Hypothesis: Persistent NF‑κB/NLRP3 inflammasome signaling in CD8⁺ T cells creates a self‑reinforcing circuit that locks the Cdkn2a (p16^INK4a) promoter into an open, transcriptionally active state via NLRP3‑dependent caspase‑1 cleavage of the histone deacetylase SIRT2. Early in life this circuit curtails excessive clonal expansion after infection, lowering the risk of autoimmunity and thus providing a selective advantage (antagonistic pleiotropy). After reproductive age, the same circuit drives irreversible senescence, exhausting T‑cell function and limiting tumor surveillance, which manifests as the observed increase in mortality and cancer incidence in older individuals.

Mechanistic rationale: NLRP3 activation leads to caspase‑1–mediated SIRT2 cleavage, reducing SIRT2‑dependent deacetylation of H3K9 at the Cdkn2a locus. Loss of SIRT2 activity permits H3K9 acetylation, recruiting BRD4 and RNA polymerase II, thereby stabilizing p16^INK4a transcription independent of DNA damage signals. This epigenetic lock explains why transient antioxidant or NF‑κB inhibitors fail to reverse senescence when administered late in life, whereas early‑life blockade prevents the establishment of the open chromatin state.

Testable predictions: (1) In young mice, conditional NLRP3 deficiency in CD8⁺ T cells will increase the magnitude of primary viral responses without elevating autoantibody titers. (2) Aged mice with the same deficiency will show no reduction in p16^INK4a^+ T‑cell frequency or improvement in tumor clearance compared with controls, indicating irreversibility. (3) Pharmacologic SIRT2 activation in aged T cells will restore H3K9 deacetylation, reduce p16^INK4a expression, and improve proliferative capacity only if administered before the epigenetic lock is established (e.g., prior to 12 months of age).

Falsifiability: If NLRP3 deficiency in young T cells does not enhance early‑life immunity or if aged NLRP3‑deficient T cells regain proliferative function comparable to naïve young cells, the hypothesis that the inflammasome‑SIRT2‑p16^INK4a axis establishes an irreversible, antagonistically pleiotropic senescence program would be refuted. Conversely, confirmation of the predicted age‑dependent outcomes would support the view that aging is a conserved, genetically tractable feature shaped by early-life immune trade-offs rather than a simple accumulation of damage.