Effect of Protein or Essential Amino Acid Supplementation During Prolonged Resistance Exercise Training in Older Adults on Body Composition,Muscle Strength,and Physical Performance Parameters: A Systematic Review

Abstract

Objectives:

Loss of muscle mass and strength with aging, sarcopenia, burdens many older adults, making identification of strategies on how to counteract it very relevant—especially to health care providers working in rehabilitation. The aim of this systematic review was to determine the effect of protein or essential amino acid (EAA) supplementation during prolonged resistance exercise training (RT) in older adults. No known stimulants of muscle protein synthesis, or ingredients with an effect on muscle strength/physical function, were allowed with the supplementation, differentiating this systematic review from others.

Data sources and methods:

In January 2017, 4 electronic databases and reference lists were searched for randomized controlled trials investigating the effect of protein or EAA supplementation during RT in older adults (mean age >60 years) on outcomes of body composition, muscle strength, and physical performance. Study selection and data extraction were performed by 2 independent reviewers.

Results

Sixteen studies (1107 participants) fulfilled the eligibility criteria. Methodologic differences between the studies disallowed a meta-analysis. Of the 16 studies, 6 found significant effects on body composition (3 studies), muscle strength (3 studies), and physical performance (2 studies) measures.

Conclusions

The evidence is weak and inconsistent, as benefit of protein or EAA supplementation during RT in older adults is only shown in some studies. The findings indicate that frail/sarcopenic older adults might benefit more than healthy older adults. Further research is needed to allow an interpretation on the importance of study population and design.

Trial registration:

PROSPERO, Reg. no.: CRD42017063808. Registered April 14, 2017.

Keywords

Resistance exercise training nutrition older adults’ health care rehabilitation systematic review

Introduction

The loss of muscle mass and strength with aging is an unavoidable process with a multifactorial etiology, and it is an important predictor of functional decline and mortality in older adults.^1,2 It is also known as sarcopenia, and it affects many older adults, with the process being accelerated after the age of 70 years.^1,2 Greater average life spans mean that functional decline associated with sarcopenia is to become even more prevalent. Thus, it is highly relevant to identify evidence-based prevention and treatment strategies—especially for those working in rehabilitation in clinical practices and other care sectors. Among older adults, resistance exercise training (RT) is recognized as an effective strategy,^3,4 and the effect of protein supplementation alone has also been documented.⁵ However, the potential additional benefit of combining the RT with a higher protein or essential amino acid (EAA) intake is less well studied. Therefore, the aim of this systematic review is to summarize results of randomized controlled trials (RCTs) investigating this in older adults with a mean age above 60 years, on measures of body composition, muscle strength, and physical function. Recent systematic reviews^5–9 and meta-analyses^10,11 have investigated this topic with inconclusive results when considered all together. This systematic review differentiates itself by allowing the protein or EAA supplementation to be the only difference between the intervention and the control groups. Thus, no multivitamins, single vitamin supplementations, or other known stimulants of muscle protein synthesis, or with an effect on muscle strength and/or physical function, are allowed together with the protein or EAA supplementation, which is to ensure that any effects can be attributed only to the latter.

Methods

This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) report. All procedures were determined in advance and registered in the international prospective register of systematic reviews (PROSPERO; https://www.crd.york.ac.uk/prospero/, registered April 14, 2017, reg. no. CRD42017063808).

Search strategy

Literature was collected from online databases of published literature. The search was conducted in January 2017 and made in the PubMed, SCOPUS, EMBASE, and Cochrane databases. The fixed terms were RCT, full text, human studies, and written in English. Specific search terms were applied for the categories population, training intervention, and supplementation. Table 1 shows the applied search terms, taken from PubMed as an example. Furthermore, the reference lists of relevant reviews and articles were searched as well. In addition, https://clinicaltrials.gov/ was screened for gray literature, with the applied search terms “Protein AND Training” in adults and seniors.

Table 1.

Applied search terms, example from PubMed.

#24 Search #6 AND #19 AND #22 AND #23

#23 Search “Randomized Controlled Trials”[Mesh] OR “Controlled Clinical Trials, Randomized” OR “Clinical Trials, Randomized” OR “Trials, Randomized Clinical”

#22 Search #20 OR #21

#21 Search “Concurrent Training”

#20 Search “Resistance Training”[Mesh] OR “Training, Resistance” OR “Strength Training” OR “Training, Strength” OR “Weight-Lifting Strengthening Program” OR “Strengthening Program, Weight Lifting” OR “Strengthening Programs, Weight-Lifting” OR “Weight Lifting Strengthening Program” OR “Weight-Lifting Strengthening Programs” OR “Weight-Lifting Exercise Program” OR “Exercise Program, Weight-Lifting” OR “Exercise Programs, Weight-Lifting” OR “Weight Lifting Exercise Program” OR “Weight-Lifting Exercise Programs” OR “Weight-Bearing Strengthening Program” OR “Strengthening Program, Weight-Bearing” OR “Strengthening Programs, Weight-Bearing” OR “Weight Bearing Strengthening Program” OR “Weight-Bearing Strengthening Programs” OR “Weight-Bearing Exercise Program” OR “Exercise Program, Weight-Bearing” OR “Exercise Programs, Weight-Bearing” OR “Weight Bearing Exercise Program” OR “Weight-Bearing Exercise Programs”

#19 Search #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18

#18 Search “Valine”[Mesh] OR “L-Valine” OR “L Valine”

#17 Search “Isoleucine”[Mesh] OR “L-Isoleucine” OR “Isoleucine, L-Isomer” OR “Isoleucine, L Isomer” OR “L-Isomer Isoleucine” OR “Alloisoleucine”

#16 Search “Leucine”[Mesh] OR “L-Leucine” OR “Leucine, L-Isomer” OR “L-Isomer Leucine” OR “Leucine, L Isomer”

#15 Search “Whey Protein”

#14 Search “Milk Proteins”[Mesh] OR “Proteins, Milk” OR “Milk Protein” OR “Protein, Milk”

#13 Search “Amino Acids, Essential” OR “Essential Amino Acids” OR “Acids, Essential Amino”

#12 Search “Amino Acids, Branched-Chain”[Mesh] OR “Acids, Branched-Chain Amino” OR “Branched Chain Amino Acids” OR “Amino Acids, Branched Chain”

