The current increase in lifespan without an equivalent increase in healthspan poses a grave challenge to the healthcare system and a severe burden on society. However, some individuals seem to be able to live a long and healthy life without the occurrence of major debilitating chronic diseases, and part of this trait seems to be hidden in their genome. In this review, we discuss the findings from studies on the genetic component of human longevity and the main challenges accompanying these studies. We subsequently focus on results from genetic studies in model organisms and comparative genomic approaches to highlight the most important conserved longevity-associated pathways. By combining the results from studies using these different approaches, we conclude that only five main pathways have been consistently linked to longevity, namely (1) insulin/insulin-like growth factor 1 signalling, (2) DNA-damage response and repair, (3) immune function, (4) cholesterol metabolism and (5) telomere maintenance. As our current approaches to study the relevance of these pathways in humans are limited, we suggest that future studies on the genetics of human longevity should focus on the identification and functional characterization of rare genetic variants in genes involved in these pathways.

中文翻译：

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人类长寿的遗传学：从变异到基因再到通路

当前寿命的延长而健康寿命却没有相应的延长，这对医疗保健系统构成了严峻的挑战，也给社会带来了沉重的负担。然而，有些人似乎能够健康长寿，而不会患上严重的慢性疾病，而这种特征的一部分似乎隐藏在他们的基因组中。在这篇综述中，我们讨论了人类长寿遗传成分的研究结果以及这些研究面临的主要挑战。随后，我们重点关注模式生物的遗传研究结果和比较基因组方法，以突出最重要的保守的长寿相关途径。通过结合使用这些不同方法的研究结果，我们得出结论，只有五种主要途径与长寿始终相关，即 (1) 胰岛素/胰岛素样生长因子 1 信号传导，(2) DNA 损伤反应和修复，( 3）免疫功能，（4）胆固醇代谢和（5）端粒维护。由于我们目前研究这些途径在人类中的相关性的方法有限，我们建议未来对人类长寿遗传学的研究应集中于这些途径所涉及的基因中罕见遗传变异的识别和功能表征。