Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance.
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/alpha-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.
Department of Biology, University College London, WC1E 6BT, United Kingdom.
Joshua J
JJ
McElwee
Eugene
E
Schuster
Eric
E
Blanc
James H
JH
Thomas
David
D
Gems
D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019992:Databases as Topic; D004330:Drosophila; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D008136:Longevity; D008954:Models, Biological; D008956:Models, Chemical; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D009841:Oligonucleotides; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin