- Cellular senescence is a fundamental biological process that plays a central role in aging and age-related diseases. It refers to a state of permanent cell cycle arrest that occurs in response to various stressors such as telomere shortening, DNA damage, oxidative stress, oncogene activation, and mitochondrial dysfunction.
- While senescence originally evolved as a protective mechanism to prevent the proliferation of damaged or potentially cancerous cells, its chronic accumulation in tissues over time has been strongly implicated in the functional decline associated with aging.
- One of the key ways senescent cells contribute to aging is through the senescence-associated secretory phenotype (SASP). Senescent cells secrete a complex mix of pro-inflammatory cytokines, chemokines, growth factors, and proteolytic enzymes that can disrupt the surrounding tissue environment. This chronic, low-grade inflammation—often referred to as “inflammaging”—can impair tissue repair, promote fibrosis, alter stem cell function, and damage nearby healthy cells, thereby accelerating tissue degeneration and organ dysfunction. SASP factors also promote the spread of senescence to neighboring cells, amplifying the detrimental effects throughout tissues.
- As organisms age, their ability to clear senescent cells via immune surveillance declines. This leads to the accumulation of senescent cells in various tissues, including the skin, lungs, adipose tissue, liver, and even the central nervous system. These cells contribute to the development and progression of numerous age-related pathologies, such as osteoporosis, atherosclerosis, type 2 diabetes, chronic kidney disease, and neurodegenerative disorders like Alzheimer’s disease. Senescent cells have also been detected in areas of tissue damage and degeneration, further linking them to age-associated functional loss.
- At the molecular level, cellular senescence is driven by key regulatory pathways involving the p53/p21^CIP1 and p16^INK4a/Rb axes. These pathways detect stress signals and enforce cell cycle arrest. Senescent cells also undergo profound epigenetic changes, including the formation of senescence-associated heterochromatin foci (SAHF), which help silence genes involved in proliferation. Despite this arrest, senescent cells remain metabolically active and maintain the secretion of SASP components, exerting long-term influence on the tissue microenvironment.
- The link between cellular senescence and organismal aging has been experimentally validated in animal models. In mice, the genetic or pharmacological clearance of senescent cells has been shown to delay the onset of age-related diseases, improve tissue regeneration, and extend healthspan. These findings have led to the development of senolytic therapies—drugs that selectively eliminate senescent cells—as a promising approach to mitigate aging and its associated disorders. Ongoing research is also investigating senomorphic agents, which suppress the harmful SASP without killing the senescent cells, as a complementary strategy.
