
8. ^ Malaguarnera M, et al. L-Carnitine treatment reduces severity of physical and
mental fatigue and increases cognitive functions in centenarians: a randomized and
controlled clinical trial. Am J Clin Nutr. (2007)
9. ^ Audrey Chanet, et al. Supplementing Breakfast with a Vitamin D and Leucine-
Enriched Whey Protein Medical Nutrition Drink Enhances Postprandial Muscle Protein
Synthesis and Muscle Mass in Healthy Older Men. J Nutr. (2017)
10. ^ Jürgen M Bauer, et al. Effects of a vitamin D and leucine-enriched whey protein
nutritional supplement on measures of sarcopenia in older adults, the PROVIDE
study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc.
(2015)
11. ^ Wolfgang Kemmler, et al. Whole-body electromyostimulation and protein
supplementation favorably affect sarcopenic obesity in community-dwelling older men
at risk: the randomized controlled FranSO study. Clin Interv Aging. (2017)
12. ^ Prashanth H Haran, Donato A Rivas, Roger A Fielding. Role and potential
mechanisms of anabolic resistance in sarcopenia. J Cachexia Sarcopenia Muscle.
(2012)

39
13. ^ Stefano Marinari, Maria Rosaria Manigrasso, Fernando De Benedetto. Effects of
nutraceutical diet integration, with coenzyme Q10 (Q-Ter multicomposite) and
creatine, on dyspnea, exercise tolerance, and quality of life in COPD patients with
chronic respiratory failure. Multidiscip Respir Med. (2013)
14. ^ Paul Flakoll, et al. Effect of beta-hydroxy-beta-methylbutyrate, arginine, and lysine
supplementation on strength, functionality, body composition, and protein metabolism
in elderly women. Nutrition. (2004)
15. ^ Newman AB, et al. Strength, but not muscle mass, is associated with mortality in
the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci.
(2006)
16. ^ Petra Wiedmer, et al. Sarcopenia - Molecular mechanisms and open questions.
Ageing Res Rev. (2021)

40
Interview: Cyriac Abby Philips, MBBS,
MD, DM (Hepatology)
 Tags: NERD Interview

 Read this article online at Examine.com

Dr. Cyriac Abby Philips is currently working as Consultant and Physician-Scientist, in The Liver
Unit and Monarch Liver Laboratory of the Cochin Gastroenterology Group, based in Kochi, under
Philip Augustine Associates. He is also the Clinical Advisor and Doctoral Advisory Committee
Member, Department of Cell and Tissue Culture at Sree Chitra Tirunal Institute for Medical
Sciences and Technology, a Central Institute under the Government of India, at Trivandrum,
Kerala.

Dr. Philips is a two-time American Association for the Study of Liver Diseases (AASLD) clinical
hepatology plenary awardee (2015, 2017) and three-time AASLD Young Investigator Award winner
(2015, 2016, 2017) and the 2017 winner of the Young Investigator Award of the European

41
Association for the Study of Liver (EASL) for his works on fecal microbiota transplantation in liver
disease, Ayurveda and herbal induced liver injury and gut microbiome in alcohol related liver
disease. He was conferred the President of India Gold in Hepatology at the Institute of Liver and
Biliary Sciences, New Delhi in 2016.

He has published over 160+ peer reviewed articles in high impact journals such as the New
England Journal of Medicine, Journal of Hepatology, Hepatology and American Journal of
Gastroenterology. He has authored over 12+ chapters on topics in cirrhosis, portal hypertension,
alcohol-associated liver disease and drug induced liver injury. He is currently editorial member,
academic and guest editor of the Indian Journal of Gastroenterology, Journal of Clinical and
Translational Hepatology, BMC Gastroenterology and Biomed Research International. His
pioneering work in the field of liver diseases has been the introduction of healthy donor fecal
transplant for severe alcoholic hepatitis and novel data on toxicology and chemical analysis of
complementary and alternative medicine (specifically AYUSH related) induced liver injury.

You can find him on Twitter at: @drabbyphilips.

Q. Can you provide us with some background on

Ayurveda? What is its history and how is it used today?
Can it be classified as a subset of "herbal
supplements," or is it in a class of its own?
Ayurveda is a traditional system of medicine that originated in India. Principles of Ayurvedic
practice are based on accounts of disease and management embodied in classical texts written by
ancient ‘sages’, such as Charaka (medicine) and Susruta (medicine and surgery), who ‘received’
such direct knowledge from other sages and through the Hindu god of medicine, Dhanvantari. This,
in principle, makes Ayurveda an ancient, traditional, faith-based system of complementary and
alternative medicine with historical roots entrenched in primeval beliefs that is still taught and
propagated in its naïve form globally.

Ayurveda forms part of the larger unified traditional system of medicine called AYUSH (Ayurveda,
Yoga and Naturopathy, Unani, Siddha and Homeopathy) that is operational in India and which is
overseen and promoted by an independent central-union ministry of AYUSH. Currently, Ayurveda
is heavily promoted and utilized as a system with ‘safer’ options and ‘time-tested’ treatments.
However, these two terms are inaccurate, since the promotion of ‘safety’ of Ayurvedic medicines
has been heavily criticized, with emerging evidence showing severe organ toxicity, such as liver
and kidney damage associated with short, intermediate, and long-term use of Ayurvedic drugs.

42
Similarly, the term ‘time-tested,’ according to valid scientific methodology, does not mean
efficacious. This makes Ayurveda a pseudoscience, with the majority of its current practice lacking
supporting evidence for efficacy and safety. None of the Ayurvedic drugs or treatment protocols are
approved or used as standard of care.

In general, Ayurveda treatments involve the use of probably safe external applications or
consumption of simple or complex combinations of herbs, metals, and minerals. These are
classified into those which are prepared according to ‘classical ancient texts’ called classical
Ayurvedic drug formulations (for example, chyawanprash) or proprietary herbal drugs that are
defined as compound formulations that are developed by individuals or pharmaceutical companies
with a proprietary right to the drug formulation and its marketing (for example, Liv.52 by
Himalaya®). In this regard, current Ayurveda practice involves the use of herbal components in
drugs, dietary supplements, and nutraceuticals. It is a much larger industry than just the
supplements industry, because of its advertised use in ‘therapeutics.’

Q. You've published quite a bit of research focused on

the health concerns of Ayurveda/herbal supplements,
particularly with respect to liver toxicity. When and
why did you first become interested in this topic?
After completing my training in Hepatology and Liver Transplant Medicine at the Institute of Liver
and Biliary Sciences, New Delhi, I returned to my home city of Kochi, situated in the South Indian
state of Kerala in the year 2016 to start my clinical practice. My interest was originally alcohol-
associated liver diseases (AALD) as Kerala, my home-state, has among the highest-burden of
alcohol use and AALD.

However, during the initial few months of my clinical practice, I started to notice many patients with
acute liver injury (acute hepatitis with jaundice) and acute liver failure (jaundice with cerebral failure
or encephalopathy) without any standard identifiable causes, such as viral infections, prescription
drugs with known liver toxicity (for example, old-world painkillers and antibiotics like anti-
tuberculosis drugs), autoimmune liver disease, etc. I then proceeded to perform liver biopsies on
these patients after receiving informed consent and found that the liver pathology was suggestive
of severe, but varied, injury patterns. These findings prompted me to deep dive into the clinical
history of the patients to determine the onset of liver injury events in retrospect. What I found was
that all of these patients, who did not have identifiable causes for their liver injury, were consuming
at times single, most times multiple, classical and proprietary Ayurvedic herbal products for various
symptoms and illnesses, ranging from ‘gas formation’ to diabetes and fatty liver, for a few days to a
few months, presuming they were “natural and safe” and hence they did not feel the need to

43
disclose this to the treating physician.

I proceeded to document this with attentiveness in the many cases that followed. I went one novel
step further to retrieve the suspected offending Ayurvedic herbal drug(s) from the patients’ home
(some almost nine hours journey by road) and subjected these medicines to chemical and
toxicology analysis (the analyses funding was borne by me from my salary, which I continue to do
so, for public health and education). What we discovered from these analyses was interesting and
novel, yet concerning. Thereafter, I published my findings as a large single series on Ayurvedic
herbal drugs and liver injury with complete chemical/toxicology analysis, in the peer-reviewed
Indian Journal of Gastroenterology (official publication of the Indian Society of Gastroenterology) in
2018[1], on which an editorial was written, titled Ayurvedic and herbal medicine-induced liver injury:
It is time to wake up and take notice[2]. This study and its findings—that “herbal” does not mean
“natural and safe”—changed the course of my work interest toward drug-induced liver injury
specifically due to the AYUSH group of drugs. I continue to work on this aspect of untested
Ayurvedic herbals, since this was a ‘hidden’ danger to public health on which there is the need to
strongly voice, through science-based evidence generation, realistic health education.

Q. Do you believe there is a place in modern medicine

for Ayurveda and herbal supplements?
Yes, I do believe that, but not in the current form. Ayurveda is not scientific, some of its aspects are
‘half-baked’, and principles of diagnosis and management are ‘thoughts that border on science’,
with current practical applications that are not evidence-based. The first step is to consider
Ayurveda a “stepping stone,” rather than the final word in disease prevention and management.

This would mean promoting Ayurveda as a pure branch of ‘translational medicine,’ in which the
application of rigorous clinical research protocols and tools, new cutting-edge technologies, and
analytics will help us identify and generate data on novel bioactive molecules or compounds that
can be then put to use in phased quality trials to promote better clinical outcomes in specific
diseases or groups of patients. The current form of Ayurveda is still ‘faith/belief’-based, running on
‘business mode,’ mostly powered by general public sentiments, and patient gullibility, both of which
are promoted through unregulated false advertisement-based selling. Use of Ayurveda should be
only for bench-to-bedside clinical-translational purposes and not as a therapy.

Q. Can Ayurveda and herbal supplements increase the

risk of (or even cause) liver injury? If so, is it the
supplements themselves or contaminants in the
44
supplements?
Contrary to popular belief, Ayurvedic herbals and herbal drugs, including those in traditional
Chinese medicine, are not safe. They can cause tremendous toxicity to human organs, and in the
process produce significant health burdens and resource utilization. Speaking strictly from
Ayurvedic herbals point of view, it is well known that contamination and adulteration have caused[3]
significant[4] heavy metal poisoning, even in large population clusters.

In addition to our original work on investigating Ayurvedic herbal drugs causing severe liver injury
and acute liver failure, we have also shown that use of Ayurvedic herbals in patients with chronic
liver disease (meaning they have an increased risk for injury) can lead to acute or chronic liver
failure, with a very low chance of surviving without a liver transplant. We published this finding in
the peer-reviewed journal, Hepatology Communications[5]. Also, traditional use of Ayurvedic
systems for management of jaundice (symptom-based management rather than disease- or
syndrome-based treatment) among patients with severe alcohol-associated hepatitis led to a high
death rate[6].

That complementary and alternative medicine use—such as Ayurvedic herbal and traditional
Chinese medicines—can cause severe liver injury and even death has also been shown in
multinational studies conducted by the Asia-Pacific Association for Study of the Liver[7]. The cause
for such adverse events can be summarized into three categories: 1) Adulteration with known
hepatotoxic agents (for example: painkillers in herbal drugs for arthritis); 2) Contamination during
manufacturing (example: heavy metals, industrial solvents from equipment), and; 3) Direct toxicity
from single or multiple herbs in Ayurvedic medicine. In the latter, toxicity can happen with known
toxic herbal components, such as pyrrolizidine alkaloids (the herb Crotalaria) due to ignorance and
poor sourcing, causing severe injury to blood vessels in the liver; or epigallocatechin gallate (green
tea extracts) that is liver toxic in high doses (unregulated herbal dietary supplements). Direct
toxicity can also happen with unknown and unidentified plant-based chemicals such as saponins,
terpenes, and anthraquinones.

Q. One of your publications, a case study on a woman

who experienced acute liver failure while taking
Herbalife products, was recently retracted. Can you
run us through what happened?
Herbal and dietary supplements causing liver failure is well documented in the literature. This is
also true of Herbalife products, on which multiple studies and publications are already available in

45
peer reviewed journals.

In August 2018, we published the first account of Herbalife-associated liver failure and death in a
young woman from the Asia-Pacific region, entitled: “Slimming to the Death: Herbalife®-Associated
Fatal Acute Liver Failure-Heavy Metals, Toxic Compounds, Bacterial Contaminants and
Psychotropic Agents in Products Sold in India,” published by Elsevier in the Journal of Clinical and
Experimental Hepatology (JCEH), the official journal of the Indian Association for the Study of the
Liver (INASL). After this was published, Herbalife employees reached out to me to show proof of
evidence. I replied saying that all the proof was present in the peer-reviewed published study.
Thereafter, Elsevier forwarded me an email from Prof. Steven McMaster of the University of
Guelph (whose activities are funded by Herbalife), who wrote a long list of issues with respect to
the article, asking Elsevier to retract my paper. Elsevier advised me to reply to the letter in a point-
by-point manner. My co-authors and I complied with a strong evidence-based rebuttal. I did not
hear from Prof. McMaster again.

Afterward, another letter, this time to the editor in chief of JCEH, was submitted by Dr. Zambrone
and colleagues who work at Planitox, a company funded by Herbalife. The editor in chief
suggested that I write a point-by-point rebuttal. I did that and both the letter and the reply were
published by the journal. Soon after, I received legal notice from DSK Legal in Delhi on behalf of
Herbalife stating that I produce more evidence. I replied to the legal notice with all proof of
evidence that built our scientifically valid study, specifying that it has undergone peer review before
being published. My report, its contents, and the patient’s family ordeal (an interview with the
deceased patient’s husband) were thereafter reported by a health journalist, who published it in the
online paper The Lede. (Other media were not willing to run the story due to fear of litigation, as
Herbalife is well known to litigate.) But little did I know that Herbalife was sending multiple legal
letters to the journal’s editor in chief, editorial assistants, the society, and its president, behind our
backs.

This led to panic in the editor in chief and the INASL president. The editor in chief called me and
said they were going to re-review the paper as per COPE guidelines to look for scientific integrity. I
agreed. He asked me to furnish original patient data, including the liver biopsy report, which meant
unmasking patient detail. I did that, too, and after completion of the repeat review, I was not notified
of any integrity issues. It was a clean, valid paper. If it was not, this would have been
communicated.

But then, suddenly, one day I received an email from Mr. Sameer Gupta of Elsevier, notifying me
that my article will be removed due to legal reasons. No choice given; they were going to remove it.
And they did. Initially, the reasons for removal were 'legal.' Later on, they modified this statement to
“This article, which was published in the March-April 2019 issue of the journal, has been removed
at the request of the JCEH’s Editor-in-Chief and the Indian National Association for the Study of the

46
Liver (INASL). INASL and JCEH no longer support the content of and conclusions drawn in the
article because the scientific methodology, analysis and interpretation of data underlying the article
were insufficient for the conclusions drawn, and, with its removal, the article can no longer be relied
upon.” This statement modification was completely false, immoral, unscientific and it was an insult
to the authors and to the spirit of science. Also note that INASL has absolutely no role in decision-
making from this article’s point of view and, at the time, the president of INASL advised the editor in
chief to remove the article and provide selfish reasons to save the journal and the society, leaving
the authors (us) to fend for ourselves. The proof to support these statements were never declared
or shared with us, since the two rounds of peer review came back clean.

So, we sent a legal notice to the journal, editor in chief and the INASL, stating they remove the
modified versions of the statement and restore the original version. To top this, the published letter
(by Zambrone et al.) and our reply to it was also removed and then retracted without notifying me
or the co-authors, and without any substantiating reasons provided by the journal or the publisher.
This, again, was handwashing from the journal and INASL to save themselves and not because of
any issues with the science we published. The statements were changed on PubMed, but remain
the same on the journal website to protect the interest of the journal and the INASL—against the
science and reasoning.

Q. Are you disputing this retraction, and if so, how and

why?
My article was removed, the removal reasons were unjustly modified without notification, and
thereafter two letters were retracted without reasons or notification, only to satisfy Herbalife’s
threats and to save the journal’s face. The publisher and the journal have been ignoring the
commotion this industry-driven unscientific practice has caused. I emailed Elsevier regarding the
issue and have not heard back from them. INASL and the journal JCEH remain ignorant to this
issue still—they like to play dead, wishing that the trouble will go away after a while. But I have
raised this issue with the Committee on Publication Ethics (COPE) for an arbitration because it was
COPE’s guidelines that were fully broken in this dirty deal. This investigation is ongoing.

Meanwhile, I have prepared an updated version of the manuscript, including raw metadata on
sample analysis, product raw metagenomic results, and a blinded patient biopsy report to be
uploaded to Zenodo (CERN research repository). Going against the journal and the publisher on
legal terms is our last resort, since we are only salaried physicians from a low-income country who
will need to struggle from both a time and financial point of view, to take the fight uphill.

Q. What changes do you think are needed to help keep

47
valid scientific findings available while also providing
room for healthy scientific debate and dispute?
Thank you for this question. The onus lies mostly on the journal and its editorial board. If a journal
has decided to publish scientifically valid findings, but one that could potentially attract conflicts and
debate, without doubt, the decision to persevere and defend such allegations must be made on the
basis of scientific credibility only, and not peer pressure and legal threats which foster escapism at
the cost of credible science. If there is solid science and evidence backing up the claims made in a
paper, the scientific community and the journal/publisher need not fret.

This is exemplified by similar publications on Herbalife in the Journal of Hepatology, which still
remain in the scientific databases, without coercion to remove or such allegations, even though the
journal is published by the same Elsevier who retracted our paper unreasonably as per advice from
the journal (JCEH) and society that owns the journal. Healthy scientific debates about concerns
should be made through letters to the editor, wherein both the parties receive the chance and the
right to defend each other’s statements. Such deliberations will nurture rational and realistic
discussions that ensure debates happen within the scientific domain—and not throw it open for
stakeholders to steer its outcome or demean science.

Q. Is there anything else you’d like our readers or

other members of the scientific community to know?
For the reader, I would like to stress that one must not be blinded by the terms ‘natural,’ ‘herbal,’
and ‘safe’—they must question it, like they question the adverse events associated with a
procedure or the side effects associated with a conventional prescription drug. Always be curious
when it comes to one’s own health. Do not blindly follow or fall for what is always advertised in the
‘positive’. If possible, have an open discussion with your primary care physician or a
specialist—who must also be ready to rationalize and be well-informed regarding alternative
medicines.

For the members of the scientific community, I would urge them to provide detailed questions on
the history of complementary and alternative medicine use to every patient they come in contact
with, mandatorily. This would help us understand health-seeking behavior to identify interventional
strategies for primary prevention and provide insights on clinical outcomes to prepare management
protocols better. If there is an observation which is novel or reportable from a public health
perspective, follow it up with validated scientific methods and generate solid evidence to bring it to
the table. Science and patient outcomes can improve this way only.

