Germline Signaling Mediates the Synergistically Prolonged Longevity Produced by Double Mutations in daf-2 and rsks-1 in C. elegans
Di Chen,
Patrick Wai-Lun Li,
Benjamin A. Goldstein,
Waijiao Cai,
Emma Lynn Thomas,
Fen Chen,
Alan E. Hubbard,
Simon Melov,
Pankaj Kapahi
Affiliations
Di Chen
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
Patrick Wai-Lun Li
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Benjamin A. Goldstein
School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA
Waijiao Cai
Institute of Traditional Chinese and Western Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Emma Lynn Thomas
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Fen Chen
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
Alan E. Hubbard
School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA
Simon Melov
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Pankaj Kapahi
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
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.
