Multifaceted Nutrition Intervention for Frail Elderly in the Community: Protocol of a Randomized Controlled Trial (The MINUTE Study)

The primary aim of the MINUTE trial is to evaluate the effects of a multifaceted nutrition intervention and a combined nutrition and exercise intervention on physical performance (SPPB score) among frail older adults.

Primary hypotheses: We hypothesize that (1) after the 3-month intervention, both the multifaceted nutrition intervention group and the combined intervention group will show a greater improvement in SPPB score compared to the control group. (2) The improvements in physical performance and frailty in the intervention groups will be mediated by concurrent reductions in systemic inflammation and beneficial alterations in the gut microbiota composition.

Secondary hypotheses: We further hypothesize that the multifaceted nutrition and exercise combined intervention will be superior to the nutrition-only intervention in improving physical performance.

The MINUTE trial is a randomized, parallel-group, controlled study involving a total of 315 participants. Participants will be randomly assigned to one of three groups: a control group that will receive routine community health management and serve as the reference for comparing the effectiveness of the active interventions, a multifaceted nutrition intervention group, or a multifaceted nutrition and exercise combined intervention group. Each group will include 105 participants and will receive a different intervention over a 3-month period, followed by a 9-month follow-up. Upon study completion, between-group comparisons will be conducted to evaluate the differential effects of the interventions. Figure 1 illustrates the study flowchart from participant inclusion through the follow-up phase. Figure 2 (graphical abstract) provides a detailed overview of the study population, design, and interventions. The trial has been registered on ClinicalTrials.gov (Identifier: NCT06547593↗).

Participants will be recruited from the senior community. We will collaborate with the Community Health Service Center to disseminate recruitment information through community physicians and neighborhood committees. Recruitment will be conducted in several stages to ensure a thorough and systematic approach: (1) Initial contact and information dissemination: Community physicians and neighborhood committees will identify potential participants who meet the basic age criteria (aged 65 years or older). They will provide these individuals with detailed information about the study, including its purpose, procedures, risks, and benefits. This information will be delivered through flyers, community announcements, and face-to-face consultations. (2) Screening and pre-selection: Potential participants will be invited to attend a preliminary screening session at the Community Health Service Center. During this session, community physicians will conduct a brief health assessment and administer the FRAIL scale to determine the frailty status. Individuals who are assessed as frail by the FRAIL scale will be considered for further evaluation. (3) Informed consent and detailed assessment: Eligible individuals will be provided with a detailed explanation of the study procedures and will be asked to provide written informed consent. Following consent, a comprehensive baseline assessment will be conducted by trained healthcare professionals. This assessment includes a review of medical history, physical examination, and evaluation of functional and mental health status.

Inclusion criteria include the following: (1) Assessed as frailty by the FRAIL scale. The FRAIL scale is a simple 5-item screening tool where frailty is defined as meeting 3 or more of the following criteria: fatigue, resistance (inability to climb one flight of stairs), ambulation (inability to walk 100 m), illnesses (≥5 comorbidities), and loss of weight (>5% in the past year). (2) Aged 65 years or older. (3) Able to provide written informed consent, after receiving a detailed explanation of the study purpose, procedures, risks, and benefits.

Exclusion criteria include the following: (1) Major comorbidities: History of major comorbidities (e.g., stroke, myocardial infarction, active cancer, or severe cardiocerebrovascular disease) that may confound study results or pose risks to participants. (2) Significant functional impairments: Participants with disability, dementia, severe visual or hearing impairments, or physical activity impairment will be excluded. These impairments will be assessed through standardized functional tests (e.g., Mini-Mental State Examination for cognitive function, visual acuity tests, and hearing assessments) and physical performance tests (e.g., gait speed and balance tests). The exclusion will be based on the potential for these impairments to limit participants’ ability to complete the study protocol or accurately report outcomes. (3) Moderate to severe mental health conditions: Participants with moderate to severe anxiety or depression will be excluded. Mental health status will be evaluated using validated screening tools (e.g., the Geriatric Depression Scale and the State-Trait Anxiety Inventory). The exclusion will be based on the potential for these conditions to affect participants’ ability to comply with the study protocol or accurately report outcomes.

