The Use of Dietary Supplements and Amino Acid Restriction Interventions to Reduce Frailty in Pre-Clinical Models
Round 1
Reviewer 1 Report
The study does not provide the methodology on which it is based to select these articles instead of others.
The authors' conclusions go against other well-founded meta-analyses on this topic with a clear methodology.
Lorenzo-López L, Maseda A, de Labra C, Regueiro-Folgueira L, Rodríguez-Villamil JL, Millán-Calenti JC. Nutritional determinants of frailty in older adults: A systematic review. BMC Geriatr. 2017 May 15;17(1):108. doi: 10.1186/s12877-017-0496-2. PMID: 28506216; PMCID: PMC5433026.
Coelho-Júnior HJ, Rodrigues B, Uchida M, Marzetti E. Low Protein Intake Is Associated with Frailty in Older Adults: A Systematic Review and Meta-Analysis of Observational Studies. Nutrients. 2018 Sep 19;10(9):1334. doi: 10.3390/nu10091334. PMID: 30235893; PMCID: PMC6165078.
It is a barely original topic with a methodology inferior to other studies already published on the subject.
They draw conclusions that cannot be demonstrated with the articles they analyze.
Author Response
Please see the attachement
Author Response File: 
Author Response.docx
Reviewer 2 Report
Dear Authors,
In order to improve the quality of the manuscript, I recommend the following corrections:
- it is necessary to add more details regarding the literature review: What databases have the authors searched? What years were the publications from? What were the inclusion and exclusion criteria?
- it should be explained why such interventions have been described - are there no other ones regarding dietary supplementation in the literature?
- did the authors find no publications on the influence of minerals such as zinc? Other antioxidants?
- in tables, references should be written as publication numbers,
- data in the tables require clarification, e.g. allicin (garlic) - so what was served? In what quantity?
- (mos) in the table - what does it mean?
- Table 1 - Liu et al. Study, 2019 - please check units,
- Table 2 - should be clarified if the publication mentions what forms of minerals were tested - organic or inorganic - this is not enough information,
- in the case of supplementation, we cannot talk about treatment! - this should be corrected throughout the publication,
Editorial corrections should be as follows:
- the manuscript is not prepared in accordance with the MDPI requirements,
- page numbering should be inserted,
- there are no correct headers and footers,
- running head should be removed,
- the authors' initials should be in the affiliations,
- please check the verses where the address of the corresponding author is given,
- please verify the correctness of the spelling of keywords,
- in the abstract there should not be words of main parts like "background", "results",
- explanation of abbreviations under the table - should be in accordance with the requirements of the journal.
Author Response
Please see the attachement
Author Response File: Author Response.docx
Reviewer 3 Report
Congratulations to the Authors for the work submitted. In this study, they reviewed current literature to search for studies investigating interventions to address frailty or overall health among healthy rodents. The manuscript is well written in all its parts, studies well summarised and critically discussed. I have some minor concerns that I list here below:
-Introduction: you briefly discussed putative causes of frailty, but I think that the concept that links frailty to aging and inflammation, as well as sex-related differences in underlying mechanisms should be added, especially in light of emerged results (I am fine with description of study results, but I would add a clearer picture of frailty and inflammatory pathways in male and female rodents in the section of putative causes of frailty;e.g. is there a link between frailty and inflammaging? which pathways are mainly involved? Is there a difference in pathophysiology of frailty and inflammaging in female and male rodents? )
-Methodology of the review needs to be implemented: add a brief description of the research strategy (main database used, time of publication, search key words). If possible, add a flow-chart representing the process of including relevant articles and excluding irrelevant ones.
-Minor spells:
a) Line 83, remove comma between "one" and "or more".
b) Line 103: add "a" before "prehormone".
c) remove "to help" from the sentence "to help to help".
Author Response
Please see the attachment
Author Response File: Author Response.docx
Reviewer 4 Report
The manuscript as written seems to cover the topic of animal model studies of frailty reasonably well. However, I did not see much about overall health or reduced risk of many types of disease in general. Vitamin D reduces risk of many more types of disease than are mentioned, which mainly relate to musculoskeletal health. Suggest that a more extensive review of overall health be added or “health” qualified such as by adding musculoskeletal or just remove health from the title.
