Background: NAD+ precursors (NMN, NR) are widely promoted as anti-aging interventions, yet senescent cells upregulate the ectoenzymes CD38 and CD157, which hydrolyze extracellular NAD+ and NMN. This creates a paradox: exogenous NAD+ precursors may be preferentially consumed by senescent cells rather than healthy tissue.

Hypothesis: In tissues with high senescent cell burden (>=15% SA-beta-gal+ cells), NAD+ precursor supplementation paradoxically increases SASP intensity by fueling senescent cell metabolism via CD38/CD157-mediated NMN capture, leading to accelerated epigenetic aging (measured by DunedinPACE and GrimAge2). Co-administration of a CD38 inhibitor (78c or apigenin) redirects NAD+ flux to non-senescent cells, converting the intervention from pro-aging to anti-aging.

Testable predictions:

1. NMN supplementation (500mg/day) in aged mice (18mo) with high senescent burden will INCREASE DunedinPACE equivalent by >=0.05 units vs. vehicle over 8 weeks
2. NMN + 78c (CD38i) will DECREASE DunedinPACE by >=0.08 units vs. NMN alone
3. Conditioned media from NMN-treated senescent fibroblasts will show 2-3x higher IL-6, MCP-1, and MMP3 vs. untreated senescent cells
4. CD38 knockout senescent cells will show no SASP amplification with NMN
5. In RA synovium (high CD38+ senescent burden), NMN monotherapy will accelerate local epigenetic age vs. NMN+apigenin combination

Clinical relevance: This reframes NAD+ supplementation as context-dependent - beneficial only when senescent cell burden is low or when combined with CD38 inhibition. Particularly relevant for rheumatic diseases where CD38+ senescent cells accumulate in inflamed joints.

Methods: Murine aging model (C57BL/6, 18mo) +/- p16-3MR senolytic clearance as positive control. Human RA synovial fibroblast cultures with replicative senescence. Multi-omic readout: NAD+ metabolomics (targeted LC-MS), SASP multiplex (Luminex), methylation arrays (EPIC v2), single-cell RNA-seq for CD38/CD157 expression mapping.