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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. LU ; Versteeg, Rogier ; Paik, Jihye and Westerhout, Ellen M. (2023) In Aging Cell 22(3).
Abstract

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... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aging, FOXO, FOXO3A, glycolysis, insulin, PI3K, skeletal muscle, SNP
in
Aging Cell
volume
22
issue
3
publisher
Wiley-Blackwell
external identifiers
  • pmid:36617632
  • scopus:85146073629
ISSN
1474-9718
DOI
10.1111/acel.13763
language
English
LU publication?
yes
id
133e3713-6fd9-46ff-8da1-f8c3daa7e6c9
date added to LUP
2023-02-16 15:08:28
date last changed
2024-03-17 07:23:28
@article{133e3713-6fd9-46ff-8da1-f8c3daa7e6c9,
  abstract     = {{<p>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.</p>}},
  author       = {{Santo, Evan E. and Ribel-Madsen, Rasmus and Stroeken, Peter J. and de Boer, Vincent C.J. and Hansen, Ninna S. and Commandeur, Maaike and Vaag, Allan A. and Versteeg, Rogier and Paik, Jihye and Westerhout, Ellen M.}},
  issn         = {{1474-9718}},
  keywords     = {{aging; FOXO; FOXO3A; glycolysis; insulin; PI3K; skeletal muscle; SNP}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Aging Cell}},
  title        = {{FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity}},
  url          = {{http://dx.doi.org/10.1111/acel.13763}},
  doi          = {{10.1111/acel.13763}},
  volume       = {{22}},
  year         = {{2023}},
}