#11 Search “Protein Meal”

#10 Search “Protein Supplementation”

#9 Search “Amino Acids”[Mesh] OR “Acids, Amino”

#8 Search “Proteins”[Mesh] OR “Protein”

#7 Search “Dietary Supplements”[Mesh] OR “Dietary Supplement” OR “Supplement, Dietary” OR “Supplements, Dietary” OR “Food Supplementation” OR “Supplementation, Food” OR “Nutraceuticals” OR “Nutraceutical” OR “Nutriceuticals” OR “Nutriceutical” OR “Neutraceuticals” OR “Neutraceutical” OR “Dietary Supplementation” OR “Dietary Supplementations” OR “Supplementation, Dietary” OR “Supplementations, Dietary” OR “Food, Supplemented” OR “Foods, Supplemented” OR “Supplemented Food” OR “Supplemented Foods” OR “Food Supplements” OR “Food Supplement” OR “Supplement, Food” OR “Supplements, Food”

#6 Search #1 OR #2 OR #3 OR #4 OR #5

#5 Search “Sarcopenia”[Mesh] OR “Sarcopenias”

#4 Search “Advanced Age”

#3 Search “Older”

#2 Search “Aging”[Mesh] OR “Senescence” OR “Biological Aging” OR “Aging, Biological”

#1 Search “Aged”[Mesh] OR “Elderly”

Inclusion and exclusion criteria

Studies included were RCTs, blinded or nonblinded, with at least one intervention group receiving RT in addition to protein or EAA supplementation or a modified diet with increased protein content for a minimum of 5 weeks. This duration was chosen to allow for a measurable change. The intervention group had to be compared with a control group receiving RT with or without a nonprotein placebo supplement. The RT could be targeting all or only specific muscle groups and was allowed to be provided with additional exercises aiming for improved cardio or balance. Studies were allowed to have additional intervention groups. The population had to be men and/or women with a mean age of 60 years. Outcomes with high relevance to older adults’ physical rehabilitation were chosen. Thus, only body composition, muscle strength, and physical function measurements were assessed. Every study needed to contain at least one end point in relation to these 3 parameters. There was no limitation on the nationality of the origin of the studies or on the publication year.

Studies were excluded if they were retrospective, uncontrolled trials, abstracts from annual scientific conferences, commentaries or reviews, and if the intervention aimed to treat a specific disease or medical condition (eg, diabetes or chronic obstructive pulmonary disease) or was given as part of a weight loss protocol. Studies were also excluded if protein supplementation was given together with other supplements known or suspected to stimulate muscle hypertrophy (single/multivitamins, creatine, specific hormones, etc), if the intervention period was less than 5 weeks, if there was no information on mean age, if it was not possible to extract data on the relevant age/intervention group, or if the study was a duplicated publication.

Selection process and data extraction

Data selection and extraction was performed by 2 independent reviewers. In case of disagreement, a third party was consulted. First, the title and abstract were screened for all references, and studies that were clearly not relevant were removed. Next, full-text papers were evaluated to determine whether they fulfilled the inclusion criteria and all eligible studies were included in this systematic review. Predefined data from the included studies were extracted (Table 2), as well as any primary and secondary outcome measures of muscle mass, muscle strength, and physical function (Table 4). To decide if it was possible to conduct a meta-analysis, the homogeneity of the studies was evaluated based on participant details, amount, type, and intensity of RT and the source, amount, frequency, and timing of the protein/placebo supplementation.

Table 2.

Characteristics of randomized controlled trials investigating the effect of protein supplementation in addition to resistance exercise training.

