Nutritional strategies for improving sarcopenia outcomes in older adults: A narrative review

Abstract

Sarcopenia is characterized by a decline in muscle strength, generalized loss of skeletal muscle mass, and impaired physical performance, which are common outcomes used to screen, diagnose, and determine severity of sarcopenia in older adults. These outcomes are associated with poor quality of life, increased risk of falls, hospitalization, and mortality in this population. The development of sarcopenia is underpinned by aging, but other factors can lead to sarcopenia, such as chronic diseases, physical inactivity, inadequate dietary energy intake, and reduced protein intake (nutrition‐related sarcopenia), leading to an imbalance between muscle protein synthesis and muscle protein breakdown. Protein digestion and absorption are also modified with age, as well as the reduced capacity of metabolizing protein, hindering older adults from achieving ideal protein consumption (i.e., 1–1.5 g/kg/day). Nutritional supplement strategies, like animal (i.e., whey protein) and plant‐based protein, leucine, and creatine have been shown to play a significant role in improving outcomes related to sarcopenia. However, the impact of other supplements (e.g., branched‐chain amino acids, isolated amino acids, and omega‐3) on sarcopenia and related outcomes remain unclear. This narrative review will discuss the evidence of the impact of these nutritional strategies on sarcopenia outcomes in older adults.

Nutritional supplements to enhance muscle protein synthesis (MPS) and improve sarcopenia outcomes in older adults.

Abbreviations

AA

amino acids

ALA

α‐linolenic acid

BCAAs

branched‐chain amino acids

BWPH

blue whiting‐derived protein hydrolysate

DHA

docosahexaenoic acid

EAA

essential amino acids

EPA

eicosapentaenoic acid

MPB

muscle protein breakdown

MPS

muscle protein synthesis

mTOR

mammalian target of rapamycin

PUFA

polyunsaturated fatty acid

RDA

recommend day allowanced

WP

whey protein

ω‐3

omega 3

1. INTRODUCTION

Sarcopenia is defined as a generalized skeletal muscle disorder associated with loss of muscle strength, decline in muscle mass, and impaired physical performance that, taken together, impacts muscle quantity and quality as a result of age and chronic disease. ¹ Recently, sarcopenia was recognized as an independent condition with an International Classification of Disease‐10 code, classified as M62.84. ² , ³ Indeed, sarcopenia has been associated with increased risk of falls, bone fractures, lower independence, poor quality of life, hospitalization, and mortality. ⁴ Although the prevalence of sarcopenia may vary depending on its definition and population studied, ⁵ it has been estimated that 10%–20% of the global population has sarcopenia, ⁶ , ⁷ , ⁸ with rates reaching up to 70% in patients with chronic diseases. ⁹

Sarcopenia can be categorized depending on its etiology as “primary sarcopenia” or “aged‐related sarcopenia” considering age as the main cause of sarcopenia, and “secondary sarcopenia” which may occur in patients with one or more chronic conditions, such as advanced organ failure, inadequate dietary energy intake, and reduced protein intake (nutrition‐related sarcopenia). ¹⁰ Certainly, sarcopenia is a complex and multifactorial pathology in which several mechanisms are involved in the development of this muscle phenotype. ¹¹

In regard to possible nutrition‐related mechanisms, sarcopenia is associated with an imbalance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB) affecting muscle protein turnover caused by anabolic resistance to dietary protein, lower consumption of protein, impaired protein digestion and absorption, and gut microbiota dysbiosis. ¹² , ¹³ In addition, several age‐related changes, such as lower physical activity, lower food consumption, and digestion alterations, could contribute to develop muscle alterations as sarcopenia. ¹⁴ , ¹⁵ Although the consumption of some nutrients, such as animal and plant‐based protein, ¹⁶ essential amino acids (EAA), ¹⁷ and creatine, ¹⁸ may improve parameters of muscle mass and function, the impact of other supplements like branched‐chain amino acids (BCAAs), isolated amino acids (AA), and omega‐3 containing supplements is inconclusive on these outcomes. Therefore, this review aims to discuss the evidence for these nutritional strategies to modulate sarcopenia and related outcomes.

