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

Autor: Frankum R; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK., Jameson TSO; College of Life and Environmental Sciences, University of Exeter, Exeter, UK., Knight BA; NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK., Stephens FB; College of Life and Environmental Sciences, University of Exeter, Exeter, UK., Wall BT; College of Life and Environmental Sciences, University of Exeter, Exeter, UK., Donlon TA; Honolulu Heart Program (HHP)/Honolulu-Asia Aging Study (HAAS), Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.; Departments of Cell & Molecular Biology and Pathology, University of Hawaii, Honolulu, HI, 96813, USA., Torigoe T; Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA., Willcox BJ; Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.; Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA., Willcox DC; Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.; Okinawa International University, Okinawa, Japan., Allsopp RC; Institute for Biogenesis Research, Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA., Harries LW; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK. L.W.Harries@exeter.ac.uk.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2022 Apr; Vol. 44 (2), pp. 1129-1140. Date of Electronic Publication: 2021 Aug 26.
DOI: 10.1007/s11357-021-00431-0
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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