Skin as a sentinel and modulator of systemic aging: a translational framework for evidence-based gerotherapeutics

Aging is increasingly recognized as a dynamic and potentially modifiable biological process, yet translation of mechanistic discoveries into clinically validated interventions that extend human healthspan remains limited. Because dermatologists can directly observe, sample, and quantify age-related changes in vivo, the skin provides an accessible platform for gerotherapeutic evaluation. As the largest and most environmentally exposed organ, the skin integrates intrinsic hallmarks of aging, including cellular senescence, mitochondrial dysfunction, extracellular matrix remodeling, epigenetic alterations, and chronic low-grade inflammation, with lifelong environmental stressors. These mechanisms manifest as structural, functional, and molecular phenotypes that can be monitored longitudinally using non-invasive technologies. Beyond serving as a visible indicator of organismal aging, cutaneous dysfunction may also influence systemic aging through inflammatory, immune, vascular, and neuroendocrine signaling. Here we examine how skin-based biomarkers and functional endpoints can support three translational priorities: aligning interventions with heterogeneous aging trajectories, defining functionally meaningful outcome measures, and responsibly integrating emerging diagnostic technologies. Anchoring gerotherapeutic development in dermatologic science may accelerate validation of interventions aimed at preserving resilience, physiological function, and independence across the lifespan.