Longevity Science

Cellular Senescence

A permanent cell cycle arrest state in which damaged cells stop dividing but remain metabolically active, secreting inflammatory signals. Accumulation of senescent cells drives tissue aging and age-related disease.

Cellular senescence is a state in which cells permanently exit the cell cycle — they can no longer divide — but remain viable and metabolically active. Senescence is a protective mechanism that prevents damaged cells from proliferating uncontrolled (a cancer-preventing function), but becomes pathological when senescent cells accumulate in tissues without clearance.

Triggers of Senescence

Cells enter senescence in response to:

  • DNA damage: double-strand breaks from oxidative stress, radiation, replication errors
  • Telomere erosion: telomeres (protective chromosome end-caps) shorten with each cell division; critically short telomeres trigger senescence arrest
  • Oncogene activation: paradoxically, activating growth-promoting mutations triggers senescence as a tumor-suppressive response
  • Oxidative stress: reactive oxygen species beyond antioxidant capacity
  • Therapy: chemotherapy and radiation cause widespread therapy-induced senescence

The Senescence-Associated Secretory Phenotype (SASP)

The most problematic feature of senescent cells is the SASP — they secrete a cocktail of pro-inflammatory cytokines (IL-6, IL-8, TNF-α), proteases (MMPs), and growth factors that:

  • Damage surrounding healthy tissue
  • Promote chronic inflammation (inflammaging)
  • Disrupt tissue structure and function
  • Recruit immune cells that may or may not clear the senescent cells
  • Potentially spread senescence to neighboring cells (“bystander effect”)

Accumulation With Age

Young organisms efficiently clear senescent cells through immune surveillance. With aging, this clearance becomes less efficient — senescent cells accumulate in tissues including joints, liver, kidney, lung, and vascular walls. The accumulation correlates with age-related tissue dysfunction.

Senolytics: Clearing Senescent Cells

Senolytics are drugs designed to selectively eliminate senescent cells:

  • Dasatinib + Quercetin (D+Q): the most studied senolytic combination; targets anti-apoptotic pathways that keep senescent cells alive; under investigation in canine and human aging studies
  • Navitoclax (ABT-263): BCL-2/BCL-XL inhibitor; potent senolytic; thrombocytopenia limits clinical use
  • Fisetin: flavonoid with senolytic activity; favorable safety profile; under investigation for canine use

The Dog Aging Project is evaluating senolytics in companion dogs. Early data from the Interventions Testing Program (ITP) in mice shows modest lifespan extension with some senolytic regimens.