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

TitleFOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity.
Publication TypeJournal Article
Year of Publication2023
AuthorsSanto EE, Ribel-Madsen R, Stroeken PJ, de Boer VCJ, Hansen NS, Commandeur M, Vaag AA, Versteeg R, Paik J, Westerhout EM
JournalAging Cell
Date Published2023 Mar
KeywordsAnimals, Forkhead Box Protein O3, Forkhead Transcription Factors, Glucose, Humans, Insulin, Longevity, Phosphatidylinositol 3-Kinases, RNA, Messenger

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‚ÄČT-allele with consistently higher insulin-stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.

Alternate JournalAging Cell
PubMed ID36617632
PubMed Central IDPMC10014046
Grant ListR56 AG048284 / AG / NIA NIH HHS / United States
Related Faculty: 
Ji-Hye Paik, Ph.D.

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