Author (year)Origin	Participant details							Training details			Training details			Protein/EAA and placebo supplement details
Author (year)Origin	N	Dropout (n total, n IG/CG) (total %)	Mean age (year ± SD/range)	Sex (F/M)	Setting (CD, NH)	Population	Study quality (0-12)^a	Duration and RT frequency	Type of RT (LL, UL)/(WM, FW, SB, RB)	Amount and/or time to do RT	RT intensity	Cardio/balance training (y/n)Supervised (y/n)/I or G (no. in group)	RT compliance % (IG/CG)	Type of intervention	Frequency (daily/with RT) and timing of ingestion	Total protein amount (g)/volume (mL)	Actual total intake (g/kg/d) or compliance (%)	Control group
Arnarson et al (2013) Iceland	161	20, 8/12 (12.4)	IG: 73.3 ± 6.0 CG: 74.6 ± 5.8	94/67	CD	Healthy	12	12 wk, 3×/wk	LL and UL/WM	10 ex. 6-8 rep. and 3 sets	75%-80% of 1-RM. Increased load by 5%-10%/wk	n/n y/G (20-30)	NR	Whey	After RT	20 g/250 mL	Actual intake: IG: 1.06 ± 0.23 CG: 0.89 ± 0.23 Compliance: NR	Isocal. (CHO)
Carlson et al (2010) Sweden	83	11, 5/6 (13.3)	IG: 84.4 ± 6.3 CG: 85.3 ± 5.5 Range: 65-99	61/22	NH	Healthy, but cognitive impaired	12	13 wk, 2.5×/wk	LL/FW	Min. of 2 ex. 8-12 rep. (45 min)	Increased load when >12 rep.	y/y y/G (3-9)	79%	Milk based	After RT	14.8 g/200 mL	Actual intake: NR Compliance: IG: 84 CG: 79	Non-isocal. (CHO) IG vs CG: 816 kJ vs 382 kJ
Chale et al (2013) USA	80	5, 3/2 (6.3)	IG: 78.0 ± 4.0 CG: 77.3 ± 3.9	NR	CD	Dependent (mobility-limited)	12	6 mo, 3×/wk	LL and UL/WM	5 ex. 10 rep. and 2 sets Increased to 12 rep. and 3 sets	80% of 1-RM	n/n y/NR	79.9 ± 20.8/70.2 ± 21.7	Whey	2×/d (after breakfast/dinner)	40 g/powder form	Actual intake: IG: 1.12 CG: 0.91 Compliance: IG: 72.1 ± 29.3 CG: 82.3 ± 21.9	Isocal. (CHO)
Daly et al (2014) Australia	100	9, 5/4 (9.0)	IG: 72.1 ± 6.4 CG: 73.6 ± 7.7	All F	CD	Healthy	8	4 mo, 2×/wk	LL and UL/SB + FW	12 ex. 12 rep. and 3 sets (45-60 min)	60%-75% of 1-RM	n/y y/G (≤8)	75/72	Lean meat sources	2×/d (lunch/dinner)	45 g/220 g	Actual intake: IG: 1.28 CG: 1.12 Compliance: IG: 81 CG: 100	Non-isocal. (rice, pasta or potato ≥1 serving/d)
Fiatarone et al (1994) USA	50	3, 0/3 (6.0)	IG: 87.2 ± 1.2 CG: 86.2 ± 1.0	16/16	NH	Healthy	8	10 wk, 3×/wk	LL/WM	Ex. NR 8 rep. and 3 sets (45 min)	80% of 1-RM	n/n y/I	97/97	Soy	1×/d (after dinner)	15 g/240 mL	Actual intake: NR compliance: IG: 99 CG: 100	Non-isocal. (CHO) IG vs CG: 360 kJ vs 4 kJ
Gryson et al (2014) France	26	3, NR/NR (11.5)	Mean: 60.8 ± 0.4	All M	CD	Healthy	10	16 wk, 3×/wk	LL and UL/WM+FW	3 ex. 8-12 rep. and 3 sets (45-60 min)	50% of 1-RM. Increased load by 10% every 2 wk	y/n y/G (NR)	100/100	Milk based IG1: (80% casein and 20% whey) IG2: leucine rich	1×/d (at breakfast or after RT on training days)	IG1 + IG2:10 g/NR	Actual intake: NR Compliance: NR	Non-isocal. (Drink w/4 g of protein)
Kim et al (2012) Japan	77	7, 4/3 (9.1)	IG: 79.5 ± 2.9 CG: 79.0 ± 2.9	All F	CD	Sarcopenic	11	3 mo, 2×/wk	LL/FW + RB	Ex. NR 8 rep. (60 min)	12-14 on the Borg Scale	n/y y/G (NR)	70.3/80.5	EAA as powder (leucine rich)	2×/d (timing optional)	6 g/powder	Actual intake: NR Compliance: NR	None
Leenders et al (2013) Netherlands	60	7, NR/NR (11.7)	IGf: 72 ± 2 CGf: 69 ± 1 IGm: 70 ± 1 CGm: 70 ± 1	29/31	CD	Healthy	11	24 wk, 3×/wk	LL and UL/WM	6 ex. LL: 8-15 rep. and 4 sets UL: 8-15 rep. and 3 sets	60% of 1-RM increased to 80%	n/n y/NR	90 ± 1	Milk based: (80% casein 20% whey)	1×/d (after breakfast)	15 g/250 mL	Actual intake: NR Compliance: NR	Non-isocal. (CHO) IG vs CG: 389 kJ vs 119 kJ
Maltais et al (2015) Canada	30	4, NR/NR (13.3)	IG1: 64 ± 4.8 IG2: 68 ± 5.6 CG: 64 ± 4.5	All M	NR	Sarcopenic	11	4 mo, 3×/wk	LL and UL/WM + FW	8 ex. 8 rep. and 3 sets (60 min)	80% of 1-RM Increased load when 8 rep. was too easy	n/n y/NR	>90	IG1: Soy + EAA IG2: Milk + EAA	After RT	IG1: 19 g/379 mL IG2: 20.53 g/375 mL	Actual intake: IG1: 1.21 ± 0.3 IG2: 0.95 ± 0.3 CG: 1.05 ± 0.2 Compliance: NR	Non-isocal. (rice milk 0.6 g/395 mL)
Mitchell et al (2015) Canada	16	NR	Mean: 74.4 ± 5.4	All M	CD	Healthy	5	12 wk, 3×/wk	LL and UL/NR	4-6 ex. 3 sets increased to 4 sets. (rep./time NR)	75% of 1-RM (3 sets) increased to 85% of 1-RM (4 sets)	n/n y/NR	NR	Chocolate milk (80% casein 20% whey)	1×/d (at breakfast or after RT on training days)	14 g/500 mL	Actual intake: NR Compliance: NR	Isocal. (CHO) 0.4 g/500 mL
Rosendahl et al (2006) Sweden	91	14, 5/9 (15.4)	IG: 85.0 ± 6.7 CG: 85.5 ± 5.5	67/24	NH	Dependent (ADL)	12	12 wk 2.5×/wk	LL/FW	Ex. NR 8-12 rep. (45 min)	13-15 RM (first 2 wk) then 8-12 RM. Increased load when >12 rep.	n/y n	75	Milk based	After RT	14.8 g/200 mL	Actual intake: NR Compliance IG: 82 CG: 78	Non-isocal. (CHO) IG vs CG: 408 kJ vs 191 kJ
Shahar et al (2013) Kuala Lumpur	34	0	IG: 65.20 ± 4.87 CG: 69.74 ± 5.46	NR	CD	Sarcopenic	5	12 wk, 2×/wk	NR/RB	9 ex. (30 min of RT)	Elastic bands, different tension levels	y/y y/G (NR)	NR	Soy	1×/d (timing optional)	F: 40 g M: 20 g/powder form	Actual intake: NR Compliance: NR	None
Thomson et al (2016) Australia	179	96, 27/38/39 (53.6)	IG1: 61.3 ± 6.9 IG2: 61.7 ± 8.3 CG: 61.5 ± 6.9 Range: 50-79	98/81	CD	Healthy	8	12 wk, 3×/wk	LL and UL/WM	5 ex. 8-12 rep 3 sets	8-RM. Increased load when >12 rep. in all 3 sets	n/n y/NR	IG1: 91.4 ± 7.3 IG2: 93.2 ± 6.8 CG: 92.9 ± 7.4	Eucaloric diet, aiming to provide 1 g protein/kg/d. In addition: IG1: milk-based IG2: soy	3×/d (at breakfast, lunch, dinner, or one time after RT on training days)	IG1 + IG2: 27 g/300-475 mL + powder + 100-200 g yoghurt	Actual intake: IG1: 1.42 ± 0.14 IG2: 1.45 ± 0.14 CG: 1.08 ± 0.05 Compliance: IG1: 97.0 ± 3.5 IG2: 98.1 ± 3.1 CG: 98.4 ± 2.2	Isocal. (orange juice + biscuits)
Tieland et al (2012) Netherlands	62	11, 5/6 (17.7)	IG: 78 ± 9 CG: 79 ± 6	41/21	CD	Frail elderly	12	24 wk, 2×/wk	LL and UL/WM	6 ex. 10-15 rep. 4 sets on LL and 3 sets on UL	50% of 1-RM increased to 75%	n/n y/I	83 ± 2	Milk-based (80% casein 20% whey)	2×/d (after breakfast/lunch)	30 g/500 mL	Actual intake: IG: 1.3 (1.1-1.5) CG: 0.9 (0.8-1.1) Compliance: NR	Isocal. (CHO)
Trabal et al (2015) Spain	30	19, 8/11 (63.3)	IG: 85 ± 8 CG: 84 ± 4	NR	NH, day care centers	Healthy	10	12 wk, 3×/wk	LL/NR	5 ex. 8 rep. 1 set increased to 2 sets of 15 rep. (40 min)	65% of 8-15 RM	n/y y/NR	NR	Leucine	2×/d (60 min after lunch/dinner)	10 g/NR	Actual intake: IG: 1.20 (1.11-1.30) CG: 1.23 (1.11-1.35) Compliance: NR	Isocal. (10 g maltodextrin)
Verdijk et al (2009) Netherlands	28	2 NR/NR (7.1)	Mean: 72 ± 2	All M	CD	Healthy	12	12 wk, 3×/wk	LL/WM	2 ex. 10-15 rep. and 4 sets, decreased to 8-10 rep. at higher intensity	60% of 1-RM (10-15 rep.) increased to 75%-80% of 1-RM (8-10 rep.)	n/n y/NR	97	Casein hydrolysate	Before and after RT	20 g/500 mL	Actual intake: IG: 1.1 ± 0.1 CG: 1.1 ± 0.1 Compliance: NR	Non-isocal. (flavored water)

