Inflammatory Profile of Older Adults in Response to Physical Activity and Diet Supplementation: A Systematic Review

Round 1

Reviewer 1 Report

The manuscript is badly written.  Formulation is very often confusing.  The manuscript lacks scientific rationalising. You compare apples with bananas;  meaning that supplements of all kinds are compared as being one and the same. The same holds for the exercise part.  Further, in table 1 you do not provide information about control groups related with exercise.   That should be thoroughly updated.

The conclusion is not supported by the data as you self mention in the discussion.

So don't conclude anything positive or negative.  The studies you cite do not give any thorough prove of effects.

 

Author Response

We truly appreciate your contributions. The changes requested can be identified in the new version of our manuscript (ijerph-2217108-R1). They are highlighted in red (corrections and modifications) and in blue (English Editing) along the document, and a point-by-point response is described below while a point-by-point response to your requests is described below:

The manuscript is badly written.  Formulation is very often confusing.  The manuscript lacks scientific rationalising. You compare apples with bananas;  meaning that supplements of all kinds are compared as being one and the same. The same holds for the exercise part.  Further, in table 1 you do not provide information about control groups related with exercise.   That should be thoroughly updated.

R= Your observations were considered, first, the manuscript was reviewed by a native English speaker and editing changes appear in blue within the manuscript. Second, we reorganized the Introduction section to support the scientific rationale and added discussion about kinds of supplements and exercise with inflammation, including the following paragraphs:

Exercise: “Is well known that exercise leads to a robust inflammatory response mainly characterized by the mobilization of leukocytes and an increase in circulating inflammatory mediators produced by immune cells and directly from the active muscle tissue. Both positive and negative effects on immune function and susceptibility to minor illness have been observed following different training protocols [4]. In elderly population the exercise interventions need to be feasible and safe for older patients, in this sense, the most common training protocols include resistance exercise, aerobic training and combined resistance and aerobic training [28]. Most of the studies included in our review included resistance exercise [17,18,20,22], some consisted of combined training [15,21,24] and the last four, consisted on different training approaches [16,19,23,25]. In a recent systematic review comparing the effects of exercise interventions on the inflammatory profile of older adults and found that most consistent exercise effects on inflammation involved the lowering of circulating levels of CRP, IL-6 and TNF-α; which seemed more prominent in healthy older adults compared to those with a specific disease or condition [28]. These results are in agreement with ours, as we found that pro-inflammatory markers IL-6, TNF-α and CRP decrease in six [15,16,17,19,20,23] of the eleven included studies. However, despite the numerous positive effects of physical exercise, some negative physiological changes occur in long-lasting heavy training with transient dysfunction of the immune system, in-creased inflammation, and oxidative stress. To counteract the negative effects of heavy training, reducing acute and chronic inflammations and supporting the immune system, with nutritional and supplementation countermeasures”.

Supplements: “For this purpose, macronutrient (Proteins, amino acids, lipids and carbohydrates) manipulation with an appropriate use of certain supplements can be considered as an intervention to reduce exercise-induced immune changes and inflammatory risk [29]. Exer-cise may cause some injuries in muscles and joints that may increase levels of inflammatory mediators. Experimental evidence suggests that the increased concentrations of pro-inflammatory cytokines observed in chronic inflammation lead to protein degradation through proteasome activation and reduced skeletal muscle protein synthesis (MPS) via protein kinase B/Akt downregulation [30]. Dairy and soy proteins contain all the essential amino acids, demonstrate sufficient absorption kinetics, and include other bioactive pep-tides that may offer nutritional benefits, in addition to those of stimulating MPS, also whey protein has antioxidative effects, because of its ability to enhance the availability of reduced glutathione and the activity of the endogenous antioxidative enzyme system. Soy protein and isoflavone-enriched soy protein, meanwhile, may counteract chronic inflammation through regulation of the NF-kB signaling pathway and cytokine production. Although evidence suggests that whey protein, soy protein, and isoflavone-enriched soy proteins may be promising nutritional interventions against the oxidative stress and chronic inflammation present in pathologic conditions and inflammaging, there is a lack of in-formation about the anabolic potential of dietary protein intake and protein supplementation in elderly people with increased systemic inflammation [30]. In addition, a decrease in the production of pro-inflammatory cytokines has been demonstrated in humans when moderate to high levels of omega-3 polyunsaturated fatty acids are taken [29].

