Mechanistic Roles of Androgen and Estrogen in Aging and Age-Related Diseases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting review article with adequate novelty. Nevertheless, some points should be addressed.

• The type of review should be reported in the abstract (literature, narrative systematic, ...?).
• The authors should add a bit more information concerning SEs, and LLPS (lines 44-47).
• The author should emphasize at the end of the introduction section the literature gap that their review article will cover.
• The authors should clearly state the basic aim of their review article at the end of the introduction section.
• A methods section should be aded after the introduction section including the inclusion and exclusion criteria, the databases used and the keywords used to perform this review article.
• In the 2nd section, the authors should separately describe the association of sex hormones with dementia and cognitive impairment in a first paragraph. Afterwards, the the authors should separately describe the association of sex hormones with frailty and the with cancer.
• The paragraph in section 3 should be split into twosmaller paragraphs.
• A discussion part is missing from the manuscript. In this part the authors should report the most significantfindings from a critical point of view.

Author Response

I appreciate this reviewer’s comments to improve my manuscript. To address the concerns raised by the reviewer, we revised the manuscript by responding to each point.

1. The type of review should be reported in the abstract (literature, narrative systematic, ...?).

This review article is a narrative review article. I describe the type of review in the abstract (P 1, Ln 10).

 

2. The authors should add a bit more information concerning SEs, and LLPS (lines 44-47).

I added more description regarding SEs and LLPS in this paragraph (P 2, Ln 53-61).

 

3. The author should emphasize at the end of the introduction section the literature gap that their review article will cover.

I emphasize the literature gap that this review article will cover (P 2, Ln 70-84). This narrative review aims to provide a comprehensive and critical analysis of the latest research on the mechanistic insights into the action of sex hormone receptors for preventing aging and age-related diseases.

 

4. The authors should clearly state the basic aim of their review article at the end of the introduction section.

I state the aim of my review at the end of the introduction section (P2, Ln 70-72, 77-84). Our goal is to investigate how the molecular mechanisms of ER or AR and their target genes are involved in in various tissue function including prevention of osteoporosis, maintenance of muscle function, and preservation of neurocognitive function in order to gain a better understanding of the intricate relationship between biological and healthy aging.

 

5. A methods section should be added after the introduction section including the inclusion and exclusion criteria, the databases used and the keywords used to perform this review article.

I made a new methods section in the revised manuscript (P 2-3, Ln 85-119). Information about the inclusion and exclusion criteria and the keywords to find useful studies referenced in this article were included in this section.

 

6. In the 2nd section, the authors should separately describe the association of sex hormones with dementia and cognitive impairment in a first paragraph. Afterwards, the authors should separately describe the association of sex hormones with frailty and the with cancer.

In response to the comments, I made two paragraphs in this section. I described the association of sex hormones with dementia and impairment in the first paragraph (P 3, Ln121-134). Then, I describe the association with frailty and sarcopenia (P 4, Ln 135-139), and the effects of hormone deprivation therapy for cancer treatment, as the reviewer suggested (P 4, Ln 139-163).

 

7. The paragraph in section 3 should be split into two smaller paragraphs.

As the reviewer indicated, I split this section into two paragraphs (P 4, Ln 164-185, Ln 186-196).

 

8. A discussion part is missing from the manuscript. In this part the authors should report the most significant findings from a critical point of view.

As the reviewer advised, I made a discussion part. I described the most significant findings about molecular and tissue specific hormone receptor function, the roles of sex hormone in dementia, the involvement of RBD for sex hormone action (P 16, Ln 555-629).

Reviewer 2 Report

Comments and Suggestions for Authors

Hormonal changes, especially the decrease in androgens and estrogens, are associated with the aging process.  These sex hormones are essential for immunological response, metabolism, and muscular maintenance, among other physiological functions.  The need for more individualized methods to hormonal interventions is shown by the variation in human hormone replacement therapy efficacy (10.3389/fphar.2018.01162; 10.3390/jpm11040311).

Even if it is a narrative review, a paragraph about methods is needed: specify search terms, database consulted, inclusion and exclusion criteria, presence of MeSH terms, and so on.

 

Author Response

I appreciate this reviewer’s comments to improve my manuscript. To address the concerns raised by the reviewer, we revised the manuscript by responding to each point.

1. Hormonal changes, especially the decrease in androgens and estrogens, are associated with the aging process. These sex hormones are essential for immunological response, metabolism, and muscular maintenance, among other physiological functions. The need for more individualized methods to hormonal interventions is shown by the variation in human hormone replacement therapy efficacy (10.3389/fphar.2018.01162; 10.3390/jpm11040311).

To address the concern, I additionally proposed the potential individualized methods to hormonal interventions by using anti-oxidants such as glutathione, polyphenol, dietary minerals, and vitamin E. I added this paper to the references (P 18, Ln 650-654).

 

2. Even if it is a narrative review, a paragraph about methods is needed: specify search terms, database consulted, inclusion and exclusion criteria, presence of MeSH terms, and so on.

I made a new methods section in the revised manuscript. Information about the inclusion and exclusion criteria and the keywords to find useful studies referenced in this article  were included in this section (P 2-3, Ln 85-119).

Reviewer 3 Report

Comments and Suggestions for Authors

The review from Ken-ichi Takayama is very well written, clearly organized and well documented. The role of sex hormones receptors in the regulation of whole body metabolism and function is fundamental and the review clearly present the recent research in the field. 

I have a minor remark regarding the citations, which are not always referenced. For exemple :

- L210 "... accquisition of drug resistance." Ref is missing

- L239 "... modulation of systemic homeostatsis "Ref is missing.

One paragraph is also missing about the negativ effects of AR and ER activation such as cell proliferation and cancer development.

Moreover, the author concludes that "The development of drugs targeting sex hormone pathways holds great promise." This statement must be qualified in light of the proven harmful effects of ERa and AR activation on the development of cancers and/or metabolic diseases.

Author Response

The review from Ken-ichi Takayama is very well written, clearly organized and well documented. The role of sex hormones receptors in the regulation of whole-body metabolism and function is fundamental and the review clearly present the recent research in the field.

I appreciate this reviewer’s comments to improve my manuscript. To address the concerns raised by the reviewer, we revised the manuscript by responding to each point.

1. I have a minor remark regarding the citations, which are not always referenced. For example: -L210 "... accquisition of drug resistance." Ref is missing- L239 "... modulation of systemic homeostatsis "Ref is missing.

I added references for these points and checked the lack of references throughout the manuscript. (Ln 271, Ln 300, and Ln136, 190, 305, 310, 373, 375, 441, 489, 525, 538, 548)

 

2. One paragraph is also missing about the negative effects of AR and ER activation such as cell proliferation and cancer development.

I appreciated the reviewer’s thoughtful comment. I added a paragraph about the negative effect of ER and AR activation in the discussion part (P 18, Ln 630-641).

 

1. Moreover, the author concludes that "The development of drugs targeting sex hormone pathways holds great promise." This statement must be qualified in light of the proven harmful effects of ERa and AR activation on the development of cancers and/or metabolic diseases.

To address the concern, I described the harmful effects of ER and AR activation, cancer and venous thromboembolism risk in the discussion part (P 18, Ln 630- 641).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author has significantly revised and improved his manuscript.