Alterations of actin in aging.

The actin cytoskeleton is a highly dynamic and evolutionarily conserved multi-protein complex that regulates cellular architecture, mechanics and intracellular organization. Although actin dynamics and organization have been extensively studied in development and some disease contexts, the role of the actin cytoskeleton in aging has only recently begun to be considered. Accumulating evidence across model organisms indicates that aging is accompanied by progressive actin disorganization, which can manifest as filament disassembly, aggregation and mislocalization, impacting cellular homeostasis. In this Review, we synthesize the current understanding of how actin integrity is maintained through chaperone networks, actin-binding proteins, transcriptional programs and post-translational modifications, and how these regulatory layers change during the aging process. We then describe how these changes emerge as links between cytoskeletal decline and core aging hallmarks, including loss of proteostasis, mitochondrial dysfunction and cellular senescence. We further examine how this actin-related cellular dysregulation contributes to age-associated diseases, including neurodegeneration, cancer and muscle degeneration. Finally, we highlight recent studies suggesting that targeted modulation of actin regulatory pathways might preserve cellular resilience and healthspan, while emphasizing the challenges and opportunities in therapeutically targeting such a fundamental cellular system.