Impaired NAD+ biosynthesis in aging
One reason that NAD+ levels drop with age is that it simply isn’t produced at the same rates from the precursor molecules available. For reasons yet unclear, the levels of NAMPT — the enzyme that generates the majority of NAD+ — diminish with age and, in turn, affect the activities of proteins dependent on NAD+. Exactly how NAMPT levels decline with age appears to depend on several factors.
Alterations to our body’s clock, or what’s known as the circadian rhythm, have been shown to contribute to age-associated NAMPT decline. Aging affects both the pace and strength of the circadian rhythm. A poorly timed or weak circadian rhythm drives the insufficient generation of NAMPT, which in turn will lead to decreases in NAD+ levels.
Another possible mechanism of age-related NAMPT decline is chronic inflammation. The damage caused by internal and environmental stressors that promote chronic inflammation accumulate with aging in different metabolic tissues including fat, skeletal muscle, and liver. In affected tissues, inflammatory signaling molecules called cytokines that can exacerbate cellular damage are released. These cytokines are reported to decrease NAMPT levels.
Inflammatory cytokines and oxidative stress appear to be major contributors to the development of chronic inflammation during aging. Since both inflammatory cytokines and oxidative stress contribute to the development of chronic inflammation during aging, chronic inflammation could be a reason by which both NAMPT-mediated NAD+ biosynthesis and circadian machinery are compromised during aging.