Glutathione in Our Diet and Its Role in the Body: From Disease Prevention to Anti-Aging

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Suggestions to Improve the Manuscript

1. The Introduction should define the main objective more clearly and earlier. The distinction between dietary glutathione, endogenous synthesis, and supplementation could also be introduced more directly.
2. The Methods section requires more detail. The literature search strategy should include clearer inclusion/exclusion criteria, search period, and justification for selecting 97 articles from the initial 366 records.
3. Some claims are presented too strongly considering the current level of evidence. Statements related to “anti-aging,” lifespan extension, and disease prevention should be phrased more cautiously, especially where human clinical evidence remains limited.
4. The manuscript would benefit from a clearer distinction between evidence from in vitro, animal, and human studies. At times, findings from experimental models are discussed as if they were directly applicable to humans.
5. Terminology and grammar should be revised carefully throughout the manuscript. There are several language inconsistencies, long sentences, and grammatical issues that reduce clarity and flow.
6. The section on glutathione supplements should discuss bioavailability limitations more critically and consistently, particularly regarding oral glutathione versus precursor-based approaches.
7. The Discussion could be strengthened by addressing unresolved controversies in the field, including variability in supplementation outcomes and the limited long-term clinical evidence.
8. The Conclusion is generally strong but could be more concise and focused on practical take-home points, particularly regarding dietary strategies versus supplementation for maintaining glutathione levels.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions corrections highlighted in green in the re-submitted file.

1. The Introduction should define the main objective more clearly and earlier. The distinction between dietary glutathione, endogenous synthesis, and supplementation could also be introduced more directly.      Response: Thank you for the suggestion; we have added a clear main objective earlier and it explicitly distinguishes three approaches: dietary GSH, endogenous synthesis, and supplementation
2. The Methods section requires more detail. The literature search strategy should include clearer inclusion/exclusion criteria, search period, and justification for selecting 97 articles from the initial 366 records.   Response: Thank you for the advice; we have reorganized the Methods section according to your suggestion. We also expanded our search and added several sources. 
3. Some claims are presented too strongly considering the current level of evidence. Statements related to “anti-aging,” lifespan extension, and disease prevention should be phrased more cautiously, especially where human clinical evidence remains limited.  Response: We agree. We changed section title from "Skin Health and Anti-Aging" to "Skin Health and Effects on Aging Markers". We also changed some of the formulations in the text: instead of “proven by studies,” we wrote “several studies have shown.” 
4. The manuscript would benefit from a clearer distinction between evidence from in vitro, animal, and human studies. At times, findings from experimental models are discussed as if they were directly applicable to humans.  Response: We specified which studies we relied on, and when discussing supplements, we included a new section in which we discussed only studies involving humans. We also added a Table No 3. 
5. Terminology and grammar should be revised carefully throughout the manuscript. There are several language inconsistencies, long sentences, and grammatical issues that reduce clarity and flow.  Response: Thank you for your comment; the text has been reviewed by an English language specialist. 
6. The section on glutathione supplements should discuss bioavailability limitations more critically and consistently, particularly regarding oral glutathione versus precursor-based approaches. Response: We included a new section in which we discussed only supplements and added new section 3.3. Absorption, Metabolism, and Bioavailability of Oral GSH
7. The Discussion could be strengthened by addressing unresolved controversies in the field, including variability in supplementation outcomes and the limited long-term clinical evidence.  Response: We added new section 3.3. Absorption, Metabolism, and Bioavailability of Oral GSH. 
8. The Conclusion is generally strong but could be more concise and focused on practical take-home points, particularly regarding dietary strategies versus supplementation for maintaining glutathione levels.. Response: Thank you for the suggestion; we have added a section before the conclusions: 3.3.4. Practical Recommendations for Maintaining Adequate GSH. We've made the conclusions a little more specific. 
   
