Impact of Omega-3 Fatty Acids Supplementation Combined with Resistance Training on Muscle Mass, Neuromuscular and Physical Function in Older Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This systematic literature review (SLR) evaluate the effect of co-intervention with n-3 PUFA and resistant training (RT) vs RT with or without placebo on muscle mass and function in elderly people. I find the overall question interesting, but there are apparently not that many studies in the field and most of them are very small, which means that the SLR and the meta-analysis cannot make any strong conclusions. This of course is not a disqualification in itself. The paper discuss some relevant points (e.g. regarding mechanisms of action), which indicate insight in the field. There are however, also some odd speculations and choices, plus a number of other things, which downgrade the evidence that the SLR provides. If these are resolved, the paper may be useful as synthesis of the state-of-the-art in the field.

 

 

 

First of all the choice of exposure. I do not find it appropriate to mix α-linolenic acid (ALA) and the long-chain derivatives (n-3 LCPUFA, EPA and DHA) and I am not sure to what extent the authors did so, because the selection criteria are not clear.

 

-        As the authors recognize in the introduction, ALA is poorly converted ton-3 LCPUFA, which are the known mediators of effects of n-3 PUFA in the body, among other on inflammation. Furthermore, RCT and meta-analysis have only been able to support beneficial effects of marine n-3 LCPUFA on biomarkers of inflammation (CRP, IL-6 and TNFα) and inflammatory diseases (main rheumatoid arthritis) - none has shown clear effects of ALA. It is therefore important to distinguish between these two types of n-3 PUFA – i.e. not to be specific (i.e. not use the combined abbreviation, n-3 PUFA) and not mix the two in the analysis.

 

-        Line 130 in the selection criteria section state: “either fish oil (mostly Ω-3), or Ω-3-6-9 blend”. Fish oil provides n-3 LCPUFA, but blends come in many forms, some with n-3 LCPUFA but many just with ALA and there is no mentioning of supplementation with ALA containing plant oils. So what exactly were included?

 

-        If both n-3 LCPUFA and ALA are included as acceptable experimental interventions, you need to provide information about what the intervention was in the individual studies in the paper. Currently Table 1 is missing, but I found it among the supplemental materials and it shows that only one study supplied ALA. I suggest you exclude it.

 

-        Furthermore, I suppose the intervention and the comparator/placebo should be similar – i.e. both supplemental or both food based, but what would be an accepted comparator if n-3 LCPUFA was given as fish?

 

 

 

The selection criteria are also unclear on other PICOTS.

 

-        The first line in the section states that both RCT and prospective studies were included (the latter to me means observational studies), but the supplementary Table S2 specifies inclusion only of RCT with a parallel or a factorial 2x2x2 design, but I am not sure I understand it correctly. RCT to me is an all-inclusive term for randomized controlled/clinical trials, so it should include RCT double-blind controlled, clinical trial and RCT open label (meaning unblinded?), which the authors mention separately. I think the authors mix search terms with the definition of the eligibility criteria.

 

-        If the criteria is strictly RCT, then it is not meaningful to extract data and present all studies in Table 1 as randomized. The description of the extraction in line 137, once again makes me wonder if I have understood it right. What is meant by “whether or not the trial was an RCT or randomized”? Does “controlled or non-controlled” refer to if the comparator was RT alone or RT with placebo?

 

-        With respect to participants, these are for all studies shown to be untrained (UT) in Table 1, but this does not appear to be an eligibility criteria – or is it? If so, there is no need to mention this for all studies. Maybe the table headline could be “Characteristics of in included RCT in untrained people.”

 

-        To be in accordance with the PRISMA guidelines, the eligibility criteria needs to be clarified – i.e. all PICOTS should be specified and this should be included in the paper itself (without the need to consult a supplementary table).

 

    

 

The selection criteria are very clear on one point, which is to only include studies with resistance training (RT).

 

-        However from Table 1, it appears that you included two studies that are not in line with this criteria, as they used strength training (ST). The Bischoff-Ferrari study is by far the largest study and thus, probably also the best designed - yet you excluded this from your analysis, but used the Rodacki study. Why? And why did you leave out the study by Kamolrat with RT?

 

-        You do not present any arguments for why you choose to include RT, but not ST. If you have any hypothesis that justifies the differential inclusion, then please present it. If not, then I think it would be better to include both RT and ST studies (maybe there are more for ST that you would then need to include). You could then do a stratified analysis to see if training type modifies the results.

 

 

 

The extraction and quality assessment section could also be better - at least more structured.

 

-        The paragraph with the RoB description is intercepted by a sentence about the effect of interest (intervention effect or ’intention-to-treat’). I suppose this relates to how the outcomes were extracted and used in meta-analysis. What did you do if the author only reported the results for complete cases or those who fulfilled some more or less pre-specified per-protocol criteria?