48
The views and opinions expressed by interviewees are their own,
and do not necessarily reflect those of Examine.

^ Go back to table of contents

49
 References
1. ^ Cyriac Abby Philips, et al. Clinical outcomes, histopathological patterns, and
chemical analysis of Ayurveda and herbal medicine associated with severe liver
injury-A single-center experience from southern India. Indian J Gastroenterol. (2018)
2. ^ Harshad Devarbhavi. Ayurvedic and herbal medicine-induced liver injury: It is time
to wake up and take notice. Indian J Gastroenterol. (2018)
3. ^ Laura Breeher, et al. A cluster of lead poisoning among consumers of Ayurvedic
medicine. Int J Occup Environ Health. (2015)
4. ^ Marek A Mikulski, et al. Toxic metals in ayurvedic preparations from a public health
lead poisoning cluster investigation. Int J Occup Environ Health. (2017)
5. ^ Cyriac Abby Philips, et al. A Single-Center Experience on Outcomes of
Complementary and Alternative Medicine Use Among Patients With Cirrhosis.
Hepatol Commun. (2019)
6. ^ Cyriac Abby Philips, et al. Outcomes and Toxicology of Herbal Drugs in Alcoholic
Hepatitis - A Single Center Experience from India. J Clin Transl Hepatol. (2019)
7. ^ Harshad Devarbhavi, et al. Drug-Induced Acute-on-Chronic Liver Failure in Asian
Patients. Am J Gastroenterol. (2019)

50
Deep Dive: Comparing the efficacy of diet,
exercise, and lifestyle modifications for
controlling childhood obesity
 Tags: Obesity, Children, Meta-analysis, Dieting, Exercise, Weight Loss, Overweight

 Study under review: The effect of diet, exercise, and lifestyle intervention on childhood
obesity: A network meta-analysis

 Read this article online at Examine.com

Quick Takes
• What was the question? What are effective methods for
controlling childhood obesity?
• How was it answered?: Researchers conducted a network
meta-analysis of randomized controlled trials that compared
the efficacy of various interventions designed to control
childhood obesity.
• Who was studied? Participants included children with
overweight and obesity and a mean age of 6–12 years old.
• What was the intervention? Interventions included diet,
exercise, multicomponent interventions, with or without
parent involvement, for a duration of 1–18 months.
• What’s the main takeaway? Many dietary, exercise, and
lifestyle interventions were found to be effective for reducing
child obesity metrics. The best methods involved letting

51
 children move on their own, or dietary changes with or
without the parents involved.
• Any caveats? Most of the studies were short term, so the
results may not be applicable to longer periods of time. In
addition, the exact treatments associated with each
intervention varied quite a bit and were not specified or
considered. Finally, there was a lot of uncertainty in the final
estimates, meaning that the rankings and effect sizes could
likely change as more evidence becomes available.

Introduction
Body mass index (BMI) is used to define childhood overweight and obesity. However, BMI works a
little differently in children than in adults. In adults, BMI is calculated by dividing weight in kilograms
by height in meters squared. In comparison, the status of a child’s weight is determined using an
age- and gender-specific percentile for BMI (referred to as BMI-for-age) because child body
composition varies by age and sex. Overweight for a child is defined[1] as a BMI-for-age equal to or
greater than the 85th percentile and less than the 95th percentile. Obesity for a child is defined as
a BMI-for-age equal to or greater than the 95th percentile. The details of BMI-for-age for both boys
and girls is shown in Figure 1.

Figure 1: BMI-for-age for girls and boys ages 2–18

52
Reference: CDC. 2000 CDC Growth Charts for the United States: Methods and Development. 2002 May.

The World Health Organization reports that childhood obesity has been steadily increasing
throughout the world. In 2019, 38 million children younger than 5 years old were overweight or
obese. Childhood overweight and obesity [2]adversely affect[2] many organ systems and can lead to
complications, including high blood pressure, adverse changes in blood lipid levels, insulin
resistance, fatty liver disease, physical limitations, and psychosocial difficulties. This is why it is
imperative to find effective ways to prevent and reverse childhood overweight and obesity.

Several [3]studies have investigated[3] the beneficial effects of individual interventions such as diet,
exercise, and lifestyle to control childhood overweight and obesity. However, there are no
systematic reviews that rank interventions to determine which work best for controlling childhood
overweight and obesity. Through the use of a network meta-analysis, this study was designed to
compare and evaluate the results of pertinent interventions in order to identify the most effective
method(s) of intervention to control childhood overweight and obesity.

The prevalence and consequences associated with childhood

53
 overweight and obesity make these conditions a serious issue that
needs to be addressed. Although there are studies that have
examined the beneficial effects of various interventions
individually, there are no systematic reviews that compare the
efficacy of several interventions or combinations of interventions
(e.g., diet, exercise, lifestyle, multicomponent) both with and
without parental involvement. The researchers conducting this
study used a network meta-analysis to compare the efficacy of
these interventions both with and without parental involvement.

What was studied?

The present study was a network meta-analysis examining the efficacy of different interventions for
children with overweight or obesity. The study was reported in accordance with the PRISMA for
Network Meta-Analyses guidance. The study was not preregistered.

The meta-analysis included randomized controlled trials conducted in 6–12-year-olds with obesity
(BMI-for-age greater than the 95th percentile) or overweight (BMI-for-age greater than the 85th
percentile and less than the 95th percentile). Studies including children with diseases or disorders
were excluded. Studies were required to have either data available to calculate or actual data for
BMI, BMI-z-score (also call BMI standard deviation score, which refers to a measurement of
relative weight adjusted for child age and sex), percent body fat, or percent overweight. Included
studies had to have direct evidence from RCTs that compared two or more interventions like
modifications involving diet, exercise, lifestyle, a combination of two of the three interventions, or all
three interventions, with or without parental involvement; or indirect evidence from RCTs that
compared an intervention group with a control group. “Lifestyle” interventions usually involved
advice or monitoring of factors like screen time, TV watching, and other everyday habits that could
affect activity levels. However, the specific lifestyle parameters of each study were not specified.
Studies in any language and from any date up to February 2019 were considered for inclusion.

The primary outcomes were changes in BMI, BMI z-score, percent body fat, or percent overweight.
Since there were so many outcomes, the researchers transformed them to standardized mean
differences (SMDs) in order to compare them directly. For a refresher on SMDs (sometimes used

54
interchangeably with the term “effect size”), check out a previous NERD sidebar on the topic here.
The authors called this combination of the outcomes an “obesity index,” so this term is used below
as well.

Once the outcomes were transformed to an obesity index, the authors conducted a network meta-
analysis to compare the outcomes to each other to determine which interventions had the biggest
effects on the obesity index. P-scores were also calculated to rank the probability of various
treatments for different outcomes from the network meta-analysis. A p-score in a network meta-
analysis represents the probability that a given treatment would rank as the best one. The lower
the p-score, the less likely the intervention is the best one.

Bias was assessed using the Cochrane Collaboration risk of bias tool[4] to evaluate the risk from
the randomization process, deviation from the intended interventions, missing outcome data,
outcome measurement, and selecting reporting results. The quality of evidence was evaluated
using the Confidence In the Results method from the Network Meta-Analysis (CINeMA)
approach[5], which is based on the GRADE (Grading of Recommendations, Assessment,
Development, and Evaluation) approach[6]. The quality of data was assessed based on within-
study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence.

The study under review was a network meta-analysis examining

the efficacy of diet, exercise, lifestyle, and combinations of these
interventions, with and without parental involvement, for the control
of childhood overweight and obesity. Participants were children
between the ages of 6 and 12 years old with overweight or obesity.
The primary outcomes were changes in bodyweight indicators.
These were combined into a single “obesity index.” Researchers
evaluated risk of bias and quality of evidence.

What were the findings?

The researchers selected a total of 24 studies conducted in several countries published between
1984 and 2017 for evaluation in the meta-analysis. Some of the main study characteristics are
summarized in Figure 2.

55
 Figure 2: Main characteristics of the included studies

The outcomes are summarized in Figure 3. The top three interventions were exercise without
parental supervision, which had the highest effect size and the largest chance of being the best
intervention, based on P-score, followed by dietary interventions with or without parental
supervision.

Figure 3: Effects of each intervention type versus no

56
 intervention, with 95% confidence intervals

The risk of bias assessment showed 5 studies with low risk, 18 studies with some concerns, and no
studies with high risk. Risk of bias was due to randomization processes, deviations from the
intended intervention(s), and concerns in the missing outcome domain because they included only
girls or did not report gender rates. The risk of bias from blinding could not be assessed because
blinding is not possible in these types of intervention studies.

The degree of heterogeneity between trials was high at 88.6%.

Exercise without parental involvement was the most effective

intervention for decreasing obesity index in children with
overweight or obesity. Diet modifications with or without parental
intervention were the next most effective interventions. There were
no studies with a high risk of bias and the quality of evidence was
low to moderate.

57
The bigger picture
Fundamentally, the cause of obesity and overweight is an energy imbalance between calories
consumed and calories expended. However, the factors that can be changed to most effectively
influence this imbalance in children is an open question, which the study under review aimed to
address.

This study found that letting children exercise without having a parent involved was the most
effective intervention in terms of decreasing the obesity index in children. It does make sense that
exercise may help with weight maintenance or loss because it burns some calories, may help
develop muscle mass, which increases resting metabolism, and it is time spent moving, rather than
sitting and eating. A study in children with obesity showed that [7]exercise increased calorie burn[7]
for at least two to three hours after exercise, and regular exercise [8]reduced the risk[8] of obesity. It
is important to note that even without weight loss, physical fitness results in health benefits for
children with overweight, so exercise is beneficial independent of its effects on weight.

In the current meta-analysis, the longest study duration examining exercise alone was only four
months, which casts doubt on the long-term benefits of exercise alone. Furthermore, there are no
studies that looked at exercise with parental involvement. Although exercise without parental
involvement may be effective in the short term, it is not clear whether parental involvement would
be necessary to maintain the weight loss, or even if additional interventions like dietary or lifestyle
modifications would be necessary.

Dieting with parental involvement and dieting without parental involvement were the next most
effective interventions. As shown in Figure 3, the confidence intervals for both interventions,
especially dieting without parental involvement, is fairly large. This means that the data are
compatible with effect sizes ranging from the very large to very small. While previous[9] studies[10]
have found that parental involvement leads to more successful obesity treatment programs, this
meta-analysis leaves the question a little more open because of the uncertainty of the effect sizes.

Overall, the strength of evidence when parents were involved was moderate, while the strength of
evidence for these interventions without parental involvement was very low. Similarly, in a [11]meta-
analysis[11] of childhood obesity prevention programs, the strength of evidence for interventions
involving physical activity conducted in schools that included home involvement was high, while the
strength of evidence for school-only interventions directed at physical activity was moderate. Thus,
while there’s still uncertainty, the overall evidence seems to suggest that parental support
influences the success of weight-loss interventions.

In this study, interventions combining diet and exercise, with or without parental involvement, were
not significantly effective for the treatment of childhood obesity. This finding is likely due to the

58
heterogeneity of the studies, which is likely related to differences in the method of exercise, type of
diet, and means or extent of parental involvement in the studies. Even so, diet and exercise without
parental involvement had a much higher P-score (0.52) than no intervention (0.09), and diet and
exercise with parental involvement had double the P-score (0.2) of no intervention. Three[12]
Cochrane[13] reviews[14] focusing on different age groups also provide support for the idea that a
multi-modal approach could have a meaningful impact on childhood weight, although they do state
that the evidence is generally short-term and low quality. Thus, it’s likely that the combination of
diet and exercise is effective to some degree, and the lack of statistical significance found in the
study under review is primarily due to the major differences between the combined studies.

The major strength of this study is that it was the first meta-analysis to use a network meta-analysis
to compare several interventions with and without parental involvement in addition to examining the
differences in efficacy between parent involvement and lack of parent involvement and each
treatment type. Critical limitations of this study include the lack of consideration of differences
between durations of programs and environments of programs (i.e., school-based, home-based, or
center-based). Also, this study can’t speak to which types of exercise, diets, and lifestyle
interventions work best because the study designs in the trials were all quite different from each
other. Finally, since the longest study involved in this meta-analysis had a duration of 18 months,
and the longest duration for exercise-specific interventions was only 4 months, this study can’t
address the longer-term efficacy of these interventions.

Despite the limitations of the current evidence, these results are mainly in-line with evidence-based
[15]practice guidelines[15] for the assessment, treatment, and prevention of pediatric obesity. These

guidelines were developed in 2017 based on two commissioned systematic reviews alongside
additional systematic reviews and other studies. The guidelines suggest promoting a healthful diet,
increased activity, and targeting environmental factors.

While exercise without parental involvement was found to be most

effective, the studies looking at exercise lasted only several
months, raising the question of whether the observed benefits
would extend to the longer term. Similar questions about longer-
term efficacy also apply to the other interventions. There is also
quite a bit of uncertainty and heterogeneity in the evidence.
Despite the uncertainty around parental involvement and
combined approaches to weight control, the results in this study,

59
 combined with outside evidence, suggest that both may have a
meaningful impact on weight. Finally, these results are in-line with
evidence-based guidelines that stress the importance of healthful
diet, activity, and environmental factors for controlling children’s
weight.

Frequently asked questions

Q. Wouldn’t the most effective intervention be different for each child? Can you really say
what the best intervention is for all children?

In 2017, the National Institutes of Health sponsored a workshop[16] called “Developing Precision
Medicine Approaches to the Treatment of Severe Obesity in Adolescents” that addressed the
potential for tailored treatment strategies. Participants concluded that individual treatments could
only be developed by achieving a better understanding of individual differences in genetics,
behaviors, environment, and physiological and psychological factors. However, the workshop
participants concluded that there were a lot of knowledge gaps that need to be filled before specific
interventions could be tailored to individual children.

Q. Is there other evidence to support using only increases in activity to control childhood
overweight and obesity?

A recent study examined whether the World Health Organization’s recommendation of 60 minutes
of moderate to vigorous physical activity per day could protect children against the occurrence of
overweight and obesity. The researchers found that children spending less than 60 minutes per
day exercising had a greater risk of occurrence of overweight and obesity than children engaging in
60 or more minutes of physical activity per day.

What should I know?

Childhood obesity is an epidemic with serious consequences for health and physical function. The
variety of factors that contribute to childhood obesity make it difficult to determine the most effective
intervention(s). This study found that children with obesity or overweight could benefit from

60
engaging in more movement on their own and dietary changes, either with or without their parents
involved. Many studies stress the importance of a combination of diet, exercise and lifestyle
modifications, and especially the involvement of parents.

Are you surprised that exercise was found to be the best

intervention in this study? See if your fellow NERD readers also
found it surprising over at the private NERD Facebook discussion
forum.

^ Go back to table of contents

61
 References
1. ^ Sarah E Barlow, Expert Committee. Expert committee recommendations regarding
the prevention, assessment, and treatment of child and adolescent overweight and
obesity: summary report. Pediatrics. (2007)
2. ^ a b Neslihan Koyuncuoğlu Güngör. Overweight and obesity in children and
adolescents. J Clin Res Pediatr Endocrinol. (2014)
3. ^ a b Callie L Brown, et al. Addressing Childhood Obesity: Opportunities for
Prevention. Pediatr Clin North Am. (2015)
4. ^ Higgins JP, et al. The Cochrane Collaboration's tool for assessing risk of bias in
randomised trials. BMJ. (2011)
5. ^ Adriani Nikolakopoulou, et al. CINeMA: An approach for assessing confidence in
the results of a network meta-analysis. PLoS Med. (2020)
6. ^ Romina Brignardello-Petersen, et al. Advances in the GRADE approach to rate the
certainty in estimates from a network meta-analysis. J Clin Epidemiol. (2018)
7. ^ a b Eric Stice, Heather Shaw, C Nathan Marti. A meta-analytic review of obesity
prevention programs for children and adolescents: the skinny on interventions that
work. Psychol Bull. (2006)
8. ^ a b E Zorba, T Cengiz, K Karacabey. Exercise training improves body composition,
blood lipid profile and serum insulin levels in obese children. J Sports Med Phys
Fitness. (2011)
9. ^ Kirsten K Davison, et al. A childhood obesity intervention developed by families for
families: results from a pilot study. Int J Behav Nutr Phys Act. (2013)
10. ^ S Marsh, et al. Family-based interventions for reducing sedentary time in youth: a
systematic review of randomized controlled trials. Obes Rev. (2014)
11. ^ a b Y Wang, et al. What childhood obesity prevention programmes work? A
systematic review and meta-analysis. Obes Rev. (2015)
12. ^ Jill L Colquitt, et al. Diet, physical activity, and behavioural interventions for the
treatment of overweight or obesity in preschool children up to the age of 6 years.
Cochrane Database Syst Rev. (2016)
13. ^ Emma Mead, et al. Diet, physical activity and behavioural interventions for the
treatment of overweight or obese children from the age of 6 to 11 years. Cochrane
Database Syst Rev. (2017)
14. ^ Lena Al-Khudairy, et al. Diet, physical activity and behavioural interventions for the
treatment of overweight or obese adolescents aged 12 to 17 years. Cochrane

62
 Database Syst Rev. (2017)
15. ^ a b Dennis M Styne, et al. Pediatric Obesity-Assessment, Treatment, and
Prevention: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab. (2017)
16. ^ Aaron S Kelly, et al. Working toward precision medicine approaches to treat severe
obesity in adolescents: report of an NIH workshop. Int J Obes (Lond). (2018)

63
Deep Dive: Do Low-Carb Diets Stoke the
Metabolic Fire?
 Tags: Meta-analysis, Metabolism, Low-Carb, Weight Loss

 Study under review: Do Lower-Carbohydrate Diets Increase Total Energy Expenditure?

An Updated and Reanalyzed Meta-Analysis of 29 Controlled-Feeding Studies

 Read this article online at Examine.com

Quick Takes
• What was the question? What effect does dietary
carbohydrate have on total energy expenditure (metabolic
rate)?
• How was it studied? Researchers conducted a meta-
analysis of controlled feeding trials to compare the effect of
low vs. high carbohydrate diets on total energy expenditure.
• Who was studied? Exact participant details were not
provided, but it’s safe to assume the participants were 18
years of age or older.
• What was the intervention? The interventions were diets
with different carbohydrate-to-fat ratios, but the same amount
of protein. The diets being compared differed in carbohydrate
content by 8–77% of total energy.
• What’s the main takeaway? When dividing studies by
duration, lower-carbohydrate diets reduced energy

64
 expenditure in studies shorter than 2.5 weeks, while they
increased energy expenditure in studies longer than 2.5
weeks.
• Any caveats? The findings that longer-duration, lower-
carbohydrate diets increased total energy expenditure is
limited to only six studies, 50% of which used the doubly-
labeled water method, which has been shown to
overestimate total energy expenditure during low-
carbohydrate diets. Other limitations, such as a lack of
preregistration and information about study quality, also call
for caution when interpreting the results.

Introduction
Weight loss is one of the most effective tools for lowering the risk of chronic diseases like diabetes
and cardiovascular disease. Weight loss requires a calorie deficit over an extended period of time,
which can occur via reduced calorie intake, increased energy expenditure, or both. It’s been
hypothesized that the macronutrient distribution of a diet affects total energy expenditure, in that
low-carbohydrate diets are successful partly due to their ability to increase the thermic effect of
food and basal metabolic rate.

There have been several studies that have examined the effects of low-carbohydrate diets on total
energy expenditure (TEE), as compared to high-carbohydrate diets. For example, one randomized
controlled trial[1] found that a low-carbohydrate diet containing 20% calories coming from carbs
increased total energy expenditure by about 100–200 kcal per day. However, another randomized
controlled trial[2] found that a very high-carbohydrate diet led to an approximate 350 kcal per day
increase in total energy expenditure, compared to a very low-carbohydrate diet. Furthermore, a
previous 2017 meta-analysis[3] of 28 studies found that a lower-carbohydrate diet reduced total
energy expenditure by about 25 kcals per day. However, the trials in that meta-analysis had a
median duration of about four days. Some have argued that there is a metabolic adaptation period

65
to low-carbohydrate diets that takes several weeks, and the proposed increase in TEE only occurs
after that adaptation period is complete.

To test this hypothesis, the authors of the present study conducted a meta-analysis to compare the
effects of diets differing in carbohydrate content on TEE over shorter and longer periods of time.

Total energy expenditure is one of the primary components that

determines weight loss. There has been speculation that differing
macronutrient profiles may have meaningful effects on total energy
expenditure, making some diets more effective for weight loss.
Randomized trials have led to conflicting results on whether lower-
carbohydrate or higher-carbohydrate diets are more effective for
fat loss. Potential interactions with diet duration have not been
considered in previous meta-analyses. The authors of the present
study used a meta-analysis to compare the effects of diets differing
in carbohydrate content on TEE over shorter and longer periods of
time.

What was studied?

The present study was a meta-analysis comparing the effect of lower carbohydrate diets to higher
carbohydrate diets and their effects on total energy expenditure in adults. The meta-analysis was
reported according to PRISMA[4] guidelines, but was not preregistered.

While participant data was not explicitly stated, it’s safe to assume this study included randomized
controlled trials in adults (18 years or older). Trials were included in the meta-analysis if they
compared lower-carbohydrate diets to higher carbohydrate diets, controlled energy intake or
bodyweight, controlled for dietary protein, provided food for participants, and utilized whole-room
calorimetry or doubly-labeled water (See Figure 1 and the sidebar) to measure TEE. The primary
outcome was change in total energy expenditure.

66
Sidebar: Doubly-labeled water 101: Two
labels are better than one
Water is made up of one oxygen and two hydrogen atoms. These atoms come in various
weights, depending on how many electrically neutral neutrons they have. Most hydrogen in
the universe has no neutrons, so it’s pretty light. The lightest form of oxygen also makes up
the majority of oxygen that exists. That means that the large majority of water in our body is
made up of the lightest oxygen and hydrogen atoms, since these are the most common.

Scientists can make artificial water made up of heavier versions of hydrogen and oxygen,
then track where the water ends up in the body. This type of water is called “doubly-
labeled,” since both its oxygen and hydrogen atoms are labeled and traceable because
they’re heavier than normal.

It turns out that the body generally eliminates all the hydrogen in water through body fluids
like urine. While some of water’s oxygen also winds up in body fluids, some of it also gets
eliminated through breathing because it’s combined with carbon while burning fuel sources
to make carbon dioxide.

This fact allows for a clever method[5] of estimating how many calories are being burned,
depicted in Figure 1: Have someone drink some doubly-labeled water, wait a while, then
see how much heavy oxygen is missing in their body fluids, relative to the amount of heavy
hydrogen there is. If you presume the missing oxygen was breathed out as carbon dioxide
produced during metabolism, some math will reveal how much energy was burned over a
period of time.

Figure 1: The doubly-labeled water method in a

nutshell

67
 While the doubly-labeled water method usually provides a good estimate of metabolism, the
math underlying the method rests on some assumptions that can depend on diet
composition. This means that if the assumptions are off, the estimated metabolic rate may
be off, if diet composition isn’t corrected for. Indeed, it’s been found[6] that the doubly-
labeled water may overestimate the amount of calories burned in the context of low-
carbohydrate diets, if adjustments aren’t made.

As shown in Figure 2, the studies ranged from 1 to 140 days, with a mean length of 13 days. The
differences in carbohydrate amount between the diets in each study ranged from 8–77% of total
energy intake coming from carbohydrates. Four trials measured TEE by doubly-labeled water,
while 25 trials used whole-room calorimetry. There were a total of 617 participants across 29
eligible trials. Of the trials, 23 were considered short-duration (17 days or less) studies, while only 6
were considered longer-duration (over 17 days) studies.

Figure 2: Study characteristics

68
The researchers conducted a meta-regression analysis and included modifying effects, such a
study duration, percentage of diet from carbohydrates, and method of assessing TEE. Sensitivity
analyses were also performed, examining different duration cut-offs (no more than 14 days
compared to more than 14 days and no more than 21 days compared to more than 21 days).

There was no apparent assessment of study quality or publication bias present in the analysis.
Heterogeneity was assessed using Cochrane’s Q [7]and I2 statistics.

The study under review was a meta-analysis and meta-regression

comparing the effect of high-carbohydrate diets to low-
carbohydrate diets on total energy expenditure, as assessed using
whole-room calorimetry or doubly labeled water. The study
adhered to PRISMA guidelines but was not preregistered.

69
What were the findings?
As shown in Figure 3, lower-carbohydrate diets reduced total energy expenditure by about 50 kcals
per day in shorter-duration studies, but increased total energy expenditure by around 135 kcals per
day in longer-duration studies. When further stratified, there was an average 15 kcal per day
decrease for each 10% decrease in carbohydrates in shorter-duration studies, but a mean 50 kcal
per day increase per 10% decrease in carbohydrates in longer-duration studies.

Figure 3: Main results

The authors reported shorter- and longer-duration studies based on whether they were longer or
shorter than 17 days, as discussed for the meta-regression. The sensitivity analysis did not change
the direction of the findings or the statistical significance. However, the effects were strengthened
when a 21 day cut-off was used (-46 kcals per day for no more than 21 days and 156.5 kcals per
day for over 21 days).

There was substantial heterogeneity among studies, with an overall heterogeneity of I2=81.6%.
However, controlling for study duration and difference in carbohydrate difference between groups
lowered the heterogeneity to an I2 =51%.

In shorter-duration studies (no more than 17 days), lower-

70
 carbohydrate diets led to a roughly 50 kcal per day decrease.
Conversely, lower-carbohydrate diets led to a roughly 135 kcal per
day increase in longer-duration studies (longer than 17 days).
There was substantial heterogeneity among studies, and much of
that heterogeneity was explained by study duration and
carbohydrate difference. The researchers did not assess study
quality or publication bias.

The bigger picture

The present meta-analysis suggests lower-carbohydrate diets may lead to transiently lower total
energy expenditure relative to higher-carbohydrate diets over a period of time of less than 2.5
weeks, but may lead to higher total energy expenditure over longer periods of time, defined as
longer than 2.5 weeks. However, there is substantial heterogeneity among the included studies,
suggesting that the specific details of each study (e.g. population, duration, percentage of diet from
carbohydrates, etc.) can have substantial effects on the outcome. Much of the heterogeneity may
be accounted for by study duration and carbohydrate difference, but moderate heterogeneity
remained after even after researchers accounted for these two factors.

These data conflict with some very tightly controlled metabolic ward experiments. For example, one
metabolic ward study[8] found that when participants transitioned from a regular diet to a very low-
carbohydrate diet, they experienced transient increases of about 80–100 kcal per day in total
energy expenditure over a short duration (less than 17 days), but this effect became unmeasurably
small (less than 50 kcal per day) after 28 days. This finding occurred concurrently with decreases
in c-peptide (a measure of insulin metabolism) and increases in nitrogen, urea, and ammonia,
which suggests increased protein metabolism for gluconeogenesis as well as ketogenesis, which
accounts for the small increases in energy expenditure. This conflicts with the present finding that
total energy expenditure actually decreased in shorter-duration studies.

There are also methodological issues that increase uncertainty about the finding of the increase in
total energy expenditure found in the longer-duration studies. In the current study, the finding of
increased total energy expenditure in the long term was dependent on only six studies. Of these
studies, half used doubly-labeled water as their measure of total energy expenditure. However,

71
doubly-labeled water may overestimate total energy expenditure in the context of low-carbohydrate
diets, raising the possibility that the boost in energy expenditure may be accounted for, in large
part, by overestimation from doubly-labeled water experiments, and not duration alone. For
example, one study[6] compared whole room calorimetry to doubly-labeled water measures for total
energy expenditure when moving from a standard diet to a low-carbohydrate diet. This study found
that doubly-labeled water overestimated total energy expenditure when compared to both whole
room calorimetry and an estimate based on body composition changes. There was an
approximately 150 kcals per day error observed when shifting to a low-carbohydrate diet, which is
on par with the magnitude of the difference observed in this study.

While it’s possible that there is a difference in energy expenditure during tightly controlled diets
containing different amounts of carbohydrate, this effect seems to have little practical significance
in free-living people adopting different weight loss diets with typical adherence. For example, meta-
analyses[9] comparing weight loss on low-carbohydrate versus higher-carbohydrate diets in free-
living people found that there are very minimal differences between them, with about a 1 kilogram
(about 2.2 lbs) difference between each approach over periods of about 12 months[10]. And even
this small difference may not be accounted for by fat, but possibly by changes in body water
content due to lower glycogen stores[11].

In addition, the present study included both in-patient studies with highly controlled environments
as well as out-patients studies in which dietary adherence was not tightly monitored. This may, in
part, account for some of the unexplained heterogeneity. A final limitation worth considering is that
the studies included in the analysis were not assessed for quality or bias, so it’s unclear how much
trust to put into the studies that were included in this meta-analysis.

The present study found that low-carbohydrate diets may decrease

energy expenditure in the short term and increase it in the long
term. However, several methodologic issues raise questions about
the accuracy of these findings.

Frequently asked questions

Q. How important are diet-related increases in TEE for weight loss?

The increases in TEE due to diet have not been shown to be major predictors of weight loss. For

72
example, one study[12] that followed women for four years found that the diet related increases in
TEE did not predict weight gain or weight loss. Furthermore, a meta-analysis found that in the
context of regular protein intake (about 15% of total calories from protein), the thermic effect of food
did not substantially affect weight loss or satiety.

Q. What components of TEE are most predictive of weight loss?

Total energy expenditure can be broken down into four main components: basal metabolic rate,
thermic effect of food, exercise thermogenesis, and non-exercise thermogenesis. Of these
components, the one that is most predictive of weight loss is non-exercise thermogenesis, i.e. the
energy spent on a regular daily routine. The same goes for preventing weight gain[13]. Although
basal metabolic rate is generally the largest component of total energy expenditure, it is not
consistently predictive of weight loss across studies.

What should I know?

The present meta-analysis suggests that lower-carbohydrate diets may decrease total energy
expenditure in the short term, but increase it in the long term. However, there are methodological
issues with the long term studies that make the accuracy of the findings uncertain. Furthermore,
this potential increase in total energy expenditure does not seem to confer a meaningful weight
loss advantage in free-living people eating different diets. Accordingly, these results should be
interpreted with caution, and more work needs to be done to fully understand the effects of low-
carbohydrate versus higher-carbohydrate diets and their longer term effects on total energy
expenditure and, maybe even more importantly, the more relevant energy balance.

Do you think the strengths of this meta-analysis outweigh its

weaknesses? Have your say over at the private NERD Facebook
forum.

^ Go back to table of contents

73
 References
1. ^ Ebbeling CB, et al. Effects of a low carbohydrate diet on energy expenditure during
weight loss maintenance: randomized trial. BMJ. (2018)
2. ^ L G Bandini, D A Schoeller, W H Dietz. Metabolic differences in response to a high-
fat vs. a high-carbohydrate diet. Obes Res. (1994)
3. ^ Hall KD, Guo J. Obesity Energetics: Body Weight Regulation and the Effects of
Diet Composition. Gastroenterology. (2017)
4. ^ Hutton B, et al. The PRISMA extension statement for reporting of systematic
reviews incorporating network meta-analyses of health care interventions: checklist
and explanations. Ann Intern Med. (2015)
5. ^ Klaas R Westerterp. Doubly labelled water assessment of energy expenditure:
principle, practice, and promise. Eur J Appl Physiol. (2017)
6. ^ a b Kevin D Hall, et al. Methodologic considerations for measuring energy
expenditure differences between diets varying in carbohydrate using the doubly
labeled water method. Am J Clin Nutr. (2019)
7. ^ Jérémie F Cohen, et al. Cochran's Q test was useful to assess heterogeneity in
likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol. (2015)
8. ^ Hall KD, et al. Energy expenditure and body composition changes after an
isocaloric ketogenic diet in overweight and obese men. Am J Clin Nutr. (2016)
9. ^ Hu T, et al. Effects of low-carbohydrate diets versus low-fat diets on metabolic risk
factors: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol.
(2012)
10. ^ Shreya Chawla, et al. The Effect of Low-Fat and Low-Carbohydrate Diets on
Weight Loss and Lipid Levels: A Systematic Review and Meta-Analysis. Nutrients.
(2020)
11. ^ C Bogardus, et al. Comparison of carbohydrate-containing and carbohydrate-
restricted hypocaloric diets in the treatment of obesity. Endurance and metabolic fuel
homeostasis during strenuous exercise. J Clin Invest. (1981)
12. ^ Weinsier RL, et al. Metabolic predictors of obesity. Contribution of resting energy
expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-
obese and never-obese women. J Clin Invest. (1995)
13. ^ J A Levine, N L Eberhardt, M D Jensen. Role of nonexercise activity thermogenesis
in resistance to fat gain in humans. Science. (1999)

74
Deep Dive: Evaluating the relationship
between training status and optimal protein
intake
 Tags: Meta-analysis, Protein, Lean Body Mass, Resistance Training, Supplementation

 Study under review: Dose-response relationship between protein intake and muscle
mass increase: a systematic review and meta-analysis of randomized controlled trials

 Read this article online at Examine.com

Quick Takes
• What was the question? What is the dose-response
relationship between protein intake and lean mass with and
without resistance training?
• How was it answered? Researchers conducted a meta-
analysis of randomized controlled trials that measured lean
body mass or fat-free mass and varied protein intake
between groups.
• Who was studied? Participants included adults without
serious illnesses. Some studies included older adults with
sarcopenia or people at risk for metabolic syndrome.
• What was the intervention? Participants received different
types of protein at dosages ranging from 0.05 to 2.38 grams
per kilogram of bodyweight per day.
• What's the main takeaway? Protein intakes up to around

75
 1.3 grams per kilogram of bodyweight helped boost lean
mass regardless of whether or not the protein was combined
with resistance training. However, only resistance-training
people continued to see incremental improvements (albeit
smaller ones) past this intake level, whereas people who
didn’t train did not benefit from doses above 1.3 grams per
kilogram bodyweight as much, suggesting that 1.3 grams is
the ideal intake amount for this group.
• Any caveats? The included studies were quite different from
each other. Some of the included studies used possibly
unreliable body composition measurements and questionable
statistical dietary adjustments, which may not have been
applicable to all the participants and introduces further
uncertainties.

Introduction
Beyond strength and looking good, having more muscle is associated with improved quality of life[1]
and reduced all-cause mortality[2], especially in the context of aging. Muscle tissues are also
associated with better blood sugar control[3], so low muscle mass is associated with increased risk
of type 2 diabetes[4] and age-related physical decline[5].

One way to help maintain or boost muscle is by ensuring adequate protein intake. But how much is
“enough,” exactly? Many studies have attempted to answer this question. Based on nitrogen
balance studies, your body needs, on average, 0.66 grams of protein per kilogram of bodyweight
per day (g/kg BW/d) to not break down muscles and other tissues for amino acids. Based on this
data, the recommended intake is at least 0.83 g/kg BW/day. However, a newer technique called
the indicator of amino acid oxidation method[6] (IAAO), suggests that this number could significantly
underestimate the actual requirements. Older adults may need up to 1.29 g/kg BW/day. For

76
bodybuilders, the requirements [7]could be up to 2.2 g/kg BW/day.

Nitrogen balance and the IAAO method

There are two main methods to estimate protein need for health and muscle building:
nitrogen balance and the indicator of amino acid oxidation method (IAAO).

NERD has covered nitrogen balance before, but in short: it’s the difference between how
much nitrogen your body is excreting versus how much is being consumed. Since nitrogen
is a key atom in amino acids (it’s part of the “amino” group), nitrogen balance can speak to
dietary protein needs. However, this method has some downsides[8], including
measurement inaccuracies and requiring a run-in period. These problems can lead to
protein needs being[9] underestimated[10].

These potential downsides led to the development[9] of the indicator of amino acid oxidation
method (IAAO[6]) for measuring protein needs. This method is based on the concept that
when one essential amino acid is deficient for protein synthesis, then all other essential
amino acids, including the “indicator” amino acid, will be oxidized for energy because
protein cannot be readily stored like carbohydrate or fat. The “indicator” essential amino
acid is labeled with a heavier version of an atom (usually 13C phenylalanine[6]).

If that essential amino acid is oxidized for energy because there’s not enough protein being
consumed and the body thus chooses to burn it for energy, the labeled 13C carbon should
wind up in exhaled carbon dioxide, where it can be measured. But as protein intake goes
up, less and less 13C will appear in the breath, since the body can stop burning it for fuel
and start using it to build its own proteins needed for muscle and other lean tissues. The
point at which the exhaled 13C stops decreasing indicates when the body is getting enough
essential amino acids to build its own proteins. This is the minimum requirement the body
needs.

This information helps answer the question of how much protein is needed, but the follow-up
question remains: does more protein provide any additional benefit? Many meta[11]-analyses[12]
have[13] evaluated[14] the effects of protein intake on muscle mass alongside resistance training.
The general consensus is that more protein intake correlates with more muscle mass in this
context. However, in the absence of resistance training, the effects of protein intake and
supplementation are less clear. Some studies[15] showed benefits, especially among under-
nourished elderly people, while other[16] meta-analyses[17] found no association in the absence of

77
resistance training.

