Aging is associated with the progressive decline of organism function and the progressive increase in risk of disease. As the average age of the population increases, we face a growing health care crisis and a lack of basic information about important regulators of the aging process. Circadian timing of organismal functions such as activity, immune regulation, food intake, and metabolism is known to decline with age in humans and animal models but the implications for the aging process are not well understood. Circadian dysfunction has been linked to neurological decline, development of cancer, and heart disease in humans, suggesting that maintenance of Circadian rhythm may be crucial for the goal of healthy aging. We hypothesize that circadian rhythm may be one crucial control point in creation of a feedforward cycle leading to organismal decline with age and that immune dysregulation may be a direct result of circadian dysregulation. Due to the benefits of invertebrate models for rapid genetic dissection of important molecular pathways, we propose to use Drosophila melanogaster as a model to determine the effects of aging on circadian rhythm of immune response and activity. We will first characterize the effects of aging on the circadian rhythm of immune response in Drosophila. We will then use circadian entrainment stimuli to determine whether entrainment of the circadian system can overcome the effects of age. Finally, we will use interventions in known pathways altering aging (particularly antioxidant overexpression and insulin signaling) to determine upstream factors that may play a role in loss of circadian rhythm. Aging is a major risk factor for development of infectious diseases as well as heart disease, cancer, Alzheimer's disease, and other conditions that lead to frailty and loss of independence. Circadian rhythm responds to light and other external cues and this regulation declines with age. The current proposal will use the Drosophila model organism to test the hypothesis that modulation of circadian function in age can improve immune response in the aged.
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