Does cellular senescence increase with age and drive inflammaging?

Age-associated senescence accumulation

• Chronological aging is characterized by a systemic increase in cellular senescence. Biomarkers such as $p16^{INK4a}$ mRNA and lysosomal senescence-associated beta-galactosidase (SA-β-gal) rise exponentially in tissues like blood, skin, brain, and kidneys.

Mechanistic drivers of systemic inflammation

• Senescent cells undergo profound transcriptional and metabolic reprogramming, secreting a complex senescence-associated secretory phenotype (SASP). This secretome contains classic pro-inflammatory cytokines (IL-1, IL-6, IL-8, TNF-α) and bioactive lipids (PGE2, PGD2-derived prostaglandins, and 15d-PGJ2) generated via upregulated COX-2 pathways.
• SASP factors (such as TGF-beta, IL-6, and IL-8) act on neighboring healthy cells, inducing paracrine (secondary) senescence. This positive feedback loop amplifies the local and systemic senescent burden.

Translational and clinical evidence

• In clinical trials of senolytic therapies, such as the Phase II AFFIRM trial using dasatinib plus quercetin (D+Q), the clearance of senescent cells significantly reduced systemic markers of sterile inflammation, demonstrating a ~31% reduction in circulating IL-6, a ~22% reduction in TNF-α, and a ~26% reduction in high-sensitivity CRP (hs-CRP) over 12 months.

Bottom line

• Strong clinical and mechanistic evidence supports the claim: aging drives the accumulation of senescent cells, which secrete a potent mix of pro-inflammatory cytokines and lipid mediators that causally drive chronic low-grade inflammation (inflammaging) through localized and paracrine positive feedback loops.