In an effort to dissect the genetic components of longevity, we have undertaken case-control studies of populations of centenarians (n = 338) and adults aged 20-70 years at several polymorphic candidate gene loci. Here we report results on two genes, chosen for their impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin-converting enzyme (ACE). We find that the epsilon 4 allele of APOE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p < 0.001), while the frequency of the epsilon 2 allele, associated previously with type III and IV hyperlipidemia, is significantly increased (p < 0.01). A variant of ACE which predisposes to coronary heart disease is surprisingly more frequent in centenarians, with a significant increase of the homozygous genotype (p < 0.01). These associations provide examples of genetic influences on differential survival and may point to pleiotropic age-dependent effects on longevity.

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We have determined serum activity and kinetic constants of angiotensin I-converting enzyme (ACE), parallel to an insertion/deletion (I/D) polymorphism in its gene, in French centenarians and controls 20–70 years of age because this enzyme could have an impact on cardiovascular risk, and thus on longevity. Both the ACE D allele and ACE D/D genotype were more frequent in centenarians in comparison with controls, without sex-related differences nor significant correlation with a cardiovascular pathology. In centenarians, I/D polymorphism was correlated with circulating ACE activity (D/D genotype, 89.0 ± 36.8 U/L; I/D genotype, 63.5 ± 26.0 U/L; and I/I genotype, 55.1 ± 39.4 U/L). The Michaelis constants for two substrates were identical whatever the genotype and were not different between centenarians and controls, i.e., 0.30 ± 0.03 mmol/L for furylacryloyl-phenylalanyl-glycyl-glycine and 1.35 ± 0.05 mmol/L for hippuryl-histidyl-leucine; for the latter, the optimal pH and activating concentration of chloride did not depend on I/D polymorphism. The maximal velocities with both substrates reflected the distribution of serum ACE activity as a function of the genotypes, in centenarians and in controls. In conclusion, plasma ACE activity is subject to a similar genotypic influence in centenarians as in adults 20–70 years of age; however, ACE itself appears to be functionally similar for each genotype. Furthermore, the D allele as well as the higher serum ACE activities associated with the D/D genotype cannot discriminate individuals at high risk for cardiovascular diseases, major causes of mortality before the age of 100 years.

We have used a PCR based method to analyze allelic frequencies in a (TG)n(AG)m microsatellite marker located in the first intron of the apolipoprotein C-II gene in French MS patients and controls. Samples were collected from 74 MS patients and from 102 controls. The distribution of microsatellite alleles differed between patients and controls (chi 2 = 7.82), showing a significant effect (P < 0.04) with MS due to the increased frequency of the allele 6 and a decrease frequency (P < 0.03) of allele I. Our study confirms that the apolipoprotein C-II region may influence susceptibility to MS.

Senescence evolves as a direct consequence of the ebbing of natural selection via antagonistic pleiotropy or active selection for alleles with early life benefits combined with harmful effects in later life (l). Resistance to activated protein C is caused by the substitution of arginine with glutamine at position 506 in the factor V gene and is due to a single point mutation in one of the two cleavage sites of activated protein C in the factor V gene. It was found to be a major factor involved in thrombophilia (from 2l to 3070 of patients with deep venous thrombosis) and is highly prevalent in the general European population (3 to