- Senescence is a state of stable and generally irreversible cell cycle arrest that occurs when cells experience certain types of stress or damage. While senescent cells no longer divide, they remain metabolically active and undergo profound changes in gene expression, morphology, and function. Originally identified as a process limiting the proliferative lifespan of normal somatic cells, senescence is now understood to play complex and dual roles in physiology, disease, aging, and cancer.
- Senescence can be triggered by a variety of intrinsic and extrinsic factors, including telomere shortening (replicative senescence), oxidative stress, DNA damage, oncogene activation, mitochondrial dysfunction, and exposure to chemotherapeutic agents (stress-induced senescence). Regardless of the trigger, senescence is maintained through the activation of key tumor suppressor pathways, primarily the p53/p21 and p16^INK4a/Rb pathways. These molecular signals enforce cell cycle exit, typically at the G1 phase, and prevent the replication of damaged or unstable genomes.
- A hallmark of senescent cells is their distinctive phenotypic and functional changes. These include an enlarged, flattened morphology, increased lysosomal content (often measured via senescence-associated beta-galactosidase activity), chromatin remodeling (such as the formation of senescence-associated heterochromatin foci, or SAHF), and most notably, the development of a senescence-associated secretory phenotype (SASP). The SASP comprises a cocktail of pro-inflammatory cytokines, chemokines, growth factors, and proteolytic enzymes that influence the surrounding tissue environment. While the SASP can promote tissue remodeling and immune cell recruitment to clear senescent cells, its chronic presence can contribute to inflammation, tissue degeneration, and cancer progression.
- Senescence serves protective roles, especially as a tumor suppressive mechanism. By halting the proliferation of damaged or pre-malignant cells, it prevents oncogenic transformation. In developmental biology, transient senescence plays roles in embryogenesis and tissue patterning. Senescent cells also contribute to wound healing by promoting tissue regeneration through paracrine signaling. However, when senescent cells accumulate in tissues—particularly in aging or in conditions with impaired immune clearance—they can have deleterious effects, fostering chronic inflammation (inflammaging), fibrosis, and age-related pathologies.
- Senescence has gained attention in the context of aging and regenerative medicine, especially due to its link with tissue dysfunction and disease. The buildup of senescent cells with age is believed to drive many aspects of physiological aging. As a result, the field of senotherapeutics is emerging, with efforts to develop senolytic drugs (which selectively eliminate senescent cells) or senostatic agents (which suppress the harmful SASP without killing the cells). Animal studies have shown that clearing senescent cells can extend healthspan and delay the onset of age-related diseases, making this a promising avenue for future therapies.
