Effect of physical activity on the risk of frailty: A systematic review and meta-analysis

Wenjing Zhao; Peng Hu; Weidi Sun; Weidong Wu; Jinhua Zhang; Hai Deng; Jun Huang; Shigekazu Ukawa; Jiahai Lu; Akiko Tamakoshi; Xudong Liu

doi:10.1371/journal.pone.0278226

. 2022 Dec 1;17(12):e0278226. doi: 10.1371/journal.pone.0278226

Effect of physical activity on the risk of frailty: A systematic review and meta-analysis

Wenjing Zhao ^1,^2,^#, Peng Hu ^3,^4,^#, Weidi Sun ⁵, Weidong Wu ⁶, Jinhua Zhang ⁷, Hai Deng ⁸, Jun Huang ⁹, Shigekazu Ukawa ¹⁰, Jiahai Lu ³, Akiko Tamakoshi ^2,^*, Xudong Liu ^4,^*

Editor: Mohammad Meshbahur Rahman¹¹

PMCID: PMC9714708 PMID: 36454790

Abstract

Objective

The relationship between physical activity (PA) and the risk of frailty has not reached a conclusive result. This systematic review with meta-analysis aimed to evaluate the effect of PA on the onset of frailty in the community-dwelling middle and older age adults by pooling data from cohort studies.

Methods

A systematic literature search was performed via PubMed, Embase, and Web of Science up to June 01, 2021. Pooled adjusted effect estimates (ES) with 95% confidence interval (CI) were calculated by using the random-effect model and by comparing the highest with lowest levels of PA. Heterogeneity was tested using the I² statistic and Q-test. The quality of evidence was evaluated by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Results

A total of ten cohort studies with 14 records were selected, and the GRADE approach classified the quality of evidence as low. In comparison with the lowest level of PA, the highest level of PA was associated with 41% decreased odds of frailty (ES: 0.59, 95% CI: 0.51–0.67; I² = 70.0%, P_{-heterogeneity} < 0.001) after pooling results from included studies. In stratified analysis by frailty assessment approach, the highest level of PA was significantly associated with 37% (ES 0.63, 95% CI: 0.52–0.77, 49% (ES: 0.51, 95% CI: 0.41–0.63), and 30% (ES: 0.70, 95% CI: 0.65–0.75) reduced odds of frailty when pooling studies using criteria of physical frailty, multidimensional model, and accumulation of disability, respectively. Stratified analyses further by PA indicators and PA assessment tools yielded similar protective effects in any subgroups.

Conclusions

This study with moderate-certainty evidence shows that a higher level of PA was associated with lower odds of frailty, and the benefits of PA for frailty prevention were independent of frailty assessment tools, PA indicators, and PA assessment methods. Findings from this study may help implement active exercise strategies to prevent frailty.

Introduction

Frailty is a transition state from healthy aging to disability. Age-related cumulative declines in physiological reserve and vulnerability to stressors promote the presence of frailty [1]. It is estimated that more than 10% of adults aged 65 years or above suffered from frailty in the world [2, 3] and the prevalence was even higher in the individuals living with cancer, heart failure, and other chronic diseases [4–6]. The frail adults aged 60 years or older living in the community are increasing globally at a speed of around 43 new cases per 1000 person-years [7]. Frailty is closely related to a range of adverse health-related events of falling [8], fractures [9], disability [10], hospitalization [11], and even mortality [12] in older residents. The failure to prevent frailty will continue to aggravate the burden of health care costs for individuals and countries [13, 14].

Physical activity (PA) can regulate the function of multiple systems in the body [1]; the dysfunction of these body system can further contribute to the development of frailty [1]. A systematic review [15], a scoping review [16], and a systematic review and meta-analysis [17] synthesized the evidence and found that exercise training can reduce the level of frailty and improve the prognosis of frailty among older adults. However, epidemiological studies on the relationship between PA and frailty did not reach to a consistent conclusion. For instance, Trombetti [18] and Pérez-Tasigchana [19] did not find any association between PA and frailty, while Borda [20] and Savela [21] reported that PA was a protective factor for frailty. A meta-analysis found that physical exercise therapy could improve mobility and physical functioning in elderly patients suffering from mobility problems, disability and/or multi-morbidity [22]; however, more original studies have been reported in the following decade, making it necessary to update the synthetic evidence. A more recent systematic review including four randomized controlled trials and two prospective cohort studies found that physical activity might be an effective intervention for preventing frailty mong people aged 65 years and older [23]; nevertheless, the intervention measures varied largely among four RCTs and one included RCT adopted combined nutrition and exercise interventions, limiting the application of the results. Moreover, this study [23] only included two cohort studies, but more cohort studies have been reported [18–21, 24–30]. In addition, there are many evaluation methods for frailty, and no unified standard has been formed [31]. Whether different methods of frailty assessment influence the association between PA and frailty onset is unclear.

Pan and colleagues published a registered protocol for systematic review and meta-analysis to demonstrate the association between PA and the risk of frailty in the old community-dwelling residents [32]; however, the related systematic review and meta-analysis has not been reported in the past three years. What’s more, this protocol [32] did not mention how to define frailty and whether synthesize the evidence by frailty definition or not.

Therefore, we conducted this systematic review and meta-analysis by synthesize evidence from cohort studies to examine the effect of PA on the onset of frailty among the community-dwelling middle and older age adults, so to provide evidence for frailty prevention for middle and order age adults.

Methods

Search strategy and selection criteria

This study was implemented according to the PRISMA guideline [33]. Three researchers (PH, WJZ, WDS) searched the literature independently. The group discussion with the other two researchers (XDL, TA) was conducted to resolve the dissidence. The literature was systematically searched from the inception to June 01, 2021, through three electronic databases of PubMed, Embase, and Web of science. The keywords and retrieval strategy were as follows: (‘physical activity’ OR ‘exercise’ OR ‘acute exercise’ OR ‘isometric exercises’ OR ‘aerobic exercise’ OR ‘physical exercise’ OR ‘endurance exercise’ OR ‘resistance exercise’ OR ‘strength exercises’ OR ‘training’ OR ‘exercise training’, OR ‘combined training’, OR ‘weight-lifting’ OR ‘running’ OR ‘jogging’ OR ‘swimming’ OR ‘walking’ OR ‘yoga’ OR ‘Tai chi’ OR ‘daily activity’ OR ‘lifestyle’ OR ‘sport’) AND (‘frailty’ OR ‘frailness’ OR ‘frailty syndrome’ OR and ‘debility’). A reverse reference citation tracking was also carried out to search for the possible literature. More details of the search strategy were shown in S1 Table.

Inclusion criteria were as follows: the exposure of PA including exposure intensity, frequency, duration, volume, step, or any specific type (such as leisure-time physical activities, occupational activities, and exercise, etc.) was reported; frailty and its assessment approaches (physical frailty, multidimensional approach, accumulation of disability, etc.) were reported; design of cohort studies; middle and older age healthy adults; the relationship between PA and frailty was evaluated; the study was published in English. Cross-sectional studies, animal studies, trials, reviews, editorials, letters, abstracts, and studies lacking data to manifest the relationship between PA and frailty were excluded after reviewing title, abstract or full-text.

Data extraction and quality assessment

The detailed information was extracted from the eligible studies including the first author of the studies, the publication year, study design, region, sample size, age (mean or median, range), the proportion of female individuals, the follow-up period, confounders, frailty assessment approach, PA assessment method, PA indicator, comparison of different PA levels and the corresponding effect estimates.

The quality of the included studies was assessed by using criteria of the Newcastle-Ottawa Scale (NOS) [34]. The maximum total score for NOS was 9 stars, including 4 for selection, 2 for comparability, and 3 for exposures assessment. A study would be classified as the quality of high (7–9 stars), moderate (4–6 stars), or low (1–3 stars) according to the total score obtained. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluated the quality of the body of evidence [35]. The GRADE approach was based on considerations such as study design, risk of bias, inconsistency, imprecision, indirectness, publication bias and other aspects reported by the included studies. The quality of the evidence was characterized as high, moderate, low, or very low.

Ethics statement

This study was approved from the Ethical Review Committee for Biomedical Research, School of Public Health, Sun Yat-sen University and from the Ethics Review Committee of Hokkaido University Graduate School of Medicine. The study was performed in accordance with the Declaration of Helsinki. The study was a systematic review and meta-analysis, the consent was waived for the study, and no patients were involved.

Statistical analysis

A meta-analysis was conducted to estimate the overall pooled effect estimates (ES) based on the adjusted odds ratio or hazard ratio and 95% confidence interval (CI), by comparing the highest with the lowest levels of PA [36]. For those studies which reported results from the comparison of the lowest with highest categories, the reciprocal method was used to transform the original effect [37]. The heterogeneity was assessed by using I² index and Q-test. I² value of more than 50% or P-value of Q-test less than 0.05 indicated heterogeneity, and then the random-effect model was used to calculate pooled ES; otherwise, the fixed-effect model would be applied [38]. Repeated analysis was further conducted to evaluate the contribution of each study to the pooled effect by omitting one study at a time. To seek the potential factors influencing the association of frailty risk with PA, subgroup analysis and meta-regression analysis were conducted based on the characteristics of the region (Europe and America, Asia), sample size (< 1000, ≥ 1000), female proportion (< 50%, ≥ 50%), age (< 70 years, ≥ 70 years), frailty assessment approach (physical frailty, accumulation of disability, or multidimensional approach), follow-up period (< 10 years, ≥ 10 years), PA indicators (Volume, frequency, intensity, duration, steps), PA assessment methods (Questionnaire or Uniaxial accelerometry sensor), and effect estimates (odds ratio, hazard ratio). The publication bias was analyzed by the Begg’s test, the Egger’s test, and the funnel plot. The P-value of the Begg’s test and the Egger’s test lower than 0.05 or the asymmetric funnel plot suggested the publication bias. All statistical analyses were conducted by using Stata 12.0 software (Stata Corporation, College Station, TX, USA).

Result

The study selection procedure is shown in Fig 1. The systematic review identified 8,193 articles from three electronic databases. About 1,749 articles were removed for duplication and 6,444 articles were removed after screening the title and the abstract. Among the 20 articles for further full-text reviewing, eight articles were excluded because the effect estimates were not provided or cannot be calculated, two were excluded for the cross-sectional design. Finally, 10 cohort articles [19–21, 24–30] were included in this systematic review and meta-analysis. The quality score of each study ranged from 6 to 9, depicting a moderate to a higher quality of included studies (S2 Table). By using GRADE approach, it is found that substantial heterogeneity was the main reason responsible for the limited quality of the evidence, whereas all plausible confounding factors were considered (S3 Table). Hence, the quality of the evidence from the outcomes evaluated by the GRADE system was assessed as low as a whole.

The general characteristics of the included studies are illustrated in Table 1. Yu et al. [30] reported the studies from three prospective cohorts in Hong Kong, Taiwan-urban and Taiwan-rural, so we divided this study into three cohorts for meta-analysis; Yuki et al. [28] evaluated the relationship between three dimensions of physical activity (daily number of walking steps, time of light-intensity physical activity, and time of moderate-to-vigorous intensity physical activity) and frailty risk among Japanese, and therefore we divided it into three records when doing meta-analysis. Among the other eight included studies, two studies were from Finland [21, 27], two from the UK [26, 29], one from Japan [25], one from the USA [24], one from Mexico [20], and one from Spain [19]. A total of 34,943 participants were included in this meta-analysis. The total samples of each study ranged from 401 to 7,420, and the frailty cases ranged from 48 to 2,300. The mean age of the participants in each study ranged from 47.5 to 75.38 years. One study only included male participants [21], and the other nine studies included both genders (approximately 44.40%–59.2% were females) [19, 20, 24–30]. The median follow-up year ranged from 3 years to 26 years. Two studies used hazard ratio to display the effect [26, 29] and others used odds ratio.

Table 1. General characteristics of the included studies^*.

Author, year, region	Total samples/, n	Frailty cases, n	Age, years, mean (SD), range	Female, n (%)	Follow-up, years, mean (SD)	Frailty assessment approach ^*	Frailty assessment approach classification	Statistical analysis	PA assessment method, PA indicator [comparison], evaluation year ^*	Effect estimator	Transformation of effect estimator by using the reciprocal of the original value ^†	Confounders
Pérez-Tasigchana et al. [19] 2020, Spain, Cohort Study	1038	107	70, ≥60	59.2	8	The FRAIL scale (fatigue, resistance, ambulation, weight loss, comorbidity)	Physical frailty	Logistic regression	Questionnaire: PA volume [vigorous/moderate Yes vs. Not], (2001)	OR 0.59 (0.34–1.01)	–	Age, gender, educational level, occupational status, BMI, abdominal obesity, hypertension, hypercholesterolemia, coronary heart disease, stroke, diabetes, history of hip fracture, cancer, and osteoarthritis
Borda et al. [20] 2020 Mexico Cohort Study	6087	2300	62.2 (8.5), >60	(44.8)	3	Frailty index (FI), (self-rated health, current health compared with prior health status, functional assessments self-reported chronic diseases, difficulty in basic ADL and instrumental ADL, self-reported common symptoms, 39 deficits)	accumulation of disability	Multivariate logistic regression model	Questionnaire: PA frequency [Exercise or hard physical ≥ 3 times/week vs. < 3 times/week], (2012)	OR 0.70 (0.70–0.80)	–	Age, sex, marital status, financial status, education level, physician visits
Savela et al. [21] 2013 Finland, Cohort Study	514	48	47.5 (4.1), NM	–	26	A modification of Fried criteria (questionnaires: shrinking, weakness, exhaustion, low PA)	Physical frailty	Multinominal logistic regression models	Questionnaire: LTPA intensity [high vs. low] (1974)	OR 0.23 (0.08–0.65)	–	Age, BMI, smoking, blood pressure, and alcohol consumption in 1974, comorbidity in 2000
Peterson et al. [24] 2009 USA, Cohort Study	2964	323	73.6 (2.9), 70–79	(51.0)	5	Gill frailty model (presence of functional limitations: gait speed < 0.60 m/s, or being unable to rise from a chair once with arms folded)	Physical frailty	Generalized estimating equation logistic regression models	Questionnaire: PA Intensity [Sedentary vs. Vigorous] (1997–1998)	OR 1.10 (0.75–1.63)	0.91 (0.61–1.33)	Age, sex, race, education, marital status, smoking status, drinking status, waist circumference, and count of diagnoses
Abe et al. [25] 2020 Japan, Cohort Study	2633	441	74.7 (6.5), ≥65	1367 (51.9)	5	the Kaigo-Yobo Checklist	Physical frailty	Multilevel multinomial logistic regression analysis	Questionnaire: PA frequency, [Exercise ≥ 3 vs < 3 days/week] (2012)	OR 0.77 (0.62–0.96)	–	Age, gender, BMI, subjective economic status, living arrangement, stroke, and diabetes
Niederstrasser et al. [26] 2019 England, Cohort Study	7420	2441	66.9 (10.1), ≥50	3945 (53.2)	12	Frailty index (disease-related symptoms, self-reported conditions, activities of daily living, mobility, cognition, chronic diseases, or self-rated health, vision, and hearing)	multidimensional approach	Cox proportional hazards regression models	Questionnaire: LTPA volume, [vigorous vs. sedentary] (2004/2005)	HR 0.46 (0.36–0.57)	–	Sex, age, pain, PA level, wealth quintiles, educational qualifications, smoking, lower body strength, loneliness and BMI and waist-hip ratio
Kolehmainen et al. [27] 2020 Finland, Cohort study	1137	319	56.0 (10.9), 60–77	522 (45.9)	13.6 (10.2)	a modification of Fried criteria (shrinking, exhaustion, weakness, low PA, and slowness)	Physical frailty	Binomial logistic regression analysis	Questionnaire: LTPA volume [high vs. Low] (1972–2007)	OR 0.38 (0.23–0.61)	–	Age at earlier life assessment, sex, BMI, education, follow-up time, earlier life chronic diseases, smoking, research centre and older age diseases.
Yuki et al. [28] 2019 Japan Cohort study	401	108	71.1 (4.3), 65–82	178 (44.4)	4.2 (3.4)	A modification of the Cardiovascular Health Study criteria (shrinking, exhaustion, weakness, low PA, and slowness)	Physical frailty	Generalized estimate equation	The uniaxial accelerometry sensor: steps number [<5000 vs. ≥5000 steps/d]; LPA [<40.3 vs. ≥40.3 min/d]; MVPA [<7.5 vs. ≥7.5 min/d] (2000.4–2002.5)	OR 1.85 (1.10–3.11) OR 1.35 (0.82–2.25) OR 1.80 (1.05–3.09)	0.54 (0.32–0.91) 0.74 (0.44–1.20) 0.56 (0.32–0.95)	Follow-up year, sex, age, body fat, education, current smoking, energy intake, number of comorbidities, and frailty status at baseline
Gil-Salcedo et al. [29] 2020 UK Cohort study	6357	445	50.4 (2.1), ≥50	1856 (29.2)	20.4 (5.9)	the Fried’s frailty phenotype (shrinking, weakness, exhaustion, low PA, slowness)	Physical frailty	Competing risk model	Questionnaire: PA duration [active vs. inactive] (1985, 1991, 1997 and 2002)	HR 0.66 (0.48–0.88)	–	Sex, ethnicity, marital status, wave of inclusion, education, occupational position, the number of morbidities at age 50, all other health behaviors.
Yu et al. (1) [30] 2017 Hong Kong Cohort study	4000	663	75.21 (6.73), ≥65	2000 (50.0)	14	The multiple deficits approach (self-reported medical and drug histories, functional assessments and psychological well-being, geriatric syndromes, 30 items)	multidimensional approach	Multiple logistic regression	Questionnaire: PA frequency [Low vs. high] (2001–2003)	OR 1.51 (1.27–1.81)	0.66 (0.55–0.79)	Sex, age, education, smoking, alcohol use, living alone, Area Under the Curve
Yu et al. (2) [30] 2017 Taiwan urban, Cohort study	963	317	75.23 (6.89), ≥65	440 (45.7)	22	The multiple deficits approach (self-reported medical and drug histories, functional assessments and psychological well-being, geriatric syndromes, 30 items)	multidimensional approach	Multiple logistic regression	Questionnaire: PA frequency [Low vs. high] (2003)	OR 2.03 (1.52–2.71)	0.49 (0.37–0.66)	Sex, age, education, smoking, alcohol use, living alone, Area Under the Curve
Yu et al. (3) [30] 2017 Taiwan rural, Cohort study	1429	538	75.38 (7.03), ≥65	687 (48.1)	22	The multiple deficits approach (self-reported medical and drug histories, functional assessments and psychological well-being, geriatric syndromes, 30 items)	multidimensional approach	Multiple logistic regression	Questionnaire: PA frequency [Low vs. high] (2003)	OR 2.29 (1.82–2.88)	0.44 (0.35–0.55)	Sex, age, education, smoking, alcohol use, living alone, Area Under the Curve

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*Abbreviation: PA: physical activity; ADL: living of activity living; BMI: body mass index; LPA: light-intensity physical activity (1.8–3.0 metabolic equivalent of task, METs); LTPA: Leisure-Time Physical Activity; MVPA: moderate to vigorous intensity physical activity (≥3 METs).

^†The transformation of effect estimator is the reciprocal the original value.

Frailty was evaluated by Fried’s or modified Fried’s criteria in four studies [21, 27–29], by Gill frailty model in one study [24], by questionnaires of the Kaigo-Yobo Checklist in one study [25], by the FRAIL scale in one study [19], by the multidimensional approach in two studies [26, 30], and by the accumulation of disability in one study [20]. The scales of the Kaigo-Yobo Checklist and the FRAIL scale were validated by Fried’s criteria and Gill frailty model was defined by the functional limitations; therefore, frailty assessed by Fried’s criteria, modified Fried’s criteria and Gill frailty model was considered as physical frailty [19, 21, 24, 25, 27–29]. One study with three records assessed PA with a uniaxial accelerometry sensor [28], and the other nine studies assessed PA with a questionnaire [19–21, 24–27, 29, 30]. Of the nine studies [19–21, 24–27, 29, 30], two studies evaluated PA with the common and official PA questionnaires for the old adults [19, 24], and the assessment of PA in other seven studies was with simple questions. Three studies assessed the PA frequency [20, 25, 30], three assessed the PA volume [19, 26, 27], two assessed the PA intensity [21, 24], one assessed the PA duration [29], and one assessed the steps and PA duration [28].

The random-effects model was used to calculate the pooled effect as the substantial heterogeneity was found (I² = 70.0%, P_{-heterogeneity} < 0.001). As shown in Fig 2, in comparison to the participants with the lowest level of physical activity, those with the highest level of physical activity were significantly associated with a decreased odds of frailty (pooled ES: 0.59, 95% CI: 0.51–0.67). Visual inspection of funnels plots did not find obvious asymmetry (Fig 3). Begg’s test (P = 0.584) and Egger’s test (P = 0.067) did not reveal any significant publication bias. Sensitivity analysis was conducted 14 times by omitting one record each time and no significant change was observed in each analysis (S1 Fig).

When stratified by frailty assessment approach and compared with participants with the lowest PA level, participants within the highest level of PA were associated with 37% (pooled ES: 0.63, 95% CI: 0.52–0.77), 49% (pooled ES: 0.51, 95% CI: 0.41–0.63) and 30% (pooled ES: 0.70, 95% CI: 0.65–0.75) reduced odds of frailty when pooling studies using criteria of physical frailty, multidimensional model, and accumulation of disability, respectively (Table 2). When stratified by PA assessment tools, a similar protective effect was observed for studies using questionnaires (pooled ES: 0.58, 95% CI: 0.50–0.68) and using Uniaxial accelerometry sensor (pooled ES: 0.61, 95% CI: 0.45–0.83), respectively. Stratified analysis was also performed according to PA indicators, the region, sample size, female proportion, age, effect estimates, and follow-up, and a consistent protective effect was found in any subgroups (Table 2). The forest plot of association between PA and the odds of frailty by PA indicators was shown in S2 Fig. The meta-regression analysis was further conducted by putting the characteristics one by one into the meta-regression model separately, and the results showed that the follow-up period (P = 0.012) contributed to the heterogeneity across the studies. Among the other characteristics, similarly no significant moderating effect was observed: region (P = 0.967), sample size (P = 0.446), female proportion (P = 0.643), age (P = 0.204), and frailty assessment approach (P = 0.168), PA measuring methods (P = 0.842), PA indicators (P = 0.647), and effect estimates (P = 0.636).

