FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity
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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.; Versteeg, Rogier; Paik, Jihye; Westerhout, Ellen M.
In: Aging Cell, Vol. 22, No. 3, e13763, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity
AU - Santo, Evan E.
AU - Ribel-Madsen, Rasmus
AU - Stroeken, Peter J.
AU - de Boer, Vincent C.J.
AU - Hansen, Ninna S.
AU - Commandeur, Maaike
AU - Vaag, Allan A.
AU - Versteeg, Rogier
AU - Paik, Jihye
AU - Westerhout, Ellen M.
N1 - Publisher Copyright: © 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - aging
KW - FOXO
KW - FOXO3A
KW - glycolysis
KW - insulin
KW - PI3K
KW - skeletal muscle
KW - SNP
U2 - 10.1111/acel.13763
DO - 10.1111/acel.13763
M3 - Journal article
C2 - 36617632
AN - SCOPUS:85146073629
VL - 22
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 3
M1 - e13763
ER -
ID: 333346390