Lipoprotein genotype and conserved pathway for exceptional longevity in humans.
Lipoprotein genotype and conserved pathway for exceptional longevity in humans.
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DOI：
10.1371/journal.pbio.0040113
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发表时间：
2006-04
期刊：
影响因子：
9.8
通讯作者：
Barzilai, Nir
中科院分区：
文献类型：
--
作者：
Atzmon, Gil;Rincon, Marielisa;Schechter, Clyde B;Shuldiner, Alan R;Lipton, Richard B;Bergman, Aviv;Barzilai, Nir
在几种动物模型中，涉及营养和脂蛋白代谢的单个基因的改变可延长寿命。由于人类的超长寿命具有家族性，因此基因多态性可能会对某些表型产生有利影响，并增加超长寿命的可能性。对一组德系犹太百岁老人 (n = 213)、他们的后代 (n = 216) 和年龄匹配的德系犹太人对照组 (n = 258) 进行了 36 个与心血管疾病 (CVD) 相关的候选基因的 66 个多态性基因分型。测试了这些基因与血清脂蛋白水平和颗粒大小、载脂蛋白 A1、B 和 C-3 水平以及与高血压、胰岛素抵抗和死亡率结果的关联。 APOC3 启动子 (rs2542052) 中 -641C 等位基因纯合性的发生率在百岁老人 (25%) 及其后代 (20%) 中高于对照组 (10%)（分别为 p = 0.0001 和 p = 0.001）。该基因型与显着降低的 APOC3 血清水平以及有利的脂蛋白水平和大小模式相关。我们发现-641C 纯合子的高血压患病率较低，胰岛素敏感性较高，这表明对 CVD 和代谢综合征具有保护作用。最后，在一项前瞻性研究队列中，具有有利的 -641C 纯合子的患者具有显着的生存优势 (p < 0.0001)。 APOC3 -641C 等位基因的纯合性与良好的脂蛋白谱、心血管健康、胰岛素敏感性和寿命相关。由于脂蛋白的调节也存在于基因改变的长寿模型中，因此它可能是影响从线虫到人类寿命的常见途径。 载脂蛋白 C3（调节脂蛋白代谢）的等位基因在百岁老人中比对照组更普遍。这种基因型与良好的脂蛋白谱、心血管健康、胰岛素敏感性和长寿相关。
Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians ( n = 213), their offspring ( n = 216), and an age-matched Ashkenazi control group ( n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the −641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) ( p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the −641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable −641C homozygote ( p < 0.0001). Homozygosity for the APOC3 −641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans. An allele of apolipoprotein C3 (which regulates lipoprotein metabolism) is more prevalent in centenarian humans than controls. This genotype is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity.