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December 31, 2022 7 min read

Age-related loss of skeletal muscle mass, strength, and function is known as sarcopenia, and is associated with an increased fall risk, disability, institutionalization, and all-cause mortality [1].

Pioneering studies indicate that skeletal muscle cross-sectional area, fiber size, and fiber number are reduced by 20–40% from adulthood to old age [2], paralleling the loss of aerobic fitness (VO2max), glucose tolerance, and anabolic hormones [3].
When a threshold of low muscle mass and strength is reached, sarcopenia is defined, predisposing elderly persons to physical disability, mobility limitations, falls, institutionalization, and death.

A conservative estimate is that more than 50 million of individuals are affected by sarcopenia and that this number will rise to more than 200 million in the next 40 years, with major economic implications for global health-care systems [1].

On October 1, 2016, an important milestone was achieved.

Sarcopenia received an International Statistical Classification of Diseases and Related Health Problems code (M62.84), which is necessary to diagnose it as a disease. This recognition urges the need to diagnose sarcopenia in clinical practice and to develop guidelines to effectively prevent or counter this condition [4].  

This recognition should lead to an increase in availability of diagnostic tools and the enthusiasm for pharmacological companies to develop drugs for sarcopenia.

Considering the growing proportion of elderly and the concurrent rise in age-associated chronic disease, research efforts are warranted to develop innovative, cost-saving, and effective countermeasures.

For many years, it’s been demonstrated that regular physical activity decelerates the intrinsic aging process of most, if not all, organ systems, reducing all-cause mortality and extending lifespan by 3–10% [5].

Although traditionally much attention has been placed on the cardiovascular system, the significance of skeletal muscle preservation is demonstrated by the fact that strength and power predict all-cause mortality independent of aerobic capacity [6].

Overcoming anabolic resistance with research proven multi-ingredient supplementation

Despite the profound benefits of resistance exercise across all age-groups, there is some evidence indicating a blunted anabolic response to contractile activity with aging. This is known by the term “anabolic resistance” [7].  

Considering this, a combination of resistance exercise with other interventional strategies may be necessary to maintain muscle health in old age.

For example, the synergism between branched-chain amino acids (BCAAs) and contractile activity is well-established [45]. We know from research that the provision of essential amino acids (EAAs) (≥10.9 g) and leucine (≥2.7 g) potentiates the anabolic response to resistance exercise, and various animal protein sources, such as whole milk (≥31 g), whey (≥25 g), and caseinate (≥30 g), contain sufficient anabolic factors to stimulate skeletal muscle gains in combination with resistance exercise [8].  

Collectively, the evidence suggests that a higher single dose (≥40 g whey), multiple daily dosing, increased total protein intake (1.2–1.6 g protein/day), or provision of additional anabolic nutrients are necessary to maximize muscle protein synthesis and maintain skeletal muscle in old age [9].

The concept of using multi-ingredient supplementation is due to its potential for simultaneously targeting several metabolic and signaling pathways to enhance skeletal muscle gains, including the major growth regulatory processes within the muscle cell (e.g., protein synthesis, protein degradation, and satellite cells), energy production, contractile function, and/or recovery.

Since multi-ingredient supplementation stimulates several processes concurrently, it theoretically ‘circumvents’ the main constraint of using traditional, single-nutrient strategies to maintain skeletal muscle in old age, e.g., anabolic resistance.

A multitude of supplements are purported to provide significant benefits for skeletal muscle strength, performance, and recovery, but relatively few are supported by sound evidence from randomized clinical trials.

Specifically, the diverse nutritional and pharmacological approaches to attenuate sarcopenia reflect the complex etiology of the condition [10], but only a handful of these are safe, well-tolerated, and could be prescribed for long-term benefits.

Beyond protein supplementation, vitamin D, polyunsaturated fatty acids (omega-3 PUFAs; EPA and DHA), and creatine have documented skeletal muscle benefits and may be safely combined with exercise therapy in older adults [11].

