Cited by 355FOXO transcription factor regulationGenetics, Aging, and Longevity in Model OrganismsMuscle Physiology and Disorders

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FOXO3: A Major Gene for Human Longevity - A Mini-Review

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Morris, Brian J., Willcox, Donald Craig, Donlon, Timothy A., Willcox, Bradley J.·2015·Gerontology

DOI 10.1159/000375235PMC PMC5403515

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Abstract

Background: The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. Objective: Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. Methods: The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword. Results: We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis. Conclusions: The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported.

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Authors: Morris, B. J., Willcox, D. C., Donlon, T. A., & Willcox, B. J.
Affiliations: University of Hawaiʻi at Mānoa (US)
Kuakini Medical Center (US)
ORCID: Morris, Brian J.
Donlon, Timothy A.
Willcox, Bradley J.
Venue: Gerontology
Publisher: S. Karger AG
Published: 2015
Volume: 61
Issue: 6
Pages: 515-525
ISSN: 0304-324X (ISSN-L)
1423-0003
DOI: 10.1159/000375235
PMC: PMC5403515
OpenAlex: W2058381071
Cited by: 353
References: 70
Citations by year: 2026: 25 · 2025: 32 · 2024: 44 · 2023: 39 · 2022: 45 · 2021: 34 · 2020: 33 · 2019: 26 · 2018: 22 · 2017: 29 · 2016: 20 · 2015: 4
FWCI: 2.42
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.karger.com/Services/SiteLicenses (vor)
www.karger.com/Services/SiteLicenses (tdm)
Locations: Gerontology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5r01ag038707-04, 5R01AG038707)
National Institute on Aging (5R01AG038707, R01-AG-038707, R01AG027060)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords: FOXO3, human longevity, healthy aging, genetic polymorphism, age-related diseases, oxidative stress, proteostasis, apoptosis, cell cycle regulation, stem cell maintenance, inflammation, energy metabolism, Hydra, lifespan
MeSH terms: Forkhead Box Protein O3, Animals, Humans, Longevity, Forkhead Transcription Factors

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FOXO3: A Major Gene for Human Longevity - A Mini-Review

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