Kane, A. E.; Chellappa, K.; Schultz, M. B.; Arnold, M.; Li, J.; Amorim, J.; Diener, C.; Zhu, D.; Mitchell, S. J.; Griffin, P. T.; Tian, X.; Petty, C.; Conway, R.; Walsh, K.; Shelerud, L.; Duesing, C.; Mueller, A.; Li, K.; McNamara, M.; Shima, R. T.; deCabo, R.; Gibbons, S. M.; Wu, L. E.; Ikeno, Y.; Baur, J. A.; Rajman, L.; Sinclair, D. A.

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.