A recent study using a protein-based multi-ingredient supplement in older adults found that whey protein, creatine, EPA/DHA, and vitamin D enhanced lean mass, strength, cognition, omega-3 index, and lowered markers of inflammation in older males [12].

  • This study incorporated 12 weeks of a multi-ingredient supplement combined with supervised, whole-body resistance exercise (2 d/week, 80% 1-RM) and high intensity interval training (1 d/week).  

Another very recent investigation tested the utility of a five-ingredient protein-based multi-ingredient supplement in combination with 12 weeks of low-intensity, home-based resistance exercise which consisted of 3 days a week of whole-body elastic band training.  

  • The multi-nutrient supplement contained lower amounts of total protein (40 g/d) and creatine (3 g/d) in a male cohort representative of the North American aging community e.g., individuals with low physical activity levels (sedentary/‘low active’), normal-to-high BMIs, and varying degrees of age-related muscle loss.
  • They found that home-based resistance exercise therapy enhances lean mass, strength, muscle-to-fat ratios, muscle quality and Type II fiber growth in older men with low physical activity levels, wide BMI range, moderate health issues, and with varying degrees of age-related muscle loss. 
  • A sub-group analysis suggests that the combination home-based resistance exercise and multi-ingredient supplement may be beneficial for mitigating sarcopenia, as the magnitude of improvements appeared to be greater in sarcopenic vs. healthy individuals [1].

See below figures for results on the study mentioned above.

Biological aging is inevitable and the etiology of sarcopenia is complex, multi-factorial, and involves dysfunction of all four basic tissue types (nerve, muscle, connective, and epithelial tissues).

Skeletal muscle growth is ultimately governed by the balance between the immediate growth regulatory processes within skeletal muscle, specifically protein turnover (synthesis and degradation), satellite cell donation, and cell death. 

These age-related decrements typically impair the growth response to standard exercise and nutritional monotherapies and the concept of using a multi-component therapy (for example, exercise, nutrition, and multi-ingredient supplementation) rests on simultaneous targeting of several pathways to potentiate skeletal muscle growth.

Research-proven supplements and their mechanisms of action

Whey/Casein:  Whey and casein are extremely high in the essential amino acids, which include the branched-chain amino acids (leucine, isoleucine, valine).  Leucine has been shown to independently stimulate muscle protein synthesis, therefore protein sources higher in leucine content typically elicit a greater stimulation of muscle protein synthesis. Leucine has been shown to independently activate the mammalian target of rapamycin (mTOR) signaling pathway through binding to Sestrin2 (an intracellular leucine sensor for the mTOR pathway) [13] which increases protein synthesis.

Creatine: Creatine plays an integral role phosphocreatine energy system, of which the primary function is to facilitate the transfer of high-energy phosphates in the production, and rapid regeneration, of adenosine triphosphate (ATP). Creatine supplementation exerts an ergogenic effect through increasing PCr stores and subsequently delaying their depletion, facilitating the rapid re-synthesis of PCr, acting as an energy buffer and potentially the modification of glycolytic lactate production [14].

Vitamin D: Vitamin D is metabolized to the active form, 1,25(OH)2D3, via the liver and kidney, and vitamin D deficiency is associated with impaired skeletal muscle function. The precise molecular machinery involved in vitamin D-dependent skeletal muscle remodeling remains elusive, however vitamin D and the vitamin D receptor may play a role in modulating satellite cell activity, protein synthesis, mitochondrial metabolism, as well as energy production through various protein pathways (i.e., akt-mTORC1, myostatin, forkhead box O3) that play a role in the maintenance of skeletal muscle mass and function [15].

Omega-3 fatty acids: Omega-3 polyunsaturated fatty acids (n3-PUFA)—especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—serve as a component of phospholipids in muscle membranes, and not only enhance protein kinase activity, but also improve mitochondrial respiratory sensitivity to ADP. Essentially, EPA and DHA may sensitize skeletal muscle of older adults to acute anabolic stimuli (e.g., resistance exercise and essential amino acids)

Below is a schematic illustration of the mechanisms through which the research-proven nutritional supplements function to promote skeletal muscle adaptation.