Table 2. Overall and subgroup meta-analyses on the association between physical activity and the risk of frailty.

Subgroups	Number of studies/records	Effect estimates (95% CI)	P_h ^*	I² (%)	P _B ^†	P _E ^#
All	14	0.59 (0.51–0.67)	< 0.001	70.0	0.584	0.067
Region
Asia	7	0.59 (0.49–0.71)	0.013	62.7	0.764	0.773
Europe and America	7	0.58 (0.46–0.73)	0.001	74.7	0.548	0.173
Sample size
<1000	5	0.53 (0.42–0.66)	0.347	10.4	0.806	0.694
≥1000	9	0.61 (0.52–0.71)	< 0.001	76.8	0.602	0.236
Female proportion
<50%	9	0.57 (0.48–0.68)	0.001	68.3	0.466	0.047
≥50%	5	0.59 (0.51–0.67)	0.003	75.6	1.000	0.815
Age
<70	5	0.68 (0.56–0.82)	0.143	41.7	0.221	0.481
≥70	9	0.55 (0.46–0.66)	0.003	65.1	0.917	0.617
Frailty assessment approach
Physical Frailty	9	0.63 (0.52–0.77)	0.068	45.1	0.175	0.038
Multidimensional model	4	0.51 (0.41–0.63)	0.019	69.9	1.000	0.288
Accumulation of disability	1	0.70 (0.65–0.75)	--	--	--	--
Follow-up period
<10 year	7	0.70 (0.66–0.75)	0.607	0.0	0.368	0.848
≥10 year	7	0.51 (0.42–0.61)	0.009	63.0	0.548	0.190
Physical activity (PA) indicators
PA frequency	5	0.61 (0.51–0.73)	< 0.001	81.0	0.221	0.261
PA volume	3	0.46 (0.38–0.56)	0.498	0.0	1.000	0.914
PA intensity	2	0.50 (0.13–1.90)	0.016	82.8	1.000	--
PA duration	3	0.66 (0.52–0.83)	0.760	0.0	1.000	0.872
Step	1	0.54 (0.32–0.91)	--	--	--	--
PA assessment methods
Questionnaire	11	0.58 (0.50–0.68)	<0.001	76.3	0.533	0.079
Uniaxial accelerometry sensor	3	0.61 (0.45–0.83)	0.646	0.0	1.000	0.396
Effect estimates
Odds ratio	12	0.60 (0.52–0.70)	<0.001	67.6	0.373	0.093
Hazard ratio	2	0.54 (0.38–0.77)	0.063	71.1	1.000	--

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* P value for heterogeneity from Q-test

^† P value from Begg’s test

^# P value from Egger’s test

Discussion

To the best of our knowledge, this study comprehensively summarized the overall effects of PA on frailty risk among the community-dwelling older residents. Based on available evidence with moderate quality involving 34,943 participants, results from this systematic review and meta-analysis suggest that a higher level of PA was significantly associated with lower odds of frailty.

This study by synthesizing 10 population-based cohort studies with 14 records showed that a higher level of physical activity was associated with 41% decreased odds of frailty (37% for physical frailty; 49% for multidimensional frailty). Sensitivity analysis, subgroup analysis, and meta-regression analysis yielded similar protective effects, indicating that our result was stable and robust. The result of our study was consistent with other reports, which showed that a higher level of physical activity was beneficial to physical function [22], muscle strength [39], and cognitive function [40]. In addition, similar protective effect of PA on the frailty was also reported by two cohort studies using linear regression model [41, 42]. Based on hourly accelerometry data, Huisingh-Scheetz et al. found that each frailty point corresponded a 7% lower mean hourly activity counts per minute among older adults by using mixed effects linear regression model [41]. Zhang et al. used multivariate linear regression models and showed that compared with participants with a continued regular PA frequency, participants with a decreased frequency were significantly more overall frailty [42].

A previous study tried to test the agreement between 35 different frailty assessment methods among the general population, and the results did not suggest to straightly pool or compare the prevalence or incidence yielded by diverse frailty scores. However, in our study, the subgroup analysis and sensitivity analysis in our study showed the similar protective effect of PA on frailty, regardless of frailty evaluation approach (physical frailty, multidimensional approach, or accumulation of disability), suggesting that PA generated essential protective effect on frailty, no matter which frailty assessment approach was adopted.

PA is a multi-dimensional module, and therefore there is no measure that can assess all facets of PA [43]. Different PA assessments may reflect different facets, and this requires more attention when pooling the results from different studies. In our study, we did a series of repeated analyses 14 times by omitting one record each time and no significant change was observed in each analysis. The stratified analysis by PA indicator also yielded a similar negative association of frailty with PA volume, PA frequency, PA intensity, and PA duration, respectively. Yuki et al. adopted a uniaxial accelerometry sensor to measure the number of steps and PA intensity [28], and other nine studies measure PA by using a questionnaire [19–21, 24–27, 29, 30]. However, similarly, we yielded a similar negative association of frailty with PA after excluding the study by Yuki et al [28]. We also tried to pool the three records reported in Yuki’s study, and consistently we observed a protective effect by PA on frailty. These manifested that diversity in the PA measurement tools or indicators didn’t influence the stability of the results. Multicomponent PA for older adults was recommended by WHO guidelines to maintain their physical fitness [44]. Consequently, no matter what type, intensity, frequency of PA, a higher level of PA in keeping moving and avoiding sedentary behaviours could yield benefits for the older adults.

Some studies showed that the duration of the follow-up period influenced the results from the longitudinal studies [45, 46]. Our study by synthesizing ten cohort studies found that the follow-up period may contribute to significant heterogeneity across the studies. However, our stratified analysis by follow-up period (<10 years vs. ≥10 years) yielded a similar beneficial effect by PA on frailty risk in both strata. One previous study [19] has also showed that a higher level of PA has a similar protective on the incidence of frailty after both longer-term and shorter-term follow-up. People in different countries had various exercise habits [47], but our stratified analysis by region (Asia vs. Europe and America) showed similar protective effects, indicating the effect of PA on frailty was not influenced by exercise habits. Age, gender, and sample size were the major confounders and varied in different studies. However, the stratified analysis in our study by sample size (< 1000 vs. ≥ 1000), female proportion (< 50% vs. ≥ 50%) and, age (< 70 years vs. ≥ 70 years) yielded the same results. These further showed the robustness of our results.

The mechanism underlying the association between PA and frailty is still unclear. However, PA has physiological effects on several inter-related physiological systems, and the latter can lead to frailty [48]. More PA can help people to control blood pressure and cholesterol, and therefore to reduce the risk of cardiovascular and metabolic diseases [49]. In skeletal muscle, PA can accelerate fatty acid oxidation, thus reducing the risk of cardiovascular diseases and type 2 diabetes mellitus [50, 51]. Regular exercise may exert characteristic changes in epigenetic mechanisms in skeletal muscle, specifically with respect to the genes associated with muscle growth and metabolism [52]. In the nervous system, keeping regular physical exercise helped to increase the blood flow to the brain and maintain the cognition function of older people [53, 54]; physical exercises seemed to maintain the longevity of motor neurons controlling the leg muscles [55, 56]. Previous researches showed that exercises can prevent older people in the community from falling [57], and even when a fall occurs, people who kept regular exercises were at a reduced risk to suffer from fractures because of the higher bone mineral density in their stronger bones [58].

Our study provides the basis for future research. First, the evidence on the associations of frailty and PA were mainly from the high-income countries rather than low-income or middle-income countries; the latter are experiencing a rapid ageing society, but the accessibility to health care resources is substantially shortage. The relevant studies in these low- or middle-income countries are encouraging. Second, instead of using a single question to assess the PA, the systematic and validified official PA questionnaire or accelerometers is encouraging to use in future studies to determine the dose-response relationship and determine the optimal exercise level for frailty prevention. Third, the definition of frailty urgently requires a consistent golden standard to facilitate the comparison between different studies. The development of tools to objectively measure frailty would help to achieve this goal.

One of the strengths of this study is that the studies included had moderate to high quality. Another strength is that all studies were cohort studies, hence the temporal sequence of causality is credible. Nevertheless, some potential limitations should be recognized in our studies. First, the frailty in the included studies was defined by different approaches, and PA was assessed by using different scales, these may result in information bias and thus may affect the consistency of the pooled results; however, the sensitivity and stratified analysis did not find any significant change. Then, the heterogeneity in some pooled analyses was significant, this may be due to the diversity of the characteristics of the subjects, the measurement of exposure, and the measurement of outcome in each study. For instance, the study conducted by Savela et al. was limited in Caucasian men of high socioeconomic status [21]; most of the included studies used self-report questionnaire to derive levels of PA, but the survey questions used in these studies varied largely. Hence, more studies with the same PA measurements and same frailty evaluation method are needed to further validate our results. Third, almost all the included studies assessed PA at the baseline, however, the longitudinally change of PA level and whether these changes influenced the incidence of frailty were unclear. This should be studied in the future. Fourth, because of the long follow-up in some studies, the missing data from those who died during follow-up may dilute the association between PA and frailty; therefore, more effective analyzed methods such as competing risk model should be considered.

In conclusion, this systematic review and meta-analysis with moderate-certainty evidence suggests that a higher level of PA was significantly related to decreased odds of frailty, and the benefits of PA for frailty prevention are independent of frailty assessment tools, PA indicators, and PA assessment methods. Findings from this study may help implement active exercise strategies to prevent frailty.

Supporting information

S1 Table. Search strategy of the study.

(DOCX)

Click here for additional data file.^{(34.9KB, docx)}

S2 Table. Detailed quality assessment of the included studies by using criteria of the Newcastle-Ottawa Scale.

(DOCX)

Click here for additional data file.^{(36.4KB, docx)}

S3 Table. Quality of evidence evaluated by GRADE approach.

(DOCX)

Click here for additional data file.^{(34.6KB, docx)}

S1 Fig. Sensitivity analyses on the association between physical activity and the risk of frailty by excluding one study each time.

(DOCX)

Click here for additional data file.^{(83.6KB, docx)}

S2 Fig. Forest plot of association between physical activity and the risk of frailty by physical activity indicators.

(DOCX)

Click here for additional data file.^{(827KB, docx)}

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.^{(32.5KB, docx)}

Acknowledgments

We would like to show our thanks to the authors of the originally published researches; their achievements are the prerequisites of our study.

Data Availability

This study is a systematic review and meta-analysis; the data was extracted from published research. The data is available by contacting the corresponding author or extracting from original published research.

Funding Statement

This study was supported by the Science and Technology Program of Guangzhou City (No.202102080404), the Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515010686), and the Univers Foundation (No.17-02-160). The funders had no roles in the design, analysis, or writing of this manuscript. There was no other additional external funding received for this study.

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(This study was supported by the Science and Technology Program of Guangzhou City (No.202102080404), the Guangdong Basic and Applied Basic Research Foundation (No. 2022A15150110X), the National Key R&D Program of China (No. 2018YFE0208000), and the Univers Foundation (No.17-02-160). The funders had no roles in the design, analysis, or writing of this manuscript.)

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Reviewer #1: PONE-D-22-03407: This manuscript presents a systematic review and meta-analysis of Effect of physical activity on the risk of frailty. The authors conducted a systematic search, identifying 10 relevant studies. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS). Meta-analysis was conducted the random-effects models.

The authors claim there was no systematic review and meta-analysis on the topic. But my search identifies 4 reviews. However, the systematic search demonstrates that there are enough studies to warrant a systematic review and meta-analysis. The quantitative analysis (including sensitivity analyses) appears to have been conducted carefully and appropriately, and the results should be of substantial interest to PLOS ONE readers and the environmental health community.

The manuscript omits several “best practices” that should be part of any systematic review, including preparation of a protocol, a clearly stated study question, and application of preferred approaches for evaluating and reporting risk of bias (or study quality, represented here by the NOS). The authors state that their review was conducted in accordance with the PRISMA guidelines, but several PRISMA recommendations have not been followed. An important challenge for this meta-analysis regardless of the endpoint, is that each study incorporates its own exposure contrast/defintion. The manuscript’s Discussion should address the interpretation of an effect estimate derived from meta-analysis of studies that differ in this important feature. It is also critical for the forest plots and tables to display the exposure contrast for each study. The manuscript contains multiple instances of inconsistent results reporting across the text, tables and figures; some specific instances are reported below.

Grammatical errors are found in places in the text.

Detailed Comments

The background should be improved by explaining the mechanism linking physical activity and frailty. There have been several systematic reviews and meta-analyses (e.g., de Vries NM, van et al. 2012;11:136–49, Theou et al 2011, Puts et a; 2017, etc and more recently a protocol by Pan et al 2019). The authors should discuss these reviews and articulate why there is the need for another review. The gap in these previous reviews should be articulated

L3/4: The objective should be stated in accordance with Population Exposure Comparator Outcome statement

L7: This is incorrect. The definition of physical activity varied widely among the studies. In some studies, it was defined as Vigorous/moderate physical activity, or exercise, or hard physical activity

>3 times/week, etc. How can the authors have derived highest and lowest PA.

L29: insert 'a' between 'at' and 'speed'

L32” delete pls ‘the’

L#36 and L#37 are the same-repetition.

L40: pls change 'preventive effect' to 'impact'

In the last sentence of the introduction, the objective of the systematic review was provided. It would be more clearer, and in accordance with recommendations by the PRISMA Statement (BMJ, 2009; 339:b2700), to identify some specific question that the systematic review is intended to address. The questions might include the populations, exposure, comparator, and outcomes of interest. These questions would also support the criteria and decisions made in literature search terms and screening/ selection of studies. The reason for restricting the studies to follow-up design should be clearly articulated in the background.

Search strategy

The PRISMA guideline recommends registration of a systematic review. The PRISMA checklist (#8) recommends presentation of the full electronic search strategy for at least one database – not provided in this manuscript.

The search strategy should be structured according to population, exposure comparator, outcome and study design.

The Eligibility criteria did not follow the PECO (S) statement. It should also be structured in accordance with Population, Exposure, Comparator, outcome (s) and study design (PECOS) statement. When stating the inclusion criteria (for example for Population) should also state the reasons for exclusion. Most of what the authors have there as inclusion and exclusion criteria are not; in accordance with the PRISMA's recommendation. For example, how can effect estimate be an inclusion/exclusion criteria. Are the authors not encouraging publication bias. This is a systematic review and a meta-analysis (which also both quantitative and qualitative reporting).

L67: With the PA types specified, the authors should give examples.

L70-71: If the authors had followed the PRISMA recommendations closely. some of what they have here as exclusion criteria would not be here. For example, animal studies, reviews, trials, letters, abstracts, etc would have been removed with search filters. Please, delete this. You did not apply your inclusion/exclusion criteria before excluding them

The authors who did the data extraction and assessment should be identified

L77-80: Newcastle-Ottawa Scale and scoring of studies: I have concerns about the use of an overall scale or score to denote study “quality.” Moreover, the developers of the PRISMA Statement do not recommend this. Some of the evaluation components may have greater impact on determining the value of a particular study for the systematic review. Others, in particular the evaluation of confounding, need to be interpreted for the direction the bias is imposing on the risk estimate (e.g., away from or toward the null). That said, it appears that the NOS scale was used to group studies in sensitivity analyses, rather than to exclude studies from the review. This is an appropriate use of scoring, although I would not know how to interpret the scale of 7 out of 9 in terms of what it really means for “quality.”

The authors should provide detailed explanation of how the NOS was applied. On comparability what are the major and minor confounders considered. A table of NOS assessment including detailed consideration for comparability for each study should be provided in the appendix.

L82: Some of the studies reported OR, others reported RR and some also reported HR. RR, HR are approximated to OR only when OR<10%. The outcome of interest is not a rare outcome and why RR=HR=OR assumption in this study. There are other ways of converting OR to HR or RR and the vice versa.

L87: I realized that the authors reported RR in the tables and ES (effect estimates) in the forest plots. Please, change all RR to ES because the measure of effect were not consistent.

In Table 1 show exposure contrast for PA. This should also be done for the plots.

L100: The flow chart was a bit messy.

For example, 0 articles identified through other sources. What are those other sources? pls delete.

Among the 6424 articles were RCTS you excluded. Are these RCTs on PA and fraility? If yes why delete them because they are also longitudinal designs.

I strongly recommend that the 8 studies that did not provide OR/HR/RR and were excluded should be included in your qualitative analysis.

L107: Provide an exposure contrast for physical activity in Table 1 and this should also be shown in the forest plots.

L130-132: The included studies varied widely on the way in which fraility and PA were measured. For example they reported PA frequency, or PA volum or PA intensity and PA duration. According to the authors PA is a multi-dimensional module and different PA assessments may reflect different facets. I do think the authors need to report overall summary effects. I recommend forest plot should reflect these differences in exposure definition and (summary estimates for each definition) also show PA contrast (e.g., low vs high).

I think the results can be presented descriptively without going through the meta-analysis, subgroup analysis and meta-regresssion

L136-137: The authors should know that funnel visualization and the Beggs method do not perform well with few studies.

L185-187: This is the more reason why i think, pooling the results is not a good idea. Analysis could be done for each PA definition as suggested above. Again gave the fact that the studies are not many.

L23-224: The authors should also discuss inherent limitations in included studies.

Other limitations in the study include the assessment of quality as against the risk of bias.

Reviewer #2: Thank you for the opportunity to review this systematic review investigating the relationship between physical activity (PA) and the risk of frailty. The topic is relevant to public health and clinicians, and the findings have the potential to contribute to the field by providing pooled estimates of the association between PA and frailty risk from cohort studies. I have a few comments and suggestions:

Introduction - Page 3 line 37: Please remove the duplicate sentence: "such as the musculoskeletal, cardiorespiratory, endocrine, and nervous systems"

Methods - Page 4 line 66: I have the impression the inclusion criteria could be improved and more detailed. Could you please use the PICO format to assist readers understanding the type of study included? I believe it is unclear how frailty outcomes were considered in this review. Also, there is no information about the population (please add the age range, if applicable). Apologies if I missed it.

Results

Table 2. The title suggests subgroup analyses only, but I think you also included the overall analyses. Please review this to inform readers table 2 includes overall and subgroup meta-analyses. Also, it is difficult to quickly identify significant poolings. Could you please bold the significant results?

Confounders. Please add information about confounders. I noticed you added a sentence in your discussion, but this may not be enough.

Adjusted analysis. Please add information on whether you included unadjusted and adjusted results in the meta-analysis. I have the impression this is unclear in your manuscript. Moreover, could you conduct metaanalysis including only adjusted analysis?

Page 7 line 133. I find it interesting that you described moderate heterogeneity for your main metaanalysis. I believe this is more likely to be classified as substantial heterogeneity (following the Cochrane Handbook). Please justify why a heterogeneity of 70% should be considered moderate in your review or reclassify it.

Suggestion: To strengthen your review, could you include the GRADE approach to summarise the certainty of evidence?

I hope some of these comments are helpful.

Thank you for conducting this study

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Reviewer #1: Yes: Dr. Reginald Quansah

Reviewer #2: No

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PLoS One. 2022 Dec 1;17(12):e0278226. doi: 10.1371/journal.pone.0278226.r002

Author response to Decision Letter 0

12 Jun 2022

Re: Effect of physical activity on the risk of frailty: a systematic review and meta-analysis (PONE-D-22-03407)

We thank the reviewers and editors for his/her valuable comments, our point-by-point responses are shown below the comments. The changes made in the revised manuscript were highlighted in red.

C = comment; R = reply

#To reviewer 1

C1: The authors claim there was no systematic review and meta-analysis on the topic. But my search identifies 4 reviews. However, the systematic search demonstrates that there are enough studies to warrant a systematic review and meta-analysis. The quantitative analysis (including sensitivity analyses) appears to have been conducted carefully and appropriately, and the results should be of substantial interest to PLOS ONE readers and the environmental health community.

R1: Thanks for reviewer’s comment. We appreciate the reviewers for the recognition of our quantitative analysis and the significance of the results. We have carefully updated literature in the manuscript accordingly:

“Physical activity (PA) can regulate the function of multiple systems in the body [1]; the dysfunction of these body system can further contribute to the development of frailty [1]. A systematic review [15], a scoping review [16], and a systematic review and meta-analysis [17] synthesized the evidence and found that exercise training can reduce the level of frailty and improve the prognosis of frailty among older adults. However, epidemiological studies on the relationship between PA and frailty did not reach to a consistent conclusion. For instance, Trombetti [18] and Pérez-Tasigchana [19] did not find any association between PA and frailty, while Borda [20] and Savela [21] reported that PA was a protective factor for frailty. A meta-analysis found that physical exercise therapy could improve mobility and physical functioning in elderly patients suffering from mobility problems, disability and/or multi-morbidity [22]; however, more original studies have been reported in the following decade, making it necessary to update the synthetic evidence. A more recent systematic review including four randomized controlled trials and two prospective cohort studies found that physical activity might be an effective intervention for preventing frailty mong people aged 65 years and older [23]; nevertheless, the intervention measures varied largely among four RCTs and one included RCT adopted combined nutrition and exercise interventions, limiting the application of the results. Moreover, this study[23] only included two cohort studies, but more cohort studies have been reported [18-21,24-30]. In addition, there are many evaluation methods for frailty, and no unified standard has been formed [31]. Whether different methods of frailty assessment influence the association between PA and frailty onset is unclear.” [lines 34-52]

C2: The manuscript omits several “best practices” that should be part of any systematic review, including preparation of a protocol, a clearly stated study question, and application of preferred approaches for evaluating and reporting risk of bias (or study quality, represented here by the NOS). The authors state that their review was conducted in accordance with the PRISMA guidelines, but several PRISMA recommendations have not been followed. An important challenge for this meta-analysis regardless of the endpoint, is that each study incorporates its own exposure contrast/defintion. The manuscript’s Discussion should address the interpretation of an effect estimate derived from meta-analysis of studies that differ in this important feature. It is also critical for the forest plots and tables to display the exposure contrast for each study. The manuscript contains multiple instances of inconsistent results reporting across the text, tables and figures; some specific instances are reported below.

R2: Thanks for valuable comments. The whole manuscript has carefully revised accordingly.

C3: Grammatical errors are found in places in the text.

R3: Thanks for comments. We have checked the gramma and revised the manuscript.

C4: The background should be improved by explaining the mechanism linking physical activity and frailty. There have been several systematic reviews and meta-analyses (e.g., de Vries NM, van et al. 2012;11:136–49, Theou et al 2011, Puts et a; 2017, etc and more recently a protocol by Pan et al 2019). The authors should discuss these reviews and articulate why there is the need for another review. The gap in these previous reviews should be articulated.

