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Cell biology

CD38

CD38 is a transmembrane glycoprotein with NAD+ glycohydrolase and ADP-ribosyl cyclase activity, expressed broadly but most abundantly on immune cells. It hydrolyses NAD+ to nicotinamide and ADP-ribose and can also generate cyclic ADP-ribose and NAADP, second messengers for calcium signalling. CD38 expression and activity rise with age, particularly in tissue-resident macrophages and other innate immune cells, where senescent cells and their secretome help drive its induction. Because CD38 is a dominant NAD+-consuming enzyme in many tissues, this age-related upregulation is a major mechanism behind systemic NAD+ decline and the associated drop in sirtuin activity and mitochondrial function. Genetic or pharmacological inhibition of CD38, for example with the selective inhibitor 78c, restores tissue NAD+ levels and improves metabolic phenotypes in aged mice.

Sources

  1. Camacho-Pereira J, Tarrago MG, Chini CCS, et al.. (2016). CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. *Cell Metabolism*doi:10.1016/j.cmet.2016.05.006
  2. Tarrago MG, Chini CCS, Kanamori KS, et al.. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. *Cell Metabolism*doi:10.1016/j.cmet.2018.03.016
  3. Covarrubias AJ, Kale A, Perrone R, et al.. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. *Nature Metabolism*doi:10.1038/s42255-020-00305-3