广西地区长寿及长寿相关表型的遗传学研究
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摘要
长寿是一个受遗传因素影响的复杂性状,也是健康老人的标志。近年来研究证明衰老和寿命延长受基因控制。这些基因多半与能量代谢有关,分别位于核和线粒体基因组内,在生命进化过程中高度保守。因此,系统研究核和线粒体基因组变异对老年长寿的影响,更好的了解长寿的原因和机制,对于降低老年性疾病的发病风险和开展一级预防,从而保障老年人的健康是非常重要的。
方法1)经生物信息学分析,确定了线粒体基因组和核内APOE基因变异为拟定的长寿关联候选基因。2)通过收集长寿家族遗传信息和长寿表型信息,并且通过case-control设计,收集长寿老人和无长寿家族史、当地一般人群的对照组。3)长寿相关表型分析：与对照组比较其相应的生理或生化测定指标和临床疾病相关的体征信息和长寿表型特征。4)长寿关联基因研究：采用群体1筛查,群体2,3验证的策略。4.1)经线粒体全基因组扫描,建立线粒体基因信息数据库和长寿群体的mtDNA系统发育进化树,并寻找长寿关联的线粒体基因及单倍组。4.2)经核内APOE基因分型,检测长寿关联的APOE基因变异。4.3)多群体验证线粒体基因及单倍组和APOE基因与长寿的关联,并进行META分析证明。4.4)探索APOE基因与线粒体基因的交互作用。5)分析长寿关联基因型对表型的影响。6)初步开展长寿关联线粒体基因变异的功能研究。7)采用多种遗传统计学软件,进行模型分析。
结果1)本研究中共收集814个长寿老人(年龄≥90岁)和1136个无长寿家族史、当地一般人群的对照组(年龄30-65岁),男女比例为1：2.8,其中,巴马壮族群体共1012人(2001年274人,2008年738人)和永福汉族群体(2008年)共938人。2)共计筛查45个相关表型,其中长寿老人与对照群体相比,有7个表型具统计学差异(SBP, DBP, FBG, TC, TG, LDL-C和BMI)。3)经线粒体全基因组测序,在巴马长寿老人中发现了225个突变(mtSNPs),并根据测序结果发现了25个线粒体单倍组。4)在2008年巴马群体中发现：单倍组F与长寿关联,在长寿组和对照组的分布频率存在明显统计学差异(21.0% vs 13.5%,p=0.01),单倍组F有利于长寿(OR:1.703,95%CI:1.153-2.514)。5)进一步分析发现单倍组F中的3个mtSNPs(m.397C＞T, m.13928G>C, m.10310G>A)与长寿长寿关联(p=0.009, OR：1.602,95%CI:1.134-2.262; p=0.021, OR:1.507,95%CI:1.075-2.114和p=0.01, OR:1.703,95%CI:1.153-2.514)。6)经与Mitomap中rCRS序列比较,发现m.13928G＞C非同义突变引起MT-ND5蛋白的一个氨基酸的改变(Ser531Thr)。进一步进行MT-ND5蛋白二级结构预测和疏水性分析显示这个氨基酸改变Ser531Thr位于第7和第8个跨膜螺旋的loop结构中,并使得ND5蛋白局部亲水性增高。7)经构建mtDNA系统发育进化树,显示巴马长寿群体属于中国南方群体。8)经核内基因组中的APOE基因分型,在2001年巴马群体中检验APOE基因变异与长寿的关联,显示长寿老人中APOEε3/ε3基因型频率(78.9%)明显高于对照人群(67.8%),并且具有统计学差异(p=0.04)；而长寿老人中APOEε3/ε4基因型频率和APOEε4等位基因频率明显低于对照群体,存在统计学差异(5.5% vs 13.7%,p=0.02和4.6% vs 10.6%,p=0.01)。9)在2008年巴马群体和2008年永福群体中验证APOE基因变异与长寿的关联,2008年巴马群体的分析结果显示长寿老人中APOEe4等位基因频率和APOEε3/ε4基因型频率明显低于对照群体,与长寿存在负关联(p=0.004, OR:0.565,95%CI:0.380-0.838和p=0.044, OR:0.626,95%CI:0.396-0.991);而APOEs3等位基因型频率和ε3／ε3基因型频率明显高于对照群体,与长寿正关联(p=0.008, OR:1.427,95%CI:1.095-1.859和p=0.007, OR:1.530,95%CI:1.124-2.083)。2008年永福群体的分析结果显示在长寿老人中APOEε4等位基因和APOEs3/ε4基因型频率明显低于对照群体,与长寿负关联(p<0.01, OR:0.29,95%CI:0.18-0.49和p<0.01, OR:0.32,95%CI:0.18-0.58),而APOEε3等位基因型和APOEε3/ε3基因型频率明显高于对照群体,与长寿正关联(p<0.01,OR:2.06,95%CI:1.52-2.78和p＜0.01,OR:2.16,95%CI:1.55-3.02).10)经多个群体Meta分析表明ε4等位基因携带者(ε3／ε4和ε4／ε4基因型总和)是影响长寿的风险因素,与长寿负关联(合并OR=0.42,95%CI：0.36-0.49)。ε3／ε3基因型是影响长寿的保护因素,与长寿正关联(合并OR=1.47,95%CI:1.25-1.74)。11)经交互作用分析mtDNA和APOE基因变异对长寿的影响,发现在APOEε4携带者中长寿老人单倍组F分布频率明显高于对照组的分布频率(28.9%vs 8.8%, p=0.010, OR:4.237,95%C1:1.335-13.446)。12)基因型-表型分析了mtDNA基因变异及APOEs4基因对长寿相关表型的影响。发现在长寿老人中单倍组F, m.13928C和m.10310G与高密度脂蛋白增高相关(p=0.03,p=0.04和p=0.03),且m.13928C与总胆固醇水平降低相关(p=0.04)。显示在长寿老人中APOEε4携带者比非APOEε4携带者的总胆固醇和低密度脂蛋白水平高(p=0.003 and p=0.012),而APOEε3/ε3携带者比未携带APOEε3/ε3的长寿老人的高密度脂蛋白水平高,有统计学差异(p=0.005)。
结论1)发现mtDNA单倍组F与长寿关联,可能是长寿的保护因素。2)发现了3个mtSNPs(m.3970C＞T, m.13928G>C, m.10310G>A)与长寿关联；其中非同义突变m.13928G>C (Ser531Thr)在功能上可能起重要的保护作用。3)2个群体证实APOEε4基因与长寿关联,可能是长寿的风险因素。4) mtDNA单倍组F与APOEε4基因可能存在有交互作用。5)提示着mtDNA基因变异和APOE基因变异可能影响长寿老人的健康表型,如血浆总胆固醇,低密度脂蛋白和高密度脂蛋白的水平。
Longevity is a complex trait with genetic inheritance, and a marker for healthy and successful aging. Recent studies demonstrated that the lifespan and aging is regulated by genes. Most of these genes are involved in energy metabolism as well as mostly highly conservative and located in nuclear and mitochondrial genome. Therefore, the systematic study of the role of nDNA and mtDNA genetic variants in healthy longevity and successful aging is very important to better understand the reason and mechanism of health longevity and to reduce the risk of aged-related diseases and improve the life quality of the elders.
Objectives:To explore'the role of nDNA and mtDNA genetic variants in healthy longevity and successful aging, we analyzed the association of nDNA and mtDNA genetic variants with healthy longevity and successful aging, and employed a preliminary study on the function mechanism of nDNA and mtDNA genetic variants.
Methods:1) By bioinformatics analysis, the mitochondrial genome and nuclear APOE gene are selected as the candidate genes associated with longevity.2) Through collecting the information of familial longevity and longevity-related phenotype and by case-control design, long-lived individuals who were 90 years old or above was selected as case sample and the local general population whose parents didn't survived to 90 years old or above was selected as control sample.3) Longevity-related phenotype analysis:the physiological or biochemical measurement index and longevity-related phenotype were compared between long-lived individuals and controls.4) The study of genes associated with longevity:identifying genes associated with longevity in population 1, and replicating genes associated with longevity in population 2 and 3.4.1) By sequencing whole mitochondrial genome, construct mtDNA phylogeny and identify mtDNA genetic variants associated with longevity.4.2) By genotyping APOE gene variants, detecting APOE gene variants associated with longevity in population 1.4.3) Replicating APOE gene variants associated with longevity in population 2 and 3, and conducting Meta-analysis in multi-populatipns.4.4) Exploring the interaction between APOE gene and mitochondrial genetics variants.5) Analyzing the effect of genes associated with longevity on the longevity-related phenotype.6) A preliminary study on the function of the mtDNA genetic variant associated with longevity.7) By a variety of statistical software packages, conducing genetic model analysis. Results:1)A total of 814"longevity" cases were classified as participants who had survived to age 90 years or more, with a total of 1136 "younger controls" less than 65 years of age, including 1012 Bama individuals(247 individuals in 2001 and 738 individuals in 2008) and 938 Yongfu individuals(in 2008). The ratio of female and male is 2.8:1.2) A total of 43 phenotypes were analyzed in this study. There were statistical significance for 7 phenotypes (SBP, DBP, FBG, TC, TG, LDL-C and BMI) between long-lived population and controls.3) By sequencing the whole mitochondrial genome, 225 mtSNPs and 25 mtDNA haplogroups were found in 20 long-lived individuals.4) Haplogroup F was found to be significantly more frequent in longevity cases (21.0%) than in local controls (13.5%) in Bama population in 2008. There were significantly statistical significance for haplogroup F between two groups (p=0.013), conferring approximately 1.7 times of the protective effect (OR:1.703,95%CI:1.153-2.514). 5)The three mtSNPs in haplogroup F m.3970C＞T, m.13928G>C, m.10310G>A) were found to be consistently associated with longevity(p=0.009, OR:1.602,95%CI: 1.134-2.262; p=0.021, OR:1.507,95%CI:1.075-2.114和1 p=0.01, OR:1.703,95%CI: 1.153-2.514).6) By the comparative analysis of rCRS sequence, the mutation m.13928G/C causes an amino acid change Ser531Thr in the MT-ND5 protein. According to the protein secondary-structure and hydrophilicity analysis, the Ser531Thr polymorphism is located in the loop structure between the 7th and 8th transmembrane helices and increases local hydrophilicity in the loop structure.7) The mtDNA phylogeny constructed showed long-lived populations could have originated from ancestor in South China.8) Compared to control subjects in Bama population in 2001, the homozygousε3/ε3 genotype frequency in long-lived population was significantly higher (78.9% versus 67.8%, p=0.04), whereas the heterozygousε3/ε4 genotype andε4 allele frequency were significantly lower (5.5%versus 13.7%, p=0.02, and 4.6%versus 10.6%, p=0.01). 9) Further replicate the association of APOE gene with longevity in Bama population in 2008 and Yongfu population in 2008. Results in Bama population in 2008 showed the APOEε3 allele and the APOE s3/s3 genotype in long-lived individuals is higher frequent than those in control subjects, positively associated with longevity (p=0.008, OR:1.427, 95%CI:1.095-1.859 and p=0.007, OR:1.530,95%CI:1.124-2.083), whereas APOEε4 allele and the APOEε3/ε4 genotype were significantly lower frequent than those in controls, negatively associated with longevity (p=0.004, OR:0.565,95%Cl:0.380-0.838 and p=0.044, OR:0.626,95%CI:0.396-0.991). Results in Yongfu population in 2008 indicated the APOEε3 allele and the APOEε3/ε3 genotype in long-lived individuals is higher frequent than those in control subjects, positively associated with longevity (p<0.01, OR:2.06,95%CI:1.52-2.78 and p<0.01,OR:2.16,95%CI:1.55-3.02), whereas APOEε4 allele and the APOEε3/e4 genotype were significantly lower frequent than those in controls, negatively associated with longevity (p<0.01,OR:0.29,95%CI: 0.18-0.49 and p<0.01, OR:0.32,95%CI:0.18-0.58).10) The results of meta-analysis in 14 populations suggestedε4-carriers (the s3/s4 andε4/ε4 genotypes) were positively associated with longevity and the APOE s3/s3 genotype was negatively associated with longevity. The combined ORs for APOEε4-carriers was OR=0.42,95%CI:0.36-0.49 and the combined ORs for APOEε3/ε3 genotype OR=1.47,95%CI:1.25-1.74.11) The effect of the interaction of mtDNA genetic variants and APOE gene on longevity was analyzed, suggesting among APOEε4-carriers, mtDNA haplogroup F was higher frequent in long-lived population than that in controls (28.9%vs 8.8%, p=0.010, OR:4.237, 95%CI:1.335-13.446).12) The relationship of FBG, TG, TC, HDL-C and LDL-C levels with mtDNA variants was tested. The results showed that there was a significant relation of TC and HDL-C levels to mtDNA variants. Haplogroup F, m.13928C and m.10310A were associated with markedly higher HDL-C levels, and m.13928C was associated with lower TC levels in long-lived cases. APOEε4-carrier was associated with significantly higher TC and LDL-C levels (p=0.003 and p=0.012), and APOEε3/s3 was associated with higher HDL-C levels (p=0.005) in long-lived individuals.
