Mechanistic insights into stem cell aging: Pathways and processes

Aging progressively alters stem cell function, undermining tissue homeostasis and contributing to age-related diseases. This review synthesises current evidence on the molecular and cellular mechanisms that drive stem cell aging, with emphasis on cellular stress responses, epigenetic regulation, telomere dynamics, metabolic control, and signalling pathway dysregulation. Accumulation of oxidative, genotoxic, and endoplasmic reticulum stress with age disrupts genomic stability and proteostasis, impairing self-renewal and regenerative capacity and, in specific contexts, promoting cellular senescence. Age-associated epigenetic alterations, including DNA methylation drift, histone modification changes, and chromatin remodelling defects, destabilise transcriptional programs required for stem cell quiescence, lineage commitment, and identity maintenance. Telomere shortening, driven by replicative history and oxidative damage, limits proliferation and induces DNA damage signalling. Senescence-associated secretory signalling affects its environments, disrupting stem cell niches and amplifying functional decline. Aging also perturbs nutrient- and energy-sensing pathways such as mTOR and AMPK, leading to impaired autophagy, mitochondrial dysfunction, and metabolic inflexibility. These signalling changes are accompanied by shifts in cellular metabolism and increased oxidative burden. Collectively, these mechanisms impair stem cell maintenance, differentiation capacity, and regenerative output. By integrating these processes, this review provides a framework for identifying regulatory targets relevant to preserving stem cell function in aging tissues.