Cell Reports
Volume 5, Issue 6, 26 December 2013, Pages 1600-1610
Journal home page for Cell Reports

Article
Germline Signaling Mediates the Synergistically Prolonged Longevity Produced by Double Mutations in daf-2 and rsks-1 in C. elegans

https://doi.org/10.1016/j.celrep.2013.11.018Get rights and content
Under a Creative Commons license
open access

Highlights

  • The daf-2 rsks-1 double mutant shows synergistic lifespan extension in C. elegans

  • AMPK mediates positive feedback regulation of DAF-16 in daf-2 rsks-1

  • Germline tissue is a key tissue in modulating this synergistic longevity

  • Inhibiting rsks-1 in the germline leads to cell-nonautonomous activation of DAF-16

Summary

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.

Cited by (0)

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

5

These authors contributed equally to this work

6

Present address: Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA 94305, USA