Targeting NAD+ in γδ T cells attenuates inflammaging and extends healthspan by restoring immune surveillance of senescent cells

Hypothesis: Pharmacological elevation of NAD+ specifically within γδ T cells reverses their pro‑inflammatory phenotype, enhances cytotoxic clearance of senescent adipocytes in visceral fat, and thereby lowers systemic inflammaging and improves metabolic health in aged organisms.

Rationale: Aging is accompanied by NAD+ depletion in multiple immune subsets, which shifts cellular metabolism toward glycolysis and suppresses SIRT1‑mediated deacetylation of NF‑κB, fostering a SASP‑driven inflammaging loop【2】(https://doi.org/10.1126/science.aax0860). Recent work shows that γδ T cells accumulate in visceral adipose tissue with age and secrete IL‑17, amplifying local inflammation and insulin resistance【4】(https://doi.org/10.1007/s11357-022-00572-w). We propose that NAD+ loss in these cells impairs their mitochondrial oxidative phosphorylation, reduces perforin/granzyme B expression, and skews them toward an IL‑17‑producing state that fails to eliminate senescent adipocytes. Restoring NAD+ should revive SIRT1 activity, improve mitochondrial fitness, and re‑establish cytotoxic function, allowing γδ T cells to surveil and kill senescent neighbors before their SASP propagates.

Testable predictions:

1. Aged mice treated with a γδ‑T‑cell‑targeted NAD+ precursor (e.g., a nanoparticle‑conjugated NMN) will show increased NAD+ levels, higher SIRT1 activity, and enhanced oxidative phosphorylation in sorted TCRγδ+ cells compared with vehicle controls.
2. These mice will exhibit reduced frequencies of IL‑17+ γδ T cells in visceral fat and increased perforin+ granzyme B+ γδ T cells correlating with decreased p16^Ink4a^‑positive senescent adipocytes (immunofluorescence and flow cytometry).
3. Systemic inflammaging markers (serum IL‑6, TNF‑α, CRP) will be lowered, and macrophage polarization will shift toward an anti‑inflammatory (M2) phenotype.
4. Metabolic readouts—fasting glucose, insulin tolerance test, and glucose‑induced ΔRQ from indirect calorimetry—will improve, reflecting enhanced metabolic flexibility.
5. Lifespan and healthspan endpoints (frailty index, grip strength, motor coordination) will be extended relative to controls.

Falsifiability: If NAD+ augmentation in γδ T cells fails to raise NAD+ or SIRT1 activity, does not alter their cytokine profile or cytotoxic granule expression, and does not reduce senescent adipocyte burden or systemic inflammaging, then the hypothesis is refuted. Conversely, a positive outcome would support the idea that immune‑intrinsic metabolic rejuvenation can uncouple inflammaging from chronological aging and precede broader systemic benefits.

This mechanistic link connects immunometabolism, senescence surveillance, and metabolic flexibility, offering a precise intervention point that extends beyond senolytic strategies by enhancing the immune system’s own capacity to maintain tissue homeostasis.