NAD+: Benefits & Research

NAD+ repletion is one of the most researched interventions in longevity science. Age-related NAD+ decline triggers a cascade of cellular dysfunction: reduced sirtuin activity, impaired DNA repair, mitochondrial deterioration, and epigenetic drift. Restoring NAD+ levels has been shown to reverse several of these hallmarks of aging in animal models.

Key findings include extended lifespan in model organisms, restoration of youthful muscle stem cell function in aged mice, improved vascular density, and reversal of age-related mitochondrial dysfunction. Human studies with NAD+ precursors have demonstrated increases in blood NAD+ levels and improvements in markers associated with biological age.

NAD+ is essential for the citric acid cycle and oxidative phosphorylation — the pathways that produce the majority of cellular ATP. Declining NAD+ impairs electron transport chain function, reducing ATP output and increasing reactive oxygen species (ROS) production. This creates a vicious cycle: mitochondrial dysfunction generates more ROS, which damages mitochondrial DNA and further impairs function.

NAD+ supplementation breaks this cycle by restoring electron transport function, improving ATP production, and reducing ROS generation. For another mitochondria-targeted approach, see SS-31, which directly stabilizes the inner mitochondrial membrane. The metabolic peptide MOTS-c also supports mitochondrial function through a different mechanism.

PARP enzymes consume NAD+ to repair damaged DNA. With aging, accumulated DNA damage increases PARP activation, which depletes NAD+ pools. This creates a competition between DNA repair (PARP) and cellular maintenance (sirtuins) for a shrinking NAD+ supply. Supplementation helps resolve this competition by providing sufficient NAD+ for both pathways simultaneously.

Research in DNA repair-deficient animal models has shown that NAD+ supplementation can improve genomic stability, reduce accumulation of DNA damage markers (γ-H2AX foci), and partially rescue DNA repair capacity.

The brain has particularly high energy demands and is vulnerable to NAD+ depletion. Research has demonstrated neuroprotective effects of NAD+ supplementation in models of Alzheimer's disease, Parkinson's disease, and traumatic brain injury. Mechanisms include SIRT1-mediated reduction of tau phosphorylation, improved mitochondrial function in neurons, and enhanced clearance of damaged mitochondria (mitophagy).

For other peptides researched in cognitive applications, see semax and dihexa.

NAD+ influences insulin sensitivity, glucose metabolism, and lipid handling through SIRT1 and SIRT3. Animal studies have shown that NAD+ repletion improves glucose tolerance, reduces hepatic steatosis (fatty liver), and enhances mitochondrial fatty acid oxidation. These metabolic effects are relevant to age-related metabolic syndrome and type 2 diabetes research.