adjusted in association studies, and the underlying statistical models assume that the risk estimate for a gene variant as well, as for an exogenous factor, is independent of age. But there is evidence that with increasing age certain genetic variants may have ei- ther an increasing or decreasing impact on the health status. Among the octogenarians of our study, the CYP1B1 432L allele frequency was significantly lower than in the reference group. Especially in male oc- togenarians, there was a marginally significant lower prevalence of the CYP1B1 432LL genotype than in women. There are plausible explanations for an as- sociation of the CYP1B1 variation with aging. The amino acid substitution V432L is located in the heme binding domain in exon 3 of CYP1B1 (Bailey et al., 1998) and has been suggested to result in an impact on the catalytic activity (Li et al., 2000). Specifically, CYP1B1 has a specific activity of o-hydroxylating estradiol to 4-hydroxyestradiol and is involved in the steroid hormone biosynthesis (Spink et al., 1994). Catechol estrogens may undergo redox cycling to semiquinone and quinone intermediates capable of reacting with biological macromolecules (Bolt et al., 1974). Furthermore, CYP1B1 is likely associated with tissue differentiation and may, thus, be considered a morphogene. Rare mutations were associated with primary congenital glaucoma (Stoilov et al., 1997), and a link to the regulation of adipocyte differentiation has been established (Alexander et al., 1998). Con- stitutive CYP1B1 protein levels in human tissues are relatively low (Murray et al., 2001). Whereas, many metabolic genes are downregulated in age-related dis- eases such as cancer (Dialyna et al., 2001). CYP1B1 is overexpressed in a variety of cancers, including those of the breast, colon, lung, esophagus, skin, lymph node, brain, and testis (Murray et al., 1997). Additionally, CYP1B1 was found associated with the integrity of the tumor suppressor gene p53. In a head and neck cancer study, a significant association be- tween the CYP1B1 V432L polymorphism and the rate of somatic p53 mutations could be revealed (Ko et al., 2001).

A pronounced pattern of allelic differences could be shown for octogenarians with and without a diagnosis of cancer during lifetime with respect to the genetic polymorphisms under study, but random variation due to small numbers of subjects and due to the large number of comparisons has to be taken into account. A significant deviation from the Hardy-Weinberg equilibrium could be demonstrated for GSTP1 I105V, with less observed heterozygous 105IV genotypes and more homozygous 105VV genotypes than expected among non-cancer octogenarians. Like CYP1B1, GSTP1 has a corresponding rationale for an asso- ciation with age-related effects. The GSTP1 I105V sequence variation is located at the substrate binding site of the enzyme and has been shown to affect en- zyme activity (Zimniak et al., 1994; Ji et al., 1997; Sundberg et al., 1998; Watson et al., 1998). Whereas, µ θ GST and GST genes cluster on chromosomes 1 and 22, respectively, GSTP1 is encoded by a single locus on chromosome 11 (Ali-Osman et al., 1997), indicating a distinct genomic evolution among the GST family. GSTP1 was found up-regulated during development (Raijmakers et al., 2001) and associ- ated with the integrity of the tumor suppressor gene p53 (Gudmundsdottir et al., 2001) and with k-ras mutations (Miyanishi et al., 2001).

One of the possible explanations of the weak association of common genetic polymorphisms in metabolic susceptibility genes with carcinogenesis and aging may come from the evolutionary perspec- tive. First, metabolic susceptibility genes are ancient genes, thus, not closely associated with key processes such as proliferation and differentiation to develop

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and maintain a complex body structure from the un- derlying wealth of genetic information. Second, the evolution of the genome has created linear chromo- somes instead of circular forms which may become a limiting factor of the life span due to the inability of conventional DNA polymerases to replicate the ends in somatic cells (Takahashi et al., 2000). Two examples of candidate genes in the aging process are the Werner syndrome gene, where the correspond- ing protein acts as a transcriptional activation factor (Oshima, 2000), and the telomerase gene, which is expressed both in cancer cells and germ cells to over- whelm the limited proliferation capacity of somatic cells.

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