2. PROTEIN DIGESTION, ABSORPTION, AND METABOLISM

Protein digestion and absorption are modified with age, as well as reduced capacity of older adults to metabolize protein. ¹⁹ This may be influenced by the finding that older adults have alterations in the secretion of important enzymes to digest protein, including pepsin. ²⁰ In addition, several alterations in the absorption of AA occur with age, as decreasing its utilization ²¹ and changes in the intestinal mucosa could contribute to lower absorption and appearance rates. ²² Moreover, disturbances in feeding time may by associated with alterations in circadian regulation of food intake that can lead to cellular aging, glucose tolerance, and insulin resistance, even though these changes in diet patterns due to circadian rhythm have not been established in patients with sarcopenia. ²³

Changes in metabolism have an important impact on older adults, contributing to the progression of muscle loss and other complications. ²⁴ Insulin resistance seems to play a central role in impairing metabolism responses by leading to accelerated protein degradation and decreased protein synthesis. ²⁴ Furthermore, it has been demonstrated that older adults need higher amounts of protein per meal (~0.40 g/kg) than younger adults (~0.24 g/kg) to stimulate MPS. ²⁵ In agreement, Wall et al. showed that, with the same meal having equal amounts of protein, older adults have a blunted response to stimulate MPS, ²⁶ suggesting an anabolic resistance to dietary protein in this population. Additionally, Milan et al. have demonstrated that with a complete high protein meal older adults display delayed digestion and absorption of AA when compared with younger adults. ²⁷ Thus, these alterations in protein digestion and absorption may impair the anabolic response to protein, suppressing MPS in older adults and contributing to the development of sarcopenia.

3. RECOMMENDATIONS FOR PROTEIN INTAKE

The existing recommended daily allowance (RDA) of protein for the general population remains 0.8 g/kg/day. However, this amount of protein represents the minimum to maintain nitrogen balance and does not take into consideration age or the level of physical activity. Thus, a higher consumption of protein has been recognized as essential to promote muscle health, particularly in older adults with sarcopenia. The current recommendations to offset losses in muscle mass suggest a consumption of 1.0–1.2 g/kg/day for older adults and 1.2–1.5 g/kg/day for patients with chronic disease (e.g., sarcopenia, hypertension, heart failure). ¹⁰ , ²⁸ , ²⁹ , ³⁰ Moreover, protein intake can reach up to 2.0 g/kg/day for critically ill patients or with marked malnutrition, with adults with severe kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m²) being an exception to the higher protein rule. ¹⁹

The main reason for increasing the RDA of protein in older adults is due to anabolic resistance which means more protein is required to reach the same rate of MPS compared to younger adults. ²⁵ Furthermore, it has been demonstrated that, in comparison to older adults (75 ± 1 year), healthy young men had a 3‐fold better responsiveness in their postprandial MPS rate after consumption of a standardized meal. ²⁶ This impaired response in MPS associated with other factors that hinder anabolic stimuli is commonly known as anabolic resistance, ³¹ but also named muscle anabolic inflexibility. ²⁶ , ³²

In addition, the distribution of protein throughout the day seems to be more important to promote gains in lean body mass, ³³ studies demonstrating that consumption of protein should follow an interval of 3–4 h with a moderate quantity of protein consumed (±20 g). ³⁴ These findings come on light in the fact that the regular diet pattern for protein is skewed with larger protein intake later in the day (e.g., 6–10 g, 12–18 g, 26–41 g of protein at breakfast, lunch, and dinner, respectively). ³⁵ Recently, a cross‐sectional study showed that older women who consumed more protein at breakfast had higher muscle volume and greater grip strength, ³⁶ suggesting that raising up the amount of protein intake in lighter meals like breakfast and lunch may have a positive effect on muscle mass and muscle strength in older adults. ³⁷

Though it may be optimal to increase the RDA for protein and protein consumption in this population, challenges such as loss of appetite, changes in dentition, digestion, and absorption make it hard to achieve even the existing RDA of 0.8 g/kg/day. ³⁸ Therefore, we must explore and optimize alternative nutritional strategies to promote processes involved in protein metabolism resulting in enhanced net protein balance.

4. SUPPLEMENTAL ANIMAL PROTEIN SOURCES

4.1. Whey protein

As briefly discussed, it is well known that older adults have an increased need for daily protein. However, in clinical practice, it is challenging to raise protein intake to the optimal level by simply increasing food consumption. In this context, protein supplementation can be a valuable tool for affected individuals. Most of the animal protein included in our diet comes from meat and dairy products (e.g., milk, cheese, yoghurt). During the production of cheese, there is a release of by‐products that through pasteurization, purification, and cooling processes become whey protein (WP) powder.

Consumption of WP was shown to acutely increase MPS above basal rates in older men, with some reports showing that consuming more than 20 g of WP seems to have no additional effect on MPS, ³⁹ suggesting that 20 g may be the optimal dose per meal for older adults at resting (Figure 1; Table 1). However, recent studies have suggested that in older adults, greater rates of MPS can be observed with higher bolus of protein (up to 40 g) with and without resistance exercise. ²⁵ , ⁴⁰ In a long‐term study, Mertz et al., after a year of WP supplementation, found that protein supplementation alone was insufficient to improve muscle mass, muscle strength parameters, and gait speed. ⁴² These results suggest that increases in MPS reported from short‐term studies may not necessarily lead to more muscle mass or functional improvement because this increased protein synthesis might be used initially for repairing structural damage in muscle cells instead of causing muscle mass accretion. It is also likely that the total protein consumed throughout the day in a free‐living situation will be a determining factor, where intakes >1.2 g/kg/body mass will be sufficient to optimize MPS.

