CD38
CD38 is a membrane glycoprotein with two enzyme jobs: it breaks down NAD+ and it cyclizes ADP-ribose. It shows up on many cells, but most heavily on immune cells. It splits NAD+ into nicotinamide and ADP-ribose, and it can also make cyclic ADP-ribose and NAADP, which are second messengers for calcium signaling. CD38 levels and activity climb with age, especially in tissue-resident macrophages and other innate immune cells. Senescent cells and the molecules they secrete help drive that rise. Because CD38 is one of the biggest NAD+ consumers in many tissues, this age-related increase is a major reason your NAD+ falls with age, dragging down sirtuin activity and mitochondrial function with it. Blocking CD38, genetically or with a drug like the selective inhibitor 78c, restores tissue NAD+ and improves metabolic health in aged mice.
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Sources
- 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 Metabolismdoi:10.1016/j.cmet.2016.05.006
- 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 Metabolismdoi:10.1016/j.cmet.2018.03.016
- Covarrubias AJ, Kale A, Perrone R, et al. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nature Metabolismdoi:10.1038/s42255-020-00305-3