Is Ferroptosis Important in Muscle Aging?
The aging of muscle tissue leading to loss of muscle mass (sarcopenia) and muscle strength (dynapenia) is a microcosm of aging in general, in that many different groups promote many different views of the relative importance of many different mechanisms. All of these mechanisms do in fact exist - muscle aging is a complex interplay of many interacting issues - but it is likely that any given view on the importance of any given specific mechanism will turn out to be wrong. The only practical way to establish the importance of a mechanism of muscle aging is to develop a means of blocking or repairing just that mechanism in isolation of all of the others, and observe the result. This applies as much to the examination of ferroptosis noted here as it does to any of the other mechanisms involved in muscle aging.
Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established.
Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.