 Furthermore, micronutrients (vitamins C, D) can play an important role in immune function; in particular, counterbalancing the negative effects of oxidative damage due to free radicals. Some of these nutrients have potential anti-inflammatory properties as assessed by the attenuated levels of IL-6, TNF-α and CRP [31]. As mentioned, there is a generalized effect of supplements enriched in protein,  amino acids, fatty acids and vitamins on the decrease of pro-inflammatory cytokines, however the mechanism of action differs between the different types of supplements”.

Finally about control groups related with exercise, not all studies included in this review report information about control groups, this support part of our conclusion referring to the need of design high quality interventions (including the use of control groups) to prove the effects of physical exercise in elderly.

The conclusion is not supported by the data as you self mention in the discussion.

R= Your observation was considered, so we added more data (including Table 3) and discussion (mentioned in the answer to your first comment) to support our conclusion.

So don't conclude anything positive or negative.  The studies you cite do not give any thorough prove of effects.

R= According to your observation, we have modified the Conclusion according to the results and discussion included in the manuscript, resulting in the following statement: “The present systematic review revealed that diet supplementation and physical activity may influence the inflammatory profile in older adults. However, positive, ambiguous or null effects will depend on the specific diet supplementation, the type, time, intensity, and frequency of physical activity realized and the design of the trial (use of control groups, duration, blinding). It is necessary that more controlled trials are performed to confirm the synergistic effect of physical activity and diet supplementation on inflammatory markers expression and regulation in the elderly population”.  

According to your observations and the English language corrections, the article has been improved substantially. We really appreciate your contributions.

Reviewer 2 Report

This systemic review was carried out according to the recommendations and standards established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The authors carried out a comprehensive Internet literature search of the following English databases Scopus, EBSCO, and PubMed, focusing on the studies with RTC protocol. The aim of the study was to evaluate the effect of exercise and dietary supplementation on the inflammatory markers in individuals aged 60 and over.

The manuscript is a well written which may arouse interest especially among gerontologists, however, some paragraphs require correction:

lines 91-92: it was stated that “Interventions of less than four weeks were excluded from the final selection.”. Was there an upper limit?

Interventions lasting more than 26 weeks were not reported. They are mentioned in the abstract (line 22). Were there interventions lasting more than 26 weeks in the analyzed papers?

line 98: I suggest clarification (of course without providing personal data).

line 102: Please clarify what exactly you mean writing “risk of bias”. How it was rated? Give examples.

line 129: “Not adequate study design”. Please clarify and give examples and more detail explanation.

Table 2: Inflammatory markers column: Please use the correct symbol for each marker (↓,↑, NS). Now, only a few ones have such symbols.

Table 2: Exercise column: In every study very different exercises are reported. I wonder if this is in any way comparable in the context of inflammatory markers. Please comment it in the paper.

lines 169-184: I don't think this paragraph is a discussion of the results. Perhaps a better place for this passage would be the Introduction.

lines: 187-191: Please include these details (seven, five, one, two) in Table 2 (Inflammatory markers column). 7+5+1+2=15 and it is not equal 11. The description may be confusing to the reader.

Author Response

We truly appreciate your contributions. The changes requested can be identified in the new version of our manuscript (ijerph-2217108-R1). They are highlighted in red (corrections and modifications) and in blue (English Editing) along the document, and a point-by-point response is described below while a point-by-point response to your requests is described below:

This systemic review was carried out according to the recommendations and standards established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The authors carried out a comprehensive Internet literature search of the following English databases Scopus, EBSCO, and PubMed, focusing on the studies with RTC protocol. The aim of the study was to evaluate the effect of exercise and dietary supplementation on the inflammatory markers in individuals aged 60 and over.

The manuscript is a well written which may arouse interest especially among gerontologists, however, some paragraphs require correction:

lines 91-92: it was stated that “Interventions of less than four weeks were excluded from the final selection.”. Was there an upper limit?

