FOXO3

forkhead box O3

Gene Information

Gene Symbol

FOXO3

Aliases

AF6q21, FOXO2, FKHRL1, FOXO3A

HGNC ID

HGNC:3821

NCBI Gene ID

2309

Ensembl Gene ID

ENSG00000118689

Gene Type

protein coding

Genomic Location

Chromosome

Assembly

GRCh38

Start Position

108,559,652

End Position

108,684,774

Number of Exons

Gene Length

125,123 bp

Overview

A transcription factor of the Fox family, FOXO3, is crucial in development. It also appears to regulate apoptotic signals in conjunction with FAS and AKT1. A homologue of FOXO3, daf-16, has been associated with ageing in roundworms, and overexpression of another homologue, dFOXO, in adult fat body of fruit flies increased longevity in females. Female mice without FOXO3 showed an ovarian phenotype of follicular activation leading to oocyte death, early depletion of functional ovarian follicles, and secondary infertility. Two studies of genetic variation within FOXO3, have found it to be associated with exceptional human longevity, among people of Japanese and German origin. The G allele of FOXO3 single nucleotide polymorphism (SNP) rs2802292 has been associated with longevity in multiple populations. G-allele carriers among combined Japanese, white and black populations have a risk reduction of 10% for total mortality.

Research Papers

20 papers in databaseSearch for More Papers

Score:

90%

Attenuation of primate aging via systemic infusion of senescence-resistant mesenchymal progenitor cells.

Cell Regen

2025

PMID: 40571786

Modification Effects

Enhanced FOXO3 activity in mesenchymal progenitor cells (MPCs); improved cellular function and gero-protective effects

Longevity Association

Slowed aging in cynomolgus macaques; improved cognitive performance, preserved brain structure, and rejuvenated immune function; substantial reduction in biological age, particularly in reproductive system, skin, lung, muscle, and hippocampus

Score:

90%

FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration.

Cell Stem Cell

2019

PMID: 30661960

Modification Effects

Genome editing to express activated FOXO3; transcriptional downregulation of CSRP1

Longevity Association

Delayed aging, increased resistance to oxidative injury in human vascular cells; vascular regeneration in mouse model of ischemic injury

Score:

90%

Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice.

Commun Biol

2021

PMID: 34103648

Modification Effects

Rps2-A226Y mutation; increased inborn error rate of mammalian translation, altered gene expression in skeletal muscle involving PGC1alpha, FOXO3, mTOR, and glucocorticoids pathways

Longevity Association

Activation of age-dependent muscle atrophy program in mice; reduced grip strength, involvement of key signaling pathways, contribution to age-related pathologies

Score:

80%

Extracellular vesicle-encapsulated miR-30c-5p reduces aging-related liver fibrosis.

Aging Cell

2024

PMID: 39269881

Modification Effects

miR-30c-5p overexpression; reduced stellate cell activation and fibrosis by targeting Foxo3

Longevity Association

Improved liver health, increased insulin sensitivity, and higher locomotor activity in aged mice; mechanism: reduced liver fibrosis and improved metabolism

Score:

80%

Effects of FOXO3 Polymorphisms on Survival to Extreme Longevity in Four Centenarian Studies.

J Gerontol A Biol Sci Med Sci

2018

PMID: 28977569

Modification Effects

FOXO3 SNPs (e.g., rs6911407, rs2253310) alter FOXO3 expression in brain tissue

Longevity Association

Association with survival to extreme longevity (>/=96 years in males, >/=100 years in females); uncommon rs9384680 genotype associated with mortality risk in elderly females

Score:

80%

Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype.

Geroscience

2023

PMID: 36881352

Longevity Association

FOXO3 longevity genotype reduces mortality risk; mechanism: modulation of stress proteins related to innate immunity, bone morphogenetic protein signaling, leukocyte migration, and growth factor response in humans

Score:

80%

Sex Difference and Interaction of SIRT1 and FOXO3 Candidate Longevity Genes on Life Expectancy: A 10-Year Prospective Longitudinal Cohort Study.

J Gerontol A Biol Sci Med Sci

2022

PMID: 34928346

Longevity Association

SIRT1 and FOXO3 polymorphisms associated with reduced mortality risk; stronger protective effect of FOXO3 in females and SIRT1 in males; mechanism: improved stress resistance

Score:

80%

GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

J Gerontol A Biol Sci Med Sci

2015

PMID: 25199915

Longevity Association

APOE and FOXO3 variants associated with longevity; 17% increased odds of longevity for FOXO3 variant in humans

Score:

80%

Lipid and Alzheimer's disease genes associated with healthy aging and longevity in healthy oldest-old.

