Abstract
Dietary restriction (DR) increases life span through adaptive changes in gene expression. To understand more about these changes, we analyzed the transcriptome and translatome of Caenorhabditis elegans subjected to DR. Transcription of muscle regulatory and structural genes increased, whereas increased expression of amino acid metabolism and neuropeptide signaling genes was controlled at the level of translation. Evaluation of posttranscriptional regulation identified putative roles for RNA-binding proteins, RNA editing, miRNA, alternative splicing, and nonsense-mediated decay in response to nutrient limitation. Using RNA interference, we discovered several differentially expressed genes that regulate life span. We also found a compensatory role for translational regulation, which offsets dampened expression of a large subset of transcriptionally down-regulated genes. Furthermore, 3' UTR editing and intron retention increase under DR and correlate with diminished translation, whereas trans-spliced genes are refractory to reduced translation efficiency compared with messages with the native 5' UTR. Finally, we find that smg-6 and smg-7, which are genes governing selection and turnover of nonsense-mediated decay targets, are required for increased life span under DR.
Highlights
Methods of dietary restriction (DR) that increase life span involve restricting nutrients without causing malnutrition
Using food dilution (Chen et al, 2009) to impose DR starting at day 1 of adulthood extended median life span of C. elegans by ~40% (Fig 1A)
Up-regulated genes were enriched for processes related to myosin and myofibril assembly, muscle contraction, locomotion, oxidation/reduction, and ion transport (Fig 1E and Table S2), whereas down-regulated genes were enriched for biological processes related to apoptosis, amino acid metabolism, defense response, epigenetic regulation, RNA metabolism, and transcription (Fig 1F and Table S2)
Summary
Methods of dietary restriction (DR) that increase life span involve restricting nutrients without causing malnutrition. DR increases resistance to stress and improves other parameters of health from yeast to mammals (Mair and Dillin, 2008), indicating that physiological responses to DR are evolutionary conserved. It is not surprising, that much attention has focused on understanding how animals adapt to DR. Identifying genetic programs that control the health benefits of DR guides efforts to develop drug mimetics, which would replace extreme dietary interventions to increase healthy longevity To support such efforts, investigators need to understand the genes involved in adapting to DR so they can determine which ones impart benefits associated with this regimen
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