Abbreviations: ADL, activities of daily living; CD, community dwelling; CG, control group; CHO, carbohydrate; EAA, essential amino acids; ex., exercises; F, female; FW, free weights; G, group supervision; I, individual supervision; IG, intervention group; isocal., isocaloric; LL, lower limb; M, male; n, no.; NH, nursing home; NR, not reported; RB, resistance bands; Rep., repetitions; RM, repetition maximum; RT, resistance training; SB, Swiss Ball; UL, upper limb; WM, weight machines; y, yes.

Refer to Table 3 for explanation.

Quality assessment

The quality of the included studies was assessed using a modified version of the Physiotherapy Evidence Database (PEDro) scale.¹² The assessment was based on 12 questions concerning the study design and statistical reporting, important regarding evaluating the risk of selection bias, ascertainment bias, and withdrawal bias. One point was given for each fulfilled criteria. Thus, a total of 12 points could be achieved, and the higher the score, the higher the quality. Furthermore, any statements of conflicts of interests were assessed for the individual studies.

Results

Selection of eligible studies

Figure 1 shows a flowchart detailing the study selection process. A total of 2679 articles were identified through the 4 database searches. After screening titles and abstracts, 43 articles were selected for full-text screening. Of these, 27 studies were excluded. Thus, 16 studies met all the eligibility criteria and were included in this review, with a total of 1107 participants. A reference list of the 27 excluded studies can be sent on request by contacting the corresponding author.

Figure 1.

Flowchart of the study selection process.

Regarding the search for gray literature in clinicaltrials.gov, a total of 378 studies were found. Of these, only 14 matched the inclusion and exclusion criteria: 5 were already included, 3 were still recruiting, 1 was active but not recruiting, 1 was terminated and 4 were completed, but it was not possible to find any published articles in the databases.

Study characteristics

Table 2 shows the characteristics of the 16 included studies, which are summarized in the following sections. Because of great methodological differences between the studies, it was not possible to conduct a meta-analysis. Thus, the results of study findings are evaluated in a descriptive manner.

Participant details

The studies are published between the years 1994 and 2016, from all over the world, and have a median study population size of 61 (16-179). The median dropout rate was 11.7% (0-63.3), reported by 15 of the studies. There was no difference in dropouts within groups (reported by 11 of the 15 studies) (Table 2). The mean age of participants in both study groups was as follows: >60 = 3 studies,^13–15 >65 = 2 studies,^16,17 >70 = 4 studies,^18–21 >75 = 3 studies,^22–24 >80 = 2 studies,^25,26 and >85 = 2 studies.^27,28 Seven studies included both men and women,^{15,16,18,24,25,27,28} 2 and 4 studies included only women^19,23 and men,^13,14,20,21 respectively, whereas 3 studies did not report on sex.^17,22,26 Regarding settings, 11 studies were conducted on older adults living in the community, whereas 4 studies were in institutionalized older adults (nursing homes),^25–28 and 1 study did not report on setting.¹⁴ Ten of the studies included healthy older adults,^{13,15,16,18–21,25–27} 3 studies included only sarcopenic older adults,^14,17,23 1 study included only frail older adults,²⁴ and 2 studies included healthy but in some way dependent older adults (mobility-limited and dependent in activities of daily living).^22,28

Study quality

The median study quality of the 16 studies is 11 (5-12). The quality of the individual studies is summarized in Table 3. The likelihood of publication bias is not assessed as only a few studies are having the same end points. All studies declare no conflicts of interest, except from 2 studies where it has not been reported.^20,28

Table 3.

Assessment of study quality.

Question	Author (year)
Question	Arnarson et al (2013)	Carlson et al (2010)^a	Chale et al (2013)	Constantin et al (2013)	Daly et al (2014)	Fiatarone et al (1994)	Gryson et al (2014)	Kim et al (2012)	Leenders et al (2013)	Maltais et al (2015)	Mitchell et al (2015)	Rosendahl et al (2006)	Shahar et al (2013)	Thomson et al (2016)	Tieland et al (2012)	Trabal et al (2015)	Verdijk et al (2009)
1. Specified eligibility criteria	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
2. Subjects randomly allocated to groups	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	NR	Y	Y	Y	Y
3.Concealed allocation	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	NR	Y	NR	Y	Y	Y	Y
4. Groups were similar at baseline regarding the most important prognostic indicators	Y	Y	Y	Y	Y	N	NR	Y	Y	Y	NR	Y	Y	Y	Y	Y	Y
5. Blinding of all subjects	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y	Y	NR	NR	Y	Y	Y
6. Blinding of all therapists who administered the therapy	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	NR	Y	NR	Y	Y	Y	Y
7. Blinding of all assessors who measured at least 1 key outcome	Y	Y	Y	Y	N	N	Y	Y	Y	Y	NR	Y	NR	Y	Y	Y	Y
8. Measures of at least 1 key outcome were obtained from more than 80% of the subjects initially allocated to groups	Y	Y	Y	NR	Y	NR	Y	Y	Y	Y	NR	Y	NR	N	Y	N	Y
9. Dropout rate between groups ≤15%	Y	Y	Y	NR	Y	NR	NR	Y	NR	NR	NR	Y	NR	N	Y	N	Y
10. Analyzed by “intention to treat”	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y
11. Results of between-groups statistical comparisons are reported for at least 1 key outcome	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y
12. Both point measures and measures of variability for at least 1 key outcome	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y

Abbreviations: N, no; NR, not reported; Y, yes.

Developed with inspiration from the PEDro (Physiotherapy Evidence Database) scale.¹²

A total score from 0 to 12 is given. Every question satisfied (illustrated by “Y”) gives a score of 1.

Intervention characteristics

Most of the studies (13 out of 16) included 2 comparison groups (RT and RT + protein/EAA supplement), whereas 3 studies used a factorial design with 3 arms (RT, RT + nutritional supplement type 1, and RT + nutritional supplement type 2).^13–15 The median duration of the combined intervention was 12.5 weeks (5-12).

Protein supplementation

The protein source is somewhat different in the 16 studies. Two studies provided whey protein,^18,22 1 study casein hydrolysate,²¹ 7 studies report that they provided a milk-based supplementation,^{13,15,16,20,24,25,28} 2 studies provided EAA (leucine),^23,26 3 studies provided soy protein,^15,17,27 1 study provided leucine in combination with soy- and milk-based protein (3 arms),¹⁴ 1 study provided the extra protein from lean meat sources,¹⁹ and 1 study provided the extra protein as a milk-based supplementation high in leucine¹³ (3 studies with 3 arms). In 5 of the 7 studies providing a milk-based supplementation, it is reported,^13,16,24 or otherwise evident from the protein source used,^15,20 that the milk-based supplementation contains 80% casein and 20% whey protein.

Regarding frequency and timing of the supplementation, in most of the studies (11 studies), the participants are daily supplemented,^{13,15–17,19,20,22–24,26,27} with the timing being somewhat different ranging from 1 to 3 times per day (Table 2). Four studies gave supplements only after RT,^14,18,25,28 which corresponded to 2.5 to 3 times per week, and 1 study gave supplements both before and after RT 3 times per week.²¹

The total amount of protein being supplemented varies among the studies with a median dose of 20 (10-45) g. In the 11 studies that provided a daily supplementation, the median intake was 27 (10-45) g/d. The 2 studies that supplemented with EAAs gave 6 and 10 g/d, respectively.^23,26 The 5 studies that gave the supplementation before and/or after RT had total doses in the range of 14.8 to 20.53 g per training session.^{14,18,21,25,28}

In 9 studies, the supplement was being provided as a ready-to-drink beverage in volumes ranging from 200 to 500 mL.^{14,16,18,20,21,24,25,27,28} Three studies provided protein or EAA powder without giving details on how it was mixed.^17,22,23 In 1 study, the extra protein was provided as lean meat sources,¹⁹ and 1 study provided the extra protein both as a ready-to-drink beverage, yoghurt, and lean meat sources.¹⁵ Two studies did not report how the supplement was provided.^13,26 Regarding the control group, in 6 studies, the control group received an isocaloric placebo supplementation^{15,18,20,22,24,26}; in 8 studies, the placebo supplementation was nonisocaloric^{13,14,16,19,21,25,27,28}; and 2 studies did not have any placebo.^17,23

Compliance to the intervention is reported in only 6 of the 16 studies.^{15,19,22,25,27,28} Combining compliance rates for the 6 studies, the median compliance is 83% (72.1-99) in the intervention groups and 90.35% (78-100) in the control groups (Table 2). Of the 16 studies, 8 have a measure of the actual total protein intake in the groups.^{14,15,18,19,21,22,24,26} Combining their results, the intervention groups have a median intake of 1.205 g protein/kg/d (0.95-1.45), whereas the control groups have a median intake of 1.065 g protein/kg/d (0.89-1.20) (Table 2).

Strength training

Training frequency varies across the studies. In 4 studies, the participants were doing RT 2 times per week^17,19,23,24; in 2 studies, it was 2.5 times per week^25,28; and in 10 studies, 3 times per week.^{13–16,18,20–22,26,27} Nine of the studies included strength exercises targeting both the lower and upper body, 6 studies included exercises only for lower body strength, and 1 study did not report on this. Nine of the studies included only RT, whereas 2 studies also included cardio and balance exercises, and 4 studies included balance exercises in addition to RT (Table 2). The type of equipment used for the RT varies between the studies. In the 14 studies stating this, weight machines, free weights, Swiss Balls, resistance bands, or a combination of up to 2 types of these equipment were used (Table 2). All training programs were progressive, targeting from 50% to 80% of 1 repetition maximum (RM). The number of different RT exercises per training session varies from ≥2 to 12 in the 14 studies reporting this. Of the 16 studies, 10 report the number of sets performed with a median of 3 sets.^1–4 In all, 14 studies report number of repetitions used doing RT. The most frequently used is 8 to 12 repetitions, also 6 to 8 repetitions and 10 to 15 repetitions are used, in the lower end and higher end, respectively. Five studies report the time used for RT, with 3 studies reporting 45 minutes and 2 studies 60 minutes (Table 2). The body position while performing the exercises is specified only in 7 studies: seated,^18,21,27 standing,^19,25 and seated + standing.^23,26 In the rest of the studies, for some of their described exercises, it is unclear whether they are performed seated, in standing, or while lying down (not shown in Table 2). In 15 studies, the RT was supervised, whereas in 1 study, this is unclear.²⁸ Eight of the studies specify the type of supervision. In 2 studies, the RT is individually supervised,^24,27 whereas in 6 studies, the supervision is conducted in groups.^{13,17-19,23,25} Only 3 of these studies report the number of participants in the groups: 20 to 30,¹⁸ ≤8,¹⁹ and 3 to 9.²⁵ Two studies specify that the RT is supervised by physiotherapists,^25,26 and in 7 studies, it is specified that the RT is performed by an exercise instructor/coach/specialist^{13,15,17–19,23,27} (not shown in Table 2). Twelve studies provide information on RT compliance. Regarding the mean compliance in both groups, 3 studies report compliance rates ≥70%,^19,22,23 2 studies ≥75%,^25,28 1 study ≥80%,²⁴ 3 studies ≥90%,^14–16 2 studies ≥95%,^21,27 and 1 study 100%.¹³ Of the 12 studies, 6 give information about the compliance rate in both/all groups, which in all 6 studies was not significantly different.^{13,15,19,22,23,27}

