NMN / NAD+ Precursors

NAD is one of the three most asked about geroprotective molecules

Peter Attia introduces the episode by explaining that NAD/NR/NMN, rapamycin, and metformin are the three molecules he gets asked about most. He sets up the framework for comparing them as geroprotective candidates.

"The first is all things that have to do with NAD, and that usually implies its precursors, NR and NMN, but also sometimes NAD itself. The second being rapamycin and the third being metformin."

No validated biomarkers of biological aging exist at the individual level

Matt Kaeberlein explains that while epigenetic clocks can predict chronological age at the population level, no one has demonstrated they work reliably to measure biological aging at the individual level. He argues functional measures like organ performance may be more telling.

"I feel like we're closer than we were 15 or 20 years ago, but we're still a ways off from that definition that I gave of having something that you can measure that in a predictive way at either the individual or the population level really tells you with any level of precision what the biological aging trajectory is."

Aging clock companies selling supplements are snake oil

Kaeberlein calls out companies that sell both an aging clock test and a supplement that claims to reverse the measured biological age, describing this as dishonest and equivalent to snake oil. He says the FDA should intervene.

"It becomes a bigger problem when the same companies are then also selling a product that they claim will reverse your biological age. That's just snake oil. I don't know any other way to say it."

NAD is the most important molecule in the body

Dr. Salzman describes NAD as probably the most important molecule in the body, involved in 500 different reactions, responsible for all major cellular functions from thinking and movement to immune and sexual function.

"most important molecule, I would say, in the body. It's involved in 500 different reactions. It's a small molecule. It's a normal metabolite, if you will. We make it. We make it in every cell. And NAD is responsible for all of the major functions for thinking or moving, for digesting or sexual function, for immune function. There isn't anything in the body that isn't touched by this amazing molecule."

Brain function is intimately linked to NAD levels in neurons

Dr. Salzman explains how functional MRI shows the brain lighting up during thinking, and how falling NAD levels slow this metabolic process, leading to brain fog, slower thinking, and impaired memory encoding.

"If NAD levels are okay and they haven't fallen significantly with aging, then that can proceed very well and you can be sharp as a tack and be, you know, completely cognizant of everything going on. But as your NAD levels fall, that metabolic process slows."

Menopause is caused by CD38-driven NAD depletion in the ovary

Dr. Salzman explains how rising CD38 levels in the ovary consume NAD and directly cause menopause by depleting the energy eggs need to be released. In animal studies, suppressing CD38 allows continued ovulation at the equivalent of 90 years of age.

"And they rise so much that so little NAD is left because it's chewing it up. That's what CD38 does. That you don't even have enough energy for the egg to leave the ovary."

We did not evolve to become elderly

Dr. Salzman explains that average human survival was 25 years until recently, so the aging problems we face in our 60s-80s were never selected for by evolution. Modern health challenges are a consequence of outliving our evolutionary programming.

"So we did not evolve to become elderly. There's no evolutionary advantage to be 80 years old."

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."