Cellular Senescence & SASP

Senescent cells accumulate with age, secreting inflammatory factors (SASP) that drive tissue dysfunction, chronic disease, and aging. Senolytic therapies selectively clear these cells.

Overview

Cellular senescence is a permanent cell cycle arrest triggered by telomere shortening, DNA damage, oncogene activation, or oxidative stress. Senescent cells resist apoptosis through upregulation of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, BCL-W). They secrete the Senescence-Associated Secretory Phenotype (SASP) — a cocktail of pro-inflammatory cytokines (IL-6, IL-8, IL-1β), chemokines, matrix metalloproteinases, and growth factors that corrupt neighboring cells and tissue architecture.

Key Steps

1. Trigger: DNA damage, telomere erosion, oncogene activation (RAS), or oxidative stress
2. p53/p21 and p16INK4a/Rb pathways enforce irreversible cell cycle arrest
3. BCL-2/BCL-XL upregulation makes senescent cells resistant to apoptosis
4. SASP activation: NF-κB and C/EBPβ drive secretion of IL-6, IL-8, MMP-3, VEGF
5. Paracrine senescence: SASP induces senescence in neighboring cells (bystander effect)
6. Immune evasion: senescent cells develop mechanisms to avoid NK cell and macrophage clearance

Disease Relevance

• Aging: Senescent cell accumulation is a hallmark of aging. Genetic clearance of p16+ senescent cells in mice extends healthspan by 25-35%. Multiple clinical trials of senolytics are underway.
• Cancer: Senescence is a tumor-suppressive mechanism (prevents damaged cell proliferation), but SASP can promote tumor growth in neighboring cells — dual role.
• Alzheimer's: Senescent astrocytes and microglia accumulate in AD brains. Senolytic treatment (D+Q) improves cognitive function in AD mouse models.

Therapeutic Targets

• Fisetin: Senolytic activity: inhibits BCL-2/BCL-XL survival pathways in senescent cells
• Quercetin: Component of D+Q senolytic cocktail; inhibits PI3K/Akt survival signaling
• Spermidine: Reduces senescent cell burden via autophagy-mediated clearance
• Rapamycin: Suppresses SASP secretion via mTOR-mediated translational control of IL-6/IL-8