Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007.
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | eng |
| Published: |
Massachusetts Institute of Technology
2007
|
| Subjects: | |
| Online Access: | http://hdl.handle.net/1721.1/38987 |
| _version_ | 1826194618189873152 |
|---|---|
| author | Bishop, Nicholas A |
| author2 | Leonard Guarente. |
| author_facet | Leonard Guarente. Bishop, Nicholas A |
| author_sort | Bishop, Nicholas A |
| collection | MIT |
| description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007. |
| first_indexed | 2024-09-23T09:58:43Z |
| format | Thesis |
| id | mit-1721.1/38987 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T09:58:43Z |
| publishDate | 2007 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/389872019-04-12T09:34:36Z Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans Bishop, Nicholas A Leonard Guarente. Massachusetts Institute of Technology. Dept. of Biology. Massachusetts Institute of Technology. Dept. of Biology. Biology. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2007. Vita. Includes bibliographical references. Dietary restriction (DR), the limitation of food intake below the ad libidum (AL) level without malnutrition, extends mean and maximum lifespan in every organism in which it has been tested. Perhaps even more significantly, DR has also been shown in animal models to slow progression of, or even prevent entirely, an array of age-dependent pathologies, including cardiovascular disease, multiple types of cancer, several neurodegenerative disorders, and diabetes. Short-term DR also reduces the risk of coronary disease and stroke in humans. Clearly, identification of the genetic mechanisms underlying these protective effects of DR would have profound implications for the development of novel medical interventions affecting diseases of aging. Recent studies of model organisms have revealed many genetic pathways that control the physiological rate of aging. However, advances in understanding DR longevity have lagged behind, especially in metazoans. Here, I use the roundworm C. elegans as a model of DR longevity and identify some of the underlying genetic mechanisms. DR profoundly alters endocrine function in mammals, but no causal role of any hormonal signal in DR longevity has been demonstrated. (cont.) I show that increased longevity of diet-restricted C. elegans requires the transcription factor skn-1 acting specifically in the ASIs, a pair of neurons in the head. DR activates skn-1 in the ASIs, which signals peripheral tissues to increase metabolic activity. These findings demonstrate that increased lifespan in a diet-restricted metazoan depends on cell-nonautonomous signaling from central neuronal cells to non-neuronal body tissues, and suggest that the ASIs mediate dietary restriction-induced longevity by an endocrine mechanism. Next, I identify sek-1, a conserved stress-responsive MAPKK, as essential for DR-induced longevity and several other physiological responses to DR. I show that sek-1 acts in the ASI neurons to maintain skn-1 expression and mediate the DR longevity response. sek-1 functions downstream of the MAPKKK nsy-1 during DR. Thus, activation of a stress-sensitive MAPK pathway in the brain may be a crucial initial event in DR-induced longevity. To summarize, I have established a three-member genetic pathway that mediates DR longevity by acting in the ASI neurons of C. elegans. by Nicholas A. Bishop. Ph.D. 2007-09-28T13:27:09Z 2007-09-28T13:27:09Z 2007 2007 Thesis http://hdl.handle.net/1721.1/38987 166352666 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 226 p. application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Bishop, Nicholas A Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans |
| title | Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans |
| title_full | Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans |
| title_fullStr | Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans |
| title_full_unstemmed | Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans |
| title_short | Genetic regulation of dietary restriction-induced longevity in Caenorhabditis elegans |
| title_sort | genetic regulation of dietary restriction induced longevity in caenorhabditis elegans |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/38987 |
| work_keys_str_mv | AT bishopnicholasa geneticregulationofdietaryrestrictioninducedlongevityincaenorhabditiselegans |