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FOXO3 longevity genotype mitigates the increased mortality risk in men with a cardiometabolic disease

Authors :
Philip M C Davy
Brian J. Morris
Bradley J. Willcox
D. Craig Willcox
Timothy A. Donlon
Randi Chen
Kamal Masaki
Richard C. Allsopp
Source :
Aging (Albany NY)
Publication Year :
2020
Publisher :
Impact Journals, LLC, 2020.

Abstract

FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991–1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMD-affected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD (P=6x10-7). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.

Details

ISSN :
19454589
Volume :
12
Database :
OpenAIRE
Journal :
Aging
Accession number :
edsair.doi.dedup.....655ecb968aa7a125aa359bf34c21f33d
Full Text :
https://doi.org/10.18632/aging.202175