After providing consent and completing the baseline assessment, participants will formally enter the study and be randomly assigned to the control group, the multifaceted nutritional intervention group, or the multifaceted nutrition and exercise combined intervention. The randomization sequence is generated by a statistician from Peking University using computer-generated random numbers. Randomization will be performed in a 1:1:1 ratio using computer-generated random numbers. There will be no blocking or stratification. The allocation will be concealed through central randomization performed by an investigator who is not involved in the assessment or recruitment, and the recruitment personnel will not have access to the group assignment tables. Given the nature of the behavioral interventions, it is not possible to blind the participants or the staff delivering the interventions (nutritionists and exercise specialists). Therefore, this is an assessor-blinded trial. Outcome assessors (staff responsible for administering the physical and cognitive tests) and data analysts will be blinded to group assignment throughout the trial. Participants will be instructed not to reveal their intervention allocation to the outcome assessors. The blinding status of the assessors will be evaluated at the end of the study by asking them to guess the group assignment of the participants.

The control group will receive routine community health management only, which represents the standard level of care currently available for frail older adults in the community. This includes monthly health education lectures on general topics (e.g., chronic disease prevention), provision of standard health education materials, and access to basic health counseling services. Critically, the control group will not receive the study’s active intervention components, such as the personalized nutritional consultations, anti-inflammatory diet guidance, provision of protein powder and whole grains, structured exercise guidance, or the intensive bi-weekly health education lectures specific to frailty and malnutrition that are delivered to the intervention groups.

In this group, a three-month multifaceted nutrition intervention will be conducted. All nutritional interventions and recommendations will be provided to participants based on professional discussions and reviews by nutrition experts from the School of Public Health at Peking University. The specific content is as follows:

(1) Daily dietary guidance: Participants will receive an anti-inflammatory dietary menu (Supplementary Table S1) designed based on the Chinese Dietary Guidelines for the Elderly (2022 Edition) and principles from the Dietary Inflammatory Index [32,33]. The diet emphasizes the intake of fruits, vegetables, whole grains, nuts, and fatty fish while reducing refined carbohydrates and saturated fats. Additionally, we will provide participants with a daily nutritional supplement containing 10 g of whey protein to address the high prevalence of sarcopenia in frail elders and support muscle protein synthesis [34], along with 50 g of whole grains to increase dietary fiber and phytochemical intake, which are associated with improved gut microbiota and reduced systemic inflammation [35,36].

(2) Personalized nutritional intervention: In response to specific health issues and diseases, we have established fixed consultation times at community hospitals, allowing elderly individuals to seek advice at designated intervals if they have health-related needs. Furthermore, we will offer on-demand online consultations with registered dietitians to promptly address the nutrition and health concerns of the elderly.

(3) Health education: Every two weeks, nutrition and health knowledge lectures (Table 2) will be conducted for elderly family caregivers and the elderly themselves, covering topics such as chronic diseases, malnutrition, and frailty.

In addition to the aforementioned nutritional measures, exercise interventions will also be included, guided by experts from the Physical Education Department at Peking University. We will provide an exercise intervention manual and a wheel diagram, guiding the elderly to follow a weekly schedule with three days dedicated to resistance exercise sessions and four days for walking, combining resistance and aerobic exercises in a scientifically alternated manner. The weekly resistance exercise program, conducted three times a week, includes eight exercise sessions: twisting towels, lifting water bottles, sit-to-stand training, obstacle crossing, walking in an 8-shape pattern, leg extensions, arm extensions, and seated straight leg raises. These sessions provide comprehensive physical training guidance for the elderly, with details available in Figure 3 and the exercise intervention manual.

To ensure the correctness and safety of the exercises, and to enhance adherence, we will implement a multifaceted support system rather than relying solely on unsupervised self-practice. This includes the following:(1)Initial supervised instruction: Prior to starting the home-based program, each participant will attend a one-on-one or small-group session with a trained exercise specialist. During this session, the specialist will demonstrate each exercise, ensure the participant can perform it with correct form, and provide personalized feedback.(2)Structured guidance materials: Participants will receive a detailed, illustrated exercise manual and a training wheel chart (Figure 3) that clearly outlines the weekly schedule, sets, and repetitions, making the program easy to follow at home.(3)Ongoing remote support: Participants will have weekly access to an exercise specialist via an online platform or telephone to ask questions, report difficulties, and receive motivational support.(4)Adherence monitoring: Participants will be asked to maintain a simple exercise diary to log their completed sessions. This will be reviewed weekly by the research team to monitor adherence and provide timely reminders if needed.(5)Integration with community healthcare: To leverage the existing community healthcare network, community hospitals and family physicians will be engaged to provide ongoing supervision. During their routine weekly interactions or health consultations, they will specifically inquire about the participants’ exercise progress, record their adherence, and offer encouragement. This integrates the intervention into the participants’ regular healthcare, providing an additional layer of personal contact and accountability.

