CD38 Inhibitor 78c Boosts NAD+ and Protects Jaw Bone in Aging Mice

Periodontitis affects roughly 47% of U.S. adults and nearly 70% of those over 65, making age a major risk amplifier. Older individuals show heightened CD38 expression in immune cells, which accelerates NAD+ degradation and impairs the cellular energy, redox balance, and immune signaling needed to control oral infection and limit bone destruction. This study asked whether pharmacologically blocking CD38 with compound 78c could reverse these deficits in a mouse model of chronic periodontitis.

The team used 40 male C57BL/6J mice divided into young (2-month) and old (18-month) cohorts. A modified oral gavage protocol—weekly palatal needle puncture plus thrice-weekly Aggregatibacter actinomycetemcomitans (Aa) inoculation—was used to establish experimental periodontitis, overcoming the usual bacterial resistance of this strain. Mice received vehicle or 78c (10 mg/kg) intraperitoneally twice daily for four weeks. Liver, spleen, and right maxillary tissues were assayed for NAD+, while left maxillary tissues underwent micro-CT and histology (H&E and TRAP staining). A separate short-term cohort of old mice received just three days of treatment to capture early gingival gene expression changes.

78c consistently elevated NAD+ across tissues. In the liver, it produced a 2.0-fold increase in young mice and a 2.5-fold increase in old mice versus vehicle controls. Spleen NAD+ rose significantly in both age groups. Critically, in old mice the right maxilla showed a 3.4-fold increase in NAD+, a result not statistically significant in young mice—suggesting that aged, inflamed jaw tissue is the tissue where CD38-driven NAD+ depletion is most pronounced and most responsive to inhibition.

Micro-CT analysis revealed that 78c significantly reduced alveolar bone loss at the 1st and 2nd molars in young mice and at the 2nd molar in old mice compared with vehicle. Ex vivo osteoclastogenesis assays confirmed a mechanistic link: bone marrow cells from 78c-treated old mice generated 1.8-fold fewer RANKL-induced osteoclasts than those from vehicle controls. Histology showed PMN infiltration in old mouse periodontal epithelium that was not prominent in young mice, and TRAP+ pre-osteoclast counts were significantly reduced by 78c in young mice. The short-term gingival study demonstrated that CD38, IL-1β, and TNF mRNAs were all significantly suppressed within three days of 78c treatment, consistent with prior in vitro evidence that 78c blocks PI3K, NF-κB, and MAPK signaling downstream of TLR activation by oral pathogens.

Old mice lost substantially more body weight (average 15–17%) than young mice (approximately 3–4%) during the study, likely reflecting both the systemic burden of infection and reduced food intake under stress—a finding that itself underscores the vulnerability of aged hosts. Taken together, the data support 78c as a dual-acting agent: it rescues NAD+ to support cellular metabolism and immune competence, while simultaneously dampening osteoclastogenic and pro-inflammatory signaling. The authors position 78c as a promising adjunct therapy for periodontal disease, especially in older adults where both NAD+ depletion and exaggerated inflammation converge.