Cells become senescent constantly throughout life, in response to damage, stress, or reaching the Hayflick limit on replication. A senescent cell ceases to replicate, grows in size, and begins to secrete a potent mix of pro-inflammatory signals. In youth, the immune system efficiently clears senescent cells. Clearance falters in later life, however, and this failure of the immune system to keep up with the pace at which senescent cells are created enables the steady accumulation of senescent cells over time. The inflammatory signaling becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging. A number of research groups and companies are focused on ways to restore the ability of the aged immune system to clear senescent cells, and time will tell as to whether this sort of approach becomes favored versus senolytic small molecule drugs that selectively stress senescent cells to cause programmed cell death.
Aging involves molecular changes that can give rise to different cell fates, one of those being cellular senescence. Senescent cells stably arrest in the cell cycle and play important roles in physiological processes and can act in a tumor-suppressive manner. However, senescent cells accumulate throughout the body with both chronological and biological aging, promoting chronic inflammation and tissue dysfunction. One of the features of senescent cells is their ability to adopt a secretory phenotype, which can act as a chemotactic gradient to attract immune cells. These infiltrating immune cells are capable of recognizing senescent cells and targeting them for destruction, thus maintaining a balance between senescent cell generation and elimination.
Unfortunately, with age, the immune system undergoes changes that alter functional capacity, referred to as immunosenescence. Immunosenescence impacts both innate and adaptive immune cells, impairing their protective functions, like immunosurveillance, or causing them to adopt a hyperinflammatory phenotype, which may further enhance senescent cell burden. These age-related changes in immune function can compromise immunosurveillance, further exacerbating senescent cell burden and its effects. Additionally, senescent cells themselves can modulate markers on their cell surface that make detection by immune cells more difficult and allow them to escape immune clearance. The role of the immune system in limiting senescent cell burden to maintain homeostasis and how immunosurveillance is compromised with age is explored. Furthermore, mechanisms by which senescent cells evade immunosurveillance and potential strategies to restore age-related deficits in immune cell-mediated clearance of senescent cells are also discussed.
Link: https://doi.org/10.3389/fgene.2026.1882818
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