Hypothesis: Boosting NAD+-dependent sirtuin activity in circulating CD8+ memory T cells restores mitochondrial function, reduces SASP production, and thereby mitigates neuroinflammation-driven hippocampal dysfunction in aged mammals.

Mechanistic rationale: Aging CD8+ T cells accumulate damaged mitochondria, leading to elevated ROS and NF-κB activation that drives a pro‑inflammatory SASP (IL‑6, TNF‑α, IL‑1β) [1]. This SASP crosses the blood‑brain barrier or signals via vagal afferents to increase microglial NLRP3 inflammasome activity, promoting Aβ/tau pathology [4]. NAD+ precursors (e.g., NR) activate SIRT3 and SIRT1, improving mitochondrial oxidative phosphorylation and deacetylating NF‑κB p65, which suppresses SASP transcription [5]. Reduced SASP lessens peripheral inflammatory pressure on the brain, allowing microglial homeostasis and preserving hippocampal neurogenesis [2].

Predictions: (1) Old mice treated with NR will show increased NAD+ levels and SIRT3 activity specifically in CD8+ memory T cells compared with vehicle. (2) These mice will exhibit lower plasma IL‑6 and TNF‑α, decreased NF‑κB p65 acetylation in sorted CD8+ T cells, and reduced hippocampal IL‑1β and NLRP3 inflammasome activation. (3) Consequently, they will display restored hippocampal neurogenesis (BrdU+/NeuN+ cells) and improved performance in spatial memory tasks (Morris water maze). (4) Genetic ablation of SIRT3 in CD8+ T cells will abolish the protective effects of NR, confirming cell‑type specificity.

Falsifiability: If NR treatment fails to raise NAD+ or SIRT3 activity in CD8+ T cells, or if SASP cytokines and neuroinflammatory markers remain unchanged despite metabolic rescue, the hypothesis is refuted. Likewise, if SIRT3‑deficient CD8+ T cells still mediate cognitive improvement, the proposed mechanism is incorrect.

Experimental design: Use 20‑month‑old C57BL/6 mice, administer NR (400 mg/kg/day) or control for 8 weeks. Isolate CD8+CD44hi memory T cells by flow cytometry, measure NAD+ enzymatic cycling, SIRT3 western blot, acetyl‑p65 levels, and cytokine secretion ex vivo. Collect plasma for IL‑6, TNF‑α ELISA. Perfuse brains, quantify hippocampal Iba1+, NLRP3, caspase‑1, and BrdU labeling. Conduct behavioral testing. Include a group with CD8‑specific SIRT3 knockout crossed to NR treatment.

Potential impact: Demonstrates that targeting a metabolic node in a single immune subset can break the immune‑brain senescence loop, offering a precision alternative to broad senolytics or anti‑inflammatory drugs.