R4: Thanks for the good suggestion. The background in the introduction has been updated as follows:

C5: L3/4: The objective should be stated in accordance with Population Exposure Comparator Outcome statement

R5: Thanks for your comment, we updated the objective in the abstract and in the introduction as follows:

“This systematic review with meta-analysis aimed to evaluate the effect of PA on the onset of frailty in the community-dwelling middle and order age adults by pooling data from cohort studies.” [Lines 3-5]

“Therefore, we conducted this systematic review and meta-analysis by synthesize evidence from cohort studies to examine the effect of PA on the onset of frailty among the community-dwelling middle and older age adults, so to provide evidence for frailty prevention for middle and order age adults.” [Lines 58-61]

C6: L7: This is incorrect. The definition of physical activity varied widely among the studies. In some studies, it was defined as Vigorous/moderate physical activity, or exercise, or hard physical activity>3 times/week, etc. How can the authors have derived highest and lowest PA.

R6: Thank you for the comment. The definition of physical activity indeed varied widely in these studies. However, in these studies, the PA indicator often was transformed to categorical variable, and then the effect of PA on the frailty risk was estimated by comparing the high category with low category (such as high vs. Low, vigorous vs. sedentary), or by comparing the low category with high category (such as Sedentary vs. Vigorous). To facilitate the pooled analysis, we transformed the comparison of “low category with high category” to the comparison of “high category with low category” by using the reciprocal method suggested by Cooper and colleague [Ref.36 : Cooper HM, Hedges LV, Valentine JC (2019) The handbook of research synthesis and meta-analysis. New York: Russell Sage Foundation].

Now we have updated the table 1 and figure 2, adding the comparison of PA levels.

C7: L29: insert 'a' between 'at' and 'speed'

R7: Thanks for your comment, we have inserted “a” accordingly. [Line 30]

C8: L32” delete pls ‘the’

R8：Thanks for your comment, “the” has been deleted accordingly. [Line 33]

C9: L#36 and L#37 are the same-repetition.

R9：Thanks for raising this question, we have revised the paragraph and deleted the repeated content. [Line35]

C10: L40: pls change 'preventive effect' to 'impact'

R10: Thanks for your comment, the paragraph in which the phrase “preventive effect” was placed has been revised.

C11: In the last sentence of the introduction, the objective of the systematic review was provided. It would be more clearer, and in accordance with recommendations by the PRISMA Statement (BMJ, 2009; 339:b2700), to identify some specific question that the systematic review is intended to address. The questions might include the populations, exposure, comparator, and outcomes of interest. These questions would also support the criteria and decisions made in literature search terms and screening/ selection of studies. The reason for restricting the studies to follow-up design should be clearly articulated in the background.

R11: Thanks for suggestion. We have revised accordingly as follows:

“Physical activity (PA) can regulate the function of multiple systems in the body [1]; the dysfunction of these body system can further contribute to the development of frailty [1]. A systematic review [15], a scoping review [16], and a systematic review and meta-analysis [17] synthesized the evidence and found that exercise training can reduce the level of frailty and improve the prognosis of frailty among older adults. However, epidemiological studies on the relationship between PA and frailty did not reach to a consistent conclusion. For instance, Trombetti [18] and Pérez-Tasigchana [19] did not find any association between PA and frailty, while Borda [20] and Savela [21] reported that PA was a protective factor for frailty. A meta-analysis found that physical exercise therapy could improve mobility and physical functioning in elderly patients suffering from mobility problems, disability and/or multi-morbidity [22]; however, more original studies have been reported in the following decade, making it necessary to update the synthetic evidence. A more recent systematic review including four randomized controlled trials and two prospective cohort studies found that physical activity might be an effective intervention for preventing frailty mong people aged 65 years and older [23]; nevertheless, the intervention measures varied largely among four RCTs and one included RCT adopted combined nutrition and exercise interventions, limiting the application of the results. Moreover, this study [23] only included two cohort studies, but more cohort studies have been reported [18-21,24-30]. In addition, there are many evaluation methods for frailty, and no unified standard has been formed [31]. Whether different methods of frailty assessment influence the association between PA and frailty onset is unclear.

C12: The PRISMA guideline recommends registration of a systematic review. The PRISMA checklist (#8) recommends presentation of the full electronic search strategy for at least one database – not provided in this manuscript. The search strategy should be structured according to population, exposure comparator, outcome and study design. The Eligibility criteria did not follow the PECO (S) statement. It should also be structured in accordance with Population, Exposure, Comparator, outcome (s) and study design (PECOS) statement. When stating the inclusion criteria (for example for Population) should also state the reasons for exclusion. Most of what the authors have there as inclusion and exclusion criteria are not; in accordance with the PRISMA's recommendation. For example, how can effect estimate be an inclusion/exclusion criteria. Are the authors not encouraging publication bias. This is a systematic review and a meta-analysis (which also both quantitative and qualitative reporting).

R12: Thanks for reviewer’s comments. The PRISMA guideline recommends registration of a systematic review; however, it is not a mandatory component. In fact, many systematic reviews published even in high-prestigious journals (such as JAMA, Lancet, JACC) also did not with a registration.

As we stated in the manuscript, we searched literatures from three datasets (PubMed, Embase, and Web of science). We used the keywords and retrieval strategy as follows: “(‘physical activity’ OR ‘exercise’ OR ‘acute exercise’ OR ‘isometric exercises’ OR ‘aerobic exercise’ OR ‘physical exercise’ OR ‘endurance exercise’ OR ‘resistance exercise’ OR ‘strength exercises’ OR ‘training’ OR ‘exercise training’, OR ‘combined training’, OR ‘weight-lifting’ OR ‘running’ OR ‘jogging’ OR ‘swimming’ OR ‘walking’ OR ‘yoga’ OR ‘Tai chi’ OR ‘daily activity’ OR ‘lifestyle’ OR ‘sport’) AND (‘frailty’ OR ‘frailness’ OR ‘frailty syndrome’ OR and ‘debility’)”. We displayed the detailed search strategy in the supplementary Table S1. We also did a reverse reference citation tracking to find potential reports. The flow-chart of literature selection can be seen in Figure 1. [Lines 64-75, supplementary table S1]

We sincerely pay more attention to the publication bias. The misunderstanding might due to the incorrect description. To make clear for readers, we have revised the paragraph related the inclusion and exclusion criteria accordingly: “Inclusion criteria were as follows: the exposure of PA including exposure intensity, frequency, duration, volume, step, or any specific type (such as leisure-time physical activities, occupational activities, and exercise, etc.) was reported; frailty and its assessment approaches (physical frailty, multidimensional approach, accumulation of disability, etc.) were reported ; design of cohort studies; middle and order age healthy adults; the relationship between PA and frailty was evaluated; the study was published in English. Cross-sectional studies, animal studies, trials, reviews, editorials, letters, abstracts, and studies lacking data to manifest the relationship between PA and frailty were excluded after reviewing title, abstract or full-text.” [Lines 76-83]

C13: L67: With the PA types specified, the authors should give examples.

R13: Thanks for suggestion. The examples of specific PA types were given as follows: “(such as leisure-time physical activities, occupational activities, and exercise, etc.)” [Line: 77-78]

C14: L70-71: If the authors had followed the PRISMA recommendations closely. some of what they have here as exclusion criteria would not be here. For example, animal studies, reviews, trials, letters, abstracts, etc would have been removed with search filters. Please, delete this. You did not apply your inclusion/exclusion criteria before excluding them

R14: Thanks for your comments. W have updated the inclusion and exclusion criteria as follows: “Inclusion criteria were as follows: the exposure of PA including exposure intensity, frequency, duration, volume, step, or any specific type (such as leisure-time physical activities, occupational activities, and exercise, etc.) was reported; frailty and its assessment approaches (physical frailty, multidimensional approach, accumulation of disability, etc.) were reported ; design of cohort studies; middle and order age healthy adults; the relationship between PA and frailty was evaluated; the study was published in English. Cross-sectional studies, animal studies, trials, reviews, editorials, letters, abstracts, and studies lacking data to manifest the relationship between PA and frailty were excluded after reviewing title, abstract or full-text” [Lines: 76-83]

C15: The authors who did the data extraction and assessment should be identified

R15: Thanks for your comments, we have added such information in the section of authors’ contributions: “Data extraction and assessment: PH, WJZ & WDS”. [Lines: 284]

C16: L77-80: Newcastle-Ottawa Scale and scoring of studies: I have concerns about the use of an overall scale or score to denote study “quality.” Moreover, the developers of the PRISMA Statement do not recommend this. Some of the evaluation components may have greater impact on determining the value of a particular study for the systematic review. Others, in particular the evaluation of confounding, need to be interpreted for the direction the bias is imposing on the risk estimate (e.g., away from or toward the null). That said, it appears that the NOS scale was used to group studies in sensitivity analyses, rather than to exclude studies from the review. This is an appropriate use of scoring, although I would not know how to interpret the scale of 7 out of 9 in terms of what it really means for “quality.” The authors should provide detailed explanation of how the NOS was applied. On comparability what are the major and minor confounders considered. A table of NOS assessment including detailed consideration for comparability for each study should be provided in the appendix.

R16: Thanks for your comments. In our manuscript, we provided the quality assessment results by using NOS (supplementary table S2). Now, we updated it and provided a more detailed table. Also, the detailed explanation was provided. [see supplementary table S2]

C17: L82: Some of the studies reported OR, others reported RR and some also reported HR. RR, HR are approximated to OR only when OR<10%. The outcome of interest is not a rare outcome and why RR=HR=OR assumption in this study. There are other ways of converting OR to HR or RR and the vice versa.

R17: Thanks for your comments. Considering that only 2 records reported HR, and other 12 records reported OR, we pooled the results using effect estimates (ES) across the manuscript. Moreover, we further conducted subgroup analysis by effect estimates, and similar protective effect was observed for the studies using OR (pool ES: 0.60, 95% CI: 0.52 - 0.70) and the studies using HR (pool ES: 0.54, 95% CI: 0.38 - 0.77). We also updated all the results across the manuscript. [see Table 2]

C18: L87: I realized that the authors reported RR in the tables and ES (effect estimates) in the forest plots. Please, change all RR to ES because the measure of effect were not consistent.

R18: Thanks for comments, we changed the RR with ES across the manuscript.

C19: In Table 1 show exposure contrast for PA. This should also be done for the plots.

R19: Thanks for comments, we added the exposure contrast for PA in the forest plots. [see table S2, Figure 2]

C20: L100: The flow chart was a bit messy. For example, 0 articles identified through other sources. What are those other sources? pls delete.

R20: Thanks for your comments. We updated the flow-chart accordingly. [see Figure 1]

C21: Among the 6424 articles were RCTS you excluded. Are these RCTs on PA and frailty? If yes why delete them because they are also longitudinal designs.

R21: Thanks for your comments. Among the RCTs we excluded, most of the RCTs were not relevant to the topic of this study. Two RCTs (de Souto Barreto et al., 2018; Li et al., 2010) conducted with multidomain intervention with frailty; however, PA is a subitem of the intervention and the effects of PA were not reported or can be calculated. Nagai et al (Nagai et al., 2018) conducted a RCT to explore PA combined with resistance training on frailty symptoms; however, the study just reported the difference between groups and cannot estimate the effect size of each single component. Given the limited available evidence from RCT study and the target to ascertain the effect of PA on frailty incidence, we limited the included study to prospective cohort study to prevent the potential bias from different study designs. In fact, in the inclusion criteria of this study, we also limited the included study to cohort study.

