George Sutphin is back! So many of you enjoyed Matt's interview with him back in March 2024 about 3HAA and NAD+ that we decided to bring him on the podcast once again to chat about the potential effects of oral NMN supplementation.

You may have heard of over-the-counter supplements aimed at boosting nicotinamide adenine dinucleotide (NAD+) levels. Underlying these supplements is the hypothesis that levels of NAD+, a central coenzyme found in all living cells and involved in innumerable biochemical reactions that include DNA repair, glycolysis, and stress responses, decrease with age. The decrease, according to supplement manufacturers, may be associated with aging and age-related disease and thus restoring NAD+ levels via supplementation is likely to increase health- and/or lifespan.

In this episode, Matt and George examine a recent finding that oral supplementation of NAD+ boosters increases molecular signatures that indicate kidney damage. They discuss the NAD+ signaling pathway, models for how NAD+ might drive kidney damage, how they would expand upon the study for further research, and more.

University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin runs a lab that investigates genetic determinants of longevity, the effects of kynurenine-based interventions on lifespan, and environmental regulators of the aging process. George, who was an aerospace engineer before he discovered the promise of geroscience, completed his PhD at the University of Washington and worked as a postdoctoral associate at the Jackson Laboratory prior to his current faculty position. He currently serves as Chairperson of the American Aging Association.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!


Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation

This is the preprint Matt and George discuss in the episode. The authors found that, contrary to their expectations that NAD+ boosters would help ameliorate kidney aging in mice, an NAD+ booster actually led to increased levels of potential kidney damage markers. These results do not conclusively demonstrate a negative effect of NAD+ boosters on kidney health, but there's smoke there, as Matt says, and the finding is worth further investigation.

NAD precursors cycle between host tissues and the gut microbiome

The gut microbiome seems to play a role in many biological processes, including NAD+ biosynthesis and metabolism. This paper suggests that the gut microbiome breaks down NAD+ intermediates such as nicotinamide riboside and nicotinamide mononucleotide into nicotinic acid, which you may know by its generic name niacin. Cells then generate NAD+ from nicotinic acid.

SS-31 and NMN: Two paths to improve metabolism and function in aged hearts

The NMN-kidney inflammation paper that Matt and George discuss in this episode has roots in this piece of research, which shares several authors with the later paper. Researchers administered two mitochondria-targeting drugs, including the NAD+ precursor NMN, to mice and found that treating mice with a combination of both drugs restored various aspects of mitochondrial and heart health.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

How might NAD+ precursors such as NMN affect people? This study reported that overweight or obese prediabetic women who had undergone menopause showed improved muscle insulin sensitivity and insulin signaling with NMN supplementation. They also experienced higher levels of downstream muscle NMN metabolites, or nicotinamide byproducts.

Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan

This paper, which George co-authored, provides a useful review of the kynurenine pathway, a major metabolic pathway for the degradation of the amino acid tryptophan that ends in the production of either kynurenic acid or NAD+. He reviews the potential roles of NAD+ and kynurenine metabolism in aging and the potential of interventions targeting components of these pathways.