IF aged male C57BL/6J mice (20–22 months) receive a sequential, combinatorial intervention consisting of intraperitoneal clodronate liposomes (200 µL of 5 mg/mL suspension, administered on days 0, 7, and 14 to deplete CD38-high tissue-resident and infiltrating macrophages) followed immediately by oral NMN supplementation (500 mg/kg/day in drinking water, days 7–42),

THEN skeletal muscle and hepatic tissue NAD+ concentrations will increase by ≥40% above NMN-alone controls, mitochondrial membrane potential (ΔΨm) will be restored toward young-mouse reference values, and mitochondrial DNA (mtDNA) heteroplasmy burden (large-scale deletions measured by long-range PCR and droplet digital PCR) will be reduced by ≥20% compared to NMN-alone aged controls within 6 weeks of treatment,

BECAUSE of the following causal chain:

1. During aging, senescent cells secrete SASP factors (IL-6, TNF-α, interferon-β) that paracrinally induce CD38 NADase expression and activity specifically in tissue macrophages and other immune cells — not in the senescent cells themselves — establishing macrophages as the dominant intercellular NAD+ sink (CD38 is induced by SASP factors from senescent cells)[https://doi.org/10.1016/j.bbrc.2019.03.199].

2. This CD38-high macrophage population continuously hydrolyzes extracellular and intracellular NAD+ and its precursors (NMN, NAD itself) via ectoenzyme activity, creating a persistent tissue-level NAD+ deficit that NMN precursor supplementation alone cannot overcome because the precursor is consumed before it reaches parenchymal cells — directly analogous to the observation that rhCD38 protein degrades NMN in cell culture, suppressing NAD+ recovery even with exogenous NMN supplementation (NMN degraded by CD38 in vitro)[https://doi.org/10.1016/j.cmet.2018.03.016].

3. Clodronate liposome administration is selectively taken up by phagocytic macrophages, triggering intracellular clodronate accumulation and apoptosis, thereby physically removing the CD38-high macrophage population from liver, muscle, spleen, and peritoneal compartments — this constitutes REPAIR by removal of damage-amplifying cells, not merely enzyme inhibition. [SPECULATIVE: the selective depletion of the CD38-high inflammatory macrophage subset, rather than all macrophages, requires that CD38 expression marks the pro-inflammatory M1-like subpopulation, which is consistent with the evidence that CD38 is SASP-induced but not yet confirmed to be exclusive to M1 macrophages in aged tissue].

4. Removal of the dominant NAD+ sink lowers the enzymatic hydrolysis rate of NMN in the extracellular and intracellular compartment, allowing orally supplemented NMN to traverse to parenchymal and mitochondria-rich cells (hepatocytes, myofibers) and be converted to NAD+ via NMNAT enzymes — particularly NMNAT3, the mitochondria-localized isoform, which when overexpressed markedly elevates both tissue and mitochondrial NAD+ and ameliorates age-associated insulin resistance (Nmnat3 overexp...

SENS category: LysoSENS

Key references: • doi.org/10.1016/j.bbrc.2019.03.199]. • doi.org/10.1016/j.cmet.2018.03.016]. • doi.org/10.1111/acel.12798]. • doi.org/10.1016/j.cell.2013.11.037]. • doi.org/10.1038/s41467-018-03421-7].