C22: I strongly recommend that the 8 studies that did not provide OR/HR/RR and were excluded should be included in your qualitative analysis.

R22: Thanks for your comments. Among 8 studies we excluded, 5 studies (Cheung et al., 2020; Ye et al., 2020; Lorenzo-López et al., 2019; Pao et al., 2018; Rogers et al., 2017) focused on the changes in frailty or the trajectories of frailty, which did not report the association between PA and frailty. One study from US explored the relationship between physical activity and frailty among older adults based on hourly accelerometry data, and the study showed that each frailty point corresponded a 7% lower mean hourly activity counts per minute by using mixed effects linear regression model (Huisingh-Scheetz et al., 2017). One study from Spain used multivariate linear regression models and showed that compared with participants with a continued regular PA frequency, participants with a decreased frequency were significantly more overall frailty (β = 1.31; 95% confidence interval = 0.99-1.63) (Zhang et al., 2020). One study conducted among 604 Japanese women showed that high exercise and high dietary varieties group was associated with lower risk of frailty (OR, 0.38, 95% CI, 0.15-0.92); however, this study did not report the effect between PA and frailty solely (OSUKA et al., 2019).

Given to the limited evidence on PA and frailty left, we added the following sentences in the discussion section: “In addition, similar protective effect of PA on the frailty was also reported by two cohort studies using linear regression model [40,41]. Based on hourly accelerometry data, Huisingh-Scheetz et al. found that each frailty point corresponded a 7% lower mean hourly activity counts per minute among older adults by using mixed effects linear regression model [40]. Zhang et al. used multivariate linear regression models and showed that compared with participants with a continued regular PA frequency, participants with a decreased frequency were significantly more overall frailty [41].” [Line 197-203, see figure 1]

C23: L107: Provide an exposure contrast for physical activity in Table 1 and this should also be shown in the forest plots.

R23: Thanks for comments, we added such information in Table 1, Figure 2, and supplementary Figure S2.

C24: L130-132: The included studies varied widely on the way in which frailty and PA were measured. For example, they reported PA frequency, PA volume or PA intensity and PA duration. According to the authors PA is a multi-dimensional module and different PA assessments may reflect different facets. I do think the authors need to report overall summary effects. I recommend forest plot should reflect these differences in exposure definition and (summary estimates for each definition) also show PA contrast (e.g., low vs high).

R24: Thanks for comments. We have provided the pooled results from all included studies and each PA indicators in table 2. Now we also added the forest plots by PA indicators in supplementary materials (see Supplementary Figure S2) and added the following sentence to the results section: “The forest plot of association between PA and frailty risk by PA indicators was shown in Figure S2.” [Lines 179-180]

C25: I think the results can be presented descriptively without going through the meta-analysis, subgroup analysis and meta-regression

R25: Thanks for the comments. In fact, almost the generalizability of the included studies was limited in specific regions. Hence, from the perspective of public health and guiding practice, we remain our view that it is necessary to conduct a pooled analysis and provide the synthetic results. Therefore, we conducted meta-analysis and subgroup analysis, drew forest plot of the relationship between PA and fragility risk and forest plot grouped according to PA indicators. We also did the meta-regression was conducted to assess the potential sources of heterogeneity.

C26: L136-137: The authors should know that funnel visualization and the Begger’s method do not perform well with few studies.

R26: Thanks for comments. Considering that only 14 records from ten studies were included, and the regression method is more sensitive than the rank correlation approach (Sterne et al., 2001), we conducted funnel plot together with Begger’s test, and Egger’s test to test the publication bias. The p-values from Begger’s test and Egger’s test were shown in Table 2.

C27: L185-187: This is the more reason why i think, pooling the results is not a good idea. Analysis could be done for each PA definition as suggested above. Again gave the fact that the studies are not many.

R27: Thanks for comments. In fact, we also did the analysis by each PA indicator, we added the results to table 2 and the forest plot to supplementary materials. [See Table 2 and Supplementary Figure S2].

C28: L23-224: The authors should also discuss inherent limitations in included studies. Other limitations in the study include the assessment of quality as against the risk of bias.

R28: Thanks for comments. The discussion has been updated by including the discussion of the limitations in included studies.

“Nevertheless, some potential limitations should be recognized in our studies. First, the frailty in the included studies was defined by different approaches, and PA was assessed by using different scales, these may result in information bias and thus may affect the consistency of the pooled results; however, the sensitivity and stratified analysis did not find any significant change. Then, the heterogeneity in some pooled analyses was significant, this may be due to the diversity of the characteristics of the subjects, the measurement of exposure, and the measurement of outcome in each study. For instance, the study conducted by Savela et al. was limited in Caucasian men of high socioeconomic status [21]; most of the included studies used self-report questionnaire to derive levels of PA, but the survey questions used in these studies varied largely. Hence, more studies with the same PA measurements and same frailty evaluation method are needed to further validate our results. Third, almost all the included studies assessed PA at the baseline, however, the longitudinally change of PA level and whether these changes influenced the incidence of frailty were unclear. This should be studied in the future. Fourth, because of the long follow-up in some studies, the missing data from those who died during follow-up may dilute the association between PA and frailty; therefore, more effective analyzed methods such as competing risk model should be considered.” [Lines 262-276]

#To reviewer 2

C1: Introduction - Page 3 line 37: Please remove the duplicate sentence: "such as the musculoskeletal, cardiorespiratory, endocrine, and nervous systems"

R1: Thanks for your suggestion, we have revised the paragraph. [Lines 34-52]

C2：Methods - Page 4 line 66: I have the impression the inclusion criteria could be improved and more detailed. Could you please use the PICO format to assist readers understanding the type of study included? I believe it is unclear how frailty outcomes were considered in this review. Also, there is no information about the population (please add the age range, if applicable). Apologies if I missed it.

R2: Thanks for your suggestion. We added the age range to the fourth column in table 1. We also updated the description of inclusion and exclusion criteria accordingly.

“Inclusion criteria were as follows: the exposure of PA including exposure intensity, frequency, duration, volume, step, or any specific type (such as leisure-time physical activities, occupational activities, and exercise, etc.) was reported; frailty and its assessment approaches (physical frailty, multidimensional approach, accumulation of disability, etc.) were reported ; design of cohort studies; middle and order age healthy adults; the relationship between PA and frailty was evaluated; the study was published in English. Cross-sectional studies, animal studies, trials, reviews, editorials, letters, abstracts, and studies lacking data to manifest the relationship between PA and frailty were excluded after reviewing title, abstract or full-text.” [Lines 76-83]

C3: Table 2. The title suggests subgroup analyses only, but I think you also included the overall analyses. Please review this to inform readers table 2 includes overall and subgroup meta-analyses. Also, it is difficult to quickly identify significant poolings. Could you please bold the significant results?

R3: Thanks for the good suggestion. We revised the title of Table 2 and we also bolded the significant results in table 2.

C4: Confounders. Please add information about confounders. I noticed you added a sentence in your discussion, but this may not be enough.

R4: Thanks for the suggestion. In fact, we have showed the confounders of each included study in the general characteristics table [Table 1].

C5: Adjusted analysis. Please add information on whether you included unadjusted and adjusted results in the meta-analysis. I have the impression this is unclear in your manuscript. Moreover, could you conduct meta-analysis including only adjusted analysis?

R5: Thanks for comments. Considering that the results of the included studies would be more reliable after adjusting for potential confounders than the unadjusted results, in this meta-analysis, we evaluated the pooled effects based on the adjusted results in each included study.

We added such information in section of statistical analysis: “A meta-analysis was conducted to estimate the overall pooled effect estimates (ES) based on the adjusted odds ratio or hazard ratio and 95% confidence interval (CI), by comparing the highest with the lowest levels of PA.” [Line 105-107]

C6: Page 7 line 133. I find it interesting that you described moderate heterogeneity for your main meta-analysis. I believe this is more likely to be classified as substantial heterogeneity (following the Cochrane Handbook). Please justify why a heterogeneity of 70% should be considered moderate in your review or reclassify it.

R6: Thanks for comments. We rechecked the classification of heterogeneity according to the Cochrane Handbook, and found that described a heterogeneity of 70% as moderate heterogeneity was inaccurate. We correct it according to your suggestions.

“The random-effects model was used to calculate the pooled effect as the substantial heterogeneity was found (I2 = 70.0%, P-heterogeneity < 0.001).” [Line 162-163]

C7: Suggestion: To strengthen your review, could you include the GRADE approach to summarise the certainty of evidence?

R7: Thanks for your suggestions. We further included the GRADE approach to evaluate the quality of the evidence. We found that the quality of the evidence from the outcomes evaluated by the GRADE system was classified as moderate (showed in Supplementary Table S3), and substantial heterogeneity was the main reason responsible for the limited quality of the evidence.

We accordingly added the following sentence to the section of Methods: “The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluated the quality of the body of evidence [29]. The GRADE approach was based on considerations such as study design, risk of bias, inconsistency, imprecision, indirectness, publication bias and other aspects reported by the included studies. The quality of the evidence was characterized as high, moderate, low, or very low.” [Line 93-98]

We accordingly added the following sentence to the section of Results: “The quality of the evidence from the outcomes evaluated by the GRADE system was assessed as moderate (Supplementary Table S3). Substantial heterogeneity was the main reason responsible for the limited quality of the evidence.” [Line 132-134]

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PLoS One. doi: 10.1371/journal.pone.0278226.r003

Decision Letter 1

Mohammad Meshbahur Rahman

28 Jun 2022

PONE-D-22-03407R1Effect of physical activity on the risk of frailty: a systematic review and meta-analysisPLOS ONE

Dear Dr. Liu,

==============================

Please submit your revised manuscript by Aug 12 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Mohammad Meshbahur Rahman, MS.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Reviewer #1: The manuscript is technically sound, statistically analysis was carefully conducted, nut i have not seen evidence that the authors have shared their data. The standard of English is improved

Reviewer #2: General comments

Thank you for addressing the reviewers’ comments in the updated version of the manuscript. Your study is interesting, and I believe it is important considering the impact of frailty on public health. I still find this study challenging to understand as the text is too long with important messages difficult to identify (e.g. certainty of evidence). Proofreading could assist, with focus on results and discussion.

Some specific comments

PRISMA checklist – Registration and protocol - Some of the items you classified as “NA - Not applicable”. This may not be correct as these items are applicable. However, I have the impression you failed to complete them. Please review this and be clear and say “not performed” for items 24 a,b,c if not performed by your team. Or, please explain why they are not applicable.

GRADE - I noticed you include GRADE as recommended – thank you. Yet, I missed seeing in your method/appendix a clear description of the GRADE parameters you used. Also, I believe the certainty of the evidence was not properly incorporated into your discussion, conclusion and abstract. Please review how GRADE is described, applied and reported across the manuscript to assist others in understanding the certainty of your findings.

Methods

Page 6, line 98: Ethical statement is likely irrelevant for this study and could be deleted.

Page 6, line 104: Please include a reference to assist readers in understanding how you are expressing your results. This is the first time I have come across “overall pooled effect estimates (ES)”. combining OR with HR. I have the impression this is not commonly issued nor recommended in the COCHRANE handbook. I could be wrong. Further details on your method may be required to guide readers.

