Summary
Peter Attia and Nick Stenson are joined by aging researcher Matt Kaeberlein for an AMA comparing three geroprotective molecules: NAD precursors (NR/NMN), rapamycin, and metformin. This is a sneak peek episode that covers the first portion of the full conversation, focusing primarily on biomarkers of aging and the challenge of measuring biological age. Note: the full discussion of NAD, rapamycin, and metformin is behind the paywall. The accessible portion features a thoughtful critique of epigenetic clocks and commercial aging tests. Kaeberlein and Attia argue that while epigenetic clocks can predict chronological age within plus or minus five years at the population level, no one has demonstrated they work reliably at the individual level. Attia expresses skepticism about companies that pair their aging clocks with supplements to show reversal of biological age, calling it akin to drawing a target around the arrow after it hits the barn. Kaeberlein favors functional biomarkers like VO2 max, grip strength, and muscle mass over methylation-based clocks. The episode sets up the framework for evaluating NAD precursors, rapamycin, and metformin by establishing what constitutes good evidence in the aging field, including the importance of studying interventions in multiple animal models before drawing conclusions for humans.
Key Points
- Three most-asked-about geroprotective molecules are NAD precursors (NR/NMN), rapamycin, and metformin; this episode sets up a framework for evaluating all three
- There are no validated biomarkers of biological aging that work reliably at the individual level; functional markers like VO2 max, grip strength, and muscle mass may be more useful than epigenetic clocks
- Approximately two dozen epigenetic clocks exist but the definitive validation experiment (predicting future outcomes in the same individuals) has never been done in mice or humans
- Commercial aging clocks paired with supplements are described as snake oil; the FDA should potentially regulate these claims
- Studying aging requires diverse animal models: yeast, worms, flies, mice, dogs, and humans each have strengths and limitations
- Caloric restriction was long thought to only slow aging, but recent evidence suggests some interventions may actually reverse molecular and functional age-related changes
- Kaeberlein advocates for broader aging signatures incorporating proteomics and metabolomics beyond just methylation patterns
- Metformin gets the most questions, followed by rapamycin, then NAD/NR/NMN; the full comparison is in the subscriber-only portion
Key Moments
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."
