Growth & survival signaling
PI3K/AKT/mTOR
Also searched as PI3K/AKT/mTOR.
The Balance here is Between Goals, on the same axis as mTOR — this is the signal that feeds it. Raised, it drives muscle mass and recovery, endothelial NO and fertility. Lowered, it is one of the most replicated longevity levers known: reduced insulin/igf-1 signaling extends lifespan across worms, flies and mice. Read the count below with care. Five benefits and one cost makes raising it look obviously right, and the longevity literature does not agree — The longevity cost of chronic insulin signaling is real and under-represented here. Treat this like mTOR: responsive after food and training, quiet the rest of the time.
In depth
Insulin-receptor and PI3K–akt signaling — the anabolic line that clears glucose, supports the vessel wall and commands cell growth.
What drives it
Fasting response reduces it.
Cohen 2004, Science 305:390 — caloric restriction lowers circulating insulin and IGF-1 (≈8-fold and 1.4-fold in rodents), quieting insulin/IGF-1–PI3K-AKT signaling. PMID 15205477. Verified: reduced calories cause a cumulative decrease in insulin release, and it is insulin signaling through PI3K that drives growth -- so fasting produces a hypoinsulinaemic state with lowered PI3K/AKT tone. the reviewers frame lower cumulative PI3K/AKT exposure as something that may reduce cancer initiation or progression -- a hypothesis carried from cancer biology, not a demonstrated clinical outcome of fasting. PMID 15205477
Oxidative stress increases it.
PTEN-redox review 2024, Antioxidants — ROS (H2O2) oxidize PTEN at its active-site cysteine, inactivating it and thereby de-repressing PI3K/AKT signaling. PMC10886030. ROS is dose-dependent: physiological ROS signals, excess ROS damages. 'Lower ROS' is therefore not universally desirable. Verified, and the mechanism is inactivation of a brake, not direct activation: H2O2 oxidizes and inactivates human PTEN via a disulfide bond between catalytic Cys-124 and Cys-71. Endogenously generated ROS following insulin, EGF or PDGF causes PTEN oxidation leading to activation of the PI3K pathway. It is reversible — peroxiredoxin II reverses PTEN oxidation. Verbatim: “It was also demonstrated that endogenously generated ROS following treatment with peptide growth factors such as insulin, EGF, or PDGF causes oxidation of PTEN leading to the activation of the PI3K pathway”. doi 10.1016/j.cellsig.2012.01.008 · PMID 22286106 · PMC10886030
Thyroid hormone conversion increases it.
Thyroid hormones acting non-genomically activate PI3K, Akt, mTOR and p70S6K; deiodinase D2 sets the local T3 concentration that drives this. 10.1152/japplphysiol.00643.2007. doi 10.1152/japplphysiol.00643.2007
What it drives
It reduces Stress-resistance switch (FOXO).
Brunet 1999, Cell 96:857 — Akt phosphorylates and inhibits FOXO forkhead factors (14-3-3 nuclear export); when insulin/IGF signaling falls during fasting, FOXO is released. PMID 10102273. Mechanism is exclusion, not suppression: Akt phosphorylates and inactivates the FOXO transcription factors, causing their nuclear exclusion and cytoplasmic degradation. FOXOs normally drive transcription promoting cell-cycle arrest, cell death and oxidative-stress handling, so removing them from the nucleus triggers survival; decreased FOXO activity also blocks transcription of the CDK inhibitors p27 and p21. the tidy 'nuclear Akt phosphorylates nuclear substrates' model is challenged — proteomic studies show most Akt substrates annotated as nuclear actually shuttle between nucleus and cytoplasm. AKT is not one switch — its two activating phosphosites govern different substrates: selectively inhibiting Ser473 weakened FOXO1/2a and FOXO3 but did not affect GSK3-beta or TSC2, while it is THR308 phosphorylation that tracks p-eNOS Ser1177 — Ser473 exerts rare effects on eNOS (PMC8255840). Which Akt site is engaged decides which downstream arm moves. PMID 10102273 · PMC8255840
It reduces Ethanol-metabolizing enzyme.
Woodcroft 2002, Hepatology 35:263 — insulin signaling (via PI3K) suppresses hepatic CYP2E1 expression; insulin deficiency/diabetes induces CYP2E1 several-fold (PI3K inhibitors block the effect). doi 10.1053/jhep.2002.30691
It increases Blood flow (nitric oxide).
