Hypothesis

Aging is driven by opposite acetyl-CoA dysregulation in myeloid and lymphoid compartments: excess nuclear acetyl-CoA in myeloid cells fuels inflammaging via ACLY‑dependent histone acetylation, while deficient nuclear acetyl-CoA in T cells limits their effector function through ACLY/ACSS2 shortage. We hypothesize that simultaneous, cell‑type‑specific correction of this metabolic‑epigenetic imbalance will break the feed‑forward loop that links immune dysfunction to systemic aging.

Mechanistic rationale

1. Myeloid‑restricted ACLY inhibition lowers nuclear acetyl-CoA, reducing H3K27ac at NF‑κB target promoters and curbing IL‑1β, IL‑6 production[1]
2. Lymphoid‑targeted ACSS2 overexpression restores nuclear acetyl-CoA from acetate, rescuing H3K9/14ac at histone gene loci and improving T‑cell proliferation[2]
3. Restored T‑cell surveillance enhances clearance of senescent myeloid cells, lowering the source of inflammaging[3]
4. Reduced inflammaging lessens tissue‑derived damage‑associated molecular patterns, decreasing further myeloid activation—a negative feedback loop.

Experimental design (testable & falsifiable)

• Model: Aged (≥20 mo) C57BL/6 mice.
• Interventions (factorial design):
  • Myeloid‑specific ACLY shRNA via LysM‑Cre.
  • T‑cell‑specific ACSS2 overexpression via CD4‑Cre.
  • Combination of both.
  • Controls: scrambled shRNA or empty vector.
• Readouts (4 wks post‑treatment):
  • Serum cytokines (IL‑6, TNF‑α, IL‑1β) by ELISA.
  • Flow cytometry for senescent myeloid (CD11b⁺Ly6C⁺PD‑L1⁺) and naïve/memory T‑cell subsets.
  • Histone acetylation ChIP‑qPCR for H3K27ac at Il6 promoter (myeloid) and H3K9ac at Hist1h1b locus (T cells).
  • Frailty index and grip strength.
  • Lifespan cohort (n=30 per group) to assess healthspan extension.

Predictions

If the hypothesis is correct, the combination group will show:

• ≥30 % reduction in serum IL‑6/TNF‑α vs single‑target or controls.
• Restoration of T‑cell histone acetylation to youthful levels.
• Decrease in senescent myeloid frequency.
• Improved frailty scores and extended median lifespan. Conversely, if acetyl‑CoA redistribution does not affect aging phenotypes, no significant differences will emerge, falsifying the claim that immune acetyl‑CoA homeostasis drives systemic aging.

Falsifiability

A null outcome—no change in inflammaging markers, T‑cell function, or longevity despite verified myeloid ACLY knock‑down and T‑cell ACSS2 over‑expression—would refute the proposed causal link. Additionally, rescuing myeloid acetyl‑CoA by acetate supplementation in the ACLY‑knockdown mice should reinstate inflammaging, confirming specificity.