Effects of taurine supplementation on metabolic health and biological aging in healthcare workers: A protocol for a triple-blinded, Bayesian-optimized phase II randomized controlled trial

Mandy H. M. Chu; Jacky K. M. Lai; Anna Lee; William K. K. Wu; Ziheng Huang; Henry M. K. Wong; Laptin Ho; Hao Su; Samantha S. M. Ho; Xinbo Xu; Warren Pavey; David J. R. Morgan; Matthew T. V. Chan; Kwok M. Ho

doi:10.1371/journal.pone.0350389

Peer Review History

Original SubmissionOctober 13, 2025
7 May 2026 Decision Letter - Diego García-Ayuso, Editor -->PONE-D-25-52928-->-->Effects of Taurine Supplementation on Metabolic Health and Biological Aging in Healthcare Workers: A Protocol for a Triple-blinded, Bayesian-Optimized Phase II Randomized Controlled Trial-->-->PLOS One Dear Dr. Ho, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jun 21 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:--> A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. --> If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors. We look forward to receiving your revised manuscript. Kind regards, Diego García-Ayuso, PhD Academic Editor PLOS One Journal Requirements: -->1. When submitting your revision, we need you to address these additional requirements.-->--> -->-->Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at -->-->https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and -->-->https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf-->--> -->-->2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.-->--> -->-->3. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 4. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: 1. Please revise the Data Availability statement to ensure that it complies with PLOS ONE policy. The current wording indicating that data will be available upon reasonable request should be clarified, including where de-identified participant-level data, data dictionary, statistical code and relevant materials will be deposited or, if restrictions apply, the exact nature of those restrictions. 2. Please ensure that statements are moderated that may imply that the trial will directly assess ageing-related diseases or establish taurine as an intervention for healthy ageing. The study appears to have been primarily designed to evaluate metabolic health markers, biological/phenotypic age indicators and related exploratory outcomes in healthcare workers. 3. Please clarify in the manuscript that, as a study protocol, no trial results are expected at this stage. The abstract "Results" section should be restricted to planned outcomes or anticipated reporting, ensuring that it does not convey the impression that results are already available. 4. Please check the manuscript and supplementary materials for minor issues with wording and formatting. Please ensure that 'Enrolment' is used consistently in Figure 1 and that the apparent stray 'F' in Table 1 under the AGEs section is corrected. 5. It is essential to clearly distinguish all secondary and exploratory outcomes, with particular attention to the microbiome, BDNF, mental health, IPAQ/CESD-R and PhenoAge-related analyses. -->--> -->-->[Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions--> -->Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.--> Reviewer #1: Yes Reviewer #2: No ******** -->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.--> Reviewer #1: Yes Reviewer #2: Yes ****** -->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.--> Reviewer #1: Yes Reviewer #2: Yes ****** -->4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: No Reviewer #2: No ****** -->5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes Reviewer #2: No ****** -->6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: Lovely description of a study, with a clear indication of the statistical Bayesian design used. Consider Enrolment in Figure 1 rather than Enrollment Reviewer #2: The manuscript entitled “Effects of Taurine Supplementation on Metabolic Health and Biological Aging in Healthcare Workers: A Protocol for a Triple-blinded, Bayesian-Optimized Phase II Randomized Controlled Trial” written by Mandy Hiu Man Chu and colleagues PROPOSES a clinical trial investigating the effects of taurine supplementation on glucose metabolisms in healthcare workers. Therapeutic avenues offered by taurine are interesting and promising hot scientific topics. However, the manuscript exhibits two main flaws: 1/ This study aims at investigating the effects of taurine supplementation on ageing-related diseases. But ageing is not systematically and strictly associated with a metabolic syndrome. Here, the main outcomes are HbA1c concentrations plasma lipid levels. But these parameters are more relevant for metabolic syndrome than ageing-related diseases. Furthermore, metabolic syndrome is mainly caused by “the lifestyle” (diet, exercise) than by ageing. 2/ There is no chapter which aims at presenting the results ? This is a scientific study which is a scientific project. Is a Scientific project able to be published in Plos one ? Although authors aim at publishing a “protocol”, is Plos One the relevant journal, and what is original in this protocol project? Consequently, this manuscript cannot be accepted in this form and could be resubmitted when results are available. ****** -->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.--> Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. --> https://doi.org/10.1371/journal.pone.0350389.r001
Revision 1
7 May 2026 Author Response May 8, 2026 Diego García-Ayuso, PhD Academic Editor PLOS One Dear Dr García-Ayuso, Thank you for your decision letter dated May 8, 2026, and for the reviewers’ constructive comments. We have revised the manuscript accordingly. Below, we provide a point-by-point response outlining the changes made. Additional Editor Comments: 1. Please revise the Data Availability statement to ensure that it complies with PLOS ONE policy. The current wording indicating that data will be available upon reasonable request should be clarified, including where de-identified participant-level data, data dictionary, statistical code and relevant materials will be deposited or, if restrictions apply, the exact nature of those restrictions. Response: We have revised our data sharing plan as follows: “Study investigators will retain primary rights to the use of the study data. Upon reasonable request to the corresponding author, the study protocol, as well as de-identified raw and summary data, will be made available. In addition, the original, unprocessed data will be published in Mendeley Data following publication of the study results. Data sharing will comply with standard confidentiality requirements; no information that could identify individuals, compromise national security, or interfere with legal processes will be disclosed.” 2. Please ensure that statements are moderated that may imply that the trial will directly assess ageing-related diseases or establish taurine as an intervention for healthy ageing. The study appears to have been primarily designed to evaluate metabolic health markers, biological/phenotypic age indicators and related exploratory outcomes in healthcare workers. Response: This is an important suggestion. We have revised our abstract as well as different parts of the manuscript, in particular the background, to focus our topic primarily around metabolic health instead of healthy aging in general. 3. Please clarify in the manuscript that, as a study protocol, no trial results are expected at this stage. The abstract "Results" section should be restricted to planned outcomes or anticipated reporting, ensuring that it does not convey the impression that results are already available. Response: We have changed the word “Results” to “Outcomes” to avoid misleading the readers that results are already available. 4. Please check the manuscript and supplementary materials for minor issues with wording and formatting. Please ensure that 'Enrolment' is used consistently in Figure 1 and that the apparent stray 'F' in Table 1 under the AGEs section is corrected. Response: We have corrected the error in Table 1: Advanced glycation end-products (AGEs): Non-invasive skin autofluorescence (by the AGE® reader); plasma methylglyoxal level (by ELISA). We have not changed the enrollment in Figure 1 to enrolment because we have used American English throughout the manuscript (versus enrolment in British English). 5. It is essential to clearly distinguish all secondary and exploratory outcomes, with particular attention to the microbiome, BDNF, mental health, IPAQ/CESD-R and PhenoAge-related analyses. Response: We have revised Table 1 to separate secondary and exploratory outcomes in the revised manuscript. Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: No Response: We have revised the Background section to strengthen the rationale for testing the potential metabolic health benefits of taurine. __________________________________ 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes Response: We understand this is a phase II trial and have separated secondary and exploratory outcomes to suggest that secondary and exploratory outcomes are hypothesis-generating instead of being definitive. ________________________________________ 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes Response: We have completed the enrollment of the target 80 participants with only one participant had adverse gastrointestinal side effects requiring cessation of the ongoing intake of the study capsules. The trial intervention remains blinded currently and we are not sure whether this participant was taking placebo or taurine. Because of the fast enrollment rate, we did not have the change to execute interim analysis so far. ________________________________________ 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: No Response: We have revised our data sharing plan as follows: “Study investigators will retain primary rights to the