Programming of lifespan by insulin/IGF-like signalling in Drosophila.

The proportion of older individuals is steadily increasing in our societies. Since age is the main risk factor for a number of debilitating, chronic diseases, this demographic change is resulting in ever-increasing human and socioeconomic costs. Understanding the biology of ageing is a key research priority because it has the potential to provide us with means to maintain health into old age.
Early-life nutrition can impact subsequent health in older humans. While the existence of this phenomenon is supported by a wealth of epidemiological evidence and corroborated by direct experimentation in mammals, the mechanistic links between early nutritional environment and age-related phenotypes remain unclear. We have recently used the fruit fly Drosophila melanogaster to elucidate the mechanisms whereby the diet consumed by young adults influences their subsequent ageing. We found that a relatively short exposure to a diet rich in sugar activates insulin/IGF-like signalling (IIS) inhibiting the transcription factor dFOXO to programme adult lifespan, curtailing subsequent survival despite a dietary improvement.
IIS pathway is present in all animals. It signals the animal's nutritional status to fine-tune its physiology. The importance of the IIS pathway is manifest in the role it plays in ageing: inhibition of IIS activity promotes longevity in all animals tested. At the same time, the pathway is a important determinant of human metabolic health. Our preliminary data show that modulating this pathway directly, independently of a dietary intervention, in early adulthood in Drosophila is sufficient to programme subsequent lifespan.
Animal responses to nutrition are complex, simultaneously mediated by several signalling pathways in response to relative and absolute amounts of multiple dietary components. To start tackling this complexity, we propose to examine directly the molecular mechanisms whereby modulation of IIS in early adult life can shape subsequent longevity in Drosophila. This will provide us with a simpler, more tractable experimental system, focused on a single, relevant, nutrient-signalling pathway. In turn, the findings will start building a coherent and comprehensive picture of how early-life nutrition affects ageing.
Our recent findings show that short-term modulation of IIS activity in just the fat body of the fly (equivalent to mammalian adipose and liver) is sufficient to change the animal's subsequent longevity. We will determine if there are other organs from which the long-term effects on ageing can be elicited. We will also determine which effectors of the pathway play a role.
Work by us and others has revealed the most-likely mechanism for the long-term effects of IIS modulation on animal physiology: IIS activity appears able to change chromatin, which is the packaging of the animal's genetic material, with long-term consequences for gene expression. We will determine the impact of IIS modulation on chromatin structure and long-term gene expression in the relevant adult tissues.
We and other groups have established that several enzymes capable of modifying or re-organising chromatin are engaged by the IIS pathway. We will examine whether any of these genes are mediating the long-term effects of IIS activity.
In summary, the project will elucidate how relatively short-term changes in the levels of IIS can cause long-term effects in an adult animal, in vivo. This will help us understand how early-life nutrition can have an impact on human ageing. This knowledge, in the long-term, has the potential to provide us with means to ensure human health and wellbeing throughout the life course.

Ageing and the associated functional decline are of growing medical, social and economic importance. Health and survival in old age are strongly influenced by an individual's current diet as well as the individual's dietary history. This long-term "memory" of past diets has been termed nutritional programming. The molecular mechanisms underlying this phenomenon remain unclear.

We have recently shown that in the fruit fly, a relatively short exposure to a diet rich in sugar activates insulin/IGF-like signalling (IIS) inhibiting the transcription factor dFOXO to programme adult lifespan, curtailing subsequent survival despite a dietary improvement. Indeed, our preliminary data confirm that manipulation of IIS in early adulthood is sufficient to impact the animal's lifespan. The most likely mechanism underlying this effect is a long-term change to chromatin architecture and the consequent, persistent effect on transcription. In this project, we propose to characterise the molecular mechanisms whereby a relatively short manipulation of IIS activity can program subsequent ageing and lifespan. We will answer three questions: What are the tissues and cell types, as well as IIS effectors, that are sufficient to elicit long-term impact on lifespan? What are the associated changes to genome-wide chromatin architecture and transcriptome? Which chromatin remodelling and/or histone modifying enzymes are engaged by IIS to effect these changes? The information obtained will be used to construct and test a hypothesis of how early life nutrition acts through IIS to determine subsequent lifespan.

Animal responses to nutrition are complex. By focusing on a single, relevant, nutrient signalling pathway we will start to unpick this complexity to understand the molecular mechanisms behind nutritional programming of lifespan. This, in turn, will help devise interventions that can improve human health and wellbeing throughout the life course.

Potential beneficiaries of this research, in short and long-term, include:

1) Public care and healthcare services (Societal and economic impact).
A substantial and ever-increasing amount of care efforts are targeted at older people. In the long-term, this basic research has the potential to result in treatments that reduce the occurrence of ageing-related health and fitness issues, in particular those linked to the metabolic syndrome, and hence will reduce the overall cost of care, including healthcare, in today's society, increasing effectiveness of a public service. There is a possibility that an intervention may allow for increased health and wellbeing of the aged, and alleviate the effects of an inappropriate early-life diet, preventing multiple, detrimental manifestations of ageing, hence further decreasing treatment cost. New treatments/interventions, including preventative approaches, aimed to increase the health and wellbeing at later ages, which may ultimately result from this research, have the potential to improve the quality of the care system.

2) Older people (Societal and economic impact).
Older people represent an ever-increasing portion of our society and often face immense personal costs due to ageing-related loss of function, decreased overall health and wellbeing, and increased occurrence of ageing-related conditions. The final aim of this research is to provide a basis for development of treatments for age-related conditions. In the long-term, this will result in tangible benefits in terms of increased quality of life, health, wellbeing and creativity and decrease in emotional and physical suffering for older people. This effect will not just be national but international. The research will also increase the awareness of others to the problems of ageing.

3) People suffering with the metabolic syndrome (Societal and economic impact).
Mostly due to changes in human nutrition, there is a growing epidemic of obesity, diabetes and the metabolic syndrome that substantially impairs the health and wellbeing of affected individuals throughout their life. This research may result in strategies to alleviate the effects of inappropriate early-life nutrition and improve the quality of life in this part of the population.

4) Economy (Economic impact).
This project will have an impact on the UK economy in several ways, both in short and long-term. Firstly, in the short-term, the project will create two new jobs as well as provide training thus creating highly skilled workers for e.g. the pharmaceutical industry. In the long-term, reduction in public care costs will liberate funds for investment into the economy. New interventions for treatment of ageing-related disease that will be developed as a result of research initiated in this project will benefit the pharmaceutical industry and hence the economy. Treatments that extend health into old age will provide more work force aiding the economy. The project will raise the research profile of the UK leading to more investments by the pharmaceutical industry. All of these will have an effect of increasing the economic performance, competitiveness and reputation of the UK.

5) Government policy (Societal and economic impact).
This project will have an impact on the UK government and its policy. In short term, this research will provide insight whether the effects of early-life nutrition on later-life outcomes could be remedied or prevented, thus informing government policy on the feasibility of this approach and whether further funding in this area of scientific enquiry is required and justified. In the long-term, the effects on the health of older people may inform government policy in numerous important areas such as healthcare and pensions.