While this review is based on analyzing interventions to reduce frailty in rodent models, the manuscript could be improved by adding a discussion of what has been found from human observational studies, especially regarding 25OHD and PTH, as well as how animal studies differ from human studies regarding findings. This is only a suggestion, and the authors are free to add it if they think it adds to the manuscript. An important thing to note in the references below that PTH, which is affected by 25OHD concentrations and age, is that it has also been found to be an independent risk factor for frailty. Not sure that can be studied in animal models.
Additional papers to consider citing found at scholar.google.com
Vitamin D: a review on its effects on muscle strength, the risk of fall, and frailty
M Halfon, O Phan, D Teta - BioMed research international, 2015 - hindawi.com
… In studies testing vitamin D supplementation, the dose of vitamin D should have been … level
of vitamin D should have been reported. In studies regarding frailty, the terminology of frailty …
Save Cite Cited by 224 Related articles
Relevance of vitamin D in the pathogenesis and therapy of frailty
O Bruyère, E Cavalier, F Buckinx… - Current opinion in …, 2017 - ingentaconnect.com
… This article reviews recently published evidence regarding the role of vitamin D in the
physiopathology of physical frailty in elderly populations and its role in the management of this …
Save Cite Cited by 69
The effect of vitamin D and frailty on mortality among non-institutionalized US older adults
E Smit, CJ Crespo, Y Michael… - European journal of …, 2012 - nature.com
… frailty to be predictive of mortality. Conversely the effects of frailty status with low vitamin D
… examine the independent and joint effects of frailty and vitamin D on all cause mortality in a …
Save Cite Cited by 90
The relationship between nutrition and frailty: Effects of protein intake, nutritional supplementation, vitamin D and exercise on muscle metabolism in the elderly. A …
I Artaza-Artabe, P Sáez-López, N Sánchez-Hernández… - Maturitas, 2016 - Elsevier
… subjects; 4) the association between frailty and vitamin D levels and vitamin D supplementation.
… and main results of the research studies of potential links between vitamin D and frailty. …
Save Cite Cited by 253
A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects (FITNESS)
NK Latham, CS Anderson, A Lee… - Journal of the …, 2003 - Wiley Online Library
… Vitamin D receptors are present in muscle, 15 and the association between vitamin D
deficiency and weakness, abnormal gait, and falls 12 suggests that vitamin D has a direct effect on …
Save Cite Cited by 498
A prospective study into change of vitamin D levels, depression and frailty among depressed older persons
…, RHS van den Brink, D Rhebergen… - … Journal of Geriatric …, 2021 - Wiley Online Library
… vitamin D is involved in frailty as well as depression, hardly any study has examined the
course of vitamin D … The objective of this study is to examine whether a change of vitamin D in …
Save Cite Cited by 6
The association of vitamin D deficiency and incident frailty in older women: the role of cardiometabolic diseases
B Buta, PP Choudhury, QL Xue… - Journal of the …, 2017 - Wiley Online Library
… suggests vitamin D deficiency is associated with developing frailty… vitamin D–frailty association.