Research indicates that multi-ingredient supplementation with whey, micellar casein, creatine, vitamin D3, EPA/DHA augments muscle gains, strength, performance and  overall muscle quality in free-living, physically inactive, older males. These benefits are seen both independently and in conjunction with supervised resistance exercise/High-intensity interval training, and home-based, low-intensity resistance exercise.

It is also demonstrated that this multi-ingredient supplementation may provide anti-inflammatory and cognitive benefits in healthy older males.

The evidence is clear that this multi-ingredient supplementation protocol may potentiate muscle gains in resistance-trained sarcopenic men, although a larger cohort, including both male and female participants, will be necessary to confirm its clinical relevance.

After reviewing the current scientific literature in this area, it is clear that the multi-ingredient supplementation protocol mentioned above is safe, well-tolerated, and an effective complement to strength training for maintenance of skeletal muscle in old age.

Get the best tasting Whey-PRO protein in 11 delicious flavors here.

1.    Nilsson, M.I., et al., A Five-Ingredient Nutritional Supplement and Home-Based Resistance Exercise Improve Lean Mass and Strength in Free-Living Elderly. Nutrients, 2020. 12(8).
2.    Lexell, J., C.C. Taylor, and M. Sjostrom, What is the cause of the ageing atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. J Neurol Sci, 1988. 84(2-3): p. 275-94.
3.    Feldman, H.A., et al., Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab, 2002. 87(2): p. 589-98.
4.    Anker, S.D., J.E. Morley, and S. von Haehling, Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle, 2016. 7(5): p. 512-514.
5.    Nilsson, M.I. and M.A. Tarnopolsky, Mitochondria and Aging-The Role of Exercise as a Countermeasure. Biology (Basel), 2019. 8(2).
6.    Katzmarzyk, P.T. and C.L. Craig, Musculoskeletal fitness and risk of mortality. Med Sci Sports Exerc, 2002. 34(5): p. 740-4.
7.    Dickinson, J.M., E. Volpi, and B.B. Rasmussen, Exercise and nutrition to target protein synthesis impairments in aging skeletal muscle. Exerc Sport Sci Rev, 2013. 41(4): p. 216-23.
8.    Gorissen, S.H.M. and O.C. Witard, Characterising the muscle anabolic potential of dairy, meat and plant-based protein sources in older adults. Proc Nutr Soc, 2018. 77(1): p. 20-31.
9.    O'Bryan, K.R., et al., Do multi-ingredient protein supplements augment resistance training-induced gains in skeletal muscle mass and strength? A systematic review and meta-analysis of 35 trials. Br J Sports Med, 2020. 54(10): p. 573-581.
10.    Rolland, Y., et al., Current and future pharmacologic treatment of sarcopenia. Clin Geriatr Med, 2011. 27(3): p. 423-47.
11.    McKendry, J., et al., Nutritional Supplements to Support Resistance Exercise in Countering the Sarcopenia of Aging. Nutrients, 2020. 12(7).
12.    Bell, K.E., et al., A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial. PLoS One, 2017. 12(7): p. e0181387.
13.    Wolfson, R.L., et al., Sestrin2 is a leucine sensor for the mTORC1 pathway. Science, 2016. 351(6268): p. 43-8.
14.    Branch, J.D., Effect of creatine supplementation on body composition and performance: a meta-analysis. Int J Sport Nutr Exerc Metab, 2003. 13(2): p. 198-226.
15.    Montenegro, K.R., et al., Mechanisms of vitamin D action in skeletal muscle. Nutr Res Rev, 2019. 32(2): p. 192-204.

Dr. Paul Henning

About Dr. Paul

I'm currently an Army officer on active duty with over 15 years of experience and also run my own health and wellness business. The majority of my career in the military has focused on enhancing Warfighter health and performance. I am passionate about helping people enhance all aspects of their lives through health and wellness. Learn more about me