ASM-3 Acid Sphingomyelinase Functions as a Positive Regulator of the DAF-2/AGE-1 Signaling Pathway and Serves as a Novel Anti-Aging Target
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{"title"=>"ASM-3 Acid Sphingomyelinase Functions as a Positive Regulator of the DAF-2/AGE-1 Signaling Pathway and Serves as a Novel Anti-Aging Target", "type"=>"journal", "authors"=>[{"first_name"=>"Yongsoon", "last_name"=>"Kim", "scopus_author_id"=>"55934221300"}, {"first_name"=>"Hong", "last_name"=>"Sun", "scopus_author_id"=>"57191822205"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84866661779", "pmid"=>"23049887", "doi"=>"10.1371/journal.pone.0045890", "pui"=>"365720724", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "scopus"=>"2-s2.0-84866661779"}, "id"=>"fc8ecfb9-f697-3b5b-bca6-60ba6787fa84", "abstract"=>"In C. elegans, the highly conserved DAF-2/insulin/insulin-like growth factor 1 receptor signaling (IIS) pathway regulates longevity, metabolism, reproduction and development. In mammals, acid sphingomyelinase (ASM) is an enzyme that hydrolyzes sphingomyelin to produce ceramide. ASM has been implicated in CD95 death receptor signaling under certain stress conditions. However, the involvement of ASM in growth factor receptor signaling under physiological conditions is not known. Here, we report that in vivo ASM functions as a positive regulator of the DAF-2/IIS pathway in C. elegans. We have shown that inactivation of asm-3 extends animal lifespan and promotes dauer arrest, an alternative developmental process. A significant cooperative effect on lifespan is observed between asm-3 deficiency and loss-of-function alleles of the age-1/PI 3-kinase, with the asm-3; age-1 double mutant animals having a mean lifespan 259% greater than that of the wild-type animals. The lifespan extension phenotypes caused by the loss of asm-3 are dependent on the functions of daf-16/FOXO and daf-18/PTEN. We have demonstrated that inactivation of asm-3 causes nuclear translocation of DAF-16::GFP protein, up-regulates endogenous DAF-16 protein levels and activates the downstream targeting genes of DAF-16. Together, our findings reveal a novel role of asm-3 in regulation of lifespan and diapause by modulating IIS pathway. Importantly, we have found that two drugs known to inhibit mammalian ASM activities, desipramine and clomipramine, markedly extend the lifespan of wild-type animals, in a manner similar to that achieved by genetic inactivation of the asm genes. Our studies illustrate a novel strategy of anti-aging by targeting ASM, which may potentially be extended to mammals.", "link"=>"http://www.mendeley.com/research/asm3-acid-sphingomyelinase-functions-positive-regulator-daf2age1-signaling-pathway-serves-novel-anti", "reader_count"=>35, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>1, "Student > Bachelor"=>7, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>1, "Student > Bachelor"=>7, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>1, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>24}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>2}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"United States"=>3}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/569921"], "description"=>"<p>(A) and (B) DAF-16::GFP cellular distributions were examined by fluorescence microscopy and tail regions of animals were shown here. For images on the body and head regions of the animals, see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone.0045890.s005\" target=\"_blank\">Figure S5</a>. Animals were examined on adult day 1 (A) or day 4 (B). (A) In the <i>rrf-3(pk1426);daf-16::gfp</i> mutant background, vector control (L4440) RNAi showed that DAF-16::GFP diffusely localized in the cytoplasm, while <i>asm-3</i>, <i>asm-1</i> or <i>asm-2</i> RNAi each induced the nuclear localization of DAF-16::GFP. RNAi inactivation of <i>daf-2</i> and <i>age-1</i> (positive controls) and RNAi inactivation of <i>daf-16</i> and <i>daf-18</i> (negative controls) were carried out in parallel. (B) In the <i>asm-3(ok1744);rrf-3(pk1426);daf-16::gfp</i> mutant background, RNAi knockdown of <i>asm-1</i>, <i>asm-2</i> or <i>asm-1/asm-2</i> (double RNAi of <i>asm-1</i> and <i>asm-2</i>) further induced the nuclear localization of DAF-16::GFP protein. (C) and (D) western blot analysis of endogenous DAF-16 protein levels. (C) Increased DAF-16 protein levels were observed in the <i>asm-3(ok1744)</i> and <i>daf-2(e1370)</i> mutants as compared with that of wild-type control. Lysates were prepared from adult day 1 animals. (D) RNAi knockdown of <i>asm-3</i> or <i>daf-2</i> each elevated DAF-16 protein level as compared with that of vector control (L4440) RNAi. The specificity of the immunodetection was verified by the disappearance of DAF-16 protein in the <i>daf-16(mgDf47)</i> null mutants or in animals treated with <i>daf-16</i> RNAi. Lysates were prepared from RNAi-treated, adult day 2 animals. In (C) and (D), quantification of the relative abundance of DAF-16 proteins was shown with the DAF-16 protein levels being normalized against the beta-actin protein levels using the ImageJ software.