FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity

Evan E. Santo*, Rasmus Ribel-Madsen, Peter J. Stroeken, Vincent C.J. de Boer, Ninna S. Hansen, Maaike Commandeur, Allan A. Vaag, Rogier Versteeg, Jihye Paik, Ellen M. Westerhout

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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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 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.

OriginalsprogEngelsk
Artikelnummere13763
TidsskriftAging Cell
Vol/bind22
Udgave nummer3
Antal sider13
ISSN1474-9718
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We would like to thank the Brodsky Lab at UCSF for providing the LHCNM2 cell line and culturing protocol. This work was supported by the National Institutes of Health [grant number AG048284]. R.R.‐M. was funded by research grants from The Danish Council for Independent Research and The Danish Diabetes Academy supported by the Novo Nordisk Foundation.

Publisher Copyright:
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

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