{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:28:10Z","timestamp":1791232090208,"version":"4.1.0"},"reference-count":34,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5489","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2000,10,6]]},"abstract":"<jats:p>\n            An insulinlike signaling pathway controls\n            <jats:italic>Caenorhabditis elegans<\/jats:italic>\n            aging, metabolism, and development. Mutations in the\n            <jats:italic>daf-2<\/jats:italic>\n            insulin receptor\u2013like gene or the downstream\n            <jats:italic>age-1<\/jats:italic>\n            phosphoinositide 3-kinase gene extend adult life-span by two- to threefold. To identify tissues where this pathway regulates aging and metabolism, we restored\n            <jats:italic>daf-2<\/jats:italic>\n            pathway signaling to only neurons, muscle, or intestine. Insulinlike signaling in neurons alone was sufficient to specify wild-type life-span, but muscle or intestinal signaling was not. However, restoring\n            <jats:italic>daf-2<\/jats:italic>\n            pathway signaling to muscle rescued metabolic defects, thus decoupling regulation of life-span and metabolism. These findings point to the nervous system as a central regulator of animal longevity.\n          <\/jats:p>","DOI":"10.1126\/science.290.5489.147","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:53:24Z","timestamp":1027763604000},"page":"147-150","source":"Crossref","is-referenced-by-count":585,"title":["Regulation of\n            <i>C. elegans<\/i>\n            Life-Span by Insulinlike Signaling in the Nervous System"],"prefix":"10.1126","volume":"290","author":[{"given":"Catherine A.","family":"Wolkow","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koutarou D.","family":"Kimura","sequence":"additional","affiliation":[{"name":"Division of Biological Science, Nagoya University, Nagoya 464-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Sum","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Ruvkun","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","unstructured":"C. E. Finch Longevity Senescence and the Genome (Univ. of Chicago Press Chicago 1990)."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5328.942"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/534"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/366461a0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/382536a0"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(88)90138-8"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/139.4.1567"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.20.11399"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.9.13.7557026"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5271.59"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/20208"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/40194"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.16.2488"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.11.1438"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81751-1"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.14.1801"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.10.3323"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/141.3.977"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05357.x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/135.2.385"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2020855"},{"key":"e_1_3_2_23_2","unstructured":"Supplementary material is available at Science Online at www.sciencemag.org\/feature\/data\/1054300.shl."},{"key":"e_1_3_2_24_2","unstructured":"GFP intensity was scored in wild-type animals after 8 days of adulthood at 25.5\u00b0C. Animals with Punc-14::GFP or Punc-54::GFP showed intense GFP fluorescence that was similar to that observed at larval stages ( Punc-14::GFP 92% of 8-day-old adults showed high GFP intensity n = 24 animals three lines; Punc-54::GFP 92% of 8-day old adults had high levels of GFP n = 37 animals one line). Animals with Pges-1::GFP showed a decrease in GFP intensity at adult day 8: 49% of animals showed intense\/moderate GFP intensity 27% showed low GFP intensity and in 23% no GFP was detectable ( n = 114 animals two lines). In some animals we observed Punc-14::GFP expression in the pharynx and\/or intestine and Pmec-7::GFP expression in additional neurons and one body-wall muscle."},{"key":"e_1_3_2_25_2","unstructured":"Aging assays were performed at 25.5\u00b0C with agar plates containing 5-fluorodeoxyuridine (FUDR; 0.1 mg\/ml) to prevent growth of progeny. Animals were grown on nematode growth medium (NGM) plates until reaching the L4 or young adult stage at 25.5\u00b0C ( age-1 strains) or at 15\u00b0C ( daf-2 strains) and then transferred to FUDR-containing plates at 25.5\u00b0C. Animals were scored every 1 to 3 days subsequently and scored as dead when they no longer responded to gentle prodding with a platinum wire. Life-span is defined as the day animals were at the L4 larval stage (time t = 0) until the day they were scored as dead. The results in Table 1 are the sum of at least two independent lines except for Pdpy-30::daf-2 and Punc-14::daf-2 which are from one line each."},{"key":"e_1_3_2_26_2","unstructured":"Neither Pdpy-30::age-1 or Punc-14::age-1 can provide maternal age-1 activity as shown by the segregation of nontransgenic dauer-arrested animals in contrast to the potent maternal rescue of dauer arrest in age-1 (m+z\u2212) animals. Thus age-1(mg44); Punc-14::age-1 and age-1(mg44); Pdpy-30::age-1 animals are (m\u2212z+) for age-1 activity in the nervous system and ubiquitously respectively. An (m\u2212z\u2212) age-1(mg44) animal develops into a long-lived dauer but cannot grow to reproductive adulthood and the life-span cannot be directly compared. Thus the rescuing activity of the strains bearing the Punc-14::age-1 and Pdpy-30::age-1 transgenes is underestimated by comparison with the m+z\u2212 age-1(mg44) but it is the only control available."},{"key":"e_1_3_2_27_2","unstructured":"L4 animals grown at 20\u00b0C were fixed in 1% paraformaldehyde and subjected to three freeze-thaw cycles and then incubated on ice for 10 minutes. Fixed animals were washed and dehydrated through an ethanol series before staining with Sudan Black B solution. The level of fat accumulation was scored by comparing the relative size and number and density of fat droplets in the intestine and hypodermis relative with positive [ age-1(mg44) (m\u2212z\u2212) and daf-2(e1370) dauers] and negative (wild-type L4 larvae) controls."},{"key":"e_1_3_2_28_2","unstructured":"Eggs were laid by gravid adults overnight at 25.5\u00b0C ( age-1 strains) or at 15\u00b0C ( daf-2 strains) and then shifted to 25.5\u00b0C. Dauer and L4 larvae or young adults were scored 3 days after egg lay. At least two independent experiments were performed for each strain and the results from each were summed."},{"key":"e_1_3_2_29_2","unstructured":"C. A. Wolkow et al. data not shown."},{"key":"e_1_3_2_30_2","unstructured":"K. Kimura and G. Ruvkun unpublished data."},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/35007534"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80546-2"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/20694"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.11.1385"},{"key":"e_1_3_2_35_2","unstructured":"We thank A. Fire O. Hobert J. McGhee B. Meyer Y. Ohshima D. Pilgrim and J. Sze for providing promoter plasmids; P. Delerme and Y. Liu for technical assistance; and I. Mori and members of the Ruvkun lab for helpful discussions. This work was supported in part by NIH grant AG14161. C.A.W. was supported by a postdoctoral fellowship from the Leukemia and Lymphoma Society. K.D.K. was supported by the Japanese Society for the Promotion of Science and CREST of Japan Science and Technology Corporation."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.290.5489.147","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T10:20:35Z","timestamp":1705141235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.290.5489.147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,10,6]]},"references-count":34,"journal-issue":{"issue":"5489","published-print":{"date-parts":[[2000,10,6]]}},"alternative-id":["10.1126\/science.290.5489.147"],"URL":"https:\/\/doi.org\/10.1126\/science.290.5489.147","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,10,6]]}}}