Effects of the Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on Frailty in Older Adults: A Cohort-based Cluster- Randomized Controlled Trial
Phase: NA
Conditions: Frailty
Sponsor: Nanjing Medical University

The Combined Intervention of Exercise, Fruit, and Vitamin Supplementation on 
Frailty in Community-Dwelling Older Adults: A Pragmatic Cluster Randomized 
Controlled Trial 
 
 
Protocol 
 
Clinicaltrials.gov Number:  NCT06225271 
 
Version 3.0 
August 3, 2023 Draft 
September 5, 2023 Modified 
January 18, 2024 Modified 
  
 
 
 
 
 
 
Nanjing Medical University 
 
 
 
 

Protocol version history 
Version Date 
Protocol Version 
Details of Changes 
August 3, 2023 
1.0 
- 
September 5, 2023 
2.0 
Adding detail description of the 
intervention  
January 18, 2024 
3.0 
Adding 
information 
on 
trial 
registration and ethical approvals  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
1 Introduction ................................................................................................................. 4 
2 Setting ......................................................................................................................... 5 
3 Participant eligibility ................................................................................................... 5 
4 Interventions ............................................................................................................... 6 
5 Outcomes .................................................................................................................. 10 
5.1 Primary outcome ............................................................................................ 10 
5.2 Secondary outcome ........................................................................................ 10 
6 Adherence to the intervention ................................................................................... 11 
7 Participant timeline ................................................................................................... 11 
8 Sample size ............................................................................................................... 11 
9 Recruitment ............................................................................................................... 12 
10 Randomization and masking ................................................................................... 12 
11 Data collection and management ............................................................................ 12 
12 Statistical analysis ................................................................................................... 13 
13 Ethics and dissemination......................................................................................... 14 
14 Publication policy ................................................................................................... 14 
 
 
 
 
 
 
 
 
 
 
 
 

1 Introduction 
Frailty, a complex clinical condition, is characterized by the progressive loss of 
physiological capacity and increased vulnerability to stress [1] [2] [3]. With a rapidly 
expanding aging population, frailty is highly prevalent, varying from 4% to 59% 
depending on measurement tools or setting [4]. Frailty is associated with adverse 
outcomes, such as falls and fractures, hospitalization, disabilities, lower quality of life, 
dementia, and early mortality [5] [6] [7].  
Remarkably, frailty is a dynamic entity and transitions between different states 
(robust, pre-frail, and frail) occur frequently over time [8]. Hence, preventing or 
slowing the progression of frailty before it precipitates significant functional decline 
is crucial for both clinical practice and public health. Current interventions for frailty 
show limited efficacy, primarily due to their initiation after the onset of pre-frailty or 
frailty, missing critical early windows for action[9-16]. Additionally, frailty manifests 
heterogeneously across physical, cognitive, and social domains, requiring 
personalised management strategies[17].   
The WHO recommends identifying vulnerable older adults and supporting them 
maintain and enhance their intrinsic capacity to prevent or reverse functional decline 
[18]. Preserving functional capacity, particularly muscle strength, is crucial for 
healthy aging and could delay frailty progression. Grip strength, a key marker of 
muscle strength, typically begins to decline around age 50, with men experiencing an 
average reduction of 5 kg per decade and women 3 kg, with further acceleration 
during hospitalization [19,20]. Decreased grip strength is generally recognized as an 
indispensable clinical manifestation of frailty [21] [3] 
Optimising outcomes may benefit from a focus on modifiable risk factors, 
emphasizing early intervention and precise population targeting. Evidence shows that 
a link between inadequate physical activity and low fruit consumption with frailty [22] 
[23] [24]. Inadequate fruit intake is associated with increased frailty risk, likely due to 
the protective effects of vitamins on physiological resilience and cellular aging[25]. 
However, combined interventions incorporating exercise, fruit intake, and vitamin 

