NMN extended lifespan only in female mice. David Sinclair's lab found the cause: a gut bacterium converts NMN to NAD+, but in males the enzyme CD38 captures the extra NAD+ and triggers inflammation
NMN extended lifespan only in female mice. David Sinclair's lab found the cause: a gut bacterium converts NMN to NAD+, but in males the enzyme CD38 captures the extra NAD+ and triggers inflammation
The laboratory of Harvard biologist David Sinclair has for the first time tested whether nicotinamide mononucleotide (NMN), one of the most popular anti-aging supplements, extends lifespan in mice. Median lifespan increased by 8.5% in females but not in males. The cause was traced to the gut: the bacterium Anaerotruncus colihominis converts NMN into NAD+ on its own, before the compound reaches the mouse's cells.
With age, NAD+, a coenzyme required by hundreds of cellular enzymes for energy production and DNA repair, drops to roughly half in both mice and humans. NMN is a precursor molecule from which cells produce NAD+. A review of 113 studies had already shown that NMN raises NAD+ in humans, but the health benefits remain unclear, and whether it extends lifespan even in mice had never been tested. A preprint from Sinclair's laboratory, posted September 21, fills that gap.
The decision to test both sexes was deliberate: in earlier experiments where the activity of the NAMPT gene, which governs NAD+ production, was altered, NAD+ levels and health improved in females while males were unaffected. Sinclair's team gave mice NMN at a dose 2 to 3 times above the clinical range, from midlife (13 months) until death. Scaled to a 70 kg human, that corresponds to roughly 3 grams per day.
NMN slowed frailty equally in both sexes across 31 markers of aging: vision, hearing, coat condition. Lifespan increased only in females: median by 8.5%, maximum by 7.9%. In males, early protection from mortality held until about two years of age but then disappeared; instead, NMN reduced fat accumulation and improved metabolism and activity.
The cause was sought in the gut microbiome. In both sexes, NMN drove a more than tenfold expansion of Anaerotruncus colihominis, a species that produces butyrate (beneficial for the gut lining) and is found more frequently in humans who live past 100. The growth of this bacterium statistically accounts for the entire reduction in frailty in both sexes and partly for the early mortality protection in males. To test causality, the bacterium was cultured in vitro with isotope-labeled NMN: it took up the compound and converted it to NAD+ within 20 hours. Part of the benefit from NMN is produced by the gut microbe itself, independent of the mouse's own cells.
In females, liver and muscle tissue showed upregulated expression of mitochondrial and DNA repair genes, a signature familiar from other interventions such as caloric restriction. In males, mitochondrial genes were downregulated while inflammatory genes were upregulated, a profile that resembles aging itself. The explanation lies in the enzymes CD38 and PARP, which consume NAD+ and fuel inflammation: their expression rose in males but not in females. This aligns with an earlier independent study in which a drug blocking CD38 also extended lifespan in male mice but not in females. The authors' hypothesis is that in males the newly produced NAD+ is intercepted by CD38 and PARP, whereas in females it remains available for mitochondrial restoration.
In females, the lifespan extension was accompanied by a slight increase in the severity of kidney inflammation. In a model of pancreatic cancer, NMN supported tumor growth and interfered with chemotherapy; in ordinary mice, no increase in tumors was observed.
David Sinclair is a co-founder and co-owner of MetroBiotech, which develops NAD+ boosters; this is disclosed in the conflict of interest statement. For years he promoted NMN without data on mammalian lifespan extension. Now his laboratory has such data, but only in females, at 2 to 3 times the clinical dose, and with increased inflammation in males. The authors suggest combining NMN with a CD38 or PARP inhibitor to provide males with the same benefit.