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

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.

Keywords: FOXO3; genetics; longevity; mortality; resilience.

Figure 1

Survival curves spanning the period from baseline (1991–1993) to Dec 31, 2019 for subjects with and without a CMD according to whether they were carriers of the longevity-associated G allele of SNP rs2802292. The survival probabilities were estimated from the Cox proportional hazard model (see Methods) h(t) = h(t0) * exp(β1*Age + β2*BMI + β3*Glucose + β4*CMD + β5*FOXO3_G + β6* (CMD*FOXO3_G)) by fixing age at 75 years, BMI at the mean, 23.5 kg/m², and glucose at the mean, 113 mg/dL (where β6 is the effect of the interaction of CMD with FOXO3 genotype (G carriers vs. TT genotype) on mortality, giving P(β6) = 0.04). The P values for comparison of survival curves for the group without any CMD for FOXO3-G carriers vs. FOXO3-TT, and comparison of survival curves for the group with a CMD for FOXO3-G carriers vs. FOXO3-TT, were P=0.97 and P=0.0002, respectively. The P-values for comparison of survival curves for FOXO3-TT carriers or for FOXO3-G carriers for those with a CMD versus those without any CMD, were P=0.000039 and P=0.28 respectively.

Figure 2

Mortality risk expressed as hazard ratio, adjusted for age, BMI and glucose, for CMD subjects and subjects without a CMD according to whether they were carriers of the longevity-associated (G) allele of the FOXO3 SNP rs2802292 (TG/GG) or were homozygous for the major (T) allele (i.e., were TT). In men with CMD and the FOXO3 longevity genotype, mortality risk was reduced to normal (i.e., did not differ significantly from that of men without CMD).