Novel pro-longevity compounds for the treatment of neurodegenerative diseases

Ageing is arguably the major biomedical challenge of the 21st century with the incidence of age-related diseases, and neurodegenerative diseases in particular, expected to increase dramatically in the coming decades. 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 (de Magalhaes et al 2012, Pharmacological Reviews 64:88-101).

In this project, we aim to identify and characterize new compounds with pro-longevity, health-promoting and neuroprotective effects that may be suitable for the treatment of neurodegenerative diseases. To achieve this, and using a network pharmacology approach applied to publicly-available drug gene expression data, we have recently identified 11 novel candidate CR mimetic drugs. 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 via CR-related processes (Calvert et al, Aging Cell, in press). To assess the potential of these compounds for the treatment of neurodegenerative conditions, we now aim to study the 11 new candidate CR mimetics for lifespan and healthspan effects in two worm models 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. Mechanisms of action will also be studied to determine whether these new compounds are working via known ageing-related pathways or if they could represent new longevity pathways.

Biomarkers and candidate genes mediating CR mimetic drugs will be explored using bioinformatics analyses of the drugs’ publicly-available gene expression data, as before (Wuttke et al, PLoS Genetics (2012) 8:e1002834). Lastly, studies in mammalian cells will be performed to assay for potential effects relevant to humans, including neuroprotection, as previously (Chen et al, Molecular Neurodegeneration (2015) 10:51; Wood et al, Genome Biology, in press).

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.

Further details about our work on aging and age-related diseases are available at:
https://www.liv.ac.uk/integrative-biology/staff/joao-de-magalhaes/

Potential applicants are encouraged to contact Dr de Magalhaes ([Email Address Removed]) in the first instance for an informal discussion.