Senescent Cells: A Therapeutic Target in Cardiovascular Diseases
, Karl H. Paul 1,3, Tohru Minamino 2,4, Jordan D. Miller 5, Amir Lerman 6, Georgina M. Ellison-Hughes 7,8, Tamar Tchkonia 1 and James L. Kirkland 1,9,*
Round 1
Reviewer 1 Report
The authors have nicely summarized the important senescence markers, signaling pathways, and potential therapeutic targets of cardiovascular system cells, which is very comprehensive. Just some minor suggestions:
1. Overall, the text is a bit too long, like the table on senescent cell markers, it’ll be nice if the authors can also use a table to list and compare the detrimental effects of certain types of senescent cells in cardiovascular diseases, followed by the illustration figure1.
2. Suggestion on adding a paragraph shortly connect and compare senescence, autophagy, and apoptosis in the cardiovascular disease pathogenesis.
Author Response
The authors have nicely summarized the important senescence markers, signaling pathways, and potential therapeutic targets of cardiovascular system cells, which is very comprehensive. Just some minor suggestions:
1. Overall, the text is a bit too long, like the table on senescent cell markers, it’ll be nice if the authors can also use a table to list and compare the detrimental effects of certain types of senescent cells in cardiovascular diseases, followed by the illustration figure1.
The detrimental effects of senescent cells in cardiovascular diseases, such as the pathological processes and specific cardiovascular diseases they contribute to, are now summarized in a table.
2. Suggestion on adding a paragraph shortly connect and compare senescence, autophagy, and apoptosis in the cardiovascular disease pathogenesis.
We have highlighted connections among senescence, autophagy, and apoptosis in cardiovascular disease pathogenesis.
Reviewer 2 Report
This is a comprehensive review on the topic of senescent cells in cardiovascular disease by expert authors. The manuscript is clearly written and well organized. I only have one minor comment:The authors discuss the effects of senolytics and justifiably state that there are no long-time observations of potential side effects. However, as these drugs eliminate some non-specific markers, it would be good to at least speculate about the potential effects on homeostasis, especially for senomorphic drugs.
Author Response
We highlighted the lack of knowledge about long-term effects of senotherapies in the revised Conclusion and discussed potential adverse effects, such as suppression of inflammation by some senomorphics.
Reviewer 3 Report
The review is well written and appropriately organized. The information is generally useful however several major conceptual weaknesses are noted.
1) Some of the information is rather general or vague and does not apply specifically to cellular senescence. An example is the description of endothelial cell senescence where such cells exhibit decreased NO and increase proinflammatory molecules. This is a general feature of EC dysfunction induced by a variety of CVD risk factors and not specific for senescent EC’s. The same can be said for the information listed in Table 1. The elements listed are general features of dysfunctional cells and not necessarily related to the senescent phenotype.
2) There is a "what comes first" feature to the senescent process which the authors do not addresses. An example is ROS which is both an initiator and an end product of senescent. Given that many senolytics (flavonoids) target ROS, a discussion of the imitations of therapies in the field should be included in the review.
3) Calorie restriction and exercise enhance health span with an observed reduction in senescent cell burden in many tissues and organs. However, these interventions have multifactorial effects. Given that senescence may, at least initially, function as a protective feature to reduce the capacity of cells to become malignant, one can speculate that reduction of cellular senescence, at least globally, may result in undesirable effects. This concept is not generally discussed in this field and should be considered.
Author Response
The review is well written and appropriately organized. The information is generally useful however several major conceptual weaknesses are noted.
1) Some of the information is rather general or vague and does not apply specifically to cellular senescence. An example is the description of endothelial cell senescence where such cells exhibit decreased NO and increase proinflammatory molecules. This is a general feature of EC dysfunction induced by a variety of CVD risk factors and not specific for senescent EC’s. The same can be said for the information listed in Table 1. The elements listed are general features of dysfunctional cells and not necessarily related to the senescent phenotype.
As pointed out, it is difficult to disentangle effects of senescent cells from those of other potentially dysfunctional cells. Therefore, it is necessary to profile cellular senescence using a combination of several senescence markers. We added the point that senescent cells can exhibit the characteristics of non-senescent dysfunctional cells and that senescent cells may contribute to CVD pathogenesis by mechanisms similar to other types of dysfunctional cells. We also added a sentence to clarify differences between senescent and non-senescent dysfunctional cells.
2) There is a "what comes first" feature to the senescent process which the authors do not address. An example is ROS, which is both an initiator and an end product of senescent. Given that many senolytics (flavonoids) target ROS, a discussion of the imitations of therapies in the field should be included in the review.
We agree there are many possible initiators of senescence, such as telomeric dysfunction, DNA damage, oncogenes, and ROS, which were briefly described in the Molecular Mechanism section and now added more discussion regarding initiators of cellular senescence, including beneficial effects of continuous administration of flavonols beyond any senolytic effects, such as antioxidant activity.
3) Calorie restriction and exercise enhance health span with an observed reduction in senescent cell burden in many tissues and organs. However, these interventions have multifactorial effects. Given that senescence may, at least initially, function as a protective feature to reduce the capacity of cells to become malignant, one can speculate that reduction of cellular senescence, at least globally, may result in undesirable effects. This concept is not generally discussed in this field and should be considered.
We agree and added discussion about this.
Reviewer 4 Report
The review is very comprehensive and properly focused on cardiovascular system and its cell types. It cites relevant studies extensively and is easy to read. I have only minor suggestions for modifications.
1. Compared to other sections, the progenitor cell paragraph is not balanced. There is not much data on these cells, partly due to the controversy in the identification and function of cardiac progenitor cells. The same also applies to endothelial progenitor cells. Thus, the senescence studies on these cells are scarce and conclusions are difficult to draw. I suggest that the authors comment on this in the end of the paragraph.
2. Exercise has been suggested to have potential senolytic effects in different tissues. This could be mentioned when discussing potential senolytic options.
Author Response
The review is very comprehensive and properly focused on cardiovascular system and its cell types. It cites relevant studies extensively and is easy to read. I have only minor suggestions for modifications.
1.Compared to other sections, the progenitor cell paragraph is not balanced. There is not much data on these cells, partly due to the controversy in the identification and function of cardiac progenitor cells. The same also applies to endothelial progenitor cells. Thus, the senescence studies on these cells are scarce and conclusions are difficult to draw. I suggest that the authors comment on this in the end of the paragraph.
We agree that is controversy regarding senescence in progenitor cells and have added comments to the paragraph.
2.Exercise has been suggested to have potential senolytic effects in different tissues. This could be mentioned when discussing potential senolytic options.
We addressed this in the Discussion.
Round 2
Reviewer 3 Report
no comment
