FOXO3

Forkhead Transcription Factor · Longevity-Associated Gene

FOXO3 is the only gene found in nearly every study of people who live past 100 – centenarians around the world tend to carry certain protective variants. When insulin is low (fasting, caloric restriction), FOXO3 turns on a whole program of stress resistance, DNA repair, and cellular cleanup. Modern diets that keep insulin chronically high keep FOXO3 permanently switched off.

Size

673 amino acids

Complexes

Monomeric TF

Key pathway

PI3K / Akt / FOXO

Controls

Stress resistance · Autophagy

View in AlphaFold Database

Why FOXO3 is Central to Longevity

FOXO3 is exceptional among longevity targets because its significance comes directly from human genetics. Multiple independent GWAS studies of centenarians – populations aged 100+ from Hawaii, Europe, and Japan – have all identified the same FOXO3 locus as associated with exceptional longevity. The protective alleles appear to increase FOXO3 activity, shifting the insulin/IGF-1 signaling setpoint.

FOXO3's target genes read like a longevity checklist: SOD2 and catalase for antioxidant defense; GADD45 for DNA repair; LC3 and BNIP3 for autophagy; BIM and FasL for apoptosis of damaged cells. Conversely, when insulin and IGF-1 are high, Akt phosphorylates FOXO3 on three residues, trapping it in the cytoplasm where it cannot reach its gene targets.

The structure shown here was predicted by Google DeepMind's AlphaFold 2 model. Colors indicate prediction confidence (pLDDT score): blue regions are predicted with very high accuracy; orange regions represent flexible or disordered segments where confidence is lower.

Interventions Targeting FOXO3

Sorted by evidence grade

B+

Caloric Restriction

Reduces IGF-1/Akt, liberating FOXO3 to activate longevity programs

B-

Rapamycin

mTOR inhibition reduces Akt activity, activating FOXO3

B+

Time-Restricted Eating

Fasting suppresses insulin/IGF-1, activating FOXO3

About this structure

This 3D model was generated by AlphaFold 2, developed by Google DeepMind and EMBL-EBI. The structure represents the full-length human FOXO3 protein (UniProt O43524). AlphaFold predictions may differ from experimentally determined structures, particularly in disordered regions. Structure data is provided under CC BY 4.0. alphafold.ebi.ac.uk