Acknowledgments: This work was supported in part by CNR grants, Progetto Finalizzato Invecchiamento and MURST grants (60%). We thank Dr. Kathryn Boyd for reading the manuscript critically.

On the whole, our findings in centenarians indicate that during the process of selection that allows a few individuals to reach the extreme limits of human life, one is not disadvantaged by the polymorphic genotypes associated with high levels of coagulation factors and high responses to environmental triggers. The "4G" allele and "4G4G" genotype associated with elevated levels of PAI-1, which predict recurrence of myocardial infarction in young men, were even more frequent in centenarians than in young individuals. It is intriguing that genotypes associated with "high-risk" phenotypes are at least as frequent or even more frequent in centenarians than in young individuals who carry a lifelong risk of atherothrombotic disease. This paradoxical finding is not isolated because other genotypes with potentially unfavorable cardiovascular effects have been found more frequently in centenarians. Schachter et al., for instance, found that the homozygous genotype for the deletion polymorphism of the angiotensin-converting enzyme, which predisposes to coronary heart disease, is more frequent in French centenarians than in adults 20 to 70 years old (39.6% versus 25.6%). On the other hand, the "e4" allele of the gene encoding apolipoprotein E, which has been associated with ischemic heart disease, was not found to be associated with an increased risk of arterial thrombosis.

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