NAD+ and Sirtuins in Aging and Disease: A Comprehensive Review
A landmark 2014 review published in Trends in Cell Biology comprehensively examined the interrelationship between NAD+ metabolism and sirtuin activity in the context of aging and disease. The authors reviewed the biochemical basis of NAD+-dependent sirtuin function and compiled evidence from multiple preclinical model systems demonstrating the consequences of age-related NAD+ decline on sirtuin-mediated cellular processes.
The review documented that NAD+ serves as an obligate substrate for all seven mammalian sirtuins, which regulate diverse cellular processes including DNA repair (SIRT1, SIRT6), mitochondrial function (SIRT3), inflammatory signaling (SIRT1, SIRT6), and metabolic homeostasis (SIRT1, SIRT3). In aged mouse models, declining NAD+ levels were associated with reduced sirtuin activity and corresponding impairments in these cellular processes. The authors proposed that the combination of sirtuin activation and NAD+ supplementation may represent an effective research strategy for investigating age-associated cellular changes.
Citation: Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends in Cell Biology. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002. PubMed PMID: 24786309
NAD+ Biosynthesis, Aging, and Disease: Therapeutic Implications
A 2018 review published in F1000Research examined the growing body of evidence linking NAD+ biosynthesis to aging and disease pathogenesis. The authors evaluated preclinical studies investigating the effects of NAD+ augmentation through various biosynthetic precursors and direct supplementation approaches in animal models of metabolic dysfunction, neurodegeneration, and cardiovascular disease.
The review highlighted that NAD+ supplementation or boosting through precursor molecules (NMN, NR) reversed age-associated phenotypes in multiple mouse models, including improvements in mitochondrial function, restoration of stem cell renewal potential, and enhanced DNA repair capacity. In models of neurodegenerative disease, NAD+ augmentation was associated with neuroprotective effects in Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis paradigms. The authors emphasized that these findings implicate NAD+ biosynthesis as a significant research target but noted that the specific mechanisms by which NAD+ augmentation produces these effects require further investigation.
Citation: Yoshino J, Baur JA, Imai SI. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metabolism. 2018;27(3):513-528. doi:10.1016/j.cmet.2017.11.002. PubMed PMID: 29249689
NAD+ in Aging Biology: Applications and Unknowns
A comprehensive 2023 review published in Endocrine Reviews evaluated the current state of NAD+ research in aging biology. The authors systematically assessed the preclinical evidence for NAD+ supplementation across multiple organ systems and disease models, identifying both established findings and critical knowledge gaps in the field.
The review documented that in normally aged mice, NAD+ augmentation through NMN or NR supplementation was associated with reductions in cataracts, improvements in neurovascular coupling, and enhanced neural stem cell renewal potential. NAD+ boosting also exerted neuroprotective effects in preclinical models of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Cockayne syndrome. However, the authors emphasized important unknowns, including the precise mechanisms linking NAD+ levels to age-associated phenotypes, the relative contributions of different NAD+-consuming enzymes to observed benefits, and the potential for off-target effects of systemic NAD+ augmentation.
Citation: Zapata-Pérez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns. Endocrine Reviews. 2023;44(6):1047-1073. doi:10.1210/endrev/bnad019. PubMed PMID: 37364580
NAD+ Metabolism in Cardiovascular Research
A 2021 review in Circulation examined the role of NAD+ metabolism in cardiac health, aging, and disease. The authors compiled preclinical evidence from multiple cardiovascular disease models in which NAD+ augmentation strategies were evaluated, including models of heart failure, ischemia-reperfusion injury, and cardiomyopathy.
The review identified direct preclinical evidence for the effects of increased NAD+ biosynthesis in multiple cardiovascular disorder models. In ischemia-reperfusion injury models, NAD+ augmentation was associated with reduced infarct size and improved cardiac function. In heart failure models, NAD+ supplementation was associated with improved mitochondrial function, reduced oxidative stress, and enhanced contractile performance. The authors noted that the cardiac-specific sirtuin SIRT3, which regulates mitochondrial protein acetylation in cardiomyocytes, appears to be a critical downstream mediator of NAD+’s cardiovascular effects.
Citation: Abdellatif M, Sedej S, Kroemer G. NAD+ Metabolism in Cardiac Health, Aging, and Disease. Circulation. 2021;144(22):1795-1817. doi:10.1161/CIRCULATIONAHA.121.056589. PubMed PMID: 34843394
Sirtuins and NAD+ in Metabolic and Cardiovascular Disease Models
A 2018 review published in Circulation Research specifically examined the roles of sirtuins and NAD+ in the development and investigation of metabolic and cardiovascular diseases. The review compiled preclinical animal studies investigating both sirtuin-activating compounds (STACs) and NAD+ boosters across multiple disease models, providing a comprehensive summary of the therapeutic potential of targeting the NAD+-sirtuin axis.
The review catalogued preclinical evidence showing that NAD+ augmentation improved outcomes in animal models of obesity-related cardiomyopathy, atherosclerosis, myocardial ischemia-reperfusion injury, and heart failure. The mechanisms identified included improved mitochondrial bioenergetics through SIRT3-mediated deacetylation, enhanced vascular endothelial function through SIRT1-dependent nitric oxide signaling, and reduced inflammatory responses through SIRT6-mediated NF-κB regulation. The authors concluded that the NAD+-sirtuin axis represents a central node in cellular metabolic and stress-response signaling with broad relevance to multiple disease models.
Citation: Kane AE, Sinclair DA. Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases. Circulation Research. 2018;123(7):868-885. doi:10.1161/CIRCRESAHA.118.312498. PubMed PMID: 30355082
Reviewed for scientific accuracy — Chameleon Peptides Research Team. Last reviewed: March 2026.