The nematode worm Caenorhabditis elegans has become a model system for the analysis of the genetics of aging. Previously, mutations in four genes, age-1, clk-1, daf-2 and daf-28 had been shown to lengthen adult life span. Based on the molecular genetic analysis of these genes, the sole function of the dauer genes age-1, daf-2 and possibly daf-28 is to regulate the activity of the forkhead-like transcription factor daf-16. daf-16 may determine life span by regulating the transcription of genes that are necessary for resistance to stresses, especially oxidative stress. Mutations in clk-1 affect behavioral and developmental timing as well as increasing mean and maximum life span. I show that mutations in the genes clk-2, clk-3 and gro-1 affect many of the same processes as clk-1 and that these four genes interact to determine the length of development and adult life span. These four Clock genes lengthen life span in a manner that is distinct from that of the dauer genes. clk-1 has been cloned and has been implicated in the regulation of metabolism. This suggests that Clock mutants may live long because they have reduced metabolic rates. I also show that mutations in 7 genes that affect feeding behavior, eat-1, eat-2, eat-3, eat-6, eat-13, eat-18 and unc-26 lengthen life span. This effect is presumably due to reduced caloric intake (caloric restriction) which has been shown to lengthen the life span of a wide variety of animals. eat-2 lengthens life span by a mechanism that is distinct from that of the dauer mutants but may be similar to that of the Clock mutants. This suggests that caloric restriction may also reduce metabolic rates, possibly through down-regulation of the Clock genes. These results indicate that life span in C. elegans is a polygenic trait, influenced by many different physiological processes. The study of genes that affect aging in C. elegans provides support for the antagonistic pleiotropy and free radical theories of aging.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.34991 |
| Date | January 1998 |
| Creators | Lakowski, Bernard C. |
| Contributors | Hekimi, Siegfried (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001610919, proquestno: NQ44483, Theses scanned by UMI/ProQuest. |
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