FIGURE 1.

Nutritional supplements to enhance muscle protein synthesis (MPS) and improve sarcopenia outcomes in older adults. BCAAs, branched‐chain amino acids; DHA, docosahexaenoic acid; EAAs, essential amino acids; EPA, eicosapentaenoic acid.

TABLE 1.

Acute and chronic clinical trials with nutritional interventions in muscle outcomes related to sarcopenia.

Studies	Duration	Doses	Resistance training	Outcomes	Main results	Pratical application
Whey protein
Holwerda et al. 40	1 session	Milk protein (1) 0 g (2) 15 g (3) 30 g (4) 45 g	2–5 sets × 10 reps—Exercise: upper and lower body	Dose‐dependent effect of milk protein concentrate associated with RT on MPS	↑ MPS for 30 g and 45 g of milk protein compared to placebo	Ingestion of ≥30 g dietary protein can significantly stimulate MPS
Yang et al. 39	1 session	WP (1) 0 g (2) 10 g (3) 20 g (4) 40 g	3 sets × 10 reps—Exercise: unilateral knee extension	Dose‐dependent effect of whey protein isolated, with and without prior RT, on MPS	↑ 65% MPS with WP 20 g compared to 0 g ↑ 90% MPS with WP 40 g compared to 0 g When associated with RT, MPS was greater than all feeding conditions alone	There is a dose‐dependent response for WP in MPS, which is further improved when associated with RT
Nabuco et al. 41	12 weeks	(1) 35 g WP pre‐ and placebo post‐RT (WP‐PLA) (2) Placebo pre‐ and 35 g WP post‐RT (PLA‐WP) (3) Placebo pre‐ and post‐RT (PLA–PLA)	3 sets × 10–12 reps—Exercise: 8 whole‐body exercises	Improvement in skeletal muscle mass (SMM), muscular strength, and functional capacity	↑ SMM, muscular strength, and functional capacity for groups associating WP pre or post‐RT in comparison with placebo	Regardless of consuming WP pre or post‐RT, WP associated with RT promotes adaptations in sarcopenia outcomes
Mertz et al. 42	1 year	(1) Carbohydrate (2 × 20 g maltodextrin + 10 g sucrose) (2) WP (2 × 20 g + 10 g sucrose) (3) Collagen protein (2 × 20 g bovine collagen protein hydrolysate + 10 g sucrose) (4) Light‐intensity RT with WP (2 × 20 g WP + 10 g sucrose) (5) High‐intensity RT with WP (2 × 20 g WP + 10 g sucrose)	3–6 sets × 6–12 reps—Exercise: upper and lower body	Quadriceps cross‐sectional area (qCSA) and muscle strength	↑ qCSA with high‐intensity RT compared to WP alone → qCSA with light‐intensity RT compared to WP alone	High‐intensity RT associated with WP may be more effective to promote changes in muscle mass
Collagen protein
Oikawa et al. 43	1 session	(1) WP 30 g/twice a day (2) Collagen 30 g/twice a day	3 sets × 8–10 reps—Exercise: unilateral knee extension	Effect of WP and collagen associated with and without RT on MPS	↑ MPS for WP with and without RT ↑ MPS for collagen only with RT MPS was greater for WP in both conditions compared to collagen	Collagen associated with RT may be more effective to promote MPS than supplementation alone
Zdzieblik et al. 44	12 weeks	(1) Collagen 15 g/day (2) Placebo	1 sets × 8–15 reps—Exercise: larger muscle groups	Improvement in muscle mass and muscle function following RT and collagen supplementation	↑ Fat free‐mass, quadriceps muscle strength, and bone mass with collagen compared to placebo ↓ Fat mass with collagen compared to placebo	Collagen may be an alternative protein source to promote body composition adaptations
Fish protein
Lees et al. 45	1 session	(1) BWPH 0.33 g/kg (2) WP (3) Isonitrogenous, non‐essential amino acid control	None	Effect of BWPH and WP on MPS and aminoacidaemia	↑ MPS for BWPH and WP compared to control ↑ Aminoacidaemia for BWPH and WP compared to control MPS and aminoacidaemia were greater for WP compared to BWPH	BWPH may be an alternative protein source of rapidly digestion to promote MPS
Plant‐based protein
Pinckaers et al. 46	1 session	(1) 30 g pea protein (2) 30 g milk protein	None	Effect of pea protein and milk protein on MPS and amioacidaemia in young males	↑ Aminoacidaemia for milk protein compared to pea protein ↑ MPS in both conditions without significant differences	Ingestion of 30 g pea protein may lead to similar MPS compared to milk protein
Pinckaers et al. 47	1 session	(1) 30 g plant‐derived protein blend (2) 30 g milk protein	None	Effect of plant‐based protein blend and milk protein on MPS and amioacidaemia in young males	↑ Aminoacidaemia for milk protein compared to plant‐based protein blend ↑ MPS in both conditions without significant differences	Ingestion of 30 g planted‐based protein blend, with a better balance of EAA, may lead to similar MPS compared to milk protein
Essential amino acids
Kim et al. 48	12 weeks	(1) 3 g leucine‐rich EAA/twice a day + exercise (EAA + Ex) (2) 3 g leucine‐rich EAA/twice a day (EAA) (3) Exercise (Ex) (4) Health education (HE)	5 min warm‐up, 30 min RT (8 exercises for the whole body), 20 min balance/gait training, and 5 min cool down	Effectiveness of exercise and EAA supplementation in enhancing muscle mass and strength	↑ Walking speed for all three intervention groups ↑ Leg muscle mass for EAA + Ex and Ex ↑ Knee extension strength only for EAA + Ex Changes in leg muscle mass and knee extension strength were greater for EAA + Ex compared to HE	Supplementing EAA isolate, containing especially leucine and BCAA, may be an alternative to improve sarcopenia outcomes