supplementation to preserve muscle strength for slowing frailty progression in at-risk 
older adults remain underexplored.       
Moreover, there are few studies exploring interventions that are suitable for long-
term implementation in community settings. Thus, the prospective cluster-randomized, 
controlled, two-armed study assesses the effect of the combined intervention of 
exercise, fruit, and vitamin supplementation on frailty among older adults aged 65-80 
years with low levels of physical activity and fruit intake. 14 villages are randomized 
in a 1:1 ratio to either the intervention or control arm. Participants in the intervention 
groups receive the combined intervention at both individual and group levels, whereas 
those in the control groups receive routine health education only. It is hypothesized 
that participants submitted to the combined intervention will present better muscle 
strength. If effective, this trial has the potential for implementation through other 
community-based effective organizing.  
2 Setting 
The evaluation is conducted at community activity centers or daycare centers in 
Wuzhong District, Suzhou. As a major economic hub in China's Yangtze River Delta 
region, Suzhou is situated in the eastern part of Jiangsu Province and features a well-
developed infrastructure. Wuzhong District, located in the central part of Suzhou, 
contains numerous community activity centers that offer adequate public spaces for 
the evaluation. A complete list of the study sites can be found on the trial's official 
government website (https://www.suzhou.gov.cn/). 
3 Participant eligibility 
Participants are included in the study if they meet the following criteria: (1) are 
permanent residents aged 65–80 years; (2) are able to walk independently both 
indoors and outdoors; (3) have total physical activity less than 1400 metabolic 
equivalent task (MET)-min/week; (4) have daily fruit intake less than 50 g; (5) have 
not taken vitamin B or vitamin C supplements in the preceding 3 months; (6) have 
sufficient Chinese proficiency to provide informed consent. 

The exclusion criteria are as follows: (1) participants who are not present at their 
residences during the survey; (2) participants who refuse to engage or fail to complete 
the questionnaire. 
4 Interventions  
Intervention Level: The intervention is implemented at both individual and group 
levels. 
Intervention Methods: 
(1) Individual-level: includes structured exercises (fitness aerobics, Baduanjin, hand 
grip ball exercises, and simple repetitive movements), fruit consumption, and vitamin 
supplementation (vitamin C and B complex); 
(2) Group-level: includes communication and discussion sessions, as well as health 
education activities. 
Frequency of Intervention: 
(1) Individual-level: exercise sessions and fruit consumption are administered three 
times per week for two months (specifically during the 1st and 6th months). Each 
session lasts at least 30 minutes and involves the consumption of a minimum of 50 
grams of fruit. Additionally, one tablet of vitamin B complex and one tablet of 
vitamin C are administered daily throughout the entire intervention period; 
(2) Group-level: a 15-minute communication and discussion session is conducted 
after each individual-level intervention. A 45-minute health education session is 
conducted during the final session of each month. 
At the individual level, the intervention is conducted 3 times weekly for 2 
months (the 1st and 6th months). To guarantee uniformity in the intervention delivery, 
it is administered at 14:00 across all groups, unless otherwise specified in particular 
circumstances. Participants gather at the nearest community activity centre. 
Community workers project fitness aerobics videos and act as trainers, calling on 
participants to stand up and join the exercises. Investigators record the start time, and 
each session lasts approximately 20 minutes. To accommodate participants' physical 
conditions and preferences, the principle is to encourage rather than enforce 
participation. If participants decline fitness aerobics, community workers distribute 

hand grip balls as an alternative. Participants are instructed to grip the ball with 
maximum strength (hold for 2 seconds, relax for 2 seconds). Finally, community 
workers guide participants to do a series of simple repetitive movements, including 
clenching fists, rubbing hands, sitting leg lift, shoulder shrug, sitting leg lift palm clap, 
and leg cross clap arm. 
The duration of exercise lasts longer than 30 minutes. The investigators 
supervise the entire process, ensuring participants' adherence to the exercise routine. 
They actively remind and encourage participants to continue exercising if they pause 
or discontinue during the session. Exercise time and any discomfort symptoms during 
exercise are recorded in detail. The investigators immediately terminate the exercise 
session if a participant experiences any discomfort.  
The fruit is divided into 50-gram portions. Various types of fruit, with priority 
given to varieties exhibiting high antioxidant capacity and locally cultivated fruits, 
including cherry tomatoes, bananas, oranges, and others, are prepared to 
accommodate the needs of different participants. For each intervention, two types of 
fruit are selected. Participants are required to consume the fruit on-site (they may 
consume more than 50 grams), and the actual amount consumed is recorded. In 
addition, information is collected on the participants' average daily fruit intake at 
home between interventions. 
During the intervention, the participants take one tablet of vitamin B complex 
daily, which contains vitamin B1 (3 mg), vitamin B2 (1.5 mg), vitamin B6 (0.2 mg), 
niacinamide (10 mg), and calcium pantothenate (1 mg), along with one separate tablet 
of vitamin C containing 100 mg daily. All supplements are manufactured by 
Huazhong Pharmaceutical Co., Ltd. Medication compliance is monitored. 
In the group-level intervention, a 15-minute communication and discussion 
session is conducted. Community health workers provide brief health education on 
preventing frailty in the local dialect and encourage participants to continue 
exercising and eating fruits at home. Furthermore, a health education session is held 
in the last session of each month, with a minimum duration of 45 minutes. The 
purpose of this session is to reinforce participants' theoretical understanding, thereby 