We aimed to determine the association of vitamin D concentration with incidence of frailty…
Save Cite Cited by 38
Vitamin D receptor polymorphisms in sex-frailty paradox
…, FR Guerini, AS Costa, A Dicitore, E Ferri, D Mari… - Nutrients, 2020 - mdpi.com
… between frailty and the vitamin D pathway as well as VDR gene profiling in a cohort of very
old women and men. In this study, we used the frailty index (FI) as measure of frailty because …
Save Cite Cited by 6
Prospective association of vitamin D with frailty status and all-cause mortality in older adults: Results from the KORA-Age Study
S Vogt, S Decke, T de Las Heras Gala, B Linkohr… - Preventive …, 2015 - Elsevier
… Our findings are generally consistent with those of previous prospective studies on vitamin
D and frailty using a frailty definition based on Fried et al. (Fried et al., 2001). In a US study in …
Save Cite Cited by 54
The association between vitamin D and inflammation with the 6‐minute walk and frailty in patients with heart failure
RS Boxer, DA Dauser, SJ Walsh… - Journal of the …, 2008 - Wiley Online Library
… frailty and these variables, the model was used to calculate predicted probabilities for each
frailty category relative to a wide range of vitamin D … of vitamin D and hsCRP on frailty status …
Save Cite Cited by 208
Sex-specific differences in the association of vitamin D with low lean mass and frailty: Results from the Berlin Aging Study II
D Spira, N Buchmann, M König, A Rosada… - Nutrition, 2019 - Elsevier
… The study aims to assess sex-specific aspects of the association between vitamin D insufficiency
and low lean mass as well as between vitamin D insufficiency and the frailty phenotype. …
Save Cite Cited by 18
PTH
PTH increases with age and lower 25(OH)D concentration
Effects of age and serum 25-OH-vitamin D on serum parathyroid hormone levels.
Valcour A, Blocki F, Hawkins DM, Rao SD.J Clin Endocrinol Metab. 2012 Nov;97(11):3989-95. doi: 10.1210/jc.2012-2276.
And is an important risk factor for CVD:
Parathyroid hormone, vitamin D, renal dysfunction, and cardiovascular disease: dependent or independent risk factors?
Anderson JL, Vanwoerkom RC, Horne BD, Bair TL, May HT, Lappé DL, Muhlestein JB.Am Heart J. 2011 Aug;162(2):331-339.e2. doi: 10.1016/j.ahj.2011.05.005.
Thus, it might be associated with frailty and with vitamin D indirectly through age.
The association of frailty with serum 25-hydroxyvitamin D and parathyroid hormone levels in older European men
A Tajar, DM Lee, SR Pye, MDL O'connell… - Age and …, 2013 - academic.oup.com
… axis and frailty remains undefined, with … parathyroid hormone (PTH) levels. Our objective
was to determine the association of frailty with serum 25-hydroxyvitamin D (25(OH)D) and PTH. …
Save Cite Cited by 97
Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population
PN Sambrook, JS Chen, LM March… - The Journal of …, 2004 - academic.oup.com
… This study of a large number of frail elderly men and women living in aged cared facilities …
In summary, serum PTH seems to be an independent predictor of time to first fall in the frail …
Save Cite Cited by 144
Association between high levels of parathyroid hormone and frailty: the Nepean Osteoporosis and Frailty (NOF) study
L Murthy, P Dreyer, P Suriyaarachchi, F Gomez… - The Journal of Frailty & …, 2018 - Springer
… Frailty is associated with poor outcomes hence identification of risks factors is pivotal. Since
the independent role of parathyroid hormone (PTH) in frailty remains unexplored, we aimed …
Save Cite Cited by 9
Serum parathyroid hormone is associated with increased mortality independent of 25-hydroxy vitamin d status, bone mass, and renal function in the frail and very old …
PN Sambrook, JS Chen, LM March… - The Journal of …, 2004 - academic.oup.com
… would predict mortality in this frail very old population, and we have measured calcaneal
ultrasound, serum 25OHD, and PTH in a prospective study of frail, very old, institutionalized …
Save Cite Cited by 150
Current and emerging biomarkers of frailty in the elderly
A Al Saedi, J Feehan, S Phu… - Clinical interventions in …, 2019 - ncbi.nlm.nih.gov
… DHEA, parathyroid hormone (PTH), VitD, and IGF1. … have shown increased levels of PTH to
correlate with frailty;47,48 … ability to predict and diagnose frailty. Despite unclear evidence for …
Save Cite Cited by 100
Association of low vitamin D levels with the frailty syndrome in men and women
M Shardell, GE Hicks, RR Miller… - … Series A: Biomedical …, 2009 - academic.oup.com
… with frailty. Vitamin D insufficiency can result in hyperparathyroidism, and thus, parathyroid
