The Public Health Need and Strategic Opportunities for the Accelerated Development of Function-Promoting Therapies for Older Adults

Recognition of the multiple roles for skeletal muscle has advanced considerably over the past decade. The skeletal muscle’s biomechanical, metabolic, and storage functions involve the conversion of chemical into mechanical energy in support of force production, maintenance of posture, and generation of movements linked to physical activity. Energy metabolism and maintenance of core temperature through the production of heat are also among its roles. The skeletal muscle stores important substrates such as amino acids that are necessary for organ-specific protein synthesis as well as neoglucogenesis. The skeletal muscle is also a major regulator of glucose metabolism (1). Importantly, the skeletal muscle communicates dynamically with other organs including bone, brain, liver, and the immune system to regulate whole body functions and homeostasis (2–5). Various factors can disturb homeostasis of the skeletal muscle to induce the development of muscle atrophy, initiate or aggravate disease states, and accelerate age-related loss of muscle mass, strength, and function. Therefore, maintaining skeletal muscle homeostasis is critical to the health and quality of life of all populations in the world. However, strategies for maintaining muscle homeostasis may differ among populations based on their intrinsic population-specific genetic differences as well as differences in their life history and their exposome (6,7). The skeletal muscle forms about 40% of the total body mass and holds 50%–75% of the overall stored body proteins (1). Damaged skeletal muscle impairs the ability to combat stress and chronic diseases, increases physical impairments/disability, decreases quality of life, and impacts the socioeconomic burden of individuals and societies. The aspects described above are particularly relevant to the population of older adults. A substantial increase in the numbers of older adults living with a physical disability is anticipated due to the rapid growth, worldwide, of the human population ≥ 65 years of age (8). Age-related loss of muscle mass, strength and function increases the risk of serious complications such as mobility limitations, falls and fractures, loss of independence, disability, metabolic disorders, and mortality (9,10). Accelerated development of function-promoting therapies to prevent and treat functional limitations and physical disabilities associated with aging and chronic diseases is, then, a public health imperative. Recognizing this need, the National Institute on Aging (NIA) held a workshop on March 20–22, 2022, entitled “Development of Function Promoting Therapies: Public Health Need, Molecular Targets, and Drug Development.” Academic investigators, representatives from the National Institutes of Health and the U.S. Food and Drug Administration, professional societies, pharmaceutical industry, and patient advocacy organizations shared their experience and ideas on how to advance the field. A global audience of 397 professionals attended this workshop. This special issue focuses on outcomes from that workshop. Speakers and discussants reviewed: A. The looming public health crisis caused by the epidemiology and societal impact of aging-related functional limitations (8). B. Advances in muscle biology including how impairments in neural activation contribute to age-related weakness and mobility limitations (11); how disruptions in multiple signaling pathways and in the crosstalk between different cell populations affect repair and maintenance of muscle mass and function (12); the role of immune competence and inflammation in the age-related decline in skeletal muscle function (13). C. The various molecular targets and potential candidate strategies for the accelerated development of function-promoting therapies including findings of preclinical studies and efficacy trials related to (14–17): a. Anabolic drugs that increase muscle mass and strength (eg, androgens, selective androgen receptor modulators, growth hormone, growth hormone secretagogues and ghrelin mimetics; myostatin and activin antagonists). b. Drugs that directly improve muscle contractility and muscle strength (eg, troponin activators). c. Drugs that target other mechanisms (orphan nuclear receptors, anti-inflammatory drugs, Mas receptor agonists, urolithin A). D. The geroscience approach using drugs specifically targeting the mechanisms of aging (eg, nicotinamide adenine dinucleotide boosters; senolytics) to treat age-related conditions (18). E. The role of physical activity and multi-dimensional exercise training to restore and increase physical functioning (19). F. Nutritional interventions including protein intake, vitamin D supplementation, caloric restriction, and the effects of other nutritional interventions such as time-restricted eating on skeletal muscles of older adults (20–22). G. Issues relevant to the design of efficacy trials, with emphasis on future well designed, adequately powered clinical trials. These will require careful definition of indication/s, study populations, and reliably measured outcomes/endpoints relevant to patients, to ensure successful execution and outcome (23). H. Lessons learned from the success of the oncology drug development programs and the Operation Warp Speed for COVID-19 Vaccine Development that can be applied to accelerate the development of function-promoting therapies (24) The lessons learned from the programs mentioned above provide a wealth of experience that can influence future strategic planning and partnerships for accelerated development of function-promoting therapies. In particular, the millions of deaths resulting from the COVID-19 pandemic worldwide have motivated complex but coordinated efforts among various stakeholders (multiple government agencies, the pharmaceutical industry, academic investigators, and others) that catalyzed the successful development and emergency use authorization of vaccines for a new infectious agent in less than a year. In aging, similar complex and coordinated efforts can be taken to accelerate the development of function-promoting therapies to address the aging-related loss of muscle mass, strength and function and the consequent serious adverse effects on healthspan and quality of life. The NIA workshop set the stage for these potential future synergistic collaborations among strategic academic, government and industry partners. The workshop aimed to facilitate the identification of biological targets for therapeutic development and the optimization of the design and expeditious implementation of clinical trials of function-promoting therapies. NIA remains committed to promoting these types of cross-disciplinary scientific discussions, networking, collaboration, and fostering of partnerships to advance science including the development of innovative function-promoting therapies. The knowledge shared in this special issue has the potential to facilitate such partnerships at national and international levels to address a pressing public health need and to enhance the health, functional independence, and quality of life of older adults worldwide. Any opinions or recommendations expressed in this publication are those of the author and do not necessarily reflect the views of the National Institutes of Health, including the National Institute on Aging, or the U.S. Department of Health and Human Services. We are grateful to all experts who participated as speakers or discussants or attended the workshop. The list of speakers is available from: https://www.nia.nih.gov/research/dgcg/development-function-promoting-therapies. The workshop “Development of Function Promoting Therapies: Public Health Need, Molecular Targets, and Drug Development, was fully and solely supported by the National Institute on Aging (NIA) funds. This supplement is sponsored by the National Institute on Aging (NIA) at the National Institutes of Health (NIH). None declared.