Category: cell_death
Cellular senescence is a stable cell-cycle arrest triggered by genotoxic stress (replicative telomere erosion, oxidative damage, oncogene activation — OIS) — initially tumor-suppressive but accumulates with age and drives "inflammaging" + age-related disease via the senescence-associated secretory phenotype (SASP). Two main routes: (1) p16^INK4a^/Rb axis — irreversible cell-cycle arrest in G1; (2) p21^CIP1^/p53 axis — initial arrest, more reversible. Hallmarks: SA-β-galactosidase activity, enlarged flattened morphology, SAHF (senescence-associated heterochromatin foci), LADs (lamin-associated domains) reorganization, lysosomal expansion. SASP: senescent cells secrete a pro-inflammatory cocktail — IL-6, IL-8, MCP-1, MMPs, GROα, TIMPs, GDF15 — driven by NF-κB + C/EBPβ + cGAS-STING (cross-link). SASP paracrine: spreads senescence to neighbors; recruits immune clearance (when functional); promotes tumor microenvironment + fibrosis when persistent. Tissue burden of p16-positive cells ↑ with age; targeted clearance in mice extends healthspan + reverses age-related dysfunction (Baker 2016 — INK-ATTAC). Senolytics: drugs that selectively kill senescent cells (which depend on anti-apoptotic SCAPs — BCL-2, BCL-xL, PI3K-AKT). Established: dasatinib + quercetin (D+Q — Kirkland canonical combo; first-in-human trials in idiopathic pulmonary fibrosis, diabetic kidney disease); fisetin (mono-senolytic, gentler); navitoclax + venetoclax (BCL-2/BCL-xL inhibitors — too toxic systemically, focal use); rapamycin/mTOR inhibitors (gerosuppression but not senolytic per se); metformin (gerosuppressive, ↓SASP); resveratrol/curcumin (modest SASP suppression). Cross-links: [[cell_cycle_cdk]] (p16/p21 arrest), [[nfkb_signaling]] (SASP transcription), [[cgas_sting_type1_ifn]] (DNA-damage trigger), [[mtor_signaling]] (gerosuppression), [[autophagy_lc3_axis]] (lysosomal-senescence).