Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila
| العنوان: | Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila |
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| المؤلفون: | Linda Partridge, Jorge Iván Castillo-Quan, Jennifer C. Regan, Andrea Foley, Janne M. Toivonen, Daniela Wieser, Ivana Bjedov, Janet M. Thornton, Helena M. Cochemé, Povilas Norvaisas, Kerri J. Kinghorn, Michael P. Murphy, Celia Lujan, Filipe Cabreiro, Nathaniel S. Woodling, Thomas P. Neufeld |
| المساهمون: | Bjedov, Ivana [0000-0001-5894-6016], Cochemé, Helena M [0000-0001-8637-0042], Foley, Andrea [0000-0003-0596-5533], Woodling, Nathaniel S [0000-0002-0298-3800], Castillo-Quan, Jorge Iván [0000-0002-6324-2854], Norvaisas, Povilas [0000-0003-4790-9820], Regan, Jennifer C [0000-0003-2164-9151], Toivonen, Janne M [0000-0002-7243-1737], Thornton, Janet [0000-0003-0824-4096], Neufeld, Thomas P [0000-0001-5659-4811], Partridge, Linda [0000-0001-9615-0094], Apollo - University of Cambridge Repository, Cochemé, Helena M. [0000-0001-8637-0042], Woodling, Nathaniel S. [0000-0002-0298-3800], Regan, Jennifer C. [0000-0003-2164-9151], Toivonen, Janne M. [0000-0002-7243-1737], Neufeld, Thomas P. [0000-0001-5659-4811], Wellcome Trust |
| المصدر: | PLOS Genetics PLoS Genetics PLoS Genetics, Vol 16, Iss 11, p e1009083 (2020) Zaguán: Repositorio Digital de la Universidad de Zaragoza Universidad de Zaragoza Zaguán. Repositorio Digital de la Universidad de Zaragoza instname PLoS Genet |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Aging, STRESS, Physiology, Gene Expression, Mitochondrion, QH426-470, Biochemistry, Fats, 0302 clinical medicine, Insulin receptor substrate, IMMUNE-RESPONSE, Autophagy-Related Protein-1 Homolog, Drosophila Proteins, Genetics (clinical), Energy-Producing Organelles, Genetics & Heredity, Cell Death, Lipids, 3. Good health, Cell biology, Mitochondria, Drosophila melanogaster, Genes, Mitochondrial, Adipose Tissue, Cell Processes, Connective Tissue, Signal transduction, Cellular Structures and Organelles, Anatomy, Life Sciences & Biomedicine, Research Article, Signal Transduction, Atg1, Autophagic Cell Death, ATG5, Longevity, INHIBITION, Biology, Bioenergetics, Protein Serine-Threonine Kinases, METABOLOMICS, 03 medical and health sciences, Downregulation and upregulation, Genetics, Autophagy, Animals, CELL, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicine and health sciences, 0604 Genetics, Science & Technology, RECEPTOR, Biology and life sciences, Cell Biology, Lipid Metabolism, Receptor, Insulin, MASS-SPECTROMETRY DATA, Gastrointestinal Tract, 030104 developmental biology, Biological Tissue, Metabolism, Gene Expression Regulation, Ageing, Insulin Receptor Substrate Proteins, Physiological Processes, Digestive System, Organism Development, SYSTEM, RESISTANCE, 030217 neurology & neurosurgery, Developmental Biology |
| الوصف: | Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention. Author summary The increasing number of people living with age-related diseases underscores the importance of ageing research to improve healthspan. Two well-studied evolutionary conserved interventions that extend lifespan and improve health are dietary restriction and down-regulation of nutrient sensing pathways, such as glucose sensing by insulin and amino acid sensing by the target-of-rapamycin signalling pathway. One common characteristic of these anti-ageing interventions is an increase in autophagy, a cellular pathway that degrades damaged proteins and organelles to supply essential building blocks and energy. To help provide a more direct link between autophagy and healthy ageing, we fine-tuned overexpression of Atg1 kinase, which is critical for autophagy induction, and measured its effect on longevity in the fruit fly Drosophila. Interestingly, we observed that a moderate increase in autophagy is beneficial in extending healthy lifespan, whereas strong autophagy up-regulation is detrimental and leads to progressive lipid loss and decreased lifespan. Moderate and stronger Atg1 overexpression displayed opposing transcriptional profiles of mitochondrial genes, being upregulated in long-lived and down-regulated in short-lived Atg1 over-expressing animals. Overall, we provide a detailed description of the phenotypes associated with varying degrees of autophagy up-regulation in vivo, demonstrating that autophagy enhancement delays ageing only when applied in moderation. |
| وصف الملف: | application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document; application/zip; text/xml |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d79f41cde8de708515e486eb71f77925Test http://zaguan.unizar.es/record/97453Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d79f41cde8de708515e486eb71f77925 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |