Maturitas 132 (2020) 57–64

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Maturitas
journal homepage: www.elsevier.com/locate/maturitas

Nutritional strategies for maintaining muscle mass and strength from middle T
age to later life: A narrative review
Alfonso J. Cruz-Jentofta,*, Bess Dawson Hughesb, David Scottc, Kerrie M. Sandersd, Rene Rizzolie
a
Servicio de Geriatría, Hospital Universitario Ramón y Cajal (IRYCIS), Ctra. Colmenar Viejo, km. 9,11 28034 Madrid, Spain
b
Bone Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111 USA
c
School of Clinical Sciences at Monash Health, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia
d
Melbourne Medical School, The University of Melbourne, Sunshine Hospital, 176 Furlong Road, St Albans, Victoria 3021, Australia
e
University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland

ARTICLE INFO ABSTRACT

Keywords: Progressive age-related reductions in muscle mass and strength (sarcopenia) can cause substantial morbidity.
Dietary supplement This narrative review summarizes evidence of nutritional interventions for maintaining muscle mass and
Muscle strength from midlife through old age. PubMed and Cochrane databases were searched to identify studies of
Skeletal dietary intake and nutritional interventions for sustaining muscle mass and strength. The benefits of progressive
Nutritional support
resistance training with and without dietary interventions are well documented. Protein and amino acid (par-
Physiology
ticularly leucine) intake should be considered, and supplementation may be warranted for those not meeting
Healthy aging
recommended intakes. Vitamin D receptors are expressed in muscle tissue; meta-analyses have shown that vi-
tamin D benefits muscle strength. Data suggest that milk and other dairy products containing different bioactive
compounds (i.e. protein, leucine) can enhance muscle protein synthesis, particularly when combined with
resistance exercise. Omega-3 s can improve muscle mass and strength by mediating cell signaling and in-
flammation-related oxidative damage; no studies were specifically conducted in sarcopenia. Low-dose anti-
oxidants (e.g. vitamins C and E) can protect muscle tissue from oxidative damage, but relevant studies are
limited. Magnesium is involved with muscle contraction processes, and data have shown benefits to muscle
strength. Acidogenic diets increase muscle protein breakdown, which is exacerbated by aging. Alkalizing
compounds (e.g. bicarbonates) can promote muscle strength. Small studies of probiotics and plant extracts have
generated interest, but few large studies have been conducted. Based on available data, dietary and
supplemental interventions may add to the benefits of exercise on muscle mass and strength; effects independent
of exercise have not been consistently shown.

1. Introduction
Muscle constitutes about 40 % of body mass and is important for
physical stability and mobility, as well as metabolic functions such as
providing amino acids to other tissues and storing and using glucose for
energy [1,2]. Muscle protein synthesis and degradation need to be
positively balanced in order to gain mass [2]. During middle age, cel-
lular and molecular changes blunt the response to nutritional stimuli
and physical activity, resulting in more muscle being broken down than
built up [3]. Muscle mass can begin declining in the 30 s, with
quantifiable reductions in absolute muscle mass observed at approxi-
mately 59 years of age [4]. Additionally, intramuscular fat increases
with age, reducing lean muscle mass used for energy metabolism [5].
Age-related changes in muscle composition and increases in in-
tramuscular fat may explain, in part, the fact that muscle strength de-
creases more rapidly than muscle mass [6]. From middle to older age,
upper-body strength declines by 2 %–12 % per decade, independent of
muscle mass loss [7]. Lower body strength declines by 3 %–4 %

Abbreviations: CKD, chronic kidney disease; DO-HEALTH, Vitamin D3/Omega-3/Home Exercise - Healthy Aging and Longevity Trial; ESPEN, European Society for
Clinical Nutrition and Metabolism; EWGSOP2, European Working Group on Sarcopenia in Older People; GFR, glomerular filtration rate; HMB, beta-hydroxy-beta-
methylbutyrate; PROT-AGE, International Study Group to Review Dietary Protein Needs with Aging; PRT, progressive resistance training; RCTs, randomized,
controlled trials; VDR, 1,25-dihydroxyvitamin D receptor; VITAL, VITamin D/OmegA-3 TriaL
⁎
Corresponding author.
E-mail addresses: alfonsojose.cruz@salud.madrid.org (A.J. Cruz-Jentoft), bess.dawson-hughes@tufts.edu (B. Dawson Hughes),
david.scott@monash.edu (D. Scott), ksanders@unimelb.edu.au (K.M. Sanders), rene.rizzoli@unige.ch (R. Rizzoli).

https://doi.org/10.1016/j.maturitas.2019.11.007
Received 5 June 2019; Received in revised form 25 October 2019; Accepted 26 November 2019
0378-5122/ © 2019 Published by Elsevier B.V.
A.J. Cruz-Jentoft, et al.
annually, even though only approximately 1 % of leg lean mass is lost
annually [8]. In healthy older adults, muscle power declines more
quickly than muscle strength [5].
Sarcopenia is a progressive skeletal muscle disorder that affects an
estimated 6 %–19 % of the general population ≥60 years of age, de-
pending on the definition applied [9]. According to current European
Working Group on Sarcopenia in Older People (EWGSOP2) consensus,
reduced muscle strength is the primary indicator of sarcopenia, while
reduced muscle quantity or quality confirms diagnosis. If low physical
performance is also observed, then sarcopenia is severe. Sarcopenia is
categorized as primary (age-related) or secondary (potentially age-re-
lated with other causative factors) and can occur acutely (e.g. during
hospitalization) or progressively [10].
Regular exercise during youth and middle age may attenuate the
risk of sarcopenia in old age [10]. Exercise stimulates muscle protein
synthesis, builds muscle mass, and fosters adaptation to physical exer-
tion [6]. Muscle protein synthesis benefits from both resistance training
and aerobic activity, and vigorous physical activity may help preserve
muscle mass and strength [11]. Importantly, exercise during middle age
reduces the risk of sarcopenia and positively predicts muscle strength
and physical performance during older age [12].
Diets containing adequate protein, fruits, vegetables, and vitamin D
may prevent loss of muscle mass [3]. Adherence to the Mediterranean
diet is associated with a lower risk for frailty and functional disability,
but no effect has been observed on sarcopenia [13]. However, a recent
systematic review of 37 randomized, controlled trials (RCTs) that as-
sessed the combined effect of exercise and various nutritional inter-
ventions including protein, amino acids, and vitamin D in older (≥60
years) healthy community-dwelling and hospitalized individuals sug-
gested that exercise beneficially affects muscle mass, strength, and
physical performance, but the additive effect of nutritional interven-
tions may be limited [14]. Critically, though, most of these RCTs did not
consider baseline nutritional status, which may have impacted the re-
sults. One high-quality RCT included in that review evaluated the effect
of vitamin D plus calcium and exercise in vitamin D-deficient subjects
and reported improvements in muscle strength and functioning [15].
Notably, an earlier meta-analysis of younger and older healthy adults
reported significant improvements in fat-free mass with progressive
resistance training (PRT) and protein supplementation [16].
The present narrative review reveals a wide variety of evidence and
conclusions on all of these topics. It was conducted to describe the
current evidence and identify nutritional interventions that may mod-
erate natural declines in muscle strength and mass during middle age
and extend peak muscle protein synthesis into old age.
1.1. Methods: search criteria
Searches were conducted of PubMed and Cochrane databases using
search terms related to these topics, including muscle protein synthesis,
sarcopenia, and muscle strength and mass. Search terms and limitations
(e.g. human trials, English language) varied between ingredients and
databases. Studies of interventions that targeted specific diseases/con-
ditions other than sarcopenia were excluded. Due to limitations in the
amount of references that could be included, an emphasis was placed
on higher-quality RCTs, systematic reviews, and meta-analyses.
2. Protein and amino acids
2.1. Protein
Protein is essential for promoting muscle mass and strength. An
analysis of National Health and Nutrition Examination Survey data
found a significant association between leg lean mass and strength and
frequent dietary protein intake (≥2 meals/day with ≥30 g/meal) [17].
The International Study Group to Review Dietary Protein Needs with
Aging (PROT-AGE) and a European Society for Clinical Nutrition and
58
Maturitas 132 (2020) 57–64
Table 1
Protein intake recommendations for adults ≥65 years of age, from the PROT-
AGE Study Groupa [18] and the ESPEN Expert Workshopb [18,19].
Health Status Protein Intake
Healthy [18,19] 1.0–1.2 g/kg body weight/day
Acute or chronic illness 1.2–1.5 g/kg body weight/day
[18,19]
Up to 2.0 g/kg body weight/day for
those with severe illness/injury or
malnutrition [18]
Severe CKD (GFR < 30 mL/min/1.73 m2) 0.6–0.8 g/kg body weight/day
[18,19]
Protein/amino acid threshold [18] 25–30 g protein/meal
containing 2.5–2.8 g leucine
Exercise in Healthy Individuals [18]
Daily physical activity [19]
Endurance exercise 30 minutes/day
Include progressive resistance training [19] 2–3 times/week for 10–15 minutes
Daily protein intake 1.2 g protein/kg body weight; consider 20 g protein
supplement after exercise
CKD, chronic kidney disease; ESPEN, European Society for Clinical Nutrition
and Metabolism; GFR, glomerular filtration rate; PROT-AGE, International
Study Group to Review Dietary Protein Needs with Aging.
a
Endorsed by the European Union Geriatric Medicine Society, International
Association of Gerontology and Geriatrics–European Region, International
Association of Nutrition and Aging, and Australian and New Zealand Society for
Geriatric Medicine [18].
b
Workshop on protein requirements in the elderly held by the ESPEN [19].
Metabolism (ESPEN) Expert Workshop developed dietary protein and
exercise recommendations for adults > 65 years of age to maintain and
regain muscle mass (Table 1) [18,19]. Evidence suggests that protein
supplements alone may offer little benefit to middle-aged and older
adults for building muscle mass and strength [20,21], which may reflect
the anabolic resistance observed in older individuals [22].
The decision to supplement protein intake and dose should be based
on background dietary protein consumption [23]. A study of func-
tionally limited men ≥65 years of age found that supplementation with
protein above recommended levels had no impact on lean body mass,
muscle strength, and muscle power [24]. Importantly, the enrolled
population had physical limitations but was not specifically sarcopenic,
which may have impacted these findings. A single-arm interventional
study showed that postexercise protein supplementation intake above a
single 20-g dose in young male weightlifters provided no additional
benefit to muscle protein synthesis [25], whereas an RCT conducted in
48 elderly men showed that a single 40-g dose of protein supple-
mentation before bed facilitated muscle protein synthesis [26]. A 2-year
RCT in older women showed that one 30-g dose of protein supple-
mentation at breakfast had no greater benefit to muscle mass, strength,
and function than a low-protein, high-carbohydrate breakfast
supplement [23]. The totality of data compiled from these studies of
different doses of protein supplementation is inconclusive. However, it
appears that intake ≥1.2 g/kg/day protein may be warranted [27,28].
Protein dosing schedules are important to consider. Twenty-four–hour
muscle protein synthesis is stimulated more effectively by protein intake
throughout the day compared with skewing intake toward the evening [29].
An RCT of overweight adults reported no incremental improvements in
muscle mass when 90 g of protein was consumed in equal versus variable
doses three times per day [30]. Research on the optimal timing of protein
supplementation relative to PRT is evolving. Studies suggest that the
greatest impact on muscle protein synthesis occurs when protein is ingested
immediately following exercise [25,31], while some experts contend that
timing is irrelevant [11]. Appropriate timing of supplementation may
depend on the protein source due to variations in digestion rates, which
impact amino acid availability [32,33]. Whey protein is
rapidly digested and absorbed; therefore, it can be ingested immediately
before, during, or after exercise [34]. Mycoprotein produces sustained
A.J. Cruz-Jentoft, et al. Maturitas 132 (2020) 57–64

Table 2
Amino acid supplements and muscle health.
Amino Acid Effects Combined With Exercise

a
Leucine Enhances muscle protein synthesis [35] and Leucine + exercise does not promote muscle protein synthesis beyond exercise alone [35]a
increases lean body weight [36]a in those ≥65 years
of age
Reduces negative effects of bed rest on muscle health
in those 45–60 years of age [37]
Beta-hydroxy-beta- Increases muscle mass; varying effect on muscle Beta-hydroxy-beta-methylbutyrate + resistance exercise may be beneficial to muscle
methylbutyrate strength and physical function in those ≥65 years of strength
age [38] a
Creatine Enhances total body mass, lean body mass, strength, Creatine + resistance training reduces adverse sarcopenia-related outcomes vs resistance
and functional performance in adults ≥45 years of training alone [39] a
age in combination with resistance training [39]a Creatine + resistance training improves lean tissue mass and strength in those ≥50 years
of age [40]
Long-term use, especially combined with resistance exercise, increases muscle strength
and lean mass in women ≥60 years of age with osteopenia or osteoporosis [41]
Beta-alanine Improves exercise performance and increases muscle Beta-alanine + resistance exercise improves body composition and muscle strength in
carnosine levels in men 18–29 years of age [42,43] women 19–23 years of age [45]
A nutritional supplement fortified with beta-alanine
significantly increases physical work capacity and 30-
second sit-to-stand time in those 63–78 years of age
[44]
L-Carnitine Does not enhance the effects of exercise on muscle in L-carnitine + exercise training does not exert additive effect in fat metabolism
men 21–25 years of age [46] L-carnitine is unlikely to be associated with enhanced exercise performance [48]
May prevent elevations in leg adiposity and increased
energy expenditure during exercise in males 26–30
years of age [47]

a
Meta-analysis.

delivery of amino acids due to its delayed absorption [33]. The impact of
the absorption rate of mycoprotein is unclear.
2.2. Amino acids
Numerous studies have investigated specific amino acid supplements
for promoting muscle protein synthesis (Table 2). Currently, the stron-
gest data for supplementation alone support leucine and its metabolite
beta-hydroxy-beta-methylbutyrate (HMB), with no obvious benefit of
one over the other. In adults ≥65 years of age, systematic reviews found
that leucine supplementation significantly increased muscle protein
synthesis in nine RCTs [35], and HMB supplementation improved muscle
mass in seven RCTs [38]. Bauer, et al. found that supplements containing
40 g of protein per day enriched with vitamin D and leucine improved
muscle mass and lower extremity muscle performance in older sarco-
penic individuals [49]. Additionally, a systematic review of studies in
adults > 45 years of age found that creatine supplementation combined
with resistance training increased muscle mass, strength, and functioning
[39].
3. Additional nutritional interventions that promote muscle mass
and strength
3.1. Omega-3 fatty acids
Omega-3 fatty acids may counteract age-related loss of muscle mass
of and improve physical performance by mediating cell signaling
function and oxidative damage associated with inflammation [50,51].
Fish oil-derived omega-3 fatty acid supplementation increases gene
expression that regulates muscle growth, structure, and inflammation
[52,53]. Studies in older adults demonstrate that omega-3 supple-
mentation after exercise augments muscle protein synthesis, suggesting
that omega-3 s may be useful for sarcopenia [22,54]. Edholm et al. [55]
reported that a diet based on United States and European Union
guidelines and that was rich in omega-3 s (36 % of energy from fat,
mainly mono- and polyunsaturated fatty acids) combined with
resistance training increased muscle power and performance in older
women (65–70 years of age). In other studies, fish oil supplements
(2–4 g/day) improved leg muscle mass and power and hand-grip
strength [56], chair-rising performance, peak muscle torque [57], and
muscle function and quality [58] in adults > 60 years of age. Logan
et al. [59] reported that supplementation with eicosapentaenoic acid
2 g/day and docosahexaenoic acid 1 g/day significantly increased lean
mass and improved Timed Get Up and Go speed in women 60–76 years
of age. Notably, no studies were specifically conducted in sarcopenia;
therefore, additional research is needed in this area.
3.2. Vitamin D
Vitamin D is known to maintain bone mineral density but is also
involved in muscle functioning [60]. An analysis of human muscle
tissue from older and middle-aged women showed that increased age
was associated with decreased expression of the intracellular 1,25-di-
hydroxyvitamin D receptor (VDR) [61]. The authors speculated that
this disordered cellular response to vitamin D could impair muscle
synthesis over time and contribute to sarcopenia. Vitamin D supple-
mentation increases VDR gene expression in muscle tissue [62] and
improves muscle-specific VDR concentrations and muscle fiber size in
older adults [63], and VDR polymorphisms are associated with hand-
grip strength [64]. Meta-analyses of older adults have reported asso-
ciations between muscle strength and vitamin D supplementation [65]
and between muscle strength and vitamin D supplementation combined
with resistance training [66]. However, a recent meta-analysis suggests
that vitamin D supplementation has no benefit on muscle strength [67];
these effects may be dependent on vitamin D deficiencies [68]. Im-
portantly, bolus high doses of vitamin D supplements (e.g. 60,000 IU/
month [69] or 500,000 IU/year [70]) can negatively impact muscle
function and increase fall risk. A recent study also suggested some ne-
gative effects of a relatively high daily dose of vitamin D3 supplements
(2800 IU or 70 μg) on muscle function in women with low vitamin D
levels [71]. In another study, vitamin D supplementation with 800 IU/
day for 12 weeks improved lower limb strength among vitamin D-in-
sufficient women, despite achieving lower post-treatment 25(OH)D le-
vels than a single dose of 300,000 IU/day [72].

59
A.J. Cruz-Jentoft, et al.