Conclusions:1) The mtDNA haplogroup F was found to be associated with healthy longevity, conferring the protective effect.2) The three mtSNPs (mt3970C>T, mt13928G>C and mt10310G>A) were found to be associated with longevity, and an amino acid changes Ser531Thr (mt13928G/C) in the MT-ND5 gene might account for the beneficial effect of F.3) it was confirmed APOE gene associated with longevity in multi-population APOEε4 gene increased the risk effect for successful aging and longevity, whereas APOEε3 gene conferred protective effect for healthy longevity.4) There could be the interaction of haplogroup F and APOE s4 gene.5) The mtDNA and APOE genetic variants possibly influence healthy phenotype of long-lived individuals, such as TC, LDL-C and HDL.
方法1)经生物信息学分析,确定了线粒体基因组和核内APOE基因变异为拟定的长寿关联候选基因。2)通过收集长寿家族遗传信息和长寿表型信息,并且通过case-control设计,收集长寿老人和无长寿家族史、当地一般人群的对照组。3)长寿相关表型分析：与对照组比较其相应的生理或生化测定指标和临床疾病相关的体征信息和长寿表型特征。4)长寿关联基因研究：采用群体1筛查,群体2,3验证的策略。4.1)经线粒体全基因组扫描,建立线粒体基因信息数据库和长寿群体的mtDNA系统发育进化树,并寻找长寿关联的线粒体基因及单倍组。4.2)经核内APOE基因分型,检测长寿关联的APOE基因变异。4.3)多群体验证线粒体基因及单倍组和APOE基因与长寿的关联,并进行META分析证明。4.4)探索APOE基因与线粒体基因的交互作用。5)分析长寿关联基因型对表型的影响。6)初步开展长寿关联线粒体基因变异的功能研究。7)采用多种遗传统计学软件,进行模型分析。
结果1)本研究中共收集814个长寿老人(年龄≥90岁)和1136个无长寿家族史、当地一般人群的对照组(年龄30-65岁),男女比例为1：2.8,其中,巴马壮族群体共1012人(2001年274人,2008年738人)和永福汉族群体(2008年)共938人。2)共计筛查45个相关表型,其中长寿老人与对照群体相比,有7个表型具统计学差异(SBP, DBP, FBG, TC, TG, LDL-C和BMI)。3)经线粒体全基因组测序,在巴马长寿老人中发现了225个突变(mtSNPs),并根据测序结果发现了25个线粒体单倍组。4)在2008年巴马群体中发现：单倍组F与长寿关联,在长寿组和对照组的分布频率存在明显统计学差异(21.0% vs 13.5%,p=0.01),单倍组F有利于长寿(OR:1.703,95%CI:1.153-2.514)。5)进一步分析发现单倍组F中的3个mtSNPs(m.397C＞T, m.13928G>C, m.10310G>A)与长寿长寿关联(p=0.009, OR：1.602,95%CI:1.134-2.262; p=0.021, OR:1.507,95%CI:1.075-2.114和p=0.01, OR:1.703,95%CI:1.153-2.514)。6)经与Mitomap中rCRS序列比较,发现m.13928G＞C非同义突变引起MT-ND5蛋白的一个氨基酸的改变(Ser531Thr)。进一步进行MT-ND5蛋白二级结构预测和疏水性分析显示这个氨基酸改变Ser531Thr位于第7和第8个跨膜螺旋的loop结构中,并使得ND5蛋白局部亲水性增高。7)经构建mtDNA系统发育进化树,显示巴马长寿群体属于中国南方群体。8)经核内基因组中的APOE基因分型,在2001年巴马群体中检验APOE基因变异与长寿的关联,显示长寿老人中APOEε3/ε3基因型频率(78.9%)明显高于对照人群(67.8%),并且具有统计学差异(p=0.04)；而长寿老人中APOEε3/ε4基因型频率和APOEε4等位基因频率明显低于对照群体,存在统计学差异(5.5% vs 13.7%,p=0.02和4.6% vs 10.6%,p=0.01)。9)在2008年巴马群体和2008年永福群体中验证APOE基因变异与长寿的关联,2008年巴马群体的分析结果显示长寿老人中APOEe4等位基因频率和APOEε3/ε4基因型频率明显低于对照群体,与长寿存在负关联(p=0.004, OR:0.565,95%CI:0.380-0.838和p=0.044, OR:0.626,95%CI:0.396-0.991);而APOEs3等位基因型频率和ε3／ε3基因型频率明显高于对照群体,与长寿正关联(p=0.008, OR:1.427,95%CI:1.095-1.859和p=0.007, OR:1.530,95%CI:1.124-2.083)。2008年永福群体的分析结果显示在长寿老人中APOEε4等位基因和APOEs3/ε4基因型频率明显低于对照群体,与长寿负关联(p<0.01, OR:0.29,95%CI:0.18-0.49和p<0.01, OR:0.32,95%CI:0.18-0.58),而APOEε3等位基因型和APOEε3/ε3基因型频率明显高于对照群体,与长寿正关联(p<0.01,OR:2.06,95%CI:1.52-2.78和p＜0.01,OR:2.16,95%CI:1.55-3.02).10)经多个群体Meta分析表明ε4等位基因携带者(ε3／ε4和ε4／ε4基因型总和)是影响长寿的风险因素,与长寿负关联(合并OR=0.42,95%CI：0.36-0.49)。ε3／ε3基因型是影响长寿的保护因素,与长寿正关联(合并OR=1.47,95%CI:1.25-1.74)。11)经交互作用分析mtDNA和APOE基因变异对长寿的影响,发现在APOEε4携带者中长寿老人单倍组F分布频率明显高于对照组的分布频率(28.9%vs 8.8%, p=0.010, OR:4.237,95%C1:1.335-13.446)。12)基因型-表型分析了mtDNA基因变异及APOEs4基因对长寿相关表型的影响。发现在长寿老人中单倍组F, m.13928C和m.10310G与高密度脂蛋白增高相关(p=0.03,p=0.04和p=0.03),且m.13928C与总胆固醇水平降低相关(p=0.04)。显示在长寿老人中APOEε4携带者比非APOEε4携带者的总胆固醇和低密度脂蛋白水平高(p=0.003 and p=0.012),而APOEε3/ε3携带者比未携带APOEε3/ε3的长寿老人的高密度脂蛋白水平高,有统计学差异(p=0.005)。
结论1)发现mtDNA单倍组F与长寿关联,可能是长寿的保护因素。2)发现了3个mtSNPs(m.3970C＞T, m.13928G>C, m.10310G>A)与长寿关联；其中非同义突变m.13928G>C (Ser531Thr)在功能上可能起重要的保护作用。3)2个群体证实APOEε4基因与长寿关联,可能是长寿的风险因素。4) mtDNA单倍组F与APOEε4基因可能存在有交互作用。5)提示着mtDNA基因变异和APOE基因变异可能影响长寿老人的健康表型,如血浆总胆固醇,低密度脂蛋白和高密度脂蛋白的水平。
Longevity is a complex trait with genetic inheritance, and a marker for healthy and successful aging. Recent studies demonstrated that the lifespan and aging is regulated by genes. Most of these genes are involved in energy metabolism as well as mostly highly conservative and located in nuclear and mitochondrial genome. Therefore, the systematic study of the role of nDNA and mtDNA genetic variants in healthy longevity and successful aging is very important to better understand the reason and mechanism of health longevity and to reduce the risk of aged-related diseases and improve the life quality of the elders.
Objectives:To explore'the role of nDNA and mtDNA genetic variants in healthy longevity and successful aging, we analyzed the association of nDNA and mtDNA genetic variants with healthy longevity and successful aging, and employed a preliminary study on the function mechanism of nDNA and mtDNA genetic variants.
Methods:1) By bioinformatics analysis, the mitochondrial genome and nuclear APOE gene are selected as the candidate genes associated with longevity.2) Through collecting the information of familial longevity and longevity-related phenotype and by case-control design, long-lived individuals who were 90 years old or above was selected as case sample and the local general population whose parents didn't survived to 90 years old or above was selected as control sample.3) Longevity-related phenotype analysis:the physiological or biochemical measurement index and longevity-related phenotype were compared between long-lived individuals and controls.4) The study of genes associated with longevity:identifying genes associated with longevity in population 1, and replicating genes associated with longevity in population 2 and 3.4.1) By sequencing whole mitochondrial genome, construct mtDNA phylogeny and identify mtDNA genetic variants associated with longevity.4.2) By genotyping APOE gene variants, detecting APOE gene variants associated with longevity in population 1.4.3) Replicating APOE gene variants associated with longevity in population 2 and 3, and conducting Meta-analysis in multi-populatipns.4.4) Exploring the interaction between APOE gene and mitochondrial genetics variants.5) Analyzing the effect of genes associated with longevity on the longevity-related phenotype.6) A preliminary study on the function of the mtDNA genetic variant associated with longevity.7) By a variety of statistical software packages, conducing genetic model analysis. Results:1)A total of 814"longevity" cases were classified as participants who had survived to age 90 years or more, with a total of 1136 "younger controls" less than 65 years of age, including 1012 Bama individuals(247 individuals in 2001 and 738 individuals in 2008) and 938 Yongfu individuals(in 2008). The ratio of female and male is 2.8:1.2) A total of 43 phenotypes were analyzed in this study. There were statistical significance for 7 phenotypes (SBP, DBP, FBG, TC, TG, LDL-C and BMI) between long-lived population and controls.3) By sequencing the whole mitochondrial genome, 225 mtSNPs and 25 mtDNA haplogroups were found in 20 long-lived individuals.4) Haplogroup F was found to be significantly more frequent in longevity cases (21.0%) than in local controls (13.5%) in Bama population in 2008. There were significantly statistical significance for haplogroup F between two groups (p=0.013), conferring approximately 1.7 times of the protective effect (OR:1.703,95%CI:1.153-2.514). 5)The three mtSNPs in haplogroup F m.3970C＞T, m.13928G>C, m.10310G>A) were found to be consistently associated with longevity(p=0.009, OR:1.602,95%CI: 1.134-2.262; p=0.021, OR:1.507,95%CI:1.075-2.114和1 p=0.01, OR:1.703,95%CI: 1.153-2.514).6) By the comparative analysis of rCRS sequence, the mutation m.13928G/C causes an amino acid change Ser531Thr in the MT-ND5 protein. According to the protein secondary-structure and hydrophilicity analysis, the Ser531Thr polymorphism is located in the loop structure between the 7th and 8th transmembrane helices and increases local hydrophilicity in the loop structure.7) The mtDNA phylogeny constructed showed long-lived populations could have originated from ancestor in South China.8) Compared to control subjects in Bama population in 2001, the homozygousε3/ε3 genotype frequency in long-lived population was significantly higher (78.9% versus 67.8%, p=0.04), whereas the heterozygousε3/ε4 genotype andε4 allele frequency were significantly lower (5.5%versus 13.7%, p=0.02, and 4.6%versus 10.6%, p=0.01). 9) Further replicate the association of APOE gene with longevity in Bama population in 2008 and Yongfu population in 2008. Results in Bama population in 2008 showed the APOEε3 allele and the APOE s3/s3 genotype in long-lived individuals is higher frequent than those in control subjects, positively associated with longevity (p=0.008, OR:1.427, 95%CI:1.095-1.859 and p=0.007, OR:1.530,95%CI:1.124-2.083), whereas APOEε4 allele and the APOEε3/ε4 genotype were significantly lower frequent than those in controls, negatively associated with longevity (p=0.004, OR:0.565,95%Cl:0.380-0.838 and p=0.044, OR:0.626,95%CI:0.396-0.991). Results in Yongfu population in 2008 indicated the APOEε3 allele and the APOEε3/ε3 genotype in long-lived individuals is higher frequent than those in control subjects, positively associated with longevity (p<0.01, OR:2.06,95%CI:1.52-2.78 and p<0.01,OR:2.16,95%CI:1.55-3.02), whereas APOEε4 allele and the APOEε3/e4 genotype were significantly lower frequent than those in controls, negatively associated with longevity (p<0.01,OR:0.29,95%CI: 0.18-0.49 and p<0.01, OR:0.32,95%CI:0.18-0.58).10) The results of meta-analysis in 14 populations suggestedε4-carriers (the s3/s4 andε4/ε4 genotypes) were positively associated with longevity and the APOE s3/s3 genotype was negatively associated with longevity. The combined ORs for APOEε4-carriers was OR=0.42,95%CI:0.36-0.49 and the combined ORs for APOEε3/ε3 genotype OR=1.47,95%CI:1.25-1.74.11) The effect of the interaction of mtDNA genetic variants and APOE gene on longevity was analyzed, suggesting among APOEε4-carriers, mtDNA haplogroup F was higher frequent in long-lived population than that in controls (28.9%vs 8.8%, p=0.010, OR:4.237, 95%CI:1.335-13.446).12) The relationship of FBG, TG, TC, HDL-C and LDL-C levels with mtDNA variants was tested. The results showed that there was a significant relation of TC and HDL-C levels to mtDNA variants. Haplogroup F, m.13928C and m.10310A were associated with markedly higher HDL-C levels, and m.13928C was associated with lower TC levels in long-lived cases. APOEε4-carrier was associated with significantly higher TC and LDL-C levels (p=0.003 and p=0.012), and APOEε3/s3 was associated with higher HDL-C levels (p=0.005) in long-lived individuals.