Outcomes

The end point measures and any effect of protein or EAA supplementation in addition to prolonged RT are summarized in Table 4.

Table 4.

Major outcome measures and summary of results.

Author (year)	Outcomes		Effect of protein/EAA	Comment^a
Arnarson et al (2013)	Body composition Muscle strength Physical function	LBM, ALBM (DXA) Knee extensor isometric MVC TUG, 6-min WD	NS	Training effect: all parameters
Carlson et al (2010)	Body composition Physical function	LBM, FM, BW, ICW (BIS) Berg balance test	NS	Training effect: Berg balance test. Negative training effect: MM and BW↓
Chale et al (2013)	Body composition Muscle strength Physical function	LBM, FM, BW (DXA), thigh CSA (CT) 1-RM leg press; L/R 1-RM knee extension, 10× chair stand time SPPB (balance test, 4-m gait speed, 5× chair stand time), stair climb speed, 400-m gait speed	NS	Training effect: all parameters
Daly et al (2014)	Body composition Muscle strength Physical function	LBM, FM, %FM, leg LBM, arm-LBM (DXA), thigh CSA (CT) 1-RM leg extension, 30-s CST 4-square step test, TUG	LBM↑ (P = .007), leg LBM↑ (P < .05) Leg extension strength↑ (P = .010)	Training effect: physical function parameters and 30-s CST
Fiatarone et al (1994)	Body composition Muscle strength Physical function	BW, BMI, mid-thigh circumference, thigh CSA (CT scan) 1-RM leg strength (sum of L/R knee and hip extensors) 6-m gait speed, stair climb speed	NS	Training effect: all parameters
Gryson et al (2014)	Body composition Muscle strength Physical function	BW, BMI, LBM, %FM, trunk-FM, ALBM (DXA) Knee extensor isometric MVC Aerobic fitness (Vo₂max, VEmax)	%FM↓ (IG1 + IG2) (P < .02) Knee extensor strength↑ (IG1 + IG2) (P < .01)	Training effect: most parameters, but increase in LBM IG1 + IG2 and decrease in CG (NS)
Kim et al (2012)	Body composition Muscle strength Physical function	LBM, ALBM, leg LBM (BIA), BMI, Calf-circumference Knee extensor isometric MVC Self-paced and maximum gait speed	NS	Training effect: ALBM and gait speed
Leenders et al (2013)	Body composition Muscle strength	LBM, FM, %FM, leg LBM, leg FM (DXA), quadriceps muscle CSA (CT), muscle fiber size (biopsy) 1-RM leg press; 1-RM leg extension; HGS, 5× chair stand time	NS	Training effect: all parameters (also when divided into men and women)
Maltais et al (2015)	Body composition Muscle strength Physical function	LBM, FM (DXA), Muscle mass index 5× chair stand time, 1-RM lateral pull-down 4-m gait speed, TUG, standing balance test, 1-leg stand	TUG (soy + EAA-group) (P < .05)	Training effect: LBM, ALBM, and at least 1 strength parameter
Mitchell et al (2015)	Body composition Muscle strength	Muscle fiber size (biopsy) 1-RM leg press, 1-RM leg extension, 1-RM chest press, knee extensor isometric MVC	NS	Training effect: all parameters
Rosendahl et al (2006)	Muscle strength Physical function	1-RM leg press, chair rise ability with arms across the chest Berg Balance test, 2.4-m self-paced and maximum gait speed	NS	Training effect: all parameters
Shahar et al (2013)	Body composition Muscle strength Physical function	LBM, %FM, muscle (kg), % body water (BIA), BW, BMI, waist circumference HGS Senior Fitness Test (20-s CST, arm curl test, hair sit-and-reach test, back scratch test, 8-ft up and go test, 6-min WD)	% Body water ↑ in CG (P < .000) 20-s CST (P < .000)	Training effect: most body composition and physical function parameters Negative training effect: HGS
Thomson et al (2016)	Body composition Muscle strength Physical function	LBM, FM, %FM (DXA), BW, BMI, waist circumference HGS, knee extensor isometric MVC, 8-RM leg press, 8-RM chest press, 8-RM knee extension, 8-RM lateral pull-down, 8-RM leg curl, total 8-RM (sum of all) 6-min WD, health-related quality of life (SF-36v2)	NS	Training effect: LBM, all strength and physical function parameters Negative training effect: BW↓, FM↓, waist circumference
Tieland et al (2012)	Body composition Muscle strength Physical function	LBM, FM, ALBM (DXA), BW 1-RM leg press, 1-RM leg extension, HGS SPSS (balance test, 4-m gait speed, 5× chair stand time)	LBM↑ (P = .006), FM↑ (P = .001), ALBM↑ (P < .001), BW (P = .009)	Training effect: all strength and physical function parameters
Trabal et al (2015)	Body composition Muscle strength Physical function	BW, BMI, mid upper arm muscle area, triceps skinfold, calf-circumference Leg flexion overcoming isometric strength PPB (standing balance test, TUG, 4-m gait speed, 5× chair stand time), health-related quality of life (SF-36), GDS, Barthel Index	MUAMA↑ (P = .002) TUG (P = .032)	Training effect: most strength and physical performance parameters Leg flexion strength IG↑ (P = .056)
Verdijk et al (2009)	Body composition Muscle strength	LBM, FM, %FM, leg LBM, %FM leg (DXA), quadriceps muscle CSA (CT and biopsy) 1-RM leg press, 1-RM leg extension	NS	Training effect: all parameters