The meta-analysis under review is the first meta-analysis that looks at the effect and dose
response of protein intake on muscle mass with and without resistance training. This study
analyzed 56 trials that examined muscle gain from protein intervention without resistance training,
which is more than double the recent largest meta-analysis[17] that included 27 trials.

Studies have shown that protein intake correlates with muscle

mass in resistance-trained people, but how much benefit protein
yields on a gram-for-gram basis for people not participating in
resistance training isn’t completely clear. The authors of the study
under review sought to determine the dose-response relationship
of protein intake on muscle mass in either situation, using the
latest evidence.

What was studied?

This meta-analysis of randomized controlled trials determined the dose-response curves over a
wide range of protein intakes, with a diverse population in terms of lean body mass (from people
with sarcopenia to bodybuilders), with and without resistance training.

The hypotheses of this study were: More protein intake would result in an increase in muscle mass
in a dose-dependent manner. Eating more protein would effectively and incrementally increase
muscle mass, especially in resistance-trained people.

The analysis included randomized controlled trials with intervention durations of at least two weeks,
although the longest trial lasted 18 months (mean of 19.8 weeks). Participant ages ranged from
18–81 years old, and none of the participants had serious illnesses. However, some of the included
clinical trials involved older adults with frailty or sarcopenia (age-related muscle loss), or who were
at high risk of metabolic syndrome. The study analyzed 138 intervention groups, which included 72
groups undergoing resistance training and 66 abstaining.

Interventions were supplemental protein, with predetermined dosages. These could be dairy (whey
and casein), soy (glycinin and conglycinin), wheat (gliadin, glutenin, and gluten), egg (albumin and

78
ovalbumin), blends of these, or unspecified types of supplemental protein. The control conditions
were iso-caloric carbohydrate drinks, less protein, or no treatment.

The analyses excluded intervention groups that took vitamin D or supplements that could promote
muscle growth beyond the effect of the intact protein, such as leucine, beta-hydroxy-beta-methyl
butyrate (HMB), and creatine. In studies with more than one control group, the analysis focused on
the control group with equal energy intake and larger differences in intervention dose.

The intervention groups consumed 0.64–3.50 (mean ± SD 1.58 ± 0.59) g/kg BW/day of total
protein, while the control groups consumed 0.52–2.00 (mean ± SD 1.04 ± 0.35) g/kg BW/day of
total protein. Supplemental protein doses in the intervention group ranged from 0.05–2.38 g/kg
BW/day.

The systematic review and meta-analysis followed the PRISMA guidelines. The study was
preregistered in the UMIN Clinical Trials Registry, with the primary outcome being muscle mass.
Secondary outcomes included muscle strength, adipose tissue mass, and body composition.
Publication bias was investigated using a funnel plot. Two authors independently evaluated study
quality and risk of bias using the Cochrane risk of bias tool.

The meta-analysis focused on two outcomes: lean body mass change in each group over the
intervention period, and the differences in lean body mass changes between the intervention and
the control group. However, the methods for measuring these outcomes were not considered in the
study. While most of the analyzed clinical trials used the more reliable DXA scans and hydrostatic
weighing, some[18] used less reliable methods, such as bioimpedance analysis.

Since the clinical trials varied widely both in terms of subjects and interventions, a random-effects
analysis was used. Despite the substantial heterogeneity (I2 = 56% with resistance training, 80%
without, and 72% overall), the entire dataset was analyzed anyway, as the researchers applied
corrections for confounding factors later.

To evaluate the dose-response relationship between protein intake (total or difference in

supplemental doses) and change in lean body mass, the authors used unadjusted and two
multivariate-adjusted models. Model 1 adjusted for age, gender, intervention period, and
parameters used in the Japanese dietary reference intake. Model 1 was also stratified by
resistance training. Model 2 adjusted for factors in model 1 and weight change.

The researchers conducting this meta-analysis analyzed

randomized controlled trials to determine if increased protein

79
 intakes would dose-dependently result in muscle gain. Participants
in these trials were healthy adults, although some had sarcopenia
or were at risk for metabolic syndrome. A total of 72 interventions
with and 66 without concomitant resistance training were included.
Interventions lasted from 2 weeks to 18 months (mean of 19.8
weeks). The difference in lean mass changes between the
intervention and control groups was the primary outcome. The
authors adjusted for a lot of variables to evaluate the dose-
response relationship, including age, gender, intervention periods,
diet, and weight change.

What were the findings?

The analysis found that total protein intake correlated with the increase in lean body mass. Also,
protein supplementation was significantly effective at improving lean body mass, with or without
resistance training. The details are laid out in Figure 1.

Figure 1: Overall and subgroup effects of protein on

lean body mass

80
In the unadjusted model and model 1, lean body mass always correlated with total protein
consumption across a wide range of intakes. For participants consuming under 1.3 g/kg BW/day of
protein, every 0.1 g/kg BW/day increase in protein intake was associated with a 0.39 kg increase in
lean body mass. For participants consuming over 1.3 g/kg BW/day of protein, each 0.1 g/kg BW/
day increase in protein intake was associated with a 0.12 kg increase in lean body mass.

81
In model 2, which accounted for bodyweight differences, lean body mass correlated with total
protein intake in the resistance training group for all doses studied (up until 3.5 g/kg BW/day).
However, more benefit was seen up to 1.3 g/kg BW/day, with about a 0.9 kg rise in lean body mass
for every g/kg BW/day of protein. While more protein supplemented by participants engaging in
resistance training still boosted lean mass, it did so about half as much (0.45 kg lean mass per g/kg
BW/day of protein). However, without resistance training, lean body mass gain was negatively
correlated with total protein intake of over 1.3 g/kg BW/day, but was beneficial below this amount
(each g/kg BW/day of protein below 1.3 yielded about 3 kg of lean mass). These effects are
depicted in Figure 2.

Figure 2: Dose-response relationship between protein

intake and after all statistical adjustments, stratified by
resistance training status

After adjusting for several factors, protein intakes up to 1.3 g/kg

82
 BW/day benefited the lean mass of both resistance trained and
non-resistance trained participants. Protein intakes above 1.3 g/kg
BW/day continued to benefit resistance trained people’s lean body
mass, but only about half as much. However, people who didn’t
train actually had lower lean body mass gains above an intake of
1.3 g/kg BW/day, suggesting that protein intakes above this
amount aren’t as useful for this population.

The bigger picture

While sufficient protein consumption is necessary and correlates with muscle mass, protein
consumption or supplementation may not be sufficient for hypertrophy. Several[11] other[12] meta-
analysis[13] and meta-regression[14] studies have demonstrated clear associations between protein
intake and muscle mass along with resistance training. However, in the absence of resistance
training, other studies suggest that eating more protein doesn’t[16] tend to increase muscle mass.
The meta-analysis under review is one of the few studies that suggests a significant impact of
increasing protein intake on muscle gain without resistance training.

However, these results also include some counterintuitive findings for non-training populations. The
first is that non-training individuals seemed to get a bigger bang for the buck, in terms of lean mass,
at lower protein intakes than people who train. One possible explanation for this may be that most
of the studies in non-training populations were in the context of weight loss, while a lot of the
studies in resistance-training individuals weren’t. Thus, the left-hand part of the curve in Figure 2
could be depicting a lean-mass sparing effect of protein under caloric restriction.

The second finding that may be counterintuitive is that people who didn’t train experienced less
benefit above 1.3 g/kg BW/day. However, recall that this only occurred under model 2, which
adjusted for bodyweight, but didn’t occur under model 1, which didn’t take bodyweight into account.
This could also be explained by the caloric restriction that many of the non-resistance training
participants underwent. That is, when weight is not accounted for, lean body mass is still boosted,
but when total bodyweight is taken into account, less protein goes to lean mass, with some
possibly going to fat mass. However, this is just speculative, the true reasons for this aren’t yet
clear.

83
The results of the study under review can be compared to another dose-response study[19] covered
in a previous NERD review. That study only covered resistance-training participants, and found the
optimal protein intake to be 1.6 g/kg BW/d, based on a breakpoint analysis. This conflicts slightly
with the 1.3 g/kg BW/day breakpoint found here, until the 95% percent confidence interval for the
estimate is taken into account, which ranged from 1.0-2.2 g/kg/ BW/day. Given the uncertainty in
that analysis, these results do roughly concord with the current study under review.

Many protein intake studies are funded by the food or supplement industry, or involve authors with
some industry association. The authors of this meta-analysis are employees of Meiji, a food
corporation. While the potential conflict of interest alone may not be cause for dismissing a study,
there are a few other reasons to question this study's results.

The first is heterogeneity: the studies that were included in this meta-analysis varied widely in their
characteristics, which may reduce the reliability of the results. Ideally, the researchers conducting
the study under review would have further stratified its results based on participant characteristics
(e.g. younger vs. older) and total caloric intake to determine if heterogeneity could be reduced.

Another non-negligible problem relating to the methodological heterogeneity of the input studies
concerns the way the input studies measured or estimated lean body mass. Some methods can be
quite unreliable, and so it may not be wise to compare them directly, as was done in the study at
hand. For example, bioimpedance body fat measurements can vary[20] by 2–3% over the course of
about 12 hours. Regular DXA scan results can be influenced by food and fluid intake. Since the
authors didn’t specify these tests or their quality control in their inclusion/exclusion criteria, the
measurement variability adds another potential source of error.

