NAD+ is a coenzyme found in all living cells and it has a vital role in energy metabolism. NAD+ levels decrease with age, and the decrease in NAD+ levels across multiple types of tissues is associated with many hallmarks of aging. These hallmarks of aging include loss of proteostasis, cellular senescence, altered epigenetics, and more. NAD+ promotes DNA repair, and its decline is associated with an increase in DNA-damaging reactive oxygen species (REDOX). NAD+ is needed for energy production in every tissue. For example, it's required to produce energy in the brain, in immune cells, and muscle tissue.
In addition to energy metabolism and redox state cell maintenance, NAD+ plays a critical role as the cofactor of NAD+ consuming enzymes such as poly (adenosine diphosphate-ribose) polymerases (PARPs) and sirtuins. These enzymes have a key role in cellular homeostasis and longevity by controlling DNA repair, genomic stability, epigenetic regulation, chromatin remodeling and gene expression. These processes and functions are fundamental to healthy aging.
Preclinical studies have firmly established an age-dependent decline of NAD+ levels, which ranges from 10% to 65%, depending on different organs and age. NAD+ decline has been associated with the development and progression of age-related pathologies such as atherosclerosis, arthritis, hypertension, Alzheimer’s, cognitive and memory decline, and diabetes. Countering this decline by boosting NAD+ production can prolong both health span and lifespan.
Declining NAD+ levels are correlated with the manifestation of many hallmarks of aging.
NAD+ and the hallmarks of aging
To help describe the progressive functional decline and increased vulnerability to diseases that comes with the aging process, aging has been categorized into nine ‘hallmarks’. Declining NAD+ levels are correlated with the manifestation of many hallmarks of aging. Figure from Aman et al18.
Mammalian cells mostly rely on intracellular generation of NAD+ to fuel NAD+ levels. One of the key pharmacological approaches to enhancing NAD+ biosynthesis is via dietary supplementation with a direct NAD+ precursor: NMN. To maintain the pool of cellular NAD+, mammals largely use a biosynthetic route called the ‘salvage pathway’ In this pathway, nicotinamide (NAM), a byproduct generated by the activities of NAD+-consuming enzymes, is converted to NMN by the rate-limiting enzyme NAMPT (nicotinamide phosphoribosyltransferase). NMN can also be generated from another NAD+ precursor, nicotinamide riboside (NR), by NR kinases (NRKs). During the last step of the salvage pathway, NMN is converted to NAD+ by NMN adenylyltransferases (NMNATs).
NAD+ intermediates in the salvage pathway
Mammals largely use a biosynthetic route called the ‘salvage pathway’ to create NAD+. In this pathway, NMN is the final step in NAD+ synthesis. Adapted from Yoshino et al. (2018)15.