Nat Commun:“起底”影响人类衰老和长寿的基因座,血铁水平竟也参与调控?

2020-07-22 王煊 生物探索

人类衰老始于体内环境平衡被打破,与年龄有关的疾病随之发作并最终导致死亡。不过,这种失衡在不同个体间存在很大差异,并取决于遗传、环境和生活方式等许多不同因素。

人类衰老始于体内环境平衡被打破,与年龄有关的疾病随之发作并最终导致死亡。不过,这种失衡在不同个体间存在很大差异,并取决于遗传、环境和生活方式等许多不同因素。衰老表型,例如健康寿命(healthspan)、总寿命以及长寿的生存率,这是所有人都感兴趣的,但是需要大量样本进行遗传学研究。


2020年7月16日,来自英国爱丁堡大学与荷兰莱顿大学的研究人员在《Nature Communications》上发表了有关衰老影响因素的最新研究成果。该报告确定了影响3种衰老表型的10个基因组位点,其中5个为首次报道。这些基因座中的大多数与血管疾病有关,丰富了先前强调的DNA损伤、细胞凋亡和体内稳态反应等衰老途径,并发现血液中的铁代谢也影响着人类的衰老。


在这项研究中,研究人员评估了已发表的大型全基因组关联研究(GWAS)中,三种不同类型的衰老表型的遗传重叠程度。发现总寿命与健康寿命和长寿密切相关,而健康寿命与长寿间的相关性较弱。随后研究人员测试了衰老性状遗传方面的差异是否与其他性状相关,发现所有三个衰老特征与动脉疾病、中风、慢性阻塞性肺疾病及受教育年限均具有相似的相关性。而健康寿命与代谢性状的相关性更强,与抑郁症和癌症呈负相关性;总寿命与饮酒量具有独特的相关性;长寿则与阿尔茨海默氏病具有独特相关性。


健康寿命、总寿命和长寿具有高度遗传相关性


之后,研究人员对健康寿命、总寿命和长寿的GWAS进行了荟萃分析,确定了全基因组意义上的24个基因座,从中筛选出显着性的10个,其中rs2643826(SLC4A7)、rs17499404(LINC02513)、rs1159806(FOXO3)、rs61905747(ZW10)和rs12830425(FGD6)这5个为首次报道。分析发现这10个基因座与几种年龄相关的疾病和表型显着相关:大多数基因座的寿命延长等位基因与心血管疾病表型的减少有关,也有基因座的保护性变异与代谢综合征的减少和认知功能下降有关。


24个在全基因组意义上被鉴定的多变量基因座


对与基因表达定量性状基因座(eQTL)共定位的目标基因座进行评估后,研究人员发现这些基因座与28个顺式基因和50个反式基因的表达共定位。进一步分析中,研究人员发现,这些基因座主要集中于血红素代谢、缺氧和早期雌激素反应等7个标志性基因集,以及细胞凋亡信号传导、化学稳态、红细胞和髓样细胞发育等32个生物学过程。


与衰老相关的基因有7个标志性的基因通路


研究人员猜测,血红素代谢和化学稳态对健康寿命、总寿命和长寿的影响可能是通过对血液中铁的生物利用度所介导的。这一点在随后的分析中得到确认,即血液中铁代谢异常可能导致许多与衰老有关的疾病进而影响寿命。


研究人员表示:“这些发现让我们很激动,这项研究表明血液中的高铁含量会损害人类的健康和寿命。若能基于此开展详细研究,或许有助于预防与衰老有关的损害”。

 

原始出处:

Paul R H J Timmers 1, James F Wilson 2 3, Peter K Joshi 4,et al.Multivariate genomic scan implicates novel loci and haem metabolism in human ageing.Nat Commun. 2020 Jul 16;11(1):3570. doi: 10.1038/s41467-020-17312-3.

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    2020-11-26 liuli5079
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    2020-09-30 liye789132251
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    2020-07-28 ms 内分泌科张

    学习

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    2020-07-24 jichang
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    2020-07-22 14757fdfm46暂无昵称

    学习了

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