Reduced nutrient availability (dietary restriction, abbreviated DR) has been shown to be the most powerful modulator of the aging process in mammals, and it doubles the lifespan of the fruit fly, Drosophila melanogaster. The presence of DR regulation of aging in many different species indicates that at least some of the molecular pathways involved in the response are conserved across species, but, with few exceptions, specific physiological mechanisms mediating it are unknown. In rodents, DR maintains most physiological processes in an apparently youthful and disease-free state. Therefore, an understanding of the molecular mechanisms by which dietary restriction acts to modify patterns of aging would likely provide important information about the causes of age-associated disease as well as the process of aging itself. We recently reported that in the fruit fly, Drosophila melanogaster, the aging effects of dietary restriction are assessed quickly and precisely by the response to a """"""""switch"""""""" from a normal to a low-calorie environment. When adult Drosophila are switched they experience a dramatic and temporally defined reduction of age-specific death rate. This observation has three important implications that are exploited in this proposal: (1) genetic disruption of the DR response can be clearly identified using demographic analysis, (2) transcriptional and physiological changes that modify patterns of aging are restricted to a known temporal window, which is vital for identifying genetic mechanisms that regulate the DR response, and (3) an aging response to DR is assessed in two weeks, which is roughly 3-4 times faster than standard lifetime assays. Using the acute response to dietary restriction (DR) in Drosophila, we will determine if the dramatic reduction of mortality that occurs upon exposure to conditions of dietary restriction is mediated through specific genetic mechanisms. Two sets of hypotheses will be tested to determine the role of specific genes and molecular pathways in the DR response. The first set was generated based on an analysis of preliminary microarray data, while the second was generated from literature linking insulin/IGF-like signaling and histone acetylation to aging and dietary restriction. We will further exploit the power of our experimental system to identify new genes and mechanisms involved in lifespan extension via dietary restriction.
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