Cellular senescence pathways

Cellular senescence pathways represent a complex network of biological processes that lead to stable, irreversible cell cycle arrest in response to various stressors such as DNA damage, telomere shortening, and oncogenic activation. These pathways are primarily governed by the p53/p21 and p16/pRB tumor suppressor axes, which prevent the proliferation of damaged or potentially cancerous cells. While senescence serves as a crucial defense mechanism and plays roles in development and wound healing, the chronic accumulation of senescent cells and their pro-inflammatory Senescence-Associated Secretory Phenotype (SASP) drive aging and numerous age-related pathologies. Therapeutic strategies, collectively known as senotherapeutics, aim to either selectively eliminate these cells (senolytics) or modulate their harmful secretions (senomorphics). Drugs like dasatinib, quercetin, and navitoclax target specific survival nodes within these pathways to alleviate the burden of senescent cells and improve healthspan.

Senolytics selectively eliminate senescent cells by inhibiting senescent cell anti-apoptotic pathways (SCAPs), such as the BCL-2/BCL-XL family, PI3K/AKT, and p53/p21/serpine nodes. Senomorphics modulate the senescence-associated secretory phenotype (SASP) by inhibiting upstream regulators like mTOR or NF-κB, thereby reducing chronic inflammation without necessarily killing the cells.