increased frequency of alleles and genotypes conferring susceptibility to cardiovascular diseases and thrombo- sis, such as PAI-1 and ACE, have been reported in centenarians (4, 7, 20). In order to explain this para- dox, which emerged from the research on centenarians, we have proposed a mathematical model suggesting that the over-crossing of the mortality curves at certain ages can explain these phenomena (21, 22). This model assumes that a genetic risk factor can confer an in- creased risk to die until a certain age, above which its impact is nullified or reversed. This phenomenon may occur because those people who survived at very ad- vanced ages have been selected by mortality forces, and thus could benefit from those genetic variants which are detrimental for younger people. For exam- ple, a profile predisposing to hypercoagulability could be beneficial at very advanced ages, but could predis- pose to cardiovascular diseases in the middle aged people (4, 20). Accordingly, the lack of GSTT1 (or other phase 2 genes) could be related to deleterious effects in young age (high risk of cancer) but it could exert long term beneficial effects on survival, by avoiding the catabolism of important substances, which have che- mopreventive effect on cancer and other diseases. In- deed, a recent study, shows that among subjects con- suming a diet rich in isothiocyanates (a lung carcinogen inhibitor), those with deletion of GSTM1 and/or GSTT1 have higher levels of this compound in the urine than subjects with the wild type genotype (23). Another possibility is that the association be- tween GSTT1 locus and longevity regards indeed a proximate locus of unknown nature whose variants are in linkage disequilibrium with the one we studied. Further studies are needed to clarify this point.

Multilocus (CYP1A1-GSTM-GSTT1) Genotypes in 87 Centenarians and 401 Control Subjects

Centenarians Control subjects CYP1A1* GSTM GSTT1 n (%) n (%) 0 0 0 21 (24) 116 (29) 1 0 0 6 (7) 34 (8) 2 0 0 0 (0) 2 (0.5) 0 2 0 27 (31) 136 (34) 1 2 0 7 (8) 35 (9) 2 2 0 1 (1) 6 (1) 0 0 2 10 (12) 39 (9) 1 0 2 4 (5) 3 (1) 0 2 2 8 (9) 28 (7) 1 2 2 3 (3) 2 (0.5)

Note. Statistical analysis: centenarians vs control subjects, x2 5 15.67; P 5 0.079. Only subjects in whom all the genes were tested are reported.

* Coding: CYP1A1, 0 5 homozygotes for the common allele; 1 5 presence of the polymorphism on one allele, 2 5 presence of the polymorphism on both alleles. GSTM1 and GSTT1, 0 5 homozygotes and heterozygotes for the common allele (which cannot be distin- guished by experimental procedures); 2 5 homozygous deletion of the allele.

1.5% in control subjects). According to the strong in- teraction between CYP1A1 and GSTT1, a significant difference in GSTT1 distribution between centenarians and control subjects occurred in CYP1A1 heterozygotes (x2 5 11.278; P 5 0.003), but not in CYP1A1 wild 5 5

The frequency of the GSTP1 polymorphism did not show any difference between centenarians and control subjects (data not shown).

In conclusion, GSTT1 can be added to the list of candidate longevity genes which have been identified so far, and it can open a new perspective on a possible “pharmacogenetics of longevity”.

DISCUSSION

In this study we confirm the lack of association be- tween GSTM1 and longevity, as previously described in a French population of centenarians (3), and we report new data for two polymorphisms in drug metab- olizing enzymes which have never been tested in cen- tenarians, namely CYP1A1 and GSTT1. We did not find any difference in the frequency of CYP1A1 in centenarians, as compared to control subjects of younger age. A significant increase in the GSTT1 ho- mozygous deletion in centenarians was observed, and this is the first report of a significant difference regard- ing drug metabolizing enzyme gene polymorphisms in centenarians. This finding is rather unexpected, as the deletion of the GST genes is considered a risk factor for cancer, causing the lack of conjugation of toxic com- pounds of environmental origin. Accordingly, a de- crease in frequency of the GSTT1 deletion in centenar- ians would be expected. However, this finding is not totally surprising and it is not the first description of an increased risk factor in centenarians. Indeed, an

ACKNOWLEDGMENTS

This work was supported by grants from AIRC “Healthy centenar- ians as a model to study genetic and cellular factors involved in cancer susceptibility”, University of Bologna ex-quota 60%, M.U.R.S.T. Projects “Genetic determinants of human longevity” and “Genetic factors involved in human aging and longevity”, Ministry of Health Project “Marcatori genetici e biologici di invecchiamento nor- male e patologico” to C.F., and M.U.R.S.T. Project “Immunogenetics of Longevity” to D. Monti.

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