consolidating the intervention's effects and fostering long-term adherence to healthy 
habits. 
A standardized on-site intervention protocol is developed to ensure the 
consistency and standardization of procedures across all intervention sites (Table 1). 
Adequate staffing and clear task allocation are essential for the orderly on-site 
implementation of the intervention. Each site is staffed with a minimum of five 
personnel, who can be flexibly assigned to different roles based on operational needs 
(Table 2). 
Table 1. Standardized on-site intervention procedures 
Step 
Workflow 
Precautions 
Check-in  
 
 
(1) Upon arrival at the intervention session, 
participants are registered by a staff member, who 
documents their name and time of attendance on a 
session-specific sheet.  
(2) 
Before 
the 
intervention 
session 
begins, 
participants are seated and encouraged to engage in 
social interaction through casual conversation. 
If no staff member is 
familiar 
with 
the 
participants, consider 
distributing name tags 
to facilitate monitoring 
and recording during 
the intervention. 
Vitamin 
Supplementation
 
 
 
(1) A staff member distributes vitamin tablets and 
water to each participant sequentially, explains the 
procedure, and instructs them to take the supplement. 
(2) The investigator documents each participant's 
vitamin consumption.  
- 
Fruit Intake  
(1) It is recommended that two fruit types be 
prepared for each session.  
(2) Pre-weighed fruit portions are distributed to each 
participant 
with 
instructions 
for 
immediate 
consumption. The actual intake is then observed and 
recorded. 
(3) For participants who prefer to avoid cold foods, 
fruit may be gently warmed using hot water prior to 
consumption. 
(4) Participants are required to consume all fruit on-
site and may not take any away. 
Diabetic 
participants 
are advised to select 
from fruits with a low 
glycemic index.  
Exercise 
 
(1) After all participants complete the friut and 
vitamin 
intervention, 
two 
staff 
members 
subsequently organize the group for physical 
- 

exercise. 
(2) A supervised session of group aerobics is 
initiated, with the start time recorded. Participants 
are provided a stress ball as needed if they are 
unwilling or unable to complete the aerobics. This 
combined session lasts 15-20 minutes. A 10-minute 
session of repeated limb movements is conducted. 
For specific exercise details, please refer to the “2.3 
Interventions” section.  
(3) Record the activity details and end time. 
Distribution 
of 
next-day 
vitamins 
The vitamin tablets for the following day are 
distributed. Participants are instructed to consume 
them the next day. Adherence is assessed during the 
subsequent intervention session. 
- 
Information 
archiving 
Following all daily intervention activities, each 
participant's 
intervention 
record 
form 
is 
photographed. The images are compiled and 
submitted to the project team for verification, data 
entry, and archiving. 
- 
 
Table 2. Staffing and responsibilities at each intervention site  
Task 
Number of Personnel 
Responsibilities 
Leader 
1 from community hospital 
1 from project team 
Coordinate and manage on-site 
activities 
Registration 
1 from community hospital 
Register participants and distribute 
name tags; Document at-home fruit 
intake and vitamin supplementation 
Distributes materials and 
records intervention data 
2 from community hospital 
1 from project team 
Distribute exercise equipment, fruit, 
and vitamins; Document fruit and 
vitamin intervention data 
Exercise instructor 
1-2 from community service 
center/day care center. 
Lead group exercises 
Exercise session monitor 
1 from community hospital 
1 from project team 
Supervise, guide, and motivate 
participants; Promptly provide stress 
balls as an alternative activity to those 
unwilling to exercise. 

5 Outcomes 
5.1 Primary outcome 
The primary outcome of the trial is the change in handgrip strength at 12 months 
from baseline. Handgrip strength is measured using a hand-held grip dynamometer. 
Participants are instructed to grip the dynamometer with their left and right hands 
respectively while standing, keeping their arms close to their bodies and straight down, 
exerting maximum force. This test is conducted 3 times, and the values are recorded 
in kilograms.  
5.2 Secondary outcome 
1) The change in handgrip strength at 6 months from baseline. The definition and 
measurement method are the same as the primary outcome. 
2) The change in frailty score at 6 months and 12 months from baseline. The 
outcome is defined as the change in the score of modifiable variables in the frailty 
index from baseline. The frailty index consists of more than 20 variables, covering 
age, physical measurements, sleep quality, history of surgery, falls, fractures, medical 
history, oral hygiene, respiratory function, and self-assessed physical function. The 
frailty index is a continuous variable, with a higher value indicating a frailer status. 
3) A composite of all-cause death, myocardial infarction, angina, and stroke 
within 12 and 24 months after enrollment. Angina is defined as receiving treatment 
for any of the following ICD codes: I20. Myocardial infarction is defined as receiving 
treatment for any of the following ICD codes: I21 or I22. Stroke is defined as 
receiving treatment for any of the following ICD codes: I60-I64. 
4) All-cause death within 12 and 24 months after enrollment.  
5) Myocardial infarction within 12 and 24 months after enrollment.   
6) Angina within 12 and 24 months after enrollment.   
7) Stroke within 12 and 24 months after enrollment.   
8) All-cause hospitalization within 12 and 24 months after enrollment. It is 
defined as any hospital admission event, irrespective of cause. 
9) The change in lipid parameters at 12 months and 24 months from baseline. 
Lipid parameters include total cholesterol (TC) and triglycerides (TG).   

10) The change in fasting blood glucose at 12 months and 24 months from 
baseline. It is measured by the Glucose Oxidase (GOD) method. 
11) Incremental cost-effectiveness ratio (ICER). It is calculated by dividing the 
difference in costs between the two interventions by the difference in their effects. 
6 Adherence to the intervention 
Completion of a single intervention is defined as engaging in at least 30 minutes 
of physical activity and consuming at least 50 grams of fruit supplementation. If the 
participants do not meet the criteria, the values will be recorded truthfully. 
Theoretically, participants in the intervention group are expected to attend 12 on-site 
interventions each month of the intervention period. Good compliance among 
participants is defined as completing 9 or more.   
If the study participant is absent more than 3 times in each intervention month, 
the expected intervention deadline should be postponed to complete the established 
number of interventions. If participants reject the plan, the reasons for their refusal 
will be recorded.  
7 Participant timeline  
Please see Figure 1. 
Figure 1. Participant flow from enrollment to the end of follow-up. 
8 Sample size  
Sample size was estimated using PASS (Power Analysis and Sample Size) 
software (version 15.0.5) based on data from previous studies. Previous studies 
showed that the Cohens’ d value was between 0.25~1.25 [26-30]. With the exception 
of one study that enrolled frail individuals with a 12-week intervention and a 4-month 
follow-up, which reported a Cohen's d of 1.25, all other studies reported Cohen's d 

values below 0.7. Based on this information, we assumed a medium effect size of 
Cohen’s d = 0.45 [31], considering probabilities of 5% for type I error, 20% for 
type II error, and 0.05 for intraclass correlation coefficient (ICC). We randomized all 
14 clusters (villages) into two arms with 1:1 ratio, and the total sample size was 
calculated to be 700 (50 participates per cluster). Estimating a conservative 25% loss 
to follow-up or drop-out, a total of 934 participants will be required.  
9 Recruitment 
Study recruitment begins in February 2024. To enhance recruitment efficiency 
and population representativeness, 14 villages/communities are selected from the 
existing Suzhou Older Adults Cohort (SOAC) using a random cluster sampling 
method. 
Potential participants are identified and their eligibility is verified by the 
investigators. All eligible participants are informed of the study objectives. 
Recruitment efforts are then conducted via telephone and door-to-door approaches, 
after which written informed consent is obtained.  
10 Randomization and masking 
To prevent contamination, individual randomization is not considered [32]. The 
randomization units are villages, and the SAS PROC PLAN process generates a 
random sequence to assign 14 clusters (villages/communities) to the intervention and 
control arms in a 1:1 allocation ratio. The random allocation sequence is generated by 
an independent statistician, the clusters are enrolled by separate personnel, and an 
independent investigator assigns the clusters to interventions. 
The randomization assignments remain concealed until the recruitment and 
collection of baseline data are completed. Due to the cluster design and the nature of 
the intervention, neither the participants nor the community health-care providers and 
research staff are blinded. However, the clinical outcome assessments are conducted 
in a blinded manner. 
11 Data collection and management 
All data collectors are trained in questionnaire content and electronic device 
operation. The anthropometric measurements are trained prior to the formal 