Page 6, line 110. Please write in full “RR” as this is a new abbreviation

Results

I am concerned you may have included in your Meta-Analysis the same participants more than once (e.g. one participant may have been included in two analyses for different outcomes). For example, Yuki (2) and Yuki (3). Are these participants from the same Taiwan urban cohort with data collected in 2003? Are they the same participants? Please review this to make sure you do not include the same sample more than once in your pooling. Same for the Finish cohort.

Also, the comparison information in Figure S2 is challenging to understand. For example, you used the same name for comparison groups in different subgroups. You included “active vs inactive” for PA duration with no reference to duration. This seems unclear to me. Could you please rename them or provide further details in the figure.

Discussion/Conclusion

Please add a sentence about the certainty of evidence as this should be part of your main findings.

I hope some of these comments are helpful.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Dr. Reginald Quansah

Reviewer #2: No

**********

PLoS One. 2022 Dec 1;17(12):e0278226. doi: 10.1371/journal.pone.0278226.r004

Author response to Decision Letter 1

13 Jul 2022

We thank the reviewers and editors for his/her valuable comments, our point-by-point responses are shown below the comments. The changes made in the revised manuscript were highlighted in red.

C = comment; R = reply

#To reviewer 1

C1: The manuscript is technically sound, statistically analysis was carefully conducted, nut i have not seen evidence that the authors have shared their data. The standard of English is improved.

R1: Thanks for the reviewer’s comment. This study is a systematic review and meta-analysis; the data was extracted from published research. The data is available by contacting the corresponding author or can be extracted from original published research.

#To reviewer 2

C1: General comments: Thank you for addressing the reviewers’ comments in the updated version of the manuscript. Your study is interesting, and I believe it is important considering the impact of frailty on public health. I still find this study challenging to understand as the text is too long with important messages difficult to identify (e.g. certainty of evidence). Proofreading could assist, with focus on results and discussion.

R1: Thanks for reviewer’s comment. The whole manuscript has carefully revised accordingly.

C2: Some specific comments: PRISMA checklist – Registration and protocol - Some of the items you classified as “NA - Not applicable”. This may not be correct as these items are applicable. However, I have the impression you failed to complete them. Please review this and be clear and say “not performed” for items 24 a,b,c if not performed by your team. Or, please explain why they are not applicable.

R2: Thanks for your suggestion, we have changed the “NA” with “not performed” in the PRISMA checklist.

C3: GRADE - I noticed you include GRADE as recommended – thank you. Yet, I missed seeing in your method/appendix a clear description of the GRADE parameters you used. Also, I believe the certainty of the evidence was not properly incorporated into your discussion, conclusion and abstract. Please review how GRADE is described, applied and reported across the manuscript to assist others in understanding the certainty of your findings.

R3: Thanks for your useful comment. We added detailed footnotes of the description of the GRADE approach for Table S3. Furthermore, we added the description of the certainty of the evidence across the manuscript accordingly.

In the abstract, we added the following sentences:

(1) “The quality of evidence was evaluated by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.” [lines 9-11]

(2) “and the GRADE approach classified the quality of evidence as moderate.” [line 12-13]

(3) “This study with moderate-certainty evidence shows that…” [line 21]

In the conclusion, we added the following sentences:

(1) “Based on available evidence with moderate quality involving 34,943 participants, results from this systematic review and meta-analysis suggest that a higher level of PA was significantly associated with a lower risk of frailty.” [186-188]

(2) “In conclusion, this systematic review and meta-analysis with moderate-certainty evidence suggests that...” [line 274]

C4: Methods: Page 6, line 98: Ethical statement is likely irrelevant for this study and could be deleted.

R4: Thanks for your useful comment. We have deleted ethical statement in the manuscript.

C5: Page 6, line 104: Please include a reference to assist readers in understanding how you are expressing your results. This is the first time I have come across “overall pooled effect estimates (ES)”. combining OR with HR. I have the impression this is not commonly issued nor recommended in the COCHRANE handbook. I could be wrong. Further details on your method may be required to guide readers.

R5: Thanks for your important comment. We have included a reference to assist readers in understanding the methods [Ref. 36]. In fact, A Jatho et al. also conducted a meta-analysis by pooling the effect estimates using the adjusted OR, RR or HR and its 95% CI from each included study. Meanwhile, we have further conducted subgroup analysis by effect estimates (odds ratio, hazard ratio) to reveal the effect of the studies reporting OR and HR as a result, respectively.

C6: Page 6, line 110. Please write in full “RR” as this is a new abbreviation

R6: Thanks for your comment. We have changed “RR” with “ES” in the manuscript.

C7: Results: I am concerned you may have included in your Meta-Analysis the same participants more than once (e.g. one participant may have been included in two analyses for different outcomes). For example, Yuki (2) and Yuki (3). Are these participants from the same Taiwan urban cohort with data collected in 2003? Are they the same participants? Please review this to make sure you do not include the same sample more than once in your pooling. Same for the Finish cohort.

R7: Thanks for your comments. In fact, Yu et al. conducted the study from different areas: Yu (1) from Hong Kong, Yu (2) from Taiwan urban, and Yu (3) from Taiwan rural; hence, they are not the same population. The study from Yuk displayed the results from different physical activity indicators, we pooled the results and further conducted the subgroup analysis by physical activity indicators.

C8: Also, the comparison information in Figure S2 is challenging to understand. For example, you used the same name for comparison groups in different subgroups. You included “active vs inactive” for PA duration with no reference to duration. This seems unclear to me. Could you please rename them or provide further details in the figure.

R8: Thanks for your comments. In fact, the names of the comparison information were from the statement of the included studies. To help readers understand, we have renamed the comparison information concretely in Figure S2 and in Figure 2 accordingly.

C9: Discussion/Conclusion: Please add a sentence about the certainty of evidence as this should be part of your main findings.

R9: Thanks for your suggestion. We added the description of the certainty of the evidence across the manuscript accordingly.

We accordingly added the following sentence to the section of Discussion: ① “Based on available evidence with moderate quality involving 34,943 participants, results from this systematic review and meta-analysis suggest that a higher level of PA was significantly associated with a lower risk of frailty.” [Line 191-192]； ② “In conclusion, this systematic review and meta-analysis with moderate-certainty evidence suggests that….” [Line 279-282].

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PLoS One. doi: 10.1371/journal.pone.0278226.r005

Decision Letter 2

Mohammad Meshbahur Rahman

18 Aug 2022

PONE-D-22-03407R2Effect of physical activity on the risk of frailty: a systematic review and meta-analysisPLOS ONE

Dear Dr. Liu,

Please submit your revised manuscript by Oct 02 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Mohammad Meshbahur Rahman, MS.

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: The manuscript is well-written and presents relevant information for public health. It has improved substantially over the last rounds of reviews. I thank the authors for their patience and willingness to adjust the manuscript. Overall, the manuscript is excellent but I have only two small comments related to GRADE and Metanalyses.

GRADE approach for Table S3:

Please include all parameters with the description you used for GRADE (e.g. Phase of investigation, Study limitations, Inconsistency, Indirectness, Imprecision, Publication bias, Effect size).

Effect size: Could you please explain why you upgraded the evidence by 1x point due to the large effect? “2 Large effect: More than 2 studies showed the effect estimates<0.5 after adjusting for confounders. (marked 1 point)”. This parameter often considers the effect size of the pooling you are evaluating, not the estimates from individual studies. In this case, I believe the ES for the pooling is 0.59, which is above 0.5, suggesting no upgrade. Please review it.

Confounder: Is this related to imprecision? Please clarify this GRADE parameter as this is not clear to the readers. “ 3 Plausible confounding would change the effect: Reduced effect for ES<<1. (marked 2 points)”

Combining OR/HR/RR:

I believe OR/HR/RR should not be combined in one metanalysis without appropriate conversations. As this method has been selected for the main analysis, I recommended the main analysis be checked by an experienced statistician before publication. My impression is that the authors do not present enough evidence to support this choice/method. Combining OR/HR/RR is not the standard approach for metanalysis, and the evidence presented by the authors is insufficient (in my view). The reference Jatho et al used another reference that explains how random-effect metanalysis is performed. This paper used an example combining only ORs.

In sum, I am concerned with the method used but less concerned with the estimate presented. The combined estimates (OR/HR) are likely to be similar to the OR and HR estimates shown separately. Your review has several included papers reporting OR and HR. I don’t think it is necessary to present an unconventional metanalysis combining them because you have separate metanalysis for OR and HR showing similar estimates.

I hope some of these comments are helpful.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

**********

PLoS One. 2022 Dec 1;17(12):e0278226. doi: 10.1371/journal.pone.0278226.r006

Author response to Decision Letter 2

7 Sep 2022

Re: Effect of physical activity on the risk of frailty: a systematic review and meta-analysis

We thank the reviewers and editors for his/her valuable comments, our point-by-point responses are shown below the comments. The changes made in the revised manuscript were highlighted in red.

C = comment; R = reply

# To Reviewer 2:

GRADE approach for Table S3:

C1: Please include all parameters with the description you used for GRADE (e.g. Phase of investigation, Study limitations, Inconsistency, Indirectness, Imprecision, Publication bias, Effect size).

R1: Thanks for your comment. We have included all the parameters that the GRADE handbook pointed out and added the footnotes for Table S3.

C2: Effect size: Could you please explain why you upgraded the evidence by 1x point due to the large effect? “2 Large effect: More than 2 studies showed the effect estimates<0.5 after adjusting for confounders. (marked 1 point)”. This parameter often considers the effect size of the pooling you are evaluating, not the estimates from individual studies. In this case, I believe the ES for the pooling is 0.59, which is above 0.5, suggesting no upgrade. Please review it.

R2: Thanks for your important comment. In fact, we have upgraded the evidence by 1 point according the GRADE handbook, which pointed out that the effect <0.5 based on direct evidence could be considered as large effect.

C3: Confounder: Is this related to imprecision? Please clarify this GRADE parameter as this is not clear to the readers. “3 Plausible confounding would change the effect: Reduced effect for ES<<1. (marked 2 points)”

R3: Thanks for your important comment. In fact, this point was pointed out according to Factors that can increase the quality of the evidence in the GRADE handbook. Plausible confounding that would reduce effect for ES<<1 could upgrade by one level. We updated the Table S3 and furtherly updated the footnotes.

C4：Combining OR/HR/RR: I believe OR/HR/RR should not be combined in one metanalysis without appropriate conversations. As this method has been selected for the main analysis, I recommended the main analysis be checked by an experienced statistician before publication. My impression is that the authors do not present enough evidence to support this choice/method. Combining OR/HR/RR is not the standard approach for metanalysis, and the evidence presented by the authors is insufficient (in my view). The reference Jatho et al used another reference that explains how random-effect metanalysis is performed. This paper used an example combining only ORs. In sum, I am concerned with the method used but less concerned with the estimate presented. The combined estimates (OR/HR) are likely to be similar to the OR and HR estimates shown separately. Your review has several included papers reporting OR and HR. I don’t think it is necessary to present an unconventional metanalysis combining them because you have separate metanalysis for OR and HR showing similar estimates.