R= There was not an upper limit, only the lower limit was defined according to the minimum recommendations in the scientific literature to improve general fitness. Thanks for your observation.

Interventions lasting more than 26 weeks were not reported. They are mentioned in the abstract (line 22). Were there interventions lasting more than 26 weeks in the analyzed papers?

R= We made a mistake in the abstract, we have corrected to 24 weeks, we apologize for that.

line 98: I suggest clarification (of course without providing personal data).

R= The Cochrane Handbook for systematic reviews suggests that two reviewers  participate in the search and selection of studies to ensure all relevant studies are included in the systematic review. We have added this information and cited the reference in Section 2.3. Thanks for your observation.

line 102: Please clarify what exactly you mean writing “risk of bias”. How it was rated? Give examples.

R= The principal risk of bias considered in randomized trials are focused on the randomization process, bias due to derivations from intended intervention, missing outcome data, or in measurement of the outcome, and in selection of the reported result. Risk of bias was rated according to Cashin & McAuley, (2020) (Ref [14]), classifying the methodological quality of studies. As example we can mention that Almeida et al. (2020) present only methodological quality of 6/10 due they don’t report a baseline comparability of the participants, also they didn’t report any blinding (participants, researchers, or analyst of data. On the other hand, the study of Rondanelli et al. (2016) has an excellent methodological quality due they report the random and concealed allocation; baseline comparability; Triple blinding  (participants; researchers, and analyst of data), they report an adequate follow-up (> 85%); intention-to-treat analysis, between-group statistical comparison, and report point measures and measures of variability.

line 129: “Not adequate study design”. Please clarify and give examples and more detail explanation.

R= The principal not adequate study design considered in this systematic review was the lack of information about control groups in both exercise and supplementation groups. Also, some studies evaluated participants from different ages, and even they report participants over 60 years old, he researchers considered not adequate study design when there didn’t exist statistical analysis by this specific age range due it was the principal outcome of the review.

Table 2: Inflammatory markers column: Please use the correct symbol for each marker (↓,↑, NS). Now, only a few ones have such symbols.

R= We have added a symbol to each marker along the column, thanks for your observation.

Table 2: Exercise column: In every study very different exercises are reported. I wonder if this is in any way comparable in the context of inflammatory markers. Please comment it in the paper.

R= According to your observation, we have added the following paragraph in the Discussion section:

“Is well known that exercise leads to a robust inflammatory response mainly characterized by the mobilization of leukocytes and an increase in circulating inflammatory mediators produced by immune cells and directly from the active muscle tissue. Both positive and negative effects on immune function and susceptibility to minor illness have been observed following different training protocols [4]. In elderly population the exercise interventions need to be feasible and safe for older patients, in this sense, the most common training protocols include resistance exercise, aerobic training and combined resistance and aerobic training [28]. Most of the studies included in our review included resistance exercise [17,18,20,22], some consisted of combined training [15,21,24] and the last four, consisted on different training approaches [16,19,23,25]. In a recent systematic review comparing the effects of exercise interventions on the inflammatory profile of older adults and found that most consistent exercise effects on inflammation involved the lowering of circulating levels of CRP, IL-6 and TNF-α; which seemed more prominent in healthy older adults compared to those with a specific disease or condition [28]. These results are in agreement with ours, as we found that pro-inflammatory markers IL-6, TNF-α and CRP decrease in six [15,16,17,19,20,23] of the eleven included studies. However, despite the numerous positive effects of physical exercise, some negative physiological changes occur in long-lasting heavy training with transient dysfunction of the immune system, in-creased inflammation, and oxidative stress. To counteract the negative effects of heavy training, reducing acute and chronic inflammations and supporting the immune system, with nutritional and supplementation countermeasures”.

lines 169-184: I don't think this paragraph is a discussion of the results. Perhaps a better place for this passage would be the Introduction.