investigation. In addition to blood pressure, height, blood oxygen, and heart rate 
variables, the remaining variables are recorded with precision up to two decimal 
places. Data are collected using electronic devices, and a paper copy is provided as a 
backup in case of electronic failure. Data quality checks are built into the e-
questionnaire, for example, limiting ranges of responses/measurements to the credible 
range, setting questions as ‘required’ to avoid missing questions, and checking for 
consistency between questions. Participants who do not complete the intervention are 
still followed up and assessed for outcome measures.  
12 Statistical analysis 
Primary analyses will be conducted based on the intention-to-treat (ITT) 
principle, with no imputation for missing endpoint data. The primary outcome will be 
the change in handgrip strength from baseline to 12 months. A generalized linear 
mixed model (GLMM) will be employed. The model will include treatment, time, and 
the treatment-by-time interaction as fixed effects. Random effects will account for 
subject, hand nested within subject, and community (cluster).  
Given the potential for type I error due to multiple comparisons, all analyses of 
secondary outcomes will be interpreted as exploratory. Changes in handgrip strength 
(from baseline to 6 months) and the frailty index (from baseline to 6 and 12 months) 
will be analyzed following the same method as the primary outcome. The effect of the 
intervention on a composite endpoint, comprising all-cause mortality, myocardial 
infarction, angina, and stroke, as well as on all-cause hospitalizations, will be 
evaluated using GLMM with a Poisson distribution. Each individual component of the 
composite outcome will be analyzed using the same method. Additionally, changes in 
total cholesterol, triglycerides, and fasting blood glucose from baseline to 12 months 
will be evaluated using a GLMM, which will include treatment as a fixed effect and 
incorporate community as a random effect to account for clustering. 
Several sensitivity analyses and subgroup analyses will assess the robustness of 
the primary outcome findings. Statistical significance will be defined as two-tailed P 
< 0.05. All analyses will be performed using R version 4.4.1.  

13 Ethics and dissemination 
All participants enrolled in this trial are provided with insurance. This RCT is 
carried out in accordance with the principles from the Helsinki Declaration. This trial 
has been approved by the Institutional Review Board of Nanjing Medical University 
(ID:2023588). The trial is registered at www.clinicaltrials.gov (ID: NCT06225271). 
14 Publication policy 
The study results will be published in an appropriate international peer-reviewed 
scientific journal. All authors must fulfil the criteria for authorship according to the 
ICMJE group. In line with the principles of data preservation and sharing, the 
steering committee will, after publication of the overall data set, consider all 
reasonable requests to make the data set available in whole or part for secondary 
analyses and scientific publication. 
 
References 
1. Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: a call 
to action. Journal of the American Medical Directors Association. Jun 
2013;14(6):392-7. doi:10.1016/j.jamda.2013.03.022 
2. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in 
elderly people. Lancet (London, England). Mar 2 2013;381(9868):752-62. 
doi:10.1016/s0140-6736(12)62167-9 
3. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: 
evidence for a phenotype. The journals of gerontology Series A, 
Biological sciences and medical sciences. Mar 2001;56(3):M146-56. 
doi:10.1093/gerona/56.3.m146 
4. Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research 
and clinical practice: A review. European journal of internal 
medicine. Jun 2016;31:3-10. doi:10.1016/j.ejim.2016.03.007 
5. Vermeiren S, Vella-Azzopardi R, Beckwée D, et al. Frailty and the 
Prediction of Negative Health Outcomes: A Meta-Analysis. Journal of 
the American Medical Directors Association. Dec 1 
2016;17(12):1163.e1-1163.e17. doi:10.1016/j.jamda.2016.09.010 
6. Yang X, Lupón J, Vidán MT, et al. Impact of Frailty on Mortality 
and Hospitalization in Chronic Heart Failure: A Systematic Review and 
Meta-Analysis. Journal of the American Heart Association. Dec 4 
2018;7(23):e008251. doi:10.1161/jaha.117.008251 
7. Kojima G, Iliffe S, Walters K. Frailty index as a predictor of 
mortality: a systematic review and meta-analysis. Age and ageing. Mar 
1 2018;47(2):193-200. doi:10.1093/ageing/afx162 

