mTOR inhibitors, AMPK activators, NAD+ precursors — the geroscience stack with actual human data.
Geroscience has four big targets. mTOR inhibition (rapamycin) is the most-cited intervention in the longevity literature — extends lifespan in every model organism tested. AMPK activation (metformin) is the most-studied small molecule on earth, with off-label longevity dosing now mainstream. NAD+ precursors (NMN, NR) target the age-related decline in NAD+ levels but produce modest clinical effect sizes.
None of these is FDA-approved for longevity. All four are used off-label by clinicians like Peter Attia and David Sinclair. The honest read: cellular and biomarker data are strong; human longevity outcomes data is years away.
Glucophage · Fortamet
The most-studied small molecule on earth. AMPK activator. Off-label longevity use is now mainstream.
Sirolimus
mTOR inhibitor. The most-cited longevity drug. Weekly off-label dosing is the standard human protocol.
Nicotinamide Mononucleotide
NAD+ precursor. The Sinclair supplement. Strong cellular data, modest clinical effect sizes.
Nicotinamide Riboside · Niagen
NAD+ precursor. Better bioavailability than NMN. The pharma-backed competitor.
| Rapamycin | Metformin | NMN | NR | |
|---|---|---|---|---|
| Mechanism | mTOR inhibition | AMPK activation | NAD+ precursor | NAD+ precursor |
| Dose | 5-10 mg / week | 500-1000 mg / day | 500-1000 mg / day | 300-1000 mg / day |
| Best evidence | Lifespan in mice | CV outcomes in T2D | Cellular NAD+ ↑ | Cellular NAD+ ↑ |
| Cost / mo | ~$150 | ~$15 | ~$30-50 | ~$60 |
Weekly rapamycin (5-10 mg) at off-label longevity dose has a different safety profile than daily transplant doses. Side effects (cytopenias, lipids, immunosuppression) are dose- and frequency-dependent. Always run with monitored bloodwork.
No. They are converging precursors to the same molecule. NR has better-documented bioavailability via NRK enzymes; NMN claims to feed NAD+ via the Slc12a8 transporter. Pick one, not both.
Some evidence suggests metformin attenuates aerobic exercise adaptations. Most clinicians dose metformin at night and exercise in the morning to minimize overlap.
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