</p>", "links"=>[], "tags"=>["induces", "localization", "fusion", "affects", "daf-16"], "article_id"=>240416, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g004", "stats"=>{"downloads"=>3, "page_views"=>118, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_asm_induces_the_nuclear_localization_of_DAF_16_GFP_fusion_protein_and_affects_the_DAF_16_protein_levels_/240416", "title"=>"Loss of <i>asm</i> induces the nuclear localization of DAF-16::GFP fusion protein and affects the DAF-16 protein levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:06:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/569636"], "description"=>"<p>For RNAi experiments, the vector alone (L4440) was used as a control. (A) <i>asm-3</i> RNAi extended animal lifespan with the mean lifespan 19% greater than that of the control in the <i>rrf-3(pk1426)</i> background (P<0.0001). (B) <i>asm-3(ok1744)</i> mutants had 14% longer lifespan than wild-type (N2) animals (P = 0.0141). (C) Knockdown of <i>asm-1</i>, <i>asm-2</i> or <i>asm-3</i> by RNAi each extended lifespan with the mean lifespan 12%, 10% or 19% greater than that of the vector control in the <i>rrf-3(pk1426)</i> background, respectively (P = 0.0068 for <i>asm-1</i> RNAi, P = 0.0258 for <i>asm-2</i> RNAi and P<0.0001 for <i>asm-3</i> RNAi). (D) Experiments were carried out in the <i>asm-3(+);rrf-3(pk1426)</i> or <i>asm-3(ok1744);rrf-3(pk1426)</i> background. <i>asm-3(ok1744</i>) mutation extended lifespan with the mean lifespan 15% greater than that of the control (P = 0.0018), and the lifespan of <i>asm-3(ok1744)</i> mutant was further enhanced by RNAi of <i>asm-1</i> or <i>asm-2</i> with the mean lifespan 30% or 28% greater than that of the control (P<0.0001 for <i>asm-1</i> RNAi or <i>asm-2</i> RNAi). Lifespan extension produced by <i>asm-3</i> mutation was inhibited by <i>daf-16</i> RNAi (P<0.0001). (E) <i>daf-16(mgDf47)</i> null mutation completely abolished lifespan extension phenotype of <i>asm-3</i> mutants. (F) Lifespan extension phenotype by <i>asm-1</i>, <i>asm-2</i> or <i>asm-3</i> RNAi shown in (C) was completely abolished by <i>daf-18(nr2037)</i> null mutation in the <i>rrf-3(pk1426);daf-18(nr2037)</i> background. Mean lifespan, P values and other details for these experiments are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone-0045890-t001\" target=\"_blank\">Table 1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone-0045890-t002\" target=\"_blank\">Table 2</a>.</p>", "links"=>[], "tags"=>["activities", "extends", "lifespan"], "article_id"=>240126, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loss_of_asm_gene_activities_extends_animal_lifespan_in_a_daf_16_or_daf_18_dependent_manner_/240126", "title"=>"Loss of <i>asm</i> gene activities extends animal lifespan in a <i>daf-16</i> or <i>daf-18</i> dependent manner.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:02:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/569702"], "description"=>"<p>(A) Loss of <i>asm-3</i> did not further increase the lifespan of <i>daf-2(e1370)</i> mutants (P = 0.463). (B) <i>asm-3(ok1744)</i> mutation enhanced the mean lifespan of the longer-lived <i>age-1(mg305)</i> mutants by 67% (P<0.0001). (C) Silencing of <i>asm-3</i> in the <i>aap-1(m889)</i> mutant background further extended the mean lifespan by 21% compared to control (L4440) RNAi (P<0.0001). (D) <i>asm-3</i> mutation did not affect lifespan of <i>pdk-1(sa709)</i> mutant animals (P = 0.8404). (E) Effects of <i>asm-3(ok1744), akt-1(mg306),</i> and <i>asm-3(ok1744);akt-1(mg306)</i> mutations on lifespan regulation. <i>asm-3</i> mutation inhibited the lifespan extension of <i>akt-1(mg306)</i> mutant (P<0.0001), but <i>akt-1</i> mutation did not seem to affect the lifespan extension of <i>asm-3(ok1744)</i> mutant (P = 0.064). Mean lifespan, P values and other details for these experiments are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone-0045890-t001\" target=\"_blank\">Table 1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone-0045890-t002\" target=\"_blank\">Table 2</a>.