Abbreviations: BCAA, branched‐chain amino acid; BWPH, blue whiting‐derived protein hydrolysate; EAA, essential amino acids; MPS, muscle protein synthesis; RT, resistance training; WP, whey protein.

Nevertheless, when supplementation of 20 g WP powder twice a day was associated with exercise, especially high‐intensity resistance exercise (60 min; 3×/week), results were augmented, leading to an increase in quadriceps muscle cross‐sectional area, higher muscle strength, and improved gait speed. ⁴² Meanwhile, Roschel et al. demonstrated that 15 g of WP supplementation twice a day associated with resistance exercise (2×/week) for 16 weeks was ineffective to improve muscle mass and muscle strength in elderly individuals. ⁴⁹ The controversial findings between studies may be related to many factors like protein dose, recruited population, sample size, study duration, and level of muscle loss/sarcopenia at baseline.

In an interesting study, Nabuco et al. assessed the timing of protein supplementation three times per week for 16 weeks in three groups that (1) received a dose of 35 g of hydrolyzed WP before and placebo after resistance exercise training, (2) the second group that had placebo before and WP after resistance exercise training, and (3) the last group that only consumed placebo before and after resistance exercise training. ⁴¹ The authors found no supplementation timing effect of WP before or after training, showing that WP associated with resistance exercise can increase functional capacity and muscle strength, regardless of the moment of supplementation. ⁴¹

Taken together, all these findings associated with the rapid digestibility and greater aminoacidemia in comparison to other proteins have placed WP as the gold standard protein supplement for maintaining or increasing muscle mass in older adults with sarcopenia.

4.2. Collagen protein

Collagen represents 30% of the protein concentration in the human body, being an important element for the extracellular matrix of muscles and tendons for force production. Collagen is found in connective tissue, cartilage, and bone of animals, including cattle, poultry, and fish, and is broken through a hydrolysis process into shorter chains of AA, known as collagen peptides. ⁴⁴ Compared to WP, collagen protein presents a different composition of AA that is higher in non‐essential AA (e.g., proline and glycine) and is not considered a complete protein source because it does not contain the EAA tryptophan.

In male patients with sarcopenia undertaking resistance exercise, 15 g of daily collagen peptide supplementation for 12 weeks was shown to improve fat‐free mass compared to resistance exercise alone (4.2 vs. 2.9 kg; respectively), with significant gains in isokinetic quadriceps strength and reduction in fat mass (−5.4 vs. −3.5 kg; respectively). ⁴⁴ Body weight gains and increments in fat‐free mass have also been reported in young men. ⁵⁰ In addition, collagen protein supplementation has been shown to improve joint pain perception in patients with osteoarthritis ⁵¹ and bone mineral density in postmenopausal women, ⁵² which may be of benefit in older adults with sarcopenia and other comorbidities.

On the other hand, assessing the effects of collagen peptide supplementation in older adults for 6 days, Oikawa et al. demonstrated that collagen was inferior to WP in increasing MPS after ingestion of 30 g twice a day. ⁴³ Another study showed that 1 year of chronic collagen protein supplementation (2 × 20g/day) was not capable of ameliorating outcomes related to muscle strength, muscle mass, and physical performance. ⁴² It is important to highlight that a great part of this anabolic response is mediated by leucine, which is present in lower amounts in collagen protein compared to WP. Although few studies with collagen protein supplementation have reported positive results, there is equivocal and insufficient robust data on its efficacy to recommend it to older adults in order to improve sarcopenia outcomes.