   

Reviewer 2 Report

Comments and Suggestions for Authors

This review summarizes the functions of GSH in the body, GSH in foods, GSH supplements, and nutritional components that may help increase GSH. The topic is interesting. GSH is an important molecule related to antioxidant defense, detoxification, immunity, mitochondrial function, neuroprotection, skin health, and aging. Therefore, organizing these topics has some value.

However, in the current manuscript, the beneficial functions of GSH are broadly introduced, but the explanation of how GSH taken from foods or supplements is actually absorbed in the body and how much effect it has is insufficient. In addition, the results of cell studies, animal studies, and human studies are mixed together, making it difficult to understand how much of the evidence can be applied to humans.

 

 

Comment 1

This manuscript explains foods rich in GSH and GSH supplements. However, it does not sufficiently explain what happens to orally ingested GSH: whether it is degraded in the digestive tract, absorbed as intact GSH, transferred into the blood, or metabolized in the liver.

Even if foods or supplements contain high levels of GSH, this does not necessarily mean that GSH levels in the body will increase. GSH may be degraded in the digestive tract, and standard oral GSH may not always be an efficient way to increase body GSH levels.Therefore, the authors should add an independent chapter explaining the absorption, degradation, transfer into the blood, and hepatic metabolism of orally ingested GSH. In addition, a figure showing how orally ingested GSH is processed in the digestive tract, blood, liver, and other tissues would help readers understand this topic more easily.

 

Comment 2

In this manuscript, the authors use expressions such as “GSH levels increased.” However, in some parts, it is unclear where GSH was measured. For example, GSH in plasma, red blood cells, lymphocytes, and the liver have different meanings. Even if GSH slightly increases in the blood, this does not necessarily mean that intracellular GSH has increased throughout the whole body. Therefore, the authors should clearly explain whether orally ingested GSH is transferred into the blood as intact GSH, used mainly in the intestine or liver, or changed only in specific cells or tissues.

 

Comment 3

This manuscript discusses various supplements and related compounds, such as GSH, GlyNAC, NAC, glycine, and γ-glutamylcysteine. However, this information is scattered throughout the text, making it difficult for readers to compare the findings. The authors should summarize human studies on GSH supplements and GSH-related compounds in a table. By organizing information such as participants, study design, dose, duration, measured outcomes, main results, and safety, readers will be able to understand which intervention was effective under which conditions. In particular, it would be useful to compare standard GSH supplements, GlyNAC, NAC, glycine, and γ-glutamylcysteine.

 

Comment 4

In the current manuscript, the results of cell studies, animal studies, and human studies are described in a similar manner. However, these types of evidence have very different meanings. Cell studies are useful for understanding the mechanisms of GSH. However, even if an effect is observed in cells, it does not necessarily mean that the same effect will occur in humans. The same is true for animal studies. Even if an effect is observed in mice or rats, the same result may not occur in humans. Therefore, the authors should separately describe what is known from cell studies, what is known from animal studies, and what is known from human studies for each topic.

 

Comment 5

The manuscript uses strong expressions such as “it has been proven.” However, many effects of GSH have not yet been fully proven. In particular, evidence in humans is still limited for chronic disease prevention, neuroprotection, anti-aging, skin improvement, and supplement effects. Therefore, instead of using strong expressions such as “proven,” the authors should use more careful wording, such as“some human studies have reported.”

 

Comment 6

The manuscript discusses the possible usefulness of GSH and GlyNAC for anti aging. However, the term anti aging gives a strong impression. For example, even if oxidative stress, inflammation, mitochondrial function, walking speed, or other markers are improved, this does not mean that lifespan is extended or that aging itself is stopped. Therefore, the authors should clearly distinguish between improvement of age-related markers and extension of lifespan or suppression of aging itself.

 

Comment 7

This manuscript includes a table of foods containing GSH. This table is useful. However, a high GSH content in foods is not the same as an increase in body GSH after eating those foods. GSH may decrease or be degraded during cooking, processing, storage, digestion, and absorption. Therefore, the authors should discuss not only the GSH content in foods, but also whether this GSH is actually used in the body.

