Summary
Drs. Spencer Nadolski and Karl join Dr. Charles Brenner, the researcher who discovered nicotinamide riboside (NR) as a vitamin precursor of NAD, for a no-nonsense discussion about NAD metabolism, NR vs NMN, and the hype around longevity supplements. Dr. Brenner provides a biochemistry primer explaining that NAD coenzymes (NAD+, NADH, NADP+, NADPH) are the central electron carriers of metabolism, essential for converting food into ATP and building every macromolecule in the body. Brenner is sharply critical of several popular longevity claims. He debunks the resveratrol/SIRT1 story entirely, explaining that resveratrol does not actually activate SIRT1, SIRT1 is not a longevity gene, and resveratrol is not orally bioavailable in humans. He also pushes back on injectable NAD, explaining that the innate immune system interprets free-floating NAD as a damage signal, causing inflammatory reactions. Brenner distinguishes NR (which has FDA GRAS status, over 100 registered clinical trials, and 8 trials showing anti-inflammatory activity in humans) from NMN, which lacks a cell transporter and is currently in legal limbo due to FDA drug development rules. The conversation covers promising clinical applications of NR including heart failure, neurodegeneration, wound repair, and COVID recovery, while firmly rejecting the claim that any supplement can stop aging.
Key Points
- NAD coenzymes (NAD+, NADH, NADP+, NADPH) are the central electron carriers of all cellular metabolism, from bacteria to whales
- NR (nicotinamide riboside) was discovered in the Brenner lab and is the largest piece of NAD that can actually enter cells; phosphorylated compounds like NMN and NAD+ cannot cross cell membranes directly
- NR has FDA GRAS status, 100+ registered clinical trials, and 8 trials demonstrating anti-inflammatory activity in humans
- NMN is NR with a phosphate group added; the phosphate must be removed before it can enter cells, and there is no specific NMN transporter
- Resveratrol is completely debunked: it does not activate SIRT1, SIRT1 is not a longevity gene, and resveratrol is not orally available in humans
- Injectable NAD triggers inflammatory immune responses because the innate immune system interprets extracellular NAD as a damage-associated molecular pattern
- NR shows promise for heart failure (preserved ejection fraction in mouse models), neuroinflammation, fatty liver, and COVID recovery
- No supplement can stop aging; the fundamentals of sleep, diet, exercise, and stress management remain the proven longevity interventions
Key Moments
NAD coenzymes are the central electron carriers of all life
Dr. Brenner explains that NAD coenzymes transfer high energy electrons from food to mitochondria to produce ATP, and are central to every metabolic process from bacteria to whales. He covers the four forms: NAD+, NADH, NADP+, and NADPH.
"the inner workings of cellular energetics, by which I literally mean all cellular energetics, energetics from bacteria to whales is the transfer of high energy electrons."
Resveratrol is completely debunked as a longevity compound
Dr. Brenner dismantles the resveratrol/SIRT1 narrative on three counts: resveratrol does not actually activate SIRT1, SIRT1 is not a longevity gene, and resveratrol is not orally bioavailable in humans. He calls it a total made-up story.
"the problem is it doesn't activate SIRT1. That's the first problem. Second is SIRT1 is not a longevity gene. Third problem is resveratrol is not orally available to humans. So the whole thing was completely."
Injectable NAD triggers inflammatory immune reactions
Dr. Brenner explains that injectable NAD is not only painful but triggers innate immune system activation because the body interprets extracellular NAD as a damage-associated molecular pattern, similar to cell-free DNA or double-stranded RNA.
"the innate immune system interprets NAD floating around as almost like a double-stranded RNA or one of these shapes, they're the innate pattern recognition receptors that recognize that as though there's some cell lysis."
NR shows dramatic results in mouse heart failure model
Dr. Brenner shares how a French molecular biologist discovered that the most highly induced gene in failing mouse hearts was nicotinamide riboside kinase 2. Supplementing those mice with NR preserved ejection fraction and multiple cardiac parameters.
"And but one month, which is two months before they're dead, the most highly induced gene is nicotinamide riboside kinase two. So this French molecular biologist, you know, writes me an email and says, what is nicotinamide riboside kinase two? I said, well, that's a fascinating result. We need to see what's happening to NAD in the failing heart. Turns out in the failing heart, NAD is plummeting."
No supplement can stop aging - lifestyle fundamentals matter most
Dr. Brenner and the hosts agree that no longevity supplement claim is backed by definitive evidence, and that sleep, diet, exercise, and stress reduction remain the proven fundamentals. Anyone claiming a supplement stops aging is essentially lying.
"if anybody claims that they're having a longevity indication, they're pretty much lying to you, right? Because you can't do a trial."
