C. elegans life span extension through mutation in the
daf-2 Ins/IGF-1 receptor or dietary restriction (DR) depends on elevated autophagic activity. Therefore, protein homeostasis is likely to play a pivotal role in determining lifespan under these conditions. We determined the transcriptional expression profile of autophagy and related genes in long-lived
daf-2 mutants and nematodes subjected to DR. The C. elegans genome encodes several genes homologous to yeast atg (AuTophaGy) genes. Although much is known about the post-translational processes governing autophagy induction and regulation, our knowledge about transcriptional regulation of atg genes is limited. We found that the expression profile of atg genes does not reflect the increased autophagic activity in
daf-2 and DR nematodes. However, the FOXA transcription factor
pha-4, which was recently shown to be required for the autophagic response to DR [2], was found upregulated in the
daf-2 mutant. Similarly, lmp (LAMP (lysosome-associated membrane protein) homolog) genes, which are possibly involved in chaperone-mediated autophagy and glo (Gut granule LOss) genes required for the presence of lysosomal gut granules in C. elegans were upregulated in
daf-2 mutants. We found a remarkably strong gene (mostly up-)regulation of several aspartyl (asp) and cysteine (cys) proteases in
daf-2 mutant and DR nematodes which is in agreement with elevated lysosomal abundance and activity under these conditions. Finally, mutation in
daf-2 elicits a strong expression of three predicted amino acid transporter genes in the lysosomal membrane, suggesting a possible role for amino acid recycling in determining lifespan of
daf-2 mutants. In conclusion, we find that elevated autophagic activity is reflected at the transcriptional level, although not for the atg genes. The role of amino acid recycling and lysosomal gut granules in life span determination deserve attention in future research. 1. Melendez, A., et al., Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science, 2003. 301(5638): p. 1387-91. 2. Hansen, M., et al., A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet, 2008. 4(2): p.
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