The Association Between Longevity-Associated FOXO3 Allele and Heart Disease in Septuagenarians and Octogenarians: The SONIC Study

Abstract

The G allele of FOXO3 gene (Single nucleotide polymorphism – SNP; rs2802292) is strongly associated with human longevity. However, knowledge of the effect of FOXO3 in older populations, men or women, with heart disease is limited. This cross-sectional study in Japan included 1836 older adults in the 70 and 80-year-old groups. DNA samples isolated from buffy coat samples of peripheral blood were used to genotype FOXO3 (rs2802292). Self-reports were used to obtain heart disease data according to physician diagnosis. Multiple logistic regression was used to test the association by adjusting for the traditional risk factor of heart disease. The prevalence of heart disease in women FOXO3 G allele carriers was higher than non-carriers (16.7 vs. 11.6%, p=.022). The prevalence of coronary heart disease was lower for FOXO3 G carriers in the 70-year-old group for both sexes (men: 9.3 vs. 4.3%, p=.042, and women: 10 vs. 9%, p=.079, respectively). The G allele was negatively associated with heart disease after adjusting for diabetes, hypertension, dyslipidemia, and smoking in men (odds ratio (OR)= 0.70, 95%confidence intervals (CI), 0.49-0.99, p=.046), although the association was weaker after full adjustment. In contrast, women carriers of the FOXO3 G allele showed a positive association with heart disease after total adjustment (OR= 1.49, 95%CI, 1.00-2.21, p=.049). In conclusion, the longevity associated G allele of FOXO3 was observed to have contrasting associations with heart disease prevalence according to sex in older Japanese. To further confirm this association, a longitudinal study and a large sample size will be required.

Targeting the redox system for cardiovascular regeneration in aging

“…It verifies age‐related loss of FOXO3A as a key regulator of endothelial aging (Zhang, Murugesan, et al., 2020 ; Zhang, Zhang, et al., 2020 ). Notably, FOXO3A has been recognized as an evolutionarily conserved transcription factor that acts in redox regulation and correlates with longevity (Klinpudtan et al., 2022 ) and a lower prevalence of cardiovascular disease in long‐lived humans (Ronnebaum & Patterson, 2010 ). Not only in aged arterial ECs, single‐nucleus RNA‐Seq verify that oxidative responses are enriched in aged CMs in both primate (Ma et al., 2021 ) and human (Koenig et al., 2022 ) hearts.…”

Energy Homeostasis Gene Nucleotide Variants and Survival of Hemodialysis Patients—A Genetic Cohort Study

“…Associations between FOXO3 rs2802292 and the prevalence of essential hypertension and improved metabolic control in diabetic patients have been shown in previous studies [70,71]. On the other hand, Klinpudtan et al reported that the longevity-associated G allele of FOXO3 rs2802292 appears to have contrasting associations with heart disease prevalence according to sex in older Japanese people [16]. The FOXO3 protein might play a protective role in chronic kidney disease by preventing mitochondrial damage and ameliorating fibrosis [72,73].…”

“…Some studies have shown that nucleotide variants in the insulin growth factor-1 (IGF-1) signaling pathway genes involved in glucose metabolism could influence human longevity [15]. For example, the forkhead box protein O3 gene (FOXO3, OMIM*602681) encoding the IGF-1 pathway downstream transcription factor (TF), forkhead box protein O3 (FOXO3), has been found to be strongly associated with human longevity and the prevalence of diabetes and arterial hypertension [16]. Previous in vitro studies found that FOXO3 plays a crucial role in regulating the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT (Protein Kinase B) metabolic pathway [17].…”

FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk

“…We subsequently showed that G-allele carriage was associated with protection against coronary artery disease (CAD)-associated mortality [13]. Another study also demonstrated the protective effect of the FOXO3 G-allele against heart disease among older Japanese men [14]. Although the exact mechanism by which FOXO3 genotype is associated with healthy aging and increased lifespan remains to be fully clarified, it has been postulated that the longevity-associated FOXO3 G-allele may serve as a 'resilience' gene by mitigating the adverse effects of chronic cardiometabolic stress on intracellular processes, thereby reducing the risk of life-threatening cardiovascular events [12,15].…”