 

Comment 8

GSH can protect normal cells from oxidative stress, but it may also protect cancer cells. High GSH levels in cancer cells may be related to resistance to anticancer drugs. Therefore, the authors should avoid expressions that broadly recommend GSH supplements to the general population. They should describe not only the beneficial effects of GSH, but also the need for caution depending on disease type and treatment status.

 

Comment 9

The manuscript states that the authors searched Taylor & Francis, PubMed, and Google Scholar, reviewed 366 articles, and used 97 articles for analysis. However, it is unclear how these articles were selected. The authors should explain the inclusion criteria, exclusion criteria, search date, types of studies included, and the selection process in more detail.

 

Comment 10

The current conclusion broadly summarizes the beneficial functions of GSH. However, what readers need to know is not only the general fact that GSH is an important molecule. Rather, I think readers need to understand which approach is most realistic and effective in humans: standard GSH supplements, GSH-containing foods, GSH precursors, or Nrf2-activating compounds. Therefore, the conclusion should summarize not only the benefits of GSH, but also the limitations of oral GSH, the lack of sufficient human studies, the potential of precursor-based strategies, and safety considerations in a balanced manner.

Comments on the Quality of English Language

There are grammatical errors, unnatural English expressions, inconsistent abbreviations, and typographical errors throughout the manuscript. In particular, the inconsistent use of GSH and SGH should be corrected. If there are many such errors, readers may also become concerned about the content itself. The manuscript should undergo English editing and terminology standardization before publication.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions corrections highlighted in green in the re-submitted file.

Comment 1

This manuscript explains foods rich in GSH and GSH supplements. However, it does not sufficiently explain what happens to orally ingested GSH: whether it is degraded in the digestive tract, absorbed as intact GSH, transferred into the blood, or metabolized in the liver.

Even if foods or supplements contain high levels of GSH, this does not necessarily mean that GSH levels in the body will increase. GSH may be degraded in the digestive tract, and standard oral GSH may not always be an efficient way to increase body GSH levels. Therefore, the authors should add an independent chapter explaining the absorption, degradation, transfer into the blood, and hepatic metabolism of orally ingested GSH. In addition, a figure showing how orally ingested GSH is processed in the digestive tract, blood, liver, and other tissues would help readers understand this topic more easily.

Response: Thank you for the suggestion.We included a new section in which we discussed only supplements and added new section 3.3. Absorption, Metabolism, and Bioavailability of Oral GSH.

Comment 2

In this manuscript, the authors use expressions such as “GSH levels increased.” However, in some parts, it is unclear where GSH was measured. For example, GSH in plasma, red blood cells, lymphocytes, and the liver have different meanings. Even if GSH slightly increases in the blood, this does not necessarily mean that intracellular GSH has increased throughout the whole body. Therefore, the authors should clearly explain whether orally ingested GSH is transferred into the blood as intact GSH, used mainly in the intestine or liver, or changed only in specific cells or tissues. 

Response: Thank you for the notice. We have provided more accurate information in the text

Comment 3

This manuscript discusses various supplements and related compounds, such as GSH, GlyNAC, NAC, glycine, and γ-glutamylcysteine. However, this information is scattered throughout the text, making it difficult for readers to compare the findings. The authors should summarize human studies on GSH supplements and GSH-related compounds in a table. By organizing information such as participants, study design, dose, duration, measured outcomes, main results, and safety, readers will be able to understand which intervention was effective under which conditions. In particular, it would be useful to compare standard GSH supplements, GlyNAC, NAC, glycine, and γ-glutamylcysteine.