</p>", "links"=>[], "tags"=>["lifespan", "mutants", "defective"], "article_id"=>240201, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_asm_3_on_lifespan_regulation_in_various_mutants_defective_in_the_daf_2_signaling_/240201", "title"=>"Effects of <i>asm-3</i> on lifespan regulation in various mutants defective in the <i>daf-2</i> signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:03:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/570109"], "description"=>"<p>Lifespan assays were carried out at 20°C. (A) and (B) Wild-type (N2) animals were plated on plates containing 30 µM desipramine (A), 5 µM clomipramine (B) or vehicle control (0 µM in panel A or B). A significant lifespan extension was observed in either desipramine-treated or clomipramine-treated wild-type animals as compared to vehicle control wild-type animals (24% increase and P<0.0001 for desipramine-treated wild-type animal; 14% increase and P = 0.0012 for clomipramine-treated wild-type animals). (C) and (D) The <i>daf-16(mgDf47)</i> mutant animals were plated on plates containing 30 µM desipramine (C), 5 µM clomipramine (D) or vehicle control (0 µM in panel C or D). No lifespan extension was observed in drug-treated <i>daf-16(mgDf47)</i> null mutant animals. Mean lifespan and P values for the experiments represented here are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone-0045890-t003\" target=\"_blank\">Table 3</a>. (E) Desipramine and clomipramine each inhibited CeASM activity. Synchronized L1 animals were treated with desipramine, clomipramine or vehicle control (see Material and Methods for details). Lysates were prepared from L4 animals and assays were performed in duplicates using [<sup>14</sup>C]-sphingomyelin. CeASM activities from all samples were normalized against that in the vehicle control (100%). Desipramine or clomipramine treatment each decreased CeASM activity by 78% or 77%, respectively (T-test *P<0.001 for desipramine and **P<0.001 clomipramine vs. vehicle control, respectively).</p>", "links"=>[], "tags"=>["asm", "inhibitors", "lifespan", "enzyme"], "article_id"=>240602, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g006", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_ASM_inhibitors_on_lifespan_regulation_and_enzyme_activity_in_C_elegans_/240602", "title"=>"Effects of ASM inhibitors on lifespan regulation and enzyme activity in <i>C. elegans</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:10:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/570012"], "description"=>"<p>(A) By qRT-PCR, mRNA expression of endogenous <i>sod-3</i> gene was increased about 3-fold in the <i>asm-3(ok1744)</i> mutant animals as compared to the wild-type (N2) animals (T-test *P<0.05 for <i>asm-3(ok1744)</i> vs. wild-type; T-test **P<0.001 for <i>daf-2(e1370)</i> vs. wild-type). RNA samples were prepared from young adults (adult day 1). (B) By qRT-PCR, mRNA expression of endogenous <i>mtl-1</i> gene was modestly increased in the <i>asm-3(ok1744)</i> mutant animals as compared to the wild-type (N2) animals (T-test *P<0.05 for <i>asm-3(ok1744)</i> vs wild-type; T-test **P<0.001, <i>daf-2(e1370)</i> vs. wild-type). In (A) and (B), RNA samples, isolated from <i>daf-2(e1370)</i> or <i>daf-16(mgDf47)</i> mutant animals, were used as positive and negative controls, respectively. Additionally, an internal control of <i>act-1</i> was used for qRT-PCR and relative mRNA expression levels of <i>sod-3</i> or <i>mtl-1</i> were normalized to that of <i>act-1</i>. (C) Increased SOD-3::GFP expression was observed when multiple <i>asm</i> genes were inactivated in the <i>asm-3(ok1744);rrf-3(pk1426);sod-3p::gfp</i> mutant background compared to the vector control (L4440) RNAi. As negative controls, RNAi of <i>daf-16</i> or <i>daf-18</i> was used. As a positive control, the <i>daf-2</i> RNAi was used. Animals, treated with the indicated RNAi molecules, were examined on adult day 3. All fluorescence microscopy images were photographed using identical exposure times.</p>", "links"=>[], "tags"=>["transcriptional"], "article_id"=>240509, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g005", "stats"=>{"downloads"=>2, "page_views"=>68, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_qRT_PCR_for_DAF_16_FOXO_transcriptional_activity_and_sod_3p_gfp_reporter_/240509", "title"=>"qRT-PCR for DAF-16/FOXO transcriptional activity and <i>sod-3p::gfp</i> reporter.