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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG045835-01
Application #
8580334
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
Program Officer
Finkelstein, David B
Project Start
2013-08-01
Project End
2018-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$339,500
Indirect Cost
$164,500
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
Katewa, Subhash D; Akagi, Kazutaka; Bose, Neelanjan et al. (2016) Peripheral Circadian Clocks Mediate Dietary Restriction-Dependent Changes in Lifespan and Fat Metabolism in Drosophila. Cell Metab 23:143-54
Chaudhuri, Jyotiska; Bose, Neelanjan; Gong, Jianke et al. (2016) A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive α-Dicarbonyl Detoxification. Curr Biol 26:3014-3025
Nelson, Christopher S; Beck, Jennifer N; Wilson, Kenneth A et al. (2016) Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila. BMC Genomics 17:867
Luis, Nuno Miguel; Wang, Lifen; Ortega, Mauricio et al. (2016) Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction. Cell Rep 17:1207-1216
Kumar, Jitendra; Barhydt, Tracy; Awasthi, Anjali et al. (2016) Zinc Levels Modulate Lifespan through Multiple Longevity Pathways in Caenorhabditis elegans. PLoS One 11:e0153513
Laye, Matthew J; Tran, ViLinh; Jones, Dean P et al. (2015) The effects of age and dietary restriction on the tissue-specific metabolome of Drosophila. Aging Cell 14:797-808
Laberge, Remi-Martin; Sun, Yu; Orjalo, Arturo V et al. (2015) MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17:1049-61
Chi, Thomas; Kim, Man Su; Lang, Sven et al. (2015) A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease. PLoS One 10:e0124150
Killilea, David W; Westropp, Jodi L; Shiraki, Ryoji et al. (2015) Elemental Content of Calcium Oxalate Stones from a Canine Model of Urinary Stone Disease. PLoS One 10:e0128374
Chatterjee, Debamita; Katewa, Subhash D; Qi, Yanyan et al. (2014) Control of metabolic adaptation to fasting by dILP6-induced insulin signaling in Drosophila oenocytes. Proc Natl Acad Sci U S A 111:17959-64

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