Regulation of mRNA translation as a conserved mechanism of longevity control
ABSTRACT Appropriate regulation of mRNA translation is essential for growth and survival and the pathways that regulate mRNA translation have been highly conserved throughout eukaryotic evolution. Translation is controlled by a complex set of mechanisms acting at multiple levels, ranging from global protein synthesis to individual mRNAs. Recently, several mutations that perturb regulation of mRNA translation have also been found to increase longevity in three model organisms: the buddingyeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Many of these translation control factors can be mapped to a single pathway downstream of the nutrient responsive target of rapamycin (TOR) kinase. In this chapter, we will review the data suggesting that mRNA translation is an evolutionarily conserved modifier of longevity and discuss potential mechanisms by which mRNA translation could influence aging and age-associated disease in different species.
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- "Interestingly, SAGA has a direct role in regulating expression of ribosomal protein genes in a manner dependent on the transcription factor Ifh1 (Cai et al., 2013; Downey et al., 2013). Ribosomal protein gene deletions are highly enriched among long-lived mutants in yeast (Mehta et al., 2010). Thus, another potential link to enhanced longevity in DUBm mutants may be through reduced ribosome biogenesis. "
ABSTRACT: We have analyzed the yeast replicative lifespan of a large number of open reading frame (ORF) deletions. Here, we report that strains lacking genes SGF73, SGF11, and UBP8 encoding SAGA/SLIK complex histone deubiquitinase module (DUBm) components are exceptionally long lived. Strains lacking other SAGA/SALSA components, including the acetyltransferase encoded by GCN5, are not long lived; however, these genes are required for the lifespan extension observed in DUBm deletions. Moreover, the SIR2-encoded histone deacetylase is required, and we document both a genetic and physical interaction between DUBm and Sir2. A series of studies assessing Sir2-dependent functions lead us to propose that DUBm strains are exceptionally long lived because they promote multiple prolongevity events, including reduced rDNA recombination and altered silencing of telomere-proximal genes. Given that ataxin-7, the human Sgf73 ortholog, causes the neurodegenerative disease spinocerebellar ataxia type 7, our findings indicate that the genetic and epigenetic interactions between DUBm and SIR2 will be relevant to neurodegeneration and aging.
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- "One of the major downstream processes regulated by mTORC1 is mRNA translation  . Mutation or RNAi knockdown of several ribosomal protein genes has been shown to extend lifespan in budding yeast and C. elegans [95, 113, 119–125]. "
ABSTRACT: The mechanistic target of rapamycin (mTOR) is a highly conserved protein that regulates growth and proliferation in response to environmental and hormonal cues. Broadly speaking, organisms are constantly faced with the challenge of interpreting their environment and making a decision between "grow or do not grow." mTOR is a major component of the network that makes this decision at the cellular level and, to some extent, the tissue and organismal level as well. Although overly simplistic, this framework can be useful when considering the myriad functions ascribed to mTOR and the pleiotropic phenotypes associated with genetic or pharmacological modulation of mTOR signaling. In this review, I will consider mTOR function in this context and attempt to summarize and interpret the growing body of literature demonstrating interesting and varied effects of mTOR inhibitors. These include robust effects on a multitude of age-related parameters and pathologies, as well as several other processes not obviously linked to aging or age-related disease.11/2013; 2013:849186. DOI:10.1155/2013/849186
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ABSTRACT: In this, the fourth installment of our annual Hot Topics review on mRNA translation and aging, we have decided to expand our scope to include recent findings related to the role of TOR signaling in aging. As new data emerge, it is clear that TOR signaling acts upstream of mRNA translation, as well as a variety of other cellular processes, to modulate longevity and healthspan in evolutionarily diverse species. This Hot Topics review will cover important new findings in this area that have occurred over the past year. These include the demonstration that the TOR substrate ribosomal S6 kinase modulates longevity in mammals, the potential for TOR inhibitors as therapeutic treatments for Alzheimer's disease, and further studies emphasizing the importance of differential translation of specific mRNAs for healthy aging and enhanced longevity.Aging cell 12/2010; 10(2):185-90. DOI:10.1111/j.1474-9726.2010.00665.x · 5.94 Impact Factor