4.3. Fish protein supplement

Seafood is gaining popularity among consumers and proponents of a healthy lifestyle because of its high‐quality protein, polyunsaturated fatty acids (PUFA), mineral content, and sustainable characteristics. ⁵³ With a growing global demand for protein due to increased population and an aging society, researchers have been trying to find new food sources to produce high‐quality protein, making fish protein hydrolysates an alternative to support healthy muscle metabolism.

The rapid response of postprandial increases in EAA, especially leucine is critical for MPS stimulation. ⁵⁴ A consumption of 0.33 g/kg of fish protein hydrolysates from Blue Whiting (Micromesistius poutassou) has demonstrated positive postprandial aminoacidemia in older adults significantly better than a non‐bioactive isonitrogenous non‐essential amino acid control and similar to WP up to 30 min, though a greater peak, close to 60 min, and larger area under the curve were reported with WP. ⁴⁵

In another study using a crossover, double‐blind, randomized design with administration of 0.25 g/kg of hydrolysates from Nile tilapia (Oreochromis niloticus) in young adults, the concentrations of EAA, BCAAs, and leucine were not different from WP and fish protein supplement. ⁵⁵ These variations in findings are probably due to differences in leucine content between fish species (Blue Whiting: 5.78 g/100 g vs. Nile tilapia: 3.38 g/100 g), dose of supplementation (Blue Whiting: 0.33 g/kg vs. Nile tilapia: 0.25 g/kg), and recruited population (older vs. young adults).

Additionally, 3 g/day of fish protein supplements (10 tablets a day) from Atlantic cod fish (Gadu morhua) have shown positive effects on glucose tolerance and lipid metabolism in overweight adults, secondary outcomes related to muscle health. ⁵⁶ Moreover, neither recovery after high‐intensity exercise nor physical performance of recreationally athletes showed any improvements after fish protein supplementation when compared to placebo. ⁵⁷ , ⁵⁸ , ⁵⁹ In older adults, consumption of 3 g of fish protein hydrolysates from Atlantic codfish for 1 year had no positive impact on grip strength and physical function assessed by gait speed and short physical performance battery (SPPB) test compared to placebo. ⁶⁰

Indeed, findings from skeletal muscle myotubes (C2C12 cells) showed that there is a significant variation in the anabolic response between fish protein hydrolysates, ⁶¹ suggesting that future clinical studies with older adults with sarcopenia are needed to consider fish protein as a nutritional strategy to enhance muscle metabolism.

5. SUPPLEMENTAL PLANT‐BASED PROTEIN SOURCES

Vegetarianism and veganism, characterized by restricting consumption of partial or entire groups of animal‐based products have recently gained attention due to increased awareness about environmental issues associated with animal protein. ²⁹ Plant‐based protein differs from animal protein in digestion, absorbability, AA profile, and content of leucine. ⁶² The slower digestion and absorbability associated with plant‐based proteins may be attributed to anti‐nutritional factors, such as fiber content and polyphenolic tannins. ⁶² It is also important to note that no single plant source contains sufficient quantities of all EAAs; therefore, to maximize MPS rates, combinations of plant‐based sources have typically been investigated. Thus, having a dietary pattern based on plant‐protein requires deliberate attention to avoid a negative impact on body composition and function.

Roschel et al. demonstrated that soy protein powder supplementation (2 × 15 g/day) for 16 weeks combined with resistance exercise training (2×/week) was not able to increase muscle mass and muscle strength in elderly individuals; however, it was not inferior to WP supplementation. ⁴⁹ Interestingly, Hevia‐Larraín et al. showed in young untrained men that, when the amount of protein consumed is equally distributed throughout the day in vegan or omnivore diet (i.e., 1.6 g/kg/day), there was no difference between groups in anabolic adaptations, such as leg lean mass and leg strength. ⁶³ This finding agrees with other studies that show the same response between plant‐based blends, ⁴⁷ pea ⁴⁶ and wheat protein ⁶⁴ in MPS rates in healthy adults when compared with conventional milk protein powder supplementation. However, recently Pinckaers et al. demonstrated in healthy older adults that MPS rates are different between omnivorous (0.45 g/kg) and plant‐based (0.45 g/kg) isocaloric and isonitrogenous meals, having higher MPS rates after omnivorous meals at rest (up to 360 min after meal). ⁶⁵ Given that, older adults may have a different response in MPS rates after plant‐based or omnivorous meals, but more studies are needed to affirm that omnivorous diets are better for older adults.

