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      ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C. elegans

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          Abstract

          Objective

          Animal lifespan is controlled through genetic pathways that are conserved from nematodes to humans. Lifespan-promoting conditions in nematodes include fasting and a reduction of insulin/IGF signaling. Here we aimed to investigate the input of the Caenorhabditis elegans homologue of the mammalian rate-limiting lipolytic enzyme Adipose Triglyceride Lipase, ATGL-1, in longevity control.

          Methods

          We used a combination of genetic and biochemical approaches to determine the role of ATGL-1 in accumulation of triglycerides and regulation of longevity.

          Results

          We found that expression of ATGL is increased in the insulin receptor homologue mutant daf-2 in a FoxO/DAF-16-dependent manner. ATGL-1 is also up-regulated by fasting and in the eat-2 loss-of-function mutant strain. Overexpression of ATGL-1 increases basal and maximal oxygen consumption rate and extends lifespan in C. elegans. Reduction of ATGL-1 function suppresses longevity of the long-lived mutants eat-2 and daf-2.

          Conclusion

          Our results demonstrate that ATGL is required for extended lifespan downstream of both dietary restriction and reduced insulin/IGF signaling.

          Highlights

          • Expression of ATGL-1 in Caenorhabditis elegans is regulated by fasting and insulin/IGF1 signaling.

          • Over-expression of ATGL-1 extends lifespan while loss-of-function mutant decreases lifespan of long-lived C. elegans models.

          • The effect of ATGL-1 on longevity may be mediated by an increase in mitochondrial oxidation.

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          Most cited references33

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          Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.

          Mobilization of fatty acids from triglyceride stores in adipose tissue requires lipolytic enzymes. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Until now, hormone-sensitive lipase (HSL) was the only enzyme known to hydrolyze triglycerides in mammalian adipose tissue. Here, we report that a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis. It is interesting that ATGL contains a "patatin domain" common to plant acyl-hydrolases. ATGL is highly expressed in adipose tissue of mice and humans. It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. Inhibition of ATGL markedly decreases total adipose acyl-hydrolase activity. Thus, ATGL and HSL coordinately catabolize stored triglycerides in adipose tissue of mammals.
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            Mammalian Mitochondria and Aging: An Update.

            Mitochondria were first postulated to contribute to aging more than 40 years ago. During the following decades, multiple lines of evidence in model organisms and humans showed that impaired mitochondrial function can contribute to age-associated disease phenotypes and aging. However, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations, there are now strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mtDNA polymerase. Currently, a substantial amount of mitochondrial research is focused on finding ways to either remove or counteract the effects of mtDNA mutations with the hope of extending the human health- and lifespan. This review summarizes the current knowledge regarding the formation of mtDNA mutations and their impact on mitochondrial function. We also critically discuss proposed pathways interlinked with mammalian mtDNA mutations and suggest future research strategies to elucidate the role of mtDNA mutations in aging.
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              The genetics of caloric restriction in Caenorhabditis elegans.

              Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                05 July 2019
                September 2019
                05 July 2019
                : 27
                : 75-82
                Affiliations
                [1]Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA
                Author notes
                []Corresponding author. Boston University School of Medicine, Department of Biochemistry, 72 East Concord St., Boston, MA, 02118, USA. kkandror@ 123456bu.edu
                [∗∗ ]Corresponding author. Boston University School of Medicine, Department of Biochemistry, 72 East Concord St., Boston, MA, 02118, USA. agrishok@ 123456bu.edu
                Article
                S2212-8778(19)30482-X
                10.1016/j.molmet.2019.07.001
                6717769
                31311719
                87a9779c-6c5b-44d8-accb-6e1b3e8f3d2d
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 20 May 2019
                : 28 June 2019
                : 2 July 2019
                Categories
                Brief Communication

                atgl-1,dietary restriction,daf-2,daf-16,longevity,c. elegans
                atgl-1, dietary restriction, daf-2, daf-16, longevity, c. elegans

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