Cellular Senescence

What it is

Senescent cells have exited the cell cycle permanently but remain metabolically active and resistant to apoptosis. They secrete a complex mix of cytokines, chemokines, proteases, and growth factors — the senescence-associated secretory phenotype (SASP) — that drives:

• Tissue remodelling.
• Chronic inflammation in neighbouring tissue (paracrine senescence).
• Senescence in nearby cells (the "bystander effect").
• Stromal dysfunction in stem-cell niches.

A small number of senescent cells in a tissue can therefore have an out-sized influence through the SASP.

Why it matters in aging

Senescent-cell burden rises with age across most tissues studied. Foundational evidence:

• Baker et al. 2011 & 2016: genetic clearance of p16^Ink4a- high cells in mice extends median lifespan by ~25% and delays multiple age-related pathologies.
• The SASP is a major driver of chronic, low-grade inflammation (inflammaging).
• Senescent cells accumulate in atherosclerotic plaque, the diabetic pancreas, the aged liver, post-radiation tissue, and many other age-related disease contexts.

Mechanism (text diagram)

        Triggers                  Enforcement              Effects
   ---------------------     ----------------------    ----------------
   Replicative exhaustion      p16Ink4a / Rb axis        Cell cycle exit
   Oncogene activation    →    p53 / p21 axis      →     Apoptosis resistance
   DNA damage                  Persistent DDR             SASP secretion
   Mitochondrial dysf.         cGAS-STING (cytosolic     ↓
   Proteostatic stress          DNA / mtDNA)             Bystander senescence
   ROS                                                    Tissue dysfunction

Mechanisms in more depth

Triggers

• Replicative exhaustion (Hayflick limit / short telomeres).
• Oncogene-induced senescence (RAS, BRAF, MYC) — a tumour suppressor mechanism gone chronic.
• DNA damage (radiation, chemotherapy, oxidative stress).
• Mitochondrial dysfunction (mitochondria-derived ROS, mtDNA leakage).
• Proteostatic stress and protein aggregation.

Enforcement pathways

• p16^Ink4a / Rb axis (the canonical aging senescence).
• p53 / p21 axis (acute stress-induced senescence).
• Persistent DNA damage response (53BP1, γH2AX foci).
• Reduced LMNB1 (nuclear-envelope changes).

SASP regulation

• NF-κB — central transcriptional driver.
• mTOR — SASP synthesis depends on translation; rapamycin blunts SASP.
• cGAS–STING — cytosolic chromatin fragments and leaked mtDNA drive interferon-type SASP.
• JAK-STAT — amplifies inflammatory SASP via IL-6 autocrine signalling.

What’s being studied

Senolytics

Drugs that selectively kill senescent cells:

• Dasatinib + quercetin (D+Q): the prototype, Kirkland lab discovery.
• Fisetin: natural flavonoid with broader cell-type efficacy; better tolerability than D+Q.
• Navitoclax (ABT-263): BCL-xL inhibitor; very potent but haematologically toxic.
• UBX-series compounds (Unity Biotechnology): local-delivery senolytics for AMD and joint disease.
• See senolytics for the full list.

Senomorphics

Drugs that silence the SASP without killing cells:

• Rapamycin — the canonical senomorphic.
• JAK inhibitors (ruxolitinib, tofacitinib).
• Metformin — partial senomorphic effects.
• STING inhibitors — emerging.

See senomorphic (concept).

Human trial landscape

First-in-human senolytic pilots:

• Idiopathic pulmonary fibrosis (Justice 2019, D+Q): improved 6-minute walk in 3 weeks.
• Diabetic kidney disease (Hickson 2019, D+Q): reduced adipose senescent-cell burden.
• Frailty (multiple ongoing trials).
• AMD (Unity UBX1325): improved visual acuity in dry AMD pilot.

No hard-endpoint mortality or major-cardiovascular-event trials yet.

Related entries

Senolytics, Senotherapeutic, Senomorphic, Chronic inflammation, Inflammaging, Telomere attrition, Judith Campisi, James Kirkland, Unity Biotechnology.