The Challenges of Finding a Drug to Treat Sarcopenia
The characteristic loss of muscle mass and strength that occurs with age leads to sarcopenia and frailty. While a few companies are targeting this age-related muscle loss via development of small molecule drugs, the recent history of this part of the field is not encouraging. None of the attempted approaches have yet improved on exercise. That may well be due to a failure to specifically target underlying mechanisms that drive degenerative aging, projects instead relying on the sort of adjustments to metabolism that are discussed in the paper referenced here, but only time will tell.
A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy.
The use of hormone replacement and myostatin-based therapies in clinical trials - aimed at promoting muscle hypertrophy - has not resulted in notable advancements in muscle strength or functional performance. The decline in sex hormones that occurs with aging is closely tied to the development of sarcopenia. However, the potential adverse effects of sex hormone replacement therapy outweigh its modest advantages in mitigating muscle aging. There is no conclusive association between circulating myostatin level and muscle aging, and myostatin-based therapy does not affect muscle aging.
While effective in promoting muscle growth, hypertrophic signaling compromises muscle protein quality control, exacerbating age-related muscle dysfunction. An alternative intervention to refine mechanistic target of rapamycin (mTOR) functions is proposed to benefit muscle health in the elderly. Both hormone replacement and myostatin-based therapies stimulate muscle growth by activating mTORC1, which controls growth by responding to nutrient availability and should be active only when nutrients are present. Yet chronic activation of mTORC1 in skeletal muscle accelerates sarcopenia development in mice. The crucial question is whether the interventions focused on increasing muscle size through mTORC1 will truly be beneficial in addressing muscle aging in humans, given that mTORC1 insensitivity is frequently seen in aged individuals
thought there was recently a receptor target that boosted later life muscle mass by 40%
Small phase I clinical trials testing the use of umbilical cord stem cells as a treatment for sarcopenia have yielded encouraging results.
"Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics." Theranostics 2021 Mar 31;11(12):5675-5685.
"Safety and efficacy of umbilical cord tissue-derived mesenchymal stem cells in the treatment of patients with aging frailty: a phase I/II randomized, double-blind, placebo-controlled study." Stem Cell Res Ther 2024 Apr 29;15(1):122
Testosterone is a small molecule which indirectly increases muscle mass and strength in aged men (it may also be effective in aged women I just don't personally know the effects on women). I say indirectly because it works primarily by increasing the user's capacity for exercise. It is generic and less than $300/year. It seems improbable to me that there will be more a effective small molecule with fewer down sides developed in the next 30 years. See Traverse Trial regarding cardiovascular risk.