Final Activity Report Summary - IIS AND AGEING (Comprehensive study of the organs and tissues through which insulin-like signalling affects lifespan in Drosophila) Ageing and its associated functional decline are of growing medical importance in industrialised societies. Recently, major scientific opportunities have opened up for ageing research. In distantly related organisms, manipulations of insulin / insulin-like growth factor signalling both extend lifespan and ameliorate loss of function and disease during ageing. The knowledge of how this pathway acts to extend lifespan can be harvested for intervention into human ageing and ageing-related diseases. This project advanced our understanding of the molecular mechanisms whereby this signalling pathway acts, in the fruit fly Drosophila melanogaster. It examined the effects on lifespan and associated traits of the manipulation of the hormonal signals central to the pathway, and identified a new component, (Imp-L2) whose overexpression can extend lifespan and whose human equivalent (IGFBP7) has been shown by others to act as a tumour suppressor. Furthermore, the project determined the targets of the drosophila FoxO, a transcription factor crucial for lifespan extension achieved through a number of different manipulations in a range of organisms. At the same time, this work has revealed the complexity of FoxO action and the evolutionary conservation of its regulon. The human FoxO (FoxO3A) has been shown by others to be strongly associated with human longevity. Hence, the targets of FoxO identified in this study are promising candidates for interventions into ageing and ageing-related diseases in humans.