* OR, odds ratio; and CI, confidence interval, for allele positivity of the variant allele.> P-value (HWE), probability for deviation from Hardy-Weinberg equilibrium.© R, reference allele; V, variant allele according to the NCBI reference sequence.

B. Pesch et al. / Toxicology Letters 151 (2004) 283–290

are referred to as anorexia of aging (MacIntosh et al., 2000). This syndrome is characterized by an unex- plained loss of food intake and body weight near the end of life (Horwitz et al., 2002). Besides malnutri- tion and depression as accompanying components of the social aging process, the lowering of body weight may be an evolutionary strategy to reduce the overall exposure to toxic metabolites (Hart et al., 1995). Or- ganisms have evolved neuroendocrine and metabolic response systems to cope with periods of food and en- ergy shortage.

recnacfosisongaidahtiwdnatuohtiw)sraey ycneuqerf <62.093.0)31.1–12.0(94.0)%1.21(4)%3.72(9)%6.06(02)%9.12(73)%9.43(95)%2.34(37V501I1PTSG ycneuqerFevitageNevitisoPevitageNevitisoP sevitagenfo 35.075.0)79.1–73.058.0(715179371MTSG 72.021.0)83.7–00.118.2(942020511TTSG .elellatnairavehtfoytivitisopelellaroflavretniecnedfinoc,ICdna;oitarsddo,ROa .muirbiliuqegrebnieW-ydraHmorfnoitaivedrofytilibaborp,)EWH(eulav-Pb .ecneuqesecnereferIBCNehtotgnidroccaelellatnairav,V;elellaecnerefer,Rc



The intracellular concentration of glutathione is re- duced in higher age (van Lieshout and Peters, 1998), accompanied by an increasing load of toxic metabo- lites and ROS (Lu et al., 1999). Therefore, there is a rationale to assume an impact of sequence variations in genes of xenobiotic metabolism in the process of senescence. Thus far, only a few studies have com- pared genotype distributions and allele frequencies of metabolic genes of the very old with younger age groups, to investigate a possible selection of genotypes during aging. In a German study on the possible role of genetic polymorphisms of three enzymes, GSTM1, N-acetyltransferase 2, and debrisoquine/sparteine hydrolase (CYP2D6) in aging, there was a lack of association with longevity (Muiras et al., 1998). By contrast, in an Italian study of polymorphisms of metabolic enzymes in healthy nonagenarians and cen- tenarians, GSTT1 deletions were significantly more prevalent than in the younger reference group (28% versus 19%), and no association with longevity could be demonstrated for the GSTM1 deletion and for CYP1A1 polymorphisms (Taioli et al., 2001).

With respect to genetic variants investigated in Germans older or younger than 80 years, so far we could not demonstrate striking differences, and the differences found have to be considered carefully with respect to a random variation because of multiple comparisons. These results confirm, that metabolic susceptibility genes have not been found as strong risk modifiers for aging and age-related diseases as expected in the 1990s (Garte, 2001). A comprehensive database of the allelic variation in common metabolic genes has been established in the International Project on Genetic Susceptibility (GSEC) containing infor- mation on over 15,000 non-cancer controls (Garte et al., 2001). Facing the large variation in the human genome, one cannot expect that a single common

B. Pesch et al. / Toxicology Letters 151 (2004) 283–290

In Caucasian GSEC males, the GSTT1 gene dele- tions were less prevalent than in females. Among the octogenarians, we could not demonstrate a significant gender difference for the sequence variations under study. Octogenarians had slightly less frequent GSTT1 deletions than the nonagenarians, and GSTM1 gene deletions were marginally more prevalent. This is in contrast to the results of an Italian study of polymor- phisms of metabolic enzymes in healthy nonagenar- ians and centenarians, where GSTT1 deletions were significantly more prevalent than in the younger ref- erence group (28% versus 19%), and no association with longevity could be demonstrated for the GSTM1 deletion and for CYP1A1 polymorphisms (Taioli et al., 2001).

gene variant may play a decisive role in either disease development or aging. Only a few rare sequence vari- ants were found strongly associated with a disease risk, such as BRCA1 with breast cancer and genes resulting in the Werner syndrome with aging.