Finally, it should be mentioned that while most of the trials analyzed enrolled Caucasian
participants, the authors used Japanese reference values, which could pose a problem. An
average Causasian is larger than a Japanese person and thus needs more nutrients. For
Japanese people, a BMI of over 23[21] is considered overweight, while in the U.S., a BMI of over 25
is considered overweight. However, the authors relied on the Japanese Dietary Reference Intake
for their modeling, without specifying which parameters were used. Dietary Reference Intake
values are typically the minimum[22] nutrient requirements needed to prevent deficiency, based on
a specified population. Since these values[23] give recommendations for calories and macro intake
by age group, and not usually by weight or activity, they may have been inappropriate for many of
the participants in this meta-analysis and may reduce the reliability of the results.

Some of the counterintuitive results in this meta-analysis could be

explained by the fact that many of the non-resistance training

84
 participants were undergoing caloric restriction. However,
methodological considerations and study heterogeneity may also
play a role. That said, these results are still in rough accordance
with previous meta-analyses.

Frequently asked questions

Q. Are protein supplements helpful for muscle gain?

Overall complete protein consumption, regardless of source, is more important than

supplementation for muscle gain and maintenance. Therefore, it is more important to eat
enough[19] complete proteins overall than to take protein supplements. Total protein intake is the
biggest predictor[16] of hypertrophy, whereas protein timing studies have had mixed results. For
bodybuilders, the suggested amount is 2.2 g/kg BW/d of total protein intake. For elderly people, the
recommended dietary intake is 1.24 g/kg BW/d. However, if you struggle to get enough protein
from your diet, protein supplements may be a helpful, accessible option.

How should the strategy for muscle gain differ between young and older people?

Generally, aging makes muscle gain harder due to age-related[24] physiological changes, such as
reduced appetite, declining muscle-promoting hormones, and increasing inflammation and insulin
resistance. Together, these factors induce a state that is often referred to as “anabolic
resistance[25].” As people age, they may become less coordinated, more injury-prone, and need
more time to recover from exercise. Their resistance training would need to take these factors into
account, as well as physical limitations and health status. Also, consuming sufficient protein may
reduce age-related sarcopenia. When appetite makes it difficult to consume enough protein, a
protein supplement may be beneficial.

Aging may blunt muscle protein synthesis, so the threshold protein intake to stimulate muscle
protein synthesis may be higher in elderly people than in younger adults. Elderly people may need
25–30 grams of high EAA (and especially leucine) protein from each meal, while younger adults
may require 20–25 grams per meal to maximize muscle protein synthesis. A breakpoint analysis[26]
compared older men (average age 71) and younger men (average age 22). They found that the
older men required about 68% more protein to maximally stimulate muscle protein synthesis.

85
What should I know?
The study under review established a dose-response relationship between protein intake or protein
supplementation and lean body mass both with and without resistance training. The analyses
found that a 0.1 g/kg BW/d increase in protein intake was associated with a 0.39 kg increase in
lean body mass for participants consuming less than 1.3 g/kg (total) BW/d. However, in participants
consuming over 1.3 g/kg BW/d of protein (total), the associated lean body mass increase was 0.12
g/kg/day. People who engaged in resistance training experienced continued benefits from more
protein after accounting for bodyweight, while the lean mass benefits for participants who were not
training peaked at around 1.3 g/kg BW/day of total intake.

There are a few limitations of this study that weaken its conclusions. The statistical analyses in this
study may have inadequately taken into account factors such as total caloric intake and age, which
have been shown to strongly influence muscle mass gain. This study also has some technical
issues that may make the results less reliable, such as the omission of lean body mass
measurement methods or the reliance on the Japanese Dietary Recommended Intakes, which are
likely too low for the Caucasian participants.

Supplement your knowledge gains (or eat whole posts) about

protein’s effects on lean mass over at the private NERD Facebook
forum!

^ Go back to table of contents

86
 References
1. ^ A Trombetti, et al. Age-associated declines in muscle mass, strength, power, and
physical performance: impact on fear of falling and quality of life. Osteoporos Int.
(2016)
2. ^ Li R, et al. Associations of Muscle Mass and Strength with All-Cause Mortality
among US Older Adults. Med Sci Sports Exerc. (2018)
3. ^ Rita Rastogi Kalyani, Mark Corriere, Luigi Ferrucci. Age-related and disease-
related muscle loss: the effect of diabetes, obesity, and other diseases. Lancet
Diabetes Endocrinol. (2014)
4. ^ Chris Ho Ching Yeung, et al. Lean mass, grip strength and risk of type 2 diabetes:
a bi-directional Mendelian randomisation study. Diabetologia. (2019)
5. ^ Chrysoula Boutari, Christos S Mantzoros. Decreasing Lean Body Mass with Age:
Challenges and Opportunities for Novel Therapies. Endocrinol Metab (Seoul). (2017)
6. ^ a b c Elango R, Ball RO, Pencharz PB. Indicator amino acid oxidation: concept and
application. J Nutr. (2008)
7. ^ Bandegan A, et al. Indicator Amino Acid-Derived Estimate of Dietary Protein
Requirement for Male Bodybuilders on a Nontraining Day Is Several-Fold Greater
than the Current Recommended Dietary Allowance. J Nutr. (2017)
8. ^ Paul B Pencharz, Ronald O Ball. Different approaches to define individual amino
acid requirements. Annu Rev Nutr. (2003)
9. ^ a b Elango R, et al. Evidence that protein requirements have been significantly
underestimated. Curr Opin Clin Nutr Metab Care. (2010)
10. ^ Paul B Pencharz, Rajavel Elango, Robert R Wolfe. Recent developments in
understanding protein needs - How much and what kind should we eat?. Appl Physiol
Nutr Metab. (2016)
11. ^ a b L Hou, et al. Effect of Protein Supplementation Combined with Resistance
Training on Muscle Mass, Strength and Function in the Elderly: A Systematic Review
and Meta-Analysis. J Nutr Health Aging. (2019)
12. ^ a b Kerry R O'Bryan, et al. Do multi-ingredient protein supplements augment
resistance training-induced gains in skeletal muscle mass and strength? A systematic
review and meta-analysis of 35 trials. Br J Sports Med. (2020)
13. ^ a b Nivine I Hanach, Fiona McCullough, Amanda Avery. The Impact of Dairy
Protein Intake on Muscle Mass, Muscle Strength, and Physical Performance in
Middle-Aged to Older Adults with or without Existing Sarcopenia: A Systematic

87
 Review and Meta-Analysis. Adv Nutr. (2019)
14. ^ a b Dominique S M Ten Haaf, et al. Effects of protein supplementation on lean body
mass, muscle strength, and physical performance in nonfrail community-dwelling
older adults: a systematic review and meta-analysis. Am J Clin Nutr. (2018)
15. ^ Heilok Cheng, et al. Systematic review and meta-analysis of the effect of protein
and amino acid supplements in older adults with acute or chronic conditions. Br J
Nutr. (2018)
16. ^ a b c M Tieland, et al. The Impact of Dietary Protein or Amino Acid
Supplementation on Muscle Mass and Strength in Elderly People: Individual
Participant Data and Meta-Analysis of RCT's. J Nutr Health Aging. (2017)
17. ^ a b Pasiakos SM, McLellan TM, Lieberman HR. The effects of protein supplements
on muscle mass, strength, and aerobic and anaerobic power in healthy adults: a
systematic review. Sports Med. (2015)
18. ^ Daniela Lopes Gomes, et al. Whey Protein Supplementation Enhances Body Fat
and Weight Loss in Women Long After Bariatric Surgery: a Randomized Controlled
Trial. Obes Surg. (2017)
19. ^ a b Morton RW, et al. A systematic review, meta-analysis and meta-regression of
the effect of protein supplementation on resistance training-induced gains in muscle
mass and strength in healthy adults. Br J Sports Med. (2018)
20. ^ F Slinde, et al. Bioelectrical impedance variation in healthy subjects during 12 h in
the supine position. Clin Nutr. (2003)
21. ^ K Shiwaku, et al. Overweight Japanese with body mass indexes of 23.0-24.9 have
higher risks for obesity-associated disorders: a comparison of Japanese and
Mongolians. Int J Obes Relat Metab Disord. (2004)
22. ^ Carbone JW, Pasiakos SM. Dietary Protein and Muscle Mass: Translating Science
to Application and Health Benefit. Nutrients. (2019)
23. ^ Satoshi Sasaki. Dietary Reference Intakes (DRIs) in Japan. Asia Pac J Clin Nutr.
(2008)
24. ^ Michael Tieland, Inez Trouwborst, Brian C Clark. Skeletal muscle performance and
ageing. J Cachexia Sarcopenia Muscle. (2018)
25. ^ Leigh Breen, Stuart M Phillips. Skeletal muscle protein metabolism in the elderly:
Interventions to counteract the 'anabolic resistance' of ageing. Nutr Metab (Lond).
(2011)
26. ^ Moore DR, et al. Protein ingestion to stimulate myofibrillar protein synthesis
requires greater relative protein intakes in healthy older versus younger men. J
Gerontol A Biol Sci Med Sci. (2015)

88
 Credits
Researchers
Antonis Damianou, MSc; Brad Dieter, PhD; Nick Milazzo, MS(c); Thomas Reichhart, MSc; Brandon
Roberts PhD, MS, CSCS; Lucas Roldos, BSc, MSc(c); Jill Ryer-Powder, PhD; Detrick Snyder,
MPH, RDN; Lucas Tafur, PhD; Nattha Wannissorn, PhD, RNH, FDN-P

Editors
Gregory Lopez, MA, PharmD

Reviewers
Stephan Guyenet, PhD & Adel Moussa, PhD

Copy Editor
Dmitri Barvinok

Infographics
Antonius Khengdro & Calla Lee

89