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2018_03_29_phd_dissertation_finalv2.pdf (4.01 MB)

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The Kruppel-like Factors in Aging and Aging Associated Pathology

Hsieh, Paishiun Nelson
http://rave.ohiolink.edu/etdc/view?acc_num=case1522942623451445

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pathology.
Aging is a progressive, global degeneration in cellular functions which occurs as homeostatic mechanisms become insufficient, leading to an age-related exponential increase in risk of mortality and age-associated disease. Aging has characteristic features shared across phylogeny and is subject to biologic control. Here I describe a regulatory pathway which modulates lifespan and healthspan of the nematode Caenorhabditis elegans via enhancement of cellular proteostasis. Specifically, direct transcriptional control of macroautophagy by the family of Kruppel like factors (KLFs) alters nematode lifespan and age-associated phenotypes. Further, the KLFs are broadly required in at least four mechanistically distinct longevity pathways, suggesting that diverse upstream signaling converges on a KLF regulatory node to effect a common pro-longevity response. The KLF-autophagy pathway is conserved in mice vasculature to regulate endothelial autophagy and vascular aging. As the KLFs are well accepted as mechanotransducers of laminar shear stress, we also suggest that KLFs mediate the effects of shear stress on endothelial autophagy. Long-lived nematodes overexpressing a KLF also are protected from neurodegeneration in a model of Parkinson’s Disease, therefore experiencing an extension of time spent free of age-associated debility. Interestingly, only an intestinal KLF is required for this effect and these nematodes do not experience lifespan extension. A putative secreted c-type lectin (ortholog for mammalian complement protein COLEC11) mediates intestinal KLF neuroprotection, linking gut signals with neuronal proteostatic mechanisms. Together, these observations outline a novel longevity pathway, in addition to known biologic mechanisms regulating aging, and define a role for the KLFs in determining organismal lifespan.
Mukesh Jain (Advisor)
George Dubyak (Committee Chair)
Jeff Coller (Committee Member)
Goutham Narla (Committee Member)
Clive Hamlin (Committee Member)
213 p.
Biology; Cellular Biology; Molecular Biology; Neurobiology; Physiology
Aging; healthspan; longevity; kruppel; autophagy; Parkinson; vascular

Recommended Citations

Citations

  • Hsieh, P. N. (2018). The Kruppel-like Factors in Aging and Aging Associated Pathology [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1522942623451445

    APA Style (7th edition)

  • Hsieh, Paishiun. The Kruppel-like Factors in Aging and Aging Associated Pathology. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1522942623451445.

    MLA Style (8th edition)

  • Hsieh, Paishiun. "The Kruppel-like Factors in Aging and Aging Associated Pathology." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522942623451445

    Chicago Manual of Style (17th edition)

case1522942623451445
274
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.