Genetic determinants of proteomic aging.

IF 4.1 Q2 GERIATRICS & GERONTOLOGY
Alexander Mörseburg, Yajie Zhao, Katherine A Kentistou, John R B Perry, Ken K Ong, Felix R Day
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Abstract

Changes in the proteome and its dysregulation have long been known to be a hallmark of aging. We derived a proteomic aging trait using data on 1459 plasma proteins from 44,435 UK Biobank individuals measured using an antibody-based assay. This metric is strongly associated with four age-related disease outcomes, even after adjusting for chronological age. Survival analysis showed that one-year older proteomic age, relative to chronological age, increases all-cause mortality hazard by 13 percent. We performed a genome-wide association analysis of proteomic age acceleration (proteomic aging trait minus chronological age) to identify its biological determinants. Proteomic age acceleration showed modest genetic correlations with four epigenetic clocks (Rg = 0.17 to 0.19) and telomere length (Rg = -0.2). Once we removed associations that were explained by a single pQTL, we were left with three signals mapping to BRCA1, POLR2A and TET2 with apparent widespread effects on plasma proteomic aging. Genetic variation at these three loci has been shown to affect other omics-related aging measures. Mendelian randomisation analyses showed causal effects of higher BMI and type 2 diabetes on faster proteomic age acceleration. This supports the idea that obesity and other features of metabolic syndrome have an adverse effect on the processes of human aging.

蛋白质组老化的遗传决定因素。
长期以来,人们一直认为蛋白质组的变化及其失调是衰老的标志。我们使用基于抗体的分析方法,从44,435名UK Biobank个体中获得1459种血浆蛋白的数据,得出了蛋白质组学衰老特征。这一指标与四种与年龄相关的疾病结果密切相关,即使在调整了实际年龄之后也是如此。生存分析显示,相对于实际年龄,一岁的蛋白质组年龄增加了13%的全因死亡率风险。我们对蛋白质组年龄加速(蛋白质组老化性状减去实足年龄)进行了全基因组关联分析,以确定其生物学决定因素。蛋白质组年龄加速与4种表观遗传时钟(Rg = 0.17 ~ 0.19)和端粒长度(Rg = -0.2)有一定的遗传相关性。一旦我们删除了由单个pQTL解释的关联,我们就留下了三个映射到BRCA1, POLR2A和TET2的信号,它们对血浆蛋白质组学衰老有明显的广泛影响。这三个基因座的遗传变异已被证明会影响其他与衰老相关的组学指标。孟德尔随机化分析显示,较高的BMI和2型糖尿病对蛋白质组学年龄加速有因果关系。这支持了肥胖和代谢综合征的其他特征对人类衰老过程有不利影响的观点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.90
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0.00%
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