Humankind has forever searched for the proverbial “Fountain of Youth.” How can “The aging process” be slowed down, or prevented entirely? Interventions that can slow mammalian aging have been rare. The two attached major articles and one editorial highlight nicotinamide adenine dinucleotide (NAD+) as a major intervention point to slow, or ameliorate, phenotypes of aging. Niacin, the official name of vitamin B3, is a precursor of NAD+. Niacin deficiency has long been known to cause pellagra. Niacin has even been found in meteorite samples on Earth.
NAD was discovered more than a century ago, and its role in cells as a redox conduit in metabolism was subsequently established. More recently, its oxidized form, NAD+, resurfaced as a key molecule in aging––in organisms ranging from yeast to mammals––by the finding that anti-aging proteins, the sirtuins, are NAD+-dependent deacylases. SIRTUINS play a key role in mitochondrial function. Aging is also associated with loss of sirtuin and mitochondrial function.
The “NAD+-Sirtuin Axis” plays a crucial role in maintaining health and staving off diseases of aging. The amount of cellular NAD+ declines during normal aging, as revealed in mice engineered to over-express SIRT1 in pancreatic β-cells. The novel phenotypes conferred in young mice by this over-expression, such as glucose tolerance and increased insulin secretion, are lost in old mice––but these symptoms can be restored by dietary supplementation with the NAD+ precursor, nicotinamide mononucleotide. Numerous subsequent studies of aging in worms and mice have shown that NAD+ replenishment is associated with better metabolic health and restores mitochondrial function. One possible explanation for NAD+ loss during aging is that “getting old” is associated with accumulation of DNA damage, which triggers chronic activation of poly(ADP-ribose)
polymerases (PARPs) and resulting depletion of the substrate used by PARP, NAD+.
Mitochondrial dysfunction in aging mammals may be due, at least in part, to a disharmony between nuclear and mitochondrial gene expression, and this phenotype can be rescued by NAD+ replenishment. This dysfunction was also demonstrated in premature aging diseases––resulting from genetic defects in DNA repair––and this deficit appears to be due to NAD+ depletion and subsequent SIRT1 inactivation. Metabolic maladies in these mice can also be corrected by supplementation with an NAD+ precursor, nicotinamide riboside. Thus, a model emerges, … in which aging is associated with PARP activation, NAD+ depletion, sirtuin inactivation, mitochondrial dysfunction, and degeneration of cells and tissues. Can this phenomenon be corrected, or forestalled, by supplementation with NAD+ precursors.
Science 17 June 2o16; 352: 1436–1443 and 1474–1477 and pp 1396–1397 [Perspectives]