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 nonproliferating, UV-killed bacteria. This work describes a novel lifespan gene that protects the worm from harmful bacteria, thus promoting survival and extending lifespan.
|Commitee:||Ashrafi, Kaveh, Heberlein, Ulrike, Kapahi, Pankaj, McIntire, Steve|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 71/02, Dissertation Abstracts International|
|Keywords:||Aging, Caenorhabditis elegans, Innate immunity, Progeria|
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