Conclusions:1) The mtDNA haplogroup F was found to be associated with healthy longevity, conferring the protective effect.2) The three mtSNPs (mt3970C>T, mt13928G>C and mt10310G>A) were found to be associated with longevity, and an amino acid changes Ser531Thr (mt13928G/C) in the MT-ND5 gene might account for the beneficial effect of F.3) it was confirmed APOE gene associated with longevity in multi-population APOEε4 gene increased the risk effect for successful aging and longevity, whereas APOEε3 gene conferred protective effect for healthy longevity.4) There could be the interaction of haplogroup F and APOE s4 gene.5) The mtDNA and APOE genetic variants possibly influence healthy phenotype of long-lived individuals, such as TC, LDL-C and HDL.
引文
1 Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature.2000;408(6809):255-262.
2 Finch CE, Tanzi RE. Genetics of aging. Science.1997;278(5337):407-411.
3 Johnson TE. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science.1990;249(4971):908-912.
4 Johnson TE, de Castro E, Hegi de Castro S, Cypser J, Henderson S, Tedesco P. Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans. Exp Gerontol.2001;36(10): 1609-1617.
5 Houthoofd K, Braeckman BP, Johnson TE, Vanfleteren JR. Extending life-span in C. elegans. Science.2004;305(5688):1238-1239.
6 Kenyon C. The plasticity of aging:insights from long-lived mutants. Cell. 2005;120(4):449-460.
7 Kenyon CJ. The genetics of aging. Nature.2010;464(7288):502-514.
8 Van Voorhies WA, Ward S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci U S A. 1999;96(20):11399-11403.
9 Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997;277(5328):942-946.
10 Honda Y, Honda S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J.1999;13(11):1385-1393.
11 Larsen PL. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc Natl Acad Sci U S A.1993;90(19):8905-8909.
12 Taub J, Lau JF, Ma C, Hahn JH, Hoque R, Rothblatt J, Chalfie M. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature. 1999;399(6732):162-166.
13 Wolkow CA, Kimura KD, Lee MS, Ruvkun G. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science.2000;290(5489):147-150.
14 Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature.1998;394(6694):694-697.
15 Lin YJ, Seroude L, Benzer S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science.1998;282(5390):943-946.
16 Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59-63.
17 Finch CE, Ruvkun G. The genetics of aging. Annu Rev Genomics Hum Genet. 2001;2(435-462.
18 Jazwinski SM. The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica.1993;91 (1-3):35-51.
19 Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999; 13(19):2570-2580.
20 Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science.2000;290(5499):2137-2140.
21 Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA,3rd, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet.1998;18(2):147-149.
22 Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature.1999;402(6759):309-313.
23 Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity:a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet.1996;97(3):319-323.
24 Skytthe A, Pedersen NL, Kaprio J, Stazi MA, Hjelmborg JV, Iachine I, Vaupel JW, Christensen K. Longevity studies in GenomEUtwin. Twin Res.2003;6(5):448-454.
25 v BHJ, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity. Hum Genet.2006; 119(3):312-321.
26 Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. Siblings of centenarians live longer. Lancet.1998;351(9115):1560.
27 Kerber RA, O'Brien E, Smith KR, Cawthon RM. Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci.2001;56(3):B130-139.
28 Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR, Stefansson K. Inheritance of human longevity in Iceland. Eur J Hum Genet.2000;8(10):743-749.
29 Reed T, Dick DM, Uniacke SK, Foroud T, Nichols WC. Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. J Gerontol A Biol Sci Med Sci.2004;59(3):227-232.
30 Zubenko GS, Stiffler JS, Hughes HB,3rd, Fatigati MJ, Zubenko WN. Genome survey for loci that influence successful aging:sample characterization, method validation, and initial results for the Y chromosome. Am J Geriatr Psychiatry.2002;10(5): 619-630.
31 Zubenko GS, Hughes HB,3rd, Zubenko WN, Maher BS. Genome survey for loci that influence successful aging:results at 10-cM resolution. Am J Geriatr Psychiatry. 2007;15(3):184-193.
32 Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity:challenges and insights. Nat Rev Genet.2006;7(6):436-448.
33 Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV. Successful aging:from phenotype to genotype. Biol Psychiatry.2007;62(4):282-293.
34 Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D. Genes involved in immune response/inflammation, IGF 1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity:the lesson of centenarians. Mech Ageing Dev.2005;126(2):351-361.
35 Lao JI, Montoriol C, Morer I, Beyer K. Genetic contribution to aging:deleterious and helpful genes define life expectancy. Ann N Y Acad Sci.2005;1057(50-63.
36 Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007;8(9):681-691.
37 Di Bona D, Vasto S, Capurso C, Christiansen L, Deiana L, Franceschi C, Hurme M, Mocchegiani E, Rea M, Lio D, Candore G, Caruso C. Effect of interleukin-6 polymorphisms on human longevity:a systematic review and meta-analysis. Ageing Res Rev.2009:8(1):36-42.
38 Bostock CV, Soiza RL, Whalley LJ. Genetic determinants of ageing processes and diseases in later life. Maturitas.2009;62(3):225-229.
39 Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, Mishto M, Invidia L, Capri M, Valensin S, Sevini F, Cevenini E, Celani L, Lescai F, Gonos E, Caruso C, Paolisso G, De Benedictis G, Monti D, Franceschi C. Genes, ageing and longevity in humans:problems, advantages and perspectives. Free Radic Res. 2006:40(12):1303-1323.
40 Corder EH, Lannfelt L, Viitanen M, Corder LS, Manton KG, Winblad B, Basun H. Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition. Arch Neurol.1996;53(5):418-422.
41 Lewis SJ, Brunner EJ. Methodological problems in genetic association studies of longevity-the apolipoprotein E gene as an example. Int J Epidemiol.2004;33(5): 962-970.
42 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science.1993;261(5123): 921-923.
43 Panza F, D'Introno A, Colacicco AM, Capurso C, Capurso S, Kehoe PG, Capurso A, Solfrizzi V. Vascular genetic factors and human longevity. Mech Ageing Dev. 2004;125(3):169-178.
44 Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA.1997;278(2): 136-140.
45 Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA.1999;282(1):40-46.
46 Smith JD. Apolipoproteins and aging:emerging mechanisms. Ageing Res Rev. 2002;1(3):345-365.
47 Salvioli S, Capri M, Santoro A, Raule N. Sevini F, Lukas S, Lanzarini C, Monti D, Passarino G, Rose G, De Benedictis G, Franceschi C. The impact of mitochondrial DNA on human lifespan:a view from studies on centenarians. Biotechnol J.2008;3(6): 740-749.
48 Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G. Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci U S A.2003;100(3):1116-1121.
49 Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimaki T, Arai Y, Hirose N, Majamaa K. A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet. 2005;13(2):166-170.
50 Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton D. Mitochondrial DNA polymorphism:its role in longevity of the Irish population. Exp Gerontol.2001;36(7):1161-1178.
51 Coskun PE, Ruiz-Pesini E, Wallace DC. Control region mtDNA variants:longevity, climatic adaptation, and a forensic conundrum. Proc Natl Acad Sci U S A.2003;100(5): 2174-2176.
52 Franceschi C, Bonafe M, Valensin S. Human immunosenescence:the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine.2000; 18(16):1717-1720.
53 Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood.2000;95(9):2860-2868.
54 Kong QP, Bandelt HJ, Sun C, Yao YG, Salas A, Achilli A, Wang CY, Zhong L, Zhu CL, Wu SF, Torroni A, Zhang YP. Updating the East Asian mtDNA phylogeny:a prerequisite for the identification of pathogenic mutations. Hum Mol Genet.2006;15(13): 2076-2086.
55 Tanaka M, Cabrera VM, Gonzalez AM, Larruga JM, Takeyasu T, Fuku N, Guo LJ, Hirose R, Fujita Y, Kurata M, Shinoda K, Umetsu K, Yamada Y, Oshida Y, Sato Y, Hattori N, Mizuno Y, Arai Y, Hirose N, Ohta S, Ogawa O, Tanaka Y, Kawamori R, Shamoto-Nagai M, Maruyama W, Shimokata H, Suzuki R, Shimodaira H. Mitochondrial genome variation in eastern Asia and the peopling of Japan. Genome Res.2004;14(10A): 1832-1850.
56 Kong QP, Yao YG, Sun C, Bandelt HJ, Zhu CL, Zhang YP. Phylogeny of east Asian mitochondrial DNA lineages inferred from complete sequences. Am J Hum Genet. 2003;73(3):671-676.
57 孔庆鹏,张亚平.人类线粒体DNA世系的系统发育关系研究.生命科学.2008；20(4)：540-548.
58 De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafe M, Monti D, Baggio G, Bertolini S, Mari D, Mattace R, Franceschi C. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J.1999:13(12):1532-1536.
59 Tanaka M, Gong JS, Zhang J, Yoneda M, Yagi K. Mitochondrial genotype associated with longevity. Lancet.1998:351(9097):185-186.
60 Cai XY, Wang XF, Li SL, Qian J, Qian DG, Chen F, Yang YJ, Yuan ZY, Xu J, Bai Y, Yu SZ, Jin L. Association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population. PLoS One.2009;4(7):e6423.
61 Alexe G, Fuku N, Bilal E, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N, Bhanot G, Tanaka M. Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population. Hum Genet.2007; 121 (3-4):347-356.
62 Bilal E, Rabadan R, Alexe G, Fuku N, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N, Ruckenstein A, Bhanot G, Tanaka M. Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan. PLoS One.2008;3(6):e2421.
63 Dato S, Passarino G, Rose G, Altomare K, Bellizzi D, Mari V, Feraco E, Franceschi C, De Benedictis G. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet.2004; 12(12):1080-1082.
64 Tanaka M. Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease. J Neurol.2002;249 Suppl 2(1111-18.
65 Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace DC. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004;303(5655):223-226.
66 Kirchman PA, Kim S, Lai CY, Jazwinski SM. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics.1999;152(1):179-190.
67 Butow RA, Avadhani NG. Mitochondrial signaling:the retrograde response. Mol Cell.2004;14(1):1-15.
68 Bellizzi D, Cavalcante P, Taverna D, Rose G, Passarino G, Salvioli S, Franceschi C, De Benedictis G. Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines. Genes Cells. 2006;11(8):883-891.
69 De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Cavalcanti S, Corsonello F, Feraco E, Baggio G, Bertolini S, Mari D, Mattace R, Yashin Al, Bonafe M, Franceschi C. Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur J Hum Genet.1998;6(6):534-541.
70 Bonafe M, Barbi C, Olivieri F, Yashin A, Andreev KF, Vaupel JW, De Benedictis G, Rose G, Carrieri G, Jazwinski SM, Franceschi C. An allele of HRAS1 3'variable number of tandem repeats is a frailty allele:implication for an evolutionarily-conserved pathway involved in longevity. Gene.2002;286(1):121-126.
71 Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, Maletta R, Nacmias B, Sorbi S, Corsonello F, Feraco E, Andreev KF, Yashin AI, Franceschi C, De Benedictis G. Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease. Hum Genet.2001;108(3):194-198.
72 Rand DM. Mitochondrial genetics of aging:intergenomic conflict resolution. Sci Aging Knowledge Environ.2005;2005(45):re5.
73 Panza F, D'Introno A, Capurso C, Colacicco AM, Seripa D, Pilotto A, Santamato A, Capurso A, Solfrizzi V. Lipoproteins, vascular-related genetic factors, and human longevity. Rejuvenation Res.2007; 10(4):441-458.
74 Paolisso G, Gambardella A, Ammendola S, Tagliamonte MR, Rizzo MR, Capurso A, Varricchio M. Preserved antilipolytic insulin action is associated with a less atherogenic plasma lipid profile in healthy centenarians. J Am Geriatr Soc.1997;45(12):1504-1509.
75 Arai Y, Hirose N, Nakazawa S, Yamamura K, Shimizu K, Takayama M, Ebihara Y, Osono Y, Homma S. Lipoprotein metabolism in Japanese centenarians:effects of apolipoprotein E polymorphism and nutritional status. J Am Geriatr Soc.2001;49(11): 1434-1441.
