Abstract
Transparent, easily-maintained, amenable to genetic manipulation, and living for only a few weeks, the nematode Caenorhabditis elegans is a leading animal model for the study of the determinants of lifespan. The original genetic screen for increased longevity identified a mutant, age-1, with a defect in one component of a signal transduction pathway. This pathway functioned as a genetic switch and governed the decision whether to enter a specialized larval form, dauer, that enables the worm to withstand the scarcity of food or other stressful conditions. These age-1 worms had an increased tendency to become dauers, but if they did not adopt the dauer developmental pathway, they lived longer than wild type worms. age-1 and other longevity mutants with dauer phenotypes are vigorous, indicating that they do not suffer from a significant energy deficit, and stress resistant. Mutation of genes encoding mitochondrial components was found to be another means of extending the lifespan of the worm, although the associated phenotypes suggest a deficiency of available energy. While there are now many documented genetic manipulations which can extend the worm's lifespan, it has been difficult to come to definite conclusions as to the mechanism (s) by which lifespan is extended. The most carefully studied mutant strains have complex changes in gene expression and metabolism making it difficult to ascertain what changes are critical.
The free radical theory of aging is the dominant biochemical theory of aging, and the phenotypes of the well-characterized longevity mutants worm can be accommodated to it. However discrete interventions to lower reactive oxygen species, or mitigate their effects, have not produced consistent easily-interpretable results in terms of lifespan extension. It has become clear that the insulin-dependent signalling mechanism that regulates lifespan in the worm functions in the context of a complex endocrine system and the hormonal control of aging is an emerging focus of research in worms and higher organisms.
Keywords: Caenorhabditis elegans, determinants of lifespan
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References
- 1.Wood W. ed. Chapter 1. Introduction to C. elegans biology in The Nematode Caenorhabditis elegans, Cold Spring Harbor Laboratory, 1988. [Google Scholar]
- 2.Garigan D., Hsu A. L., Fraser A. G., Kamath R. S., Ahringer J., and Kenyon C. (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: A role for heat-shock factor and bacterial proliferation. Genetics, 161, 1101–1112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Klass M. R. (1983) A method for the isolation of longevity mutants in the nematode Caenorhabditis-elegans and initial results. Mech. Ageing Dev., 22, 279–286. [DOI] [PubMed] [Google Scholar]
- 4.http://genetics.mgh.harvard.edu/RuvkunWeb/projects.html; and http://www.biotech.missouri.edu/DauerWorld/Dauers/Background.html
- 5.Larsen P. L. (1993) Aging and resistance to oxidative damage in Caenorhabditis-elegans. P.N.A.S., 90, 8905–8909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Voorhies W. (2003) Is lifespan extension in single gene long-lived Caenorhabditis elegans mutants due to hypometabolism? Exp. Gerontol, 38, 615–618. [DOI] [PubMed] [Google Scholar]
- 7.Houthoofd K., Braeckman B. P., Johnson T. E., and Vanfleteren J. R. (2003) Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans. Exp. Geront., 38, 947–954. [DOI] [PubMed] [Google Scholar]
- 8.Cypser J. R., and Johnson T. E. (2003) Hormesis in Caenorhabditis elegans dauer-defective mutants. Biogeront., 4, 203–214. [DOI] [PubMed] [Google Scholar]
- 9.Murphy C. T., McCarroll S. A., Bargmann C. I., Fraser A., Kamath R. S., Ahringer J., Li H., and Kenyon C. (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature, 424, 277–284. [DOI] [PubMed] [Google Scholar]
- 10.McElwee J., Bubb K., and Thomas J. H. (2003) Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell, 2, 341–341. [DOI] [PubMed] [Google Scholar]
- 11.Hekimi S., and Guarente L. (2003) Genetics and the specificity of the aging process. Science, 299, 1351–1354. [DOI] [PubMed] [Google Scholar]
- 12.Feng J. L., Bussiere F., and Hekimi S. (2001) Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev. Cell, 1, 633–644. [DOI] [PubMed] [Google Scholar]
- 13.Lee S. S., Lee R. Y. N., Fraser A. G., Kamath R. S., Ahringer J., and Ruvkun G. (2003) A systematic RNAi screen identifies a critical role for mitochondria in C-elegans longevity. Nat. Genet., 33, 40–48. [DOI] [PubMed] [Google Scholar]
- 14.Tissenbaum H. A., and Guarente L. (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410, 227–230. [DOI] [PubMed] [Google Scholar]
- 15.Yokoyama K., Fukumoto K., Murakami T., Harada S., Hosono R., Wadhwa R., Mitsui Y., and Ohkuma S. (2002) Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot-2 (mortalin)/mthsp70/Grp75. FEBS Lett., 516, 53–57. [DOI] [PubMed] [Google Scholar]
- 16.Beckman K., and Ames B. (1998) The free radical theory of aging. Physiol. Rev., 78, 548–571. [DOI] [PubMed] [Google Scholar]
- 17.Keaney M., and Gems D. (2003) No increase in lifespan in Caenorhabditis elegans upon treatment with the superoxide dismutase mimetic EUK-8. Free Radical Biol. Med., 34, 277–282. [DOI] [PubMed] [Google Scholar]
- 18.Senoo-Matsuda N., Yasuda K., and Tsuda M. (2001) A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans. J. Biol. Chem., 276, 41553–41558. [DOI] [PubMed] [Google Scholar]
- 19.Rea S., and Johnson T. E. (2003) A metabolic model for life span determination in Caenorhabditis elegans. Dev. Cell, 5, 197–203. [DOI] [PubMed] [Google Scholar]
- 20.Wolkow C. A. (2002) Life span: getting the signal from the nervous system getting the signal from the nervous system. Trends Neurosci., 25(4), 212–216. [DOI] [PubMed] [Google Scholar]
- 21.Tatar M., Bartke A., and Antebi A. The endocrine regulation of aging by insulin-like signals. Science, 299, 1346–1350. [DOI] [PubMed] [Google Scholar]
- 22.Holzenberger M., Dupont J., Ducos B., Leneuve P., Geloen A., Even P. C., Cervera P., and Le Bouc Y. (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature, 421, 182–187. [DOI] [PubMed] [Google Scholar]
- 23.Finkel T., and Holbrook N. J. (2000) Oxidants, oxidative stress and the biology of ageing. Nature, 408, 239–247. [DOI] [PubMed] [Google Scholar]
- 24.Johnson T. E. (2003) Advantages and disadvantages of Caenorhabditis elegans for aging research. Exp. Gerontol, 38, 1329–1332. [DOI] [PubMed] [Google Scholar]