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The role of the ribosome in the regulation of longevity and lifespan extension

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The most energy‐consuming process that a cell must undertake to stay viable is the continuous biogenesis of ribosomes for the translation of RNA into protein. Given the inextricable links between energy consumption and cellular lifespan, it is not surprising that mutations and environmental cues that reduce ribosome biogenesis result in an extension of eukaryotic lifespan. This review goes into detail describing recent discoveries of different and often unexpected elements that play a role in the regulation of longevity by virtue of their ribosome biogenesis functions. These roles include controlling the transcription and processing of ribosomal RNA (rRNA), the translation of ribosomal protein (RP) genes, and the number of ribosomes overall. Together these findings suggest that a fundamental mechanism across eukaryotic species for extending lifespan is to slow down or halt the expenditure of cellular energy that is normally absorbed by the manufacturing and assembly of new ribosomes. WIREs RNA 2016, 7:198–212. doi: 10.1002/wrna.1325 This article is categorized under: Translation > Ribosome Structure/Function RNA Processing > Splicing Mechanisms
Illustration of pathways during cell growth. A basic schematic of the pathways that are activated (depicted by the blue boxes with green upwards arrows) or inhibited (depicted by the grey boxes and red downwards arrows) by extracellular nutrients and growth factors and eventually lead to the increased transcription of rRNA, RP genes, and the assembly of new ribosomes.
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Autophagy prevents insoluble protein accumulation. Mutations resulting in RP insolubility (black stars) likely found on older, more error‐prone DNA result in the accumulation of deleterious protein aggregates. Autophagy driven by reduced insulin or mTOR signaling (and perhaps NO?) can recycle previously synthesized RPs and reduce the need for newly synthesized, possibly insoluble RPs. In contrast, inhibiting autophagy by increased insulin/mTOR signaling or autophagy‐specific mutations result in the accumulation of protein aggregates.
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How rRNA expression is regulated temporally and by growth or caloric restriction. A circadian cycle is depicted with the changing NAD+/NADH ratios. The rDNA locus is found acetylated (red circles labeled ‘Ac’) in growth conditions and when NADH levels are high. Caloric restriction and high NAD+ levels lead to SIRT1 expression and formation of the eNoSC complex that methylates (green circles labeled ‘Me’) and silences the rDNA locus. The result is cessation of rRNA transcription.
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Illustration of pathways during lifespan extension. An overview of the main topics covered in this review and how they link to the repression of ribosome biogenesis, the activation of autophagy, and the extension of cellular lifespan. The grey boxes and circles with red downwards arrows depict proteins, RNAs, or pathways that are down regulated. The blue boxes and circles with green upwards arrows depict proteins, RNAs, or pathways that are upregulated.
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Translation > Ribosome Structure/Function
RNA Processing > Splicing Mechanisms

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