Journal of Dermatologic Science and Cosmetic Technology · Sep 2026
Molecular Mechanisms of Cellular Senescence and Targeted Intervention with Natural Bioactive Compounds
By Zhang S, Ma S, Li H et al.
Senescent cells translate molecular damage into tissue dysfunction through the senescence-associated secretory phenotype (SASP), contributing to chronic inflammation and age-related organ decline. This review examines the major mechanisms of cellular senescence, including persistent DNA damage response, epigenetic alterations, autophagy dysfunction, mitochondrial dysfunction, and SASP-associated inflammatory networks. We further discuss two categories of natural bioactive compound-based interventions: senolytics and senomorphics. Senolytic agents such as quercetin, fisetin, and procyanidin C1 selectively eliminate senescent cells by targeting anti-apoptotic mechanisms involving BCL-2 and PI3K/AKT. Senomorphic compounds, including rapamycin, resveratrol, pterostilbene, urolithin A, and spermidine, reduce SASP activity through regulation of NF-κB, mTORC1, p38 MAPK, and cGAS-STING signaling, as well as restoration of mitochondrial and metabolic homeostasis. Despite promising preclinical findings, clinical translation is limited by poor bioavailability, inadequate target specificity, and heterogeneity among senescent cells. Single-cell and multi-omic analyses may improve the identification of senescent subpopulations and guide stratified treatments. Nanodelivery platforms and optimized dosing regimens may further enhance tissue exposure and therapeutic selectivity.