Listen to this episode of Longevity by Design on Apple Podcasts, Spotify, and Google Podcasts
How can you increase NAD+ levels? And do higher NAD+ levels really lead to better metabolic health? What does the research say on their benefits for longevity? These topics and more are discussed in the latest episode of Longevity by Design with Dr. Joe Baur.
Dr. Baur, Professor at the Perelman School of Medicine of the University of Pennsylvania, has made key contributions to the understanding of how metabolism and dietary factors influence longevity, for example, resveratrol’s effect on insulin sensitivity. His lab looks at small molecules like NAD+ to understand how they can mimic the health-promoting effects of caloric restriction in rodents.
Episode highlights
- 8:08-10:13: What are the Potential Benefits of Resveratrol Supplements?
- 17:36-19:53: How Does NAD Affect Metabolism?
- 22:49-25:13: Do NAD+ levels decline with age?
- 25:14- 31:27: How to Combat Declining NAD Levels as You Age
- 43:54- 49:12: How do NAD Analogs Affect Target Tissues?
- 50:11-51:06: What are the potential health benefits of taking NMN?
- 54:17- 1:04:21: Safety, Dosage, and Benefits of NMN + NR Supplements
- 1:04:22-1:04:31: Should you take NMN supplements?
What roles does NAD+ have on metabolism?
NAD+ (nicotinamide adenine dinucleotide) is a vital metabolic cofactor that plays a central role in cellular energy production. NAD+ accepts high-energy electrons during glycolysis and the citric acid cycle and transfers them to the electron transport chain to generate ATP.
NAD+ levels decline as we age. This reduction impairs metabolic health in several ways. Decreased NAD+ leads to reduced activity of sirtuins, a family of NAD-dependent enzymes important for longevity. Lower NAD+ also causes mitochondrial dysfunction, disrupting cellular metabolism. As a result, insulin resistance increases when NAD+ levels drop. So, restoring NAD+ levels has become a strategy of interest among anti-aging scientists.
What are the NAD+ precursors?
Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) serve as precursors for NAD+ levels in the body, which is why these supplements rose in popularity. NR, in particular, may offer advantages over other precursors. NR can enter cells via a different pathway by converting to NMN through a reaction catalyzed by the enzyme nicotinamide riboside kinase. However, whether NMN itself can directly cross cell membranes has been debated. If NMN must first be dephosphorylated outside cells into NR, then supplementing NMN provides no advantages. However, some evidence suggests that certain tissues can transport NMN, allowing it to increase NAD+ more efficiently. Overall, both NR and NMN supplements appear to raise NAD+ levels effectively, but the specifics of their absorption continue to be studied in both animal and human models.
How does resveratrol impact metabolism?
Resveratrol, a polyphenol found in red wine, has been extensively studied for its metabolic effects. Much of the initial interest stemmed from the discovery that resveratrol can activate SIRT1, a longevity-linked sirtuin that relies on NAD+. Rodent studies also find that resveratrol can improve insulin sensitivity and protect against obesity. However, human trials have found more modest effects on diabetes at the doses tested thus far.
While resveratrol may still hold promise for reducing Alzheimer's beta-amyloid plaques and improving endothelial function, its mechanisms of action remain unclear. The link between resveratrol and sirtuins in humans is in question, suggesting that other molecular targets likely contribute to its biological effects.
How to increase NAD+ levels
Because a decline in NAD+ levels is linked to aging, scientists are exploring interventions to help maintain or even raise NAD+ levels. Calorie restriction has been shown to boost NAD+ levels in rodent models. Fasting regimens like intermittent fasting or time-restricted feeding can mimic calorie restriction and raise NAD+ as well.
Ketogenic diets are another option, though they tend to alter the ratio of NAD+ to NADH rather than the total level. By burning fat instead of glucose for fuel, ketogenic diets favor oxidation of the NAD pool. This shift from NADH back to NAD+ may activate sirtuins. However, more research is needed to understand how ketosis impacts NAD+ metabolism in the long term.
Exercise may also elevate NAD+ by stimulating its biosynthesis.
Safety, Dosage, and Benefits of NMN + NR Supplements
NMN supplements are hotly debated among longevity scientists for their safety and efficacy. According to Dr. Baur, human trials have tested doses of NMN and NR up to 2 grams per day without adverse effects identified after several months. Doses above 3 grams per day may increase the risk of liver toxicity. However, limited data is available on the long-term effects of supplementation in humans.
Potential benefits of NMN supplementation
In published studies to date, the benefits of NMN supplementation are modest. Some studies show that insulin sensitivity can improve in those who supplement, yet findings are inconsistent between trials. NR and NMN can increase NAD+ levels in blood cells, but the effects in other tissues remain unclear. Anecdotal findings show that some users report higher energy, improved sleep, and faster nail growth. That said, rigorous evidence linking these subjective effects to NAD+ supplementation still needs further exploration. As research continues, optimal dosing strategies and relevant biomarkers must be better defined.
Key takeaways
Efforts to develop anti-aging therapies by increasing NAD+ show promise, but clinical application is still in its infancy. Combining supplementation with lifestyle approaches like exercise may have synergistic benefits on metabolism. More research is needed to clarify optimal dosing, tissue-specific effects, and long-term safety and efficacy in humans. Dr. Baur advises maintaining a healthy lifestyle to support metabolic health while the science continues to evolve on these molecules and aging.
Similar Longevity By Design episodes we think you would love:
- The Effect of Food on Longevity with Dr. Eric Verdin
- Genetics and Lifestyle Factors of Centenarians
- Mechanisms of Aging with Dr. Andrea Maier
