Chronic inflammation and CD38 overexpression emerge as the dominant molecular drivers of progressive intracellular NAD⁺ depletion during menopause and aging — a mechanistic link that clarifies why postmenopausal women face accelerated metabolic decline. As estrogen falls, CD38 (an NAD⁺-consuming ectoenzyme upregulated by inflammatory cytokines) depletes cellular NAD⁺ reserves, compounding mitochondrial dysfunction, impaired DNA repair via sirtuins and PARP, chronic inflammatory signaling, and immunosenescence. NAD⁺ precursors NMN and NR show biological promise in experimental models but face real translational barriers: pharmacokinetic instability, inconsistent tissue bioavailability, and heterogeneous clinical responses.
The CD38-inflammation axis is an underappreciated finding here and aligns with recent rodent studies showing CD38 inhibitors can partially restore NAD⁺ levels and metabolic function in aged females. What's missing from the current evidence base is exactly what this review concedes: long-term randomized trials specifically in perimenopausal and postmenopausal women, with tissue-specific NAD⁺ readouts rather than proxy biomarkers. The estrogen-NAD⁺ crosstalk also warrants attention — estrogen itself modulates NAMPT, the rate-limiting enzyme in NAD⁺ biosynthesis, meaning hormonal loss creates a compounding biosynthetic deficit.
As a narrative review synthesizing PubMed, Scopus, and Web of Science literature, this carries no novel clinical data. Its value is conceptual scaffolding for researchers and clinicians. For adults considering NMN or NR supplementation, the science is promising but not yet prescriptive — particularly for menopausal women, who represent an underserved and biologically distinct population in NAD⁺ research.
