Polymorphisms of Drug-Metabolizing Enzymes in Healthy Nonagenarians and Centenarians: Differences at GSTT1 Locus

*Laboratorio Epidemiologico, Ospedale Policlinico IRCCS, Milan, Italy; Institute of Internal Medicine, University of Milan, Milan, Italy; Italian National Research Centers on Aging, INRCA, Ancona, Italy; Department of Experimental Pathology, University of Bologna, Bologna, Italy; Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy; iAtherosclerosis Prevention Centre, Department of Internal Medicine, University of Genoa, Genoa, Italy; and **Genetics Research Institute, Strada della Carita` 10, 20135 Milan, Italy. Received January 5, 2001. View (1). They are the best example of successful aging and represent a valuable model for studying the genetic factors impinging on survival (risk factors for cancer and other major age-related diseases) (2). In fact, some risk factors for age-related diseases are hyporepresented in centenarians (3), whilst others are unexpectedly present in healthy centenarians at equal or even increased frequency compared to controls (47). Nevertheless, a number of studies revealed that in centenarians important changes occur in genetic variability of loci that are not risk factors for specific diseases but are rather responsible for modulating the individual capacity to cope with stress, such as Tyrosine Hydroxylase and mitochondrial DNA (8, 9).

In this scenario, enzymes involved in the metabolism of potentially dangerous endogenous and exogenous compounds are likely to play a major role in human longevity. A variety of polymorphisms have been reported in these genes and have been associated with susceptibility to cancer (10) and other age-related diseases such as Parkinson's disease (11). Among these candidate genes, there are Phase 1 (oxidation, activation) and Phase 2 (conjugation, detoxification) drug-metabolizing genes, such as cytochrome P450 genes and glutathione S-transferase enzymes (GST). Cytochrome P450 genes are involved in the first step of the metabolism of polycyclic aromatic hydrocarbons contained in tobacco smoke, whilst GST genes are involved in the detoxification of several drugs, environmental substances, and carcinogenic compounds. In particular, common polymorphisms leading to a complete deletion of the gene cause a loss of GST functional activity. Individuals with such gene deletions exhibit decreased conjugation activity and are consequently exposed to higher internal doses of potentially toxic intermediary metabolites from xenobiotic agents.

Data on the frequency of polymorphisms in some phase 1 genes (CYP2E1 (12), CYP2C19 (14), CYP2D6 (13, 14)) and phase 2 genes (NAT2 (13, 14), GSTM1 (13)), as well as other polymorphisms associated with cancer susceptibility, i.e., p53 (15, 16), did not show any difference between centenarians and the general population. In this study, we focused our attention on other members of the phase 1 gene family (CYP1A1) and phase 2 genes (GSTT1 and GSTP1) never studied before in centenarians, as well as on a gene that has been studied in French centenarians with negative results (GSTM1) (13). The hypothesis was that the frequency of the least favorable polymorphisms should be lower in centenarians than that observed in the general population.

Genotype Frequency of Drug-Metabolizing Gene Polymorphisms in Centenarians and Younger Subjects

Centenarians Control subjects 
(n=94) (n=418) 
Genes Genotypes n (%) n (%) 
CYP1A1 Wild typea 70 (77)b 328 (79) 
Heterozygous 20 (22) 81 (19) 
Homozygous 1 (1) 9 (2) 
GSTM1 Nullc 47 (53) 211 (51) 
Present 41 (47) 198 (49) 
GSTT1 Nullc 25 (28) 76 (19) 
Present 63 (72) 330 (82) 

x2=0.10, P=0.74; GSTT1, x2=4.18, P=0.03.

a Wild type refers to the homozygotes for the common allele (absence of the restriction site polymorphism), heterozygous refers to the presence of the polymorphism on one allele, homozygous refers to the presence of the polymorphism on both alleles.

b 

MATERIALS AND METHODS

Nonagenarians and centenarians in good health, i.eBenedictis, G., Bertolini, S., Barbi, C., Monti, D., and Franceschi, C. (2001). Lack of association between GSTM1 and longevity was confirmed in this study, as previously reported in a French population of centenarians. We also found no difference in the frequency of CYP1A1 in centenarians compared to control subjects of younger age. However, we did observe a significant increase in the homozygous deletion of GSTT1 in centenarians, which is unexpected as the deletion of GST genes is generally considered a risk factor for cancer. This finding suggests that GSTT1 may be a candidate longevity gene and could open up new perspectives on the pharmacogenetics of longevity.

The difference between centenarians and control subjects was mainly due to the CYP1A1-GSTM1-GSTT1 combinations 1-0-2 and 1-2-2 (Table 2), both containing the combination of CYP1A1 heterozygotes and GSTT1 deletion genotypes. The frequency of alleles and genotypes conferring susceptibility to cardiovascular diseases and thrombosis, such as PAI-1 and ACE, has been reported to increase in centenarians. To explain this paradox, a mathematical model has been proposed suggesting that certain genetic risk factors can confer an increased risk of death until a certain age, after which their impact is nullified or reversed. This phenomenon may occur because those who survive at very advanced ages have been selected by mortality forces and could benefit from those genetic variants that are detrimental to younger people.