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

is a prominent longevity gene. To date, no-one has examined whether longevity-associated genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated 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 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 (=6x10). However, those men with a CMD who had the longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of with lifespan. Our study provides novel insights into the basis for the long-established role of as a longevity gene. We suggest that the longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.