Oncotarget

2017

PMID: 28206976

Longevity Association

Lower likelihood of APOEepsilon4 and haptoglobin HP2 alleles in 'Super-Seniors'; association with healthy aging and longevity in Europeans, mechanism involves lipid and cholesterol metabolism

#10

Score:

80%

KIT in oocytes: a key factor for oocyte survival and reproductive lifespan.

EBioMedicine

2024

PMID: 39067135

Modification Effects

Postnatal deletion of KIT expression in oocytes; loss of ovarian reserve, impaired folliculogenesis, and ovarian function

Longevity Association

Reduced reproductive lifespan in mice; mechanism: impaired oocyte survival and ovarian follicle maintenance

#11

Score:

80%

Effect of circRNA_FOXO3 rs12196996 polymorphism and FOXO3 rs2232365 polymorphism on survival rate and severity of intensive care unit-acquired sepsis.

Bioengineered

2022

PMID: 35156517

Modification Effects

rs12196996 GG and rs2232365 AA polymorphisms; altered expression of circRNA_FOXO3, FOXO3, and miR-23a

Longevity Association

Prolonged survival in ICU-acquired sepsis patients; mechanism: increased miR-23a, IL-10, and decreased pro-inflammatory cytokines

#12

Score:

80%

Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension.

Am J Hypertens

2016

PMID: 26476085

Modification Effects

FOXO3 SNPs (rs2802292, rs2253310, rs2802288); altered gene expression or function

Longevity Association

Lower blood pressure and reduced essential hypertension risk in Japanese women; 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP

#13

Score:

80%

Longevity-Associated FOXO3 Genotype and its Impact on Coronary Artery Disease Mortality in Japanese, Whites, and Blacks: A Prospective Study of Three American Populations.

J Gerontol A Biol Sci Med Sci

2017

PMID: 27694344

Modification Effects

FOXO3 G allele of rs2802292 SNP; potential impact on inflammation through TNF-alpha levels

Longevity Association

Protection against CAD mortality in Japanese, Whites, and Blacks; 15%, 9%, and 3% population-attributable risk reduction, respectively; potential mechanism: reduced inflammation

#14

Score:

80%

FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk.

J Hypertens

2024

PMID: 38009316

Modification Effects

FOXO3 G-allele (rs2802292 SNP); altered resilience and longevity properties

Longevity Association

Mitigated risk of cerebral microinfarcts with hypertension; 63.2% prevalence in studied population, significant interaction between FOXO3 G-allele and hypertension (P = 0.020) in human males

#15

Score:

80%

Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage.

J Hypertens

2022

PMID: 35943066

Modification Effects

FOXO3 G allele; potentially mitigates adverse effects of chronic cardiometabolic stress

Longevity Association

Attenuated risk of intracerebral haemorrhage with hypertension; 46.5% of participants carried FOXO3 G allele, in Japanese American men

#16

Score:

80%

FOXO3 longevity genotype mitigates the increased mortality risk in men with a cardiometabolic disease.

Aging (Albany NY)

2020

PMID: 33260156

Modification Effects

FOXO3 longevity-associated single nucleotide polymorphisms; altered gene expression or function

Longevity Association

19% reduced mortality risk (hazard ratio 0.81) in men with cardiometabolic disease; mechanism: protection against cardiometabolic stress

#17

Score:

80%

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.

Aging Cell

2021

PMID: 34227219

Modification Effects

Inhibition of neuromuscular acetylcholine receptor subunit unc-38; activation of FOXO/DAF-16 downstream targets

Longevity Association

Lifespan and healthspan extension in C. elegans; mechanism: DAF-16 signaling and reduced neuromuscular acetylcholine receptor activity

#18

Score:

80%

miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7.

Cell Death Dis

2014

PMID: 25077541

Modification Effects

miR-17 targets ADCY5 and IRS1; upregulates MKP7, FoxO3, LC3B, and HIF1alpha; downregulates mTOR, c-myc, cyclin D1, and JNK

Longevity Association

Extended lifespan in mice; mechanism: inhibition of cellular senescence mediated by MKP7, enhanced autophagy, and repression of apoptosis

#19

Score:

80%

Control of Oocyte Reawakening by Kit.

PLoS Genet

2016

PMID: 27500836

Modification Effects

KitD818V allele: constitutively-active; KitL allele: loss-of-function; Foxo3 protein localization affected

#20

Score:

80%

Selenoprotein P deficiency protects against immobilization-induced muscle atrophy by suppressing atrophy-related E3 ubiquitin ligases.

Am J Physiol Endocrinol Metab

2023

PMID: 36947851

Modification Effects

Selenoprotein P (SeP) deficiency; suppression of atrophy-related E3 ubiquitin ligases and upstream transcription factors FoxO1, FoxO3, and KLF15

Longevity Association

Protection against immobilization-induced muscle atrophy in mice; potential therapeutic target for sarcopenia, mechanism: reduced reductive stress

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