3.3. Antioxidants
3.3.1. Vitamins C and E
Two RCTs in adults suggest that vitamin E supplementation reduces
exercise-induced oxidative damage [73,74]. However, a meta-analysis
of 14 RCTs investigating exercise combined with different forms, doses,
and durations of vitamin E supplementation reported no significant
protection against exercise-induced oxidative stress or muscle damage
[75]. Results from one RCT suggest that higher doses of vitamin C
supplements may blunt the cellular adaptations of muscle to exercise in
healthy individuals, based on markers of mitochondrial content and
antioxidant enzyme activity [76]. Additionally, vitamin E supplements
administered with high doses of vitamin C hampered cellular adapta-
tions to exercise and did not attenuate muscle oxidative stress in
healthy subjects [77,78]. Administration of high doses of both vitamins
C and E supplements had no effect on muscle mass following a strength
training program in RCTs conducted in elderly males [79,80]. Thus,
high doses of vitamins C and E supplements likely provide no additional
clinical benefit and may have negative effects on cellular responses to
exercise. Additional research using lower doses may be warranted.
3.3.2. Selenium
Selenium is an antioxidant mineral that can prevent muscle degen-
eration by protecting against oxidative damage [81]. An RCT found that
a micronutrient supplement containing selenium helped preserve anti-
oxidant response and muscle adaptation in 20 triathletes [82]. Ad-
ditionally, Johansson et al. [83] demonstrated that community-dwelling
elderly subjects using selenium and coenzyme Q10 supplements experi-
enced improvements in physical performance and vitality.
3.4. Magnesium
Magnesium stores decline with age, which may factor into sarco-
penia because of the role of magnesium in muscle contraction and
relaxation and interactions with calcium for maintaining musculoske-
letal health [84]. A cross-sectional study in women (34–83 years of age)
found significant positive associations between higher dietary magne-
sium intake and muscle mass and leg muscle power [85]. A study of 26
male athletes with inadequate dietary magnesium intake showed that
magnesium supplementation was directly associated with trunk flexion
and rotation and handgrip strength [86]. Similarly, an RCT in 139
healthy women > 65 years of age found that weekly exercise and
magnesium supplementation significantly improved total Short
Physical Performance Battery scores, including five-time chair-stand,
tandem balance evaluation, and 4-meter walking speeds [87].
3.5. Phytonutrients/polyphenols
Polyphenols and other phytonutrients are plant-derived compounds
with anti-inflammatory and antioxidant properties that may help to
mediate inflammatory processes resulting in muscle damage [88]. Po-
megranate juice is considered a rich source of these compounds [89].
The data supporting these nutrients are limited at this time because the
RCTs we identified have only been conducted in small populations of
younger adults. An RCT demonstrated that supplementation with ella-
gitannin from pomegranate extract significantly improved recovery of
muscle strength after exercise in 16 younger, recreationally active
males [90]. Another RCT in nine males 20–22 years of age with
Olympic weightlifting experience demonstrated that pomegranate juice
accelerated muscle recovery kinetics and enzymatic antioxidant de-
fenses both acutely and up to 48 h after intensive weightlifting [89].
Furthermore, tea catechin supplementation combined with exercise
effectively improved muscle mass in older sarcopenic women [91],
which was supported by a subsequent RCT that reported improvements
in sarcopenic obesity [92]. However, the modest transient increases in
plasma antioxidant capacity following consumption of tea and green
60
Maturitas 132 (2020) 57–64
tea catechins need to be demonstrated in larger human studies.
3.6. Dairy products
Milk and other dairy products contain many of the bioactive com-
ponents that have been shown to enhance muscle protein synthesis (e.g.
protein, and leucine), particularly when combined with resistance ex-
ercise [93]. One study conducted in healthy, nontrained younger adults
reported that consuming milk products stimulated amino acid uptake
and muscle protein synthesis following resistance training [94]. Those
findings are supported by at least two other studies using a milk/whey
protein concentrate [95]. Also, the combination of exercise with a milk
fat globule supplement reduced signs of frailty and improved muscle
mass in frail older women [96].
3.7. Probiotics
Intestinal microbiota can influence muscle metabolism by enhan-
cing nutrient absorption and digestion and improving energy efficiency.
Gastrointestinal microbiota produce short-chain fatty acids for energy
and reduce inflammatory cytokines that break down muscle proteins
[97]. Probiotic supplements can also enhance muscle-preserving effects
[97]. Although large studies with high-quality evidence demonstrating
benefit are lacking, interest has been generated by findings from
smaller RCTs. A probiotic supplement containing Lactobacillus and Bi-
fidobacterium provided protection from gains in fat mass and preserved
lean mass in healthy younger males consuming a high-fat, high-energy
diet [98]. Consuming a calcium supplement with Bacillus coagulans
maintained muscle integrity and attenuated inflammatory response
during intense military training in males [99]. Furthermore, Strepto-
coccus thermophilus FP4 and Bifidobacterium breve BR03 supplementa-
tion reduced performance deficits and acute inflammatory response
following muscle-damaging exercise in 15 younger, resistance-trained
men [100].
4. Acid-base balance of the diet
Inadequate fruit and vegetable intake increases the diet’s net acid
load, which is associated with loss of muscle mass. In addition, acido-
genic diets may stimulate proteolysis and amino acid catabolism, in-
creasing muscle-protein breakdown [3]. With aging, the ability to ex-
crete hydrogen ions declines, and other means are employed to preserve
a neutral pH. These include bone resorption, a process that releases
alkali into the circulation, and also muscle degradation, which facil-
itates the renal excretion of hydrogen [101]. Alkalinizing bicarbonate
supplements reduce bone resorption and urinary nitrogen excretion
[102].
In healthy younger men, whey protein supplementation plus a po-
tassium bicarbonate-enriched diet restored the oxidative capacity of
muscle fiber impaired by bed rest [103]. A controlled trial in young
men demonstrated that sodium bicarbonate supplementation improved
maximal accumulated oxygen deficit following exercise [104], while a
short-term alkalinizing diet improved exercise performance in re-
creationally active younger men and women [105]. Dawson-Hughes
et al. [106] demonstrated that three months of potassium bicarbonate
supplementation reduced nitrogen excretion and improved muscle
performance in women ≥50 years of age. Another study reported that
spirulina, an alkaline algal species rich in protein, prevented skeletal
muscle damage [107]. Study participants (N = 16) also experienced
postexercise delay in exhaustion and reduced muscle damage as as-
sessed by blood oxidative markers.
5. Conclusion
Strategies to potentially forestall loss of muscle mass and strength
and reduce the risk of sarcopenia could be important considerations for
A.J. Cruz-Jentoft, et al.
middle-aged and older adults. The benefits of exercise in stimulating
muscle protein synthesis and building muscle mass are well known, and
protein is essential for promoting muscle mass. Evidence suggests that
protein supplementation is most effective in combination with PRT. In
middle-aged and older adults, protein supplementation may also re-
quire enrichment with leucine/HMB and vitamin D to be effective, and
there are questions about the timing and dose that are most effective.
Clear direction related to timing and dose of protein and type of ex-
ercise is unclear, as the available data continue to evolve.
Some data support the use of omega-3 fatty acid supplements for
counteracting age-related loss of muscle mass and improving physical
performance, and vitamin D supplements appear to promote muscle mass,
but not muscle strength. The antioxidant vitamins C and E supplements
are not protective at high doses and may even be harmful; however, more
research is needed that evaluates the effects of lower doses. The evidence
supporting a beneficial effect of magnesium supplements is promising, but
additional RCTs are required. For both polyphenols and probiotics, study
populations are exceedingly small, but the available data appear to be
positive. Lastly, there are only a few studies on nutrients to improve acid-
base balance, and they have been conducted mostly in young men. In
total, these results indicate that it is not clear whether the addition of these
nutritional interventions provides any additional benefit beyond exercise
alone. Large-scale, ongoing RCTs, such as VITAL (VITamin D/OmegA-3
TriaL) [108] and DO-HEALTH (Vitamin D3/Omega-3/Home Exercise -
Healthy Aging and Longevity Trial) [109], may provide important data.
Research agenda
• Is protein supplementation alone adequate in older populations, or
should it be enriched with, for example, vitamin D and leucine? Are
any effects dose related? Do effects depend on baseline protein in-
take?
• What is the target population (e.g. age, health status, exercise his-
tory) that should be considered to receive these interventions?
• What specific dose of protein is beneficial in middle-aged versus
elderly individuals, and what is the optimal timing of ingestion?
• What are the risks of increasing protein intake in middle-aged
adults?
• Are there benefits of improving intake through the diet rather than
relying on supplements?
• Are combinations of ingredients more effective than individual in-
gredients?
• Is the schedule of administration important?
• Are nutritional interventions consistently more effective when
combined with exercise? Does baseline muscle status have an im-
pact?
• Can research establish a simple test for a baseline threshold of
adequate nutritional status for muscle health in middle-aged and
older people below which nutritional intervention is appropriate
and likely to be beneficial?
• What specific doses are ideal for each nutritional intervention?
Contributors
Alfonso J. Cruz-Jentoft participated in study conceptualization, data
curation, formal analysis, and writing, review, and editing of the
manuscript.
Bess Dawson Hughes participated in study conceptualization, data
curation, investigation, and writing, review, and editing of the manu-
script.
David Scott participated in study conceptualization and writing,
review, and editing of the manuscript.
Kerrie M. Sanders participated in study conceptualization, data
curation, investigation, and writing, review, and editing of the manu-
script.
Rene Rizzoli participated in study conceptualization, data curation,
61
Maturitas 132 (2020) 57–64
investigation, and writing, review, and editing of the manuscript.
All authors saw and approved the final version.
Declaration of Competing Interest
Alfonso J. Cruz-Jentoft has received speaker fees from Abbott
Nutrition, Fresenius, Nestlé, Nutricia, Sanofi-Aventis, and consulting
fees from Abbott Nutrition, Boehringer Ingelheim Pharma, Nestlé,
Pfizer, and Regeneron, and has worked on research projects with
Novartis, Nutricia, and Regeneron.
Bess Dawson Hughes has received consulting fees from Intrinsic
Therapeutics and TTY Biopharma Co, Ltd and investigator-initiated
research funding from DSM and Pfizer.
David Scott has received speaker fees from Amgen Australia and
consulting fees from Pfizer, Inc. USA.
Kerrie M. Sanders has received speaker fees from Amgen Australia
and Sanofi-Aventis.
Rene Rizzoli has received consulting fees from Danone, EffRx
Pharmaceuticals SA, Nestlé, ObsEva, Pfizer, Radius Health, Sandoz, and
TEVA/Theramex.
Funding
Pfizer Consumer Healthcare sponsored the preparation of this re-
view, but had no involvement in the collection, analysis, and inter-
pretation of data or in the writing of this manuscript. Pfizer Consumer
Healthcare did approve the final version for publication. On August 1,
2019, Pfizer Consumer Healthcare became part of GSK Consumer
Healthcare.
Provenance and peer review
This article has undergone peer review.
Acknowledgments
Medical writing support was provided by Dennis Stancavish,
Jacqueline Mahon and Carla Resvanis of Peloton Advantage, LLC, and
was funded by Pfizer.
References
[1] A. Buoite Stella, G. Gortan Cappellari, R. Barazzoni, M. Zanetti, Update on the
impact of omega 3 fatty acids on inflammation, insulin resistance and sarcopenia:
a review, Int. J. Mol. Sci. 19 (1) (2018), https://doi.org/10.3390/ijms19010218.
[2] D.J. Weinert, Nutrition and muscle protein synthesis: a descriptive review, J. Can.
Chiropr. Assoc. 53 (3) (2009) 186–193.
[3] D.J. Millward, Nutrition and sarcopenia: evidence for an interaction, Proc. Nutr.
Soc. 71 (4) (2012) 566–575, https://doi.org/10.1017/s0029665112000201.
[4] I. Janssen, S.B. Heymsfield, Z.M. Wang, R. Ross, Skeletal muscle mass and dis-
tribution in 468 men and women aged 18-88 yr, J. Appl. Physiol. 89 (1) (1985)
81–88, https://doi.org/10.1152/jappl.2000.89.1.81 2000.
[5] A.J. Cruz-Jentoft, J.P. Baeyens, J.M. Bauer, Y. Boirie, T. Cederholm, F. Landi,
F.C. Martin, J.P. Michel, Y. Rolland, S.M. Schneider, E. Topinkova,
M. Vandewoude, M. Zamboni, Sarcopenia: European consensus on definition and
diagnosis: Report of the European Working Group on Sarcopenia in Older People,
Age Ageing 39 (4) (2010) 412–423, https://doi.org/10.1093/ageing/afq034.
[6] R. Rizzoli, J.C. Stevenson, J.M. Bauer, L.J. van Loon, S. Walrand, J.A. Kanis,
C. Cooper, M.L. Brandi, A. Diez-Perez, J.Y. Reginster, The role of dietary protein
and vitamin D in maintaining musculoskeletal health in postmenopausal women: a
consensus statement from the European Society for Clinical and Economic Aspects
of Osteoporosis and Osteoarthritis (ESCEO), Maturitas 79 (1) (2014) 122–132,
https://doi.org/10.1016/j.maturitas.2014.07.005.
[7] V.A. Hughes, W.R. Frontera, M. Wood, W.J. Evans, G.E. Dallal, R. Roubenoff, M.A.
Fiatarone Singh, Longitudinal muscle strength changes in older adults: influence of
muscle mass, physical activity, and health, J. Gerontol. A Biol. Sci. Med. Sci. 56 (5)
(2001) B209–217.
[8] B.H. Goodpaster, S.W. Park, T.B. Harris, S.B. Kritchevsky, M. Nevitt,
A.V. Schwartz, E.M. Simonsick, F.A. Tylavsky, M. Visser, A.B. Newman, The loss of
skeletal muscle strength, mass, and quality in older adults: the health, aging and
body composition study, J. Gerontol, A Biol. Sci. Med. Sci. 61 (10) (2006)
1059–1064.
[9] G. Shafiee, A. Keshtkar, A. Soltani, Z. Ahadi, B. Larijani, R. Heshmat, Prevalence of
A.J. Cruz-Jentoft, et al.
sarcopenia in the world: a systematic review and meta-analysis of general popu-
lation studies, J. Diabetes Metab. Disord. 16 (2017) 21, https://doi.org/10.1186/
s40200-017-0302-x.
[10] A.J. Cruz-Jentoft, G. Bahat, J. Bauer, Y. Boirie, O. Bruyere, T. Cederholm,
C. Cooper, F. Landi, Y. Rolland, A.A. Sayer, S.M. Schneider, C.C. Sieber,
E. Topinkova, M. Vandewoude, M. Visser, M. Zamboni, Sarcopenia: revised
European consensus on definition and diagnosis, Age Ageing 48 (1) (2019) 16–31,
https://doi.org/10.1093/ageing/afy169.
[11] P.J. Atherton, K. Smith, Muscle protein synthesis in response to nutrition and
exercise, J. Physiol. (Paris) 590 (5) (2012) 1049–1057, https://doi.org/10.1113/
jphysiol.2011.225003.
[12] T. Akune, S. Muraki, H. Oka, S. Tanaka, H. Kawaguchi, K. Nakamura,
N. Yoshimura, Exercise habits during middle age are associated with lower pre-
valence of sarcopenia: the ROAD study, Osteoporos. Int. 25 (3) (2014) 1081–1088,
https://doi.org/10.1007/s00198-013-2550-z.
[13] R. Silva, N. Pizato, F. da Mata, A. Figueiredo, M. Ito, M.G. Pereira, Mediterranean
diet and musculoskeletal-functional outcomes in community-dwelling older
people: a systematic review and meta-analysis, J. Nutr. Health Aging 22 (6) (2018)
655–663, https://doi.org/10.1007/s12603-017-0993-1.
[14] C. Beaudart, A. Dawson, S.C. Shaw, N.C. Harvey, J.A. Kanis, N. Binkley,
J.Y. Reginster, R. Chapurlat, D.C. Chan, O. Bruyere, R. Rizzoli, C. Cooper,
E.M. Dennison, Nutrition and physical activity in the prevention and treatment of
sarcopenia: systematic review, Osteoporos. Int. 28 (6) (2017) 1817–1833, https://
doi.org/10.1007/s00198-017-3980-9.
[15] D. Bunout, G. Barrera, L. Leiva, V. Gattas, M.P. de la Maza, M. Avendano,
S. Hirsch, Effects of vitamin D supplementation and exercise training on physical
performance in Chilean vitamin D deficient elderly subjects, Exp. Gerontol. 41 (8)
(2006) 746–752, https://doi.org/10.1016/j.exger.2006.05.001.
[16] N.M. Cermak, P.T. Res, L.C. de Groot, W.H. Saris, L.J. van Loon, Protein supple-
mentation augments the adaptive response of skeletal muscle to resistance-type
exercise training: a meta-analysis, Am. J. Clin. Nutr. 96 (6) (2012) 1454–1464,
https://doi.org/10.3945/ajcn.112.037556.
[17] J.P. Loenneke, P.D. Loprinzi, C.H. Murphy, S.M. Phillips, Per meal dose and fre-
quency of protein consumption is associated with lean mass and muscle perfor-
mance, Clin. Nutr. 35 (6) (2016) 1506–1511, https://doi.org/10.1016/j.clnu.
2016.04.002.
[18] J. Bauer, G. Biolo, T. Cederholm, M. Cesari, A.J. Cruz-Jentoft, J.E. Morley,
S. Phillips, C. Sieber, P. Stehle, D. Teta, R. Visvanathan, E. Volpi, Y. Boirie,
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.
14 (8) (2013) 542–559, https://doi.org/10.1016/j.jamda.2013.05.021.
[19] N.E. Deutz, J.M. Bauer, R. Barazzoni, G. Biolo, Y. Boirie, A. Bosy-Westphal,
T. Cederholm, A. Cruz-Jentoft, Z. Krznaric, K.S. Nair, P. Singer, D. Teta, K. Tipton,
P.C. Calder, Protein intake and exercise for optimal muscle function with aging:
recommendations from the ESPEN Expert Group, Clin. Nutr. 33 (6) (2014)
929–936, https://doi.org/10.1016/j.clnu.2014.04.007.
[20] A. Arnarson, O. Gudny Geirsdottir, A. Ramel, K. Briem, P.V. Jonsson,
I. Thorsdottir, Effects of whey proteins and carbohydrates on the efficacy of
resistance training in elderly people: double blind, randomised controlled trial,
Eur. J. Clin. Nutr. 67 (8) (2013) 821–826, https://doi.org/10.1038/ejcn.2013.40.
[21] K.D. Weisgarber, D.G. Candow, J.P. Farthing, Whey protein and high-volume
resistance training in postmenopausal women, J. Nutr. Health Aging 19 (5) (2015)
511–517, https://doi.org/10.1007/s12603-015-0454-7.
[22] G.I. Smith, P. Atherton, D.N. Reeds, B.S. Mohammed, D. Rankin, M.J. Rennie,
B. Mittendorfer, Dietary omega-3 fatty acid supplementation increases the rate of
muscle protein synthesis in older adults: a randomized controlled trial, Am. J. Clin.
Nutr. 93 (2) (2011) 402–412, https://doi.org/10.3945/ajcn.110.005611.
[23] K. Zhu, D.A. Kerr, X. Meng, A. Devine, V. Solah, C.W. Binns, R.L. Prince, Two-year
whey protein supplementation did not enhance muscle mass and physical function
in well-nourished healthy older postmenopausal women, J. Nutr. 145 (11) (2015)
2520–2526, https://doi.org/10.3945/jn.115.218297.
[24] S. Bhasin, C.M. Apovian, T.G. Travison, K. Pencina, L.L. Moore, G. Huang,
W.W. Campbell, Z. Li, A.S. Howland, R. Chen, P.E. Knapp, M.R. Singer, M. Shah,
K. Secinaro, R.V. Eder, K. Hally, H. Schram, R. Bearup, Y.M. Beleva,
A.C. McCarthy, E. Woodbury, J. McKinnon, G. Fleck, T.W. Storer, S. Basaria, Effect
of protein intake on lean body mass in functionally limited older men: a rando-
mized clinical trial, JAMA Intern. Med. 178 (4) (2018) 530–541, https://doi.org/
10.1001/jamainternmed.2018.0008.
[25] O.C. Witard, S.R. Jackman, L. Breen, K. Smith, A. Selby, K.D. Tipton, Myofibrillar
muscle protein synthesis rates subsequent to a meal in response to increasing doses
of whey protein at rest and after resistance exercise, Am. J. Clin. Nutr. 99 (1)
(2014) 86–95, https://doi.org/10.3945/ajcn.112.055517.
[26] I.W. Kouw, A.M. Holwerda, J. Trommelen, I.F. Kramer, J. Bastiaanse, S.L. Halson,
W.K. Wodzig, L.B. Verdijk, L.J. van Loon, Protein ingestion before sleep increases
overnight muscle protein synthesis rates in healthy older men: a randomized
controlled trial, J. Nutr. 147 (12) (2017) 2252–2261, https://doi.org/10.3945/jn.
117.254532.
[27] T. Stokes, A.J. Hector, R.W. Morton, C. McGlory, S.M. Phillips, Recent perspectives
regarding the role of dietary protein for the promotion of muscle hypertrophy with
resistance exercise training, Nutrients 10 (2) (2018), https://doi.org/10.3390/
nu10020180.
[28] D.A. Traylor, S.H.M. Gorissen, S.M. Phillips, Perspective: protein requirements and
optimal intakes in aging: Are we ready to recommend more than the
Recommended Daily Allowance? Adv. Nutr. 9 (3) (2018) 171–182, https://doi.
org/10.1093/advances/nmy003.
[29] M.M. Mamerow, J.A. Mettler, K.L. English, S.L. Casperson, E. Arentson-Lantz,
62
Maturitas 132 (2020) 57–64
M. Sheffield-Moore, D.K. Layman, D. Paddon-Jones, Dietary protein distribution
positively influences 24-h muscle protein synthesis in healthy adults, J. Nutr. 144
(6) (2014) 876–880, https://doi.org/10.3945/jn.113.185280.
[30] J.L. Hudson, J.E. Kim, D. Paddon-Jones, W.W. Campbell, Within-day protein
distribution does not influence body composition responses during weight loss in
resistance-training adults who are overweight, Am. J. Clin. Nutr. 106 (5) (2017)
1190–1196, https://doi.org/10.3945/ajcn.117.158246.
[31] W.J. Smiles, J.L. Areta, V.G. Coffey, S.M. Phillips, D.R. Moore, T. Stellingwerff,
L.M. Burke, J.A. Hawley, D.M. Camera, Modulation of autophagy signaling with
resistance exercise and protein ingestion following short-term energy deficit, Am.
J. Physiol. Regul. Integr. Comp. Physiol. 309 (5) (2015) R603–612, https://doi.
org/10.1152/ajpregu.00413.2014.
[32] R.L. Thomson, G.D. Brinkworth, M. Noakes, J.D. Buckley, Muscle strength gains
during resistance exercise training are attenuated with soy compared with dairy or
usual protein intake in older adults: A randomized controlled trial, Clin. Nutr. 35
(1) (2016) 27–33, https://doi.org/10.1016/j.clnu.2015.01.018.
[33] M.V. Dunlop, S.P. Kilroe, J.L. Bowtell, T.J.A. Finnigan, D.L. Salmon, B.T. Wall,
Mycoprotein represents a bioavailable and insulinotropic non-animal-derived
dietary protein source: a dose-response study, Br. J. Nutr. 118 (9) (2017) 673–685,
https://doi.org/10.1017/s0007114517002409.
[34] P.T. Reidy, D.K. Walker, J.M. Dickinson, D.M. Gundermann, M.J. Drummond,
K.L. Timmerman, M.B. Cope, R. Mukherjea, K. Jennings, E. Volpi, B.B. Rasmussen,
Soy-dairy protein blend and whey protein ingestion after resistance exercise in-
creases amino acid transport and transporter expression in human skeletal muscle,
J. Appl. Physiol. 116 (11) (1985), https://doi.org/10.1152/japplphysiol.01093.
2013 (2014) 1353-1364.
[35] Z.R. Xu, Z.J. Tan, Q. Zhang, Q.F. Gui, Y.M. Yang, The effectiveness of leucine on
muscle protein synthesis, lean body mass and leg lean mass accretion in older
people: a systematic review and meta-analysis, Br. J. Nutr. 113 (1) (2015) 25–34,
https://doi.org/10.1017/s0007114514002475.
[36] B. Komar, L. Schwingshackl, G. Hoffmann, Effects of leucine-rich protein
supplements on anthropometric parameter and muscle strength in the elderly: a
systematic review and meta-analysis, J. Nutr. Health Aging 19 (4) (2015)
437–446, https://doi.org/10.1007/s12603-014-0559-4.
[37] K.L. English, J.A. Mettler, J.B. Ellison, M.M. Mamerow, E. Arentson-Lantz,
J.M. Pattarini, R. Ploutz-Snyder, M. Sheffield-Moore, D. Paddon-Jones, Leucine
partially protects muscle mass and function during bed rest in middle-aged adults,
Am. J. Clin. Nutr. 103 (2) (2016) 465–473, https://doi.org/10.3945/ajcn.115.
112359.
[38] H. Wu, Y. Xia, J. Jiang, H. Du, X. Guo, X. Liu, C. Li, G. Huang, K. Niu, Effect of
beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults:
a systematic review and meta-analysis, Arch. Gerontol. Geriatr. 61 (2) (2015)
168–175, https://doi.org/10.1016/j.archger.2015.06.020.
[39] M.C. Devries, S.M. Phillips, Creatine supplementation during resistance training in
older adults-a meta-analysis, Med. Sci. Sports Exerc. 46 (6) (2014) 1194–1203,
https://doi.org/10.1249/mss.0000000000000220.
[40] D.G. Candow, E. Vogt, S. Johannsmeyer, S.C. Forbes, J.P. Farthing, Strategic
creatine supplementation and resistance training in healthy older adults, Appl.
Physiol. Nutr. Metab. 40 (7) (2015) 689–694, https://doi.org/10.1139/apnm-
2014-0498.
[41] B. Gualano, A.R. Macedo, C.R. Alves, H. Roschel, F.B. Benatti, L. Takayama,
A.L. De Sa Pinto, F.R. Lima, R.M. Pereira, Creatine supplementation and resistance
training in vulnerable older women: a randomized double-blind placebo-con-
trolled clinical trial, Exp. Gerontol. 53 (2014) 7–15, https://doi.org/10.1016/j.
exger.2014.02.003.
[42] T. Stellingwerff, H. Anwander, A. Egger, T. Buehler, R. Kreis, J. Decombaz,
C. Boesch, Effect of two beta-alanine dosing protocols on muscle carnosine
synthesis and washout, Amino Acids 42 (6) (2012) 2461–2472, https://doi.org/
10.1007/s00726-011-1054-4.
