Altered signalling from germline to intestine pushes daf-2;pept-1 Caenorhabditis elegans into extreme longevity.
The insulin-like signalling pathway is a central regulator of development, metabolism, stress resistance and lifespan in eukaryotes. Caenorhabditis elegans daf-2(e1370) animals with a loss-of-function mutation in the insulin-like receptor live twice as long as wild-type animals, and the additional knockout of the intestinal di- and tripeptide transporter pept-1 further increases lifespan by 60%. In assessing the underlying molecular mechanisms for this phenomenon, microarray-based transcriptome data sets of daf-2(e1370) and daf-2(e1370);pept-1(lg601) animals were compared with a focus on genes that showed significantly higher changes in expression levels in daf-2;pept-1 than in daf-2. We identified 187 genes with at least fourfold decreased transcript levels and 170 with more than a fourfold increase. A large fraction of the down-regulated genes encode proteins involved in germline proliferation and reproduction. The DAF-9/DAF-12 signalling cascade was identified as a prime pathway that mediates the longevity of daf-2;pept-1 with a strict dependance on DAF-16. Loss of DAF-9/DAF-12 or KRI-1 reduces the lifespan of daf-2;pept-1 to that of the daf-2 mutant. Amongst the DAF-16 target genes, numerous enzymes involved in the defence of reactive oxygen species were with increased expression level in daf-2;pept-1. On a functional level, it was demonstrated that amongst those, a high de novo synthesis rate of glutathione is most important for the longevity phenotype of this strain. Taken together, a close interdependence of endocrine hormone signalling from germline to intestine was identified as an essential element in the control of the extreme longevity of C. elegans lacking a proper function of the insulin receptor and lacking the intestinal peptide transporter.
Spanier
Britta
B
ZIEL Research Center of Nutrition and Food Sciences, Technische Universität München, Freising, Germany. spanier@wzw.tum.de
Rubio-Aliaga
Isabel
I
Hu
Hao
H
Daniel
Hannelore
H
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D017238:Genes, Helminth / Q000235:genetics; D005854:Germ Cells / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D012098:Reproduction / Q000235:genetics; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D005978:Glutathione