Non-Pharmacological Interventions for Age-Related Sarcopenia

Abstract

Sarcopenia is a progressive loss of muscle strength and muscle mass occurring with aging, and is associated with a number of poorer health outcomes (such as falls, injuries, reduced overall survival, cognitive decline, and metabolic disorders). Physical inactivity and poor nutrition are important risk factors in the development of sarcopenia, and this review highlights the evidence for exercise (one of the most important and effective strategies in combatting age-related muscle loss) as well as nutrition in sarcopenia. Targeted supplementation with fatty acids (including omega-3 fatty acids and monounsaturated fatty acids), silkworm pupae extract, probiotics, and curcumin are also reviewed. Vitamin D status is also important to muscle health, and interventions including vitamin D supplementation are discussed.

Introduction

Sarcopenia, a progressive and involuntary age-related decline in muscle mass, strength, and function, is associated with a number of adverse health outcomes. It can significantly impact a person's mobility, lead to reductions in quality of life (QOL), and contribute to falls and injuries (which in turn can lead to more extended hospitalizations and rehabilitation for those affected). Sarcopenia is tied to poor overall survival, metabolic disorders, cognitive decline, and general mortality.^1,2

A number of mechanisms are thought to be involved in the development and progression of sarcopenia. A progressive loss of motor neurons during aging (with remaining motor neurons not adequately reinnervating affected muscle fibers) is thought to lead to sarcopenia by decreasing both muscle fiber size and number over time. Both quantitative and qualitative alterations to muscle structure and function are involved in the development of sarcopenia.² Muscle fiber composition may shift with aging towards more slow-twitch fibers, with reduced glucose transporter (GLUT4) activity occurring in fast-twitch fibers. This may reduce the ability of muscle tissue to optimally respond to insulin and utilize glucose as fuel.³

Mammalian target of rapamycin (mTOR) also plays a key role in protein synthesis and homeostasis, and modulates the balance between muscle hypertrophy and degradation by regulating skeletal muscle's anabolic and catabolic signaling. Dysfunctional activity of protein kinase B (Akt)/mTOR is thought to contribute to the sarcopenia seen with aging (see Sidebar). Circulating levels of insulin-like growth factor-1 have also been shown to be lower in older people compared to younger individuals.⁴ Alterations in these key regulators are thought to contribute to abnormal skeletal muscle autophagy (with the combination of reduced autophagy and excessive apoptosis promoting skeletal muscle atrophy over time).^5,6

While age is the best-known risk factor for the occurrence of sarcopenia, other factors may also increase risk. Smoking, excessive sleep duration, and diabetes are all associated with an increased occurrence of sarcopenia.¹ Physical inactivity and poorer nutrition are also key drivers, with inadequate protein intake and lack of exercise thought to be two of the most important risk factors.⁷ The consumption of a more pro-inflammatory diet (as assessed by the dietary inflammatory index [DII]) has been shown in multiple meta-analyses to correlate with sarcopenia.^8,9 Inflammation in general may also be problematic, as higher levels of inflammatory cytokines are closely tied to the development of sarcopenia in elderly people.¹⁰ The many hormonal or endocrine changes that occur with aging may also contribute to sarcopenia (such as reductions in testosterone and dehydroepiandrosterone [DHEA]).¹¹ Anabolic resistance may also be an important driver of age-related muscle atrophy.¹² In women, early menopause (menopause occurring before age 45) or premature ovarian insufficiency (menopause occurring before age 40) may increase the risk of sarcopenia.¹³

Mammalian Target of Rapamycin and Sarcopenia: A Delicate Balance

- Complete relationship between mammalian target of rapamycin (mTOR) activity and sarcopenia seen with aging is complex and is still being elucidated.

- mTOR activation is essential for muscle hypertrophy.

- Paradoxically, mTOR activity may actually become excessive or hyperactive in aging skeletal muscle tissue.⁵⁹

- Sustained activation of mTOR complex 1 activity may then lead to a loss of extracellular signaling sensitivity, promoting muscle atrophy.⁵⁹

- Higher activity of mTORC1-ribosomal protein S6 kinase in muscle of older rats, mice and humans is associated with sarcopenia.⁶⁰

- Partial inhibition of mTOR has been demonstrated to counteract muscle atrophy in preclinical models of sarcopenia of aging.⁶¹

- This suggests modulation may be key, since appropriate mTOR activation (i.e., in response to exercise or protein intake) would be required for muscle protein synthesis, while too much mTOR activity could be detrimental.

