Although the R allele has been credited with enhancing LDL oxidation and reducing HDL protective effect, it also produces higher levels of paraxonase activity in serum, (Blatter Garin et al., 1994), the effect of which is largely unknown. Interestingly Europeans tend to have a bimodal paraoxonase activity with high or low activity subjects and a preponderance of low activity subjects. Conversely, Asian and Oriental populations have a preponderance of high paraoxonase activity subjects (Gledmacher et al., 1988) and it is food for thought that Japan has currently the longest life expectancy in the world. Recently Kuremoto et al. (2003), reported that the RR genotype of PON1 was more protective against lipoprotein oxidation and CHD in Japanese subjects. 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., 1977; Yamada et al., 1998). However increased paraxonase might theoretically have some protective but unrecognised effect in the oldest age group or throughout life. The PON group of enzymes are well conserved throughout nature in mammalian species (Primo-Parmo et al., 1996) suggesting that the role of PON may be much more ancient and broader than modern cardiovascular disease in man. Ageing causes a shift in the redox balance towards oxidative stress (Ames et al., 1993) and PON1 is sensitive to oxidative stress with its activity not

I.M. Rea et al. / Experimental Gerontology 39 (2004) 629–635

only being reduced by excessive accumulation of lipid peroxides (Aviram et al., 1999), smoking (James et al., 2000; Jarvik et al., 2002) but also in diabetes (Kao et al., 1998) while conversely antioxidant vitamins A and E and dietary factors such as polyphenols (Fuhrman and Aviram, 2002) in wine and tea, apparently increase it (Durrington et al., 2002). Interestingly a recent study suggested that older subjects carrying the R allele had reduced lipid peroxidation after tomato juice was added to their diet (Bub et al., 2002). There is a 40% variation in PON1 with PON1 192 genotype characterising 46% of this variation, PON1 55 approxi- mately 16% (Garin et al., 1997) and the rest depending on nutritional or unidentified factors (Mackness et al., 1997b; Fuhrman et al., 2002). Unfortunately neither PON1 serum levels nor activity were measured in this study both of which would have made an important contribution to our under- standing of the relationship between genotypes and PON1 activity in the oldest age groups.

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