Resveratrol and Extra Virgin Olive Oil: Protective Agents Against Age-Related Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors provide a review on the potential protective effects of resveratrol and extra virgin olive oil against age-related diseases. This overview highlights their mechanisms of action, health benefits, and the scientific evidence supporting their roles in promoting longevity and cognitive health. It was concluded that incorporating these compounds into a balanced diet may offer significant benefits for aging populations, supporting cognitive health and reducing the risk of chronic diseases. Furthermore, continued research is essential to fully understand their mechanisms and optimize their use in clinical settings. Future research should focus on investigating the synergistic effects of resveratrol and EVOO when consumed together, as they may enhance each other's bioavailability and efficacy in promoting health; conducting extensive clinical trials to confirm the long-term benefits of these compounds in various populations, particularly in aging individuals; further exploring the molecular pathways through which resveratrol and EVOO exert their effects, including their interactions with gut microbiota and metabolic pathways. This review is interesting and fairly straightforward. It is concise, good structure and pertinent references are cited. However, I have some recommendations for consideration.    

1.      Figure 2. In my opinion, this figure would be better represented by a Venn diagram. This will be more appropriate to depict overlapping and unique mechanistic features of resveratrol and EVOO.

2.      The authors should elaborate on the synergistic effects of resveratrol and EVOO particularly since both agents operate through similar mechanisms.

3.      It would be very helpful to provide a summary table of preclinical and clinical lines of evidence including disease site, dosage/treatment regimen etc.  

4.      It would also be helpful to the reader if a figure depicting sites of action of both resveratrol and EVOO can be provided.

5.      The authors need to elaborate and emphasize the novelty aspect of their review findings.

Author Response

Thank you for your thoughtful review and constructive comments on our manuscript regarding the protective effects of resveratrol and EVOO against age-related diseases. We appreciate your insights and recommendations, which will enhance the clarity and depth of our review. Below, we address each of your suggestions in detail:

1. Figure 2 Representation: We agree that a Venn diagram would effectively illustrate the overlapping and unique mechanistic features of resveratrol and EVOO, and we added a Figure 3 to present the information more clearly, highlighting the shared pathways and distinct actions of both compounds. At the same time, we think that Figure 2 is also plaing its still needed, as it demonstrates not mechanisms, but effects of the compounds.

2. Synergistic Effects Elaboration: We acknowledge the importance of discussing the synergistic effects of resveratrol and EVOO, particularly given their similar mechanisms of action, and we expand this section including figure 3, and also updated a whole manuscript with some additional findings.

3. Summary Table of Evidence: we decided to add doses in text where it was possible. Our primary goal is to maintain the conciseness and readability of the review, and incorporating dosage information within the relevant sections of the text, we can emphasize on mechanisms and effects of resveratrol and EVOO.

4. Figure Depicting Sites of Action: We hope that Figure 3 is appropriate.

5. Emphasizing Novelty: We recognize the need to highlight the novelty of our findings more explicitly. In our revision, we added more data on negative outcomes to make the text more unbiased, and broadened the discussion on the approaches to improve resveratrol bioavailability 

We believe that these revisions will strengthen our manuscript significantly and provide readers with clearer insights into the potential benefits of incorporating resveratrol and EVOO into a balanced diet for aging populations. Thank you once again for your valuable feedback; we look forward to submitting an improved version of our manuscript that addresses all your recommendations.

Reviewer 2 Report

Comments and Suggestions for Authors

The review provides an overview of the potential of resveratrol and extra virgin olive oil as therapeutic agents against age-related diseases. Its strength lies in its detailed mechanistic explanations and integration of clinical evidence, but it is limited by a lack of critical analysis, redundancy and insufficient discussion of translational challenges. Therefore, I believe the article lacks an element of novelty given the number of review articles summarising the various health benefits, particularly focusing on the antioxidant, anti-inflammatory and sirtuin-activating properties of resveratrol and EVOO polyphenols.

Future iterations should aim to provide a more nuanced discussion of resveratrol's efficacy, practical limitations and applicability to different populations.

