APOE genotype and biological age impact inter-omic associations related to bioenergetics.

IF 3.9 3区 医学 Q2 CELL BIOLOGY
Aging-Us Pub Date : 2025-05-03 DOI:10.18632/aging.206243
Dylan Ellis, Kengo Watanabe, Tomasz Wilmanski, Michael S Lustgarten, Andres V Ardisson Korat, Gwênlyn Glusman, Jennifer Hadlock, Oliver Fiehn, Paola Sebastiani, Nathan D Price, Leroy Hood, Andrew T Magis, Simon J Evans, Lance Pflieger, Jennifer C Lovejoy, Sean M Gibbons, Cory C Funk, Priyanka Baloni, Noa Rappaport
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引用次数: 0

Abstract

Apolipoprotein E (APOE) modifies human aging; specifically, the ε2 and ε4 alleles are among the strongest genetic predictors of longevity and Alzheimer's disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. In the present study, we analyzed multi-omic association patterns across APOE genotypes, sex, and biological age (BA) axes in 2,229 community dwelling individuals. Our analysis, supported by validation in an independent cohort, identified diacylglycerols as the top APOE-associated plasma metabolites. However, despite the known opposing aging effects of the allele variants, both ε2- and ε4-carriers showed higher diacylglycerols compared to ε3-homozygotes. 'Omics association patterns of ε2-carriers and increased biological age were also counter-intuitively similar, displaying significantly increased associations between insulin resistance markers and energy-generating pathway metabolites. These results demonstrate the context-dependence of the influence of APOE, with ε2 potentially strengthening insulin resistance-like pathways in the decades prior to imparting its longevity benefits. Additionally, they provide an atlas of APOE-related 'omic associations and support the involvement of bioenergetic pathways in mediating the impact of APOE on aging.

APOE基因型和生物年龄影响与生物能量学相关的组间关联。
载脂蛋白E (APOE)改变人类衰老;具体来说,ε2和ε4等位基因分别是长寿和阿尔茨海默病(AD)风险的最强遗传预测因子。然而,它们影响衰老的详细机制尚不清楚。在本研究中,我们分析了2229个社区居民的APOE基因型、性别和生物年龄(BA)轴的多组关联模式。我们的分析得到了独立队列验证的支持,确定二酰基甘油是apoe相关的血浆代谢物。然而,尽管已知等位基因变体具有抗衰老作用,但与ε3纯合子相比,ε2-和ε4-携带者均显示出更高的二酰基甘油含量。ε2携带者与生物年龄增加的组学关联模式也与直觉相反,显示胰岛素抵抗标志物与能量生成途径代谢物之间的关联显著增加。这些结果证明了APOE影响的环境依赖性,ε2可能在赋予其长寿益处之前的几十年里加强胰岛素抵抗样途径。此外,他们还提供了APOE相关的组学关联图谱,并支持生物能量途径参与介导APOE对衰老的影响。
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来源期刊
Aging-Us
Aging-Us CELL BIOLOGY-
CiteScore
10.00
自引率
0.00%
发文量
595
审稿时长
6-12 weeks
期刊介绍: Information not localized
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