8. Frost R, Avgerinou C, Kalwarowsky S, et al. Enabling health and 
maintaining independence for older people at home (HomeHealth trial): 
a multicentre randomised controlled trial. Lancet (London, England). 
Nov 2023;402 Suppl 1:S42. doi:10.1016/s0140-6736(23)02071-8 
9. Apóstolo J, Cooke R, Bobrowicz-Campos E, et al. Effectiveness of 
interventions to prevent pre-frailty and frailty progression in older 
adults: a systematic review. JBI database of systematic reviews and 
implementation reports. Jan 2018;16(1):140-232. doi:10.11124/jbisrir-
2017-003382 
10. Chen CC, Chen CN, Lai IR, Huang GH, Saczynski JS, Inouye SK. 
Effects of a modified Hospital Elder Life Program on frailty in 
individuals undergoing major elective abdominal surgery. Journal of 
the American Geriatrics Society. Feb 2014;62(2):261-8. 
doi:10.1111/jgs.12651 
11. de Labra C, Guimaraes-Pinheiro C, Maseda A, Lorenzo T, Millán-
Calenti JC. Effects of physical exercise interventions in frail older 
adults: a systematic review of randomized controlled trials. BMC 
geriatrics. Dec 2 2015;15:154. doi:10.1186/s12877-015-0155-4 
12. Frost R, Belk C, Jovicic A, et al. Health promotion interventions 
for community-dwelling older people with mild or pre-frailty: a 
systematic review and meta-analysis. BMC geriatrics. Jul 20 
2017;17(1):157. doi:10.1186/s12877-017-0547-8 
13. Giné-Garriga M, Roqué-Fíguls M, Coll-Planas L, Sitjà-Rabert M, 
Salvà A. Physical exercise interventions for improving performance-
based measures of physical function in community-dwelling, frail 
older adults: a systematic review and meta-analysis. Archives of 
physical medicine and rehabilitation. Apr 2014;95(4):753-769.e3. 
doi:10.1016/j.apmr.2013.11.007 
14. Teh R, Barnett D, Edlin R, et al. Effectiveness of a complex 
intervention of group-based nutrition and physical activity to 
prevent frailty in pre-frail older adults (SUPER): a randomised 
controlled trial. The lancet Healthy longevity. Aug 2022;3(8):e519-
e530. doi:10.1016/s2666-7568(22)00124-6 
15. Thomson KH, Rice S, Arisa O, et al. Effectiveness and cost-
effectiveness of oral nutritional supplements in frail older people 
who are malnourished or at risk of malnutrition: a systematic review 
and meta-analysis. The lancet Healthy longevity. Oct 2022;3(10):e654-
e666. doi:10.1016/s2666-7568(22)00171-4 
16. Wu SY, Cheng YY, Chang HY, et al. Efficacy of Dietary 
Intervention with Group Activities on Dietary Intakes, Frailty Status, 
and Working Memory: A Cluster-Randomized Controlled Trial in 
Community Strongholds. Nutrients. Apr 19 
2023;15(8)doi:10.3390/nu15081976 

