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FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity
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 (FOX...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014046/ https://www.ncbi.nlm.nih.gov/pubmed/36617632 http://dx.doi.org/10.1111/acel.13763 |
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author | Santo, Evan E. Ribel‐Madsen, Rasmus Stroeken, Peter J. de Boer, Vincent C. J. Hansen, Ninna S. Commandeur, Maaike Vaag, Allan A. Versteeg, Rogier Paik, Jihye Westerhout, Ellen M. |
author_facet | Santo, Evan E. Ribel‐Madsen, Rasmus Stroeken, Peter J. de Boer, Vincent C. J. Hansen, Ninna S. Commandeur, Maaike Vaag, Allan A. Versteeg, Rogier Paik, Jihye Westerhout, Ellen M. |
author_sort | Santo, Evan E. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10014046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100140462023-03-15 FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity Santo, Evan E. Ribel‐Madsen, Rasmus Stroeken, Peter J. de Boer, Vincent C. J. Hansen, Ninna S. Commandeur, Maaike Vaag, Allan A. Versteeg, Rogier Paik, Jihye Westerhout, Ellen M. Aging Cell Research Articles 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. John Wiley and Sons Inc. 2023-01-08 /pmc/articles/PMC10014046/ /pubmed/36617632 http://dx.doi.org/10.1111/acel.13763 Text en © 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Santo, Evan E. Ribel‐Madsen, Rasmus Stroeken, Peter J. de Boer, Vincent C. J. Hansen, Ninna S. Commandeur, Maaike Vaag, Allan A. Versteeg, Rogier Paik, Jihye Westerhout, Ellen M. FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
title |
FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
title_full |
FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
title_fullStr |
FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
title_full_unstemmed |
FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
title_short |
FOXO3A‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
title_sort | foxo3a‐short is a novel regulator of non‐oxidative glucose metabolism associated with human longevity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014046/ https://www.ncbi.nlm.nih.gov/pubmed/36617632 http://dx.doi.org/10.1111/acel.13763 |
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