Protein biogenesis machinery is a driver of replicative aging in yeast

Abstract

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

The Natural Variation in Lifespans of Single Yeast Cells Is Related to Variation in Cell Size, Ribosomal Protein, and Division Time

“…Plotting the total fluorescence intensity (calculated from the size in μm 2 multiplied by the average fluorescence intensity) for each age gave an indication of the total amount of Rpl13A present in each cell throughout its lifespan (Fig 4B), and at the population level showed an increase to occur with age (S3 Fig panel B). This is in agreement with literature suggesting an increase of ribosomes to occur with aging in yeast [31,46]. Plotting the average intensity on its own however indicated that the concentration of ribosomes within the enlarging cell tends to slightly decrease with age (Fig 4C, S3 Fig panel C).…”

“…Previous work has shown that many ribosome deletions, including Rpl13A, result in increased lifespan for yeast [25], and that the translation machinery such as the ribosomes are implicated as a driving force in the aging process [31]. Therefore, we expected a negative correlation would exist between ribosome concentration in single cells and lifespan, such that at any given age, cells with lower concentrations of ribosomes would be more likely to be the longer-lived cells in the population.…”

“…Cell size has both been suggested to be independent from replicative lifespan [13–17], and causal to it [18–20] and has also previously been studies in microfluidic devices [9–12,21–23]. Ribosomes, which are involved in cell size control [14], have been robustly shown to extend lifespan when knocked out in yeast and higher organisms [24–30], and have also been causally implicated in aging [31]. Cell division time has been found to be negatively correlated to lifespan when looking at the population level [15,32], and positively correlated to lifespan when assessing the mother cells separate from the population ([33] S7A Fig therein).…”

Multigenerational silencing dynamics control cell aging

“…For example, potential candidates include genes in other heterochromatic regions, such as subtelomeric genes that encode metabolic enzymes or have mitochondrial functions (33), or Sir2-repressed genes with prolongevity functions (34), or critical processes influenced by rDNA transcription, such as ribosomal biogenesis, a potential regulator of yeast aging (35,36). Interestingly, a recent study (37) demonstrated that aggregation of a cell-cycle regulator, but not the previously reported loss of silencing at HM loci (38), causes sterility in old yeast cells.…”

Fantastic nuclear envelope herniations and where to find them

“…For example, while the NPC scaffold is extremely long lived, particularly in post-mitotic cells like neurons[78–80], the GLFG-rich Nup116 is lost from replicatively-old NPCs in budding yeast[81,82]. This observation is telling as nup116Δ NPCs have also been shown to acquire double-membrane seals after a shift to a non-permissive growth temperature resulting in morphologically-identical herniations as those associated with defective NPC assembly[52].…”