Cellular senescence and senescence-associated secretory phenotypes

Cellular senescence refers to a permanent state of cell cycle arrest manifested primarily by the senescence-associated secretory phenotype (SASP), acting as a key driver of organismal aging and age-related diseases. It can be categorized into active senescence (or programmed senescence) and passive senescence that is induced by senescent stressors, including replication, oncogene, tissue damage, quiescence, and many others. SASP is a complex secretory mixture containing proinflammatory cytokines, chemokines, growth factors, extracellular matrix remodelers, damage-associated molecular patterns, and extracellular vesicles. Via autocrine and paracrine signaling, SASP exerts dual functions, that is, acute transient SASP mediates tumor suppression, wound healing, and development, whereas chronic persistent SASP promotes sustained inflammation, fibrosis, and disease progression. SASP is dynamic and regulated by multiple signaling pathways including ATM, p38 MAPK, cGAS-STING, which sense senescence stimuli such as DNA damage and oncogenic activation, and subsequently activate NF-κB and C/EBPβ to drive SASP expression. SASP is highly heterogeneous, varying with senescence types, duration, and cell lineages. Senomorphic therapy targeting SASP mitigates tissue damage without eliminating senescent cells, offering advantages over senolytic approaches. Representative agents include rapamycin, metformin, resveratrol, and spermidine. Clinical translation faces challenges including inaccurate quantitative measurement of aging, SASP heterogeneity, undefined intervention windows, off-target effects, and potential loss of beneficial SASP functions. Future strategies demand selective SASP inhibition to preserve beneficial signaling while suppressing detrimental components, with long-term efficacy validated by physiological functional assessments .