NMN Modulates Microbiome and Metabolism Linked to Healthy Aging

At any given moment, we are made up of tens of trillions of cells made from innumerable biomolecules. And every day, many of these cells turn over, requiring a constant supply of biomolecules. But when we age, the metabolism of most biomolecules — from the amino acids, lipids, and sugars that make up proteins, fats, and carbohydrates, respectively, to the nucleotides that make up our DNA and RNA — sputters. Even the supply of a molecule called nicotinamide adenine dinucleotide (NAD+), which vitally fuels many essential cell functions like biomolecule metabolism, gets tarnished by aging. Not only does aging alter the metabolism of our cells, but it also affects the trillions of microbes in our gut (the microbiome) that provide many biomolecule building blocks.

Research from Nia and colleagues demonstrates that oral supplementation with nicotinamide mononucleotide (NMN) — an essential NAD+ precursor — might be an effective strategy to promote healthy aging by affecting cellular metabolism and microbiome composition. Published in Frontiers in Nutrition, this study shows that NMN supplementation altered the metabolism of specific amino acids, components of nucleotides, and NAD+ in a manner that may promote healthier aging in mice. Moreover, the researchers observed longer chromosomal ends called telomeres, which shorten with aging, in mice and volunteers who received short-term NMN treatments. These findings suggest that oral NMN supplementation in the pre-aging stage might effectively promote healthy aging.

NMN gets a grip on some of aging’s levers

Metabolism

There’s evidence that tweaking biological processes related to nutrient sensing and metabolism can promote healthy aging. That’s why Nia and colleagues looked at the effects of short-term NMN supplementation on the metabolites in the pre-aging mice. NMN supplementation notably altered the metabolites related to specific nucleotides, protein building blocks (amino acids), and NAD+. These findings are relevant because previous research has reported decreases in the levels of these biomolecules in aged mice or other organisms used to study aging, such as flies and nematodes.

Microbiome

There is also a link between the gut microbiome and healthy aging. An age-related reduction in microbiome diversity (microbial dysbiosis) can cause a breakdown in the health of the intestine, further impacting late-life health. In addition, immune health can disrupt the balance of the gut microbiota, reducing healthy aging.

Gut microbiota-targeted interventions have been conducted to promote healthy aging and improve host health. Research has shown that food can promote healthy aging via gut microbiota and relevant metabolites. Also, gut microbiota transplantation of young donors is evident to promote brain and immune system aging in older recipients. The gut microbiota and the metabolites they produce have critical effects on aging and longevity.

In the present study, the reduced abundance of fecal Proteobacteria in the NMN-supplemented mice suggests that NMN might have perturbed certain harmful microbes. Proteobacteria include pathogenic representatives, such as Enterobacter species, which may cause infection and disease. In addition, Mucispirillum, which shows a protective effect against Salmonella infection, was seen in the NMN-treated older mice and correlated with key metabolic changes.

Telomere length

Another important aging biomarker is the length of telomeres — complexes at the end of chromosomes that protect the stability of chromosomes from recombination. Previously, the administration of NMN has been proved to maintain telomere length in the liver of mice. Nia and colleagues found that specific immune cells, called peripheral blood mononuclear cells (PBMCs), demonstrated longer telomeres in pre-aging mice treated with NMN for 40 days. Perhaps more importantly, the length of telomeres increased in the PBMCs of volunteers after supplementing for 30 days.

Next steps in NMN and aging research

Although this study has some promising findings regarding the effect of NMN on processes implicated in aging, some questions loom and remain unanswered. For example, the study did not clarify the link between the metabolite changes and varied microbial composition in response to the NMN supplementation. Further validation of specific metabolite changes corresponding to distinct microbial families coupled with their downstream biological effects will be important to the effects of NMN supplementation on the host.

Perhaps unexpectedly, in this study, oral NMN administration increased Helicobacter abundance in pre-aging mice. Some Helicobacter species are pathogenic bacteria that can cause gastric diseases, so enriching these gut microbes with NMN administration should be deeply and carefully confirmed further. Also, whether altered microbiota or metabolomics are associated with elongated telomeres is still unclear. The researchers claim that they are planning a more comprehensive study to explore the impact of NMN on gut health of aging mice, mainly focusing on Helicobacter and Akkermansia abundance. 

Furthermore, there are certain limitations to the present study which pave the way to research broader realms of this concept. Namely, the clinical study performed by Nia and colleagues was extremely rudimentary and small in number. They did not conduct a placebo-controlled trial and only enrolled a few subjects. In the clinical study, they also did not measure the blood NMN metabolism and fecal microbiota.

Ultimately, we need more research on NMN’s effects on aging in humans to understand the quantity and duration of NMN supplementation needed to promote healthy aging at any given life stage.

References:

Niu KM, Bao T, Gao L, et al. The Impacts of Short-Term NMN Supplementation on Serum Metabolism, Fecal Microbiota, and Telomere Length in Pre-Aging Phase. Front Nutr. 2021;8:756243. Published 2021 Nov 29. doi:10.3389/fnut.2021.756243