TABLE 3. Triglyceride Levels in the Three Genotypes of the 4G5G and R353Q Polymorphisms

TABLE 2. Distribution of Genotype Combinations in Centenarians and Control Subjects

Centenarians Control Subjects (n=101) (n=60) 4G4G 121±69*(n=38) 69±19(n=20) 4G5G 125±82(n=52) 82±34 (n=25) 5G5G 88±37(n=11) 65±23(n=13) 353RR 122±79(n=66) 76±28 (n=35) 353RQ 116±67(n=28) 70±26 (n=20) 353QQ 93±49 (n=3) 78±39 (n=4)

Centenarians, Control Subjects, Genotype n (%) n (%) GG"455 353RR 4G4G 18(15.1) 12(9.4) 4G5G 24 (20.2) 20(15.6) 5G5G 7 (6.0) 15(11.7) 353RQ 4G4G 7 (5.9) 12(9.4) 4G5G 8 (6.7) 12(9.4) 5G5G 1 (0.8) 2(1.6) 353QQ 4G4G 0 2(1.6) 4G5G 2(1.7) 3 (2.3) 5G5G 2(1.7) 2(1.6) -455 GA 353RR 4G4G 13(10.9) 6 (4.7) 4G5G 16(13.5) 22(17.1) 5G5G 2(1.7) 5 (3.9) 353RQ 4G4G 3 (2.5) 3 (2.3) 4G5G 10(8.4) 4(3.1) 5G5G 1 (0.8) 5 (3.9) AA-455 353RR 4G4G 1 (0.8) 0 4G5G 0 2(1.6) 5G5G 1 (0.8) 0 353RQ 4G4G 0 1 (0.8) 4G5G 3 (2.5) 0 X2=26.88; P=.076.

The results of this study in centenarians on the of gene polymorphisms associated with cardiovascular risk factors are compatible with the belief that the basis of suc cessful aging is complex and multifactorial. It is likely that unidentified factors compensate for potentially unfavorable genotypes in centenarians. For instance, it can be hypoth esized that the association of 4G with longevity arises because linkage disequilibrium with a locus counteracting the putative unfavorable effect of elevated PAI-1 levels off sets the risk conferred by hypofibrinolysis and creates favor able long-term effects. We should also consider the pos sibility of a cohort effect when comparing centenarians with individuals <30 years old, because young individuals may not have been exposed to the same environmental factors to which centenarians had been exposed at the ages. It is also possible that among elderly people who escaped atherothrombotic disease, it is actually to have reduced fibrinolytic activity. The general conclu sion that can be drawn from the study is that there is no evi dence that possession of genotypes associated with circulating levels of fibrinogen, factor VII, and PAI-1 reduces the chance of survival to the age of 100 years without evi dent atherothrombotic disease.

from http://ahajournals.org by on March 13, 2020

ciation between triglycerides and the factor VII genotype 353RR. Hence, the interaction between triglycerides and PAI-1 genotypes found in patients with non-insulin depen dent diabetes mellitus17 was also present in centenarians. The relatively small sample is perhaps an explanation for the lack of association between triglyceride levels and the 4G4G genotype in young, healthy individuals.

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 dis advantaged 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 indi viduals. 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 para doxical finding is not isolated, because other genotypes with potentially unfavorable cardiovascular effects have been found more frequently in centenarians. Schachter et al,18 for instance, found that the homozygous genotype for the deletion polymorphism of the angiotensin-converting enzyme, which predisposes to coronary heart disease,19,20 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,21'22 was

On the whole, our findings in centenarians indicate during the process of selection that allows a few to reach the extreme limits of human life, one is not dis advantaged by the polymorphic genotypes associated high levels of coagulation factors and high responses environmental triggers. The

G allele and

G

G associated with elevated levels of PAI-

, which recurrence of myocardial infarction in young men, even more frequent in centenarians than in young indi viduals. It is intriguing that genotypes associated "high-risk" phenotypes are at least as frequent or even frequent in centenarians than in young individuals carry a lifelong risk of atherothrombotic disease. This doxical finding is not isolated, because other with potentially unfavorable cardiovascular effects been found more frequently in centenarians. Schachter al,

for instance, found that the homozygous genotype the deletion polymorphism of the enzyme, which predisposes to coronary heart is more frequent in French centenarians than in adults to

years old (

% versus

%). On the other the e

allele of the gene encoding apolipoprotein E, has been associated with ischemic heart disease,

'

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