Purushothaman, K‐Raman

BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert systemic metabolic and anti-inflammatory effects that may be relevant to cellular senescence, a key driver of skin aging. However, human cutaneous data are lacking. OBJECTIVE To explore whether systemic GLP-1RA therapy translates to a detectable reduction in cutaneous senescence, quantified by epidermal p21 expression and supported by AI-driven facial imaging. MATERIALS AND METHODS In this controlled observational pilot study, 3 male adults (GLP-1RA n = 2; GLP-1RA–naïve control n = 1) underwent 3-mm punch biopsies from a standardized, sun-protected gluteal site to isolate intrinsic aging. Senescence was quantified through blinded whole-epidermis digital annotation of p21-positive nuclei. Clinical phenotypes were assessed using noninvasive cheek measurements and AI-based facial age estimation. RESULTS The cohort demonstrated divergence in senescence-associated biomarkers correlating with GLP-1RA exposure. The GLP-1RA–naïve control exhibited 8.0% ( n = 2,062 nuclei) epidermal senescence. By contrast, participants with 163 and 62 days of GLP-1RA exposure showed reduced senescence burdens of 2.4% ( n = 2,045) and 0.6% ( n = 1,636), respectively. Automated facial age estimation remained concordant with chronological age across subjects. CONCLUSION Systemic GLP-1RA exposure is associated with a substantial reduction in epidermal p21 expression in some subjects, suggesting a senomorphic effect and supporting further mechanistic studies at the interface of metabolic regulation and skin aging.

Objective: Diabetes mellitus affects over 25% of adults aged 65+ in the United States and is associated with a heightened risk of developing diabetic foot ulcers. Accumulation of senescent cells within the wound microenvironment can impair cutaneous repair, and senolytic therapies offer a promising approach to accelerate wound healing. Approach: In this study, topical fisetin, a flavonoid that promotes apoptosis of senescent cells, was evaluated for its impact on diabetic wound repair. Full-thickness excisional wounds were created on the dorsal skin of diabetic (db/db) mice. Animals were randomized to receive either topical vehicle ( n = 12) or fisetin ( n = 12) for three consecutive days per week, and wound healing outcomes were longitudinally assessed. Results: Topical fisetin significantly increased the ratio of healthy dermis to granulation by day 7 ( p = 0.04) and reduced dermal fibrosis by day 21 ( p = 0.03). Fisetin decreased p16+ cells ( p = 0.01) but increased p21+ cells ( p = 0.02) at day 7 in the dermis, indicating varied effects on senescent cells. M1 macrophages (CD80+) were decreased in the fisetin-treated group ( p = 0.05) at day 21, accompanied by a decrease in pro-inflammatory senescence-associated secretory phenotype cytokines, tumor necrosis factor alpha ( p = 0.03), and interleukin-1beta ( p = 0.01) at day 7. Innovation: Fisetin is the first topical seno-modulatory agent shown to enhance wound repair when administered after injury onset. Its favorable safety and efficacy in both modulating senescence and inflammation highlight its potential as a novel therapy for diabetic wounds. Conclusion: Topical fisetin enhances diabetic wound healing by reducing fibrosis and promoting healthy dermal regeneration through senescence and inflammation modulation. Saranya Wyles, MD, PhD