Regulation of mRNA Translation as a Conserved Mechanism of Longevity Control
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.
Available from: Weiwei Dang
- "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. "
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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.
Cell Reports 07/2014; 8(2). DOI:10.1016/j.celrep.2014.06.037 · 8.36 Impact Factor
Available from: Janine Kirstein
- "chronic stress, aging), stress pathways often start to fail, leading to protein aggregation and cellular death, which is often described in age-related diseases like Alzheimer’s diseases, Parkinson and Huntington’s disease [21, 22]. Interestingly, deletion or inhibition of translation components, such as ribosomal proteins, initiation factors and regulatory kinases, were reported to increase life span [17, 23]. But how can alterations in the translational machinery have positive effects on longevity? "
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ABSTRACT: The production of newly synthesized proteins is a key process of protein homeostasis that initiates the biosynthetic flux of proteins and thereby determines the composition, stability and functionality of the proteome. Protein synthesis is highly regulated on multiple levels to adapt the proteome to environmental and physiological challenges such as aging and proteotoxic conditions. Imbalances of protein folding conditions are sensed by the cell that then trigger a cascade of signaling pathways aiming to restore the protein folding equilibrium. One regulatory node to rebalance proteostasis upon stress is the control of protein synthesis itself. Translation is reduced as an immediate response to perturbations of the protein folding equilibrium that can be observed in the cytosol as well as in the organelles such as the endoplasmatic reticulum and mitochondria. As reduction of protein synthesis is linked to life span increase, the signaling pathways regu-lating protein synthesis might be putative targets for treatments of age-related diseases. Eukaryotic cells have evolved a complex system for protein synthesis regulation and this review will summarize cellular strategies to regulate mRNA translation upon stress and its impact on longevity.
Current Genomics 02/2014; 15(1):66-75. DOI:10.2174/1389202915666140210210542 · 2.34 Impact Factor
Available from: Matt Kaeberlein
- "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]. "
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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(1):849186. DOI:10.1155/2013/849186
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