Estimates for the prevalence of sarcopenia vary depending on the definition utilized; for an excellent scoping review of almost a dozen definitions of sarcopenia (based on low muscle mass as appendicular skeletal muscle mass/height² ratio, low muscle strength [grip strength], and low muscle performance/function [gait speed]), see Stuck et al.'s 2023 paper.¹⁴ In a multinational study of community-dwelling Europeans age 70+, the prevalence of sarcopenia ranged from 0.7% up to 16.8%, depending on the criteria utilized.¹⁵ Other studies report prevalences of sarcopenia ranging from 5% to 22% in the elderly. The pooled prevalence for all definitions of sarcopenia in systematic reviews has been reported at 10%–16%. Higher rates of sarcopenia are also seen in people with specific conditions, including those with kidney disease, liver disease, surgical patients, and people with cancer.¹

It is important to note that many of the factors that contribute to sarcopenia are also implicated in the development of osteopenia or osteoporosis (aging, inactivity, environmental factors, and endocrine factors), and the co-occurrence of these two processes together (termed osteosarcopenia) is also highly prevalent.^16,17 More than any other group, people with osteosarcopenia may be at the highest risk of functional declines.¹⁸

When does the loss of muscle mass and strength begin? After the age of 30, muscle mass declines by roughly 3%–8% each decade of life.¹¹ The rate of decline is even greater after age 60, and by age 75, muscle mass decreases at a rate of 0.64%–0.7% per year in women and 0.8%–0.98% per year in men, while muscle strength declines by 2.5%–3% per year in women and 3%–4% per year in men.¹² While muscle loss and changes are a normal part of aging, even among those who are healthy, physically active, and well-nourished, it is important to note that functional losses vary significantly in different individuals.² What can we do to ensure that these functional declines are minimized, and that our patients are retaining as much muscular strength, muscle mass, and functionality as possible as they age? This article delves into the non-pharmacologic interventions that have been shown to address aging-related sarcopenia.

Exercise

By far, the most important and effective strategy in combatting age-related sarcopenia is physical activity. As mentioned above, improper regulation of autophagy in aging skeletal muscle is thought to be a contributor to the development of sarcopenia. Indeed, muscle mass reductions in preclinical models of sarcopenia have been shown to be associated with deficient autophagy and upregulated apoptosis, with these processes being driven by a number of changes in various autophagy-regulating proteins. Muscle mass decline is seen in conjunction with reduced levels of Beclin1 and Bcl-2 (a key target in the formation of autophagosomes, and an apoptosis suppressor, respectively), excess accumulation of p62 (a protein that binds other ubiquinated proteins, targeting them for destruction by proteasomes), and decreased mitochondrial function. In preclinical models, exercise has been shown to reverse these alterations, increasing Beclin1 and Bcl-2, reducing p62, and enhancing mitochondrial function in muscle cells. Additionally, exercise has been shown to downregulate Akt, mTOR, and FoxO3a (Forkhead box O3) signaling, restoring proper autophagy function.⁵

Exercise interventions show consistent benefits in people with sarcopenia. In Monti et al.'s two-year randomized clinical trial (RCT), 45 elderly people (mean age 78.7 ± 5.9 years) with sarcopenia (using DEXA [dual-energy X-ray absorptiometry] scan criteria for sarcopenia defined by the Foundation for the National Institutes of Health [FNIH] Sarcopenia Project) were randomized to either a control or intervention group. Control group subjects underwent “healthy aging lifestyle education” classes once a month. Intervention group participants completing exercise training three times a week for two years, with a combination of aerobic, strength, and balance training, as well as receiving nutritional advice (individualized to achieve total daily energy intake of 25–30 kcal/kg; average protein intake of ≥1.0–1.2 g/kg daily, and serum 25 hydroxy-vitamin D [25OHD] level of 30 ng/mL).¹⁹

At the conclusion of the trial, control group subjects demonstrated a 12.7% reduction in vastus lateralis muscle cross-sectional area, a 5.5% reduction in pennation angle (a measure of contractile strength), and a 5.5% reduction in fascicle length (P < 0.001 for each). C-terminal agrin fragment (CAF) was also measured as a biomarker of neuronal health/neuromuscular junction stability. CAF decreased by 6.2% in control group subjects. While intervention group participants experienced a reduction in muscle cross-sectional area as well (−8.4%, P < 0.001), pennation angle, fascicle length, and CAF levels were maintained, and exercisers also improved their performance on the Short Physical Performance Battery (P = 0.007).¹⁹

Even shorter, home-based exercise programs are sufficient to benefit people with sarcopenia. In Sen et al.'s three-month multicenter RCT, 100 subjects with sarcopenia were randomized to either a control group or to home exercise. Home exercisers completed a progressive training program with strength training, stretching, posture, balance, and gait-based components. Compared to control group participants, exercisers saw a number of improvements by the three-month timepoint. This included significant gains on the six-minute walking test as well as in the Berg Balance Scale score, significant improvements in QOL, and significant reductions in the timed up and go test scores.²⁰

Which type or combination of exercise is most effective in addressing age-related sarcopenia? Numerous trials have been conducted in an effort to answer this question, with the result being a handful of meta-analyses comparing various forms or combinations of exercise training. These studies are summarized in Table 1.

Table 1.

Meta-Analyses of Exercise Interventions in People with Sarcopenia

Author	Subjects	Findings
Park and Roh²⁴	3063 adults age >60 with sarcopenia from 32 controlled studies	Comparing combined exercise and nutrition intervention with controls, the WMD was 0.20 kg/m², 1.56 kg, and 0.08 m/s for SMI, handgrip, and gait speed, respectively (all statistically significant). Exercise outperformed nutrition-based interventions.
Zhao et al.²³	569 subjects with sarcopenia ages 60–91 from 13 studies	Meta-analysis compared various forms of resistance training. Resistance band training (40–60 minutes >3 times/week for ≥12 weeks) was found to be most effective (Hedges's g = 0.629, 95% CI = 0.090–1.168, P < 0.05).
Geng et al.²²	2485 patients from 30 RCTs	Compared seven different forms of exercise and nutrition interventions. Compared with other interventions (aerobic exercise, mixed exercise, nutrition, resistance plus nutrition, mixed exercise plus nutrition, electric stimulation plus nutrition), resistance exercise led to better gains in muscle mass, strength, and physical function.
Shen et al.²¹	3728 subjects with sarcopenia from 42 RCTs	Compared varying exercise and nutrition interventions. Participant median age was 72.9 years; median follow-up was 12 weeks. Resistance training with/without nutrition and combination resistance/aerobic/balance exercise were most effective for improving QOL. Adding nutrition interventions to exercise had a greater effect on handgrip strength than exercise alone.

CI, confidence interval; QOL, quality of life; SMI, skeletal muscle index; WMD, weighted mean difference.

These meta-analyses compared varying exercise-based, and in some cases nutrition-based, interventions in people with sarcopenia.^21

–24 While many interventions were beneficial, exercise, and in particular resistance training exercise, stands out in these studies for its benefits on muscle strength, muscle mass, physical function, and QOL. This is consistent with recommendations from the British Geriatric Society, which specify that resistance exercise is currently recommended as first-line treatment for sarcopenia. The same group recommends a frequency of exercise training of two times per week.²⁵ In Zhao et al.'s 2023 meta-analysis, a “dose” of 40–60 minutes resistance training >3 times/week for ≥12 weeks was found to be most effective in people with sarcopenia.²³

Exercise also provides numerous benefits that may indirectly influence muscle strength and mass. A 24-week posture, strength, and motricity training program in older adults with sarcopenia has been shown to improve gait, walking speed, and neuromuscular function.²⁶ Resistance training in older adults also leads to improvements in brain levels of neurometabolites (such as ratio of total N-acetyl aspartate, total choline, glutamate-glutamine complex, and myo-inositol relative to total creatine, as assessed by proton magnetic resonance spectroscopy) associated with brain health preservation, and these improvements correlate with muscle strength gains seen with training.²⁷ Additionally, people with sarcopenia who undergo resistance training have been shown to experience reductions in sleep apnea, improved sleep quality, and increases in interleukin-10 and interleukin-1 receptor antagonist (IL-1ra) levels, which would be associated with a reduction in inflammation. These findings are important since sleep deprivation has negative effects on muscle health, as does excess inflammation.²⁸

Nutrition

An additional area of extensive research in sarcopenia is nutrition. While a number of dietary strategies have been investigated, a focus on protein intake and supplementation is a prevalent strategy, and for good reason. Poor nutritional intake, especially protein-energy malnutrition, is very common among older adults, and is associated with both reduced muscle mass and function, as well as an increased occurrence of frailty.²⁹ Poor protein intake later in life may have an especially outsized impact; because of metabolic changes that occur with aging, ingestion of a particular amount of dietary protein in an older person results in lower muscle protein synthesis (MPS) than would be seen in a younger person consuming the identical amount of protein.³⁰

Leucine Content of Select Foods (Listed in Grams of Leucine Per 100 Grams Food Source)

Whey protein^a	11.00–13.50 g
Parmesan cheese	2.88 g
Smoked salmon	2.07 g
Skinless turkey breast	2.00 g
Rabbit	1.99 g
Skinless chicken breast	1.96 g
Beef (rump)	1.89 g
Skinless chicken wings	1.72 g
Baked ham	1.70 g
Sardines or mackerel	1.64 g
Salmo-	1.50 g
Skinless turkey thigh	1.44 g
Mozarella cheese	1.40 g
Millet	1.39 g
Cashews	1.28 g
Corn-	1.17 g
Egg	1.04 g
Lowfat Greek yogurt	0.71 g
Dried chickpeas, boiled	0.55 g
Canned kidney beans	0.51 g
Goat's milk	0.43 g
Cow's milk	0.42 g

Varies by product (isolate, concentrate, native whey, etc).

