title: Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans.
abstract: Inhibition of DAF-2 (insulin-like growth factor 1 [IGF-1] receptor) or RSKS-1 (S6K), key molecules in the insulin/IGF-1 signaling (IIS) and target of rapamycin (TOR) pathways, respectively, extend lifespan in Caenorhabditis elegans. However, it has not been clear how and in which tissues they interact with each other to modulate longevity. Here, we demonstrate that a combination of mutations in daf-2 and rsks-1 produces a nearly 5-fold increase in longevity that is much greater than the sum of single mutations. This synergistic lifespan extension requires positive feedback regulation of DAF-16 (FOXO) via the AMP-activated protein kinase (AMPK) complex. Furthermore, we identify germline as the key tissue for this synergistic longevity. Moreover, germline-specific inhibition of rsks-1 activates DAF-16 in the intestine. Together, our findings highlight the importance of the germline in the significantly increased longevity produced by daf-2 rsks-1, which has important implications for interactions between the two major conserved longevity pathways in more complex organisms.
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing, Jiangsu 210061, China. Electronic address: chendi@nju.edu.cn.
authors: Di
authors: D
authors: Chen
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Patrick Wai-Lun
authors: PW
authors: Li
authors: School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Benjamin A
authors: BA
authors: Goldstein
authors: Institute of Traditional Chinese and Western Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors: Waijiao
authors: W
authors: Cai
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Emma Lynn
authors: EL
authors: Thomas
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, 12 Xuefu Road, Pukou District, Nanjing, Jiangsu 210061, China.
authors: Fen
authors: F
authors: Chen
authors: School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Alan E
authors: AE
authors: Hubbard
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Simon
authors: S
authors: Melov
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA. Electronic address: pkapahi@buckinstitute.org.
authors: Pankaj
authors: P
authors: Kapahi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors; D005854:Germ Cells / Q000378:metabolism*; D018095:Germ-Line Mutation; D007413:Intestinal Mucosa / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C571892:Rsks-1 protein, C elegans; D055372:AMP-Activated Protein Kinases