Regulation of mRNA Translation as a Conserved Mechanism of Longevity Control
Department of Pathology, University of Washington, Seattle, Washington, USA.Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 01/2010; 694:14-29. DOI: 10.1007/978-1-4419-7002-2_2
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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- "Normally, the larger mother cell gives rise to a smaller daughter cell and retains aging factors such as damaged proteins and extrachromosomal rDNA (ribosomal DNA) circles (ERCs). Old mother cells need longer to form a bud and cannot retain the various senescence factors anymore leading to a prematurely aging daughter cell with nearly the same size as its mother cell (Bitterman et al., 2003; Mehta et al., 2010; Shcheprova et al., 2008). It is strain dependent how many buds a mother cell can form overall. "
ABSTRACT: Serial repitching of brewing yeast inoculates is an important economic factor in the brewing industry, as their propagation is time and resource intensive. Here, we investigated whether replicative aging and/or the population distribution status changed during serial repitching in three different breweries with the same brewing yeast strain but different abiotic backgrounds and repitching regimes with varying numbers of reuses. Next to bud scar numbers the DNA content of the Saccharomyces pastorianus HEBRU cells was analyzed. Gene expression patterns were investigated using low-density microarrays with genes for aging, stress, storage compound metabolism and cell cycle. Two breweries showed a stable rejuvenation rate during serial repitching. In a third brewery the fraction of virgin cells varied, which could be explained with differing wort aeration rates. Furthermore, the number of bud scars per cell and cell size correlated in all 3 breweries throughout all runs. Transcriptome analyses revealed that from the 6(th) run on, mainly for the cells positive gene expression could be seen, for example up-regulation of trehalose and glycogen metabolism genes. Additionally, the cells' settling in the cone was dependent on cell size, with the lowest and the uppermost cone layers showing the highest amount of dead cells. In general, cells do not progressively age during extended serial repitching.
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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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- "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? "
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.
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