76 Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA.2003;290(15):2030-2040.
77 杨泽,郑陈光,吕泽平,陈进超,韦俊兴,韦勇,王辰,屈彦纯,孙亮,杨斯雷,史晓红,唐雷,郑卫东,梁永锡,夏宁,王沥,金峰,梁积英,胡才有,吴森.广西红水河流域长寿老人相关基因研究.中国老年保健医学.2004；2(2)：7-11.
78 Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, Yi C, Kreuziger J, Baldi P, Wallace DC. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res.2007;35(Database issue):D823-828.
79 Castri L, Melendez-Obando M, Villegas-Palma R, Barrantes R, Raventos H, Pereira R, Luiselli D, Pettener D, Madrigal L. Mitochondrial polymorphisms are associated both with increased and decreased longevity. Hum Hered.2009;67(3):147-153.
80 Gundry CN, Dobrowolski SF, Martin YR, Robbins TC, Nay LM, Boyd N, Coyne T, Wall MD, Wittwer CT, Teng DH. Base-pair neutral homozygotes can be discriminated by calibrated high-resolution melting of small amplicons. Nucleic Acids Res. 2008;36(10):3401-3408.
81 Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhal. J Lipid Res.1990;31(3):545-548.
82 Davignon J, Bouthillier D, Nestruck AC, Sing CF. Apolipoprotein E polymorphism and atherosclerosis:insight from a study in octogenarians. Trans Am Clin Climatol Assoc.1988;99(100-110.
83 Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet.1994;6(1):29-32.
84 Louhija J, Miettinen HE, Kontula K, Tikkanen MJ, Miettinen TA, Tilvis RS. Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians. Arterioscler Thromb.1994;14(7):1084-1089.
85 Hirose N, Homma S, Arai Y, Kawamura M, Hasegawa H, Ishida H, Shimizu K, Osono Y, Homma A, Nakamura Y. [Tokyo Centenarian Study.4. Apolipoprotein E phenotype in Japanese centenarians living in the Tokyo Metropolitan area]. Nippon Ronen Igakkai Zasshi.1997;34(4):267-272.
86 Jian-Gang Z, Yong-Xing M, Chuan-Fu W, Pei-Fang L, Song-Bai Z, Nui-Fan G, Guo-Yin F, Lin H. Apolipoprotein E and longevity among Han Chinese population. Mech Ageing Dev.1998; 104(2):159-167.
87 Gerdes LU, Jeune B, Ranberg KA, Nybo H, Vaupel JW. Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men:apolipoprotein E gene is a "frailty gene," not a "longevity gene". Genet Epidemiol.2000;19(3):202-210.
88 Blanche H, Cabanne L, Sahbatou M, Thomas G. A study of French centenarians:are ACE and APOE associated with longevity? C R Acad Sci Ⅲ.2001;324(2):129-135.
89 Wang X, Wang G, Yang C, Li X. Apolipoprotein E gene polymorphism and its association with human longevity in the Uygur nationality in Xinjiang. Chin Med J (Engl).2001;114(8):817-820.
90 Panza F, Solfrizzi V, Colacicco AM, Basile AM, D'Introno A, Capurso C, Sabba M, Capurso S, Capurso A. Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer's disease patients and centenarians. Neuroreport.2003; 14(4): 605-608.
91 Choi YH, Kim JH, Kim DK, Kim JW, Lee MS, Kim CH, Park SC. Distributions of ACE and APOE polymorphisms and their relations with dementia status in Korean centenarians. J Gerontol A Biol Sci Med Sci.2003;58(3):227-231.
92 Stakias N, Liakos P, Tsiapali E, Goutou M, Koukoulis GN. Lower prevalence of epsilon 4 allele of apolipoprotein E gene in healthy, longer-lived individuals of Hellenic origin. J Gerontol A Biol Sci Med Sci.2006;61(12):1228-1231.
93 Tan Q, Kruse TA, Christensen K. Design and analysis in genetic studies of human ageing and longevity. Ageing Res Rev.2006;5(4):371-387.
94 刘辉.长寿研究中长寿人群和对照组的确定.中国老年学杂志.2007；27(7)：678-679.
95 Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC. Classification of European mtDNAs from an analysis of three European populations. Genetics.1996; 144(4):1835-1850.
96 Macaulay V, Richards M, Hickey E, Vega E, Cruciani F, Guida V, Scozzari R, Bonne-Tamir B, Sykes B, Torroni A. The emerging tree of West Eurasian mtDNAs:a synthesis of control-region sequences and RFLPs. Am J Hum Genet.1999;64(1): 232-249.
97 Richards MB, Macaulay VA, Bandelt HJ, Sykes BC. Phylogeography of mitochondrial DNA in western Europe. Ann Hum Genet.1998;62(Pt 3):241-260.
98 姚永刚,孔庆鹏,张亚平.人类线粒体DNA变异的检测方法和思路.动物学研究.2001;22(4)：321-331.
99 Yao YG, Nie L, Harpending H, Fu YX, Yuan ZG, Zhang YP. Genetic relationship of Chinese ethnic populations revealed by mtDNA sequence diversity. Am J Phys Anthropol.2002; 118(1):63-76.
100 Li H, Cai X, Winograd-Cort ER, Wen B, Cheng X, Qin Z, Liu W, Liu Y, Pan S, Qian J, Tan CC, Jin L. Mitochondrial DNA diversity and population differentiation in southern East Asia. Am J Phys Anthropol.2007;134(4):481-488.
101 Derenko M, Malyarchuk B, Grzybowski T, Denisova G, Dambueva 1, Perkova M, Dorzhu C, Luzina F, Lee HK, Vanecek T, Villems R, Zakharov I. Phylogeographic analysis of mitochondrial DNA in northern Asian populations. Am J Hum Genet. 2007;81(5):1025-1041.
102 Yao YG, Zhang YP. Phylogeographic analysis of mtDNA variation in four ethnic populations from Yunnan Province:new data and a reappraisal. J Hum Genet. 2002;47(6):311-318.
103 Chen F, Wang SY, Zhang RZ, Hu YH, Gao GF, Liu YH, Kong QP. Analysis of mitochondrial DNA polymorphisms in Guangdong Han Chinese. Forensic Sci Int Genet. 2008;2(2):150-153.
104 Kivisild T, Tolk HV, Parik J, Wang Y, Papiha SS, Bandelt HJ, Villems R. The emerging limbs and twigs of the East Asian mtDNA tree. Mol Biol Evol.2002:19(10): 1737-1751.
105 Yao YG, Kong QP, Bandelt HJ, Kivisild T, Zhang YP. Phylogeographic differentiation of mitochondrial DNA in Han Chinese. Am J Hum Genet.2002;70(3): 635-651.
106 Ji Y, Zhang AM, Jia X, Zhang YP, Xiao X, Li S, Guo X, Bandelt HJ, Zhang Q, Yao YG. Mitochondrial DNA haplogroups M7bl'2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese families with the m.11778G->a mutation. Am J Hum Genet.2008;83(6):760-768.
107Tharaphan P, Chuenkongkaew WL, Luangtrakool K, Sanpachudayan T, Suktitipat B, Suphavilai R, Srisawat C, Sura T, Lertrit P. Mitochondrial DNA haplogroup distribution in pedigrees of Southeast Asian G11778A Leber hereditary optic neuropathy. J Neuroophthalmol.2006;26(4):264-267.
108 Wu CC, Chiu YH, Chen PJ, Hsu CJ. Prevalence and clinical features of the mitochondrial m.1555A>G mutation in Taiwanese patients with idiopathic sensorineural hearing loss and association of haplogroup F with low penetrance in three families. Ear Hear.2007;28(3):332-342.
109 Fuku N, Park KS, Yamada Y, Nishigaki Y, Cho YM, Matsuo H, Segawa T, Watanabe S, Kato K, Yokoi K, Nozawa Y, Lee HK, Tanaka M. Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am J Hum Genet. 2007;80(3):407-415.
110 Takasaki S. Mitochondrial haplogroups associated with Japanese centenarians, Alzheimer's patients, Parkinson's patients, type 2 diabetic patients and healthy non-obese young males. J Genet Genomics.2009;36(7):425-434.
111 Koh KK. Effects of estrogen on the vascular wall:vasomotor function and inflammation. Cardiovasc Res.2002;55(4):714-726.
112 Lenaz G, Fato R, Genova ML, Bergamini C, Bianchi C, Biondi A. Mitochondrial Complex I:structural and functional aspects. Biochim Biophys Acta.2006; 1757(9-10): 1406-1420.
113 Lio P. Phylogenetic and structural analysis of mitochondrial complex 1 proteins. Gene.2005;345(1):55-64.
114 Iglesias T, Caubin J. Zaballos A, Bernal J, Munoz A. Identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) as a thyroid hormone regulated gene by whole genome PCR analysis. Biochem Biophys Res Commun.1995;210(3): 995-1000.
115 Kazuno AA, Munakata K, Nagai T, Shimozono S, Tanaka M, Yoneda M, Kato N, Miyawaki A, Kato T. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet.2006;2(8): e128.
116 Pello R, Martin MA, Carelli V, Nijtmans LG, Achilli A, Pala M, Torroni A, Gomez-Duran A, Ruiz-Pesini E, Martinuzzi A, Smeitink JA, Arenas J, Ugalde C. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet.2008; 17(24): 4001-4011.
117 Ilveskoski E, Perola M, Lehtimaki T, Laippala P, Savolainen V, Pajarinen J, Penttila A, Lalu KH, Mannikko A, Liesto KK, Koivula T, Karhunen PJ. Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men:an autopsy study. Circulation.1999;100(6):608-613.
118 Vincent B, Smith JD. Astrocytes down-regulate neuronal beta-amyloid precursor protein expression and modify its processing in an apolipoprotein E isoform-specific manner. Eur J Neurosci.2001; 14(2):256-266.
119 Tesseur I, Van Dorpe J, Spittaels K, Van den Haute C, Moechars D, Van Leuven F. Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol.2000; 156(3):951-964.
120 Mahley RW, Huang Y. Apolipoprotein E:from atherosclerosis to Alzheimer's disease and beyond. Curr Opin Lipidol.1999;10(3):207-217.
1 Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity:a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet.1996;97(3):319-323.
2 Skytthe A, Pedersen NL, Kaprio J, Stazi MA, Hjelmborg JV, lachine I, Vaupel JW, Christensen K. Longevity studies in GenomEUtwin. Twin Res.2003;6(5):448-454.
3 v BHJ, lachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity. Hum Genet.2006; 119(3):312-321.
4 Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. Siblings of centenarians live longer. Lancet.1998;351(9115):1560.
5 Kerber RA, O'Brien E, Smith KR, Cawthon RM. Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci.2001;56(3):B130-139.
6 Harris JR, Pedersen NL, McClearn GE, Plomin R, Nesselroade JR. Age differences in genetic and environmental influences for health from the Swedish Adoption/Twin Study of Aging. J Gerontol.1992;47(3):P213-220.
7 Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity:challenges and insights. Nat Rev Genet.2006;7(6):436-448.
8 Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, Ferguson KC, Heller J, Platt DM, Pasquinelli AA, Liu LX, Doberstein SK, Ruvkun G. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev.2001; 15(6): 672-686.
9 Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature. 1996;382(6591):536-539.
10 Ogg S, Ruvkun G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell.1998;2(6):887-893.
11 Larsen PL, Albert PS, Riddle DL. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics.1995;139(4):1567-1583.
12 Paradis S, Ruvkun G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev.1998; 12(16):2488-2498.
13 Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev.1999;13(11):1438-1452.
14 Taub J, Lau JF, Ma C, Hahn JH, Hoque R, Rothblatt J, Chalfie M. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature. 1999;399(6732):162-166.
15 Van Voorhies WA, Ward S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci U S A. 1999;96(20):11399-11403.
16 Thomas JH, Birnby DA, Vowels JJ. Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. Genetics. 1993; 134(4):1105-1117.
17 Inoue T, Thomas JH. Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation. Dev Biol.2000;217(1):192-204.
18 Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature.2000;408(6809):255-262.
19 Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59-63.
20 Lakowski B, Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A.1998;95(22):13091-13096.
21 Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature.1999;402(6763):804-809.
22 Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W. Muller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science.2000:289(5487):2122-2125.
23 Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell.1999;96(3):329-339.
24 Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 1998:19(2):171-174.
25 Sze JY, Victor M, Loer C, Shi Y, Ruvkun G. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature.2000;403(6769): 560-564.
26 Hobert O, Mori I, Yamashita Y, Honda H, Ohshima Y, Liu Y, Ruvkun G. Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron.1997; 19(2):345-357.
27 Hsin H, Kenyon C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature.1999;399(6734):362-366.
28 Antebi A, Yeh WH, Tait D, Hedgecock EM, Riddle DL. daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev.2000; 14(12):1512-1527.
