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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. [ABSTRACT FROM AUTHOR]

Low birthweight ( LBW) individuals and offspring of women with gestational diabetes mellitus ( GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both prenatal and postnatal nongenetic factors, and it remains unknown to what extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared with nongenetic and epigenetic risk determinants and disease mechanisms. [ABSTRACT FROM AUTHOR]