Biology subjects

Partridge, L.

Publications and source records attributed to Partridge, L..

5 recordsLinked to original sources

bioRxiv2018

Using the drug-protein interactome to identify anti-ageing compounds for humans

Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.\n\nAuthor SummaryHuman life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.

bioinformatics↗

bioRxiv2018

A computational model of the escape response latency in the Giant Fiber System of Drosophila melanogaster

The Giant Fiber System (GFS) is a multi-component neuronal pathway mediating rapid escape response in the adult fruit-fly Drosophila melanogaster, usually in the face of a threatening visual stimulus. Two branches of the circuit promote the response by stimulating an escape jump followed by flight initiation. Our recent work demonstrated an age-associated decline in the speed of signal propagation through the circuit, measured as the stimulus-to-muscle depolarization response latency. The decline is likely due to the diminishing number of inter-neuronal gap junctions in the GFS of ageing flies. In this work, we presented a realistic conductance-based, computational model of the GFS that recapitulates our experimental results and identifies some of the critical anatomical and physiological components governing the circuit's response latency. According to our model, anatomical properties of the GFS neurons have a stronger impact on the transmission than neuronal membrane conductance densities. The model provides testable predictions for the effect of experimental interventions on the circuit's performance in young and ageing flies.

neuroscience↗

bioRxiv2018

Ras inhibition by trametinib treatment in Drosophila attenuates gut pathology in females and extends lifespan in both sexes

Females of most species live longer than do males. Furthermore, lifespan-extending interventions in laboratory model organisms are often more effective in females (Regan and Partridge 2013). For instance, genetic and pharmacological suppression of activity of the insulin/insulin-like signalling - target of rapamycin (IIS-TOR) network generally extends female lifespan more than that of males in both Drosophila and mice (Clancy et al. 2001; Selman et al. 2009). We previously showed that attenuation of Ras-dependent IIS signalling by treatment with the FDA-approved MEK inhibitor, trametinib extends lifespan in females (Slack et al. 2015). Here, we demonstrate that trametinib treatment has beneficial effects on female-specific, age-related gut pathologies, similar to those obtained through dietary restriction (Regan et al. 2016). Importantly, we identify Ras inhibition as an effective lifespan-extending manipulation in males as well as females, pointing to parallel mechanisms of lifespan extension by trametinib in both sexes.

physiology↗

bioRxiv2018

Gene Expression-Based Drug Repurposing to Target Ageing

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.

systems biology↗

bioRxiv2016

Drug repurposing for ageing research using model organisms

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against ageing, despite many genes and pathways shown to be important in the ageing process and numerous studies demonstrating that genetic interventions can lead to a healthier ageing phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate ageing in the invertebrates C. elegans and Drosophila. Our approach combines information on genetic effects on ageing, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate ageing. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating ageing, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human ageing.

pharmacology and toxicology↗