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J. Biol. Chem., Vol. 279, Issue 43, 44533-44543, October 22, 2004
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From the
Department of Biology, University College London, WC1E 6BT,
European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom, and the ¶Department of Genome Science, University of Washington, Seattle, Washington 98195
In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/
-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed down-regulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated.
Received for publication, June 3, 2004 , and in revised form, August 9, 2004.
* This work was supported by grants from the Wellcome Trust, Functional Genomic Analysis of Aging (to J. J. M., E. S., E. B., and D. G.), and from the Royal Society (to D. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains Fig. 1, Tables IIII, additional text, and additional Refs. 17.
|| To whom all correspondence should be addressed: Dept. of Biology, University College London, Gower St., London WC1E 6BT, UK. Tel.: 44-207-679-4381; Fax.: 44-207-679-7096; E-mail: david.gems{at}ucl.ac.uk.
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