Adapted from Rondanelli et al.,³⁴ Landi et al.,⁶³ Devries et al.,⁶² and Hamarsland et al.⁶¹

The Society for Sarcopenia, Cachexia, and Wasting Disease recommends a protein intake of 1.0–1.5 g/kg body weight per day for individuals with existing sarcopenia, while estimated protein requirements for the prevention of sarcopenia in older adults range from 1.0 to 1.2 g/kg body weight, with requirements being higher (1.2–1.5 g/kg body weight) in those with particular health conditions.^30,31 In a large multinational study of community-dwelling adults age 55 and older, the incidence of inadequate protein intake (falling under a recommended daily allowance of 0.8 g/kg body weight per day) was 21.5%. Incidence rose to 46.7% utilizing a cut-off value of 1.0 g/kg body weight per day, and 70.8% for 1.2 g/kg body weight per day.³² The prevalence of inadequate protein intake is also higher in women, people with low appetite, those with higher body mass index (BMI), and among people living in residential care facilities.^32,33

This may be especially relevant when it comes to higher biological value proteins such as leucine. Regular leucine intake stimulates the synthesis of muscle proteins, and low serum leucine levels are correlated with lower grip strength and skeletal muscle indexes. International guidelines propose a recommended leucine intake in the elderly of 3 g with each meal (see Sidebar for food sources), three times daily, to prevent lean mass loss, and a total protein intake of 25–30 g per meal (three times daily).³⁴

A number of trials have been conducted on leucine supplementation, or whey protein (a good source of leucine) supplementation, in people with existing sarcopenia to determine efficacy. In a 2022 systematic review and meta-analysis of RCTs of leucine-based supplementation in older adults with sarcopenia, 6 RCTs including a total of 699 participants were assessed. Leucine supplementation was found to lead to improvements in overall muscle strength, muscle mass, and performance compared to controls (standardized mean difference [SMD] = 0.939; 95% confidence interval [CI] 0.440–1.438; P < 0.001). Focusing in particular on muscle strength, this parameter improved significantly for people supplementing leucine (SMD = 0.794; 95% CI 0.104–1.485; P = 0.024).³⁵

In a 2021 umbrella review of systematic reviews and meta-analyses, 15 systematic reviews of varying forms of nutrient supplementation were assessed. Interventions included supplementation with proteins, essential amino acids (AAs), leucine, β-hydroxy-β-methylbutyrate, creatine, and multinutrients (with or without exercise training). Quality of the reviews was generally low to moderate, so the level of evidence supporting most recommendations was also considered low to moderate. The best available evidence was for leucine, which had a significant effect on muscle mass in older adults with sarcopenia. The authors concluded that no significant effect of leucine supplementation could be found in healthy subjects in this analysis, however, and there was no clear effect on either muscle strength or physical performance with leucine.³⁶

A 2023 systematic review and meta-analysis specifically examined the effects of whey protein supplementation in elderly people with sarcopenia. Ten studies with a total of 2498 participants were included. Duration of included trials ranged from 4 to 52 weeks, although most of the included studies were 13 weeks in duration. Mean study duration was 17.4 ± 13.1 weeks. Doses of whey protein utilized in the included trials ranged from 20 g daily, up to 80 g daily. Whey protein supplementation had no significant effect on handgrip strength or appendicular muscle mass, nor on body weight or chair and stand tests.³⁷

In a separate 2023 systematic review and meta-analysis, whey protein supplements did show some benefits in older people with sarcopenia. Analyzing data from 7 RCTs with 591 participants, the overall pooled mean difference estimate for handgrip strength showed a significant +2.31 kg difference for people combining whey protein with resistance training, compared to resistance training alone (95% CI 0.01–4.6; P < 0.001). Note that effect sizes were small, and the quality of the available evidence was determined to be low.³⁸

Why might we sometimes see these mixed results with various forms of AA and protein supplementation in people with sarcopenia, and why might some trials fail to show significant effects? It has been suggested that the duration of supplementation may be a relevant factor, and that longer periods of protein supplementation may be necessary to perceive meaningful differences. Additionally, while branched chain amino acids (BCAAs, leucine, isoleucine, and valine) do stimulate MPS, a full complement of all nine essential AAs may be required for optimal synthesis, especially in the setting of exercise training. For example, the difference in MPS achieved with more comprehensive protein supplementation versus equivalent BCAAs in isolation may be up to 50%. On top of this, protein supplementation in the setting of suboptimal overall protein intake, poor quality protein intake, or uneven protein intake distribution over the course of the day may all be factors that impact the results achieved with supplementation.³⁶

