Treating age‐related loss of muscle mass and function: Where should we be focusing?

Increased life expectancy across developed countries has highlighted the personal and societal value of healthy ageing. A well-functioning neuromuscular system is fundamental to quality of life and functional independence. The systemic deterioration of tissue and organ function during ageing is reflected in the diverse cellular and molecular mechanisms implicated in the age-related loss of muscle mass and strength and its extreme form, termed sarcopenia. Proposed contributors include neurodegeneration, impaired proteostasis, deficient regeneration, systemic hormonal decline, chronic inflammation, and dysregulation of muscle-resident cell populations such as muscle stem cells, fibro-adipogenic progenitors and immune cells. Recent efforts have added granularity to our understanding of the molecular response of muscle to ageing and started to unravel the cellular origins of these signals. Advancements in cell-targeting strategies (e.g. AAV capsids and antibody-targeted therapeutics) are opening new avenues for targeted interventions. Nonetheless, this raises the salient question - what should treatments for age-related muscle wasting target? While anabolic and catabolic signalling within muscle fibres has been the primary target of strategies to counteract age-related muscle loss, these efforts may be futile if impairment in other cell types such as muscle stem cells and motor neurons drive the wasting process. Furthermore, individual differences in activity, nutrition, sex, comorbidities and genetics are likely to influence the predominant mechanisms driving age-related muscle wasting. This multifactorial condition may therefore require a multifactorial solution, with scientists focusing on diverse causal mechanisms to identify and develop effective interventions.