The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring

<p>Abstract</p> <p>Background</p> <p>Studies on heteroplasmy occurring in the mitochondrial DNA (mtDNA) control region (CR) in leukocytes of centenarians and younger subjects have shown that the C150T somatic transition is over-represented in centenarians. However, whether the occurrence/accumulation of heteroplasmy is a <it>phenotypic consequence </it>of extreme ageing or a <it>genetically controlled event </it>that may favor longevity is a question that deserves further attention. To clarify this point, we set up a Denaturing High Performance Liquid Chromatography (DHPLC) protocol to quantify mtDNA CR heteroplasmy. We then analyzed heteroplasmy in leukocytes of centenarians (100 subjects), their offspring and nieces/nephews (200 subjects, age-range 65–80 years, median age 70 years), and in leukocytes of 114 control subjects sex- and age-matched with the relatives of centenarians.</p> <p>Results</p> <p>The centenarians and their descendants, despite the different ages, showed similar levels of heteroplasmy which were significantly higher than levels in controls. In addition we found that heteroplasmy levels were significantly correlated in parent-offspring pairs (r = 0.263; p = 0.009), but were independent of mtDNA inherited variability (haplogroup and sequence analyses).</p> <p>Conclusion</p> <p>Our findings suggest that the high degree of heteroplasmy observed in centenarians is genetically controlled, and that such genetic control is independent of mtDNA variability and likely due to the nuclear genome.</p

A study of the average effect of the 3'APOB-VNTR polymorphism on lipidemic parameters could explain why the short alleles (<35 repeats) are rare in centenarians

Abstract Background In studies on the genetics of human aging, we observed an age-related variation of the 3'APOB-VNTR genotypic pool (alleles: Short, S, Medium, M, 35–39 repeats; Long, L, >39 repeats) with the homozygous SS genotype showing a convex frequency trajectory in a healthy aging population. This genotype was rare in centenarians, thus indicating that the S alleles are unfavorable to longevity, while common in adults, thus indicating a protective role at middle age. This apparent paradox could be due to possible effects exerted by the above polymorphism on lipidemic parameters. Aim of the work was to get insights into these puzzling findings Methods We followed a double strategy. Firstly, we analyzed the average effects of S (αS), M (αM), and L (αL) alleles on lipidemic parameters in a sample of healthy people (409 subjects aged 20–102 years) recruited in Calabria (southern Italy). The (αS), (αM), and (αL) values were estimated by relating 3'APOB-VNTR genotypes to lipidemic parameters, after adjustment for age, sex and body mass index (multiple regression). Then, we analyzed the S alleles as susceptibility factors of Cardiovascular Atherosclerotic Disease (CD) in CD patients characterized either by low serum HDL-Cholesterol or by high serum LDL-Cholesterol (CD-H and CD-L patients, 40 and 40 subjects respectively). The Odds Ratios (OR) were computed for carriers of S alleles in CD-H and CD-L patients matched for origin, sex and age with controls extracted from the sample of healthy subjects. Results By the analysis of the healthy sample group we found that the S alleles lower the average values of serum Total Cholesterol (αS = -5.98 mg/dL with [-11.62 ÷ -0.74] 95% confidence interval) and LDL-Cholesterol (αS = -4.41 mg/dL with [-8.93 ÷ -0.20] 95% confidence interval) while the alleles M and L have no significant effect on the lipidemic phenotype. In line with these findings, the analysis of CD patients showed that the S alleles are protective as for CD-L (O.R. = 0.55 with [0.21 ÷ 0.98] 95% confidence interval) while neutral as for CD-H (O.R. = 0.75 with [0.32 ÷ 1.60] 95% confidence interval). Conclusion On the whole, the S alleles would be advantageous in adults (by protecting from CD-L) while dangerous in the elderly, probably by lowering serum cholesterol below a critical threshold. This could explain the convex frequency trajectory of SS genotypes previously observed in a healthy aging population.</p

The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring-4

<p><b>Copyright information:</b></p><p>Taken from "The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring"</p><p>http://www.biomedcentral.com/1471-2164/8/293</p><p>BMC Genomics 2007;8():293-293.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2014781.</p><p></p

The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring-5

<p><b>Copyright information:</b></p><p>Taken from "The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring"</p><p>http://www.biomedcentral.com/1471-2164/8/293</p><p>BMC Genomics 2007;8():293-293.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2014781.</p><p></p>en the height of the Heteroplasmic peak and the Total height of homoplasmic plus heteroplasmic peaks. Bars denote the standard deviation in triplicate experiments. The observed values were used to fit a 2degree polynomial function y = βx + βx

The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring-2

<p><b>Copyright information:</b></p><p>Taken from "The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring"</p><p>http://www.biomedcentral.com/1471-2164/8/293</p><p>BMC Genomics 2007;8():293-293.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2014781.</p><p></p

The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring-3

<p><b>Copyright information:</b></p><p>Taken from "The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring"</p><p>http://www.biomedcentral.com/1471-2164/8/293</p><p>BMC Genomics 2007;8():293-293.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2014781.</p><p></p