GeroProtect · Developing Geroprotectors to Prevent Polymorbidity

Advancing age is the major risk factor for disability and illness, including cardiovascular, metabolic and neu-rodegenerative disease and cancer. The increasing incidence of older people in European countries is posing major medical, social and economic challenges, and there is an urgent need to find ways of compressing late-life morbidity. Ageing has proved malleable to genetic and pharmacological interventions in laboratory animals, and at least some of the mechanisms are conserved over large evolutionary distances. Reduced activity of the nutrient-sensing insulin/insulin-like growth factor/TOR signalling network can increase health and combat ageing-related disease in laboratory animals, with increasing evidence of its importance in human ageing. There is thus a prospect for pharmacological intervention to prevent more than one ageing-related condition, rather than tackling diseases one by one and as they arise. The aim of this research programme is to evaluate the potential for pharmacological prevention of ageing-related decline in humans with a polypill targeting the nutrient-sensing network. We find that three licensed drugs, lithium, rapamycin and trametinib, act independently, at different nodes in the network, to increase lifespan in the fruitfly Drosophila, implying that the network controls more than one underlying mechanism of ageing, and that a polypill of these drugs could be particularly effective. We shall test this idea in mice, and assess the underlying mechanisms in Drosophila and mice. We have found that suppression of the Ras signalling branch of the network, which has a well known role in human cancer, can extend lifespan in both the fruitfly Drosophila and mice, and we shall assess its role in humans. Interventions that ameliorate ageing often have sex-specific effects, and we shall investigate the mechanisms leading to these for the nutrient-sensing network. The outputs of the work will inform future clinical trails in humans.