NAD+ Decline Is Now Recognized as a Hallmark of Aging
Landmark consensus paper establishes NAD+ depletion alongside genomic instability and telomere attrition as a defining feature of biological aging
Credit: National Institute on Aging
Abstract
Over 200 studies now show that the age-related decline of nicotinamide adenine dinucleotide (NAD+) is not a correlate of aging but a causal driver of multiple aging hallmarks. This review synthesizes data demonstrating that NAD+ depletion directly contributes to mitochondrial dysfunction, DNA repair impairment, epigenetic alterations, and chronic inflammation.
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme present in every living cell. It serves as a substrate for sirtuins (SIRT1 through 7), poly(ADP-ribose) polymerases (PARPs), and CD38/CD157 ectoenzymes. These enzymes regulate DNA repair, gene expression, calcium signaling, and immune function, the basic machinery of cellular survival.
Yoshino et al. first quantified the age-related NAD+ decline in 2011, showing that tissue NAD+ in mice drops by about 50% between youth and old age. Human data followed. Massudi et al. (2012) measured NAD+ in human skin and found the same downward trajectory, tracking with rising oxidative damage and falling PARP activity.
The mechanism behind this depletion came into focus with Camacho-Pereira et al.'s 2016 paper in Cell Metabolism. CD38, an NAD+-consuming ectoenzyme, increases in expression with age across visceral adipose tissue and other organs. Their CD38 knockout mice kept youthful NAD+ levels and avoided age-related metabolic decline. The implication: increased consumption of NAD+, not decreased production alone, drives the deficit.
Preclinical supplementation data has been encouraging. Mills et al. (2016) gave mice long-term NMN and saw suppressed age-associated weight gain, improved energy metabolism, better insulin sensitivity, and more physical activity. Gene expression patterns in the treated mice resembled those of younger animals.
Human trials are catching up to the mouse data. Yoshino et al. (2021) ran a randomized, double-blind, placebo-controlled trial, published in Science, and found that NMN supplementation improved muscle insulin sensitivity and insulin signaling in prediabetic postmenopausal women. No prior human trial had produced this kind of rigorous metabolic evidence for NAD+ precursors.
NAD+ restoration also appears to protect neurons. Hou et al. (2018) supplemented NR in an Alzheimer's mouse model and saw decreased neuroinflammation, reduced phosphorylated tau, and better cognitive function. The treatment worked through the SIRT3-DRP1 axis, promoting mitophagy and clearing damaged mitochondria that otherwise fuel neurodegeneration.
Imai and Guarente proposed the NAD World hypothesis in 2014, arguing that systemic NAD+ biosynthesis mediated by NAMPT coordinates aging across tissues. As organisms age, NAMPT levels drop, circulating eNAMPT in extracellular vesicles declines, and a body-wide NAD+ deficit takes hold. Epigenetic drift and cellular senescence accelerate.
Combination therapies that both boost NAD+ synthesis (via precursor supplementation) and reduce NAD+ consumption (via CD38 inhibitors) may prove synergistic. Several Phase II trials are testing this dual approach in patients with heart failure, cognitive decline, and sarcopenia.
References
- 1.Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).
- 2.Massudi, H. et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS ONE 7, e42357 (2012).
- 3.Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016).
- 4.Mills, K. F. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016).
- 5.Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021).
- 6.Hou, Y. et al. NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc. Natl Acad. Sci. USA 115, E1876–E1885 (2018).
- 7.Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).
Article Information
Author Contributions
All authors contributed equally to the conception, analysis, and writing of this article. Correspondence should be addressed to the first author.
Competing interests: The authors declare no competing interests.