R= Thanks for your observation, the paragraph has been removed form the Discussion section and the principal ideas of this were added to the Introduction section, including the following sentence: “The clinical consequences of inflammaging can be severe and include increased risk of the metabolic syndrome, which includes the triad of hypertension, hyperglycemia and dyslipidemia, type 2 diabetes, cardiovascular disease, chronic kidney disease, cancer, de-pression, neurodegenerative and autoimmune diseases, osteoporosis and sarcopenia [7,8], this reinforces the urgent need to establish treatments or interventions to reduce or avoid factors related to the develop of these pathological conditions”.

lines: 187-191: Please include these details (seven, five, one, two) in Table 2 (Inflammatory markers column). 7+5+1+2=15 and it is not equal 11. The description may be confusing to the reader.

R= According to your comment, we have added a new Table (Table 3) to a better description of the biological sample and technical approach of each study, also we have corrected it for a better understanding for the reader. Thank you.

According to your observations and the English language corrections, the article has been improved substantially. We really appreciate your contributions.

Reviewer 3 Report

Reviewer Recommendation and Comments for Manuscript Number:

ijerph-2217108

 

“Inflammatory Profile of Older Adults in Response to Physical Activity and Diet Supplementation: A Systematic Review”

 

These are my general/specific comments:

 

GENERAL:

 

The current manuscript is very interesting and reviews the pertinent evidence from the current literature conveying the reported phenomenon of “inflammaging”, its occurrence with aging, as well as its response to physical activity and nutritional perturbations. The manuscript was informative and brings the reviewer (and audience) up to date with respect to the current evidence, yet there are relatively minor limitations to the manuscript in its current form.  Overall, the manuscript has marginal/moderate editorial (grammar, language, etc.,) modifications that should easily be addressed. Even though there are limitations in the manuscript’s present form, the authors should be able to address these points for full consideration of acceptance.

 

SPECIFIC:

 

TITLE

1. None

 

ABSTRACT

1. None

 

INTRODUCTION

1. Page 1, Line 34: Add “comma” following “Chronic,” and Add “Hyphen” between “low-grade”. Please modify this descriptor throughout the manuscript for consistency.
2. Page 1, Line 35: Add “and disease” following “health”
3. Page 1, Line 43: Add “may” prior to “develop”
4. Page 1, Line 43: Change “develops” to “develop”
5. Page 2, Line 45: Please provide a Reference(s) here for the initial introduction of “inflammaging”
6. Page 2, Line 46: Throughout the manuscript the authors refer to “inflammaging” in quotations (or not); please be consistent with the use of quotations (or not). Given that inflammaging is an accepted phenomenon in the scientific literature, the authors need only provide the Reference(s) for inflammaging (multiple Refs provided below) there is no need for quotations
1. Peake J, Della Gatta P, Cameron-Smith D. Aging and its effects on inflammation in skeletal muscle at rest and following exercise-induced muscle injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 298:R1485–95.
2. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 2013; 13:875–87.
3. Rader EP and Baker BA. Inflammaging and the age-specific responsiveness to stretch-shortening contractions. Exerc. Sport Sci. Rev., Vol. 45, No. 4, pp. 195–200, 2017.

 

7. Page 2, Line 53: Change “pathway” to “pathways”
8. Page 2, Line 55: Add either “a/the” prior to “relationship”
9. Page 2, Line 56: Change “…it results also in…” to “…to it impacting…”
10. Page 2, Line 60: Change “are” to “is”
11. Page 2, Line 60: Change “autonomy” to “independence”
12. Page 2, Line 61: Change “…health negative…” to “…negative health…”
13. Page 2, Line 65: Delete “practice of”
14. Page 2, Line 71:  Add either “a/the” prior to “main”

 

METHODS and MATERIALS

1.                  Page 2, Line 93: Change “synergic” to “synergistic”

2.                  Page 3, Line 99: Change “duplicated” to “duplicate”

3.                  Page 3, Line 100: Change “previously” to “previous”

 

RESULTS

            None

 

