An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo.

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Celia Lujan, Eleanor Jane Tyler, Simone Ecker, Amy Philomena Webster, Eleanor Rachel Stead, Victoria Eugenia Martinez-Miguel, Deborah Milligan, James Charles Garbe, Martha Ruskin Stampfer, Stephan Beck, Robert Lowe, Cleo Lucinda Bishop, Ivana Bjedov
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引用次数: 0

Abstract

Background: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.

Methods: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.

Results: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.

Conclusions: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

体外和体内抗衰老化合物的快速筛选平台。
背景:在细胞水平抑制或延缓衰老标志已被认为是延长生物体寿命和延长健康寿命的途径。因此,人们对抗衰老药物的发现产生了浓厚的兴趣。然而,目前这需要进行费时费力的长寿分析。在这里,我们提出了一种新的筛选读数,用于加快发现抑制体外细胞群老化并能延长体内寿命的化合物:方法:我们利用 Illumina 甲基化阵列监测了培养中的成人原代人类细胞长期传代过程中的 DNA 甲基化变化。这使我们能够开发、测试和验证 CellPopAge Clock,它是一种带有底层算法的表观遗传时钟,在现有的表观遗传时钟中独一无二,其设计旨在体外检测抗衰老化合物。此外,我们还测量了衰老标志物,并在果蝇体内进行了长寿实验,以进一步验证我们发现新型抗衰老化合物的方法。最后,我们将我们的表观遗传时钟与其他可用的表观遗传时钟进行对比,以巩固其在原代细胞培养中的实用性和专业性:我们开发了一种新型表观遗传时钟--CellPopAge Clock,用于精确监测成人原代细胞群体的年龄。我们发现,CellPopAge Clock 可以检测到使用雷帕霉素或曲美替尼这些公认的长寿药物治疗的人类原代细胞的衰老速度。然后,我们利用 CellPopAge Clock 作为筛选工具,鉴定可延缓细胞群衰老的化合物,发现了新型抗衰老药物 torin2 和 dactolisib (BEZ-235)。我们证明,用抗衰老化合物处理的人类原代细胞的表观遗传衰老延迟伴随着衰老和衰老生物标志物的减少。最后,我们利用专门配制的holidic培养基,提高了药物在果蝇体内的生物利用率,从而将我们的筛选平台扩展到了体内。我们的研究表明,新型抗衰老药物 torin2 和 dactolisib(BEZ-235)能延长果蝇的寿命:我们的方法扩大了 CpG 甲基化分析的范围,可以利用人体细胞在体外和体内准确、快速地检测药物的抗衰老潜力,为测试人们所寻求的抗衰老化合物和老年保护剂提供了一个新的加速发现平台。
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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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