CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism

Summary

Nicotinamide Adenine Dinucleotide (NAD) levels decrease during aging, and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.

Graphical Abstract

CD38/NADase increases during aging, and causes NAD decline and subsequent mitochondrial dysfunction.

ETOC blurb

Why do NAD levels decrease with age? Camacho et al. now reveal that increased expression of the NADase CD38 is responsible for NAD decline and mitochondrial dysfunction in older mice in a SIRT3-dependent manner. CD38 also metabolizes the NAD precursor NMN and modulates the response to NAD-replacement therapy in vivo.