From the Department of Biological, Geological, and Environmental Sciences (BiGeA), Laboratory of Molecular Anthropology and Centre for Genome Biology (C.G.), University of Bologna, Italy.
School of Anthropology and Museum Ethnography, University of Oxford, United Kingdom (C.G.).
Circ Res. 2018 Sep 14;123(7):745-772. doi: 10.1161/CIRCRESAHA.118.312562.
Human longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequences for biomedicine. The genetics of human longevity is still poorly understood despite several investigations that used different strategies and protocols. Here, we argue that such rather disappointing harvest is largely because of the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan seems to be the result of an intriguing mixture of gene-environment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological, and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status, and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as genome-wide association study and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as apolipoprotein E, Forkhead box O3, interleukin 6, insulin-like growth factor-1, chromosome 9p21, 5q33.3, and somatic mutations among others. The major results of this approach suggest that (1) the genetics of longevity is highly population specific; (2) small-effect alleles, pleiotropy, and the complex allele timing likely play a major role; (3) genetic risk factors are age specific and need to be integrated in the light of the geroscience perspective; (4) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the 3 genetics of human body, that is, nuclear, mitochondrial, and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.
人类的长寿是一个复杂的特征，对于生物医学来说，要理清其基础具有重大的理论和实践意义。尽管已经进行了多次不同策略和方案的研究，但人类长寿的遗传学仍然知之甚少。在这里，我们认为，之所以没有取得令人满意的结果，主要是因为人类长寿表型的复杂性。达到人类寿命极端的几十年的能力似乎是基因-环境相互作用的有趣混合的结果。因此，人类长寿的遗传学在这里被描述为一种高度依赖背景的现象，处于新的综合、生态和进化视角内，并呈现出一种动态的过程，无论是在历史上还是个人层面上。在这种观点下，对现有文献进行了仔细审查，特别关注了一些相对被忽视的因素（性别、个人传记、家庭、人口祖先、社会结构、经济地位和教育等）。讨论了最强大和最常用的工具（如全基因组关联研究和全基因组测序）的优缺点，重点关注了突出出现的基因和区域，如载脂蛋白 E、叉头框 O3、白细胞介素 6、胰岛素样生长因子 1、9p21 染色体、5q33.3 以及体细胞突变等。这种方法的主要结果表明：(1) 长寿的遗传学具有高度的种群特异性；(2) 小效应等位基因、多效性和复杂的等位基因定时可能起着主要作用；(3) 遗传风险因素是特定于年龄的，需要根据衰老科学的观点进行整合；(4) 长寿遗传学与与年龄相关的疾病（尤其是心血管疾病）的遗传学之间存在密切关系。最后，强调了迫切需要对人类身体的核、线粒体和微生物组这三种遗传学之间的广泛未探索的相互作用采取全球方法。我们推测，这里提出的综合方法将有助于增加上述收获。
