Supplements for Longevity & Their Efficacy | Dr. Peter Attia

Summary

Dr. Peter Attia and Andrew Huberman conduct a deep dive into the NAD pathway and its role in longevity, examining whether supplementing with NR, NMN, or intravenous NAD has meaningful scientific support for extending lifespan or healthspan. The conversation spans the broader framework of longevity approaches — from behavioral interventions to geroprotective molecules like rapamycin — and rigorously evaluates the evidence (or lack thereof) behind popular longevity supplements.

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Key Takeaways

• Rapamycin is the single most evidence-supported geroprotective molecule available, being one of only two interventions (alongside caloric restriction) proven to extend lifespan across multiple species in rigorous testing.
• NAD levels decline with age, but what’s actually declining is likely redox potential (the NAD/NADH ratio) rather than total NAD, which complicates the rationale for supplementation.
• NR and NMN have failed to extend lifespan in the Interventions Testing Program (ITP), the most rigorous mammalian longevity testing platform available.
• NR is more bioavailable orally than NMN because NMN cannot cross the cell membrane directly due to its phosphate group; sublingual NMN bypasses this somewhat.
• Resveratrol, despite enormous hype, failed in every meaningful lifespan study outside of one highly artificial mouse model involving extreme fatty liver disease.
• Statistical significance ≠ clinical significance — several NMN/NR human studies showed technically significant results that had no meaningful real-world health impact.
• Caloric restriction and sirtuins operate through independent, parallel pathways — the long-held assumption that CR works through sirtuin activation has been disproven.
• The ITP has validated very few molecules: rapamycin, canagliflozin (SGLT2 inhibitor), acarbose, and 17-alpha estradiol (males only) have extended lifespan in mice; metformin and NR have not.
• Blood glucose regulation — independent of weight loss — appears to be a robust longevity signal, as both acarbose and canagliflozin extended mouse lifespan without reducing body weight.

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Detailed Notes

The Four Categories of Longevity Approaches

Attia proposes a framework for thinking about longevity interventions:

1. Essential behavioral inputs — sleep, movement (Zone 2 cardio, resistance training), and nutrition. Everyone does these; the question is whether they’re done in a health-promoting way.
2. Disease-targeting molecules — drugs that directly reduce the risk of cardiovascular disease, cancer, neurodegeneration, and metabolic disease (e.g., statins, PCSK9 inhibitors, SGLT2 inhibitors, GLP-1 agonists).
3. Geroprotective molecules — compounds that target Hallmarks of Aging independent of specific disease (e.g., rapamycin, targeting mTOR).
4. Comprehensive/aggressive stacking — combining all of the above, as exemplified by figures like Bryan Johnson.

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Rapamycin & mTOR Inhibition

• Attia personally takes 8 mg of rapamycin once per week, cycling approximately 2 months on / 1 month off due to canker sores (affecting ~10% of users).
• mTOR (mammalian target of rapamycin) is the primary nutrient-sensing pathway driving cellular growth; its inhibition mimics aspects of caloric restriction.
• Rapamycin and caloric restriction are the only two interventions proven to extend lifespan across multiple model organisms (yeast, worms, flies, and mice).
• The landmark ITP experiment showed rapamycin extended lifespan even when started at 21 months of age (~equivalent to a 60-year-old human).
• The dog aging study (led by Matt Kaeberlein) is expected to report results in 2026 and will provide critical evidence in a higher-order mammal. Attia helped close a $2.5M funding gap to keep the study alive after NIH funding was pulled.

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Sirtuins & the Caloric Restriction Myth

• In the late 1990s, Matt Kaeberlein’s lab showed overexpressing Sir2 (a sirtuin) extended yeast lifespan.
• A separate experiment showed caloric restriction also extended lifespan in yeast — leading to the hypothesis that CR works through sirtuins.
• A 2004 paper by Kaeberlein and Brian Kennedy used a third yeast strain and showed CR and sirtuin overexpression independently and additively extended lifespan — they are parallel pathways, not the same pathway.
• The only mammalian evidence for sirtuin overexpression extending lifespan: one transgenic mouse overexpressing SIRT6 — male mice lived 10–15% longer; female mice showed no effect.
• Downstream effects of sirtuin activation believed to be beneficial:
  • Improved mitochondrial biogenesis
  • Enhanced DNA repair
  • Suppression of SASP (senescence-associated secretory phenotype) from senescent cells

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Resveratrol: The Cautionary Tale

• Resveratrol gained fame as a sirtuin activator found in grape skins/red wine.
• The one mouse study showing benefit used a highly artificial model: mice force-fed extreme high-fat diets until fatty livers encroached on their thoracic cavity. Resveratrol “rescued” these mice.
• When the ITP tested resveratrol at doses recommended by the original researchers: no effect on lifespan whatsoever.
• The “French paradox” explanation (red wine → resveratrol → longevity) is invalid — the doses needed to replicate mouse studies would require drinking body-weight quantities of wine.

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The NAD Pathway: Biology

• NAD (nicotinamide adenine dinucleotide) is involved in 500–600 enzymatic pathways, primarily as an electron shuttle (NAD ↔ NADH) in the electron transport chain — not consumed, just recycled.
• A small fraction of NAD is used as a substrate by sirtuins for DNA repair — it is actually consumed in this process.
• NAD levels decline with age (~20% reduction in blood over four decades in humans; ~60% decline in skin; ~15–20% in brain, based on animal data).
• Critically, a 2015 PNAS study found that as NAD declines with age, NADH rises proportionally — suggesting total NAD+NADH is relatively stable, and what’s declining is redox potential, not absolute NAD.

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NR vs. NMN vs. IV NAD

Key structural difference:

• NR (nicotinamide riboside) → can cross cell membranes directly; orally bioavailable
• NMN (nicotinamide mononucleotide) → NR + a phosphate group; cannot cross cell membranes directly when taken orally; the phosphate is cleaved in the gut, converting it back to NR anyway
• IV NAD → bypasses gut but is not orally bioavailable; expensive ($300–$1,000/infusion)

Attia’s personal protocol:

• Takes 8 mg rapamycin/week, PCSK9 inhibitor, bempedoic acid, SGLT2 inhibitor
• Takes sublingual NMN (~1,500 mg/day), primarily for subjective effects (energy, faster hair/nail growth) — not based on longevity evidence
• Has done IV NAD infusions (~5–6 times); first 10 minutes are deeply uncomfortable (chest pressure, leg cramps, nausea); feels better afterward but attributes some of this to placebo

Huberman’s approach:

• Takes oral NMN and sometimes NR
• Reports subjective energy improvement; acknowledges this is anecdotal (n=1) and likely unrelated to lifespan extension

Important note on mouse dosing: Studies showing NMN/NR efficacy in mice use 500–1,000 mg/kg.