specific effect of this region of chromosome 19 on longevity was confirmed by examination of an apo C-I polymorphism, which is within 10 kb of apo E. Davi- gnon et al. [5] found a significant decrease in the apo E4 allele frequency in Canadian female octogenarians, which was not found in the males. Although both our study and that of Davignon et al. [5] failed to detect an apo E:apo C-I association in males, this may have been revealed by a larger sample size. However, gender differences in apo E-related risks for late-onset diseases are not particularly surprising. Previous studies have reported a stronger association between apo E4 and Alzheimer’s disease (AD) in females [19,20]. For exam- ple, in families with late-onset Alzheimer’s disease, fe- male apo E4 heterozygotes have higher risks for AD than those without apo E4, but the risks to het- erozygote women are no greater than those for ho- mozygotes. In men, the apo E4 homozygotes have higher risks than the heterozygotes and non-apo E4 carriers, but there was no significant difference in risks between apo E4 heterozygotes and non-apo E4-carriers [20]. In addition, recent work suggests that apo E has a significant effect on a larger set of lipid:apolipoprotein parameters in females compared to males [21].

remain significant when we re-analysed our data after the observed genotypes of the older men were com- pared to those in the young group computed from their allele frequencies, according to expectations of Hardy- Weinberg equilibrium. However, the importance of the ACE gene in longevity and the possibility of sex-specific effects was supported by our findings of different ACE genotypes in the elderly women and men. Our old individuals were younger than the French centenarians (see Fig. 1). It is possible that the deleterious effects of the I allele manifest at an earlier age in males than in females.

Schachter et al. explained the apparently paradoxical results they observed by suggesting that high blood pressure may be a protective factor in very old age [3]. However, the effects of this locus on longevity may involve non-cardiovascular manifestations, since neu- roendocrine [23] and immunomodulator [24] activities have been proposed for this enzyme. A correlation between ACE activity in cortical tissue and increasing age may suggest an adaptive response to increasing needs during ageing [25].

These studies highlight the importance of investigat- ing genotype variation, in addition to allelic variation, in genetic studies of survival into old age. Genetic influences in the individual are determined by genotypes and it is possible that certain combinations of deleteri- ous and comparatively protective genotypes may result in an effect being masked if only allele frequencies are considered. This may occur if the impact of a het- erozygous genotype is not midway between the two related homozygous states and if the frequency of a risk-related homozygous genotype is comparatively low. Such a scenario may be operating at the ACE locus. If the rare I:I genotype is deleterious and if the I:D and D:D genotypes are associated with similar risks, then it will be difficult to detect a change in the allele frequencies unless a larger sample is studied.

codon interchanges associated with apo E2, E3 and E4 are functionally associated with increasing risks for early death is suggested by earlier findings that the apo E4 allele is under-represented and apo E2 is over-repre- sented in centenarians [3]. Apo E2 is not overrepre- sented in our elderly population. Perhaps this can be explained by the younger age of our sample. Alterna- tively, this finding and the relatively stronger influence of the apo C-I gene would be compatible with at least two other possibilities. First, other DNA variants in this region of chromosome 19 may also be of functional significance. Second, apo E2 may in certain cases be associated with a greater risk than apo E3. For in- stance, apo E2:3 individuals have greater risks of carotid artery atherosclerosis than apo E3:3 ho- mozygotes [22].

There are a number of advantages of studying geno- types associated with longevity alongside disease-spe- cific analyses. First, loci like apo E and maybe ACE may impact on different disease systems. Thus, the quantitative effect of allelic variation on longevity will be difficult to predict from disease-specific studies. Sec- ond, it is possible that a given allele can be beneficial and deleterious at various stages of life, or that rela- tively deleterious and relatively beneficial functional variants are in linkage disequilibrium with alleles at a locus. This is possibly exemplified by the apparently paradoxical decrease in the I:I ACE genotype in elderly men, since studies of this locus in the context of coro- nary risk implicated the D allele as being deleterious. Clarification of the overall effect of a genotype is vital, if therapies are to be considered which interfere with a

ACE has been implicated as a risk factor for coro- nary artery disease in numerous studies. The DD geno- type has been previously considered as the deleterious allele, as it is more prevalent in myocardial infarction survivors and in victims of sudden cardiac death. The study of Schachter et al. [3] revealed an apparently paradoxical result, since the D allele was found in excess in the centenarians. We felt that this interesting result was important to replicate, since the centenarian and control populations were not precisely matched for geographical location and the controls ranged from 20–70 years. Of these centenarians 87% were women [3]. Although our data showed a similar trend, the reduction in the ACE I:I genotype in the elderly indi- viduals was confined to the men. This trend did not

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