The proposed lower anabolic properties of plant‐ versus animal‐derived proteins may be compensated by (i) consuming a greater amount of plant‐based protein to counterbalance the lesser quality; (ii) using specific blends of plant‐based proteins to create a more balanced AA profile; (iii) fortifying plant‐based protein with the specific AA that is deficient (e.g., leucine, lysine, and methionine); (iv) extraction and purification of protein from whole food to isolate and improve the concentration of a protein. ⁶²

These findings suggested that source of protein may not determine muscle adaptations when adequate adjustment is performed and total daily protein is achieved. However, we are still missing studies applying plant‐based protein in older adults with sarcopenia to draw conclusive responses.

6. AMINO ACID SUPPLEMENTATION

6.1. Essential amino acids

Following the principle that protein synthesis depends on the availability of more than a single AA, including especially EAA, it is reasonable to think that supplementation of several AA, other than leucine isolate, can improve MPS. ¹⁷ EAA (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) are not produced endogenously, while non‐essential AA (alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine) are produced from metabolic processes and not necessary to be consumed in regular diet. ⁶⁶ In certain conditions, like illness and stress, several non‐essential AA, such as arginine, cysteine, glutamine, glycine, proline, and tyrosine, may turn momentarily into EAA, being classified as conditionally essential. ⁶⁶

Given the importance of consuming EAA for MPS, Markofski et al. demonstrated that 15 g/day of EEA supplementation alone or combined with moderate aerobic exercise acutely stimulate MPS pre‐ and post‐intervention of 24 weeks in older adults. In EEA associated with aerobic exercise, there was an increase in muscle strength but no improvement in lean body mass. ⁶⁷ Additionally, Kim et al. showed that 6 g/day supplementation of EEA with multicomponent exercise training (2×/week) for 3 months led to increased muscle strength, walking speed, and leg muscle mass, while exercise alone was able to improve only walking speed. ⁴⁸

Therefore, consumption of EAA seems to play a role in increasing MPS and to be a promising supplement for this population, but more studies are needed to confirm the beneficial effects of EAA supplementation in older adults with sarcopenia. In addition, future studies should study the quantity and timing of EAA supplementation to improve sarcopenia outcomes.

6.2. Leucine

In the early 2000s, studies started to show the important role of leucine in MPS. Anthony et al. demonstrated in an animal model that acute ingestion of leucine stimulated MPS via stimulation of eIF4G‐eIF4E complex and regulating activation of p70S6K. ⁶⁸ , ⁶⁹ In humans, Nair et al. showed that leucine decreased MPB during infusion. ⁷⁰ Nowadays, it is well established that leucine is directly involved in modulating protein turnover via the mammalian target of rapamycin (mTOR) pathway. ⁷¹ Given the importance of leucine in MPS, several studies have tried to demonstrate the effects of leucine supplementation isolate or in combination with other compounds in patients with sarcopenia.

Martinez‐Arnau et al. have demonstrated that supplementation of 6 g/day of leucine for 13 weeks was not able to improve lean body mass when compared to placebo; however, the intervention group have improvement in walking time, showing that it can lead to better muscle function. ⁷² Similarly, another study showed that 10 g/day of leucine with resistance training for 12 weeks improved walking velocity and tended to increase muscle strength (p = .056) and muscle power assessed by chair stand test (p = .085) in comparison to maltodextrin as placebo. ⁷³

In addition, supplementation of 15 g/day of milk protein with an additional 4.2 g of leucine for 6 days led to an increase in MPS when compared with a supplementation of 15 g/day of milk protein with 1.3 g of leucine, demonstrating the importance of higher amounts of leucine to elicit better muscle anabolic response. ⁷⁴ In an umbrella review based on systematic reviews and meta‐analysis, leucine supplementation had a significant impact on increasing muscle mass in older adults with sarcopenia. ⁷⁵ For instance, Atherton et al. have demonstrated that acute supplementation of a protein drink (10 g) with addition of leucine (4.2 g) after resistance exercise increase significantly MPS and p70S6K phosphorylation in older adults when compared with only protein drink. ⁷⁶ In addition, Wilkinson et al. found that 1.5 g of leucine‐enriched EAAs stimulated MPS in the same levels of 40 g of WP in older adults. ⁷⁷

Even though leucine plays an important role in MPS, it is well known that other AAs need to be present to support effective MPS. Kang et al. demonstrated that supplementation of enriched protein (protein 20 g [casein 50% + WP 40% + soy 10%, total leucine 3000 mg], vitamin D 800 IU [20 μg], calcium 300 mg, fat 1.1 g, carbohydrate 2.5 g) twice a day for 12 weeks significantly increased muscle mass, but not muscle strength, of older adults when compared with placebo. ⁷⁸ In agreement with these findings, Roschel et al. did not find an effect of leucine supplementation (3 × 2.5 g/day) with resistance exercise (2×/week) for 16 weeks on muscle strength when compared with placebo in frail individuals. ⁴⁹

Moreover, older adults need higher amounts of leucine to have an optimal MPS, supported by findings showing that better response with 2.8 g of leucine but not with 1.7 g, while young adults had a significantly increment in both conditions. ⁷⁹ Therefore, the consumption of leucine is extremely important for older adults to reduce muscle loss or even promote gains in muscle mass, and achieving higher amounts of leucine is essential for optimizing MPS (Figure 1).

