Fight Aging!

In today's open access paper, the authors report on their investigation of the effects of nicotinamide mononucleotide (NMN) supplementation on the gut microbiome in mice. The gut microbiome changes with age, exhibiting a loss of helpful populations that produce metabolites necessary to health, and the growth in harmful populations that provoke chronic inflammation. Rejuvenating the aged gut microbiome via fecal microbiota transplantation from a young individual has been shown to improve health and extend life in short-lived species. Thus there is some interest in evaluating the effects on the gut microbiome produced by interventions thought to improve late-life health.

I should say that I think much of the current enthusiasm for vitamin B3 derivatives such as NMN and nicotinamide riboside (NR) is probably misplaced. The clinical evidence from human trials is just not that compelling, and exercise appears to produce better outcomes in NAD metabolism and mitochondrial function. The point of interest to take away from the study here is that there may be both beneficial and harmful changes produced in the gut microbiome by NMN supplementation (and thus likely also by NR, niacin, and similar approaches). It isn't only the helpful microbial populations that are boosted in numbers and diversity by a supply of NMN.

The researchers also looked at telomere length in mice and humans, and found it lengthened by NMN supplementation, but this data is not very interesting. Telomere length is measured in a blood sample, and is thus an assessment of only white blood cells. Average telomere length is a blurred measure of cell replication pace and cell replacement pace; telomeres shorten with each cell division in somatic cells, and newly created somatic cells, the daughters of stem cells, have long telomeres. White blood cells replicate aggressively in response to stress, infection, and similar prompts. Their telomere status isn't necessarily all that representative of the body as a whole, and varies widely on short time frames. Correlations between white blood cell telomere length, health, and aging, only emerge in large populations, and even then the correlations are poor or non-existent in many studies.

The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase

We probed the changes in the fecal microbiota and metabolomes of pre-aging male mice (C57BL/6, age: 16 months) following the oral short-term administration of nicotinamide mononucleotide (NMN). The complex interplay between age and the microbiota is well-described in several studies. The changes in the composition, diversity, and functional characters of the microbiota were observed over time. It was reported that the abundance of Proteobacteria is positively linked with aging. Proteobacteria include pathogenic representatives, such as Enterobacter spp., which may cause infection and disease. In the present study, the reduced abundance of fecal Proteobacteria in the NMN-supplemented mice suggests that NMN might have perturbed certain harmful microbes.

Surprisingly, a widely accepted probiotic strain Akkermansia (Verrucomicrobiota phylum) was lowered in the fecal microbiota of NMN-supplemented mice. In contrast, a previous study has reported that NMN administration enriches the abundance of Akkermansia muciniphila. We conjecture that the observed differences in the outcomes may be attributed to the difference in the age of the mice used in the experiments. We clearly observed that the Akkermansia abundance was negatively correlated to nicotinamide, tryptophan, and indole as well as their derivatives, which might have inhibited its growth.

Nicotinamide mononucleotide increases the abundance of butyric acid-producing Turicibacter which exhibits anti-fatigue activity, implying that NMN administration might reinforce vitality by promoting the growth of Turicibacter. Unexpectedly, in this study, oral NMN administration increased Helicobacter abundance in pre-aging mice. Some Helicobacter spp. are known as pathogenic bacteria that can cause gastric diseases, its enrichment with NMN administration should be deeply and carefully confirmed further.

In addition to these top dominant genera, the correlation analysis demonstrated that Mucispirillum was greatly associated with the altered serum metabolites. Mucispirillum was positively correlated with the metabolites relevant to purine, nicotinate, and nicotinamide metabolism, as well as arginine and proline metabolism. Mucispirillum schaedleri showed a protective effect against Salmonella enterica ser. Typhimurium colitis by interfering with the invasion gene expression. These upregulated metabolites might have beneficial effects on the inhibition of pathogenic adhesion in the gut mucus.

It is not yet fully understood how these metabolites change with the varied microbial composition in response to the NMN supplementation. Further validation of specific metabolite changes corresponding to specific microbial genera coupled with their downstream biological effects will be important to the effects of NMN supplementation on the host.