hormone (PTH… as a potential mediator in the relationship between 25(OH)D levels and frailty. …
Save Cite Cited by 208
Association of Frailty with Serum Vitamin D and Parathyroid Hormone Levels
Ş Göçer, Ö Balbaloğlu - Acıbadem Üniversitesi Sağlık Bilimleri …, 2022 - scholar.archive.org
… effect of vitamin D and parathyroid hormone (PTH) in frailty syndrome are limited. Therefore,
we aimed to evaluate the relationship between frailty and serum vitamin D and PTH levels. …
Regarding inflammation
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
L Ferrucci, E Fabbri - Nature Reviews Cardiology, 2018 - nature.com
… In this section of the Review, we summarize available evidence to suggest that chronic
inflammation is both a risk factor and a pathogenic mechanism in CVD. Moreover, because …
Save Cite Cited by 1023
Inflammation markers predicting frailty and mortality in the elderly
M De Martinis, C Franceschi, D Monti… - … and molecular pathology, 2006 - Elsevier
… inflammation markers as synthetic measures of lifelong attrition combined with genetic tendency
to develop an inflammatory … additional inflammation markers useful for risk assessment …
Save Cite Cited by 379
Inflammation and frailty in older women
SX Leng, QL Xue, J Tian, JD Walston… - Journal of the …, 2007 - Wiley Online Library
… These findings indicate significant risk gradients for frailty even within the normal range
of total WBC counts. They provide additional supportive evidence for a low-grade systemic …
Save Cite Cited by 453
Inflammation and frailty in the elderly: a systematic review and meta-analysis
P Soysal, B Stubbs, P Lucato, C Luchini, M Solmi… - Ageing research …, 2016 - Elsevier
… ) were not associated with frailty. In conclusion, frailty and pre-frailty are associated with higher
inflammatory parameters and in … 1b) levels were not associated with higher risk of frailty. …
Save Cite Cited by 554
The association between obesity and the frailty syndrome in older women: the Women's Health and Aging Studies
CS Blaum, QL Xue, E Michelon… - Journal of the …, 2005 - Wiley Online Library
… associations between the frailty syndrome and obesity in older women. The frailty syndrome
was … of the association between obesity and inflammation 14 and between inflammation and …
Save Cite Cited by 494
Relevance of oxidative stress and inflammation in frailty based on human studies and mouse models
M Álvarez-Satta, A Berna-Erro… - Aging (Albany …, 2020 - ncbi.nlm.nih.gov
… in vitamin E and frailty. Similar inconsistent results were found in studies for vitamin A and
… (MARK-AGE) study shows that physical frailty is significantly associated with lower levels of …
Save Cite Cited by 21
Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty
NJW Rattray, DK Trivedi, Y Xu, T Chandola… - Nature …, 2019 - nature.com
… and a key regulator of inflammation, which has been implicated as a risk factor for … frailty
level 61 . In the present study observed white blood cell levels were directly correlated with frailty …
Save Cite Cited by 42
Altered immune system in frailty: genetics and diet may influence inflammation
O Pansarasa, C Pistono, A Davin, M Bordoni… - Ageing research …, 2019 - Elsevier
… Dietary: Supporting the role of vitamin D in frailty, a recent study, analyzing the relationship
between various nutritional parameters and frailty, found only low serum vitamin D levels to …
Save Cite Cited by 51
Nutrition and inflammation in older individuals: focus on vitamin D, n-3 polyunsaturated fatty acids and whey proteins
A Ticinesi, T Meschi, F Lauretani, G Felis, F Franchi… - Nutrients, 2016 - mdpi.com
… increased risk of anemia (OR 1.46, 95% CI 1.06–2.02), while subjects with anemia of chronic
inflammation had a significantly higher prevalence of vitamin … , nutrition and physical frailty. …
Save Cite Cited by 96
Endocrine and inflammatory markers as predictors of frailty
MTE Puts, M Visser, JWR Twisk… - Clinical …, 2005 - Wiley Online Library
… Vitamin D deficiency has been shown to occur in patients with inflammatory bowel disease,
41 and vitamin … Studies in mice have shown that supplementation with vitamin D can protect …
Save Cite Cited by 352
Comment: Lifespan as used in Figure 1, spears to be incorrect. Life expectancy is probably the correct word:
Lifespan - an overview | ScienceDirect Topics
https://0-www-sciencedirect-com.brum.beds.ac.uk › medicine-and-dentistry
Lifespan is defined as the maximum number of years that a human can live, while life expectancy is the average total number of years that a human achieves ...
