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Circadian regulation of mitochondrial uncoupling and lifespan

Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. Th...

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Autores principales: Ulgherait, Matt, Chen, Anna, McAllister, Sophie F., Kim, Han X., Delventhal, Rebecca, Wayne, Charlotte R., Garcia, Christian J., Recinos, Yocelyn, Oliva, Miles, Canman, Julie C., Picard, Martin, Owusu-Ansah, Edward, Shirasu-Hiza, Mimi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174288/
https://www.ncbi.nlm.nih.gov/pubmed/32317636
http://dx.doi.org/10.1038/s41467-020-15617-x
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author Ulgherait, Matt
Chen, Anna
McAllister, Sophie F.
Kim, Han X.
Delventhal, Rebecca
Wayne, Charlotte R.
Garcia, Christian J.
Recinos, Yocelyn
Oliva, Miles
Canman, Julie C.
Picard, Martin
Owusu-Ansah, Edward
Shirasu-Hiza, Mimi
author_facet Ulgherait, Matt
Chen, Anna
McAllister, Sophie F.
Kim, Han X.
Delventhal, Rebecca
Wayne, Charlotte R.
Garcia, Christian J.
Recinos, Yocelyn
Oliva, Miles
Canman, Julie C.
Picard, Martin
Owusu-Ansah, Edward
Shirasu-Hiza, Mimi
author_sort Ulgherait, Matt
collection PubMed
description Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, upregulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents overproliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.
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spelling pubmed-71742882020-04-28 Circadian regulation of mitochondrial uncoupling and lifespan Ulgherait, Matt Chen, Anna McAllister, Sophie F. Kim, Han X. Delventhal, Rebecca Wayne, Charlotte R. Garcia, Christian J. Recinos, Yocelyn Oliva, Miles Canman, Julie C. Picard, Martin Owusu-Ansah, Edward Shirasu-Hiza, Mimi Nat Commun Article Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, upregulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents overproliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target. Nature Publishing Group UK 2020-04-21 /pmc/articles/PMC7174288/ /pubmed/32317636 http://dx.doi.org/10.1038/s41467-020-15617-x Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ulgherait, Matt
Chen, Anna
McAllister, Sophie F.
Kim, Han X.
Delventhal, Rebecca
Wayne, Charlotte R.
Garcia, Christian J.
Recinos, Yocelyn
Oliva, Miles
Canman, Julie C.
Picard, Martin
Owusu-Ansah, Edward
Shirasu-Hiza, Mimi
Circadian regulation of mitochondrial uncoupling and lifespan
title Circadian regulation of mitochondrial uncoupling and lifespan
title_full Circadian regulation of mitochondrial uncoupling and lifespan
title_fullStr Circadian regulation of mitochondrial uncoupling and lifespan
title_full_unstemmed Circadian regulation of mitochondrial uncoupling and lifespan
title_short Circadian regulation of mitochondrial uncoupling and lifespan
title_sort circadian regulation of mitochondrial uncoupling and lifespan
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174288/
https://www.ncbi.nlm.nih.gov/pubmed/32317636
http://dx.doi.org/10.1038/s41467-020-15617-x
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