The goal of this proposal is to determine how circadian rhythms impact nutrient dependent changes in lifespan. Circadian systems organize critical physiological and behavioral functions by coordinating gene expression and metabolic processes throughout the organism. Disruption of circadian clocks has been linked to accelerated aging and is a risk factor for age-related diseases, such as cancer and diabetes. However, the underlying mechanisms of this association remain unknown. It is becoming evident that in addition to light, nutrients provide significant input into modulating circadian systems, especially peripheral clocks. We hypothesize that circadian clocks impact aging and age-related disease by modulating inputs from nutrients and nutrient sensing pathways. We propose to use D. melanogaster to investigate the link between circadian clocks and aging for the following reasons: 1) their fast generation time and short lifespan, 2) ease of genetic manipulation, 3) established genetic models for understanding aging and disease, 4) an excellent track record for understanding of the biology of circadian clocks, and 5) the conservation of many biological processes and signaling pathways between mammals and invertebrates. Our preliminary evidence demonstrates cross-talk between circadian mechanisms and nutrient sensing pathways on multiple levels. We observed that dietary restriction (DR), which is known to extend lifespan in many species, impacts the circadian clocks. DR led to an increase in amplitude of circadian expression of various circadian clock gene in the whole body. We have demonstrated that circadian clocks are also required for the protective effects of DR on lifespan. Furthermore, we have found that circadian clocks play an important role in enhancing triglyceride turnover which we recently demonstrated is required for the lifespan extension upon DR. To understand the mechanisms by which circadian clocks impact aging, especially in the context of DR, we will undertake the following aims: 1) Determine the impact of nutrients on circadian clocks in an age- dependent and tissue-specific manner, 2) Investigate the role of circadian clocks on nutrient-dependent lifespan changes, 3) Determine how circadian influence the TOR/ILS longevity pathways and fat metabolism, and 4) Determine the downstream mechanisms underlying the contribution of circadian factors to lifespan extension. This will be examined using our preliminary data from circadian genome wide expression profiling upon DR. We will determine how nutrients impact the circadian clocks and whether modulation of circadian clocks and their targets modulate lifespan. These studies have the potential to be paradigm-shifting for the understanding of aging and age-related diseases and initiate the sub-discipline of 'chronogerontology'. In addition to providing a novel amenable target for treatments for age-associated pathologies, they could change research practice in biomedical labs by demonstrating the need to take time-of-day into account in all manipulations/measurements related to aging.
This project will address how peripheral circadian clocks impact the aging process, especially in response to nutrient manipulation. In addition to providing insight into molecular mechanisms that underlie aging, these studies may provide novel and amenable targets, based upon the manipulation of daily rhythms, to treat age-related pathologies which are a growing concern in the US.
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