It is also interesting to note that several studies combining whey protein with or without leucine, with the addition of vitamin D supplementation at modest doses ranging from 100 to 800 IU daily, have shown this combination improves lean mass and physical function in people with sarcopenia.^39
–41 Vitamin D plays multiple roles in muscle tissue. It regulates gene expression, neuromuscular function, the production of anti-inflammatory cytokines, and muscle differentiation. Vitamin D status has been shown to be linked to changes in muscle mass and muscle strength, and optimizing Vitamin D status may help maintain appropriate muscle function in older people. Sufficient circulating concentrations of vitamin D may also be required to increase muscle mass in response to exercise and protein supplementation.^41,42

For these reasons, it seems possible that the results from studies that do not include vitamin D status/supplementation along with protein supplementation and/or exercise training might be impacted by this omission. Certainly, in terms of translating this information to clinical practice, elderly persons should also avoid vitamin D deficiency, which may exacerbate muscle atrophy and increase the risk of sarcopenia.^43,44

Additional Nutritional Supplements or Nutritional Factors

Aside from protein or AA supplementation, additional dietary factors or nutritional supplements may offer support in people with sarcopenia, or in older people looking to optimize muscular health. These include fatty acid supplementation, silkworm pupae extract (SPE), probiotics, and curcumin.

Dietary intake or supplementation of fatty acids

Beginning with fatty acid supplementation, both medium chain fatty acids (MCFAs) and polyunsaturated fatty acids (PUFAs) may influence muscle strength or hypertrophy. MCFAs are straight-chain saturated fats, and with their short chain lengths (aliphatic tails 6–12 carbons in length), can be readily metabolized in the body as an immediate energy source. Medium-chain triglycerides (MCTs), a form of MCFA, can be easily supplemented as oils. These fats are shown to increase ghrelin levels, which in turn stimulate the secretion of growth hormone, leading to improved MPS. Additionally, MCT is thought to enhance fatty acid oxidation capacity in muscle tissue, leading to an increased energy supply that can be utilized during muscle activation.⁴⁵ PUFAs, on the other hand, can be derived from fish oil. Omega-3 PUFAs are thought to mediate muscle transcription changes that result in an anabolic effect, while also increasing the expression of muscle tissue mitochondrial regulator genes.⁴⁶

A 2023 RCT demonstrated the benefits of MCT supplementation in combination with exercise among people at higher risk of frailty. Subjects were healthy but sedentary adults age 60–75 with low or normal BMI (BMI 19–24 kg/m²). Participants were randomized to one of four groups:

Control group: 6 g long-chain triglyceride (LCT) daily.

Decanoic acid supplement: 6 g MCT daily, with 1.4–1.95 g octanoic acid and 3.5–4.0 g decanoic acid daily.

Low-dose octanoic acid supplement: 4 g LCT and 2 g MCT daily, with 1.2–1.4 g octanoic acid and 0.4–0.5 g decanoic acid daily.

High-dose octanoic acid supplement: 6 g MCT daily, with 3.7–4.1 g octanoic acid and 1.1–1.5 g decanoic acid daily.

Participants in all groups were also directed to walk for 40 ± 10 minutes, two days per week, at their usual pace. A total of 120 subjects were enrolled, and 119 completed the 12-week trial. While MCT did not induce changes in muscle mass in this study, by the completion of the trial, both MCT groups (6 g daily) showed improved muscle strength (assessed by knee extension strength, P < 0.05 for both), an effect not seen in the control group. Left-hand maximum grip strength also significantly increased from baseline in both groups that received 6 g MCT per day (P < 0.05 for both). All groups also experienced a significant improvement in walking (timed up & go test) (P < 0.05). MCT was also well-tolerated, with no adverse effects noted. The authors concluded that the combination of exercise and MCT supplementation offered benefits to muscle strength not seen with use of LCT, in people at higher risk of developing sarcopenia.⁴⁵

In a 2019 RCT, MCT oil was supplemented in elderly (age 85.5 ± 6.8 years) nursing home residents for three months. Sixty-four participants were randomized to one of three groups:

“Positive control” group: Leucine (in a modest dose of 1.2 g) and cholecalciferol (also in a modest dose of 20 μg, or 800 international units [IU]) with 6 g/day MCT.

MCT group: 6 g MCT daily.

“Negative control” or LCT group: 6 g LCT daily.

Forty-eight participants completed the trial. At the three-month timepoint, subjects in the MCT group had a 48.1% increase in muscle function compared to the LCT group (as measured by 10-second leg open and close test performance, P < 0.05). MCT group participants also experienced a 27.8% increase in a measure of swallowing ability and a 7.5% increase in the Functional Independence Measure (FIM) score (which assesses ability to complete activities of daily living [ADLs]) compared to those in the LCT group (P < 0.05 for both). Note that the “positive control” group participants who also received vitamin D3 and leucine in addition to MCT, outperformed the MCT-alone group. At three months, the % increases in the leg open and close test, swallowing test scores, and total FIM for the leucine and D group were 73.8%, 44.4%, and 8.9%, while increases in the MCT-only group were 48.1%, 27.8%, and 7.5%, respectively.⁴⁷ This highlights the concept that combined interventions may be more effective for supporting muscle tissue health than the use of isolated nutrients.

Moving from MCFAs to PUFAs, both the addition of food sources/dietary omega-3 fatty acids (O3FAs) and supplemental O3FA have been employed as strategies to improve muscle mass or function in older adults. In Strandberg et al.'s 2019 RCT, 63 women ages 65–70 who were already recreationally active were randomized to either resistance training plus a PUFA-rich diet, resistance training only, or a control group, for 24 weeks. Participants who were randomized to resistance training underwent supervised, progressive exercise training twice per week for the duration of the trial. Women in the PUFA group were instructed to include salmon, mackerel, and herring in the diet to achieve a fish/seafood intake ≥500 g/week. Muscle biopsy of the vastus lateralis was used to determine skeletal muscle gene expression profiles.

For subjects in the diet group, the omega 6 to O3FAs ratio significantly decreased by 42%, and serum docosahexaenoic acid (DHA) significantly increased, as markers of dietary compliance. At the conclusion of the trial, skeletal muscle gene expression of proinflammatory cytokine interleukin 1-beta (IL-1β) decreased significantly, while mTOR expression was significantly upregulated in the diet group only (P < 0.05 for both). Additionally, in the diet group, a significant hypertrophy of fast type IIA muscle fibers was also observed, an alteration not seen in the control or exercise-only groups (+23% in the diet group, P < 0.05).⁴⁸

A 2011 blinded RCT examined fish oil supplementation as a source of PUFA in healthy older adults (age 71 ± 2 years). Sixteen subjects were randomized to either an O3FA supplement or a corn oil supplement control. Participants supplemented with 4 g fish oil daily (containing a total of 1.86 g eicosapentaenoic acid [EPA] and 1.50 g DHA) or an equal amount of corn oil for eight weeks. The rate of MPS and phosphorylation of anabolic signaling pathway elements were evaluated before and after supplementation during basal and postabsorptive conditions. Additionally, these same factors were examined after subjects received an infusion of insulin and intravenous AAs to achieve plasma and AA concentrations equivalent to a normal postprandial range (hyperinsulinemia-hyperaminoacidemia state).

The corn oil control had no effect on MPS rate or muscle anabolic signaling elements. While fish oil supplementation had no significant effect on basal MPS, it did increase the rate of MPS seen during the hyperaminoacidemia-hyperinsulinemia state (from 0.009% ± 0.005%/hour above basal values to 0.031% ± 0.003%/hour above basal values; P < 0.01). This change was also accompanied by a significantly greater increase in the phosphorylation of intramuscular signal transduction proteins (mTOR Ser2448, the AKT target site in mTOR, P = 0.08; and p70s6k [ribosomal protein S6 kinase], P < 0.01). The authors concluded that fish oil may increase muscle anabolic signaling activity as well as the insulin/AA-mediated increase in MPS, and that this study may offer evidence for an interaction of O3FAs with muscle protein metabolism.⁴⁹

The same group performed a 2015 RCT in 60 healthy non-exercising older adults (ages 60–85), who were randomized to either fish oil (N = 40) or corn oil as a placebo (N = 20), this time for six months. Dosing for this study was identical to that used in the trial above (4 g fish oil daily, equivalent amount of corn oil). Of the initial 60 participants, 44 completed the trial (29 in the fish oil group and 15 in the control group). After six months, fish oil supplementation led to increases in thigh volume, handgrip strength, and one-repetition maximum (1-RM) muscle strength compared to the placebo (3.6% for thigh volume, 2.3 kg for handgrip strength, and 4.0% for 1-RM muscle strength, P < 0.05 for all).⁵⁰

The authors then used muscle biopsy samples from the study above to assess the effects of fish oil supplementation on the muscle transcriptome. They selected 10 subjects from the fish oil group who had the greatest hypertrophic response as evidenced by change in thigh muscle volume, and 10 subjects from the control group matched for age, sex, BMI, and protocol compliance. This “best responder” method of selection was chosen by the authors in an effort to improve the chances of detecting potentially small changes in muscle gene expression. Using this method, they found that fish oil supplementation led to increases in the expression of genes regulating mitochondrial function, while decreasing expression in pathways regulating proteolysis and mTOR inhibition.⁴⁶

