More than You Wanted to Know About NAD+ in Metabolism and Aging

Manipulating levels of nicotinamide adenine dinucleotide (NAD+) so as to improve mitochondrial function in older individuals is a popular topic these days, particularly now that numerous groups are selling supplements alleged to raise NAD+ levels usefully. These might be thought of as a form of exercise mimetic drug, in the cases where they actually perform. Even given an intriguing early human trial, this is most likely a road to only minor benefits in the matter of aging. At 90, even the best of former athletes looks like a 90-year old, with a significant degree of dysfunction, and a high chance of failing to live to see 91. The research community can and must achieve better results than this class of intervention, by focusing on repair of underlying damage rather than compensatory adjustment of faltering cellular machinery.

In recent years, interest in nicotinamide adenine dinucleotide (NAD+) biology has significantly increased in many different fields of biomedical research. A number of new studies have revealed the importance of NAD+ biosynthesis for the pathophysiologies of aging and aging-related diseases. NAD+ is an essential component of cellular processes necessary to support various metabolic functions. The classic role of NAD+ is a co-enzyme that catalyzes cellular redox reactions, becoming reduced to NADH, in many fundamental metabolic processes.

There are five major precursors and intermediates to synthesize NAD+: tryptophan, nicotinamide, nicotinic acid, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). In mammals, a major pathway of NAD+ biosynthesis is the salvage pathway from nicotinamide. Nicotinamide is converted to NMN, a key NAD+ intermediate, by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway. NMNATs then convert NMN into NAD+. NAMPT plays a critical role in regulating cellular NAD+ levels.

It is now becoming a consensus that NAD+ levels decline at cellular, tissue/organ, and organismal levels during the course of aging. Activities of NAD+-consuming enzymes are affected by this NAD+ decline, contributing to a broad range of age-associated pathophysiologies. Sirtuins are a family of NAD+-dependent deacetylases/deacylases which have central roles in translating NAD+ changes to the regulation of many regulatory proteins for metabolism, DNA repair, stress response, chromatin remodeling, circadian rhythm, and other cellular processes.

A significant cause for this age-associated NAD+ decline is the decrease in NAMPT-mediated NAD+ biosynthesis. It has been shown that the expression of Nampt at both mRNA and protein levels is reduced over age in a variety of tissues. This age-associated decrease in Nampt expression causes a reduction in NAD+ in those same tissues, affecting the activities of NAD+-dependent enzymes and redox reactions within the cell and leading to functional decline. Therefore, supplementation with NAD+ intermediates, such as NMN and NR, can effectively restore the NAD+ pool and cellular functions in aged animals.


Back to top button