Results:

The prevalence of allelic variants (Figure 1), as well as the distribution of acetylator genotypesIt has been suggested that these polymorphisms could modulate the risk of liver cirrhosis in ethanol abusers [21, 22], but this has not been confirmed by us [23]. Figure 2 shows the frequency of major CYP2D6 allelic variants in nonagenarians and in younger controls. The assignment as defective or active alleles has been done according to published studies [13, 15, 25-29]. There is an excess of homozygote CYP2D6 EMs in patients with hepatocellular carcinoma [17], and an excess of phenotypic slow acetylators among urothelioma patients exposed to nitrazepam (NAT2) among others. Taken together, these data suggest that specific combinations of enzymatic polymorphisms could influence the risk of developing some forms of cancer. Nevertheless, patients in this study were not smokers and were not affected by chronic liver disease, which are usually necessary for the development of lung and liver cancers, respectively. Smoking and drinking habits or chronic liver disease are usually incompatible with extreme longevity due to the high risk of death at an earlier age caused by diseases not related to these polymorphisms (atherosclerosis, chronic bronchitis, extrahepatic organic sequelae of alcohol abuse, etc.). The findings obtained in this comparative study make the selection of subjects for control groups easier for studies on diseases affecting people older than 50, as young healthy people are easier to find and recruit. Another point raised by this study is that age-related differences in drug response and toxicity cannot be attributed to a different prevalence of functional genes of the studied drug-metabolizing enzymes, namely CYP2D6, CYP2E1, and NAT2, in very aged people. The genes studied here encode enzymes that are responsible for the metabolism of several drugs. These include tricyclic antidepressants, neuroleptics, beta-blockers and other antiarrhythmics (CYP2D6); paracetamol, chlorzoxazone, and ethanol (CYP2E1) and hydrazines, arylamines, pyrazolones, caffeine, and nitrazepam (NAT2) among others. Any genetic selection in older people would determine differences in the metabolism of these drugs compared with younger subjects.

There are no specific combinations of CYP, E, and NAT genotypes associated with extreme longevity. The distribution of these types is similar in healthy very old people to that of the general population. Other factors, not only genetic but also related to lifestyle, determine the chance of reaching advanced age. It is reasonable to use younger controls when studying the distribution of these polymorphisms in diseases affecting older groups.

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