Final Report Summary - ERA (Experimental Research into Ageing)
Advancing age is the major cause of serious illness, including cancer, diabetes, cardiovascular disease and dementia. There is therefore an urgent need to find ways of helping older people to maintain their health and function and to avoid disease. Medical research and clinical treatment have generally considered each disease of ageing as a separate entity, mainly by tackling each one after it has presented with clinical symptoms. However, recent research into the ageing process itself has revealed that these diseases are not entirely separate. Rather, during ageing maintenance of the genome, of the functioning of cells and organs, and of the circulation becomes weaker, and these kinds of malfunction can increase the risk of several age-related conditions together. Simple dietary, pharmacological and genetic interventions in laboratory animals can produce broad improvements in health during ageing, with a reduced impact of multiple age-related conditions. These interventions are preventative, by delaying or preventing diseases, rather than curing them once they have appeared. The aim of much research into ageing is therefore to understand the mechanisms by which these interventions improve health, and to use the findings as the basis of a broad-spectrum, preventative medicine for the diseases of human ageing.
This research programme focused on two well established interventions that have been shown to improve health during ageing, based upon nutrition and the mechanisms that sense it. Dietary restriction, in which intake of food is restricted while avoiding malnutrition, produces a very broad-spectrum in health during ageing in diverse organisms including monkeys. A nutrient-sensing signaling network that includes insulin signaling responds to nutrients to regulate metabolism and other traits, and reducing its activity with genetic changes or drugs can also improve health during ageing and extend lifespan, with increasing evidence it can do so in humans. In this research programme we aimed to answer three important questions about these interventions. First, given that we already know that the protein part of the diet is important for the effects of dietary restriction, we identified which components of the protein are important, and found that we could produce a simple prediction based on the genome of the organism. This finding is important for understanding how efficiently proteins are used, which is important for animal production, for humans with compromised nutrition, and for avoiding weight gain. Second we found that mice that are allowed to eat as much as they like until middle age become unresponsive to dietary restriction. They become slim, but they show no increase in survival. We found that gene important in metabolism of fats become locked down by a chemical alteration that prevents them from responding normally to dietary restriction. Humans may become similarly unresponsive to the beneficial effects of lowered food intake as they get older, and it will be important to understand if the mechanisms responsible can be targeted with drugs. Thirdly, we found that a particular part of the nutrient-sensing network, called the Ras pathway, which is very important in many human cancers, plays a key role in the chain of events by which the nutrient-sensing network can improve health during ageing. This pathway is highly susceptible to pharmacological intervention with drugs developed to treat cancer, and it will be important to determine if these drugs have a broader therapeutic range than is currently realized.
This research programme focused on two well established interventions that have been shown to improve health during ageing, based upon nutrition and the mechanisms that sense it. Dietary restriction, in which intake of food is restricted while avoiding malnutrition, produces a very broad-spectrum in health during ageing in diverse organisms including monkeys. A nutrient-sensing signaling network that includes insulin signaling responds to nutrients to regulate metabolism and other traits, and reducing its activity with genetic changes or drugs can also improve health during ageing and extend lifespan, with increasing evidence it can do so in humans. In this research programme we aimed to answer three important questions about these interventions. First, given that we already know that the protein part of the diet is important for the effects of dietary restriction, we identified which components of the protein are important, and found that we could produce a simple prediction based on the genome of the organism. This finding is important for understanding how efficiently proteins are used, which is important for animal production, for humans with compromised nutrition, and for avoiding weight gain. Second we found that mice that are allowed to eat as much as they like until middle age become unresponsive to dietary restriction. They become slim, but they show no increase in survival. We found that gene important in metabolism of fats become locked down by a chemical alteration that prevents them from responding normally to dietary restriction. Humans may become similarly unresponsive to the beneficial effects of lowered food intake as they get older, and it will be important to understand if the mechanisms responsible can be targeted with drugs. Thirdly, we found that a particular part of the nutrient-sensing network, called the Ras pathway, which is very important in many human cancers, plays a key role in the chain of events by which the nutrient-sensing network can improve health during ageing. This pathway is highly susceptible to pharmacological intervention with drugs developed to treat cancer, and it will be important to determine if these drugs have a broader therapeutic range than is currently realized.