Exploring links between circadian clocks and aging Summary: Age-related decline in the physiological and cognitive functions in humans is of great concern to society and there is an urgent need to identify the biological mechanisms that support healthy aging and longevity. Recent evidence suggests that the biological (circadian) clocks are important for maintaining health during aging. Circadian clocks are endogenous molecular regulators that coordinate daily changes in the level of gene expression, physiological functions and behavior with external day/night cycles. Disruption of circadian clocks in mammals result in accelerated aging and increased age-related pathologies such as cancer and neurodegenerative diseases. Data from our laboratory demonstrated that disruption of circadian clock in the model organism Drosophila melanogaster also leads to premature aging and compromised longevity.
The aim of this proposal is to test the hypothesis that deregulation of circadian network is causally linked to aging in Drosophila. We plan to investigate the relationship between circadian systems and aging by focusing on two aims: a) we will attempt to increase the expression of declining clock genes via transgenic manipulations, and determine whether these treatments can enhance the amplitude of per and tim circadian oscillations in old flies. This will allow us to identify the molecular defects that cause age-related decay of circadian network and help us attempt to reverse this decay by genetic interventions b) Test if high amplitude of circadian oscillations support longevity and health during aging. Our results should provide critical information regarding links between strong circadian clocks and longevity. The fruitfly Drosophila is an excellent model to address these links due to its short lifespan (~60 days) and conservation of clock genes and aging mechanisms between flies and humans. Insights obtained from this innovative exploratory research will lead to a better understanding of the mechanisms that link rhythmic oscillations of the circadian system with health and longevity. The outcomes of this exploratory research proposal may point to novel ways to maintain optimal health during aging in humans by enhancement of the circadian systems.

Public Health Relevance

Age-related decline in various life functions in humans is of great concern for society, and there is an urgent need to identify the biological mechanisms that support healthy aging and longevity. Recent evidence suggests that the biological (circadian) clocks play important roles in maintaining health during aging. The proposed studies will uncover the molecular mechanisms that cause age related decay of the circadian clock mechanism. Insights obtained from this work performed on a model organism may lead to novel ways of increasing longevity in humans by enhancing the circadian clock amplitude in aging individuals.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Mackiewicz, Miroslaw
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Oregon State University
Schools of Arts and Sciences
United States
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Rakshit, Kuntol; Giebultowicz, Jadwiga M (2013) Cryptochrome restores dampened circadian rhythms and promotes healthspan in aging Drosophila. Aging Cell 12:752-62
Tevy, Maria Florencia; Giebultowicz, Jadwiga; Pincus, Zachary et al. (2013) Aging signaling pathways and circadian clock-dependent metabolic derangements. Trends Endocrinol Metab 24:229-37
Rakshit, Kuntol; Wambua, Rebecca; Giebultowicz, Tomasz M et al. (2013) Effects of exercise on circadian rhythms and mobility in aging Drosophila melanogaster. Exp Gerontol 48:1260-5
Rakshit, Kuntol; Krishnan, Natraj; Guzik, Elýýbieta M et al. (2012) Effects of aging on the molecular circadian oscillations in Drosophila. Chronobiol Int 29:5-14
Beaver, Laura M; Klichko, Vladimir I; Chow, Eileen S et al. (2012) Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster. PLoS One 7:e50454
Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S et al. (2012) Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol Dis 45:1129-35