[43] J.L. Mate-Munoz, J.H. Lougedo, M.V. Garnacho-Castano, P. Veiga-Herreros,
M.D.C. Lozano-Estevan, P. Garcia-Fernandez, F. de Jesus, J. Guodemar-Perez,
A.F. San Juan, R. Dominguez, Effects of beta-alanine supplementation during a 5-
week strength training program: a randomized, controlled study, J. Int. Soc. Sports
Nutr. 15 (19) (2018), https://doi.org/10.1186/s12970-018-0224-0.
[44] W.P. McCormack, J.R. Stout, N.S. Emerson, T.C. Scanlon, A.M. Warren, A.J. Wells,
A.M. Gonzalez, G.T. Mangine, E.Ht. Robinson, M.S. Fragala, J.R. Hoffman, Oral
nutritional supplement fortified with beta-alanine improves physical working ca-
pacity in older adults: a randomized, placebo-controlled study, Exp. Gerontol. 48
(9) (2013) 933–939, https://doi.org/10.1016/j.exger.2013.06.003.
[45] J.J. Outlaw, A.E. Smith-Ryan, A.L. Buckley, S.L. Urbina, S. Hayward,
H.L. Wingfield, B. Campbell, C. Foster, L.W. Taylor, C.D. Wilborn, Effects of beta-
alanine on body composition and performance measures in collegiate women, J.
Strength Cond. Res. 30 (9) (2016) 2627–2637, https://doi.org/10.1519/jsc.
0000000000000665.
[46] C.E. Shannon, R. Ghasemi, P.L. Greenhaff, F.B. Stephens, Increasing skeletal
muscle carnitine availability does not alter the adaptations to high-intensity in-
terval training, Scand. J. Med. Sci. Sports 28 (1) (2018) 107–115, https://doi.org/
10.1111/sms.12885.
[47] F.B. Stephens, B.T. Wall, K. Marimuthu, C.E. Shannon, D. Constantin-Teodosiu,
I.A. Macdonald, P.L. Greenhaff, Skeletal muscle carnitine loading increases energy
expenditure, modulates fuel metabolism gene networks and prevents body fat
accumulation in humans, J. Physiol. (Paris) 591 (18) (2013) 4655–4666, https://
doi.org/10.1113/jphysiol.2013.255364.
[48] J.K. Lee, J.S. Lee, H. Park, Y.S. Cha, C.S. Yoon, C.K. Kim, Effect of L-carnitine
supplementation and aerobic training on FABPc content and beta-HAD activity in
human skeletal muscle, Eur. J. Appl. Physiol. 99 (2) (2007) 193–199, https://doi.
A.J. Cruz-Jentoft, et al.
org/10.1007/s00421-006-0333-3.
[49] J.M. Bauer, S. Verlaan, I. Bautmans, K. Brandt, L.M. Donini, M. Maggio,
M.E. McMurdo, T. Mets, C. Seal, S.L. Wijers, G.P. Ceda, G. De Vito, G. Donders,
M. Drey, C. Greig, U. Holmback, M. Narici, J. McPhee, E. Poggiogalle, D. Power,
A. Scafoglieri, R. Schultz, C.C. Sieber, T. Cederholm, 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-con-
trolled trial, J. Am. Med. Dir. Assoc. 16 (9) (2015) 740–747, https://doi.org/10.
1016/j.jamda.2015.05.021.
[50] P.C. Calder, Mechanisms of action of (n-3) fatty acids, J. Nutr. 142 (3) (2012),
https://doi.org/10.3945/jn.111.155259 592S-599S.
[51] A. Saini, A.P. Sharples, N. Al-Shanti, C.E. Stewart, Omega-3 fatty acid EPA im-
proves regenerative capacity of mouse skeletal muscle cells exposed to saturated
fat and inflammation, Biogerontology 18 (1) (2017) 109–129, https://doi.org/10.
1007/s10522-016-9667-3.
[52] J. Yoshino, G.I. Smith, S.C. Kelly, S. Julliand, D.N. Reeds, B. Mittendorfer, Effect of
dietary n-3 PUFA supplementation on the muscle transcriptome in older adults,
Physiol. Rep. 4 (11) (2016), https://doi.org/10.14814/phy2.12785.
[53] C. Custodero, R.T. Mankowski, S.A. Lee, Z. Chen, S. Wu, T.M. Manini, J. Hincapie
Echeverri, C. Sabba, D.P. Beavers, J.A. Cauley, M.A. Espeland, R.A. Fielding,
S.B. Kritchevsky, C.K. Liu, M.M. McDermott, M.E. Miller, R.P. Tracy,
A.B. Newman, W.T. Ambrosius, M. Pahor, S.D. Anton, Evidence-based nutritional
and pharmacological interventions targeting chronic low-grade inflammation in
middle-age and older adults: a systematic review and meta-analysis, Ageing Res.
Rev. 46 (2018) 42–59, https://doi.org/10.1016/j.arr.2018.05.004.
[54] A.Z. Lalia, S. Dasari, M.M. Robinson, H. Abid, D.M. Morse, K.A. Klaus, I.R. Lanza,
Influence of omega-3 fatty acids on skeletal muscle protein metabolism and mi-
tochondrial bioenergetics in older adults, Aging (Albany NY) 9 (4) (2017)
1096–1129, https://doi.org/10.18632/aging.101210.
[55] P. Edholm, E. Strandberg, F. Kadi, Lower limb explosive strength capacity in
elderly women: effects of resistance training and healthy diet, J. Appl. Physiol.
(1985) 123 (1) (2017) 190–196, https://doi.org/10.1152/japplphysiol.00924.
2016.
[56] G.I. Smith, S. Julliand, D.N. Reeds, D.R. Sinacore, S. Klein, B. Mittendorfer, Fish
oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older
adults, Am. J. Clin. Nutr. 102 (1) (2015) 115–122, https://doi.org/10.3945/ajcn.
114.105833.
[57] C.L. Rodacki, A.L. Rodacki, G. Pereira, K. Naliwaiko, I. Coelho, D. Pequito,
L.C. Fernandes, Fish-oil supplementation enhances the effects of strength training
in elderly women, Am. J. Clin. Nutr. 95 (2) (2012) 428–436, https://doi.org/10.
3945/ajcn.111.021915.
[58] M. Da Boit, R. Sibson, S. Sivasubramaniam, J.R. Meakin, C.A. Greig, R.M. Aspden,
F. Thies, S. Jeromson, D.L. Hamilton, J.R. Speakman, C. Hambly, A.A. Mangoni,
T. Preston, S.R. Gray, Sex differences in the effect of fish-oil supplementation on
the adaptive response to resistance exercise training in older people: a randomized
controlled trial, Am. J. Clin. Nutr. 105 (1) (2017) 151–158, https://doi.org/10.
3945/ajcn.116.140780.
[59] S.L. Logan, L.L. Spriet, Omega-3 fatty acid supplementation for 12 weeks increases
resting and exercise metabolic rate in healthy community-dwelling older females,
PLoS One 10 (12) (2015), https://doi.org/10.1371/journal.pone.0144828
e0144828.
[60] S.B. Tanner, S.A. Harwell, More than healthy bones: a review of vitamin D in
muscle health, Ther. Adv. Musculoskelet. Dis. 7 (4) (2015) 152–159, https://doi.
org/10.1177/1759720X15588521.
[61] H.A. Bischoff-Ferrari, M. Borchers, F. Gudat, U. Durmuller, H.B. Stahelin, W. Dick,
Vitamin D receptor expression in human muscle tissue decreases with age, J. Bone
Miner. Res. 19 (2) (2004) 265–269, https://doi.org/10.1359/jbmr.2004.19.2.265.
[62] R.M. Pojednic, L. Ceglia, K. Olsson, T. Gustafsson, A.H. Lichtenstein, B. Dawson-
Hughes, R.A. Fielding, Effects of 1,25-dihydroxyvitamin D3 and vitamin D3 on the
expression of the vitamin D receptor in human skeletal muscle cells, Calcif. Tissue
Int. 96 (3) (2015) 256–263, https://doi.org/10.1007/s00223-014-9932-x.
[63] L. Ceglia, S. Niramitmahapanya, M. da Silva Morais, D.A. Rivas, S.S. Harris,
H. Bischoff-Ferrari, R.A. Fielding, B. Dawson-Hughes, A randomized study on the
effect of vitamin D(3) supplementation on skeletal muscle morphology and vi-
tamin D receptor concentration in older women, J. Clin. Endocrinol. Metab. 98
(12) (2013), https://doi.org/10.1210/jc.2013-2820 E1927-1935.
[64] Z. Xia, Q. Man, L. Li, P. Song, S. Jia, S. Song, L. Meng, J. Zhang, Vitamin D receptor
gene polymorphisms modify the association of serum 25-hydroxyvitamin D levels
with handgrip strength in the elderly in Northern China, Nutrition 57 (2019)
202–207, https://doi.org/10.1016/j.nut.2018.05.025.
