Abstract P176: Genes That Increase Human Lifespan By Protecting Against Risk Of Death From Cardiometabolic Diseases

Abstract

Further to our FOXO3 findings last year, we asked whether other longevity gene variants work by mitigating mortality risk from aging-related diseases. In a longitudinal study, 3,584 American men of Japanese ancestry from the Kuakini Honolulu Heart Program were followed from baseline (Exam 4, 1991-93) until Dec 31, 2019 (1% of men) or death (99%). At baseline, 2,512 subjects had either diabetes (n=1,010), hypertension (n=1,919) or coronary heart disease (CHD; n=738), and 1,072 lacked any cardiometabolic diseases (CMD). DNA samples for genotyping were obtained at baseline. Genotype frequencies of SNPs in MAP3K5 , PIK3R1 , GHR, CTGF , EGFR , FLT1 , SIRT5 and SIRT7 were compared between subjects with and without ageing-related diseases . In subjects with CMD, MAP3K5 rs2076260 longevity-associated genotypes CC and CC + TT were associated with longer lifespan (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12-1.35, p= 2.5x10 -5 ] in a major allele homozygote model, and 1.22 [95% CI: 1.11-1.33, p= 1.10x10 -5 ] in a heterozygote disadvantage model) compared with CT . For diabetes, hypertension and CHD, HR p -values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. For PIK3R1 , subjects with cardiovascular disease (CVD) having the longevity-associated genotypes TT / CC of SNP rs7709243 had survival curves similar to those of subjects without a CVD (HR 1.26 [95% CI, 1.14-1.39; p =0.0000043]). In contrast, survival curves of subjects with the CT genotype were significantly lower compared with survival curves of subjects without a CVD ( p =0.0000012 compared with TT / CC , and p =0.0000028 compared with CT ). For GHR SNP rs4130113 , in a heterozygote disadvantage model GG vs longevity-associated AG genotype was associated with reduced mortality risk from hypertension (HR 1.23 [95% CI, 0.94-1.41; p =0.0041]). Men without CVD showed no association of longevity-associated genotype with lifespan. For each gene, men without the disease outlived men with disease ( p < 10 -6 ), but genotype had no effect on lifespan. In conclusion, for MAP3K5 , PIK3R1 and GHR , but not other longevity genes, longevity genotype increases lifespan only in individuals who have CMD, CVD or hypertension, likely by protection against disease-related cellular stress.