Ellis Dylan, Watanabe Kengo, Wilmanski Tomasz, Lustgarten Michael S, Korat Andres V Ardisson, Glusman Gwênlyn, Hadlock Jennifer, Fiehn Oliver, Sebastiani Paola, Price Nathan D, Hood Leroy, Magis Andrew T, Evans Simon J, Pflieger Lance, Lovejoy Jennifer C, Gibbons Sean M, Funk Cory C, Baloni Priyanka, Rappaport Noa
Institute for Systems Biology, Seattle, WA 98109, USA.
Present address: Department of Medical Artificial Intelligence and Data Science, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan.
Aging (Albany NY). 2025 May 3;17(5):1105-1138. doi: 10.18632/aging.206243.
Apolipoprotein E () 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 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 -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 , with ε2 potentially strengthening insulin resistance-like pathways in the decades prior to imparting its longevity benefits. Additionally, they provide an atlas of -related 'omic associations and support the involvement of bioenergetic pathways in mediating the impact of on aging.
载脂蛋白E（）影响人类衰老；具体而言，ε2和ε4等位基因分别是寿命和阿尔茨海默病（AD）风险最强的遗传预测因子之一。然而，其影响衰老的详细机制仍不清楚。在本研究中，我们分析了2229名社区居住个体在基因型、性别和生物学年龄（BA）轴上的多组学关联模式。我们的分析在一个独立队列中得到验证支持，确定二酰甘油是最相关的血浆代谢物。然而，尽管已知等位基因变体具有相反的衰老效应，但与ε3纯合子相比，ε2和ε4携带者的二酰甘油水平更高。ε2携带者与生物学年龄增加的“组学关联模式也出人意料地相似，胰岛素抵抗标志物与能量产生途径代谢物之间的关联显著增加。这些结果证明了载脂蛋白E影响的背景依赖性，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，它们提供了一份与载脂蛋白E相关的“组学关联图谱，并支持生物能量途径参与介导载脂蛋白E对衰老的影响。