29 Sgro CM, Partridge L. A delayed wave of death from reproduction in Drosophila. Science.1999;286(5449):2521-2524.
30 Branicky R, Benard C, Hekimi S. clk-1, mitochondria, and physiological rates. Bioessays.2000;22(1):48-56.
31 Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature.1998;394(6694):694-697.
32 Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev.1999; 13(19):2570-2580.
33 Kim S, Benguria A, Lai CY, Jazwinski SM. Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae. Mol Biol Cell.1999; 10(10):3125-3136.
34 Ashrafi K, Lin SS, Manchester JK, Gordon JI. Sip2p and its partner snf1 p kinase affect aging in S. cerevisiae. Genes Dev.2000;14(15):1872-1885.
35 Kirchman PA, Kim S, Lai CY, Jazwinski SM. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics.1999; 152(1):179-190.
36 Lin YJ, Seroude L, Benzer S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science.1998;282(5390):943-946.
37 Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science.2000;290(5499):2137-2140.
38 Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA,3rd, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet.1998;18(2):147-149.
39 Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature.1999;402(6759):309-313.
40 Reed T, Dick DM, Uniacke SK, Foroud T, Nichols WC. Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. J Gerontol A Biol Sci Med Sci.2004;59(3):227-232.
41 Zubenko GS, Stiffler JS, Hughes HB,3rd, Fatigati MJ, Zubenko WN. Genome survey for loci that influence successful aging:sample characterization, method validation, and initial results for the Y chromosome. Am J Geriatr Psychiatry.2002; 10(5): 619-630.
42 Lewis SJ, Brunner EJ. Methodological problems in genetic association studies of longevity-the apolipoprotein E gene as an example. Int J Epidemiol.2004;33(5): 962-970.
43 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science.1993;261(5123): 921-923.
44 Panza F, D'Introno A, Colacicco AM, Capurso C, Capurso S, Kehoe PG, Capurso A, Solfrizzi V. Vascular genetic factors and human longevity. Mech Ageing Dev. 2004; 125(3):169-178.
45 Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA.1997;278(2): 136-140.
46 Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA.1999;282(1):40-46.
47 Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanche H, Thomas G, Perls TT, Daly MJ, Puca AA. Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci U S A.2003; 100(24): 14115-14120.
48 Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA.2003;290(15):2030-2040.
49 Garasto S, Rose G, Derango F, Berardelli M, Corsonello A, Feraco E, Mari V, Maletta R, Bruni A, Franceschi C, Carotenuto L, De Benedictis G. The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects. Ann Hum Genet.2003;67(Pt 1):54-62.
50 De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Yashin AI, Bonafe M, Franceschi C. Age-related changes of the 3'APOB-VNTR genotype pool in ageing cohorts. Ann Hum Genet.1998;62(Pt 2):115-122.
51 Varcasia O, Garasto S, Rizza T, Andersen-Ranberg K, Jeune B, Bathum L, Andreev K, Tan Q, Yashin AI, Bonafe M, Franceschi C, De Benedictis G. Replication studies in longevity:puzzling findings in Danish centenarians at the 3'APOB-VNTR locus. Ann Hum Genet.2001;65(Pt 4):371-376.
52 Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D. Genes involved in immune response/inflammation, IGF 1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity:the lesson of centenarians. Mech Ageing Dev.2005; 126(2):351-361.
53 Dandona P, Aljada A, Bandyopadhyay A. Inflammation:the link between insulin resistance, obesity and diabetes. Trends Immunol.2004;25(1):4-7.
54 Chamorro A. Role of inflammation in stroke and atherothrombosis. Cerebrovasc Dis. 2004;17 Suppl 3(1-5.
55 Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, Mishto M, Invidia L, Capri M, Valensin S, Sevini F, Cevenini E, Celani L, Lescai F, Gonos E, Caruso C, Paolisso G, De Benedictis G, Monti D, Franceschi C. Genes, ageing and longevity in humans:problems, advantages and perspectives. Free Radic Res. 2006;40(12):1303-1323.
56 Andersen HR, Jeune B, Nybo H, Nielsen JB, Andersen-Ranberg K, Grandjean P. Low activity of superoxide dismutase and high activity of glutathione reductase in erythrocytes from centenarians. Age Ageing.1998;27(5):643-648.
57 De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Cavalcanti S, Corsonello F, Feraco E, Baggio G, Bertolini S, Mari D, Mattace R, Yashin AI, Bonafe M, Franceschi C. Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur J Hum Genet.1998;6(6):534-541.
58 Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet. 1993;3(1):73-76.
59 Adkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase:glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet.1993;52(3):598-608.
60 Garin MC, James RW, Dussoix P, Blanche H, Passa P, Froguel P, Ruiz J. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest.1997;99(1):62-66.
61 Marra M, Marchegiani F, Antonicelli R, Sirolla C, Spazzafumo L, Olivieri F, Franceschi C, Testa R, Paolisso G, James RW, Boemi M, Parati G. The PON1192RR genotype is associated with a higher prevalence of arterial hypertension. J Hypertens. 2006;24(7):1293-1298.
62 Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature.2003;421(6919):182-187.
63 Bonafe M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity:cues for an evolutionarily conserved mechanism of life span control. J Clin Endocrinol Metab.2003;88(7):3299-3304.
64 Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A.2008; 105(37):13987-13992.
65 Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, lida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature.1997;390(6655):45-51.
66 Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res.2005;96(4):412-418.
67 Bonafe M, Olivieri F, Mari D, Baggio G, Mattace R, Berardelli M, Sansoni P, De Benedictis G, De Luca M, Marchegiani F, Cavallone L, Cardelli M, Giovagnetti S, Ferrucci L, Amadio L, Lisa R, Tucci MG, Troiano L, Pini G, Gueresi P, Morellini M, Sorbi S, Passeri G, Barbi C, Valensin S, Monti D, Deiana L, Pes GM, Carru C, Franceschi C. P53 codon 72 polymorphism and longevity:additional data on centenarians from continental Italy and Sardinia. Am J Hum Genet.1999;65(6): 1782-1785.
68 Bonafe M, Olivieri F, Mari D, Baggio G, Mattace R, Sansoni P, De Benedictis G, De Luca M, Bertolini S, Barbi C, Monti D, Franceschi C. p53 variants predisposing to cancer are present in healthy centenarians. Am J Hum Genet.1999;64(1):292-295.
69 van Heemst D, Mooijaart SP, Beekman M, Schreuder J, de Craen AJ, Brandt BW, Slagboom PE, Westendorp RG. Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol.2005;40(1-2):11-15.
70 Morita H, Kurihara H, Sugiyama T, Hamada C, Yazaki Y. A polymorphic variant C1367R of the Werner helicase gene and atherosclerotic diseases in the Japanese population. Thromb Haemost.1999;82(1):160-161.
71 Castro E, Edland SD, Lee L, Ogburn CE, Deeb SS, Brown G, Panduro A, Riestra R, Tilvis R, Louhija J, Penttinen R, Erkkola R, Wang L, Martin GM, Oshima J. Polymorphisms at the Werner locus:II.1074Leu/Phe,1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet.2000;95(4):374-380.
72 Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV. Successful aging:from phenotype to genotype. Biol Psychiatry.2007;62(4):282-293.
73 Santoro A, Salvioli S, Raule N, Capri M, Sevini F, Valensin S, Monti D, Bellizzi D, Passarino G, Rose G, De Benedictis G, Franceschi C. Mitochondrial DNA involvement in human longevity. Biochim Biophys Acta.2006;1757(9-10):1388-1399.
74 Salvioli S, Capri M, Santoro A, Raule N, Sevini F, Lukas S, Lanzarini C, Monti D, Passarino G, Rose G, De Benedictis G, Franceschi C. The impact of mitochondrial DNA on human lifespan:a view from studies on centenarians. Biotechnol J.2008;3(6): 740-749.
75 Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G. Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci U S A.2003;100(3):1116-1121.
76 Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimaki T, Arai Y, Hirose N, Majamaa K. A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet. 2005; 13(2):166-170.
77 Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton D. Mitochondrial DNA polymorphism:its role in longevity of the Irish population. Exp Gerontol.2001;36(7):1161-1178.
78 Coskun PE, Ruiz-Pesini E, Wallace DC. Control region mtDNA variants:longevity, climatic adaptation, and a forensic conundrum. Proc Natl Acad Sci U S A.2003; 100(5): 2174-2176.
19 Franceschi C, Bonafe M, Valensin S. Human immunosenescence:the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine.2000; 18(16):1717-1720.
80 Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood.2000;95(9):2860-2868.
81 Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC. Classification of European mtDNAs from an analysis of three European populations. Genetics.1996:144(4):1835-1850.
82 Macaulay V, Richards M, Hickey E, Vega E, Cruciani F, Guida V, Scozzari R, Bonne-Tamir B, Sykes B, Torroni A. The emerging tree of West Eurasian mtDNAs:a synthesis of control-region sequences and RFLPs. Am J Hum Genet.1999:64(1): 232-249.
83 Richards MB, Macaulay VA, Bandelt HJ, Sykes BC. Phylogeography of mitochondrial DNA in western Europe. Ann Hum Genet.1998;62(Pt 3):241-260.
84 De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafe M, Monti D, Baggio G, Bertolini S, Mari D, Mattace R, Franceschi C. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J.1999;13(12):1532-1536.
85 Alexe G. Fuku N, Bilal E, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N, Bhanot G, Tanaka M. Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population. Hum Genet.2007; 121 (3-4):347-356.
86 Bilal E, Rabadan R, Alexe G, Fuku N, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N. Ruckenstein A, Bhanot G, Tanaka M. Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan. PLoS One.2008;3(6):e2421.
87 Dato S, Passarino G, Rose G, Altomare K, Bellizzi D, Mari V, Feraco E, Franceschi C, De Benedictis G. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet.2004;12(12):1080-1082.
88 Tanaka M. Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease. J Neurol.2002;249 Suppl 2(1111-18.
89 Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace DC. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004;303(5655):223-226.
90 Salvioli S, Bonafe M, Capri M, Monti D, Franceschi C. Mitochondria, aging and longevity--a new perspective. FEBS Lett.2001;492(1-2):9-13.
91 Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, Giorgio M, Pelicci PG. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem.2004;279(24):25689-25695.
92 Butow RA, Avadhani NG. Mitochondrial signaling:the retrograde response. Mol Cell.2004;14(1):1-15.
93 Bellizzi D, Cavalcante P, Taverna D, Rose G, Passarino G, Salvioli S, Franceschi C, De Benedictis G. Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines. Genes Cells. 2006;11(8):883-891.
94 Bonafe M, Barbi C, Olivieri F, Yashin A, Andreev KF, Vaupel JW, De Benedictis G, Rose G, Carrieri G, Jazwinski SM, Franceschi C. An allele of HRAS1 3'variable number of tandem repeats is a frailty allele:implication for an evolutionarily-conserved pathway involved in longevity. Gene.2002;286(1):121-126.
95 Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, Maletta R, Nacmias B, Sorbi S, Corsonello F, Feraco E, Andreev KF, Yashin Al, Franceschi C, De Benedictis G. Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease. Hum Genet.2001; 108(3):194-198.
96 Rand DM. Mitochondrial genetics of aging:intergenomic conflict resolution. Sci Aging Knowledge Environ.2005;2005(45):re5.
97 Gravina S, Vijg J. Epigenetic factors in aging and longevity. Pflugers Arch.459(2): 247-258.
98 Fraga MF. Genetic and epigenetic regulation of aging. Curr Opin Immunol. 2009;21(4):446-453.
99 Tra J, Kondo T, Lu Q, Kuick R, Hanash S, Richardson B. Infrequent occurrence of age-dependent changes in CpG island methylation as detected by restriction landmark genome scanning. Mech Ageing Dev.2002; 123(11):1487-1503.
100 Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One.2007;2(9):e895.
101 So K, Tamura G, Honda T, Homma N, Endoh M, Togawa N, Nishizuka S, Motoyama T. Quantitative assessment of RUNX3 methylation in neoplastic and non-neoplastic gastric epithelia using a DNA microarray. Pathol Int.2006;56(10): 571-575.
102 Calvanese V, Lara E, Kahn A, Fraga MF. The role of epigenetics in aging and age-related diseases. Ageing Res Rev.2009;8(4):268-276.
103 Vijg J, Dolle ME. Large genome rearrangements as a primary cause of aging. Mech Ageing Dev.2002; 123(8):907-915.
104 Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A.2005; 102(30):10604-10609.
105 Haigis MC, Guarente LP. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev.2006;20(21):2913-2921.
106 Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell.2008; 135(5):907-918.
107 Sommer M, Poliak N, Upadhyay S, Ratovitski E, Nelkin BD, Donehower LA, Sidransky D. DeltaNp63alpha overexpression induces downregulation of Sirtl and an accelerated aging phenotype in the mouse. Cell Cycle.2006;5(17):2005-2011.
