Geroscience hypothesis posits that aging itself is the underlying major risk factor for age-related chronic diseases, including Alzheimer's Disease (AD); therefore, delaying aging delays disease, including AD. This proposal will examine the reciprocal relationship between circadian rhythm disruption (CRD) and AD pathology. Circadian rhythms, which are intimately interlinked with cellular metabolism, orchestrate the coordinated expression and function of multiple pathways that support normal cellular function and repair in both neural and peripheral tissues. Circadian rhythms deteriorate with aging, and Alzheimer's patients show disrupted circadian rhythm. However, the causal role of CRD for AD is not clear. The proposal will assess the relationship between circadian rhythm disruption and AD pathology, will test whether improvement in circadian rhythms delay the onset and progression of AD. and will attempt to identify underlying molecular mechanisms. Well-characterized Drosophila melanogaster (fruit fly) models of AD with Drosophila genetic tools will be used to test the impact of genetic or environmental CRD on the onset and severity of the multiorgan functional decline in AD. One feature of CRD is the lack of feeding consolidation to daylight hours in diurnal animals. To restore aspects of circadian rhythm in older flies, animals will be subject to time-restricted feeding (TRF) in which food is provided to flies only during the 12 h day time. TRF does not reduce daily caloric intake and imparts a molecular signature that is distinct from that under caloric restriction. Disease onset and severity will be assessed in TRF, and ad lib fed (ALF) flies to determine if TRF is an effective behavioral intervention for AD. To test the molecular pathways mediating the opposite effects of CRD and TRF on AD pathologies, time-series transcriptomes from these flies will be analyzed to find candidate pathways. The functional significance of these pathways will be tested by expressing genetic gain of function and loss of function alleles in AD flies. Our novel in vivo genetic-transgenic Drosophila disease model coupled with ultrastructural, functional, metabolic, and transcriptome techniques will generate unbiased insights into the mechanistic basis of accelerated aging in production of AD. Successful completion of this project will provide a deeper molecular understanding of the interaction between circadian rhythm and genetic risk of AD. Additionally, this research will assess the efficacy of a behavioral intervention that would have a high potential for adoption in humans.

Public Health Relevance

Sleep and circadian rhythm deteriorate with aging and compromise the function of the brain and body. This proposal suggests a method for investigating how chronic circadian rhythm disruption, which is intimately interlinked with cellular metabolism, affects Alzheimer's disease (AD) pathology. Conversely, optimum eating time will be used a novel intervention to optimize circadian rhythm and reduce the severity of AD pathology.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Mackiewicz, Miroslaw
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Salk Institute for Biological Studies
La Jolla
United States
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