Nadiia Kryzhanovska, MD, PhD, reviews the literature surrounding NAD+ as a potential therapy to tackle the onset of ageing. The Magic of NAD+: A Major Player in Anti-Ageing.
In 2015, KAEBERLEIN ET AL. described the primary preventive methods against age-associated diseases1. They included dietary restriction, exercise, mechanistic targets for rapamycin (mTOR) inhibitors, metformin and acarbose, NAD precursors and sirtuin activators, modifiers of senescence and telomere dysfunction, hormonal and circulating factors, and mitochondria-targeted therapeutics1. In this article, we will look at NAD precursors and treatments.
Having been discovered by Harden and Young in 19062, nicotinamide adenine dinucleotide (NAD+) brought the Nobel prize to Dr Hans von Euler-Chelpin in 19293. NAD+ was discovered as a ‘cozymase’ necessary for fermentation. Later we got to know it is a cofactor for other enzymes involved in cellular energy metabolism, as well as for the adaptive responses of cells to bioenergetic and oxidative stress, such as glycolysis, fatty acid b-oxidation, and the Krebs cycle. At the same time, the reduced form of NAD+ (NADH) is a primary hydride donor in the production of adenosine triphosphate (ATP) via anaerobic glycolysis and mitochondrial oxidative phosphorylation4.
Nowadays, the importance of NAD+ has expanded to that of a top regulator of numerous cell signalling pathways, playing a major role in ageing and age-related diseases5,6.
The majority of findings from recent studies links compromised NAD+ to ageing-associated traits (hallmarks). First, there may be impaired autophagy and mitophagy in human cells and animal models, resulting in mounting mistakes in lysosome-targeting and recycling mechanisms. Second, this age-associated deterioration results in the accumulation of damaged molecules and mitochondria; therefore, this intracellular and extracellular waste leads to cell dysfunction or death7,8.
AD+ is consumed in many catabolic pathways — in the cytosol, NAD+ is reduced to NADH by lactate dehydrogenase during anaerobic glycolysis9. In mitochondria, the three Krebs cycle enzymes, isocitrate dehydrogenase, a-ketoglutarate dehydrogenase, and malate dehydrogenase, reduce NAD+ to NADH. And NADH serves as the primary means of reducing complex I (NADH dehydrogenase) to fuel oxidative phosphorylation, generating NAD+, and ultimately reducing oxygen to H2O and producing adenosine triphosphate10.