108 Baur JA, Pearson KJ, Price NL, Jamieson HA. Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S. Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG. Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature.2006;444(7117):337-342.
2 Finch CE, Tanzi RE. Genetics of aging. Science.1997;278(5337):407-411.
3 Johnson TE. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science.1990;249(4971):908-912.
4 Johnson TE, de Castro E, Hegi de Castro S, Cypser J, Henderson S, Tedesco P. Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans. Exp Gerontol.2001;36(10): 1609-1617.
5 Houthoofd K, Braeckman BP, Johnson TE, Vanfleteren JR. Extending life-span in C. elegans. Science.2004;305(5688):1238-1239.
6 Kenyon C. The plasticity of aging:insights from long-lived mutants. Cell. 2005;120(4):449-460.
7 Kenyon CJ. The genetics of aging. Nature.2010;464(7288):502-514.
8 Van Voorhies WA, Ward S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci U S A. 1999;96(20):11399-11403.
9 Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997;277(5328):942-946.
10 Honda Y, Honda S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J.1999;13(11):1385-1393.
11 Larsen PL. Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc Natl Acad Sci U S A.1993;90(19):8905-8909.
12 Taub J, Lau JF, Ma C, Hahn JH, Hoque R, Rothblatt J, Chalfie M. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature. 1999;399(6732):162-166.
13 Wolkow CA, Kimura KD, Lee MS, Ruvkun G. Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science.2000;290(5489):147-150.
14 Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature.1998;394(6694):694-697.
15 Lin YJ, Seroude L, Benzer S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science.1998;282(5390):943-946.
16 Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59-63.
17 Finch CE, Ruvkun G. The genetics of aging. Annu Rev Genomics Hum Genet. 2001;2(435-462.
18 Jazwinski SM. The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica.1993;91 (1-3):35-51.
19 Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999; 13(19):2570-2580.
20 Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science.2000;290(5499):2137-2140.
21 Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA,3rd, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet.1998;18(2):147-149.
22 Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature.1999;402(6759):309-313.
23 Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity:a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet.1996;97(3):319-323.
24 Skytthe A, Pedersen NL, Kaprio J, Stazi MA, Hjelmborg JV, Iachine I, Vaupel JW, Christensen K. Longevity studies in GenomEUtwin. Twin Res.2003;6(5):448-454.
25 v BHJ, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity. Hum Genet.2006; 119(3):312-321.
26 Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. Siblings of centenarians live longer. Lancet.1998;351(9115):1560.
27 Kerber RA, O'Brien E, Smith KR, Cawthon RM. Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci.2001;56(3):B130-139.
28 Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR, Stefansson K. Inheritance of human longevity in Iceland. Eur J Hum Genet.2000;8(10):743-749.
29 Reed T, Dick DM, Uniacke SK, Foroud T, Nichols WC. Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. J Gerontol A Biol Sci Med Sci.2004;59(3):227-232.
30 Zubenko GS, Stiffler JS, Hughes HB,3rd, Fatigati MJ, Zubenko WN. Genome survey for loci that influence successful aging:sample characterization, method validation, and initial results for the Y chromosome. Am J Geriatr Psychiatry.2002;10(5): 619-630.
31 Zubenko GS, Hughes HB,3rd, Zubenko WN, Maher BS. Genome survey for loci that influence successful aging:results at 10-cM resolution. Am J Geriatr Psychiatry. 2007;15(3):184-193.
32 Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity:challenges and insights. Nat Rev Genet.2006;7(6):436-448.
33 Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV. Successful aging:from phenotype to genotype. Biol Psychiatry.2007;62(4):282-293.
34 Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D. Genes involved in immune response/inflammation, IGF 1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity:the lesson of centenarians. Mech Ageing Dev.2005;126(2):351-361.
35 Lao JI, Montoriol C, Morer I, Beyer K. Genetic contribution to aging:deleterious and helpful genes define life expectancy. Ann N Y Acad Sci.2005;1057(50-63.
36 Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007;8(9):681-691.
37 Di Bona D, Vasto S, Capurso C, Christiansen L, Deiana L, Franceschi C, Hurme M, Mocchegiani E, Rea M, Lio D, Candore G, Caruso C. Effect of interleukin-6 polymorphisms on human longevity:a systematic review and meta-analysis. Ageing Res Rev.2009:8(1):36-42.
38 Bostock CV, Soiza RL, Whalley LJ. Genetic determinants of ageing processes and diseases in later life. Maturitas.2009;62(3):225-229.
39 Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, Mishto M, Invidia L, Capri M, Valensin S, Sevini F, Cevenini E, Celani L, Lescai F, Gonos E, Caruso C, Paolisso G, De Benedictis G, Monti D, Franceschi C. Genes, ageing and longevity in humans:problems, advantages and perspectives. Free Radic Res. 2006:40(12):1303-1323.
40 Corder EH, Lannfelt L, Viitanen M, Corder LS, Manton KG, Winblad B, Basun H. Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition. Arch Neurol.1996;53(5):418-422.
41 Lewis SJ, Brunner EJ. Methodological problems in genetic association studies of longevity-the apolipoprotein E gene as an example. Int J Epidemiol.2004;33(5): 962-970.
42 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science.1993;261(5123): 921-923.
43 Panza F, D'Introno A, Colacicco AM, Capurso C, Capurso S, Kehoe PG, Capurso A, Solfrizzi V. Vascular genetic factors and human longevity. Mech Ageing Dev. 2004;125(3):169-178.
44 Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA.1997;278(2): 136-140.
45 Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA.1999;282(1):40-46.
46 Smith JD. Apolipoproteins and aging:emerging mechanisms. Ageing Res Rev. 2002;1(3):345-365.
47 Salvioli S, Capri M, Santoro A, Raule N. Sevini F, Lukas S, Lanzarini C, Monti D, Passarino G, Rose G, De Benedictis G, Franceschi C. The impact of mitochondrial DNA on human lifespan:a view from studies on centenarians. Biotechnol J.2008;3(6): 740-749.
48 Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G. Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci U S A.2003;100(3):1116-1121.
49 Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimaki T, Arai Y, Hirose N, Majamaa K. A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet. 2005;13(2):166-170.
50 Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton D. Mitochondrial DNA polymorphism:its role in longevity of the Irish population. Exp Gerontol.2001;36(7):1161-1178.
51 Coskun PE, Ruiz-Pesini E, Wallace DC. Control region mtDNA variants:longevity, climatic adaptation, and a forensic conundrum. Proc Natl Acad Sci U S A.2003;100(5): 2174-2176.
52 Franceschi C, Bonafe M, Valensin S. Human immunosenescence:the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine.2000; 18(16):1717-1720.
53 Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood.2000;95(9):2860-2868.
54 Kong QP, Bandelt HJ, Sun C, Yao YG, Salas A, Achilli A, Wang CY, Zhong L, Zhu CL, Wu SF, Torroni A, Zhang YP. Updating the East Asian mtDNA phylogeny:a prerequisite for the identification of pathogenic mutations. Hum Mol Genet.2006;15(13): 2076-2086.
55 Tanaka M, Cabrera VM, Gonzalez AM, Larruga JM, Takeyasu T, Fuku N, Guo LJ, Hirose R, Fujita Y, Kurata M, Shinoda K, Umetsu K, Yamada Y, Oshida Y, Sato Y, Hattori N, Mizuno Y, Arai Y, Hirose N, Ohta S, Ogawa O, Tanaka Y, Kawamori R, Shamoto-Nagai M, Maruyama W, Shimokata H, Suzuki R, Shimodaira H. Mitochondrial genome variation in eastern Asia and the peopling of Japan. Genome Res.2004;14(10A): 1832-1850.
56 Kong QP, Yao YG, Sun C, Bandelt HJ, Zhu CL, Zhang YP. Phylogeny of east Asian mitochondrial DNA lineages inferred from complete sequences. Am J Hum Genet. 2003;73(3):671-676.
57 孔庆鹏,张亚平.人类线粒体DNA世系的系统发育关系研究.生命科学.2008；20(4)：540-548.
58 De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafe M, Monti D, Baggio G, Bertolini S, Mari D, Mattace R, Franceschi C. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J.1999:13(12):1532-1536.
59 Tanaka M, Gong JS, Zhang J, Yoneda M, Yagi K. Mitochondrial genotype associated with longevity. Lancet.1998:351(9097):185-186.
60 Cai XY, Wang XF, Li SL, Qian J, Qian DG, Chen F, Yang YJ, Yuan ZY, Xu J, Bai Y, Yu SZ, Jin L. Association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population. PLoS One.2009;4(7):e6423.
61 Alexe G, Fuku N, Bilal E, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N, Bhanot G, Tanaka M. Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population. Hum Genet.2007; 121 (3-4):347-356.
62 Bilal E, Rabadan R, Alexe G, Fuku N, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N, Ruckenstein A, Bhanot G, Tanaka M. Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan. PLoS One.2008;3(6):e2421.
63 Dato S, Passarino G, Rose G, Altomare K, Bellizzi D, Mari V, Feraco E, Franceschi C, De Benedictis G. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet.2004; 12(12):1080-1082.
64 Tanaka M. Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease. J Neurol.2002;249 Suppl 2(1111-18.
65 Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace DC. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004;303(5655):223-226.
66 Kirchman PA, Kim S, Lai CY, Jazwinski SM. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics.1999;152(1):179-190.
67 Butow RA, Avadhani NG. Mitochondrial signaling:the retrograde response. Mol Cell.2004;14(1):1-15.
68 Bellizzi D, Cavalcante P, Taverna D, Rose G, Passarino G, Salvioli S, Franceschi C, De Benedictis G. Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines. Genes Cells. 2006;11(8):883-891.
69 De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Cavalcanti S, Corsonello F, Feraco E, Baggio G, Bertolini S, Mari D, Mattace R, Yashin Al, Bonafe M, Franceschi C. Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur J Hum Genet.1998;6(6):534-541.
70 Bonafe M, Barbi C, Olivieri F, Yashin A, Andreev KF, Vaupel JW, De Benedictis G, Rose G, Carrieri G, Jazwinski SM, Franceschi C. An allele of HRAS1 3'variable number of tandem repeats is a frailty allele:implication for an evolutionarily-conserved pathway involved in longevity. Gene.2002;286(1):121-126.
71 Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, Maletta R, Nacmias B, Sorbi S, Corsonello F, Feraco E, Andreev KF, Yashin AI, Franceschi C, De Benedictis G. Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease. Hum Genet.2001;108(3):194-198.
72 Rand DM. Mitochondrial genetics of aging:intergenomic conflict resolution. Sci Aging Knowledge Environ.2005;2005(45):re5.
73 Panza F, D'Introno A, Capurso C, Colacicco AM, Seripa D, Pilotto A, Santamato A, Capurso A, Solfrizzi V. Lipoproteins, vascular-related genetic factors, and human longevity. Rejuvenation Res.2007; 10(4):441-458.
74 Paolisso G, Gambardella A, Ammendola S, Tagliamonte MR, Rizzo MR, Capurso A, Varricchio M. Preserved antilipolytic insulin action is associated with a less atherogenic plasma lipid profile in healthy centenarians. J Am Geriatr Soc.1997;45(12):1504-1509.
75 Arai Y, Hirose N, Nakazawa S, Yamamura K, Shimizu K, Takayama M, Ebihara Y, Osono Y, Homma S. Lipoprotein metabolism in Japanese centenarians:effects of apolipoprotein E polymorphism and nutritional status. J Am Geriatr Soc.2001;49(11): 1434-1441.
76 Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA.2003;290(15):2030-2040.
77 杨泽,郑陈光,吕泽平,陈进超,韦俊兴,韦勇,王辰,屈彦纯,孙亮,杨斯雷,史晓红,唐雷,郑卫东,梁永锡,夏宁,王沥,金峰,梁积英,胡才有,吴森.广西红水河流域长寿老人相关基因研究.中国老年保健医学.2004；2(2)：7-11.
78 Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, Yi C, Kreuziger J, Baldi P, Wallace DC. An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res.2007;35(Database issue):D823-828.
79 Castri L, Melendez-Obando M, Villegas-Palma R, Barrantes R, Raventos H, Pereira R, Luiselli D, Pettener D, Madrigal L. Mitochondrial polymorphisms are associated both with increased and decreased longevity. Hum Hered.2009;67(3):147-153.
80 Gundry CN, Dobrowolski SF, Martin YR, Robbins TC, Nay LM, Boyd N, Coyne T, Wall MD, Wittwer CT, Teng DH. Base-pair neutral homozygotes can be discriminated by calibrated high-resolution melting of small amplicons. Nucleic Acids Res. 2008;36(10):3401-3408.
81 Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhal. J Lipid Res.1990;31(3):545-548.
82 Davignon J, Bouthillier D, Nestruck AC, Sing CF. Apolipoprotein E polymorphism and atherosclerosis:insight from a study in octogenarians. Trans Am Clin Climatol Assoc.1988;99(100-110.
83 Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet.1994;6(1):29-32.
84 Louhija J, Miettinen HE, Kontula K, Tikkanen MJ, Miettinen TA, Tilvis RS. Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians. Arterioscler Thromb.1994;14(7):1084-1089.
85 Hirose N, Homma S, Arai Y, Kawamura M, Hasegawa H, Ishida H, Shimizu K, Osono Y, Homma A, Nakamura Y. [Tokyo Centenarian Study.4. Apolipoprotein E phenotype in Japanese centenarians living in the Tokyo Metropolitan area]. Nippon Ronen Igakkai Zasshi.1997;34(4):267-272.
86 Jian-Gang Z, Yong-Xing M, Chuan-Fu W, Pei-Fang L, Song-Bai Z, Nui-Fan G, Guo-Yin F, Lin H. Apolipoprotein E and longevity among Han Chinese population. Mech Ageing Dev.1998; 104(2):159-167.
87 Gerdes LU, Jeune B, Ranberg KA, Nybo H, Vaupel JW. Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men:apolipoprotein E gene is a "frailty gene," not a "longevity gene". Genet Epidemiol.2000;19(3):202-210.
88 Blanche H, Cabanne L, Sahbatou M, Thomas G. A study of French centenarians:are ACE and APOE associated with longevity? C R Acad Sci Ⅲ.2001;324(2):129-135.
89 Wang X, Wang G, Yang C, Li X. Apolipoprotein E gene polymorphism and its association with human longevity in the Uygur nationality in Xinjiang. Chin Med J (Engl).2001;114(8):817-820.
90 Panza F, Solfrizzi V, Colacicco AM, Basile AM, D'Introno A, Capurso C, Sabba M, Capurso S, Capurso A. Apolipoprotein E (APOE) polymorphism influences serum APOE levels in Alzheimer's disease patients and centenarians. Neuroreport.2003; 14(4): 605-608.
91 Choi YH, Kim JH, Kim DK, Kim JW, Lee MS, Kim CH, Park SC. Distributions of ACE and APOE polymorphisms and their relations with dementia status in Korean centenarians. J Gerontol A Biol Sci Med Sci.2003;58(3):227-231.
92 Stakias N, Liakos P, Tsiapali E, Goutou M, Koukoulis GN. Lower prevalence of epsilon 4 allele of apolipoprotein E gene in healthy, longer-lived individuals of Hellenic origin. J Gerontol A Biol Sci Med Sci.2006;61(12):1228-1231.
93 Tan Q, Kruse TA, Christensen K. Design and analysis in genetic studies of human ageing and longevity. Ageing Res Rev.2006;5(4):371-387.
94 刘辉.长寿研究中长寿人群和对照组的确定.中国老年学杂志.2007；27(7)：678-679.
95 Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC. Classification of European mtDNAs from an analysis of three European populations. Genetics.1996; 144(4):1835-1850.
96 Macaulay V, Richards M, Hickey E, Vega E, Cruciani F, Guida V, Scozzari R, Bonne-Tamir B, Sykes B, Torroni A. The emerging tree of West Eurasian mtDNAs:a synthesis of control-region sequences and RFLPs. Am J Hum Genet.1999;64(1): 232-249.
97 Richards MB, Macaulay VA, Bandelt HJ, Sykes BC. Phylogeography of mitochondrial DNA in western Europe. Ann Hum Genet.1998;62(Pt 3):241-260.
98 姚永刚,孔庆鹏,张亚平.人类线粒体DNA变异的检测方法和思路.动物学研究.2001;22(4)：321-331.
99 Yao YG, Nie L, Harpending H, Fu YX, Yuan ZG, Zhang YP. Genetic relationship of Chinese ethnic populations revealed by mtDNA sequence diversity. Am J Phys Anthropol.2002; 118(1):63-76.
100 Li H, Cai X, Winograd-Cort ER, Wen B, Cheng X, Qin Z, Liu W, Liu Y, Pan S, Qian J, Tan CC, Jin L. Mitochondrial DNA diversity and population differentiation in southern East Asia. Am J Phys Anthropol.2007;134(4):481-488.
101 Derenko M, Malyarchuk B, Grzybowski T, Denisova G, Dambueva 1, Perkova M, Dorzhu C, Luzina F, Lee HK, Vanecek T, Villems R, Zakharov I. Phylogeographic analysis of mitochondrial DNA in northern Asian populations. Am J Hum Genet. 2007;81(5):1025-1041.
102 Yao YG, Zhang YP. Phylogeographic analysis of mtDNA variation in four ethnic populations from Yunnan Province:new data and a reappraisal. J Hum Genet. 2002;47(6):311-318.
103 Chen F, Wang SY, Zhang RZ, Hu YH, Gao GF, Liu YH, Kong QP. Analysis of mitochondrial DNA polymorphisms in Guangdong Han Chinese. Forensic Sci Int Genet. 2008;2(2):150-153.
104 Kivisild T, Tolk HV, Parik J, Wang Y, Papiha SS, Bandelt HJ, Villems R. The emerging limbs and twigs of the East Asian mtDNA tree. Mol Biol Evol.2002:19(10): 1737-1751.
105 Yao YG, Kong QP, Bandelt HJ, Kivisild T, Zhang YP. Phylogeographic differentiation of mitochondrial DNA in Han Chinese. Am J Hum Genet.2002;70(3): 635-651.
106 Ji Y, Zhang AM, Jia X, Zhang YP, Xiao X, Li S, Guo X, Bandelt HJ, Zhang Q, Yao YG. Mitochondrial DNA haplogroups M7bl'2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese families with the m.11778G->a mutation. Am J Hum Genet.2008;83(6):760-768.
107Tharaphan P, Chuenkongkaew WL, Luangtrakool K, Sanpachudayan T, Suktitipat B, Suphavilai R, Srisawat C, Sura T, Lertrit P. Mitochondrial DNA haplogroup distribution in pedigrees of Southeast Asian G11778A Leber hereditary optic neuropathy. J Neuroophthalmol.2006;26(4):264-267.
108 Wu CC, Chiu YH, Chen PJ, Hsu CJ. Prevalence and clinical features of the mitochondrial m.1555A>G mutation in Taiwanese patients with idiopathic sensorineural hearing loss and association of haplogroup F with low penetrance in three families. Ear Hear.2007;28(3):332-342.
109 Fuku N, Park KS, Yamada Y, Nishigaki Y, Cho YM, Matsuo H, Segawa T, Watanabe S, Kato K, Yokoi K, Nozawa Y, Lee HK, Tanaka M. Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am J Hum Genet. 2007;80(3):407-415.
110 Takasaki S. Mitochondrial haplogroups associated with Japanese centenarians, Alzheimer's patients, Parkinson's patients, type 2 diabetic patients and healthy non-obese young males. J Genet Genomics.2009;36(7):425-434.
111 Koh KK. Effects of estrogen on the vascular wall:vasomotor function and inflammation. Cardiovasc Res.2002;55(4):714-726.
112 Lenaz G, Fato R, Genova ML, Bergamini C, Bianchi C, Biondi A. Mitochondrial Complex I:structural and functional aspects. Biochim Biophys Acta.2006; 1757(9-10): 1406-1420.
113 Lio P. Phylogenetic and structural analysis of mitochondrial complex 1 proteins. Gene.2005;345(1):55-64.
114 Iglesias T, Caubin J. Zaballos A, Bernal J, Munoz A. Identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) as a thyroid hormone regulated gene by whole genome PCR analysis. Biochem Biophys Res Commun.1995;210(3): 995-1000.
115 Kazuno AA, Munakata K, Nagai T, Shimozono S, Tanaka M, Yoneda M, Kato N, Miyawaki A, Kato T. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet.2006;2(8): e128.
116 Pello R, Martin MA, Carelli V, Nijtmans LG, Achilli A, Pala M, Torroni A, Gomez-Duran A, Ruiz-Pesini E, Martinuzzi A, Smeitink JA, Arenas J, Ugalde C. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet.2008; 17(24): 4001-4011.
117 Ilveskoski E, Perola M, Lehtimaki T, Laippala P, Savolainen V, Pajarinen J, Penttila A, Lalu KH, Mannikko A, Liesto KK, Koivula T, Karhunen PJ. Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men:an autopsy study. Circulation.1999;100(6):608-613.
118 Vincent B, Smith JD. Astrocytes down-regulate neuronal beta-amyloid precursor protein expression and modify its processing in an apolipoprotein E isoform-specific manner. Eur J Neurosci.2001; 14(2):256-266.
119 Tesseur I, Van Dorpe J, Spittaels K, Van den Haute C, Moechars D, Van Leuven F. Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol.2000; 156(3):951-964.
120 Mahley RW, Huang Y. Apolipoprotein E:from atherosclerosis to Alzheimer's disease and beyond. Curr Opin Lipidol.1999;10(3):207-217.
1 Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity:a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet.1996;97(3):319-323.
2 Skytthe A, Pedersen NL, Kaprio J, Stazi MA, Hjelmborg JV, lachine I, Vaupel JW, Christensen K. Longevity studies in GenomEUtwin. Twin Res.2003;6(5):448-454.
3 v BHJ, lachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity. Hum Genet.2006; 119(3):312-321.
4 Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L. Siblings of centenarians live longer. Lancet.1998;351(9115):1560.
5 Kerber RA, O'Brien E, Smith KR, Cawthon RM. Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci.2001;56(3):B130-139.
6 Harris JR, Pedersen NL, McClearn GE, Plomin R, Nesselroade JR. Age differences in genetic and environmental influences for health from the Swedish Adoption/Twin Study of Aging. J Gerontol.1992;47(3):P213-220.
7 Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity:challenges and insights. Nat Rev Genet.2006;7(6):436-448.
8 Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, Ferguson KC, Heller J, Platt DM, Pasquinelli AA, Liu LX, Doberstein SK, Ruvkun G. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev.2001; 15(6): 672-686.
9 Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature. 1996;382(6591):536-539.
10 Ogg S, Ruvkun G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell.1998;2(6):887-893.
11 Larsen PL, Albert PS, Riddle DL. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics.1995;139(4):1567-1583.
12 Paradis S, Ruvkun G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev.1998; 12(16):2488-2498.
13 Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev.1999;13(11):1438-1452.
14 Taub J, Lau JF, Ma C, Hahn JH, Hoque R, Rothblatt J, Chalfie M. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature. 1999;399(6732):162-166.
15 Van Voorhies WA, Ward S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci U S A. 1999;96(20):11399-11403.
16 Thomas JH, Birnby DA, Vowels JJ. Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. Genetics. 1993; 134(4):1105-1117.
17 Inoue T, Thomas JH. Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation. Dev Biol.2000;217(1):192-204.
18 Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature.2000;408(6809):255-262.
19 Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59-63.
20 Lakowski B, Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A.1998;95(22):13091-13096.
21 Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature.1999;402(6763):804-809.
22 Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W. Muller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science.2000:289(5487):2122-2125.
23 Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell.1999;96(3):329-339.
24 Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 1998:19(2):171-174.
25 Sze JY, Victor M, Loer C, Shi Y, Ruvkun G. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature.2000;403(6769): 560-564.
26 Hobert O, Mori I, Yamashita Y, Honda H, Ohshima Y, Liu Y, Ruvkun G. Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron.1997; 19(2):345-357.
27 Hsin H, Kenyon C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature.1999;399(6734):362-366.
28 Antebi A, Yeh WH, Tait D, Hedgecock EM, Riddle DL. daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev.2000; 14(12):1512-1527.
29 Sgro CM, Partridge L. A delayed wave of death from reproduction in Drosophila. Science.1999;286(5449):2521-2524.
30 Branicky R, Benard C, Hekimi S. clk-1, mitochondria, and physiological rates. Bioessays.2000;22(1):48-56.
31 Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature.1998;394(6694):694-697.
32 Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev.1999; 13(19):2570-2580.
33 Kim S, Benguria A, Lai CY, Jazwinski SM. Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae. Mol Biol Cell.1999; 10(10):3125-3136.
34 Ashrafi K, Lin SS, Manchester JK, Gordon JI. Sip2p and its partner snf1 p kinase affect aging in S. cerevisiae. Genes Dev.2000;14(15):1872-1885.
35 Kirchman PA, Kim S, Lai CY, Jazwinski SM. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics.1999; 152(1):179-190.
36 Lin YJ, Seroude L, Benzer S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science.1998;282(5390):943-946.
37 Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science.2000;290(5499):2137-2140.
38 Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA,3rd, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet.1998;18(2):147-149.
39 Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature.1999;402(6759):309-313.
40 Reed T, Dick DM, Uniacke SK, Foroud T, Nichols WC. Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging. J Gerontol A Biol Sci Med Sci.2004;59(3):227-232.
