Muscle growth in response to resistance exercise is attenuated in older individuals, the result of much the same set of processes that lead to sarcopenia, the name given to the characteristic loss of muscle mass and strength that occurs with age. Resistance exercise is clearly still beneficial in later life, judging by the reduction in mortality risk that results, but can it be made more beneficial? Undoubtedly yes, given the appropriate technology to address the underlying root causes of degenerative aging, but all too few such technologies exist at the present time. The use of senolytic therapies to destroy harmful, inflammatory senescent cells is one of the few such technologies, and a plausible approach to improving muscle function in older people, but alas is not mentioned in this paper. The focus here is instead on established ways to tinker with the operation of metabolism in muscle tissue, with results on muscle growth in response to exercise that tend to be modest at best.

The acute anabolic responses to feeding and exercise were found to be dampened in old subjects compared to their young counterparts, thus limiting their recovery and muscle growth. It has been hypothesized that the blunted increase in protein synthesis following acute muscle loading may influence the smaller gains in lean tissue following resistance exercise training in older adults. As such, supplementation of high-quality protein may improve anabolic response to a single bout of exercise. Specific amino acid supplements are available, in the forms of essential amino acids (EAAs), branched-chain amino acids (BCAAs), and leucine. Leucine-rich EAA supplementation enhanced muscle strength following exercise. It is important to note, however, that prolonged protein supplementation with whey or casein, in the setting of a training program, does not appear to improve the exercise response in elderly patients. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine which directly activates mTOR, has also been investigated and increased lean muscle mass and strength in sarcopenic individuals.

Chronic, age-related inflammation in skeletal muscle may play a role in aging-associated muscle loss. NF-κB, a master transcriptional regulator of inflammation, becomes upregulated in skeletal muscle with aging. This has led to investigations of whether NF-κB inhibition using commercially available NSAIDs can improve the maintenance of muscle mass. The efficacy of NF-κB inhibition, using commercially available NSAIDs, on the maintenance of muscle mass and strength in response to exercise has been explored in many clinical studies in elderly patients. A 3-month bout of resistance exercise in elderly patients with knee osteoarthritis, NSAIDs therapy resulted in a mild improvement in muscle strength, however, without hypertrophy. Other studies found that NSAID treatment augmented training-induced improvement in strength with associated muscle hypertrophy and limited muscle catabolism. Others have instead shown that NSAID supplementation does not improve skeletal muscle strength or function during physical training. As such, the use of NSAIDs during exercise remains controversial.

Testosterone has emerged as another potential supplement to exercise for the elderly population. Multiple studies have demonstrated that testosterone levels decrease with age. Testosterone administration to elderly patients increases both muscle mass and maximal voluntary strength in a dose-dependent fashion, possibly by the induction of myogenic gene expression. Despite this assertion, the additional benefits of physiological testosterone replacement in elderly patients remains unclear. A prospective study demonstrated increased upper body strength following testosterone treatment of elderly patients with low to normal serum testosterone, but this treatment did not offer any benefit beyond resistance exercise alone.

The growth hormone (GH) axis is another area that has received attention as a potential supplement for exercise therapy for the elderly. GH is made in the pituitary gland and promotes IGF-1 expression in skeletal muscle. IGF-1, in turn, stimulates the Akt/mTOR pathway which promotes muscle anabolism and protein synthesis in response to exercise. In elderly patients, GH treatment increases lean body mass and decreases fat-to-muscle ratio from baseline, although it is unclear as to whether this was attributable to increased skeletal muscle mass. However, multiple studies have shown that healthy elderly patients do not see any additional benefit in strength or muscle hypertrophy with GH supplementation as compared to exercise alone, even at 6-month follow-up. Despite the integral role of the GH/IGF axis on muscle development or hypertrophy, it does not appear to have a therapeutic benefit in physical training in healthy individuals.