The NAD+ downward spiral
NAD+ biosynthesis, mainly mediated by NAMPT and NAD+ consumption by NAD+ consuming enzymes, are in a delicate balance so that perturbations to either side can cause significant derailment of the system. A vicious cycle may exist in which molecular mechanisms involved in the aging process, such as oxidative stress, DNA damage, senescence, and inflammation, lead to tissue NAD+ decline, which subsequently exacerbates the processes that caused its decline in the first place.
As NAD+ is a common substrate between PARPs and SIRT1, there is a competition between their activities. If NAMPT-mediated NAD+ biosynthesis is disturbed or if NAD+ consumption is increased because of chronic DNA damage that elicits PARP activation, the intracellular NAD+ pool is decreased, and SIRT1 activity is reduced, causing an organism’s functional decline.
For example, PARP is chronically activated in aging worms and mice (liver or skeletal muscle). A possible explanation for these findings is that aging is associated with an increase in chronic nuclear DNA damage, which leads to NAD+ depletion by PARP. Since the loss of SIRT1 or SIRT6 activity exacerbates DNA damage may create an autocatalytic downward spiral in the nucleus with NAD+ deficit as the nexus.
Deleting PARP1 and PARP2 enhances SIRT1 activity, resulting in increased mitochondrial content, metabolism, and protection from diet-induced obesity. In mice lacking PARP1, there was a systemic elevation in NAD+ levels, SIRT1 activity, and metabolic benefits in these mice. Notably, PARP inhibitors boost NAD+ levels and increase SIRT1 activity to restore mitochondrial fitness and function.
Parallel findings were also reported for mice with the elimination of another NAD+-consuming enzyme, CD38, as shown previously. CD38-dependent modulation of NAD+ can alter the activity of SIRT1 and other sirtuins, as well as other NAD+-consuming enzymes, and affect cellular signaling and metabolism. These studies show clearly that PARP, CD38, and the nuclear sirtuins all compete for the same pool of NAD+, and inhibition of PARP or CD38 has the potential of activating sirtuins.
To close the loop, there is some evidence indicating that levels of NAMPT decline during replicative senescence of human smooth muscle cells and in peripheral tissue of old mice, such as white adipose tissue and skeletal muscle. Senescence also activates the expression of CD38 in tissue-resident macrophages, and proinflammatory signaling molecules released from senescent cells increase the activity and the expression level of CD38.