Aging is the number one risk factor for most cancers and neurodegenerative diseases. Studies in several systems indicate that aged and diseased cells have alterations in metabolism, autophagy, and generally accumulate dysfunctional mitochondria. Mitochondria are highly dynamic organelles and supply much of the chemical energy and intermediates required for cellular function. Selective autophagy of mitochondria (mitophagy) is the sole known mechanism for mitochondrial turnover. I hypothesize that the improper clearance of damaged mitochondria contributes to aging and age- related pathologies. However, the genes that regulate mitophagic processes are not well understood, especially in regard to aging tissues. Thus, the identification of mitophagic elements that interact with autophagy and longevity pathways will contribute to our understanding of aging biology. Here, I propose to pursue these studies by exploring three broad questions: 1) what are the consequences of dietary restriction and altered nutrient sensing pathways on autophagy/mitochondrial dynamics? The hypothesis to be tested is that dietary restriction and inhibition of the major nutrient sensing pathways (insulin/IGF-1 and TOR) promote longevity by altering autophagic flux and improve mitochondrial function. 2) What is the normal temporal and tissue-specific regulation of mitophagy induction, expansion, lysosomal fusion, and mitophagic flux? I will characterize mitophagic progression in different cells and tissues, and at different stages of the animal's life. My hypothesis is that aging tissues will have impaired mitophagy. 3) Can an increase in autophagy gene expression in the adult fly improve health-span and tissue homeostasis? My hypothesis is that treatments that promote autophagy also increase mitophagy to improve overall mitochondrial and tissue function. The work described in this proposal will bring about essential knowledge in an important area of aging research. A fundamental understanding of how mitochondria are turned over is critical to enhance our comprehension of aging, and may provide insights into the development of therapies.

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Studies in several systems indicate that aged and diseased cells generally accumulate dysfunctional mitochondria;here I propose to use the model organism Drosophila melanogaster to investigate the relationship between autophagy, mitochondrial turnover, and aging. My long-term goal is to identify novel targets for anti-aging therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F08-Q (20))
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Finkelstein, David B
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Icreverzi, Amalia; de la Cruz, Aida Flor A; Walker, David W et al. (2015) Changes in neuronal CycD/Cdk4 activity affect aging, neurodegeneration, and oxidative stress. Aging Cell 14:896-906