遗传mtDNA对长寿的贡献:来自1.76亿对亲属关系的扩展谱系的证据。

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-09-03 DOI:10.1016/j.ebiom.2025.105911
S Alexandra Burt, S Mason Garrison, Xuanyu Lyu, Joseph L Rodgers, Sarah L Carroll, Ken R Smith, Michael D Hunter
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引用次数: 0

摘要

背景:线粒体是具有自身DNA (mtDNA)的类细菌细胞器,存在于人体几乎所有细胞的细胞质中。由于线粒体对维持生命至关重要,因此遗传mtDNA可能是长寿的关键病因学因素。不幸的是,能够量化mtDNA遗传贡献的生物计量方法还没有出现。方法:我们直接利用mtDNA独特的母系遗传模式来估计其对寿命的影响(定义为出生队列中最长寿的10%的幸存者)。我们利用犹他州人口数据库(UPDB)在1700年至1925年间出生的1,018,929名个体中确定了176,348,110个独特的亲属关系,并提供了母系与父系关系的信息。研究发现:在第一、第二、第三、第四和第五度亲属中,母系亲属的长寿结果比非母系亲属更相似。方差成分分析表明,核DNA遗传率为23-26%,mtDNA遗传率至少为5%,尽管mtDNA仅构成约16.6 k个碱基对(而核DNA为2,875,002 k个碱基对)。此外,拥有长寿亲属的母系后代意味着平均多活11.3个月。解释:这些结果共同表明,mtDNA可能是异常长寿的重要因素。本项目由美国国家老龄研究所(NIA)的r01 - ag073189和R01-AG022095资助。我们也感谢来自犹他大学国家癌症研究所、犹他大学个性化健康项目和犹他临床与转化科学研究所的P30-CA2014基金的部分支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Contributions of inherited mtDNA to longevity: evidence from extended pedigrees with 176 million kinship pairs.

Contributions of inherited mtDNA to longevity: evidence from extended pedigrees with 176 million kinship pairs.

Contributions of inherited mtDNA to longevity: evidence from extended pedigrees with 176 million kinship pairs.

Background: Mitochondria are bacteria-like organelles with their own DNA (mtDNA) that exist in the cellular cytoplasm of almost every cell in the human body. Because mitochondria are critical for sustaining life, it follows that inherited mtDNA could be a key aetiologic element underlying longevity. Unfortunately, biometric approaches able to quantify heritable contributions of mtDNA have not been available.

Methods: We directly leveraged the unique matrilineal inheritance pattern of mtDNA to estimate its effects on longevity (defined as the top 10% oldest survivors within their birth cohort). We employed the Utah Population Database (UPDB) to identify 176,348,110 unique kinship links amongst 1,018,929 individuals born between 1700 and 1925 with information on matrilineal versus patrilineal relatedness.

Findings: Across 1st, 2nd, 3rd, 4th, and 5th degree kin, matrilineal relatives were more similar in their longevity outcomes than were non-maternal relatives. Variance component analyses indicated nuclear DNA heritability of 23-26% and mtDNA heritability of at least 5% - despite mtDNA constituting only ∼16.6 k base pairs (versus 2,875,002 k base pairs for nuclear DNA). Moreover, sharing the maternal line of a longevous relative translated to an average of 11.3 months extra years of life.

Interpretation: Results collectively suggest that mtDNA may be an important element of unusually long lifespans.

Funding: This project was supported by RF1-AG073189 and R01-AG022095 from the National Institute on Aging (NIA). We also acknowledge partial support through grant P30-CA2014 from the National Cancer Institute, University of Utah, and from the University of Utah's program in Personalized Health and Utah Clinical and Translational Science Institute.

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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