Subhash Katewa is an Assistant Research Professor at the Buck institute, and the first author of an exciting paper recently published in Cell metabolism titled “Peripheral circadian clocks mediate dietary restriction dependent changes in lifespan and fat metabolism in Drosophila”. Subhash and his coauthors showed that circadian clocks are required for the two major effects of dietary restriction- lifespan extension and metabolic adaptation.
SAGE sat down with Subhash to discuss the main findings of this paper, and the implications that his research will have on the fields of aging and cancer.
1. How would you explain the main findings from this paper to the lay audience or, say, your grandmother?
This is an easy question, because the main finding from this paper is one of those important, yet taken for granted, messages that everyone believes, including my grandmother. If I tell her that the main finding from my paper is that “to live a long and healthy life you have to monitor what you eat, how much you eat, and when you eat, and that eating too much and eating at the wrong times of the day will have detrimental effects on your lifestyle,” her response will be “I taught this to your dad 70 years ago.” However, one key finding to add is that if you eat less you will have improved circadian clocks, specifically reduced protein intake.
2. What’s the most significant finding from the paper?
The most significant finding is that the peripheral circadian clocks (and not the central clocks) are required for the metabolic adaptation that happens on dietary protein restriction. Furthermore, we observed that upon dietary restriction there is an increase in the amplitude of circadian clock gene expression, especially in peripheral tissues.
3. What were the technological or conceptual innovations from this study?
Conceptually, we are the first ones to show that circadian clocks are required for the protective effects of dietary restriction. This will give impetus to the new field of chronogerontology (how clocks affect the aging process). Technically, we used an unbiased lipidomics approach to identify a novel set of triglycerides (medium-chain triglycerides) that are circadianally regulated upon ad libitum and restricted diets.
4. How did you initiate the project?
Previously, I showed that, under dietary restriction conditions, animals show both an increase in synthesis and also breakdown of fat (Katewa et. al. 2012). So one puzzling question has been how one can have both an increase in synthesis and degradation of triglycerides. I hypothesized that these two things may be happening at different times of the day, and hence I started looking at circadian clocks.
5. What was the role of your collaborators in the project?
This project would not have been possibly without my collaborators. I have several collaborators (both from within and outside of Buck) in this project and they all have played a huge role in this project. Amita Sehgal (University of Pennsylvania) and Jaga Giebultowicz (Oregon State University) provided expertise in circadian biology, reagents, and guidance throughout the study. At the Buck, several labs including the Kapahi, Ramanathan, and Brem labs provided their help and expertise. Arvind, Neelanjan, David, and Sonnet helped with the lipidomics; Rachel, Chris, and Daniel Promislow (University of Washington) with biostatistics; and Kazutaka Akagi provided his immuno-histochemistry and molecular expertise. Tim, along with Misha, Marysia, and Jen from the Kapahi lab, helped with lifespan data collection and analysis.
6. What’s next after this paper for this field?
Understanding the molecular mechanisms of how nutrients signals improve oscillation of clocks and their targets will be the next step.
7. What were the major hurdles in completing this study?
The biggest hurdle was to identify what lipids (mainly di- and triglycerides) are cycling under dietary restricted conditions. It took a lot of standardization and hard work, but we finally managed to obtain a clear separation and identified about 250 different di- and triglycerides from fly extracts.
8. What’s next for you after this study?
I have identified a novel set of transcriptional regulators that modulate the amplitude of circadian clocks under dietary restriction conditions. Understanding their molecular function and role under dietary restriction will be the next step.
9. How does the work relate to other findings from the lab or the Buck?
I have shown previously that dietary restriction induces a metabolic adaptation that is required for the increased lifespan that is observed upon dietary restriction (Katewa et. al. 2012). The key observation was a paradoxical increase in both the synthesis as well as breakdown of fat. With this current study, I am able to show that this behavior is regulated by peripheral circadian clocks.
10. What is the “big picture” of your findings and how will they impact the field of aging research?
It is well know that circadian clocks dampen with age. Our work shows that dietary restriction can attenuate this age-related decline of circadian clocks and even improve them. In recent years, several molecular mechanisms or pathways for the protective effects of dietary restriction have been proposed, yet the question that is neglected is when are these pathways activated? Do different cells or tissues show activation/inactivation at the same time or at different times of the day? And most importantly, you need well-functioning clocks to reap the benefits of dietary interventions that extend lifespan. I think one key way this will impact the field is that researchers will have to think of the timing of their experiments and when they measure behavioral or molecular changes. Thus, this work should contribute to initiating the sub-field of chronogerontology.
Dr. Katewa is interested in understanding how circadian clocks regulate metabolism, aging and 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 associated with accelerated aging and is a risk factor for several age-related diseases, such as cancer, obesity and diabetes. However, the underlying mechanisms are not known. More importantly, circadian regulation is ignored in most studies of aging even though it can frequently explain discrepant findings. Dr. Katewa’s interdisciplinary research is at the intersection of circadian and aging biology and could dramatically alter the way in which aging is studied and treated.
Dr. Katewa received his PhD from M.S. University of Baroda in India and completed postdoctoral training at University of Iowa and at the Buck Institute. During his postdoctoral work Dr. Katewa made a significant discovery that dietary restriction leads to significant enhancement of mitochondrial function and that this is necessary for the lifespan extension by dietary restriction (Cell, 2009, 139(1):149-160). In a follow-up study he showed that the enhanced mitochondrial functions are a prerequisite for fatty acid synthesis and subsequent oxidation indicating a change in energy metabolism upon dietary restriction (Cell Metab. 2012, 16(1):97-103).