6.3. Branched‐chain amino acids

Composed of leucine, isoleucine, and valine, BCAAs are important EAA in MPS and insulin metabolism, being associated with fat‐free mass and cross‐sectional area in older adults. ⁸⁰ In addition, a higher consumption of BCAAs has been associated with a higher handgrip strength in this population. ⁸¹

Interestingly, Fuchs et al. showed that acute infusion of 6 g of BCAAs increases MPS up to 2 h, whereas 30 g of milk (providing an equivalent amount of BCAAs) maintained higher MPS for 5 h in older adults, showing that BCAAs may play a role in MPS, though most of this effect is attributed to the presence of leucine and the association of protein. ⁸²

Although an increase in handgrip strength, gait speed, and skeletal muscle index have been reported within 5 weeks of supplementation with 2 × 3.6 g/day of BCAAs in pre‐sarcopenic older adults, patients significantly decreased these parameters by the end of the 12‐week intervention. ⁸³ Moreover, another study showed that 16 weeks of supplementation of BCAAs (0.21 g total BCAA/kg) alone was not capable of increasing score in SPPB, but when supplementation was associated with elastic‐band exercises a significant increase on SPPB was observed. ⁸⁴

In a meta‐analysis of 35 randomized clinical trials, Bai et al. demonstrated that BCAAs may have a beneficial effect on improving muscle strength (MD = 0.35 kg, 95% CI [0.15–0.55]; p = 0.0007), muscle mass (MD = 0.25 kg, 95% CI [0.10–0.40]; p = 0.0008), and physical performance (MD = 0.29, 95% CI [0.00–0.57]; p = 0.05) in older adults with sarcopenia, although most of the studies included had potential bias and high heterogeneity. ⁸⁵

Therefore, BCAAs may be a potential strategy to improve outcomes associated with sarcopenia, but more studies with better design are needed for conclusive responses. In addition, reaching a greater amount of protein quality with a favorable AA profile may be more important to promote muscle gains and muscle function than supplementing isolated AAs.

7. CREATINE SUPPLEMENTATION

Creatine is synthesized in the kidneys and liver but can also be obtained from animal products, such as meat. Creatine is mainly stored as phosphocreatine in skeletal muscle, ⁸⁶ by combining inorganic phosphate to creatine that restores the level of adenosine triphosphate. ⁸⁶ In older adults, several studies using creatine associated with resistance training have demonstrated that creatine supplementation (~3–5 g/day) can improve accretion of muscle mass, muscle strength, and other physical parameters. ⁸⁷ , ⁸⁸ However, clinical trials have used different doses of creatine, regimes of use, and duration of resistance exercise training.

Candow et al. have demonstrated that 0.1 g/kg/day of creatine supplementation after resistance training for 32 weeks improved lean tissue mass, leg and chest press strength in older adults (Figure 1). ⁸⁹ Similarly, Bernat et al. found an improvement in leg press and total lower body strength after 8 weeks of high velocity resistance training combined with 0.1 g/kg/day. ⁹⁰ Interesting, Gualano et al. found that 20 g/day for 5 days followed by 5 g/day for 23 weeks, associated with resistance training, increased appendicular lean mass, muscle strength, and function in vulnerable older women. ⁹¹ However, in the same study, they found that supplementation of creatine, without resistance training was not capable of improving muscle function but led to an increase in appendicular lean mass. In agreement, Roschel et al. found no effect of creatine supplementation (2 × 3 g/day), alone or in combination with WP (2 × 15 g/day), both combined with resistance exercise training (2×/week), in muscle mass, muscle strength and functional performance in elderly individuals. ⁴⁹

Devries and Phillips performed a meta‐analysis with 357 older adults and showed an improvement in fat‐free mass (MD = 1.33 kg, 95% CI [0.79–1.86]; p < .0001), increase in chest (MD = 1.75 kg, 95% CI [0.56–2.91]; p = .004) and leg press strength (MD = 3.25 kg, 95% CI [0.47–6.03]; p = .02), and in sit‐to‐stand 30s repetitions (MD = 1.93 reps, 95% CI [0.19–3.67]; p = .03) after creatine supplementation. ⁹² These findings are supported by Chilibeck et al. in other meta‐analysis including 22 studies and 721 participants. ⁸⁸

Therefore, creatine supplementation may be an effective tool, when associated with resistance training, to improve gains in muscle mass, muscle strength, and function in older adults with sarcopenia. This may also be important in the context of a global move toward increased plant‐based dietary consumption. As creatine levels are lower in vegans ⁹³ and vegetarians, creatine supplementation may be more important in this cohort for the prevention of sarcopenia.

