Multiomic longitudinal analysis of lifespan predictors in the short-lived killifish Nothobranchius furzeri

短命鳉鱼 Nothobranchius Furzeri 寿命预测因子的多组学纵向分析

• 批准号: 513826488
• 负责人: Professor Dr. Alessandro Cellerino, Ph.D.
• 金额: --
• 依托单位: Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513826488?language=en
• 关键词: Multiomic; longitudinal; analysis; lifespan; predictors

Understanding the molecular and genetic underpinnings of lifespan determination and aging is of paramount importance for biomedical research. An understudied aspect of aging relates to inter-individual differences in aging phenotypes that are best revealed by longitudinal investigations of age-related molecular and physiological changes to correlate their modulation with differences in lifespan. Canonical vertebrate models, such as rodents and small teleosts, however, have lifespans of several years that represent a biological limit for their practical use as models of aging. The killifish Nothobranchius furzeri inhabits habitats in the African savannah that are subject to seasonal desiccation and shows a captive lifespan of few months replicating many key aspects of vertebrate aging. This organism is now established as an alternative experimental model to investigate vertebrate aging. In our preliminary work, we performed a longitudinal RNA-seq study and correlated gene expression in fin biopsies obtained at young adult age with age at death and revealed that measureable differences in gene expression at young age can be detected between short- and long-lived individuals. In our preliminary work, we also developed an epigenetic clock for N. furzeri using a cross-sectional dataset and also developed a neural network for prediction of lifespan based on RNA-seq. The first aim of the present project is to extend this longitudinal approach to correlated splicing, DNA methylation and microbiome with individual lifespan to unravel the connections between these different layers. The second aim of the project is to use artificial intelligence to provide a surrogate measure of lifespan based on the above data and validate it by experimental manipulations. This lifespan predictor will enable to test effects of pharmacological intervention reducing both the number of animals and the time required and the cost of the experimentation with important implications also for animal welfare. More specifically, the predictor is supposed to be applied before and after a pharmacological treatment to test whether the treatment results in an extension of predicted lifespan on an individual basis.

了解生命决定和衰老的分子和遗传基础对生物医学研究至关重要。 衰老的一个未充分研究的方面涉及衰老表型的个体间差异，这些差异最好通过对与年龄相关的分子和生理变化的纵向调查来揭示，以将其调制与寿命差异相关联。 然而，典型的脊椎动物模型，如啮齿动物和小型硬骨鱼，具有几年的寿命，这代表了它们作为衰老模型的实际用途的生物学限制。鳉鱼Nothobranchius furzeri栖息在非洲萨凡纳的栖息地，受到季节性干燥，并显示了几个月的圈养寿命复制脊椎动物衰老的许多关键方面。这种生物体现在被建立为研究脊椎动物衰老的替代实验模型。在我们的初步工作中，我们进行了纵向RNA-seq研究，并将年轻成年时获得的鳍活检组织中的基因表达与死亡时的年龄相关联，并揭示了在短寿命和长寿命个体之间可以检测到年轻时基因表达的可测量差异。在我们的初步工作中，我们还开发了N的表观遗传时钟。furzeri使用横截面数据集，并开发了一个基于RNA-seq的神经网络来预测寿命。本项目的第一个目标是将这种纵向方法扩展到相关的剪接、DNA甲基化和微生物组与个体寿命，以解开这些不同层之间的联系。该项目的第二个目标是使用人工智能根据上述数据提供寿命的替代测量，并通过实验操作进行验证。该寿命预测器将能够测试药物干预的效果，从而减少动物数量和所需时间以及实验成本，这对动物福利也具有重要意义。更具体地说，预测器应该在药物治疗之前和之后应用，以测试治疗是否导致个体预测寿命的延长。