Fulton 1999, Nature — Akt (downstream of PI3K) directly phosphorylates eNOS at Ser1177/1179, activating the enzyme and NO production. PMID 10376602. Fulton 1999 showed AKT directly phosphorylates eNOS and activates the enzyme, producing nitric oxide; eNOS mutated at the AKT site was resistant to phosphorylation and activation; activation-deficient AKT attenuated VEGF-stimulated NO production. Dimmeler 1999 independently showed that inhibiting PI3K/AKT, OR MUTATING serine-1177 on eNOS, prevented eNOS activation — while mimicking Ser1177 phosphorylation directly enhanced enzyme activity. Gain-of-function, loss-of-function, and site-directed mutagenesis, replicated across two labs (OMIM 164730). AKT is not one switch — its two activating phosphosites govern different substrates: selectively inhibiting Ser473 weakened FOXO1/2a and FOXO3 but did not affect GSK3-beta or TSC2, while it is THR308 phosphorylation that tracks p-eNOS Ser1177 — Ser473 exerts rare effects on eNOS (PMC8255840). Which Akt site is engaged decides which downstream arm moves. PMID 10376602 · PMC8255840
It increases Cell survival.
Datta 1997, Cell 91:231 — PI3K/Akt phosphorylates the bcl-2-family member bad, inactivating it to suppress apoptosis and promote cell survival. PMID 9346240. Akt directly regulates cell survival by inhibiting pro-apoptotic signals — named specifically as bad and the FOXO transcription factors. The survival effect is therefore de-repression: Akt does not switch on a survival program so much as remove two death signals. this is the arm that makes Akt an oncogenic node — the same review frames it as a cancer therapy target, so 'more Akt signaling' is not straightforwardly desirable. Akt is not one switch — its two activating phosphosites govern different substrates: selectively inhibiting Ser473 weakened FOXO1/2a and FOXO3 but did not affect GSK3-beta or TSC2, while it is THR308 phosphorylation that tracks p-eNOS Ser1177 — Ser473 exerts rare effects on eNOS (PMC8255840). Which Akt site is engaged decides which downstream arm moves. PMID 9346240 · PMC8255840
It increases Growth restraint.
Manning & Cantley 2007, Cell 129:1261 — PI3K/Akt activates mTORC1 (via TSC2), driving growth signaling. Hub caveat: the same review notes well over 100 reported AKT substrates and states that not all have been rigorously validated. Any single AKT arrow is one of a very large fan-out.
It reduces Blood-sugar support.
Manning & Cantley 2007, Cell 129:1261 — Akt, downstream of PI3K, drives GLUT4 translocation and glucose uptake. Same hub caveat: 100+ AKT substrates, not all rigorously validated.
It increases Muscle.
Named among the core mechanisms across six sarcopenia reviews: protein metabolism, mitochondrial dysfunction, chronic inflammation, and neuromuscular junction degeneration, with regulation of inflammation primarily targeting inhibition of NF-kB signaling and elevated PGC-1-alpha OR PAX7 expression reversing mitochondrial OR satellite cell dysfunction. doi 10.3390/ijms26146740 · PMC13074595
It increases Recovery.
10.1038/ncb1101-1014 — Recovery is assembled from the sarcopenia and VO2max literatures; none of the papers cited studied recovery itself. doi 10.1038/ncb1101-1014
It increases Female fertility.
The central finding is that reactive oxygen species ARE required, not merely harmful: ROS in the ovary regulate ovarian steroid hormone production, follicle synthesis, maturation, ovulation, and tubal function. ROS and antioxidant levels regulate the microenvironment of the follicular fluid, which determines which follicle becomes dominant. ROS can trigger ovulation in mature GRAAF follicles, and any change in this ROS level can disrupt ovulation. So an antioxidant claim here cuts both ways - the requirement is redox homeostasis, not suppression. Excess oxidative stress damages the oocyte through mitochondrial dysfunction, follicular atresia, meiotic errors, DNA damage and telomere shortening; too little disrupts the ovulatory trigger itself. Scale: infertility affects approximately 10-15 percent of couples, with nearly half the cases attributed to female reproductive dysfunction. doi 10.3390/antiox12081490 · PMID 40712896 · PMC10666387
It increases Fat import gate.
Insulin signaling through PI3K-AKT translocates FATP1 to the plasma membrane to increase fatty-acid uptake. PMID 11970897
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.