R4: Thanks for your helpful comment. Indeed, there is limited evidence combined OR/HR/RR in a mate-analysis. We have consulted experienced statisticians at Sun Yat-sen University. Considering that our study included 12 records using OR as effect estimates and only 2 records using HR as effect estimates, we pooled the effect estimates using the adjusted OR/HR and its 95% CI from each included study as Jatho et al did in the main analysis. In the meanwhile, to differ the effect of the studies reporting OR and HR, we further conducted subgroup analysis by effect estimates. For the results of subgroup analysis did not changed remarkably, we still used the results of the main analysis with relatively more included studies.

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PLoS One. doi: 10.1371/journal.pone.0278226.r007

Decision Letter 3

Mohammad Meshbahur Rahman

5 Oct 2022

PONE-D-22-03407R3Effect of physical activity on the risk of frailty: a systematic review and meta-analysisPLOS ONE

Dear Dr. Liu,

Please submit your revised manuscript by Nov 19 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Mohammad Meshbahur Rahman, MS.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: Thank you for attempting to address my questions and concerns in your response. Below I list some of my remaining concerns as I believe the information provided in your response was insufficient and not well supported by the literature. I imagine it may be time-consuming to address these comments. Apologies for this fourth revision. Yet, I cannot recommend this paper for publication if I have concerns with critical aspects of the method and main findings. I would appreciate it if you could review the points below:

C1: GRADE description

Page 6, line 97 – I still find it difficult to understand your GRADE findings. In the method, you mentioned that GRADE was used but did not provide a description of each parameter. Again, in table S3, you mention the GRADE decisions with no descriptions of the parameters (e.g. Study limitations: No serious risk of bias was found. Indirectness: no. Imprecision: no.). Based on the current information provided in the manuscript, it is not possible for readers to understand how you applied GRADE in your study. This needs to be corrected before publication

Please provide a clear description for each GRADE parameter in your method or Table S3 (e.g. Imprecision: We downgraded if there were <400 participants).

C2: Effect size upgrade (related to what I described above).

It is still unclear if you have upgraded (or not) due to the large magnitude of the effect. Could you please review this? I have the impression you should not upgrade this parameter. Your estimate of effect is 0.59 (0.51 to 0.67), which is above 0.5 (the suggested parameter to upgrade is <0.5). Therefore, it should not be upgraded based on effect size. Please note that none of your estimates presents in Table 2 is below 0.5.

C4: Combining OR/HR. There is no quality evidence supporting your method to combine OR/HR in your main metanalysis. You also mentioned that the evidence supporting this approach is limited. If there is no high-quality evidence supporting this decision, please only present the meta-analysis for OR and HR separately. Please note the main findings of your review is based on a questionable Meta-Analysis, and, in my view, this is concerning. I am happy to accept this method if the Editor supports your decision.

Abstract findings: Most of your results are ORs and the interpretation should be framed in terms of odds, not in terms of risk. ORs help to understand the magnitude of an effect but are often mistaken for relative risk ratios. Please review your abstract to express your results as odds. Some references:

Norton EC, Dowd BE, Maciejewski ML. Odds Ratios—Current Best Practice and Use. JAMA. 2018;320(1):84–85. doi:10.1001/jama.2018.6971

Andrade C. Understanding relative risk, odds ratio, and related terms: as simple as it can get. J Clin Psychiatry. 2015 Jul;76(7):e857-61. doi: 10.4088/JCP.15f10150. PMID: 26231012.

Once again, I hope some of these comments/suggestions are helpful.

Reviewer #3: The research procedure of this paper is standardized and the process is comprehensive, which is a complete meta-analysis relatively. However, I note that the authors searched only three databases during the literature search, including PubMed, Embase, and Web of science, omitting The Cochrane Library database. In addition, several important Chinese databases have been omitted, such as CNKI, WanFang Data and the VIP database, and the included studies included samples from Hong Kong and Taiwan, China. How did the authors ensure the scientific validity of the findings?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

**********

PLoS One. 2022 Dec 1;17(12):e0278226. doi: 10.1371/journal.pone.0278226.r008

Author response to Decision Letter 3

13 Oct 2022

Re: Effect of physical activity on the risk of frailty: a systematic review and meta-analysis (PONE-D-22-03407R3)

C = Comment， R = Reply

To Reviewer #2:

C1: GRADE description: Page 6, line 97 – I still find it difficult to understand your GRADE findings. In the method, you mentioned that GRADE was used but did not provide a description of each parameter. Again, in table S3, you mention the GRADE decisions with no descriptions of the parameters (e.g. Study limitations: No serious risk of bias was found. Indirectness: no. Imprecision: no.). Based on the current information provided in the manuscript, it is not possible for readers to understand how you applied GRADE in your study. This needs to be corrected before publication. Please provide a clear description for each GRADE parameter in your method or Table S3 (e.g. Imprecision: We downgraded if there were <400 participants).

R1: Thanks for reviewer’s suggestion. We have modified the Table S3, so the information can be clearer displayed.

We also added the following description in the results section: “By using GRADE approach, it is found that substantial heterogeneity was the main reason responsible for the limited quality of the evidence, whereas all plausible confounding factors were considered (Supplementary Table S3). Hence, the quality of the evidence from the outcomes evaluated by the GRADE system was assessed as low as a whole.” [Lines: 134-138]

C2: Effect size upgrade (related to what I described above). It is still unclear if you have upgraded (or not) due to the large magnitude of the effect. Could you please review this? I have the impression you should not upgrade this parameter. Your estimate of effect is 0.59 (0.51 to 0.67), which is above 0.5 (the suggested parameter to upgrade is <0.5). Therefore, it should not be upgraded based on effect size. Please note that none of your estimates presents in Table 2 is below 0.5.

R2. Thanks for reviewer’s suggestion. We have modified the Table S3, so the information can be clearer displayed. We also added the following description in the results section: “By using GRADE approach, it is found that substantial heterogeneity was the main reason responsible for the limited quality of the evidence, whereas all plausible confounding factors were considered (Supplementary Table S3). Hence, the quality of the evidence from the outcomes evaluated by the GRADE system was assessed as low as a whole.” [Lines: 134-138]

C3: Combining OR/HR. There is no quality evidence supporting your method to combine OR/HR in your main metanalysis. You also mentioned that the evidence supporting this approach is limited. If there is no high-quality evidence supporting this decision, please only present the meta-analysis for OR and HR separately. Please note the main findings of your review is based on a questionable Meta-Analysis, and, in my view, this is concerning. I am happy to accept this method if the Editor supports your decision.

R3: Thanks for reviewer’s comments. In our study we only included cohort studies, though two methods of logistic regression and Cox regression were used among these studies. We calculated the whole effects by synthesizing results from all included studies (ES=0.59, 95% CI= 0.51-0.67), and did the stratified analysis according their analyzed methods (for logistic regression: ES=0.60, 95% CI= 0.52-0.70); for cox regression, ES =0.54, 95% CI= 0.38-0.77). We believe this can enhance the robustness and credibility of the results.

C4: Abstract findings: Most of your results are ORs and the interpretation should be framed in terms of odds, not in terms of risk. ORs help to understand the magnitude of an effect but are often mistaken for relative risk ratios. Please review your abstract to express your results as odds. Some references: Norton EC, Dowd BE, Maciejewski ML. Odds Ratios—Current Best Practice and Use. JAMA. 2018;320(1):84–85. doi:10.1001/jama.2018.6971. Andrade C. Understanding relative risk, odds ratio, and related terms: as simple as it can get. J Clin Psychiatry. 2015 Jul;76(7):e857-61. doi: 10.4088/JCP.15f10150. PMID: 26231012. Once again, I hope some of these comments/suggestions are helpful.

R4. Thanks for reviewer’s helpful suggestion. We have modified the abstract accordingly. The “risk” was replaced with the “odds”. We also update the description in the sections of results and discussion.

To Reviewer #3:

C1: The research procedure of this paper is standardized and the process is comprehensive, which is a complete meta-analysis relatively. However, I note that the authors searched only three databases during the literature search, including PubMed, Embase, and Web of science, omitting The Cochrane Library database. In addition, several important Chinese databases have been omitted, such as CNKI, WanFang Data and the VIP database, and the included studies included samples from Hong Kong and Taiwan, China. How did the authors ensure the scientific validity of the findings?

R1: Thanks for reviewer’s comments. We only considered PubMed, Embase, and Web of science, this was because that almost the vast majority of high-quality Chinese Journals are included into these three datasets. The Cochrane Library database was also considered, as PubMed also included the Cochrane Database of Systematic Reviews. Hence, searched three databases of PubMed, Embase, and Web of science could include nearly all publications. In addition, a reverse reference citation tracking was also carried out to search for the possible literature.

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PLoS One. doi: 10.1371/journal.pone.0278226.r009

Decision Letter 4

Mohammad Meshbahur Rahman

14 Nov 2022

Effect of physical activity on the risk of frailty: a systematic review and meta-analysis

PONE-D-22-03407R4

Dear Dr. Liu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Mohammad Meshbahur Rahman, MS.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I want to thank all authors for extensively revising the manuscript. The current version of manuscript found impressive and publishable in PLOS ONE.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: (No Response)

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: (No Response)

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4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: (No Response)

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6. Review Comments to the Author

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

**********

PLoS One. doi: 10.1371/journal.pone.0278226.r010

Acceptance letter

Mohammad Meshbahur Rahman

21 Nov 2022

PONE-D-22-03407R4

Effect of physical activity on the risk of frailty: a systematic review and meta-analysis

Dear Dr. Liu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Mr. Mohammad Meshbahur Rahman

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Search strategy of the study.

(DOCX)

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S2 Table. Detailed quality assessment of the included studies by using criteria of the Newcastle-Ottawa Scale.

(DOCX)

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S3 Table. Quality of evidence evaluated by GRADE approach.

(DOCX)

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S1 Fig. Sensitivity analyses on the association between physical activity and the risk of frailty by excluding one study each time.

(DOCX)

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S2 Fig. Forest plot of association between physical activity and the risk of frailty by physical activity indicators.

(DOCX)

Click here for additional data file.^{(827KB, docx)}

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.^{(32.5KB, docx)}

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Data Availability Statement

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PERMALINK

Effect of physical activity on the risk of frailty: A systematic review and meta-analysis

Wenjing Zhao

Peng Hu

Weidi Sun

Weidong Wu

Jinhua Zhang

Hai Deng

Jun Huang

Shigekazu Ukawa

Jiahai Lu

Akiko Tamakoshi

Xudong Liu

Roles

Abstract

Objective

Methods

Results

Conclusions

Introduction

Methods

Search strategy and selection criteria

Data extraction and quality assessment

Ethics statement

Statistical analysis

Result

Fig 1. Flow chart of the study selection process.

Table 1. General characteristics of the included studies*.

Fig 2. Forest plot of association between physical activity and the risk of frailty.

Fig 3. Funnel plots with pseudo 95% confidence limits for the association between physical activity and the risk of frailty.

Table 2. Overall and subgroup meta-analyses on the association between physical activity and the risk of frailty.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Mohammad Meshbahur Rahman

Roles

Author response to Decision Letter 0

Decision Letter 1

Mohammad Meshbahur Rahman

Roles

Author response to Decision Letter 1

Decision Letter 2

Mohammad Meshbahur Rahman

Roles

Author response to Decision Letter 2

Decision Letter 3

Mohammad Meshbahur Rahman

Roles

Author response to Decision Letter 3

Decision Letter 4

Mohammad Meshbahur Rahman

Roles

Acceptance letter

Mohammad Meshbahur Rahman

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 1. General characteristics of the included studies^*.