The Hallmarks of Aging: From Molecular Mechanisms to Clinical Translation.

Aging is a gradual process of structural and functional decline, marked by erosion of physiological integrity, adaptive capacity, and resilience, and by a concomitant increase in vulnerability to disease, disability, and death. The hallmarks of aging framework provides a widely used and experimentally tractable taxonomy of molecular and cellular processes associated with aging. In 2023, López-Otín and colleagues expanded the framework from nine to twelve hallmarks by adding disabled macroautophagy, chronic inflammation, and dysbiosis. Here, we evaluate the mechanistic and translational evidence for all twelve hallmarks. We also examine RNA-processing defects and extracellular matrix remodeling as candidate processes without classifying either as an additional hallmark. Experimental studies in model organisms support causal roles for several hallmarks. However, their causal priority, necessity, sufficiency, tissue specificity, and relevance to human aging remain unresolved. Clinical translation is limited by pleiotropy, compensatory responses, heterogeneous trajectories, uncertain biomarkers, and the long period required to detect meaningful outcomes. Future geroscience studies should treat hallmarks as provisional causal modules within interacting physiological networks, select mechanism-linked and function-centered endpoints, and test interventions against prospectively defined claims.