The CDKN2A/B locus drives immune senescence through p16INK4a expression, which in turn fuels inflammaging and tissue decline [2]. We hypothesize that preventing p16INK4a induction specifically in hematopoietic stem and progenitor cells (HSPCs) maintains a youthful immune compartment, thereby breaking the feedback loop where senescent immune cells accelerate organismal aging. If HSPC-intrinsic CDKN2A/B repression preserves lymphoid output and reduces senescent T‑cell accumulation, then systemic markers of aging should improve even without direct senolytic clearance of peripheral tissues.

Mechanistically, Jmjd3‑mediated H3K27 demethylation promotes CDKN2A/B transcription during stress‑induced senescence [5]. Targeting Jmjd3 in HSPCs could therefore lock the locus in a repressed state via compensatory PRC2 activity, limiting p16INK4a induction downstream. This would preserve CD28/CD27 expression on naïve T cells, sustain thymic export, and lower circulating SASP factors such as IL‑6 and TNF‑α [2]. Reduced immune‑derived inflammaging would lessen paracrine senescence induction in non‑hematopoietic tissues, creating a cascade‑like delay in multi‑organ degeneration.

Testable predictions: (1) Conditional knockout of Jmjd3 in mouse HSPCs (Vav‑Cre;Jmjd3^fl/fl) will show decreased p16INK4a mRNA and protein in circulating CD4⁺ and CD8⁺ T cells compared with wild‑type aged controls. (2) These mice will exhibit higher frequencies of recent thymic emigrants (CD4⁺CD8⁻CD62L⁺CCR7⁺) and improved naïve‑to‑memory T‑cell ratios. (3) Serum SASP cytokine levels will be significantly lower at 24 months of age. (4) Histological analysis will reveal reduced p16INK4a‑positive senescent cells in liver, kidney, and adipose tissue despite no direct senolytic treatment. (5) Median lifespan will be extended by at least 15 % relative to littermate controls, with delayed onset of age‑related pathology such as glucose intolerance and aortic stiffness.

Falsifiable outcomes: If Jmjd3 loss in HSPCs fails to reduce p16INK4a in peripheral lymphocytes, or if immune parameters remain unchanged while tissue senescence persists, the hypothesis would be refuted. Conversely, observing immune rejuvenation without a corresponding decrease in peripheral senescent cells would support the notion that immune surveillance is a primary driver, not merely a passive victim, of aging. This positions epigenetic reprogramming of the hematopoietic niche as a proximal lever to modulate the tempo of organismal decline.