Nicotinamide Riboside Affects the Gut Microbiome Differently in Mice and Humans
Strategies shown to modestly slow aging have quite different outcomes in short-lived versus long-lived mammals. Every intervention that touches on the mechanisms associated with calorie restriction, the stress responses that dial up the activities of cellular housekeeping mechanisms such as autophagy, has a larger effect on mouse life span than human life span most likely because these mechanisms evolved in the context of seasonal famine. The reproductive life span of a short-lived species must lengthen considerably to pass through an additional season of famine into the comparative plenty that follows, but that isn't true of a long-lived species such as our own.
What are the mechanisms that mediate this difference between species, however? This question is comparatively little explored, in large part because cellular metabolism is ferociously complicated, even before one layers the interplay of different organs and tissues on top of the complexity of cellular processes. Then there is the question of our fellow travelers, the microbial populations of the intestine. The activities of the gut microbiome are attracting more attention of late, and as today's open access paper suggests, the microbiome may turn out to play a role in species differences in response to potentially age-slowing interventions.
Nicotinamide riboside (NR) is a supplement derived from vitamin B3 that acts to make up for age-related shortfalls in the production of nicotinamide adenine dinucleotide (NAD), thereby improving mitochondrial function. NAD is essential to the mitochondrial process of packaging chemical energy store molecules, the adenosine triphosphate (ATP) used to power cellular operations. With age the various pathways for synthesizing and recycling NAD become less efficient, and some effort has been put towards assessing ways to restore this portion of mitochondrial biochemistry. So far the results have not been all that impressive, no better than structured exercise programs at best, and a number of failed clinical trials at worst. Still, perhaps this can shed some light on why we might expect results in rodents to be materially different from results in people for this class of intervention.
The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice.
In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR.
Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.