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Metabolism

CD38 as a driver of ageing

Nature Reviews Endocrinology (2025)Cite this article

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The decline of nicotinamide adenine dinucleotide (NAD⁺) levels with age is a fundamental driver of metabolic frailty and mitochondrial deterioration. Although numerous studies had documented this phenomenon, the precise molecular mechanisms remained elusive. In 2016, a landmark study by Camacho-Pereira and colleagues pinpointed the NADase CD38 as the key factor in age-related NAD⁺ depletion, with an important role in mitochondrial dysfunction. By unravelling this mechanism, the work enables a rethinking of both the biology of ageing and the therapeutic landscape of metabolic disease.

The authors demonstrated that CD38 expression and activity rise sharply with advancing age across diverse mouse tissues. This increase was tightly coupled to a progressive fall in NAD⁺ levels. In CD38-deficient mice, NAD⁺ concentrations were preserved into advanced age, and mitochondria retained respiratory capacity, oxygen consumption and membrane potential similar to that seen in young mice. Knockout models not only maintained mitochondrial health but also revealed that overexpression of CD38 precipitates accelerated metabolic decline, underlining its causal role. The preservation of mitochondrial health depended on the continued activity of SIRT3, a mitochondrial deacetylase whose function is contingent on NAD⁺ availability. Without CD38, mitochondrial proteins remained appropriately deacetylated, enabling sustained oxidative metabolism. These results elevate CD38 from an obscure NAD-hydrolysing enzyme to a gatekeeper of metabolic resilience in ageing organisms.

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References

Original article

  • 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)

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  1. Department of Biochemistry and Molecular Cell Biology (IBMZ), Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Subhajit Dutta

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  1. Subhajit Dutta
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Correspondence to Subhajit Dutta.

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Dutta, S. CD38 as a driver of ageing. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01211-y

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