Senescent keratinocytes, fibroblasts, and melanocytes that resist clearance accumulate in aged skin and secrete the senescence-associated secretory phenotype (SASP) — a cocktail of pro-inflammatory mediators that degrades extracellular matrix, disrupts pigmentation, impairs barrier function, and drives fibrosis via progressive DNA damage accumulation. Two therapeutic paradigms emerge: senolytics selectively eliminate already-formed senescent cells and can be dosed intermittently (every 2–4 weeks due to senescent cells' inability to divide); senomorphics suppress SASP activity without killing senescent cells and require continuous administration. Crucially, upstream interventions targeting p16, pRB, p53, or p21 — which prevent senescent cell formation — carry cancer and wound-healing risks by disrupting transient, protective senescence.
This review consolidates a rapidly maturing field where skin serves as an unusually tractable translational model: it's accessible, visually scorable, and biopsyable, making it ideal for proof-of-concept senotherapeutic trials before systemic application. The intermittent dosing logic for senolytics is mechanistically sound and clinically significant — it mirrors the dasatinib-plus-quercetin protocols already in human trials for pulmonary fibrosis and aging frailty. The distinction between eliminating persisting senescent cells versus blocking their secretome is underappreciated in dermatology practice. Limitations here are inherent to a review format: direct comparative efficacy data across specific agents in human skin remains sparse. Still, framing skin as a gerotherapeutic platform rather than merely a cosmetic target is a conceptually important shift — one that could accelerate senolytic validation timelines for systemic aging indications.
