Nutrient sensing — mTOR, AMPK & caloric restriction mimetics
One of 6 mechanistic pathways to ⏳ Longevity & healthspan · 12 options
The most conserved longevity mechanism across every species tested. Persistent nutrient abundance signals growth; scarcity signals repair and maintenance. Everything in this pathway is a way of telling the cell that food is scarce when it isn't.
Fasting insulin and IGF-1 are the two readable outputs of the nutrient-sensing system this whole pathway targets. They also tell you whether an intervention is doing anything, which nothing else here does.
Fasting InsulinHbA1c (Hemoglobin A1c)IGF-1 (Insulin-like Growth Factor 1)Uric AcidComprehensive Metabolic Panel (CMP)⏳ Longevity Baseline covers these in one panel →
What engages this pathway
Ordered by how directly each one acts on the mechanism above — never by how much trial evidence exists. Each links to its full breakdown with dosing, half-life and vendor.
💉 Rapamycin
mTOR inhibition is the single most reproducible pharmacological lifespan extension in mammals — the NIA Interventions Testing Program replicated it repeatedly, including in mice started late in life. Human longevity data does not exist; the immunosuppression at transplant doses is why intermittent low-dose protocols are what people actually discuss.
💉 Metformin
AMPK activation and complex-I inhibition. The TAME trial was designed to test it as a geroprotector and has struggled for funding. Note the awkward finding that it blunts exercise adaptation, which matters if training is your other longevity intervention.
💉 Acarbose
Extended lifespan in the ITP, more strongly in male mice. Flattens glucose excursions and feeds colonic fermentation — two plausible mechanisms for one cheap approved drug.
💉 Canagliflozin
Also extended male mouse lifespan in the ITP. SGLT2 inhibition produces a mild caloric deficit plus ketone elevation.
💉 AICAR
Direct AMPK activation — the exercise-mimetic route into the same nutrient-sensing switch.
💉 MOTS-c
AMPK activation from a mitochondrially-encoded peptide. Levels decline with age, which is the argument for restoring them.
💉 17-alpha-Estradiol
Extended male mouse lifespan in the ITP without feminising effects — it appears to work through hypothalamic inflammation and metabolic signalling rather than classical estrogen receptors. One of the strangest and most interesting ITP results.
🧬 Berberine
AMPK activation with genuine human metabolic data. The accessible version of this pathway.
🧬 Dihydroberberine
The same argument with better absorption.
🧬 Calcium AKG
Extended lifespan and compressed morbidity in mice. AKG is a TCA intermediate and a cofactor for the dioxygenases that regulate DNA methylation — which is a mechanistically rich place to be.
🧬 Spermidine
Dietary spermidine intake correlates with lower all-cause mortality in prospective human cohorts. It induces autophagy, which is a mechanism that connects the epidemiology to something real.
🧬 Green Tea (EGCG)
EGCG has mTOR-inhibiting and AMPK-activating activity in vitro, and green tea consumption tracks with lower mortality in Japanese cohorts.
The other 5 routes to longevity & healthspan
Pick the pathway that matches where you are actually stuck. An appetite drug does nothing for someone who already undereats.
Want the protocols behind these?
Dosing schedules, stacking, cycle timing and Coach Cam's notes live inside the Academy — plus the full interactive Vault.
Join the Academy — $10/mo →← Open this pathway in the interactive Vault
Frequently asked questions
The most conserved longevity mechanism across every species tested. Persistent nutrient abundance signals growth; scarcity signals repair and maintenance. Everything in this pathway is a way of telling the cell that food is scarce when it isn't.
12 options are mapped to this pathway in the Vault, including Rapamycin, Metformin, Acarbose, Canagliflozin. They are grouped by the mechanism they act through rather than ranked by how much trial evidence exists — 5 carry clinical validation and 5 are mechanistic predictions.
Fasting insulin and IGF-1 are the two readable outputs of the nutrient-sensing system this whole pathway targets. They also tell you whether an intervention is doing anything, which nothing else here does. The markers worth checking are Fasting Insulin, HbA1c (Hemoglobin A1c), IGF-1 (Insulin-like Growth Factor 1), Uric Acid.
Unproven is not the same as ineffective. Of the 12 options on this pathway, 5 have clinical validation and 5 are graded theoretical — meaning the mechanism is sound but the specific human trial has not been run, which is true of a great deal of what works in this space. Nothing on this page is ordered by evidence tier, because sorting by trial count would bury the compounds you came looking for.