17. Dent E, Martin FC, Bergman H, Woo J, Romero-Ortuno R, Walston JD. 
Management of frailty: opportunities, challenges, and future 
directions. Lancet (London, England). Oct 12 2019;394(10206):1376-
1386. doi:10.1016/s0140-6736(19)31785-4 
18. Beard JR, Officer A, de Carvalho IA, et al. The World report on 
ageing and health: a policy framework for healthy ageing. Lancet 
(London, England). May 21 2016;387(10033):2145-2154. 
doi:10.1016/s0140-6736(15)00516-4 
19. Man W, Yuxia W, Canqing Y, et al. Descriptive Analysis of 
Skeletal Muscle Mass and Handgrip Strength in Adults from Ten Regions 
of China. Chinese Journal of Epidemiology. 2019;40(4):376-381. 
doi:10.3760/cma.j.issn.0254-6450.2019.04.002 
20. Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle 
strength changes in older adults: influence of muscle mass, physical 
activity, and health. The journals of gerontology Series A, 
Biological sciences and medical sciences. May 2001;56(5):B209-17. 
doi:10.1093/gerona/56.5.b209 
21. Fan J, Yu C, Guo Y, et al. Frailty index and all-cause and cause-
specific mortality in Chinese adults: a prospective cohort study. The 
Lancet Public health. Dec 2020;5(12):e650-e660. doi:10.1016/s2468-
2667(20)30113-4 
22. Fung TT, Struijk EA, Rodriguez-Artalejo F, Willett WC, Lopez-
Garcia E. Fruit and vegetable intake and risk of frailty in women 60 
years old or older. The American journal of clinical nutrition. Dec 
10 2020;112(6):1540-1546. doi:10.1093/ajcn/nqaa256 
23. Ruangsuriya J, Wongpoomchai R, Srichairatanakool S, Sirikul W, 
Buawangpong N, Siviroj P. Guava Fruit and Acacia pennata Vegetable 
Intake Association with Frailty of Older Adults in Northern Thailand. 
Nutrients. Mar 11 2022;14(6)doi:10.3390/nu14061192 
24. García-Esquinas E, Rahi B, Peres K, et al. Consumption of fruit 
and vegetables and risk of frailty: a dose-response analysis of 3 
prospective cohorts of community-dwelling older adults. The American 
journal of clinical nutrition. Jul 2016;104(1):132-42. 
doi:10.3945/ajcn.115.125781 
25. Izadi M, Sadri N, Abdi A, et al. Harnessing the fundamental roles 
of vitamins: the potent anti-oxidants in longevity. Biogerontology. 
Feb 7 2025;26(2):58. doi:10.1007/s10522-025-10202-5 
26. Kwon J, Yoshida Y, Yoshida H, Kim H, Suzuki T, Lee Y. Effects of 
a combined physical training and nutrition intervention on physical 
performance and health-related quality of life in prefrail older 
women living in the community: a randomized controlled trial. Journal 
of the American Medical Directors Association. Mar 2015;16(3):263.e1-
8. doi:10.1016/j.jamda.2014.12.005 

27. Haider S, Dorner TE, Luger E, et al. Impact of a Home-Based 
Physical and Nutritional Intervention Program Conducted by Lay-
Volunteers on Handgrip Strength in Prefrail and Frail Older Adults: A 
Randomized Control Trial. PloS one. 2017;12(1):e0169613. 
doi:10.1371/journal.pone.0169613 
28. Kim H, Suzuki T, Kim M, et al. Effects of exercise and milk fat 
globule membrane (MFGM) supplementation on body composition, physical 
function, and hematological parameters in community-dwelling frail 
Japanese women: a randomized double blind, placebo-controlled, 
follow-up trial. PloS one. 2015;10(2):e0116256. 
doi:10.1371/journal.pone.0116256 
29. Chen B, Li M, Zhao H, et al. Effect of Multicomponent 
Intervention on Functional Decline in Chinese Older Adults: A 
Multicenter Randomized Clinical Trial. The journal of nutrition, 
health & aging. 2023;27(11):1063-1075. doi:10.1007/s12603-023-2031-9 
30. Kapan A, Winzer E, Haider S, et al. Impact of a lay-led home-
based intervention programme on quality of life in community-dwelling 
pre-frail and frail older adults: a randomized controlled trial. BMC 
geriatrics. Jul 19 2017;17(1):154. doi:10.1186/s12877-017-0548-7 
31. Sullivan GM, Feinn R. Using Effect Size-or Why the P Value Is Not 
Enough. Journal of graduate medical education. Sep 2012;4(3):279-82. 
doi:10.4300/jgme-d-12-00156.1 
32. Barbui C, Cipriani A. Cluster randomised trials. Epidemiology and 
psychiatric sciences. Dec 2011;20(4):307-9. 
doi:10.1017/s2045796011000515