Abbreviations: ALBM, appendicular lean body mass; BIA, bioimpedance analysis; BIS, bioimpedance spectroscopy; BW, body weight; CSA, cross-sectional area; CST, chair stand test; GDS, Geriatric Depression Scale; CT, computed tomography scan; EAA, essential amino acid; FM, fat mass; HGS, handgrip strength; ICW, intracellular water; L, left; LBM, lean body mass (synonym with fat-free mass); MVC, maximum voluntary contraction; MUAMA, mid upper arm muscle area; MVE, maximum voluntary extension; RM, repetition maximum; R, right; PPB, physical performance battery; S, significant result (P ≤ .05); SPPB, Short Physical Performance Battery; TUG, Timed Up and Go; VE_max, maximum ventilation; VO_2max, maximum oxygen uptake; NS, nonsignificant result (P > .05); WD, walking distance; 30-s CST, 30-second chair stand test. ↑ = increase; ↓ = decrease.

“Training effect” refers to improvements in both groups. “Negative training effect” refers to decline in both groups.

Body composition

In total, 15 studies investigated the effect on body composition with 22 different outcomes assessed in total. The most frequent outcome is lean body mass (LBM) (12 studies), followed by measures of fat mass (kg and/or %) (10 studies), body mass index, and body weight (7 studies), thigh or quadriceps cross-sectional area (5 studies), and appendicular LBM and leg LBM (4 studies). Assessment of LBM was performed using dual-energy X-ray absorptiometry in 9 studies, bioimpedance analysis in 2 studies, and bioelectrical impedance spectroscopy in 2 studies (Table 4). Of the 15 studies, 4 find a significant effect of protein and/or EAA supplementation on 8 different outcomes assessed in total.^13,19,24,26 Two studies find an positive effect on LBM,^19,24 1 study on leg LBM,¹⁹ 1 study on appendicular LBM,²⁴ 1 study on mid upper arm muscle area,²⁶ and 1 study on body weight.²⁴ Regarding measures of fat mass, 1 study finds a significant increase in fat mass (kg) in the intervention group,²⁴ whereas another study finds a significant larger decrease in fat mass (%) in the 2 intervention groups compared with the control group.¹³ Furthermore, 1 study finds a significant increase in body water (%) in the control group compared with the intervention group where the value does not change.¹⁷

Muscle strength

A total of 15 studies investigated the effect on muscle strength with 19 different outcomes assessed in total. Of these, 5 outcomes are measures of upper body strength, whereas 14 outcomes are measures of lower body strength. The most frequent outcome is 1 RM leg press (6 studies), followed by knee extension isometric maximal voluntary contraction (MVC), 1-RM leg extension, 5× chair stand test (5 studies each), and handgrip strength (4 studies) (Table 4). Of the 15 studies, 3 find a significant effect of protein and/or EAA supplementation on 3 different outcomes: 1 study on leg extension strength,¹⁹ 1 study on knee extension isometric MVC,¹³ and the last study on 20-second chair stand test.¹⁷ A fourth study finds a tendency toward a positive effect on leg flexion strength (P = .056).²⁶ No studies find a negative effect.

Physical function

A total of 13 studies investigated the effect on physical function with 20 different outcomes assessed in total. Of these, 5 outcomes measure gait speed but during different distances, and 4 outcomes assess balance in some way. Combining the measures of gait speed and balance, the most frequent outcome is gait speed (8 studies), balance (7 studies), and timed up-and-go test (TUG) (4 studies) (Table 4). Of the 15 studies, 2 find a significant effect of protein and/or EAA supplementation on the TUG test.^14,26 No studies find a negative effect.

Effect of RT

All of the studies find a positive effect of the training intervention, defined as an improvement in both groups for the outcome assessed. In some studies, the training effect is seen for all 3 parameters (body composition, muscle strength, and physical function), and in others, it is only certain parameters (Table 4). Three studies find a negative effect of RT, defined as a decrease/deterioration in both groups for the outcome assessed. One study finds that muscle mass and body weight decreases²⁵; one study finds that fat mass, body weight, and waist circumference decreases¹⁵; and the last study finds that handgrip strength decreases.¹⁷

Discussion

The aim of this systematic review was to summarize the results of RCTs investigating the effect of protein or EAA supplementation during prolonged RT on body composition, muscle strength, and physical function parameters in older adults. Thus, it adds knowledge about effective primary and secondary prevention strategies and interdisciplinary rehabilitation practices to counteract sarcopenia in this population. This is relevant for those working in rehabilitation, eg, clinical, residential, and community settings. Also, to the healthy older adults, who themselves want to delay the development or progression of sarcopenia and loss of independence, this review is relevant. Sixteen studies were eligible and included in this review. Despite strict inclusion and exclusion criteria, the identified studies were too different with respect to their study design (intervention and RT protocols, outcomes assessed, tests and techniques used to assess outcomes, and population) to allow for statistical pooling of the data. Of the 16 studies, 6 find a significant effect of protein and/or EAA supplementation during prolonged RT on one or more end points of body composition (3 studies); (not counting those studies finding changes in body water and fat mass), muscle strength (3 studies); and physical function (2 studies). Thus, altogether, the evidence of an additive effect is weak and inconsistent. Furthermore, this review supports previous literature showing that RT is a potent strategy to counteract age-related decline in LBM and strength.²⁹ All studies have at least one outcome parameter (many have several or all of them) showing an independent effect of RT, manifested as an improvement in both groups. The study finding a negative effect on muscle mass and body weight hypothesizes that this could be due to dietary intakes below requirements.²⁵

This is the first systematic review on this topic to exclude RCTs if the intervention, besides protein or EAA, consisted of other ingredients known to stimulate muscle protein synthesis and/or affect muscle strength or physical performance. For example, some studies find an effect of vitamin D on muscle mass and strength with supplementation doses as low as 0.5 to 1 µg/d,³⁰ and a meta-analysis found evidence that creatine supplementation has an effect on body weight, LBM, and muscle strength when combined with RT.³¹ Another example is fish oil supplementation that has been shown to enhance the effect of RT in elderly women.³² In this review, we want to be sure that any effects can be attributed only to the extra protein or EAA supplementation. It is relevant to know the effectiveness of individual components, eg, in daily clinical practice, where some interventions might be more expensive or harder to adhere to than others. However, it is known that protein/EAA source matter in relation to muscle building.³³ Also, the influence of the timing in the intake of protein/EAA in relation to the RT is investigated in many studies, with more ambiguous results.³⁴ It is, however, not the specific aim of this review to address these explicit research questions, even though different indications from the included studies, of what might give the highest treatment effects, are sought.

