The Biological Mechanisms of Frailty: Focusing on Cellular Senescence

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Abstract
Frailty is a multifaceted clinical syndrome characterised by diminished physiological reserve and heightened vulnerability to stressors, predominantly affecting older adults. Increasing evidence implicates cellular senescence (a largely irreversible state of cell-cycle arrest accompanied by the senescence-associated secretory phenotype) as a central mechanistic driver in the pathogenesis of frailty. The aim of this review is to provide an overview of cellular senescence and examine how the accumulation of senescent cells across multiple organ systems disrupts tissue homeostasis, thereby promoting systemic inflammation and functional decline. Within this context, the role of circulating senescence-associated secretory phenotype factors as both drivers and potential biomarkers of frailty is explored. Furthermore, this review discusses the potential of emerging interventions targeting the senescent cell burden (senolytic and senomorphic agents) and non-pharmacological approaches to mitigate frailty-associated functional decline. Finally, the clinical implications of linking cellular senescence to frailty are outlined, and key priorities for future research aimed at improving risk stratification and therapeutic intervention are highlighted.

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