Can TORC1 and FoxO activity explain the effects of early-life diet on subsequent, later-life health?

The number and proportion of older people in the UK are steadily increasing. Advancing age is a major risk factor for loss of function, frailty and disease. The demographic change is hence resulting in mounting personal and societal costs that should be urgently addressed, by compressing the period of ill health at the end of life. Our growing understanding of the biology of ageing can provide new points of interventions to delay or prevent its ill-effects. Human health in old age is predominantly shaped by environmental and lifestyle factors, including nutrition. We consume complex mixtures of nutrients, in amounts and at times that are determined by different eating habits. Interestingly, an older person’s current health is not only shaped by the nutrition they currently consume but also their dietary history. Diets in very early life, childhood or early adulthood have all been noted to trigger long-term, persistent effects on health. Thus, to promote healthy ageing, we need not only to understand current nutritional requirements, but also how long-term effects of past nutritional exposures arise and are maintained, so that we can identify ways to mitigate any of their detrimental consequences. A complex nutrient-responsive signalling network fine-tunes metabolism, physiology and the ageing process in response to diet. Our own work to date has aimed to untangle some of this complexity. We do this mainly using the fruit fly as an animal model; its short lifespan facilitates rapid discovery; its physiology and ageing are shaped by nutrients in a manner similar to humans; its nutrient signalling network has equivalent components and function to that of humans. Thus, although flies are not humans, they provide a powerful context for revealing the many shared molecular, cellular and physiological mechanisms. In our recent work we have started to explore how the activity of the nutrient-signalling network itself can result in long-lasting effects on health. We have directly modulated the activity of two highly conserved, key nodes in the Drosophila network, TORC1 and FoxO, and uncovered molecular mechanisms by which they generate long-term physiological effects. These signalling nodes respond to different nutrients and they mediate their responses in different cell types, suggesting independent, parallel mechanisms. This information provides us with a scientific opportunity to experimentally test if these mechanisms can also explain how earlier nutrition affects health and longevity in old age. Specifically, we will study three nutritional interventions that have lasting effects on physiology and ageing in Drosophila and mammals: high sugar diet, intermittent fasting and amino acid restriction. Importantly, we will also examine whether damaging effects of earlier dietary habits can be counteracted later in life. We propose to test this possibility experimentally by manipulating the nutrient signalling network in older individuals with different nutritional histories. Our proposed research is made possible by our preliminary work and by the wealth of genetic tools available in the fruit fly that allow the activity of the nutrient signalling network to be manipulated in specific cells and at specific times in an animal’s life, and which can be combined with nutritional and pharmacological interventions. Importantly, the knowledge gained in the study will facilitate the design of interventions to remedy long-term, detrimental effects, potentially also contributing to a reduction in health inequalities during ageing.