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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2016)

Understanding the evolutionary links between an animal’s reproductive state and its rate of aging has been of interest to scientists since the field of aging research first began. Contrary to the “Disposable Soma Theory” on the evolution of aging, which proposes that the greedy germline poses an unavoidable cost to the rest of the body, studies exploring germline-less C. elegans have revealed that the longevity afforded these animals is due to complex and highly regulated molecular mechanisms, rather than just a change in resource allocation from progeny production to somatic tissue maintenance. The fact that lifespan benefits are seen when the germline tissues are disrupted in worms, flies, grasshoppers, rats and humans excitingly suggests an evolutionarily conserved pathway linking reproductive tissues to aging. This study aimed to uncover the upstream effectors of this longevity pathway, in order to determine how the germline functions to prevent life extension in normal intact C. elegans. Unbiased genetic and biochemical screens were performed to find genes and proteins involved in the KRI-1-mediated activation of DAF-16, which occurs upon germline-ablation and is integral to the resulting longevity. Many overlapping factors were found using these complimentary techniques, validating the combined genetic/biochemical approach. One particular gene of interest found to promote DAF-16 activity in germline-less worms was itr-1, a gene encoding the worm’s only IP3-responsive Ca2+ channel. However, RNAi knockdown of itr-1 not only decreased the lifespan of germline(-) worms, but did so in germline(+) worms as well, suggesting ITR-1 plays more broad role in lifespan regulation. Consistent with this, itr-1(RNAi) was found to impair DAF-16 activity in the intestine of two daf-2 mutants (e1370 and e1368), and also greatly inhibit the lifespan of these long-lived strains. Thus, ITR-1 appears to act as a more general longevity promoting factor in C. elegans, possibly working through regulation of intestinal DAF-16. Interestingly though, ITR-1 was also shown to regulate activity of several other components of germline-less longevity, specifically SKN-1, DAF-12 and the MitoUPR. Thus, ITR-1 may actually control lifespan through regulation of multiple downstream pathways. Understanding these pathways will be of great interest for future research.

    Cover page: Deciphering How the Germline Inhibits Longevity
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2018)
    The widely conserved heat-shock response, regulated by heat-shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In Caenorhabditis elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental-arrest phenotype of a heat-shock factor mutant. Here, we show that loss of the conserved translational activator rsks-1/S6 kinase, a downstream effector of mechanistic Target of Rapamycin (mTOR) kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor by activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the mTOR pathway during C. elegans development.
      Cover page: The mTOR Target S6 Kinase Arrests Development in Caenorhabditis elegans When the Heat-Shock Transcription Factor Is Impaired
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