Vitamin D should be included in Figure 2 since higher 25(OH)D is associated with reduced risk of many diseases. Mendelian randomization studies are considered almost as good as RCTs in determining causality:
Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large European cohorts
…, W März, ME Kleber, A Tomaschitz, D Grove-Laugesen… - Nutrients, 2019 - mdpi.com
The aim of this study was to determine if increased mortality associated with low levels of
serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian …
Save Cite Cited by 27
Non-linear associations of 25-hydroxyvitamin D concentrations with risk of cardiovascular disease and all-cause mortality: results from The Health Improvement …
FL Crowe, R Thayakaran, N Gittoes, M Hewison… - The Journal of steroid …, 2019 - Elsevier
… ) reported in recent clinical trials of vitamin D supplementation. The aim of this study … 25-hydroxyvitamin
D (25(OH)D with risk of incident CVD and all-cause mortality, as well as the risk …
Save Cite Cited by 15
Serum 25-hydroxyvitamin D levels predict cancer survival: a prospective cohort with measurements prior to and at the time of cancer diagnosis
TE Robsahm, S Tretli, PA Torjesen… - Clinical …, 2019 - ncbi.nlm.nih.gov
… Circulating 25-hydroxyvitamin D (25-OHD) levels have been inversely associated with cancer
death, but the nature of this relationship is unclear. We investigated this association using …
Save Cite Cited by 16
396 Selenium is a trace essential metal that is involved in forming
397 selenoproteins, where the metal binds to cysteine residues
Comment:
Selenium is a metalloid (an element intermediate in properties between the metals and the nonmetals).
Thus, replace metal with mineral or metalloid
- Danik, J. S.; Manson, J. E. Vitamin D and Cardiovascular Disease. Curr Treat Options Cardiovasc Med 2012, 14 (4),
613 414–424. https://0-doi-org.brum.beds.ac.uk/10.1007/s11936-012-0183-8.
Comment: This reference is too old.
Author Response
Please see the attachment
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
The authors refer: "While there is no single definition of frailty, it can be viewed as accelerated aging that increases susceptibility to adverse health outcomes including hospitalization, falls, and mortality”
However, they cite an article where the concept of frailty is: "Frailty is theoretically defined as a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with everyday or acute stressors is comprised“.
It seems inappropriate to me to cite another author creating a new or different concept from the one they make in their article, in addition this fact may mislead some readers not familiar with the subject, making them to think that the definition of frailty is not clear.
The article cited by the authors dates from 2011, later in 2015 the world health organization WHO, establishes the frailty criterion: “Frailty is a progressive age-related decline in physiological systems that results in decreased intrinsic capacity reserves, conferring extreme vulnerability to stressors and increasing risk of a variety of adverse health outcomes".
World Health Organization (2015). World report on aging and health. Luxembourg. Available at: http://apps.who.int/iris/bitstream/10665/186463/1/9789240694811_eng.pdf?ua=1 [Last access: 12/13/2017]
World Health Organization (2017).
The authors refer on several occasions to the concept of “preclinical models of frailty”. They don't define what this concept means nor do they refer to other authors who previously allude to this concept, which makes it very difficult to understand what they allude to.
As I mentioned in my first review, other authors review this topic with systematic reviews, a narrative review has the problem of article selection bias by not making a systematic selection of articles.
The authors mix animal studies with human studies, and mix studies that measure frailty with studies that measure aging
Author Response
Please see attachment
Author Response File: Author Response.docx
Reviewer 2 Report
The authors took into account all my suggestions. Moreover, they extended the manuscript with the necessary aspects.
Reviewer 4 Report
Well done. I endorse this manuscript for publication.
Author Response
Thank you very much.
