Decision letter | Time line of redox events in aging postmitotic cells

Open accessCopyright infoDownload PDFRelated contenteLife Lens

Time line of redox events in aging postmitotic cells

Decision letter

Karsten Weis, Reviewing editor, University of California-Berkeley, United States

eLife posts the editorial decision letter and author response on a selection of the published articles (subject to the approval of the authors). An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown. Reviewers have the opportunity to discuss the decision before the letter is sent (see review process). Similarly, the author response typically shows only responses to the major concerns raised by the reviewers.

Thank you for choosing to send your work entitled “Time line of redox events in aging postmitotic cells” for consideration at eLife. Your article has been evaluated by a Senior Editor and 3 reviewers, one of whom, Karsten Weis, is a member of our Board of Reviewing Editors.

The Reviewing Editor and the other reviewers discussed their comments before we reached this decision, and the Reviewing Editor has assembled the following comments based on the reviewers' reports.

This paper reports the intriguing observation that chronologically aging yeast cells undergo a sudden redox collapse. Using a proteome-wide approach, the authors follow the oxidation status of cysteine residues in a large cohort of proteins over time. This analysis indicates that oxidation increases with aging and reaches its maximum ∼24 hours before the viability of the cells starts to collapse. Clustering analysis indicates that different groups of proteins are oxidized at different time points. Interestingly, a small cluster of very early oxidized proteins includes proteins, which are potentially involved in redox homeostasis. Moreover, proteins known to be particularly sensitive to oxidation by ROS are not among the early targets and in general do not stand out as major targets of the oxidation waves, which take place during chronological aging. Furthermore, oxidation significantly precedes loss of fitness, and oxidation increase itself is preceded by reduction of NAPDH levels and changes in the GSH redox potential. The authors argue that their results do not support the ROS hypothesis for aging, and instead they hypothesize that a collapse in redox homeostasis contributes to chronological aging.

Altogether, the data presented in this manuscript are convincing and the analysis is very thorough. However, the conclusions that can be drawn from these studies about the role of oxidation in aging are somewhat limited by the fact that the authors cannot easily perturb the redox homeostasis machinery and test whether it affects the longevity of the cells. Thus, the manuscript would be strengthened if the authors could directly test whether lower NADH levels or lowering of the redox potential caused aging. Nevertheless, the observations and hypotheses reported in this paper are extremely intriguing and thought-provoking, and should be published. The authors should consider the following comments raised by the reviewers:

1. The authors argue that it is not possible to lower the activity of NADPH thioredoxin reductase (Trr) as loss of this enzyme affects fitness in their strain background. However, it should be possible to lower the dose of Trr, e.g. ,using weaker promoters, or in heterozygous diploids to test a potential role of this enzyme in aging. Alternatively, the authors could consider the overexpression of the non-phosphorylated NADP-dependent glyceraldehyde-3-phosphate dehydrogenase, gapN, from either S. mutans or B. cereus, although there is some concern that the results of overexpression experiments might be difficult to interpret. At the very least the authors should expand their discussion on the limitations of their study.

2. The authors should include a discussion of the nature of the proteins present in cluster F. Proteins in this cluster are remarkably resistant to the general redox status of the cell and hence might play an important role in promoting longevity.

3. A previous study by Burtner and colleagues (2009) has argued that it is acetate toxicity and pH change, rather than oxidation, that causes a loss of viability in post-mitotic cells. Therefore, it seems warranted that the authors discuss the different models. Experimentally, the authors could consider testing if ras2Δ and sch9Δ mutants that extend stationary phase survival also delays the drop in NADPH and oxidation. In this context, deletions of SPT5 would also be very informative as this mutant displays both reduced NADPH and acetate levels. The Burtner model would predict an extended life span whereas the current work would predict the opposite.