Cells and organisms have sophisticated stress responses to adapt to conditions where the availability of food or O2 is limited. These strategies that allow for survival in lean times can also increase lifespan, as animal lifespan can be increased by reducing either O2 or food consumption. Understanding how to manipulate stress response pathways could have important clinical applications to delay or reduce a host of age-associated conditions. This goal is hampered by current gaps in our understanding of fundamental stress response pathways, especially how multiple stresses interact physiologically. We have discovered that specific hypoxic conditions disrupt proteostasis, the coordination of protein production, folding, quality control, and degradation that preserves the integrity of the proteome. We further show that fasting can protect against the effects of hypoxia on proteostasis. The aak-2 subunit of AMP-activated kinase (AMPK), a conserved energy sensor, is a central regulator of these effects. In fed animals, AMPK mediates the hypoxia-induced disruption of proteostasis. However, AMPK has the opposite role in fasted animals, which require aak-2 is required to protect proteostasis. The goal of the proposed research is to reveal mechanisms that underlie the different effects of hypoxia, and AMPK activation, in fed and fasted animals. We will then use our ability to manipulate proteostasis with hypoxia and food deprivation to test the hypothesis that defects in proteostasis pathways drive aging and the associated physiological decline. A focus of these experiments is on revealing processes that mediate changes in the aggregation of toxic proteins that are associated with progressive neurodegenerative diseases. Understanding how hypoxia signaling can modulate proteostasis may suggest new therapeutic strategies for these devastating diseases. Moreover, the results of this research will provide unique insight into fundamental features of how organisms respond when faced with multiple environmental stimuli, and begin to reveal how homeostatic responses to different stress conditions are integrated.
The proposed research is relevant to public health because it will reveal new ways that cells and organisms respond to decreased O2, and provide insight into the physiological effects of fasting in animals. This is important, as defects in nutrient regulatin and the response to low O2 are associated with human diseases, ranging from cardiovascular disease and diabetes to cancer. Many of these conditions are more prevalent with age. Therefore, a basic molecular and genetic understanding of the cellular processes by which the response low O2 and food interact will provide a foundation to develop novel therapeutic strategies for many devastating diseases.
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