Looking in more detail into the eligible studies, no obvious resemblances, such as intervention dosage, timing, protein source, or RT regimen, exist between those studies finding a significant effect and those who does not. An exception is regarding the study population investigated. It points toward that those who are most weak might benefit more. Of the 6 studies finding a significant effect, 2 of them included only sarcopenic older adults^14,17 and 1 of them included frail older adults.²⁴ Three of the studies included healthy older adults^13,19,26 but the study by Trabal et al²⁶ included only healthy nursing home residents who were very old, with mean ages above 84 years. They do not report how many of the included participants were sarcopenic, but with the prevalence being as high as 50% after the age of 80 years,² we assume that a great part of these participants were sarcopenic. Also, among nursing home residents, the prevalence of malnutrition is higher than in community dwelling,³⁵ and malnutrition is a great risk factor for the development of sarcopenia.² As a contrast, of the 10 studies finding no significant effects, 9 of them were performed on healthy older adults,^{15,16,18,20–22,25,27,28} and only 1 of them included sarcopenic participants.²³ Further research is needed to confirm whether those who are most weak truly benefit more than those who are healthy. This knowledge will be very relevant for health care providers in the daily clinical practice working with rehabilitation of older adults.

A hypothesis expressed in many previous reviews and meta-analyses^5–10 is that those individuals with a low habitual dietary intake of protein might benefit more from protein supplementation with respect to gains in muscle mass and strength. This would most likely apply to sarcopenic or frail institutionalized older adults, as this is a population at higher risk of a low dietary intake when compared with healthy community-dwelling older adults.³⁵ It could also be speculated that chronic or acutely ill older adults with increased protein requirements,³⁶ might benefit more. In this review, only 9 studies report the baseline protein intake of their participants,^{14,16–19,21,22,24,26} which is in the range of 0.85 to 1.25 g protein/kg/d (Table 2). Older adults are recommended to consume 1.0 to 1.2 g protein/kg/d.³⁶ Therefore, the study participants’ quite high habitual protein intakes could, according to the above-mentioned hypothesis, be the reason why some of the studies fail to find any additional effects. Having said this, 4 of the 6 studies finding a significant effect report baseline mean habitual intakes ≥1 g protein/kg/d in both groups.^14,19,24,26 However, in support of the hypothesis, older adults who are exercising or otherwise active are recommended intakes of 1.2 g protein/kg/d or higher.³⁶

Most of the included studies have a high quality (Table 3), which is a strength for the overall conclusion of this review. This said, only 5 of the studies specify the number of subjects needed to obtain adequate power,^{15,16,18,19,24} and of those, only 3 studies actually manage to recruit this number of participants.^16,18,24 In a meta-analysis conducted by Cermak et al,¹⁰ no significant effects were seen in the individual 5 studies conducted on older adults, but an effect was evident when results were pooled (total n = 215).¹⁰ In another meta-analysis conducted by Hidayat et al,¹¹ an overall significant effect was seen when combining all studies, but in a subgroup analysis, it was shown that the effect was significantly higher in those studies with ≥55 participants compared with those studies with <55 participants.¹¹ Thus, study size matters, and if most of the studies included in this review are statistically underpowered, this could also be an explanation for why many of the studies fail to show an effect of protein or EAA supplementation in addition to prolonged RT.

Another strength of the included studies in this review is the quite high compliance to both the supplementation and the RT (Table 2). This said, a major confounding factor is the participants’ level of daily physical activity besides the RT intervention, which can have a major impact on the amount of LBM aggregation and muscle strength improvement. Only 2 studies report the total physical activity time for the 2 groups during the intervention period,^14,19 and 1 study mentions that the habitual physical activity level did not differ between the groups at baseline and did not change over time.¹⁶ Another major confounding factor is the actual intake of total protein from the diet and the supplements. Only half of the studies in this review measure the total protein intake, and of the 8 remaining studies, only 3 of them measure compliance to the supplements. Several questions arise without these measures. Is the supplemental dose insufficient or is it because the participants are noncompliant? Or is the lack of effect due to a reduction in dietary protein intake secondary to a reduction in appetite caused by the protein supplementation, which could lead to no substantial changes in total protein intake between groups?

Limitations of this systematic review are the low number of eligible studies and the fact that pooling of data was not possible due to the broad range of rehabilitation intervention strategies. The potential influence of publication bias is also present. Furthermore, the populations investigated have many potential confounding factors such as comorbidities and side effects to medications. As this review excluded older adults with specific medical conditions, such as diabetes or chronic obstructive pulmonary disease, the findings only apply to older adults with general age-related medical conditions. Furthermore, none of the studies included exclusively malnourished or hospitalized older adults, which would be very interesting populations to investigate in future research. The heterogeneity of the rehabilitation interventions and populations investigated in the included studies means that conclusions should be taken with precautions. Ideally, future research studies should be conducted in a more similar manner to allow for meta-analysis and to provide stronger evidence-based recommendations on the best rehabilitation strategies for specific populations of older adults.

Conclusions

The evidence is weak and inconsistent, as benefit of protein or EAA supplementation in addition to RT is shown in some studies but not all. This review indicates that frail and sarcopenic older adults might benefit more than healthy older adults. This is especially relevant for those working in the primary care sector. However, further research is needed to verify this and to allow for an interpretation on the importance of study design/rehabilitation strategies and population.

Footnotes

Acknowledgements

Public trials registry: The study has been registered at PROSPERO, Centre for Reviews and Dissemination, with registration number CRD42017063808.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

JG conceived the overall study draft. JG, RJP, and AMB created the detailed review protocol. JG and RJP searched the databases, and extracted the relevant data. JG drafted the manuscript, apart from the methods section, drafted by RJP. All authors reviewed the article critically and contributed significantly to the final content, which they all approved of.

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