FOXO3A genotype is strongly associated with human longevity
Open accessAbstract
Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 ( P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.
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Polymorphisms in two IIS pathway genes, the IGF-1 receptor and the downstream FOXO3 transcription factor, have been associated with longevity and healthy ageing in humans.
“Polymorphisms in two IIS pathway genes, the IGF-1 receptor and the downstream FOXO3 transcription factor, have been associated with longevity and healthy ageing in humans (62–64).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [64]
Allele variants at FOXO3 are associated with extreme longevity in humans.
“Indeed, allele variants at the FOXO3 locus are associated with extreme longevity (centenarians) in humans (for example, Willcox et al., 2008).”
From The Aging Epigenome (2016) · cites this paper as Willcox et al., 2008
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- Authors
- Willcox, B. J., Donlon, T. A., He, Q., Chen, R., Grove, J. S., Yano, K., Masaki, K. H., Willcox, D. C., Rodriguez, B., & Curb, J. D.
- Affiliations
- Kuakini Medical Center (US)
- University of Hawaiʻi at Mānoa (US)
- Pacific Health Research and Education Institute (US)
- *Pacific Health Research Institute, 846 South Hotel Street, Honolulu, HI 96813;
- Corresponding author
- Willcox, Bradley J.
- Masaki, Kamal H.
- Curb, J. David
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-09-16
- Volume
- 105
- Issue
- 37
- Pages
- 13987-13992
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2544566
- OpenAlex
- W1992444358
- Cited by
- 983
- References
- 67
- Citations by year
- 2026: 37 · 2025: 39 · 2024: 44 · 2023: 47 · 2022: 45 · 2021: 52 · 2020: 61 · 2019: 52 · 2018: 43 · 2017: 63 · 2016: 63 · 2015: 62 · 2014: 75 · 2013: 65 · 2012: 65
- FWCI
- 16.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hawaii Community Foundation (Grant 2004-0463, 2004-0463)
- National Institutes of Health (5u01ag019349-08, n01hc005102-027)
- National Institute on Aging (N01-HC-05102, 5 U01 AG019349-05, K08AG022788, K08 AG22788-02, N01‐AG‐4‐2149, U01-AG019349, R01AG027060)
- National Heart, Lung, and Blood Institute (N01 HC005102, N01 HC 05102)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- FOXO3, human longevity, insulin/IGF-1 signaling pathway, aging, genetic association, healthy aging, cancer prevalence, cardiovascular disease, self-reported health, physical function, cognitive function, insulin sensitivity, homozygosity
- MeSH terms
- Forkhead Box Protein O3, Aged, Aged, 80 and over, Genotype, Health, Humans, Longevity, Male, Phenotype, Case-Control Studies, Forkhead Transcription Factors
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