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:08:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/570312"], "description"=>"<p>All the assays were carried out at 20°C and on regular NGM plates. For Set #4, assays were carried out on plates containing FuDR (50 µg/ml) to avoid the internal hatching of the <i>asm-3(ok1744);age-1(mg305)</i> mutant animals. Each experiment was individually grouped and statistical analyses were carried out for the experiment data set and the wild-type control data set in each group (P values). In addition, statistical analyses were carried out for the survival data of the assayed single mutant (marked as *) and the corresponding double mutant containing the <i>asm-3(ok1744)</i> allele (*P values). In Set #6, P value between <i>asm-3(ok1744)</i> and <i>asm-3(ok1744);akt-1(mg306)</i> is 0.064. Each set of the lifespan experiments was repeated at least two independent times and similar results were obtained. Data from representative sets of experiments are shown. Greater than 50 worms were counted for each strain in each experiment.</p>", "links"=>[], "tags"=>["lifespan", "assays", "mutant"], "article_id"=>240808, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.t002", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_adult_lifespan_assays_in_various_mutant_backgrounds_/240808", "title"=>"Summary of adult lifespan assays in various mutant backgrounds.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-09-25 00:13:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/570339"], "description"=>"<p>N2 (wild-type) or <i>daf-16(mgDf47)</i> mutant animals were assayed on plates either containing desipramine (30 µM), clomipramine (5 µM), or no drug control (0 µM). All the lifespan assays were carried out at 20°C. Mean lifespan, relative mean lifespan and statistical analyses (P values) for each assay were listed. Standard error of the mean, SEM, is included in parenthesis. Each set of the lifespan experiments was repeated at least three independent times and similar results were obtained. Data from representative sets of experiments are shown. Greater than 50 worms were counted for each condition in each experiment.</p>", "links"=>[], "tags"=>["genetics and genomics", "physiology", "Biochemistry"], "article_id"=>240839, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.t003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_drug_treatment_on_animal_lifespan_/240839", "title"=>"Effects of drug treatment on animal lifespan.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-09-25 00:13:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/570197"], "description"=>"<p><i>asm-3</i> functions downstream of <i>daf-2</i>, acting either in parallel to <i>age-1</i>/<i>aap-1</i> (A) or working together with <i>age-1/aap-1</i> (B), leading to activation of <i>pdk-1</i> and <i>akt-1,</i> and then suppression of <i>daf-16.</i></p>", "links"=>[], "tags"=>["genetics and genomics", "physiology", "Biochemistry"], "article_id"=>240689, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g007", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_model_of_asm_3_function_/240689", "title"=>"A model of <i>asm-3</i> function.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:11:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/569838"], "description"=>"<p>(A) Loss of <i>asm-3</i> enhanced dauer formation of <i>daf-2(e1370)</i> mutants at the semi-permissive temperature 22.5°C. (B) <i>asm-3</i> mutation greatly enhanced dauer arrest phenotype of <i>age-1(mg305)</i> mutants at 22.5°C. (C) <i>asm-3</i> mutation did not affect dauer arrest induced by the <i>pdk-1(sa709)</i> mutation at 27°C. The mutant animals carrying <i>sa709</i> allele formed dauer at 27°C but not at 25°C. (D) <i>asm-3</i> mutation partially suppressed the dauer arrest phenotype of <i>akt-1(mg306)</i> mutants at 27°C. No dauers at 25°C were observed for the <i>akt-1(mg306)</i> mutant animals with or without the presence of the <i>asm-3(ok1744)</i> allele. (E) <i>asm-3</i> mutation had no effect on dauer arrest phenotype of <i>daf-7(e1372)</i> mutants at either 22.5°C or 25°C. The <i>asm-3(ok1744)</i> allele by itself did not induce dauer formation at either 22.5°C or 25°C. Error bars indicate standard deviation from triplicates. Details including total worm numbers used in the assay are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045890#pone.0045890.s007\" target=\"_blank\">Table S1</a>.