Calorie Restriction and Hallmarks of Aging in Drosophila

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Project Summary Aging is associated with functional decline in metabolic, physiological, proliferative, and tissue homeostasis leading to deterioration on the organismal level. The identification of therapeutic strategies that prevent or postpone age-related decline has become an urgent goal of biomedical science research. Aging has been linked with an array of conserved cellular processes and molecular pathways marked as hallmarks. However, relationship between the hallmarks has not been clearly defined. Determination of the interaction among hallmarks would open more realistic opportunity for identification of novel therapeutic targets to decelerate organismal aging. We will determine trajectories and relationships between two hallmarks of aging – deregulated nutrient sensing and mitochondrial dysfunction – by using our model of accelerated or decelerated aging. Calorie restriction (CR) delays the onset of age-related changes, decreases the rate of aging, and extends the life span in a variety of species. Our preliminary data show that shifting flies from a high-calorie to a low-calorie diet immediately decreases fly mortality, affects metabolism, and extends survivorship. In contrast, shifting from a low diet to a high diet accelerates aging. Dynamic metabolic adaptations to available nutrients are reflected in the tissue-specific transcriptome, which provides an excellent model to uncover rapid changes in the hallmarks of aging to start dissecting their relationship. Our project is designed to determine interactions between nutrient sensing and mitochondrial function in flies, in which the rate of aging is reduced or accelerated by shifting flies to different diets. We will use an integrated experimental and genetic approach that includes analysis of changes in metabolism, transcriptome, metabolome, mitochondrial function, and physiological markers of fly health. We propose the following specific aims: Determine effects of rapid change in aging rate on deregulated nutrient sensing by using an integrated approach involving the study of metabolism, and determination of the transcriptomic and targeted metabolomics profile in different tissues of shifted flies (Aim 1). Determine effects of change in the aging rate on mitochondrial dysfunction (Aim 2). Determine interactions between the two hallmarks by using our model of accelerated and decelerated aging by performing epistatic analysis (Aim 3). Our proposed study will advance our basic knowledge on the molecular and physiological mechanisms underlying interactions among hallmarks of aging and determine how their hierarchy affects organismal aging. Hallmarks of aging are highly conserved across species, suggesting that our findings could be translated to mammalian organisms.