[65] S.W. Muir, M. Montero-Odasso, Effect of vitamin D supplementation on muscle
strength, gait and balance in older adults: a systematic review and meta-analysis,
J. Am, Ariz. Geriatr. Soc. J. 59 (12) (2011) 2291–2300, https://doi.org/10.1111/j.
1532-5415.2011.03733.x.
[66] A.E. Antoniak, C.A. Greig, The effect of combined resistance exercise training and
vitamin D3 supplementation on musculoskeletal health and function in older
adults: a systematic review and meta-analysis, BMJ Open 7 (7) (2017), https://doi.
org/10.1136/bmjopen-2016-014619 e014619.
[67] H. Rosendahl-Riise, U. Spielau, A.H. Ranhoff, O.A. Gudbrandsen, J. Dierkes,
Vitamin D supplementation and its influence on muscle strength and mobility in
community-dwelling older persons: a systematic review and meta-analysis, J.
Hum. Nutr. Diet. 30 (1) (2017) 3–15, https://doi.org/10.1111/jhn.12394.
[68] K.A. Stockton, K. Mengersen, J.D. Paratz, D. Kandiah, K.L. Bennell, Effect of vi-
tamin D supplementation on muscle strength: a systematic review and meta-
analysis, Osteoporos. Int. 22 (3) (2011) 859–871, https://doi.org/10.1007/
s00198-010-1407-y.
63
Maturitas 132 (2020) 57–64
[69] H.A. Bischoff-Ferrari, B. Dawson-Hughes, E.J. Orav, H.B. Staehelin, O.W. Meyer,
R. Theiler, W. Dick, W.C. Willett, A. Egli, Monthly high-dose vitamin D treatment
for the prevention of functional decline: a randomized clinical trial, JAMA Intern.
Med. 176 (2) (2016) 175–183, https://doi.org/10.1001/jamainternmed.2015.
7148.
[70] K.M. Sanders, A.L. Stuart, E.J. Williamson, J.A. Simpson, M.A. Kotowicz,
D. Young, G.C. Nicholson, Annual high-dose oral vitamin D and falls and fractures
in older women: a randomized controlled trial, JAMA 303 (18) (2010) 1815–1822,
https://doi.org/10.1001/jama.2010.594.
[71] L.S. Bislev, L. Langagergaard Rodbro, L. Rolighed, T. Sikjaer, L. Rejnmark, Effects
of vitamin D3 supplementation on muscle strength, mass, and physical perfor-
mance in women with vitamin D insufficiency: a randomized placebo-controlled
trial, Calcif. Tissue Int. (2018), https://doi.org/10.1007/s00223-018-0443-z.
[72] M. Apaydin, A.G. Can, M. Kizilgul, S. Beysel, S. Kan, M. Caliskan, T. Demirci,
O. Ozcelik, M. Ozbek, E. Cakal, The effects of single high-dose or daily low-dosage
oral colecalciferol treatment on vitamin D levels and muscle strength in post-
menopausal women, BMC Endocr. Disord. 18 (1) (2018) 48, https://doi.org/10.
1186/s12902-018-0277-8.
[73] L.A. Silva, C.A. Pinho, P.C. Silveira, T. Tuon, C.T. De Souza, F. Dal-Pizzol,
R.A. Pinho, Vitamin E supplementation decreases muscular and oxidative damage
but not inflammatory response induced by eccentric contraction, J. Physiol. Sci. 60
(1) (2010) 51–57, https://doi.org/10.1007/s12576-009-0065-3.
[74] M. Meydani, W.J. Evans, G. Handelman, L. Biddle, R.A. Fielding, S.N. Meydani,
J. Burrill, M.A. Fiatarone, J.B. Blumberg, J.G. Cannon, Protective effect of vitamin
E on exercise-induced oxidative damage in young and older adults, Am. J. Physiol.
264 (5 Pt 2) (1993) R992–998, https://doi.org/10.1152/ajpregu.1993.264.5.
R992.
[75] V. Stepanyan, M. Crowe, N. Haleagrahara, B. Bowden, Effects of vitamin E sup-
plementation on exercise-induced oxidative stress: a meta-analysis, Appl. Physiol.
Nutr. Metab. 39 (9) (2014) 1029–1037, https://doi.org/10.1139/apnm-2013-
0566.
[76] M.C. Gomez-Cabrera, E. Domenech, M. Romagnoli, A. Arduini, C. Borras,
F.V. Pallardo, J. Sastre, J. Vina, Oral administration of vitamin C decreases muscle
mitochondrial biogenesis and hampers training-induced adaptations in endurance
performance, Am. J. Clin. Nutr. 87 (1) (2008) 142–149, https://doi.org/10.1093/
ajcn/87.1.142.
[77] D. Morrison, J. Hughes, P.A. Della Gatta, S. Mason, S. Lamon, A.P. Russell,
G.D. Wadley, Vitamin C and E supplementation prevents some of the cellular
adaptations to endurance-training in humans, Free Radic. Biol. Med. 89 (2015)
852–862, https://doi.org/10.1016/j.freeradbiomed.2015.10.412.
[78] G. Paulsen, K.T. Cumming, G. Holden, J. Hallen, B.R. Ronnestad, O. Sveen,
A. Skaug, I. Paur, N.E. Bastani, H.N. Ostgaard, C. Buer, M. Midttun, F. Freuchen,
H. Wiig, E.T. Ulseth, I. Garthe, R. Blomhoff, H.B. Benestad, T. Raastad, Vitamin C
and E supplementation hampers cellular adaptation to endurance training in hu-
mans: a double-blind, randomised, controlled trial, J. Physiol. (Paris) 592 (8)
(2014) 1887–1901, https://doi.org/10.1113/jphysiol.2013.267419.
[79] T. Bjornsen, S. Salvesen, S. Berntsen, K.J. Hetlelid, T.H. Stea, H. Lohne-Seiler,
G. Rohde, K. Haraldstad, T. Raastad, U. Kopp, G. Haugeberg, M.A. Mansoor,
N.E. Bastani, R. Blomhoff, S.B. Stolevik, O.R. Seynnes, G. Paulsen, Vitamin C and E
supplementation blunts increases in total lean body mass in elderly men after
strength training, Scand. J. Med. Sci. Sports 26 (7) (2016) 755–763, https://doi.
org/10.1111/sms.12506.
[80] A.K. Stunes, U. Syversen, S. Berntsen, G. Paulsen, T.H. Stea, K.J. Hetlelid,
H. Lohne-Seiler, M.P. Mosti, T. Bjornsen, T. Raastad, G. Haugeberg, High doses of
vitamin C plus E reduce strength training-induced improvements in areal bone
mineral density in elderly men, Eur. J. Appl. Physiol. 117 (6) (2017) 1073–1084,
https://doi.org/10.1007/s00421-017-3588-y.
[81] J.L. Zhang, Z.W. Zhang, A.S. Shan, S.W. Xu, Effects of dietary selenium deficiency
or excess on gene expression of selenoprotein N in chicken muscle tissues, Biol.
Trace Elem. Res. 157 (3) (2014) 234–241, https://doi.org/10.1007/s12011-014-
9893-y.
[82] S. Palazzetti, A.S. Rousseau, M.J. Richard, A. Favier, I. Margaritis, Antioxidant
supplementation preserves antioxidant response in physical training and low an-
tioxidant intake, Br. J. Nutr. 91 (1) (2004) 91–100.
[83] P. Johansson, O. Dahlstrom, U. Dahlstrom, U. Alehagen, Improved health-related
quality of life, and more days out of hospital with supplementation with selenium
and coenzyme Q10 combined. Results from a double blind, placebo-controlled
prospective study, J. Nutr. Health Aging 19 (9) (2015) 870–877, https://doi.org/
10.1007/s12603-015-0509-9.
[84] M. Barbagallo, M. Belvedere, L.J. Dominguez, Magnesium homeostasis and aging,
Magnes. Res. 22 (4) (2009) 235–246, https://doi.org/10.1684/mrh.2009.0187.
[85] A.A. Welch, E. Kelaiditi, A. Jennings, C.J. Steves, T.D. Spector, A. MacGregor,
Dietary magnesium is positively associated with skeletal muscle power and indices
of muscle mass and may attenuate the association between circulating C-reactive
protein and muscle mass in women, J. Bone Miner. Res. 31 (2) (2016) 317–325,
https://doi.org/10.1002/jbmr.2692.
[86] D.A. Santos, C.N. Matias, C.P. Monteiro, A.M. Silva, P.M. Rocha, C.S. Minderico,
L. Bettencourt Sardinha, M.J. Laires, Magnesium intake is associated with strength
performance in elite basketball, handball and volleyball players, Magnes. Res. 24
(4) (2011) 215–219, https://doi.org/10.1684/mrh.2011.0290.
[87] N. Veronese, L. Berton, S. Carraro, F. Bolzetta, M. De Rui, E. Perissinotto,
E.D. Toffanello, G. Bano, S. Pizzato, F. Miotto, A. Coin, E. Manzato, G. Sergi, Effect
of oral magnesium supplementation on physical performance in healthy elderly
women involved in a weekly exercise program: a randomized controlled trial, Am.