Response: We agree. When discussing supplements, we included a new section in which we discussed only studies involving humans. We also added a Table No 3.  Different Supplementation Strategies and GSH Response

Comment 4

In the current manuscript, the results of cell studies, animal studies, and human studies are described in a similar manner. However, these types of evidence have very different meanings. Cell studies are useful for understanding the mechanisms of GSH. However, even if an effect is observed in cells, it does not necessarily mean that the same effect will occur in humans. The same is true for animal studies. Even if an effect is observed in mice or rats, the same result may not occur in humans. Therefore, the authors should separately describe what is known from cell studies, what is known from animal studies, and what is known from human studies for each topic.

Response: Thanks for a comment. We specified which studies we relied on

Comment 5

The manuscript uses strong expressions such as “it has been proven.” However, many effects of GSH have not yet been fully proven. In particular, evidence in humans is still limited for chronic disease prevention, neuroprotection, anti-aging, skin improvement, and supplement effects. Therefore, instead of using strong expressions such as “proven,” the authors should use more careful wording, such as“some human studies have reported.”

Response: We agree.  We changed some of the formulations in the text: instead of “proven by studies,” we wrote “several studies have shown.” 

Comment 6

The manuscript discusses the possible usefulness of GSH and GlyNAC for anti aging. However, the term anti aging gives a strong impression. For example, even if oxidative stress, inflammation, mitochondrial function, walking speed, or other markers are improved, this does not mean that lifespan is extended or that aging itself is stopped. Therefore, the authors should clearly distinguish between improvement of age-related markers and extension of lifespan or suppression of aging itself.

Response: We agree. We changed section title from "Skin Health and Anti-Aging" to "Skin Health and Effects on Aging Markers".

Comment 7

This manuscript includes a table of foods containing GSH. This table is useful. However, a high GSH content in foods is not the same as an increase in body GSH after eating those foods. GSH may decrease or be degraded during cooking, processing, storage, digestion, and absorption. Therefore, the authors should discuss not only the GSH content in foods, but also whether this GSH is actually used in the body.

Response: We have included a few notes at the end of the chapter and a new  section 3.3. Absorption, Metabolism, and Bioavailability of Oral GSH.

Comment 8

GSH can protect normal cells from oxidative stress, but it may also protect cancer cells. High GSH levels in cancer cells may be related to resistance to anticancer drugs. Therefore, the authors should avoid expressions that broadly recommend GSH supplements to the general population. They should describe not only the beneficial effects of GSH, but also the need for caution depending on disease type and treatment status.

Response: We have been discussed this in the first version of article (407-411 lanes now). We also noted this in the part of Practical Recommendations. 

Comment 9

The manuscript states that the authors searched Taylor & Francis, PubMed, and Google Scholar, reviewed 366 articles, and used 97 articles for analysis. However, it is unclear how these articles were selected. The authors should explain the inclusion criteria, exclusion criteria, search date, types of studies included, and the selection process in more detail.

Response: Thank you for the advice; we have reorganized the Methods section according to your suggestion. We also expanded our search and added several sources. 

 Comment 10

The current conclusion broadly summarizes the beneficial functions of GSH. However, what readers need to know is not only the general fact that GSH is an important molecule. Rather, I think readers need to understand which approach is most realistic and effective in humans: standard GSH supplements, GSH-containing foods, GSH precursors, or Nrf2-activating compounds. Therefore, the conclusion should summarize not only the benefits of GSH, but also the limitations of oral GSH, the lack of sufficient human studies, the potential of precursor-based strategies, and safety considerations in a balanced manner. 

Response: Thank you for your comment. We have reviewed the abbreviations and updated the list ; the text has been reviewed by an English language specialist. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have adequately addressed the comments through clearer presentation of the study objective, improved methodological description, and a more balanced interpretation of the current evidence. The revised manuscript now better distinguishes between experimental and human data, provides a more critical discussion of glutathione supplementation and bioavailability, and improves the overall clarity and scientific rigor of the review.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have appropriately improved the manuscript as much as possible.
I appreciate the authors’ revisions.
I recommend acceptance of this version.