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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2009)

To date, many genes and pathways regulating lifespan have been identified in the nematode Caenorhabditis elegans. Over 20 years of research have uncovered conserved roles for insulin signaling, metabolism, dietary restriction, and reproductive signaling in the control of lifespan. Yet, despite this work, we still lack a complete picture of aging. To identify new components of lifespan regulation, we undertook two RNAi-based screens. In the first, we searched for genes which, when knocked down, accelerate aging in C. elegans. Using lifespan analysis as well as analysis of tissue morphology, we identified five potential "progeria regulators". These five genes, four of which were independently identified by other researchers, negatively regulate lifespan. Further work will determine their exact role in aging regulation.

A separate RNAi screen for components of dietary restriction-mediated longevity also identified a negative regulator of lifespan. mrvl-1 encodes a MARVEL-domain containing membrane protein which is partially localized to the Golgi apparatus. RNAi inhibition of mrvl-1 significantly shortens lifespan and accelerates aging while overexpression extends lifespan in C. elegans. Using transcriptional profiling to identify genes involved in mrvl-1-regulation of aging, we found significant overlap with the lifespan-regulating daf-2/insulin/IGF-1 signaling pathway as well as with the innate immune response in C. elegans. Investigations into the immune activity of mrvl-1 revealed that whereas RNAi treatment causes increased sensitivity to the bacterial pathogen Pseudomonas aeruginosa, overexpression of mrvl-1 increases resistance. As bacterial food sources may potentially pose a late-life hazard to C. elegans, mrvl-1 likely helps the worm cope with the detrimental effects of proliferating and pathogenic bacteria. Indeed, mrvl-1 overexpression no longer extends the lifespan of animals fed non-proliferating, UV-killed bacteria. This work describes a novel lifespan gene that protects the worm from harmful bacteria, thus promoting survival and extending lifespan.

    Cover page: A search for longevity genes in <i>C. elegans</i> identifies a MARVEL domain-containing protein regulating innate immunity and lifespan
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2013)
    In long-lived C. elegans insulin/IGF-1 pathway mutants, the life-extending FOXO transcription factor DAF-16 is present throughout the animal, but we find that its activity in a single tissue can delay the aging of other tissues and extend the animal's life span. To better understand the topography of DAF-16 action among the tissues, we analyzed a collection of DAF-16-regulated genes. DAF-16 regulated most of these genes in a cell-autonomous fashion, often using tissue-specific GATA factors to direct their expression to specific tissues. DAF-16 could also act cell nonautonomously to influence gene expression. DAF-16 affected gene expression in other cells, at least in part, via the lipid-gene regulator MDT-15. DAF-16, and probably MDT-15, could act cell nonautonomously in the endoderm to ameliorate the paralysis caused by expressing Alzheimer's Aβ protein in muscles. These findings suggest that MDT-15-dependent intercellular signals, possibly lipid signals, can help to coordinate tissue physiology, enhance proteostasis, and extend life in response to DAF-16/FOXO activity.
      Cover page: Direct and Indirect Gene Regulation by a Life-Extending FOXO Protein in C. elegans: Roles for GATA Factors and Lipid Gene Regulators
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2013)
      Animals have many ways of protecting themselves against stress; for example, they can induce animal-wide, stress-protective pathways and they can kill damaged cells via apoptosis. We have discovered an unexpected regulatory relationship between these two types of stress responses. We find that C. elegans mutations blocking the normal course of programmed cell death and clearance confer animal-wide resistance to a specific set of environmental stressors; namely, ER, heat and osmotic stress. Remarkably, this pattern of stress resistance is induced by mutations that affect cell death in different ways, including ced-3 (cell death defective) mutations, which block programmed cell death, ced-1 and ced-2 mutations, which prevent the engulfment of dying cells, and progranulin (pgrn-1) mutations, which accelerate the clearance of apoptotic cells. Stress resistance conferred by ced and pgrn-1 mutations is not additive and these mutants share altered patterns of gene expression, suggesting that they may act within the same pathway to achieve stress resistance. Together, our findings demonstrate that programmed cell death effectors influence the degree to which C. elegans tolerates environmental stress. While the mechanism is not entirely clear, it is intriguing that animals lacking the ability to efficiently and correctly remove dying cells should switch to a more global animal-wide system of stress resistance.
        Cover page: A Shift to Organismal Stress Resistance in Programmed Cell Death MutantsCreative Commons 'BY' version 4.0 license
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