FoxO
Forkhead box O transcription factors (FOXO1/3/4) that act as key downstream targets of PI3K/Akt and mTOR signalling; they are excluded from the nucleus by Akt, with an mTORC2/SGK contribution, so catalytic or mTORC2-directed inhibition promotes nuclear entry and transcription of stress-response and longevity genes, whereas rapamycin can raise Akt activity through feedback relief and leave them cytoplasmic.
The stress-resistance programme mTOR switches off. A family of 'stress-response' gene switches that Akt normally keeps locked out of the nucleus. When Akt activity drops they move into the nucleus and turn on genes linked to stress resistance and longevity. Rapamycin does not reliably do this: by releasing a feedback loop it can even raise Akt activity, leaving these switches outside the nucleus.
mTORC2 is required for signalling to Akt–FOXO but not to S6K1 (GUE2006), which is the genetic evidence that this arm belongs to mTORC2 rather than mTORC1. In C. elegans, TOR and rapamycin extend lifespan through SKN-1/Nrf and DAF-16/FoxO (ROB2012) – invertebrate evidence, not human.
TL;DR. FoxO appears in 6 curated studies in Oliver's mTOR Atlas: 4 in animal models; 2 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| FOXO1/3 activates Longevity mechanism: functional-consequence · this link in full · on the map table | Part of how this pathway affects lifespan runs through stress-resistance genes switched on by FOXO – so far shown mainly in simple animals like worms, not yet in mammals. Holds under: An invertebrate result, and the two arms must not be merged. ROB2012's title reads 'TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO', but its own abstract splits them: the DAF-16/FoxO requirement belongs to genetic TORC1 inhibition, while the rapamycin effect is SKN-1-dependent and DAF-16-INDEPENDENT. Not shown in mammals in this corpus. not tested in people · emerging, few independent studies | A | ROB2012 |
| Akt/PKB inhibits FOXO1/3 mechanism: phosphorylation · this link in full · on the map table | Akt tags FOXO proteins and keeps them out of the nucleus; this specific link belongs to mTORC2, not mTORC1. Holds under: Mouse knockouts and cell lines; FOXO isoform contributions differ by tissue. This Akt output depends on mTORC2. Deleting rictor or mLST8 in mice removed Akt signalling to FOXO while S6K1 was spared (GUE2006), and SIN1, an essential mTORC2 subunit, controls Akt Ser473 phosphorylation and which substrates Akt reaches (JAC2006). The mTORC2-to-Akt step itself is the separate edge MTORC2-AKT. plausible in people, not shown directly · settled in the literature | M | GUE2006, JAC2006, BRU1999 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 4 |
| M | Molecular — cells, biochemistry, structure | 2 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response DEN2026 Transcription factor Spalt-related (Salr) is a novel mTORC1 inhibitor in Drosophila activated by the integrated stress response, restricting anabolic growth and lipid storage during nutrient stress. Salr responds to a distinct, ISR-driven cue, acting convergently with FoxO rather than downstream of it. |
| 2018 | A | In Vivo Decoding Mechanisms of the Temporal Patterns of Blood Insulin by the Insulin-AKT Pathway in the Liver KUB2018 The in-vivo follow-up to KUB2012. In rat liver, all temporal patterns of blood insulin were encoded at the insulin receptor, and downstream molecules decoded them selectively through AKT: S6K read the additional (pulse-like) secretion, G6Pase the basal secretion via FoxO1, GSK3-beta all of it. Modelling tied the selectivity to network structure, sensitivity and time constants. Shows that pattern decoding is not only a cell-culture effect. |
| 2008 | A | A role for autophagy in the extension of lifespan by dietary restriction in C. elegans HAN2008 Makes autophagy a necessary step between dietary restriction and a longer life, not a side effect of it: blocking autophagy genes abolishes the lifespan extension produced both by dietary restriction and by TOR inhibition. The paper is equally careful about what autophagy cannot do on its own, because autophagy still runs in animals lacking DAF-16/FOXO and yet those animals are not long-lived. Boundary: worms; necessity was shown, sufficiency was not. |
| 2007 | A | Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans HAN2007 The authors systematically tested whether lowering protein synthesis extends lifespan in the worm C. elegans. Reducing ribosomal proteins, the S6 kinase homologue rsks-1 or translation-initiation factors increased lifespan, and these perturbations, like TOR inhibition, increased resistance to heat stress. Different kinds of translation inhibition split into two groups: one that needed the FOXO transcription factor DAF-16 for the lifespan and stress effects and one that did not. The results linked TOR, but not sir-2.1, to the lifespan extension caused by dietary restriction in worms, and suggested that neither TOR inhibition nor dietary restriction works simply by reducing total protein synthesis. Boundary: Nematode only, with gene knockdown by RNAi or mutation; drafted from the abstract only, so effect sizes and which TOR experiments were new in this paper are not given here. |
| 2026 | M | mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia DAB2026 mTORC1 inhibitors upregulate CD20 via the AKT-FOXO1 axis and promote B-lineage maturation in B-cell precursor ALL, enhancing the antitumor efficacy of anti-CD20 monoclonal antibodies -- including in high-risk IKZF1-deleted disease -- providing a rationale for combining mTORC1 inhibition with CD20-directed immunotherapy. |
| 1999 | M | Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor BRU1999 Akt phosphorylates the Forkhead transcription factor FKHRL1 (a FOXO family member), driving its cytoplasmic retention via 14-3-3 binding and blocking Fas-ligand-driven apoptosis — the discovery that placed FOXO transcription factors downstream of Akt/PI3K survival signalling. |
Related entities
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