The Science Behind NAD+
What is NAD+?
Nicotinamide Adenine Dinucleotide (NAD+) is a coenzyme found in every living cell, where it plays a central role in energy metabolism, DNA repair, and cellular signaling. NAD+ levels decline naturally with age — by middle age, tissue NAD+ can fall to roughly half of youthful levels. This decline has been linked to reduced mitochondrial function, impaired DNA repair capacity, and several hallmarks of aging. Modern research has focused on restoring NAD+ through direct supplementation and NAD+ precursors such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), which the body converts into NAD+ via the salvage pathway — the source of roughly 85% of the body's NAD+.
NAD+ Activates Sirtuins and Supports Mitochondrial Function
NAD+'s central mechanism runs through the sirtuins, a family of proteins (SIRT1–SIRT7) that regulate energy metabolism, DNA repair, and cellular stress resistance, but require NAD+ as fuel to function. As NAD+ levels rise, sirtuin activity increases, which in turn improves mitochondrial biogenesis and genomic stability. A 2025 mechanistic review described this cascade as central to NAD+-boosting strategies: restoring NAD+ activates sirtuins and DNA repair enzymes, improving mitochondrial function and reducing inflammation. Because NAD+ also fuels PARP enzymes involved in DNA damage repair, adequate levels are considered important for maintaining cellular resilience against everyday oxidative and metabolic stress.
It Supports Healthy Aging and Longevity Pathways
NAD+'s role in sirtuin activation has made it a focal point of longevity research. A comprehensive 2025 review of NAD+-boosting interventions concluded that raising cellular NAD+ — whether through precursors, exercise, or caloric restriction — activates sirtuins and DNA repair enzymes, improves mitochondrial function and genomic stability, reduces inflammation, and restores healthy metabolic signaling, translating into improved tissue function and extended healthspan in animal models. That said, a 2026 review of the sirtuin field was careful to note that while oral NAD+ precursors show measurable biochemical effects in humans, large outcome trials confirming longevity benefits are still lacking — an important distinction between promising mechanism and proven long-term outcome.
It Supports Cardiovascular Health
NAD+ decline is increasingly linked to vascular aging, including arterial stiffness and endothelial dysfunction — early drivers of cardiovascular disease. In a six-week clinical trial in hypertensive patients, supplementation with the NAD+ precursor NMN raised NAD+ levels by 43% and was associated with reduced blood pressure and improved endothelial function. Related human research in pre-hypertensive volunteers similarly found improved endothelial function after eight weeks of NMN supplementation, supporting the idea that restoring NAD+ helps blood vessels dilate more efficiently by reducing oxidative stress and boosting mitochondrial energy in vascular tissue. Researchers note that trials remain relatively small and short-term, and NAD+ support is best viewed as a complement to — not a replacement for — established cardiovascular care.
NAD+ Supports Brain Health and Cognitive Function
The brain is highly energy-demanding, and preclinical research suggests declining NAD+ contributes to age-related cognitive decline. In aged mice, restoring NAD+ with NMN rescued blood flow responses in the brain, improved spatial working memory, and enhanced gait coordination — effects the researchers linked to sirtuin-dependent improvements in mitochondrial function within brain blood vessels. A related 2025 study found that the NAD+ precursor NR restored healthier microglial (brain immune cell) activity in aged mice and improved performance on spatial memory and recognition memory tasks. Human data in this area remain earlier-stage than the animal research, but these findings support continued investigation into NAD+'s role in preserving cognitive function with age.
It Enhances Physical Performance and Muscle Function
NAD+ availability in skeletal muscle declines with age, and restoring it has shown measurable effects on physical performance. In a six-week randomized, double-blind, placebo-controlled trial of 48 recreationally trained runners, NMN supplementation improved ventilatory threshold and oxygen utilization efficiency in skeletal muscle. Separately, a clinical trial in older adults found NMN supplementation more than doubled blood NAD+ levels and improved walking speed and grip strength, while another trial reported a sustained rise in six-minute walking distance alongside increased serum NAD+ levels over 60 days. Findings are more mixed for single bouts of acute exercise, where short-term NR supplementation has not consistently altered whole-body metabolic responses — suggesting NAD+'s benefits for physical performance may build with sustained use rather than appear immediately.
Conclusion
NAD+ is a foundational coenzyme with a well-established mechanistic role in mitochondrial energy production, DNA repair, and sirtuin-driven cellular resilience. Human trials — largely using NAD+ precursors — show encouraging early signals for cardiovascular function, physical performance, and cognitive support, alongside a strong preclinical case for its role in aging biology. While larger and longer human trials are still needed to confirm long-term outcomes, NAD+'s central role in cellular energy metabolism makes it one of the most actively studied targets in the science of aging.
References
Covarrubias, A.J., et al. (2025). Boosting NAD+ for Anti-Aging: Mechanisms, Interventions, and Opportunities. ChemRxiv.
Link: https://doi.org/10.26434/chemrxiv-2025-nl80r
Note: Preprint, not yet peer-reviewed.
Yang, S., et al. (2025). An Updated Review on the Mechanisms, Pre-Clinical and Clinical Comparisons of Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR). Food Frontiers.
Link: https://iadns.onlinelibrary.wiley.com/doi/10.1002/fft2.511
Note: Open-access via Wiley.
Gallagher, D., et al. (2026). Sirtuins: NAD+ Link, Evidence and Limits. Ageing Research Reviews. PMID: 41655607.
Note: PRISMA review; check PubMed for full access.
Zhang, Y., et al. (2025). Framing the NAD+ field: clinical potential and unresolved questions. Nature Aging.
Link: https://doi.org/10.1038/s43587-025-00947-6
Note: May require subscription.
Chini, C.C.S., et al. (2024). Nicotinamide Mononucleotide Supplementation: Understanding Metabolic Variability and Clinical Implications. PMC.
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC11205942/
Note: Open-access.
Vascular aging-targeted intervention based on NAD+ elevation as a novel measure to treat hypertension. (2025). Springer Nature Research Communities.
Link: https://communities.springernature.com/posts/vascular-aging-targeted-intervention-based-on-nad-elevation-as-a-novel-measure-to-treat-hypertension
Note: Summary of a 6-week clinical trial in hypertensive patients.
How NAD+ Boosters Impact Blood Pressure. (2026). Ubie Doctor's Note.
Link: https://ubiehealth.com/doctors-note/nad-boosters-blood-pressure-impact-physician-md-8251q3
Note: Clinician-reviewed summary of endothelial function trials.
Tarantini, S., et al. (2019). Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. GeroScience / Redox Biology.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7741797/
Note: Open-access, PMC.
Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice. (2025). GeroScience.
Link: https://link.springer.com/article/10.1007/s11357-025-01959-1
Note: May require subscription.
Liao, B., et al. (2021). Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. Journal of the International Society of Sports Nutrition.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265078/
Note: Open-access, PMC.
Yi, L., et al. (2022). NMN increases blood NAD+ levels and 6-minute walking distance. GeroScience.
Link: https://www.nad.com/news/nmn-increases-nad-enhances-physical-performance
Note: Summary of a randomized, placebo-controlled trial.
A Current List of Completed NMN Human Trials. (2026). Renue By Science.
Link: https://renuebyscience.com/pages/a-current-list-of-completed-nmn-human-trials
Note: Aggregates multiple published human NMN trials, including Igarashi et al. and the Uthever NMN 60-day trial.
Church, R., et al. (2020). Nicotinamide Riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise. bioRxiv.
Link: https://www.biorxiv.org/content/10.1101/2020.06.23.143446.full.pdf
Note: Preprint; included for balance on short-term/acute exercise findings.