Silkworm pupae extract

A single randomized double-blinded placebo-controlled trial has been conducted on an extract of silkworm pupae in older adults with low muscle mass. The rationale for this supplement in sarcopenia is based on its high nutritional value. SPE contains 18 AAs (including all essential AAs), and is composed of roughly 62% protein and 30% fatty acids. It is also a source of bioactive peptides and phenols. SPE is a natural by-product of silk production, and for every kilogram of raw silk produced, 2 kg of SPE is produced as a by-product. SPE is traditionally consumed in northeast India as a food and folk medicine, and has been demonstrated to possess antioxidant, anticarcinogenic, antidiabetic, and antigenotoxic properties.⁵¹

In their 2023 RCT, Choi et al. randomized 54 participants with relatively low skeletal muscle mass and normal BMI (64.4 ± 6.1 years of age; BMI, 23.8 ± 2.4 kg/m²) to either a placebo (N = 27) or SPE (N = 27) for 12 weeks. Those in the intervention group took 1000 mg SPE supplement daily. All subjects also underwent exercise training, with 30–60 minutes walking ≥3 days/week for the 12 weeks of the trial.

Using both an intention-to-treat (ITT) and per-protocol (PP) analysis, there was no significant impact of SPE supplementation on knee strength by 12 weeks compared to placebo. Additionally, there were no significant differences in body composition, QOL, physical activity, or overall caloric intake between the groups. However, handgrip strength improved significantly in the SPE group. Using ITT analysis, both right and left handgrip strength improved significantly in the SPE group compared to placebo (1.94 kg, 95% CI 0.08–3.79; P = 0.041 for right handgrip strength, and 1.83 kg, 95% CI 0.25–3.41; P = 0.024 for left). Similarly, PP analysis also revealed a significant effect of SPE on handgrip strength (2.07 kg, 95% CI 0.15–3. 98; P = 0.035 for right handgrip strength, and 2.21 kg, 95% CI 0.60–3.83; P = 0.008 for left handgrip strength). SPE was well tolerated and there were no significant adverse effects with supplementation.⁵²

Probiotics

The gut microbiome impacts muscle health by modulating inflammation, antioxidant status, insulin sensitivity, energy production, and anabolism.⁵³ Gut bacteria are also involved in cytokine modulation and the production of short chain fatty acids or gut peptides that influence myocyte function. The resilience of gut microbiota may be reduced with aging, rendering gut bacteria more vulnerable to changes from lifestyle, medication use, or illness. Ticinesi et al. have even proposed a “gut-muscle axis,” based on the concept that gut flora might mediate the effects of nutrition on skeletal muscle.⁵⁴

This link between the microbiome and muscle health has led to studies of probiotics in sarcopenia, and a number of in vivo studies in mice have demonstrated that probiotic supplementation favorably impacts muscle mass and physical function by promoting enhanced mitochondrial function, reduction of oxidative stress, or a decrease in low-grade inflammation. Transplanting the microbiota of higher-functioning older adults into mice has even been shown to result in improvements in animal muscle mass, compared to transplanting microbiota from older adults with poor physical function. Probiotics might enhance anabolism by improving protein digestion and absorption, and by competing with pathogenic bacteria that stimulate the production of pro-inflammatory cytokines.⁵³

In a 2023 systematic review and meta-analysis, Prokopidis et al. examined 24 studies on probiotic supplementation and muscle mass, muscle strength and lean mass. All included RCTs compared probiotic to placebo in adult subjects. Included trials ranged in duration from 4 to 18 weeks (most were 12 weeks in duration), and used a wide range of doses of probiotics, from 40 million colony forming units (CFU) to 110 billion CFU daily, mostly in varying combinations of Lactobacillus and Bifidobacterium. Some RCTs were in healthy subjects, while others were in overweight or obese subjects, or people with specific health conditions, such as frailty, chronic heart failure, or metabolic syndrome.

In this analysis, muscle mass was significantly improved with probiotic supplementation (SMD: 0.42, 95% CI 0.10–0.74, P = 0.009) compared to placebo. Six RCTs also demonstrated a significant increase in global muscle strength with probiotic use (SMD: 0.69, 95% CI 0.33–1.06, P = 0.0002). There were no significant changes in total lean mass with use of probiotics compared to placebo. In subgroup analysis, probiotics had a greater effect on muscle mass in people <age 50 compared to older individuals.⁵³ While this analysis was not specific to only elderly people or those with sarcopenia, it does demonstrate the ability of probiotics to affect muscle strength and mass.

What about combining probiotics with additional nutrients to support muscle health? Rondanelli et al. performed a double-blind placebo-controlled RCT of leucine, O3FA, and probiotic supplementation in elderly people with demonstrated sarcopenia. A total of 50 subjects (79.7 ± 4.8 years of age, BMI 22.2 ± 2.1 kg/m²) were randomized to either the nutritional intervention (N = 22) or a placebo (N = 28) for two months. The intervention group received a powdered supplement containing O3FA 500 mg (64.71% EPA, 29.41% DHA and remaining 5.88% omega-3 fats in general), leucine (2.5 g), and a probiotic (Lactobacillus paracasei PS23 at a dose of 30 billion CFU). The placebo group received an isocaloric, flavor-matched placebo powder.

