CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism
Camacho-Pereira J, Tarragó MG, Chini CCS, et al.
Key finding
CD38 upregulation with age is the primary driver of tissue NAD+ decline; CD38 loss preserves NAD+ and mitochondrial function via SIRT3.
Summary
Landmark paper identifying CD38 — an NAD+-consuming ecto-enzyme — as the principal driver of age-related NAD+ decline in mammalian tissues. Using CD38-knockout mice, Camacho-Pereira and colleagues showed that old CD38-/- animals retained youthful NAD+ levels across liver, muscle, and adipose tissue, whereas wild-type tissues exhibited the canonical 50-70% drop by 24 months of age. CD38 protein expression increased with age in multiple tissues, and pharmacological CD38 inhibition (78c and related compounds) was sufficient to rescue tissue NAD+ in aged wild-type mice. The NAD+ restoration in CD38-/- animals reversed mitochondrial dysfunction in a SIRT3-dependent fashion, normalizing oxygen consumption, membrane potential, and metabolic flexibility. This established CD38 as the dominant NADase in aging mammals, reframed the NAD+ decline as an enzymatic consumption problem rather than a biosynthetic deficit, and opened CD38 inhibition as a therapeutic axis distinct from precursor supplementation.
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