NAD+ (nicotinamide adenine dinucleotide) is a signaling molecule naturally present in every cell of the body and is critical for DNA repair, cellular energy production, and gene expression. (1,2) NAD+ levels naturally decline with age.
Conversely, increasing NAD+ levels may enhance physiological function and extend healthy human lifespan making repletion of this important molecule an essential target for age optimization.
Increasing Cellular NAD+
The most direct way to support NAD+ levels is to supplement the body with nicotinamide mononucleotide (NMN), a direct and stable precursor to NAD+. NMN is derived from vitamin B3, or nicotinamide.
Direct supplementation with NAD+ is ineffective for increasing systemic NAD+ levels due to the molecule’s propensity to break down in the gut. By comparison, NMN has a unique cellular transporter, Slc12a8, that facilitates direct uptake into cells. Once inside the cell, NMN is rapidly transformed into NAD+, repleting the body’s NAD+ pool. (8) Nicotinamide riboside (NR) is another NAD+ precursor popular in the longevity space; however, it must go through an additional metabolic step that converts it into NMN before entering cells.
NAD+ Metabolism Necessitates Methylation Support
Methylation is a biochemical process in which methyl (-CH3) groups are added to molecules within the body, impacting processes such as NAD+ metabolism.
Methylation keeps the NAD+ cycle running smoothly by removing excess NAM, an intermediate in the “Salvage Pathway,” a biochemical pathway that recycles NAD+.
When NAD+ levels increase in the body due to supplementation with NAD+ precursors such as NMN, excess NAM builds up and can inhibit the body’s ability to continue generating NAD+.
Trimethylglycine, riboflavin, and vitamin B12 are nutrients that provide methyl groups to methylate NAM, allowing it to be excreted. Simultaneous supplementation of methylation nutrients alongside NMN may thus optimize NAD+ bioenergetics, allowing you to experience the full potential of NMN supplementation.
The Role of NAD+ in Aging
Research is showing how influential NAD+ can be for longevity as it targets many key age management processes within the body, including:
Cellular energy production
NAD+ is found in the mitochondria of every cell of the body, except red blood cells, which do not harbor mitochondria. Inside the mitochondria, NAD+ carries high-energy electrons in the processes that create cellular energy (ATP), including glycolysis, the tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation. A deficiency of cellular energy is associated with age-related health declines. (3)
NAD+ is a coenzyme for sirtuins, a crucial family of longevity-promoting proteins. SIRT1 pathways are believed to be the primary pathways through which NAD+ exerts longevity benefits.
NAD+ is also a cofactor for CD38, also known as “cyclic ADP ribose hydrolase.” CD38 is a glycoprotein found on the surface of many immune cells, including white blood cells. CD38 is a significant utilizer of NAD+ during the aging process because it is increased by the chronic inflammatory process characteristic of aging, referred to as “inflammaging.” (4,5)
NAD+ is a cofactor for PARPs (poly ADP-ribose polymerase), a family of enzymes involved in DNA repair, the maintenance of genomic integrity, and programmed cell death. High levels of PARP activity to repair cellular damage can deplete NAD+.
Stem cell support
Restoration of healthy tissue levels of NAD+ may improve metabolic function in muscle, brain, and bone stem cells. (6,7) Stem cells are the “baby” cells of the body that allow tissues to regenerate themselves.