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      Germline Signals Deploy NHR-49 to Modulate Fatty-Acid β-Oxidation and Desaturation in Somatic Tissues of C. elegans

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          Abstract

          In C. elegans, removal of the germline extends lifespan significantly. We demonstrate that the nuclear hormone receptor, NHR-49, enables the response to this physiological change by increasing the expression of genes involved in mitochondrial β-oxidation and fatty-acid desaturation. The coordinated augmentation of these processes is critical for germline-less animals to maintain their lipid stores and to sustain de novo fat synthesis during adulthood. Following germline ablation, NHR-49 is up-regulated in somatic cells by the conserved longevity determinants DAF-16/FOXO and TCER-1/TCERG1. Accordingly, NHR-49 overexpression in fertile animals extends their lifespan modestly. In fertile adults, nhr-49 expression is DAF-16/FOXO and TCER-1/TCERG1 independent although its depletion causes age-related lipid abnormalities. Our data provide molecular insights into how reproductive stimuli are integrated into global metabolic changes to alter the lifespan of the animal. They suggest that NHR-49 may facilitate the adaptation to loss of reproductive potential through synchronized enhancement of fatty-acid oxidation and desaturation, thus breaking down some fats ordained for reproduction and orchestrating a lipid profile conducive for somatic maintenance and longevity.

          Author Summary

          Much is known about how increasing age impairs fertility but we know little about how reproduction influences rate of aging in animals. Studies in model organisms such as worms and flies have begun to shed light on this relationship. In worms, removing germ cells that give rise to sperm and oocytes extends lifespan, increases endurance and elevates fat. Fat metabolism and hormonal signals play major roles in this lifespan augmentation but the genetic mechanisms involved are poorly understood. We show that a gene, nhr-49, enhances worm lifespan following germ-cell removal. NHR-49 is increased in animals that lack germ cells by conserved longevity proteins, DAF-16 and TCER-1. NHR-49, in turn, increases levels of genes that help burn fat and convert saturated fats into unsaturated forms. Through synchronized enhancement of these processes, NHR-49 helps eliminate excess fat delegated for reproduction and converts lipids into forms that favor a long life. NHR-49 impacts these processes during aging in normal animals too, but using different regulatory mechanisms. Our data helps understand how normal lipid metabolic processes can be harnessed to adapt to physiological fluctuations brought on by changes in the reproductive status of animals.

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          Most cited references 53

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          Regulation of aging and age-related disease by DAF-16 and heat-shock factor.

          The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2-insulin/IGF-1 receptor mutations to extend life-span. Our findings suggest this is because HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
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            Obesity, cigarette smoking, and telomere length in women.

            Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.
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              Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library.

              The recently completed Caenorhabditis elegans genome sequence allows application of high-throughput (HT) approaches for phenotypic analyses using RNA interference (RNAi). As large phenotypic data sets become available, "phenoclustering" strategies can be used to begin understanding the complex molecular networks involved in development and other biological processes. The current HT-RNAi resources represent a great asset for phenotypic profiling but are limited by lack of flexibility. For instance, existing resources do not take advantage of the latest improvements in RNAi technology, such as inducible hairpin RNAi. Here we show that a C. elegans ORFeome resource, generated with the Gateway cloning system, can be used as a starting point to generate alternative HT-RNAi resources with enhanced flexibility. The versatility inherent to the Gateway system suggests that additional HT-RNAi libraries can now be readily generated to perform gene knockdowns under various conditions, increasing the possibilities for phenome mapping in C. elegans.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                December 2014
                4 December 2014
                : 10
                : 12
                Affiliations
                [1 ]Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
                [2 ]Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
                [3 ]Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, United States of America
                University of California San Francisco, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AG. Performed the experiments: AG RR FRGA KH HG JW SWC. Analyzed the data: AG CPO RR FRGA JW. Contributed reagents/materials/analysis tools: CPO JW KRY. Wrote the paper: AG. Intellectual input in study development: CPO JW KRY.

                [¤]

                Current address: Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

                Article
                PGENETICS-D-14-01216
                10.1371/journal.pgen.1004829
                4256272
                25474470

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 20
                Funding
                This study was funded by the Ellison Medical Foundation's New Scholars in Aging award (AG-NS-0879-12; http://www.ellisonfoundation.org/node/4775) and an American Federation for Aging Research grant ( http://www.afar.org/grantees/years/2011-recipient-grant-summaries) to AG, and grants from the National Institute of Health to KRY (CA020535) and CPO (5 DP5 OD009189-04). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Lipids
                Lipid Metabolism
                Metabolism
                Cell Biology
                Signal Transduction
                Cell Signaling
                Nuclear Receptor Signaling
                Developmental Biology
                Organism Development
                Aging
                Genetics
                Animal Genetics
                Invertebrate Genetics
                Organisms
                Animals
                Invertebrates
                Nematoda
                Caenorhabditis
                Physiology
                Physiological Processes
                Homeostasis
                Homeostatic Mechanisms
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Genetics

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