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

Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 03/2001; 280(5):1389-1392. DOI: 10.1006/bbrc.2001.4280


Drug metabolizing enzymes are involved in the detoxification of several drugs, environmental substances, and carcinogenic compounds, and their polymorphisms have been associated with risk for a variety of cancer. In this paper, we compared the frequency of polymorphisms in cytochrome P450-1A1 gene (CYP1A1), a phase 1 gene (oxidation, activation), and of two polymorphisms of glutathione S-transferase enzymes (GSTM1, GSTT1), two phase 2 genes (conjugation, detoxification). Two groups were studied and compared, i.e., 94 nonagenarians and centenarians and 418 control subjects of younger age. A significant difference in the proportion of nonagenarians and centenarians homozygotes for a GSTT1 deletion (28%) was observed in comparison to control subjects (19%, P = 0.03). The distribution of the other gene polymorphisms did not differ in the two groups. These findings on phase 2 drug-metabolizing enzyme gene polymorphisms may help in disentangling gene–environmental interactions which can have a role in successful aging and longevity, as well as in cancer incidence in the oldest old.

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Available from: Stefano Bertolini, Dec 25, 2013
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    • "Identification of genuine aging genes may uncover " master genes " that increase our understanding of many age-related diseases. There are a number of biological pathways that have been reported important in human aging, including lipid/cholesterol metabolism [GO:0006629; GO:0008203] (APOE, PON1, CETP) (Barzilai et al., 2003; de Chaves and Narayanaswami, 2008; Efrat and Aviram, 2010), immune system processes [GO:0002376] (IL6 and IL10) (Jylhävä and Hurme, 2009), drug metabolism [KEGG:hsa00982] (GSTT1) (Glatt et al., 2007; Taioli et al., 2001), energy metabolism in mitochondria (SIRT3) (Polito et al., 2010), and insulin receptor signaling pathway [GO:0008286] (IGF1R, FOXO3A, KLOTHO) (Arking et al., 2005; Suh et al., 2008; Willcox et al., 2008). Insights into human aging have been gained from studying model organisms. "
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    ABSTRACT: Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.
    Neurobiology of aging 03/2012; 33(8):1849.e5-18. DOI:10.1016/j.neurobiolaging.2012.02.014 · 5.01 Impact Factor
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    • "ndidate longevity gene , and it can open a new perspective on a possible " pharmacoge - netics of longevity . " These findings on phase 2 drug - metabolizing enzyme gene polymorphisms may help in disentangling gene environmental interactions that can have a role in successful aging and longevity , as well as in cancer incidence in the oldest old ( Taioli et al . 2001 ) . The biochemical , phenotypic , and genetic variations in a cohort of Ashkenazi Jewish centenarians , their offspring , and offspring - matched controls have been studied showing a gender - specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians . Sequence analysis of the IGF1 and IGF1 re"
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    ABSTRACT: The number of centenarians is growing worldwide. This specific cohort has aroused the attention of scientists worldwide and is considered one of the most valuable models to study the mechanisms involved in the aging process. In fact, they have reached the extreme limits of human life span and, most important of all, they show relatively good health being able to perform their routine daily life. Because they have escaped the common lethal diseases, the role of their genetic background has been brought into focus. In fact, sequence variations, in a variety of pro- or anti-inflammatory cytokine genes, have been found to influence successful ageing and longevity. The key role played by cytokines has been also confirmed in centenarians as we know that inflammation has been related to several pathological burdens (e.g., obesity, atherosclerosis, and diabetes). Successful ageing seems to be related to an optimal functioning of the immune system, pointing out that polymorphisms for the immune system genes, which are involved in the regulation of immune-inflammatory responses, may play a key role in the genetics of ageing. This review provides an update in the field of ageing related to inflammation and genetics.
    Human Biology 08/2011; 83(4):531-59. DOI:10.3378/027.083.0407 · 0.85 Impact Factor
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    • "Age-related disturbances in glutathione reductase activity have been also reported [28, 29]. Besides, frequency of homozygotes for glutathione transferase GSTT1 deletion increases with age [30]. Epidemiological studies have shown that advancing age is associated with an increased prevalence of hypertension [31] and genetic effect on blood pressure is modulated by age [32]. "
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