NAD+ degradation as a cause of age-related decline
There are many enzymes that consume NAD+ known to mediate a plethora of fundamental cellular processes. Three major enzymes are the PARPs, CD38, and SARM1.
PARPs are major NAD+ consumers. Among many PARP family members, PARP1 and PARP2 are major NAD+ consumers, responding to DNA strand breaks and facilitating the DNA repair process. During aging, PARP activation, possibly due to constant DNA damage from internal and external stressors like oxidative stress and UV-radiation, respectively, appears to contribute to significant decreases in intracellular NAD+.
CD38 is one of the primary enzymes that consume NAD+ in mammals and can modulate the NAD+ levels. Studies have shown that CD38 protein levels increase in multiple tissues and organs over age, contributing to NAD+ decline. Also, CD38 levels and activity are induced by cytokines and bacterial toxins. So, the chronic inflammation observed during aging could lead to an increase in expression of CD38 and subsequently cause NAD+ decline.
The use of NAD+ by the enzyme SARM1 is central to the degeneration of axons after injury and in the initiation phases of several neurodegenerative diseases. NAD+ depletion mediated by SARM1 leads to the degeneration of damaged neurons, a key event in early stages of age-related neuronal disorders, such as Parkinson’s disease, Alzheimer’s disease, and Amyotrophic Lateral Sclerosis (ALS).