</p>", "links"=>[], "tags"=>["dauer", "mutants", "defective"], "article_id"=>240337, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.g003", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_asm_3_on_dauer_formation_regulation_in_various_mutants_defective_in_the_daf_2_signaling_/240337", "title"=>"Effects of <i>asm-3</i> on dauer formation regulation in various mutants defective in the<i>daf-2</i> signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-25 00:05:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/570279"], "description"=>"<p>RNAi treatments, initiated at L1 stage, were continued throughout the assay time. Lifespan assays were performed at 20°C. Each experiment was individually grouped and statistical analyses of the data sets were carried out using the vector (L4440) control as the reference in each group (P value). In Set #3, the second set of statistical analyses was carried out for all the survivor data derived from the <i>asm-3(ok1744);rrf-3(pk1426)</i> strain, using the corresponding vector (L4440) control in this strain (marked as *) as the reference for this subgroup (*P values). Each set of the lifespan experiments was repeated at least two independent times and similar results were obtained. Data from representative sets of experiments are shown. Greater than 50 worms were counted for each RNAi-inducing condition in each experiment.</p>", "links"=>[], "tags"=>["lifespan", "assays", "rnai-mediated"], "article_id"=>240776, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0045890.t001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_adult_lifespan_assays_after_RNAi_mediated_gene_inactivation_/240776", "title"=>"Summary of adult lifespan assays after RNAi-mediated gene inactivation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-09-25 00:12:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/301404", "https://ndownloader.figshare.com/files/301443", "https://ndownloader.figshare.com/files/301500", "https://ndownloader.figshare.com/files/301570", "https://ndownloader.figshare.com/files/301614", "https://ndownloader.figshare.com/files/301678", "https://ndownloader.figshare.com/files/301719"], "description"=>"<div><p>In <em>C. elegans</em>, the highly conserved DAF-2/insulin/insulin-like growth factor 1 receptor signaling (IIS) pathway regulates longevity, metabolism, reproduction and development. In mammals, acid sphingomyelinase (ASM) is an enzyme that hydrolyzes sphingomyelin to produce ceramide. ASM has been implicated in CD95 death receptor signaling under certain stress conditions. However, the involvement of ASM in growth factor receptor signaling under physiological conditions is not known. Here, we report that <em>in vivo</em> ASM functions as a positive regulator of the DAF-2/IIS pathway in <em>C. elegans</em>. We have shown that inactivation of <em>asm-3</em> extends animal lifespan and promotes dauer arrest, an alternative developmental process. A significant cooperative effect on lifespan is observed between <em>asm-3</em> deficiency and loss-of-function alleles of the <em>age-1</em>/PI 3-kinase, with the <em>asm-3; age-1</em> double mutant animals having a mean lifespan 259% greater than that of the wild-type animals. The lifespan extension phenotypes caused by the loss of <em>asm-3</em> are dependent on the functions of <em>daf-16</em>/FOXO and <em>daf-18</em>/PTEN. We have demonstrated that inactivation of <em>asm-3</em> causes nuclear translocation of DAF-16::GFP protein, up-regulates endogenous DAF-16 protein levels and activates the downstream targeting genes of DAF-16. Together, our findings reveal a novel role of <em>asm-3</em> in regulation of lifespan and diapause by modulating IIS pathway. Importantly, we have found that two drugs known to inhibit mammalian ASM activities, desipramine and clomipramine, markedly extend the lifespan of wild-type animals, in a manner similar to that achieved by genetic inactivation of the <em>asm</em> genes. Our studies illustrate a novel strategy of anti-aging by targeting ASM, which may potentially be extended to mammals.</p> </div>", "links"=>[], "tags"=>["asm-3", "sphingomyelinase", "functions", "signaling", "pathway", "serves", "anti-aging"], "article_id"=>119438, "categories"=>["Physiology", "Biochemistry", "Genetics"], "users"=>["Yongsoon Kim", "Hong Sun"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0045890.s001", "https://dx.doi.org/10.1371/journal.pone.0045890.s002", "https://dx.doi.org/10.1371/journal.pone.0045890.s003", "https://dx.doi.org/10.1371/journal.pone.0045890.s004", "https://dx.doi.org/10.1371/journal.pone.0045890.s005", "https://dx.doi.org/10.1371/journal.pone.0045890.s006", "https://dx.doi.org/10.1371/journal.pone.0045890.s007"], "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/ASM_3_Acid_Sphingomyelinase_Functions_as_a_Positive_Regulator_of_the_DAF_2_AGE_1_Signaling_Pathway_and_Serves_as_a_Novel_Anti_Aging_Target/119438", "title"=>"ASM-3 Acid Sphingomyelinase Functions as a Positive Regulator of the DAF-2/AGE-1 Signaling Pathway and Serves as a Novel Anti-Aging Target", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-09-25 02:37:18"}

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Relative Metric

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