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The rs2802292, rs2764264 and rs13217795 variants of  FOXO3  have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the  FOXO3  gene. We performed a comprehensive assessment of  FOXO3  isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated  FOXO3  isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes.  FOXO3  isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length  FOXO3  isoforms in peripheral blood and a decrease in truncated  FOXO3  isoforms in skeletal muscle RNA. We suggest that the longevity effect of  FOXO3  SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated  FOXO3  isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality.

Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels