Описание
The ageing of the population has created an urgent need to develop approaches targeting the ageing process. In model organisms, the process of ageing can be manipulated by both genetic manipulations and dietary interventions. Most notably, caloric restriction (CR), a reduction in calorie intake without malnutrition, extends longevity and retards age-related diseases, including neurodegeneration. Developing CR mimetics, compounds that reproduce the health and longevity benefits of CR without its side-effects, is therefore of widespread medical and commercial interest.
Using a network pharmacology approach applied to publicly-available drug gene expression data, we have recently identified 11 novel candidate CR mimetics. Five of these have already been tested in the roundworm C. elegans, an established model of ageing and of CR, with four significantly extending lifespan. In order to advance in the translational pathway, it is essential that we now demonstrate that these compounds can be applied to specific diseases. In this project, we aim to study the 11 new candidate CR mimetics for lifespan and healthspan effects in two worm odels of neurodegenerative diseases: a dnj-14 null mutant model of adult-onset neuronal ceroid lipofuscinosis and a worm model of frontotemporal dementia expressing a human Tau mutant, parkinsonism-17. There is considerable current interest in repurposing drugs for the treatment of neurodegenerative conditions. We expect to identify new drugs with potential for the treatment of neurodegenerative diseases that we can then take on to further and longer studies in mammalian models. Though additional studies will be necessary beyond this project, this work can culminate in the development of new treatments for neurodegenerative diseases.