At the completion of the trial, appendicular lean mass increased significantly in the probiotic/nutrient group (P < 0.05), while it was unchanged in the placebo group. Significant improvement was also seen for the Tinetti scale (a measure of walking and fall risk), physical performance (as assessed by the short physical performance battery [SPPB]), and handgrip strength (4.09 kg) (P < 0.05 for all). Visceral adiposity also decreased significantly in the intervention group compared to placebo group (−0.69 g, 95% CI −1.09 to 0.29, vs. 0.27 g, 95% CI: −0.11 to 0.65, P = 0.001). Total AA profiles and plasma levels of valine, leucine, isoleucine also significantly increased in the intervention group compared to placebo (P = 0.001). The authors noted that L. paracasei supplementation may improve AA absorption from plant proteins, augmenting postprandial levels of blood AAs, and that L. paracasei PS23 has specifically been shown to reduce inflammation at the level of muscle tissue.⁵⁵

Curcumin

Curcumin, the anti-inflammatory constituent from turmeric root (Curcuma longa) may have a number of beneficial effects on muscle. Preclinical studies demonstrate the ability of curcumin to prevent muscle degeneration (by reducing the expression of genes involved in muscle degradation and improving gene expression pertaining to protein synthesis) and protect muscle health. Curcumin may enhance muscle cell mitochondrial function, relieve oxidative stress, and help maintain muscle satellite cell function or number.⁵⁶

In a double-blind, placebo-controlled RCT, 30 healthy elderly participants (69.8 ± 5 years of age) were randomized to either a proprietary bioavailable form of curcuminoids, containing a complete natural turmeric matrix, at a dose of 500 mg daily, or a placebo, for three months. At the completion of the trial, placebo group participants had a slight decrease in handgrip strength, while curcumin group subjects experienced a significant improvement in handgrip (+1.43%, P < 0.001). In addition to this, placebo group subjects experienced a 4.5% decrease in weight-lifting strength (evaluated as the number of times the subject could lift a 2 kg weight), while curcumin group subjects experienced a 6.1% increase in weight-lifting capacity. Curcumin supplementation also resulted in a 5.5% increase in time/distance covered (via cycling, walking, or stair-climbing) before feeling fatigued, compared to a 2.3% increase in the placebo group (a non-significant difference at P = 0.09). There were no adverse events and curcumin was well-tolerated.¹⁰

Discussion

Sarcopenia involves a progressive decline in muscle mass and muscle strength, and has strong impacts on mobility, ADLs, and QOL. Sarcopenia also contributes to frailty and is correlated with poorer overall survival, metabolic disease, and even cognitive decline. Sarcopenia involves numerous physiological and systemic alterations seen with aging, such as increased oxidative stress, hormonal changes, and higher levels of inflammation.

Because low levels of physical activity or sedentary behavior are main drivers of muscle loss, exercise represents a key strategy in both the prevention and treatment of sarcopenia. Both aerobic and resistance exercise can slow the rate of muscle mass and strength loss that occurs with aging. While both types of exercise are highly important, resistance training has larger effects on muscle mass and strength. Recommended “dosing” for exercise varies, from a modest recommendation of twice a week, to the 40–60 minutes of resistance training >3 times/week mentioned in the literature.²³ For those who wish to be aggressive with the prevention or management of sarcopenia, a high level of physical activity may be most protective.⁵⁷

Aside from exercise, high quality nutrition and protein intake are also key for muscle health during aging. Being malnourished or at risk of malnutrition are significantly associated with the risk of sarcopenia, and older adults are historically at a higher risk of inadequate dietary protein intake. The nutrition plan for each person should be personalized, as well as sensitive to the individual's health status and comorbidities. Utilizing the recommendation for protein intake of 1.0–1.5 g/kg body weight per day from the Society for Sarcopenia, Cachexia, and Wasting Disease, a 160-pound (72.5 kg) person would need to consume 72.5–109 g of protein daily, or roughly 24–36 g of protein with each of three meals daily. Protein supplementation (leucine, whey protein, etc.) might also be considered in the appropriate individual. Additional supplementation of fatty acids, curcumin, or even probiotics might be considered as well, based on the available evidence.

Furthermore, all patients with sarcopenia should be screened for vitamin D deficiency, and the Society for Sarcopenia, Cachexia, and Wasting Disease advises that vitamin D should be supplemented in any patient with sarcopenia whose serum level falls under 100 nmol/L, equivalent to 40 ng/mL.³⁰▪

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