8. PUFA ON SKELETAL MUSCLE PROTEIN TURN OVER

Omega 3 (ω‐3), a PUFA found in fish and seafood, plays an important role in metabolic diseases and cardiovascular health with anti‐inflammatory and antioxidant properties. ⁹⁴ PUFA includes α‐linolenic acid, stearidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, and docosahexaenoic acid (DHA). ⁹⁴ , ⁹⁵ The Food and Agricultural Organization (FAO) recommends a total ω‐3 PUFA intake of 0.5%–2% per day.

Interestingly, Smith et al. showed that 6 months of supplementing ω‐3 (4 × 1 g pills/day providing 1.86 g of EPA and 1.50 g of DHA/day) in older adults increased thigh muscle volume, handgrip strength, and 1‐repetition maximum muscle strength when compared with control group. ⁹⁶ In addition, another study found a modest, but significant, increase in muscle strength in older adults after 6 months of ω‐3 supplementation (four soft gels/day, 1000 mg/capsule with ~675 mg EPA and ~300 mg DHA, providing a total dosage of 3.9 g n3‐PUFA/day). ⁹⁷

In a mechanistic study, Smith et al. ⁹⁸ found that 8 weeks of dietary supplementation with ω‐3 (4 g/day containing 1.86 g of EPA and 1.50 g of DHA) led to an increase in MPS, possibly mediated by the activation of p70S6K in the mTOR signaling pathway, an important protein responsible for controlling growth and cell survival. ⁹⁹ Brook et al. had similar findings, whereby supplementation with ω‐3 (1860 mg of EPA and 1540 mg of DHA) increased total fat free mass in older women as well as additional strength and functional gains when compared with a placebo. ¹⁰⁰

On the other hand, the DO‐HEALTH Research Group did not find any significant effect of ω‐3 supplementation (1 g/day of ω‐3 containing 330 mg of EPA and 660 mg of DHA from marine algae) on physical performance in lower extremity function as measured by performance‐based test that includes three components: walking velocity, 5‐time repeated chair stand test, and SPPB after 3 years of follow‐up of 2157 older adults. ¹⁰¹ Thus, the supplementation of ω‐3 in older adults, especially in sarcopenia, to improve MPS and outcomes associated with sarcopenia needs further explanation and research.

9. CONCLUSIONS

Nutritional supplement strategies involving animal (e.g., WP, collagen, and fish protein) and plant‐based protein (e.g., wheat, pea, and soy protein), EAA (e.g., leucine), and PUFAs (e.g., ω‐3) have been presented as tools to improve MPS, though it may not reflect chronic adaptations in muscle mass and muscle function. When associated with resistance exercise, supplementation with these compounds shows more consistent results in increasing muscle strength, muscle mass, and physical performance, important criteria to screen, diagnose, and determine severity of sarcopenia, respectively. However, more studies with these nutritional strategies including patients with sarcopenia, not just elderly individuals, and assessing outcomes associated with sarcopenia should be further performed to guide accurate clinical practice in this population.

10. AUTHOR CONTRIBUTIONS

Conceptualization, B.P.C.; G.W.P.F. and S.v.H.; Writing ‐ original draft preparation, B.R.G.S.; Writing ‐ review and editing, B.R.G.S.; B.P.C; G.W.P.F.; S.v.H; Supervision, S.v.H.; Final version approval, B.R.G.S.; B.P.C; G.W.P.F.; S.v.H.

FUNDING INFORMATION

BRG‐S is supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, #88887.829284/2023‐00).

CONFLICT OF INTEREST STATEMENT

S.v.H. has been a paid consultant for and/or received honoraria payments from Amomed, AstraZeneca, Bayer, Boehringer Ingelheim, BRAHMS, Edwards Lifesciences, MSD, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Respicardia, Roche, Servier, Sorin, and Vifor. S.v.H. reports research support from Amgen, AstraZeneca, Boehringer Ingelheim, Pharmacosmos, IMI, and the German Center for Cardiovascular Research (DZHK). All other authors do not have a conflict of interest to report.

ETHICS STATEMENT

The information discussed within this article has been conducted in accordance with ethical guidelines. Any potential conflicts of interest has been disclosed and no data from human subjects were collected for this study.

Goes‐Santos BR, Carson BP, Fonseca GWP, von Haehling S. Nutritional strategies for improving sarcopenia outcomes in older adults: A narrative review. Pharmacol Res Perspect. 2024;12:e70019. doi: 10.1002/prp2.70019

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.