Several groups have postulated that polymorphisms in genes responsible for the metabolism of xenobiotics may influence longevity by determining the susceptibility of an individual to environmental influences. However, no association has been found to date between human longevity and genetic polymorphisms in several drug-metabolising enzymes, including NAT2, GSTM1, CYP2D6, and CYP2E1 (Muiras et al., 1998; Agundez et al., 1997; Bathum et al., 1998; Playfer et al., 1977cardiovascular disease. Toxicol. Environ. Chem., Hasselwander, O., Savage, D.A., Master, D., Loughrey, C.M., Mamee, P.T., Middleton, D., Nicholls, D.P., Maxwell, A.P., Young, I.S., Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients. Kidney Int., References are important in order to maximize the quality of life of elderly people. Longevity is a complex trait resulting from the interaction between multiple genetic and environmental factors. At the beginning of this study, we had hypothesized that the 192R allele, in view of its association with CHD, would be less frequent in very elderly survivors such as centenarians and nonagenarians compared to younger control populations. However, counterintuitively we found that the 192R allele frequency was modestly enriched in the oldest survivors and that there was no sex-specific influence, which seemed to argue against a cardiovascular-related mechanism of effect. The 192R allele is associated with high PON activity using paraoxon as a substrate and it may be that this allele does afford additional protection against various environmental toxins or damaging oxidative stress situations. It is well recognized that association studies may be subject to spurious results, particularly because of small numbers of cases and controls, lack of an appropriate control group, poorly defined phenotype, and population admixture. We believe that these issues are less important in our study as the findings appear similar across two European countries and the number of subjects in the very oldest cohort and their control groups is large. An alternative explanation is that the 192R allele is in linkage disequilibrium with a functional neighboring gene awaiting identification. Further work will be required to elucidate more precisely the role of paraoxonase in human biology and to see if our findings can be replicated in other independent populations or in a Northern European Heart Project. Int. J. Sport Nutr. Exerc. Metab. (Suppl.), SS Bub, A., Barth, S., Watzl, B., Briviba, K., Herbert, B.M., Luhrmann, P.M., Neuhauser-Berthold, J., Rechkemmer, G., Paraoxonase Q- polymorphism is associated with reduced lipid peroxidation in R-allele-carrier but not in QQ homozygous elderly subjects on a tomato-rich diet. Eur. J. Nutr., Davies, H.G., Richter, R.J., Keifer, M., Broomfield, C.A., Sowalla, J., Furlong, C.E., The effect of the human serum paraoxonase polymorphism is reversed with diaoxon, soman and sarin. Nat. Genet., Durrington, P.N., Mackness, B., Mackness, M.I., The hunt for nutritional and pharmacological modulators of Paraoxonase. Atherosclerosis Thromb. Vasc. Biol., Frisoni, G.B., Louhija, J., Geroldi, C., Trabucchi, M., Longevity and the epsilon allele of apolipoprotein E: the Finnish Centenarians Study. J. Gerontol. A Biol. Sci. Med. Sci., Fuhrman, B., Aviram, M., Preservation of paraoxonase activity by wine flavonoids: possible role in the protection of LDL from lipid peroxidation. Ann. NY Acad. Sci., Garin, M.-C., James R.W., Dussoix, P., Blanche H., Passa P., Froguel P., Ruiz J.l.; Paraoxonase polymorphism Met-Leu is associated with modified serum concentrations of the enzyme. J. Clin. Invest., Gledmacher, V., Mallinckrodt, M., Diepgen, T.L., The human paraoxonase polymorphism and specificity. Toxicol. Environ. Chem., Hasselwander, O., Savage, D.A., Master, D., Loughrey, C.M., Mamee, P.T., Middleton, D., Nicholls, D.P., Maxwell, A.P., Young, I.S.; Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients. Kidney Int., Acknowledgments: Dr. Rea thanks General Practitioner colleagues, the patients, and Ms. Anne Murphy, research nurse for dedicated work in the community. I.M. Rea et al./Experimental Gerontology 39 (2004) 629-635 Miller, S.A., Dykes, D.D., Polesky H.F.; A simple procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., Muiras M.-L., Verasdonck P., Cottet F.,coronary artery disease in Japanese subjects. J. Atheroscler. Thromb., Leviev, H., Poirier, O., Nicaud, V., Evans, A., Kee, F., Arveile, D., Morrison, C., Cambien, F., James, R.W., High expressor paraxonase PON gene promoter polymorphisms are associated with a reduced risk of vascular disease in younger coronary patients. Atherosclerosis, Mackness, M.I., Arrol, S., Abbott, C.A., Durrington, P.N., Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein-associated paraoxonase. Atherosclerosis, Mackness, M.I., Arrol, S., Mackness, B., Durrington, P.N., Alloenzymes of paraoxonase and the effectiveness of high-density lipoproteins in protecting low-density lipoprotein against lipid peroxidation. Arterioscler. Thromb. Vasc. Biol., Jiang-Gang, Z., Yong-Xing, M., Chuan-Fu, W., Pei-Fang Li., Song-Bai Nui-Fan G., Guo-Yin F., Lin H. Apolipoprotein E longevity among Han Chinese population. Mech. Ageing Dev., Kao Y.L., Donaghue K., Chan A., Knight J., Silink A.. An association of paraoxonase PON gene is associated with diabetic retinopathy IDDM. J. Clin. Endocrinol. Metab., Katzman R.. Apolipoprotein E and Alzheimer's disease. Curr. Neurobiol., Kervinen K., Savolainen M.J.. Salokannel J.. Hynninen A.. Heikkinen Ehnholm C.. Koistinen M.J.. Kesaniemi Y.A.. E and B polymorphisms-longevity factors assessed in Atherosclerosis, Kuremoto K., Watanabe Y., Ohmura H., Shimada K., Mokuno Daida H.. R/R genotype of human paraoxonase (PON) is protective against lipoprotein oxidation and coronary artery