Journal
CELL REPORTS
Volume 5, Issue 6, Pages 1600-1610Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.11.018
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Funding
- NIH National Center for Research Resources
- Mitani lab, School of Medicine, Tokyo Women's Medical University
- American Foundation for Aging Research
- Hillblom Foundation
- Nathan Shock Startup award
- Nathan Shock Center [NIH P30AG025708]
- NIH [R01AG038688, RL1AAG032113, 3RL1AG032113-03S1]
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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, germlinespecific 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.
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