Abstract
The roles and regulatory mechanisms of transcriptome changes during aging are unclear. It has been proposed that the transcriptome suffers decay during aging owing to age‐associated down‐regulation of transcription factors. In this study, we characterized the role of a transcription factor DAF‐16, which is a highly conserved lifespan regulator, in the normal aging process of Caenorhabditis elegans. We found that DAF‐16 translocates into the nucleus in aged wild‐type worms and activates the expression of hundreds of genes in response to age‐associated cellular stress. Most of the age‐dependent DAF‐16 targets are different from the canonical DAF‐16 targets downstream of insulin signaling. This and other evidence suggest that activation of DAF‐16 during aging is distinct from activation of DAF‐16 due to reduced signaling from DAF‐2. Further analysis showed that it is due in part to a loss of proteostasis during aging. We also found that without daf‐16, dramatic gene expression changes occur as early as on adult day 2, indicating that DAF‐16 acts to stabilize the transcriptome during normal aging. Our results thus reveal that normal aging is not simply a process in which the gene expression program descends into chaos due to loss of regulatory activities; rather, there is active transcriptional regulation during aging.
Highlights
Phenylalanine metabolism Histidine metabolismCysteine and methionine metabolism Glycolysis / Gluconeogenesis Lysosome Metabolic pathways.
Retinol metabolism Glycerophospholipid metabolism Starch and sucrose metabolism Ascorbate and aldarate metabolism Longevity regulating pathway − multiple species Longevity regulating pathway − worm mTOR signaling pathway FoxO signaling pathway ErbB signaling pathway MAPK signaling pathway
Pantothenate and CoA biosynthesis Fatty acid biosynthesisNeuroactive ligand−receptor interaction Mannose type O−glycan biosynthesis Arginine biosynthesis Fatty acid elongation Lysosome Terpenoid backbone biosynthesis Propanoate metabolism Arginine and proline metabolism Biosynthesis of amino acids Tryptophan metabolism Lysine degradation Oxidative phosphorylation Fructose and mannose metabolism Protein export Phagosome Carbon metabolism.
Summary
Cysteine and methionine metabolism Glycolysis / Gluconeogenesis Lysosome Metabolic pathways. Retinol metabolism Glycerophospholipid metabolism Starch and sucrose metabolism Ascorbate and aldarate metabolism Longevity regulating pathway − multiple species Longevity regulating pathway − worm mTOR signaling pathway FoxO signaling pathway ErbB signaling pathway MAPK signaling pathway
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