Nicotinamide adenine dinucleotide, or NAD, is a coenzyme present in all living cells. NAD exists in two forms: the oxidized form, NAD+, and the reduced form, NADH. This molecule is central to sustaining cellular health and function. Without sufficient levels, the fundamental processes that keep cells alive would quickly slow down.
NAD’s Essential Function in Cellular Metabolism
The primary function of NAD in the cell is to act as a shuttle for electrons in numerous metabolic reactions. In its oxidized form, NAD+, the molecule accepts high-energy electrons released during the breakdown of nutrients like glucose and fatty acids. When it accepts these electrons, it becomes the reduced form, NADH. This process is critical for the cellular energy production that occurs mostly within the mitochondria. NADH then delivers its cargo of electrons to the electron transport chain, which ultimately generates adenosine triphosphate (ATP), the main energy currency of the cell. This constant cycling between NAD+ and NADH drives the Krebs cycle and oxidative phosphorylation.
If NAD levels decline, this metabolic machinery becomes less efficient because the cell runs out of electron acceptors. The entire process of converting food into usable energy slows down, which can impair function across various tissues and organs. Maintaining a proper balance of the NAD+/NADH ratio is connected to cellular viability and the overall health of the organism.
Mechanisms Driving the Age-Related Decline
The decline of NAD with age is not primarily due to a failure to synthesize the molecule, but rather an increase in the number of enzymes that consume it. Two major enzyme families contribute to this age-related depletion: Poly-ADP-ribose polymerases (PARPs) and CD38.
PARPs are DNA repair enzymes that become highly active in response to the DNA damage that accumulates over a lifetime. When a cell detects a break in its DNA, PARP enzymes use NAD+ as a substrate to facilitate the repair process. This acute consumption of NAD+ can dramatically deplete cellular stores, trading the cell’s energy resource for genomic stability.
The second major consumer, CD38, is an enzyme whose expression and activity increase significantly with age, particularly in inflammatory cells. CD38 acts as an NADase, cleaving NAD+ and its precursors to form other signaling molecules, effectively removing the coenzyme from the cellular pool. Inflammation, which increases with age, is a key driver for the heightened activity of CD38, establishing a link between chronic inflammation and NAD+ depletion.
Nutritional and Lifestyle Approaches to Support Levels
Because NAD+ is consumed rapidly and its levels decline with age, supporting its availability is often achieved through precursor molecules. These compounds are readily converted into NAD+ via the salvage pathway, the primary recycling system in mammalian cells. Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) are two studied precursors, both forms of vitamin B3.
When NR is taken, it is converted into NMN, the immediate precursor to NAD+. NMN then enters the cell and is converted directly to NAD+ by the enzyme NMNAT. Both NR and NMN bypass a rate-limiting step in the NAD+ synthesis pathway, making them effective at boosting intracellular NAD+ concentrations.
Beyond supplementation, specific lifestyle interventions can stimulate NAD+ synthesis and conservation.
Exercise
Exercise, particularly intense physical activity, increases the expression of the enzyme NAMPT, which is the rate-limiting step in the salvage pathway. This increased NAMPT activity helps the cell recycle more of the nicotinamide byproduct back into NAD+.
Caloric Restriction
Caloric restriction, such as intermittent fasting or time-restricted feeding, also positively influences NAD+ levels. When cells sense low energy availability, it activates a cellular sensor called AMPK, which promotes NAMPT expression. This metabolic stress response promotes cellular resilience and increases the availability of NAD+. Foods rich in B3 vitamins, such as fish, poultry, and certain vegetables, provide the raw materials that fuel these synthesis pathways.
The Role of NAD in DNA Repair and Sirtuin Activity
The importance of NAD+ extends beyond energy production to include the regulation of cellular longevity and stability. NAD+ serves as the fuel for a family of regulatory enzymes called Sirtuins (SIRT1-SIRT7). These enzymes help regulate metabolism, maintain genomic stability, and manage cellular stress.
Sirtuins function as deacetylases, meaning they remove acetyl groups from various proteins, including histones that package DNA. This activity requires the consumption of NAD+, and the resulting deacetylation can silence genes or facilitate DNA repair. When NAD+ levels decline with age, the activity of Sirtuins is directly impaired, weakening the cell’s ability to maintain its DNA and respond to stress.
Sirtuin 1 (SIRT1) requires NAD+ to regulate key transcription factors and enhance mitochondrial efficiency. The availability of NAD+ directly links the cell’s metabolic state to its ability to perform these protective functions, highlighting why restoring NAD+ levels is a major focus in aging research.