Older adults with seropositive rheumatoid arthritis often remain clinically controlled yet show persistent inflammaging, low NAD+ tone, and accelerated immune-cell epigenetic aging. I hypothesize that the timing of NAD+ restoration relative to senescent-cell clearance is decisive: intermittent senolytic treatment followed 48 to 72 hours later by NAD+ precursor repletion will reduce monocyte and CD8 T-cell epigenetic age more than senolytic therapy alone, NAD+ precursors alone, or concurrent same-day combination therapy.

Mechanistic rationale: senescent synovial and myeloid cells are enriched for CD38 and other NAD+-consuming programs. If NAD+ precursors are given before or during incomplete senescent-cell clearance, part of the metabolic subsidy may be captured by residual SASP-active CD38-high cells, blunting rejuvenation. A short delay after senolysis should instead shift NAD+ salvage toward non-senescent immune and stromal compartments, improving mitochondrial respiration and lowering inflammatory tone.

Testable predictions:

1. In adults aged 55 years or older with RA in low disease activity or remission, delayed-sequence therapy will reduce GrimAge or DunedinPACE-derived immune-cell age acceleration at 12 weeks more than concurrent combination or either monotherapy.
2. The delayed sequence will produce a larger rise in whole-blood NAD+/NADH ratio and a larger fall in circulating IL-6, TNF-related SASP markers, and soluble CD38.
3. Benefit will be strongest in participants with high baseline p16INK4a expression or high CD38+ monocyte burden.
4. Concurrent dosing will show smaller gains despite similar drug exposure, supporting a sequence-dependent rather than dose-dependent effect.

Minimal study design: four-arm randomized pilot trial comparing senolytic alone, NAD+ precursor alone, concurrent combination, and senolytic followed 48 to 72 hours later by NAD+ precursor repletion; with prespecified methylation, metabolomic, and immunophenotyping endpoints.

Falsification: the hypothesis is weakened if concurrent and delayed combination arms perform equivalently across epigenetic, metabolic, and inflammatory readouts, or if delayed dosing fails to enrich benefit in high-CD38/high-senescence participants.

This is a geroscience hypothesis at the intersection of senolytics, NAD+ metabolism, epigenetic clocks, mitochondrial function, and autoimmune aging.