use of the study data. Upon reasonable request to the corresponding author, the study protocol, as well as de-identified raw and summary data, will be made available. In addition, the original, unprocessed data will be published in Mendeley Data following publication of the study results. Data sharing will comply with standard confidentiality requirements; no information that could identify individuals, compromise national security, or interfere with legal processes will be disclosed.” _____________________________ 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No Response: We have revised our manuscript for stylistic and grammatical improvement and we believe this has improved the clarity of the manuscript. ________________________________________ 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Lovely description of a study, with a clear indication of the statistical Bayesian design used. Response: Thank you for our time to review our work. Consider Enrolment in Figure 1 rather than Enrollment Response: We have not changed the enrollment in Figure 1 to enrolment because we have used American English throughout the manuscript (versus enrolment in British English). Reviewer #2: The manuscript entitled “Effects of Taurine Supplementation on Metabolic Health and Biological Aging in Healthcare Workers: A Protocol for a Triple-blinded, Bayesian-Optimized Phase II Randomized Controlled Trial” written by Mandy Hiu Man Chu and colleagues PROPOSES a clinical trial investigating the effects of taurine supplementation on glucose metabolisms in healthcare workers. Therapeutic avenues offered by taurine are interesting and promising hot scientific topics. However, the manuscript exhibits two main flaws: 1/ This study aims at investigating the effects of taurine supplementation on ageing-related diseases. But ageing is not systematically and strictly associated with a metabolic syndrome. Here, the main outcomes are HbA1c concentrations, plasma lipid levels. But these parameters are more relevant for metabolic syndrome than ageing-related diseases. Furthermore, metabolic syndrome is mainly caused by “the lifestyle” (diet, exercise) than by ageing. Response: This is an important suggestion. We have extensively revised our abstract as well as different parts of the manuscript, in particular the background, to focus our topic primarily around metabolic health instead of healthy aging in general. That said, growing evidence suggests that many lifestyle factors are related to health aging (or a back of it, resulting in accelerated biological aging), 2/ There is no chapter which aims at presenting the results? This is a scientific study which is a scientific project. Is a Scientific project able to be published in Plos one? Although authors aim at publishing a “protocol”, is Plos One the relevant journal, and what is original in this protocol project? Consequently, this manuscript cannot be accepted in this form and could be resubmitted when results are available. Response: We believe PLOS One specifically welcomes publication of protocols and it is widely recommended to have the study protocol published before analysis of the results for transparency reasons. We expect completion of 6-month follow up of the last enrolled participant by September 2026 and will have the full results by late 2026 or early 2027. It is, therefore, important to publish the trial protocol before September 2026 when we will analyze the results. ________________________________________ 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ________________________________________ Thank you very much again for all the constructive comments and suggestions which have substantially improved our manuscript. Yours sincerely, KM Professor Kwok M. Ho on behalf of all authors Attachments Attachment Submitted filename: Response to Editor and Reviewers comments.PLOS.One.docx https://doi.org/10.1371/journal.pone.0350389.r002
13 May 2026 Decision Letter - Diego García-Ayuso, Editor Effects of Taurine Supplementation on Metabolic Health and Biological Aging in Healthcare Workers: A Protocol for a Triple-blinded, Bayesian-optimized Phase II Randomized Controlled Trial PONE-D-25-52928R1 Dear Dr. Ho, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Diego García-Ayuso, PhD Academic Editor PLOS One Additional Editor Comments (optional): Please consider slightly moderating a few narrative expressions related to longevity and healthy aging (e.g., “longevity amino acids”, “flattening the biological age curve”, “cheating death”), in keeping with the neutral tone generally preferred for clinical trial protocols. Reviewers' comments: https://doi.org/10.1371/journal.pone.0350389.r003
Formally Accepted
Acceptance Letter - Diego García-Ayuso, Editor PONE-D-25-52928R1 PLOS One Dear Dr. Ho, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Diego García-Ayuso Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0350389.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .