Interestingly, it has been shown that tumor necrosis factor-α (TNF-α), one of major inflammatory cytokines, and oxidative stress significantly reduce NAMPT and NAD+ levels in primary hepatocytes 45. TNF-α also suppresses CLOCK/BMAL-mediated clock gene transcription in the liver and SCN of TNF-α-treated mice 51. Since both inflammatory cytokines and oxidative stress contribute to the development of chronic inflammation during aging 52, chronic inflammation could be a reason by which both NAMPT-mediated NAD+ biosynthesis and CLOCK/BMAL-mediated circadian machinery are compromised during aging (Figure 3). If found true, strategies to suppress chronic inflammation and sustain NAD+ biosynthesis and circadian function with aging might be effective in maintaining sirtuin activity and possibly robust health 9.
A second mechanism of NAD+ decline was suggested by analysis of PARP1 knockout mice 53. There was a systemic elevation in NAD+ levels, SIRT1 activity, and metabolic benefits in these mice. Moreover, chemical inhibitors of PARP1 exerted similar effects. Parallel findings were also reported for mice with a knock out in another NAD+-consuming enzyme, CD38, as shown previously 54, 55. 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.
Nevertheless, how does this relate to the decline in NAD+ with aging? A recent study showed that PARP was chronically activated in aging worms and mice (liver or skeletal muscle), leading to an increase in poly-ADP-ribosylation of cellular proteins 18. Moreover, PARP activation closely corresponds to reduced NAD+ levels and increased acetylation of a canonical SIRT1 substrate, PGC-1α. This follows findings that knockout mutations in PARP1 increase NAD+ levels and SIRT1 activity in mice 53. 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 (Figure 4, left). The fact that loss of SIRT1 or SIRT6 activity exacerbates DNA damage 12 may create an autocatalytic downward spiral in the nucleus with NAD+ depletion as the nexus.