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Free keywords:
ageing
drug repurposing
gene expression
the connectivity map
Abstract:
Ageing is the largest risk factor for a variety of non-communicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both life- and health-span. Ageing is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target-centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat ageing in human brain. Using multiple gene expression datasets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterise ageing. Then, we compared these changes in gene expression with drug perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as anti-ageing drugs by reversing the detrimental changes that occur during ageing, others by mimicking the cellular defense mechanisms. The drugs that we identified included significant number of already identified pro-longevity drugs, indicating that the method can discover de novo drugs that meliorate ageing. The approach has the advantages that, by using data from human brain ageing data it focuses on processes relevant in human ageing and that it is unbiased, making it possible to discover new targets for ageing studies. This article is protected by copyright. All rights reserved.
