Molecular inhibition of RAS signalling to target ageing and age-related health

Abstract

ABSTRACT The RAS/MAPK pathway is a highly conserved signalling pathway with a well-established role in cancer. Mutations that hyperactivate this pathway are associated with unregulated cell proliferation. Evidence from a range of model organisms also links RAS/MAPK signalling to ageing. Genetic approaches that reduce RAS/MAPK signalling activity extend lifespan and also improve healthspan, delaying the onset and/or progression of age-related functional decline. Given its role in cancer, therapeutic interventions that target and inhibit this pathway's key components are under intense investigation. The consequent availability of small molecule inhibitors raises the possibility of repurposing these compounds to ameliorate the deleterious effects of ageing. Here, we review evidence that RAS/MAPK signalling inhibitors already in clinical use, such as trametinib, acarbose, statins, metformin and dihydromyricetin, lead to lifespan extension and to improved healthspan in a range of model systems. These findings suggest that the repurposing of small molecule inhibitors of RAS/MAPK signalling might offer opportunities to improve health during ageing, and to delay or prevent the development of age-related disease. However, challenges to this approach, including poor tolerance to treatment in older adults or development of drug resistance, first need to be resolved before successful clinical implementation.