J. Clin. Nutr. 100 (3) (2014) 974–981, https://doi.org/10.3945/ajcn.113.080168.
[88] K.S. Beyer, J.R. Stout, D.H. Fukuda, A.R. Jajtner, J.R. Townsend, D.D. Church,
A.J. Cruz-Jentoft, et al.
R. Wang, J.J. Riffe, T.W.D. Muddle, K.A. Herrlinger, J.R. Hoffman, Impact of
polyphenol supplementation on acute and chronic response to resistance training,
J. Strength Cond. Res. 31 (11) (2017) 2945–2954, https://doi.org/10.1519/jsc.
0000000000002104.
[89] A. Ammar, M. Turki, O. Hammouda, H. Chtourou, K. Trabelsi, M. Bouaziz,
O. Abdelkarim, A. Hoekelmann, F. Ayadi, N. Souissi, S.J. Bailey, T. Driss, S. Yaich,
Effects of pomegranate juice supplementation on oxidative stress biomarkers fol-
lowing weightlifting exercise, Nutrients 9 (8) (2017), https://doi.org/10.3390/
nu9080819.
[90] J.R. Trombold, J.N. Barnes, L. Critchley, E.F. Coyle, Ellagitannin consumption
improves strength recovery 2-3 d after eccentric exercise, Med. Sci. Sports Exerc.
42 (3) (2010) 493–498, https://doi.org/10.1249/MSS.0b013e3181b64edd.
[91] H. Kim, T. Suzuki, K. Saito, H. Yoshida, N. Kojima, M. Kim, M. Sudo, Y. Yamashiro,
I. Tokimitsu, Effects of exercise and tea catechins on muscle mass, strength and
walking ability in community-dwelling elderly Japanese sarcopenic women: a
randomized controlled trial, Geriatr. Gerontol. Int. 13 (2) (2013) 458–465,
https://doi.org/10.1111/j.1447-0594.2012.00923.x.
[92] H. Kim, M. Kim, N. Kojima, K. Fujino, E. Hosoi, H. Kobayashi, S. Somekawa,
Y. Niki, Y. Yamashiro, H. Yoshida, Exercise and nutritional supplementation on
community-dwelling elderly Japanese women with sarcopenic obesity: a rando-
mized controlled trial, J. Am. Med. Dir. Assoc. 17 (11) (2016) 1011–1019, https://
doi.org/10.1016/j.jamda.2016.06.016.
[93] A.R. Josse, S.M. Phillips, Impact of milk consumption and resistance training on
body composition of female athletes, Med. Sport Sci. 59 (2012) 94–103, https://
doi.org/10.1159/000341968.
[94] T.A. Elliot, M.G. Cree, A.P. Sanford, R.R. Wolfe, K.D. Tipton, Milk ingestion sti-
mulates net muscle protein synthesis following resistance exercise, Med. Sci.
Sports Exerc. 38 (4) (2006) 667–674, https://doi.org/10.1249/01.mss.
0000210190.64458.25.
[95] C.J. Mitchell, R.A. McGregor, R.F. D’Souza, E.B. Thorstensen, J.F. Markworth,
A.C. Fanning, S.D. Poppitt, D. Cameron-Smith, Consumption of milk protein or
whey protein results in a similar increase in muscle protein synthesis in middle
aged men, Nutrients 7 (10) (2015) 8685–8699, https://doi.org/10.3390/
nu7105420.
[96] H. Kim, T. Suzuki, M. Kim, N. Kojima, N. Ota, A. Shimotoyodome, T. Hase,
E. Hosoi, H. Yoshida, Effects of exercise and milk fat globule membrane (MFGM)
supplementation on body composition, physical function, and hematological
parameters in community-dwelling frail Japanese women: a randomized double
blind, placebo-controlled, follow-up trial, PLoS One 10 (2) (2015), https://doi.
org/10.1371/journal.pone.0116256 e0116256.
[97] L.B. Bindels, N.M. Delzenne, Muscle wasting: the gut microbiota as a new ther-
apeutic target? Int. J. Biochem. Cell Biol. 45 (10) (2013) 2186–2190, https://doi.
org/10.1016/j.biocel.2013.06.021.
[98] K.L. Osterberg, N.E. Boutagy, R.P. McMillan, J.R. Stevens, M.I. Frisard,
J.W. Kavanaugh, B.M. Davy, K.P. Davy, M.W. Hulver, Probiotic supplementation
attenuates increases in body mass and fat mass during high-fat diet in healthy
young adults, Obesity Silver Spring (Silver Spring) 23 (12) (2015) 2364–2370,
64
Maturitas 132 (2020) 57–64
https://doi.org/10.1002/oby.21230.
[99] Y. Gepner, J.R. Hoffman, E. Shemesh, J.R. Stout, D.D. Church, A.N. Varanoske,
H. Zelicha, I. Shelef, Y. Chen, H. Frankel, I. Ostfeld, Combined effect of Bacillus
coagulans GBI-30, 6086 and HMB supplementation on muscle integrity and cy-
tokine response during intense military training, J. Appl. Physiol. (1985) 123 (1)
(2017) 11–18, https://doi.org/10.1152/japplphysiol.01116.2016.
[100] R. Jager, M. Purpura, J.D. Stone, S.M. Turner, A.J. Anzalone, M.J. Eimerbrink,
M. Pane, A. Amoruso, D.S. Rowlands, J.M. Oliver, Probiotic Streptococcus ther-
mophilus FP4 and Bifidobacterium breve BR03 supplementation attenuates per-
formance and range-of-motion decrements following muscle damaging exercise,
Nutrients 8 (10) (2016), https://doi.org/10.3390/nu8100642.
[101] A.A. Welch, Nutritional influences on age-related skeletal muscle loss, Proc. Nutr.
Soc. 73 (1) (2014) 16–33, https://doi.org/10.1017/s0029665113003698.
[102] B. Dawson-Hughes, S.S. Harris, N.J. Palermo, C. Castaneda-Sceppa,
H.M. Rasmussen, G.E. Dallal, Treatment with potassium bicarbonate lowers cal-
cium excretion and bone resorption in older men and women, J. Clin. Endocrinol.
Metab. 94 (1) (2009) 96–102, https://doi.org/10.1210/jc.2008-1662.
[103] A. Bosutti, M. Salanova, D. Blottner, J. Buehlmeier, E. Mulder, J. Rittweger,
M.H. Yap, B. Ganse, H. Degens, Whey protein with potassium bicarbonate
supplement attenuates the reduction in muscle oxidative capacity during 19 days
of bed rest, J. Appl. Physiol. (1985) 121 (4) (2016) 838–848, https://doi.org/10.
1152/japplphysiol.00936.2015.
[104] G.M. Brisola, W.E. Miyagi, H.S. da Silva, A.M. Zagatto, Sodium bicarbonate sup-
plementation improved MAOD but is not correlated with 200- and 400-m running
performances: a double-blind, crossover, and placebo-controlled study, Appl.
Physiol. Nutr. Metab. 40 (9) (2015) 931–937, https://doi.org/10.1139/apnm-
2015-0036.
[105] M. Limmer, A.D. Eibl, P. Platen, Enhanced 400-m sprint performance in moder-
ately trained participants by a 4-day alkalizing diet: a counterbalanced, rando-
mized controlled trial, J. Int. Soc. Sports Nutr. 15 (1) (2018) 25, https://doi.org/
10.1186/s12970-018-0231-1.
[106] B. Dawson-Hughes, C. Castaneda-Sceppa, S.S. Harris, N.J. Palermo, G. Cloutier,
L. Ceglia, G.E. Dallal, Impact of supplementation with bicarbonate on lower-ex-
tremity muscle performance in older men and women, Osteoporos. Int. 21 (7)
(2010) 1171–1179, https://doi.org/10.1007/s00198-009-1049-0.
[107] H.K. Lu, C.C. Hsieh, J.J. Hsu, Y.K. Yang, H.N. Chou, Preventive effects of Spirulina
platensis on skeletal muscle damage under exercise-induced oxidative stress, Eur.
J. Appl. Physiol. 98 (2) (2006) 220–226, https://doi.org/10.1007/s00421-006-
0263-0.
[108] S.S. Bassuk, J.E. Manson, I.M. Lee, N.R. Cook, W.G. Christen, V.Y. Bubes,
D.S. Gordon, T. Copeland, G. Friedenberg, D.M. D’Agostino, C.Y. Ridge,
J.G. MacFadyen, K. Kalan, J.E. Buring, Baseline characteristics of participants in
the VITamin D and OmegA-3 TriaL (VITAL), Contemp. Clin. Trials 47 (2016)
235–243, https://doi.org/10.1016/j.cct.2015.12.022.
[109] DO-HEALTH / vitamin D3 - omega3 - home exercise - healthy ageing and long-
evity trial (DO-HEALTH) NCT01745263. < https://clinicaltrials.gov/ct2/show/
NCT01745263 > , 2018 (Accessed December 18, 2018.).