Title: Association between six candidate genes and early aging in a population

Authors: Yongjing Xia, Ren Gueguen, Monique Vincent-Viry, Gerard Siest, and Sophie Visvikis

Affiliation: Laboratoire du Centre de Medecine Preventive and Unit INSERM 525, Departement Statistique du Centre de Medecine Preventive, Vandoeuvre-les-Nancy, France

Introduction:

The objective of this study was to examine the association between an aging indicator previously defined from a nationwide population study and lipids and apolipoproteins, angiotensin-converting enzyme, paraoxonase activities, and six candidate genes related to the aging process.

Methods:

Two hundred and fifty-six healthy Caucasian men (69.8±4.0 years) were included in the study. Total cholesterol, triglycerides, HDL-cholesterol, lipoprotein(a), apolipoprotein A1, B and E concentrations, and the activities of paraoxonase, arylesterase, and angiotensin-converting enzymes were determined by standardized laboratory methods. A multiplex assay was used to genotype the studied polymorphisms: apolipoprotein E, lipoprotein lipase, paraoxonase, methylenetetrahydrofolate reductase, cystathionine -synthase and angiotensin-converting enzymes.

Results:

Paraoxonase polymorphism at codon 192 (Gln/Arg) was the only one significantly associated with the aging indicator. Gln homozygotes were more advanced in aging compared with Arg allele carriers. It was also observed that the aging indicator was positively correlated with serum concentrations of total cholesterol, triglycerides and apolipoprotein B and negatively with the activities of basal and stimulated paraoxonase and arylesterase. Multiple regression analysis showed that triglycerides and basal paraoxonase activity explain 13.6% of the variance of the aging indicator.

Conclusions:

Triglyceride concentration and paraoxonase gene and activities may contribute to the aging process. These results need to be verified in further studies on a larger sample size.

Background:

Cardiovascular disease (CVD) is age-related and a leading cause of death worldwide. Elderly individuals who have avoided CVD should possess a protective and biological background in both genetic profiles and plasma constituents against CVD. Consequently, many studies have investigated genetic polymorphisms and serum variables associated with CVD in a general healthy elderly population to search for the biological factors contributing to successful aging. Therefore, we chose to examine the associations between lipids, apolipoproteins, ACE and PON activities, six common bi-allele polymorphisms, and the aging indicator (AI), representing the difference of biological age (BA) from chronological age (CA). The studied candidate genes are apolipoprotein E, lipoprotein lipase, paraoxonase, methylenetetrahydrofolate reductase genes, cystathionine -synthase and angiotensin-converting enzymes. The polymorphisms of these genes are: apoE at codons 112/158 (2, 3, 4 alleles), ACE (Alu insertion/deletion alleles, I/D), MTHFR (Ala222Val or 677C/T), PON (Gln192Arg), LPL (Ser447Ter) and CBS (Ile278Thr).

ApoE is one of the major proteins of several lipoprotein particles and plays a central role in lipoprotein metabolism. Human apoE gene is located on chromosome 19 and has three common alleles, designated as 2, 3, 4, encoding three major apoE isoforms, E2, E3 and E4. The difference in these three isoforms lies in the substitution of amino acid at codons 112 and 158. In comparison with the most common isoform E3, E2 is associated with higher concentrations of apoE and triglycerides (TG) and lower total cholesterol (TC), whereas E4 is related to lower concentrations of apoE and TG and higher TC in plasma in European populations. Many studies have confirmed that the 4 allele is a genetic risk factor for both CVD and Alzheimer's disease with unfavored longevity, whereas 2 is regarded as a protective factor resulting in longevity, according to a French centenarian population study, although 1% of apoE 2/2 carriers suffer from hypertriglyceridemia.

ACE is an enzyme which catalyzes the generation of angiotensin II and also inactivates bradykinin, the two peptides playing a key role in modulating vascular tone. Serum ACE levels are under genetic control, and up to 50% of the variation is due to the I/D polymorphismof cardiovascular disease (CVD) and mortality (11). However, our study did not find any association between the PON gene variants and the risk of CVD in the elderly. The association found between PON genetic polymorphism and aging may be related to the hydrolysis of hydroperoxides by PON, which provides protection against oxidative stress and oxidative modifications of lipoproteins. The results suggest that higher PON activity is beneficial for successful aging.

We also found a significant association between TG concentration and aging, with elevated TG concentrations leading to acceleration of the aging process. This finding is independent of the common genetic polymorphism of apoE and may be linked to nutritional habits and energy metabolism in middle-aged subjects.