DISCUSSION

1. Page 8, Line 163: Add “with” following “together”
2. Page 8, Line 164: Change “provides” to “provide”
3. Page 8, Line 164: Change “… that even there exist a large number…” to “…that a number…” and Add “exists” following “evidence”
4. Page 8, Line 169: Add “The” prior to “inflammation”
5. Page 8, Line 175: Change to “…chronic, low-grade…” as stated previously by this reviewer
6. Page 8, Line 182: Add “semicolon” following “sarcopenia [27]”
7. Page 8, Line 192: Add “hyphen” following “Chronic”
8. Page 8, Line 195: Change “synergically” to “synergistically”
9. Page 8, Line 202: Change “in the other hand” to “on the other hand”
10. Page 8, Line 205: Change to “…chronic, low-grade…”
11. Page 9, Line 235: Add “comma” following “control”
12. Page 9, Line 249: Add “hyphen” following “pro-“
13. Page 9, Line 257: Change “inflammation” to “inflammatory”
14. Page 10, Line 268: Change “could” to “may”
15. Page 10, Line 269: Change “kind” to “type or specific”
16. Page 10, Line 269: Delete “consumed”
17. Page 10, Line 271: Change “to realized” to “that”
18. Page 10, Line 271: Add “…are performed…” prior to “to confirm”
19. Page 10, Line 271: Change “synergic” to “synergistic”
20. Page 10, Line 272: Change “markers” to “marker”

 

REFERECES

1. None

 

FIGURE LEGENDS/FIGURES

1. None

 

Author Response

We truly appreciate your contributions. The changes requested can be identified in the new version of our manuscript (ijerph-2217108-R1). They are highlighted in red (corrections and modifications) and in blue (English Editing) along the document, and a point-by-point response is described below while a point-by-point response to your requests is described below:

“Inflammatory Profile of Older Adults in Response to Physical Activity and Diet Supplementation: A Systematic Review”

 These are my general/specific comments:

 GENERAL:

 The current manuscript is very interesting and reviews the pertinent evidence from the current literature conveying the reported phenomenon of “inflammaging”, its occurrence with aging, as well as its response to physical activity and nutritional perturbations. The manuscript was informative and brings the reviewer (and audience) up to date with respect to the current evidence, yet there are relatively minor limitations to the manuscript in its current form.  Overall, the manuscript has marginal/moderate editorial (grammar, language, etc.,) modifications that should easily be addressed. Even though there are limitations in the manuscript’s present form, the authors should be able to address these points for full consideration of acceptance.

 SPECIFIC:

 TITLE

1. None

 ABSTRACT

1. None

 INTRODUCTION

1. Page 1, Line 34: Add “comma” following “Chronic,” and Add “Hyphen” between “low-grade”. Please modify this descriptor throughout the manuscript for consistency.

R= Your observation was considered and we corrected this along the document for consistency, thank you.

1. Page 1, Line 35: Add “and disease” following “health”

R= Your recommendation was considered, thank you.

1. Page 1, Line 43: Add “may” prior to “develop”

R= Your recommendation was considered, thank you.

1. Page 1, Line 43: Change “develops” to “develop”

R= Your recommendation was considered, thank you.

1. Page 2, Line 45: Please provide a Reference(s) here for the initial introduction of “inflammaging”

R= The required reference was provided, thank you.

1. Page 2, Line 46: Throughout the manuscript the authors refer to “inflammaging” in quotations (or not); please be consistent with the use of quotations (or not). Given that inflammaging is an accepted phenomenon in the scientific literature, the authors need only provide the Reference(s) for inflammaging (multiple Refs provided below) there is no need for quotations
1. Peake J, Della Gatta P, Cameron-Smith D. Aging and its effects on inflammation in skeletal muscle at rest and following exercise-induced muscle injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 298:R1485–95.
2. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 2013; 13:875–87.
3. Rader EP and Baker BA. Inflammaging and the age-specific responsiveness to stretch-shortening contractions. Exerc. Sport Sci. Rev., Vol. 45, No. 4, pp. 195–200, 2017.

 R= We have eliminated quotations at referring to inflammaging to be consistent along the manuscript, supporting it with a reference provided by you, thank you.

1. Page 2, Line 53: Change “pathway” to “pathways”

R= Your recommendation was considered, thank you.