Specific comments:

- In the abstract, the Authors list the keywords and databases they used. This is not a systematic review written in accordance with PRISMA (Preferred reporting items for systematic reviews and meta-analyses) systematic review, so such information is unnecessary in the article and especially in the abstract.

- The article is not formatted according to the requirements of the journal and contains editorial errors (e.g. lines 342 and 749: Error! Reference source not found.)

- In my opinion, there are too few figures in the review to illustrate the mechanisms of action of resveratrol and EVOO, and Figure 2 is of poor quality.

- The literature is not formatted according to the journal's requirements.

- Although the article is detailed, it tends to present results uncritically, often highlighting positive results without adequately addressing conflicting results. For example, although some studies show cognitive benefits from resveratrol, the article downplays inconsistencies in the data, such as studies reporting no significant improvements in certain populations.

- The focus on SIRT1 as the primary mechanism of action of resveratrol risks oversimplifying the effects of resveratrol. Recent research suggests that resveratrol interacts with numerous molecular targets beyond sirtuins, such as AMPK and the estrogen receptor. The article could benefit from a broader exploration of these pathways.

- Although the article mentions the low bioavailability of resveratrol, it does not explore in detail strategies to overcome this limitation. Nanotechnology, conjugation with lipids or combination therapies could be discussed as potential solutions.

- Certain sections, such as the discussion of reproductive health, lack the depth and clarity of other parts of the article. While the sections on neuroprotection and cardiovascular health are robust, the section on reproductive health relies on limited evidence and does not adequately address the variability in outcomes reported across studies.

 

- There is considerable overlap between sections discussing similar mechanisms. For example, the repeated emphasis on the antioxidant and anti-inflammatory properties of resveratrol in different health areas makes the narrative somewhat redundant.

Author Response

Thank you for your thoughtful and constructive feedback on our review regarding the potential of resveratrol and EVOO as therapeutic agents against age-related diseases. We acknowledge your concerns about the lack of critical analysis and the need for a more nuanced discussion of resveratrol's efficacy, practical limitations, and applicability to different populations. 

1. Keywords and Databases in Abstract: We appreciate your observation regarding the inclusion of keywords and databases in the abstract. We removed this information.

2. Formatting and Editorial Errors: We apologize for any formatting issues and editorial errors present in the manuscript. We do not see such problems in our versions even after all fields are refreshed, so we suggest it was a technical problem.

3. Figures Quality and Quantity: We added an additional figure depicting action mechanism and uploaded a pdf version of hi-res figures.

4. Literature Formatting: as we suggest, there was a technical error (if the problem was in references found in (1), but not in [1]).

5. Critical Analysis of Results: We appreciate your feedback regarding the presentation of results. In our revisions, we included a more critical analysis by highlighting conflicting data, either on resveratrol, or EVOO.

6. Broader Mechanistic Exploration: We agree that focusing solely on SIRT1 oversimplifies resveratrol's effects. We expanded our discussion and included other molecular targets such as AMPK and estrogen receptors, providing a more comprehensive overview of resveratrol's mechanisms of action.

7. Strategies to Overcome Bioavailability Issues: We acknowledge that while we mentioned low bioavailability, we did not explore strategies to address this limitation in sufficient detail, and we included a discussion in an updated version.

8-9. Depth of Discussion and overlaps: We appreciate your feedback, and we revised a manuscript adressing the previous commentaries.

We believe that these revisions will significantly strengthen our manuscript by enhancing its critical analysis and depth while addressing your valuable suggestions. Thank you once again for your insightful comments; we look forward to submitting an improved version that meets your expectations and those of the journal's readership.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed all concerns and have adequately revised their manuscript. I have no further comments.

Author Response

Thank you for your positive feedback on our manuscript. We greatly appreciate your acknowledgment of the revisions we made in response to your initial concerns.

Thank you once again for your time and support!

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have corrected the article according to the reviewer's requirements, only the References section is still not presented according to the journal's requirements.

Author Response

Thank you for your constructive feedback on our manuscript. We apologize for the oversight regarding the References section. We found MDPI guideline and revised the formatting accordingly.

Thank you for your attention to detail and for helping us improve our work! We look forward to submitting the revised manuscript shortly.