CD38 Inhibitors Emerge as a New Class of Anti-Aging Therapeutics
Small-molecule CD38 inhibitors prevent age-related NAD+ decline and extend healthspan in preclinical models, with three candidates entering Phase I human trials
Credit: Mayo Clinic
Abstract
CD38 is a major NAD+-consuming enzyme whose expression rises sharply with age. This review examines the evidence that CD38 drives age-related NAD+ decline and evaluates emerging pharmacological strategies to inhibit CD38 as a therapeutic approach to restore NAD+ homeostasis in aging.
CD38 started its scientific life as a lymphocyte surface antigen. It has since been identified as the primary NADase in mammalian tissues, responsible for breaking NAD+ into nicotinamide and ADP-ribose. Its role in aging turns out to be central.
Camacho-Pereira et al. (2016) made the pivotal finding: CD38 expression climbs with age across multiple tissues. In aged mice, CD38 levels in visceral adipose tissue jump roughly 2.5-fold, coinciding with a 50% drop in tissue NAD+. Their CD38 knockout mice were fully protected from age-related NAD+ decline and kept youthful mitochondrial function.
Senescent cells drive this increase. Covarrubias et al. (2020) showed that senescent cells secrete inflammatory cytokines that push CD38 expression up in neighboring non-senescent cells, especially macrophages and endothelial cells. A feed-forward loop takes hold: senescent cells promote CD38-mediated NAD+ consumption, which causes more cellular dysfunction, which promotes more senescence.
Natural CD38 inhibitors exist. Flavonoids like apigenin, quercetin, and luteolin inhibit CD38 in vitro. Escande et al. (2013) fed apigenin to mice and saw higher tissue NAD+ and protection from high-fat diet metabolic dysfunction. The problem: these natural compounds lack the bioavailability and potency for clinical use.
Pharmaceutical companies have stepped in. Three synthetic CD38 inhibitors entered Phase I clinical trials as of early 2026. These molecules show 100- to 1,000-fold greater potency than natural flavonoids, with optimized oral bioavailability and selectivity.
The combination approach may be the most promising: inhibit CD38 to slow NAD+ consumption while supplementing with precursors to boost NAD+ synthesis. In aged mice, this dual strategy restored tissue NAD+ to youthful levels. Neither approach matched that result on its own.
References
- 1.Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016).
- 2.Covarrubias, A. J. et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat. Metab. 2, 1265–1283 (2020).
- 3.Escande, C. et al. Flavonoid apigenin is an inhibitor of the NAD+ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62, 1084–1093 (2013).
- 4.Chini, C. C. S. et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat. Metab. 2, 1284–1304 (2020).
Article Information
Author Contributions
All authors contributed equally to the conception, analysis, and writing of this article. Correspondence should be addressed to the first author.
Competing interests: The authors declare no competing interests.
