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FOXO3A-short is a n...
FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity
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- Santo, Evan E. (author)
- Weill Cornell Medical College
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- Ribel-Madsen, Rasmus (author)
- Novo Nordisk Foundation,Danish Diabetes Academy
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- Stroeken, Peter J. (author)
- Academic Medical Center of University of Amsterdam (AMC)
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- de Boer, Vincent C.J. (author)
- Wageningen University
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- Hansen, Ninna S. (author)
- University of Copenhagen
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- Commandeur, Maaike (author)
- Academic Medical Center of University of Amsterdam (AMC)
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- Vaag, Allan A. (author)
- Lund University,Lunds universitet,Translationell diabetesforskning,Forskargrupper vid Lunds universitet,Translational Diabetes Research,Lund University Research Groups,University of Copenhagen
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- Versteeg, Rogier (author)
- Academic Medical Center of University of Amsterdam (AMC)
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- Paik, Jihye (author)
- Weill Cornell Medical College
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- Westerhout, Ellen M. (author)
- Academic Medical Center of University of Amsterdam (AMC)
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(creator_code:org_t)
- 2023-01-08
- 2023
- English.
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In: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 22:3
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Abstract
Subject headings
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- Intronic single-nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby influencing lifespan. Here, we identify a primate-specific FOXO3A transcriptional isoform, FOXO3A-Short (FOXO3A-S), encoding a major longevity-associated SNP, rs9400239 (C or T), within its 5′ untranslated region. The FOXO3A-S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A-S mRNA. Assessment of the relationship between the FOXO3A-S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T-allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C-allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C-allele represses glycolysis independently of PI3K signaling, while overexpression of the T-allele represses glycolysis only in a PI3K-inactive background. Supporting this finding inducible knockdown of the FOXO3A-S C-allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A-S-derived protein(s), which in turn alters the relationship between FOXO3A-S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A-S T-allele with consistently higher insulin-stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Keyword
- aging
- FOXO
- FOXO3A
- glycolysis
- insulin
- PI3K
- skeletal muscle
- SNP
Publication and Content Type
- art (subject category)
- ref (subject category)
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Aging Cell
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- By the author/editor
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Santo, Evan E.
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Ribel-Madsen, Ra ...
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Stroeken, Peter ...
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de Boer, Vincent ...
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Hansen, Ninna S.
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Commandeur, Maai ...
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show more...
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Vaag, Allan A.
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Versteeg, Rogier
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Paik, Jihye
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Westerhout, Elle ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Physiology
- Articles in the publication
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Aging Cell
- By the university
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Lund University