Protein biogenesis machinery is a driver of replicative aging in yeast.
Protein biogenesis machinery is a driver of replicative aging in yeast.
复制标题
蛋白质生物发生机制是酵母复制衰老的驱动力。
DOI：
10.7554/elife.08527
复制
发表时间：
2015-12-01
期刊：
影响因子：
7.7
通讯作者：
Heinemann M
中科院分区：
文献类型：
--
作者：
Janssens GE;Meinema AC;González J;Wolters JC;Schmidt A;Guryev V;Bischoff R;Wit EC;Veenhoff LM;Heinemann M
An integrated account of the molecular changes occurring during the process of cellular aging is crucial towards understanding the underlying mechanisms. Here, using novel culturing and computational methods as well as latest analytical techniques, we mapped the proteome and transcriptome during the replicative lifespan of budding yeast. With age, we found primarily proteins involved in protein biogenesis to increase relative to their transcript levels. Exploiting the dynamic nature of our data, we reconstructed high-level directional networks, where we found the same protein biogenesis-related genes to have the strongest ability to predict the behavior of other genes in the system. We identified metabolic shifts and the loss of stoichiometry in protein complexes as being consequences of aging. We propose a model whereby the uncoupling of protein levels of biogenesis-related genes from their transcript levels is causal for the changes occurring in aging yeast. Our model explains why targeting protein synthesis, or repairing the downstream consequences, can serve as interventions in aging. DOI: http://dx.doi.org/10.7554/eLife.08527.001 Aging is a complex process, and so many scientists use baker’s yeast as a simpler model to understand it. Although many genes that influence aging have been found, all the generated knowledge is still rather fragmented. It also remains difficult to disentangle cause and consequence. That is to say, sometimes a gene that looks like it might cause aging could simply be a gene that responds to an age related phenomenon. To unravel this puzzle of cause and effect, it is necessary to first get an idea on a system level of everything that changes as an organism ages. Now, Janssens, Meinema et al. have managed to map many of the molecular changes that occur as baker’s yeast ages; this is something that has yet to be achieved for any other organism. The work first involved developing a new way of growing baker’s yeast to keep and generate large cohorts of aging yeast cells in a constant environment. It also required the use of a mathematical ‘un-mixing’ tool to separate the data obtained from the aging cohort from the data from the young offspring that the yeast produce while they age. Janssens, Meinema et al. measured both the majority of the transcriptome and much of the proteome of baker’s yeast throughout its reproductive lifespan. The “transcriptome” refers to the collection of RNA molecules in the cell, which are produced whenever a gene is expressed. The “proteome” refers to all the proteins in the cell, which are translated from the RNA transcripts by the cell’s so-called “translational machinery”. These experiments revealed that this yeast’s proteome reflects its transcriptome less and less as it ages. In particular, this ‘uncoupling’ of the proteome from the transcriptome was seen most strongly for the proteins related to the cell’s translational machinery; these proteins accumulated with age relative to their transcripts. Janssens, Meinema et al. then conducted a computational network-based analysis of the data. This indicated that the uncoupling is the driving force behind the aging process. Many of the other molecular changes that occur with aging were predicted to be consequences of this uncoupling. These findings give a framework for many observations in the existing literature. However, it remains unclear why proteins related to translational machinery are overrepresented in aging yeast in the first place. This question should be explored in future work. DOI: http://dx.doi.org/10.7554/eLife.08527.002