41 Zubenko GS, Stiffler JS, Hughes HB,3rd, Fatigati MJ, Zubenko WN. Genome survey for loci that influence successful aging:sample characterization, method validation, and initial results for the Y chromosome. Am J Geriatr Psychiatry.2002; 10(5): 619-630.
42 Lewis SJ, Brunner EJ. Methodological problems in genetic association studies of longevity-the apolipoprotein E gene as an example. Int J Epidemiol.2004;33(5): 962-970.
43 Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science.1993;261(5123): 921-923.
44 Panza F, D'Introno A, Colacicco AM, Capurso C, Capurso S, Kehoe PG, Capurso A, Solfrizzi V. Vascular genetic factors and human longevity. Mech Ageing Dev. 2004; 125(3):169-178.
45 Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A, Gandy S. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA.1997;278(2): 136-140.
46 Haan MN, Shemanski L, Jagust WJ, Manolio TA, Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA.1999;282(1):40-46.
47 Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanche H, Thomas G, Perls TT, Daly MJ, Puca AA. Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci U S A.2003; 100(24): 14115-14120.
48 Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA.2003;290(15):2030-2040.
49 Garasto S, Rose G, Derango F, Berardelli M, Corsonello A, Feraco E, Mari V, Maletta R, Bruni A, Franceschi C, Carotenuto L, De Benedictis G. The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects. Ann Hum Genet.2003;67(Pt 1):54-62.
50 De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Yashin AI, Bonafe M, Franceschi C. Age-related changes of the 3'APOB-VNTR genotype pool in ageing cohorts. Ann Hum Genet.1998;62(Pt 2):115-122.
51 Varcasia O, Garasto S, Rizza T, Andersen-Ranberg K, Jeune B, Bathum L, Andreev K, Tan Q, Yashin AI, Bonafe M, Franceschi C, De Benedictis G. Replication studies in longevity:puzzling findings in Danish centenarians at the 3'APOB-VNTR locus. Ann Hum Genet.2001;65(Pt 4):371-376.
52 Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D. Genes involved in immune response/inflammation, IGF 1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity:the lesson of centenarians. Mech Ageing Dev.2005; 126(2):351-361.
53 Dandona P, Aljada A, Bandyopadhyay A. Inflammation:the link between insulin resistance, obesity and diabetes. Trends Immunol.2004;25(1):4-7.
54 Chamorro A. Role of inflammation in stroke and atherothrombosis. Cerebrovasc Dis. 2004;17 Suppl 3(1-5.
55 Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, Mishto M, Invidia L, Capri M, Valensin S, Sevini F, Cevenini E, Celani L, Lescai F, Gonos E, Caruso C, Paolisso G, De Benedictis G, Monti D, Franceschi C. Genes, ageing and longevity in humans:problems, advantages and perspectives. Free Radic Res. 2006;40(12):1303-1323.
56 Andersen HR, Jeune B, Nybo H, Nielsen JB, Andersen-Ranberg K, Grandjean P. Low activity of superoxide dismutase and high activity of glutathione reductase in erythrocytes from centenarians. Age Ageing.1998;27(5):643-648.
57 De Benedictis G, Carotenuto L, Carrieri G, De Luca M, Falcone E, Rose G, Cavalcanti S, Corsonello F, Feraco E, Baggio G, Bertolini S, Mari D, Mattace R, Yashin AI, Bonafe M, Franceschi C. Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur J Hum Genet.1998;6(6):534-541.
58 Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet. 1993;3(1):73-76.
59 Adkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase:glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet.1993;52(3):598-608.
60 Garin MC, James RW, Dussoix P, Blanche H, Passa P, Froguel P, Ruiz J. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest.1997;99(1):62-66.
61 Marra M, Marchegiani F, Antonicelli R, Sirolla C, Spazzafumo L, Olivieri F, Franceschi C, Testa R, Paolisso G, James RW, Boemi M, Parati G. The PON1192RR genotype is associated with a higher prevalence of arterial hypertension. J Hypertens. 2006;24(7):1293-1298.
62 Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature.2003;421(6919):182-187.
63 Bonafe M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity:cues for an evolutionarily conserved mechanism of life span control. J Clin Endocrinol Metab.2003;88(7):3299-3304.
64 Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A.2008; 105(37):13987-13992.
65 Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, lida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature.1997;390(6655):45-51.
66 Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res.2005;96(4):412-418.
67 Bonafe M, Olivieri F, Mari D, Baggio G, Mattace R, Berardelli M, Sansoni P, De Benedictis G, De Luca M, Marchegiani F, Cavallone L, Cardelli M, Giovagnetti S, Ferrucci L, Amadio L, Lisa R, Tucci MG, Troiano L, Pini G, Gueresi P, Morellini M, Sorbi S, Passeri G, Barbi C, Valensin S, Monti D, Deiana L, Pes GM, Carru C, Franceschi C. P53 codon 72 polymorphism and longevity:additional data on centenarians from continental Italy and Sardinia. Am J Hum Genet.1999;65(6): 1782-1785.
68 Bonafe M, Olivieri F, Mari D, Baggio G, Mattace R, Sansoni P, De Benedictis G, De Luca M, Bertolini S, Barbi C, Monti D, Franceschi C. p53 variants predisposing to cancer are present in healthy centenarians. Am J Hum Genet.1999;64(1):292-295.
69 van Heemst D, Mooijaart SP, Beekman M, Schreuder J, de Craen AJ, Brandt BW, Slagboom PE, Westendorp RG. Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol.2005;40(1-2):11-15.
70 Morita H, Kurihara H, Sugiyama T, Hamada C, Yazaki Y. A polymorphic variant C1367R of the Werner helicase gene and atherosclerotic diseases in the Japanese population. Thromb Haemost.1999;82(1):160-161.
71 Castro E, Edland SD, Lee L, Ogburn CE, Deeb SS, Brown G, Panduro A, Riestra R, Tilvis R, Louhija J, Penttinen R, Erkkola R, Wang L, Martin GM, Oshima J. Polymorphisms at the Werner locus:II.1074Leu/Phe,1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet.2000;95(4):374-380.
72 Glatt SJ, Chayavichitsilp P, Depp C, Schork NJ, Jeste DV. Successful aging:from phenotype to genotype. Biol Psychiatry.2007;62(4):282-293.
73 Santoro A, Salvioli S, Raule N, Capri M, Sevini F, Valensin S, Monti D, Bellizzi D, Passarino G, Rose G, De Benedictis G, Franceschi C. Mitochondrial DNA involvement in human longevity. Biochim Biophys Acta.2006;1757(9-10):1388-1399.
74 Salvioli S, Capri M, Santoro A, Raule N, Sevini F, Lukas S, Lanzarini C, Monti D, Passarino G, Rose G, De Benedictis G, Franceschi C. The impact of mitochondrial DNA on human lifespan:a view from studies on centenarians. Biotechnol J.2008;3(6): 740-749.
75 Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G. Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci U S A.2003;100(3):1116-1121.
76 Niemi AK, Moilanen JS, Tanaka M, Hervonen A, Hurme M, Lehtimaki T, Arai Y, Hirose N, Majamaa K. A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects. Eur J Hum Genet. 2005; 13(2):166-170.
77 Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton D. Mitochondrial DNA polymorphism:its role in longevity of the Irish population. Exp Gerontol.2001;36(7):1161-1178.
78 Coskun PE, Ruiz-Pesini E, Wallace DC. Control region mtDNA variants:longevity, climatic adaptation, and a forensic conundrum. Proc Natl Acad Sci U S A.2003; 100(5): 2174-2176.
19 Franceschi C, Bonafe M, Valensin S. Human immunosenescence:the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine.2000; 18(16):1717-1720.
80 Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P. Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood.2000;95(9):2860-2868.
81 Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC. Classification of European mtDNAs from an analysis of three European populations. Genetics.1996:144(4):1835-1850.
82 Macaulay V, Richards M, Hickey E, Vega E, Cruciani F, Guida V, Scozzari R, Bonne-Tamir B, Sykes B, Torroni A. The emerging tree of West Eurasian mtDNAs:a synthesis of control-region sequences and RFLPs. Am J Hum Genet.1999:64(1): 232-249.
83 Richards MB, Macaulay VA, Bandelt HJ, Sykes BC. Phylogeography of mitochondrial DNA in western Europe. Ann Hum Genet.1998;62(Pt 3):241-260.
84 De Benedictis G, Rose G, Carrieri G, De Luca M, Falcone E, Passarino G, Bonafe M, Monti D, Baggio G, Bertolini S, Mari D, Mattace R, Franceschi C. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J.1999;13(12):1532-1536.
85 Alexe G. Fuku N, Bilal E, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N, Bhanot G, Tanaka M. Enrichment of longevity phenotype in mtDNA haplogroups D4b2b, D4a, and D5 in the Japanese population. Hum Genet.2007; 121 (3-4):347-356.
86 Bilal E, Rabadan R, Alexe G, Fuku N, Ueno H, Nishigaki Y, Fujita Y, Ito M, Arai Y, Hirose N. Ruckenstein A, Bhanot G, Tanaka M. Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan. PLoS One.2008;3(6):e2421.
87 Dato S, Passarino G, Rose G, Altomare K, Bellizzi D, Mari V, Feraco E, Franceschi C, De Benedictis G. Association of the mitochondrial DNA haplogroup J with longevity is population specific. Eur J Hum Genet.2004;12(12):1080-1082.
88 Tanaka M. Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease. J Neurol.2002;249 Suppl 2(1111-18.
89 Ruiz-Pesini E, Mishmar D, Brandon M, Procaccio V, Wallace DC. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science. 2004;303(5655):223-226.
90 Salvioli S, Bonafe M, Capri M, Monti D, Franceschi C. Mitochondria, aging and longevity--a new perspective. FEBS Lett.2001;492(1-2):9-13.
91 Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, Giorgio M, Pelicci PG. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem.2004;279(24):25689-25695.
92 Butow RA, Avadhani NG. Mitochondrial signaling:the retrograde response. Mol Cell.2004;14(1):1-15.
93 Bellizzi D, Cavalcante P, Taverna D, Rose G, Passarino G, Salvioli S, Franceschi C, De Benedictis G. Gene expression of cytokines and cytokine receptors is modulated by the common variability of the mitochondrial DNA in cybrid cell lines. Genes Cells. 2006;11(8):883-891.
94 Bonafe M, Barbi C, Olivieri F, Yashin A, Andreev KF, Vaupel JW, De Benedictis G, Rose G, Carrieri G, Jazwinski SM, Franceschi C. An allele of HRAS1 3'variable number of tandem repeats is a frailty allele:implication for an evolutionarily-conserved pathway involved in longevity. Gene.2002;286(1):121-126.
95 Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, Maletta R, Nacmias B, Sorbi S, Corsonello F, Feraco E, Andreev KF, Yashin Al, Franceschi C, De Benedictis G. Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease. Hum Genet.2001; 108(3):194-198.
96 Rand DM. Mitochondrial genetics of aging:intergenomic conflict resolution. Sci Aging Knowledge Environ.2005;2005(45):re5.
97 Gravina S, Vijg J. Epigenetic factors in aging and longevity. Pflugers Arch.459(2): 247-258.
98 Fraga MF. Genetic and epigenetic regulation of aging. Curr Opin Immunol. 2009;21(4):446-453.
99 Tra J, Kondo T, Lu Q, Kuick R, Hanash S, Richardson B. Infrequent occurrence of age-dependent changes in CpG island methylation as detected by restriction landmark genome scanning. Mech Ageing Dev.2002; 123(11):1487-1503.
100 Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, Jaenisch R, Laird PW, Akbarian S. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One.2007;2(9):e895.
101 So K, Tamura G, Honda T, Homma N, Endoh M, Togawa N, Nishizuka S, Motoyama T. Quantitative assessment of RUNX3 methylation in neoplastic and non-neoplastic gastric epithelia using a DNA microarray. Pathol Int.2006;56(10): 571-575.
102 Calvanese V, Lara E, Kahn A, Fraga MF. The role of epigenetics in aging and age-related diseases. Ageing Res Rev.2009;8(4):268-276.
103 Vijg J, Dolle ME. Large genome rearrangements as a primary cause of aging. Mech Ageing Dev.2002; 123(8):907-915.
104 Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A.2005; 102(30):10604-10609.
105 Haigis MC, Guarente LP. Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev.2006;20(21):2913-2921.
106 Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell.2008; 135(5):907-918.
107 Sommer M, Poliak N, Upadhyay S, Ratovitski E, Nelkin BD, Donehower LA, Sidransky D. DeltaNp63alpha overexpression induces downregulation of Sirtl and an accelerated aging phenotype in the mouse. Cell Cycle.2006;5(17):2005-2011.
108 Baur JA, Pearson KJ, Price NL, Jamieson HA. Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S. Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG. Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature.2006;444(7117):337-342.