1. Page 2, Line 55: Add either “a/the” prior to “relationship”

R= This sentence has been modified according to the reviewers recommendation, resulting in the following: “The clinical consequences of inflammaging can be severe and include increased risk of the metabolic syndrome, which includes the triad of hypertension, hyperglycemia and dyslipidemia, type 2 diabetes, cardiovascular disease, chronic kidney disease, cancer, de-pression, neurodegenerative and autoimmune diseases, osteoporosis and sarcopenia [7,8], this reinforces the urgent need to establish treatments or interventions to reduce or avoid factors related to the develop of these pathological conditions”.

1. Page 2, Line 56: Change “…it results also in…” to “…to it impacting…”

R= This sentence has been modified according to the reviewers recommendation, resulting in the sentence mentioned in the last comment, thank you.

1. Page 2, Line 60: Change “are” to “is”

R= Your recommendation was considered, thank you.

1. Page 2, Line 60: Change “autonomy” to “independence”

R= Your recommendation was considered, thank you.

1. Page 2, Line 61: Change “…health negative…” to “…negative health…”

R= Your recommendation was considered, thank you.

1. Page 2, Line 65: Delete “practice of”

R= Your recommendation was considered, thank you.

1. Page 2, Line 71:  Add either “a/the” prior to “main”

R= We added “a” to improve the redaction, thank you.

 METHODS and MATERIALS

1. Page 2, Line 93: Change “synergic” to “synergistic”

R= Your recommendation was considered, thank you.

2. Page 3, Line 99: Change “duplicated” to “duplicate”

R= Your recommendation was considered, thank you.

3. Page 3, Line 100: Change “previously” to “previous”

R= Your recommendation was considered, thank you.

 

RESULTS

            None

 DISCUSSION

1. Page 8, Line 163: Add “with” following “together”

R= Your recommendation was considered, thank you.

1. Page 8, Line 164: Change “provides” to “provide”

R= Your recommendation was considered, thank you.

1. Page 8, Line 164: Change “… that even there exist a large number…” to “…that a number…” and Add “exists” following “evidence”

R= The recommended changed were made, thanks for your observation.

1. Page 8, Line 169: Add “The” prior to “inflammation”

R= According to the reviewers recommendations, this paragraph has been reorganized and removed to the Introduction section, thank you.

1. Page 8, Line 175: Change to “…chronic, low-grade…” as stated previously by this reviewer

R= Your observation was considered and we corrected this along the document for consistency, thank you.

1. Page 8, Line 182: Add “semicolon” following “sarcopenia [27]”

R= The requested punctuation change was made, thanks for your observation.

1. Page 8, Line 192: Add “hyphen” following “Chronic”

R= Your observation was considered and we corrected this along the document for consistency, thank you.

1. Page 8, Line 195: Change “synergically” to “synergistically”

R= Your recommendation was considered, thank you.

1. Page 8, Line 202: Change “in the other hand” to “on the other hand”

R= Your recommendation was considered, thank you.

1. Page 8, Line 205: Change to “…chronic, low-grade…”

R= Your observation was considered and we corrected this along the document for consistency, thank you.

1. Page 9, Line 235: Add “comma” following “control”

R= The requested comma was added, thanks for your observation.

1. Page 9, Line 249: Add “hyphen” following “pro-“

R= Your recommendation was considered, thank you.

1. Page 9, Line 257: Change “inflammation” to “inflammatory”

R= Your recommendation was considered, thank you.

1. Page 10, Line 268: Change “could” to “may”

R= Your recommendation was considered, thank you.

1. Page 10, Line 269: Change “kind” to “type or specific”

R= Your recommendation was considered, thank you.

1. Page 10, Line 269: Delete “consumed”

R= Your recommendation was considered, thank you.

1. Page 10, Line 271: Change “to realized” to “that”

R= Your recommendation was considered, thank you.

1. Page 10, Line 271: Add “…are performed…” prior to “to confirm”

R= Your recommendation was considered, thank you.

1. Page 10, Line 271: Change “synergic” to “synergistic”

R= Your recommendation was considered, thank you.

1. Page 10, Line 272: Change “markers” to “marker”

R= Your recommendation was considered, thank you.

 REFERECES

1. None

 FIGURE LEGENDS/FIGURES

1. None

According to your observations, the article has been improved substantially. We really appreciate your contributions.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

N/A