NAD+ Deficiency Is a Common Central Pathological Factor of a Number of Diseases and Aging: Mechanisms and Therapeutic Implications

Significance: Increasing evidence has indicated critical roles of nicotinamide adenine dinucleotide, oxidized form (NAD(+)) in various biological functions. NAD(+) deficiency has been found in models of a number of diseases such as cerebral ischemia, myocardial ischemia, and diabetes, and in models of aging. Applications of NAD(+) or other approaches that can restore NAD(+) levels are highly protective in these models of diseases and aging. NAD(+) produces its beneficial effects by targeting at multiple pathological pathways, including attenuating mitochondrial alterations, DNA damage, and oxidative stress, by modulating such enzymes as sirtuins, glyceraldehyde-3-phosphate dehydrogenase, and AP endonuclease. These findings have suggested great therapeutic and nutritional potential of NAD(+) for diseases and senescence. Recent Advances: Approaches that can restore NAD(+) levels are highly protective in the models of such diseases as glaucoma. The NAD(+) deficiency in the diseases and aging results from not only poly(ADP-ribose) polymerase-1 (PARP-1) activation but also decreased nicotinamide phosphoribosyltransferase (Nampt) activity and increased CD38 activity. Significant biological effects of extracellular NAD(+) have been found. Increasing evidence has suggested that NAD(+) deficiency is a common central pathological factor in a number of diseases and aging. Critical Issues and Future Directions: Future studies are required for solidly establishing the concept that "NAD(+) deficiency is a common central pathological factor in a number of disease and aging." It is also necessary to further investigate the mechanisms underlying the NAD(+) deficiency in the diseases and aging. Preclinical and clinical studies should be conducted to determine the therapeutic potential of NAD(+) for the diseases and aging.