 

-        The following paragraph specifies an Omega-3 score – an additional study quality variable. This was assigned to the trials based on: a) 3 items for participant exclusion on baseline status or intake, b) 1 item on compliance (verified change in O3I – or other biomarkers of intake?) and c) 1 item for study duration (for which there is no specified selection criteria – does that mean you include all from a few days to years?). I do not understand why n-3 LCPUFA dose is not included – I would downgrade the  study that use Calanus oil, which provides too little to give a detectable effect). The authors need to justify why the score as such and the chosen aspects should be of specific importance for study quality.

 

-        If the score is used, then it would make most sense to just make one baseline item (a), as they to me are really just three measures of the same thing. If participants took fish oil or had a significant intake of fish, this would reflect on the O3I. Furthermore, I do not expect any study would use all three criteria, but rather one or the other. Anyway, I do not see the point in having this criteria, when most of the studies provided >2 g/day of n-3 LCPUFA.

 

 

 

The presentation of the results are repetitive and boring – you need to “tell the story”.

 

-        The main results are repeated many times – the same data in Table 2 and in the Forest plots in Figures 4-7. It is OK to have a table for overview and the plots for detail, but the text that refers to the plots provide the data in full for the third time – some of the data are given once again in the discussion.

-        Furthermore, I do not understand the choice of data to show. It seems like cherry picking to only show the plot for the significant measure of physical function and not those for walking ability (which I would expect should be in line with that for chair-rise) and UG.

-        You could make the Result section more informative – not just providing tables and figure and referring to these and repeating the data in the text. I suggest that you use the text to focus on “the story” across all the analyses (main, stratified and sensitivity).

-        Maybe it would be a good idea to let the overview table give an overview of the whole story – i.e. include the results of the stratified analysis that are most relevant.

-        I find that some of the stratified analyses are irrelevant. With only nine studies in total, it seems unreasonable to make more than two strata and the studies should be evenly distributes among the strata (equal number of studies/people). This means that you would have to select the strata cut-offs based on the designs of the included studies. The most relevant stratified analyses in my mind would be on the overall RoB score (red vs green+yellow), n-3 LCPUFA vs ALA (if you choose not to exclude the ALA study) and n-3 LCPUFA dose with a cut-off that divides the studies evenly in high vs low. Or would it be possible to replace with a meta-regression analysis?

-        Furthermore, the results of the stratified analysis should not be evaluated based on p-values in the strata, but only on the p-value for subgroup difference and overlaps between the estimates in the strata as well as a reduction in heterogeneity.

-        It is a good thing to do sensitivity analysis – a bit extensive to do all the leave-one-out analysis, but OK. However, I think it would be most relevant to focus on sensitivity analyses with exclusion of main outlier – design and data wise – this could be an alternative to stratified analysis where you have too few studies (e.g. analysis with exclusion of the study by Rodacki, the Calanus oil, the ALA study etc.).

 

 

 

Minor comments

 

-        Section 3.2. should be called Study characteristics.

 

-        Figure 2 and 3 present the same data somewhat differently, but I think Figure 2 shows it all.

 

-        Table 1 is hard to read. Make sure to carefully select and include the most relevant (put the minor details in a supplemental table). Furthermore, give comparable information (e.g. currently doses for EG and CG are a mix of doses of specific fatty acids and total amount of oil or what?).

 

-        You ought to clean up with respect to abbreviations - e.g. Table 1 use four for RT and four for ST.

 

-        The text throughout the manuscript needs some proof reading and removal of repetitive words (e.g. remove twice in the sentence line 368-369).

 

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear editor of the journal, greetings

Thank you for choosing me as a reviewer.

This article examines the consumption of omega-3 in the elderly. The title describes the work and research activity well. The abstract can be written better and more complete in terms of entry criteria, years of study, etc.

There are breaks between paragraphs in the title. They must be connected.

The necessity and importance of the work should be expressed.

Entry criteria, limiting years must be specified in the method. The method should be perfected.

The discussion should be better. Discuss the reasons for the effectiveness of different doses. Does gender have an effect on the response to supplement use or not? The discussion will be more comprehensive.

 

Comments on the Quality of English Language

Dear editor of the journal, greetings

Thank you for choosing me as a reviewer.

This article examines the consumption of omega-3 in the elderly. The title describes the work and research activity well. The abstract can be written better and more complete in terms of entry criteria, years of study, etc.

There are breaks between paragraphs in the title. They must be connected.

The necessity and importance of the work should be expressed.

Entry criteria, limiting years must be specified in the method. The method should be perfected.

The discussion should be better. Discuss the reasons for the effectiveness of different doses. Does gender have an effect on the response to supplement use or not? The discussion will be more comprehensive.

 

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Edited and its can be publish 

Comments on the Quality of English Language

Good