The primary outcome is physical performance, assessed by the change in the Short Physical Performance Battery total score from baseline to the three-month assessment (time point). The SPPB is a well-validated tool ranging from 0 (worst) to 12 (best), assessing balance, gait speed, and lower limb strength. The change will be analyzed as a continuous variable, and the between-group difference will be expressed as the mean difference with a 95% confidence interval.

(1) Frailty status, assessed by the change in the Frailty Index score from baseline to the 3-month, 6-month, and 12-month assessments. The change will be analyzed as a continuous variable. Changes in frailty trajectories, as measured by the Frailty Index.

(2) Changes in intrinsic capacity: the intrinsic capacity is measured using the World Health Organization’s (WHO) Integrated Care for Older People (ICOPE) approach.

(3) Malnutrition risk assessment, measured by the Malnutrition Risk Assessment Form for older adults.

(4) Frailty recovery rates, defined as the proportion of participants transitioning from a frail to a pre-frail or robust state.

(5) Cognition function is evaluated using the Mini-Mental State Examination (MMSE).

(6) Sleep condition is evaluated using the Pittsburgh Sleep Quality Index.

(7) Participant satisfaction and acceptability are evaluated using a self-administered scale.

(8) Serum protein: serum total protein, albumin, and transferrin.

(9) Urine 8-hydroxyguanosine (8-oxo-Gsn): urine oxidation marker 8-hydroxyguanosine (8-oxo-Gsn) level.

(10) Serum inflammatory factors: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), insulin-like growth factor-1 (IGF-1), C-X-C-motif chemokine 10 (CXCL10), and chemokine C-X3-C-based ligand 1 (CX3CL1) in serum using ELISA.

(11) Changes in serum differential metabolites: using nontargeted metabolomics methods to examine the changes in serum differential metabolites in each group before and after intervention and explore the mechanism of intervention.

(12) Changes in gut microbiota: using the 16S sequencing method to detect changes in gut microbiota and differential bacterial genera among groups.

Biological samples will be collected at baseline and upon completion of the three-month intervention following an overnight fast. Approximately 10 mL of venous blood will be drawn into serum separator tubes and allowed to clot at room temperature for 30 min, followed by centrifugation at 3000 rpm for 10 min to isolate serum. Concurrently, first-morning void urine samples (approximately 10 mL) will be collected by participants using sterile containers. The resulting serum and urine supernatant will then be aliquoted into 1.5 mL cryovials under standardized protocols. All aliquots will be immediately frozen and stored at −80 °C in the laboratory of Peking University School of Public Health until subsequent batch analysis.

Serum samples will be analyzed for inflammatory biomarkers—including CRP, IL-6, TNF-α, IGF-1, CXCL10, and CX3CL1—using commercially available ELISA kits. Non-targeted metabolomic profiling of serum will be conducted via liquid chromatography–mass spectrometry (LC-MS), while urinary 8-oxo-Gsn will be quantified using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Gut microbiota composition will be assessed through 16S rRNA gene sequencing performed on fecal samples collected at home by participants using provided kits and returned to the laboratory under cold chain conditions.

Any residual biological samples will be destroyed after the completion of all planned analyses. The informed consent process includes explicit provision for obtaining participant permission regarding the future use of de-identified samples for additional research related to aging and nutrition.

An adverse event (AE) is defined as any untoward medical occurrence in a participant during the study period, regardless of its causal relationship with the intervention. All AEs will be monitored throughout the study and systematically collected during the monthly health counseling, bi-weekly lectures, and at each assessment time point (3, 6, and 12 months) using open-ended questions and specific inquiries about common issues, such as falls, musculoskeletal pain, gastrointestinal discomfort, and allergies.

AEs will be graded for severity (mild, moderate, and severe) and their relationship with the intervention (unrelated, possibly related, and probably related) by the principal investigator. All AEs will be recorded in a standardized form. Serious adverse events (SAEs) will be reported to the PKU IRB within 24 h of awareness.

The sample size calculation was based on the anticipated effect of the intervention on the change in the Short Physical Performance Battery (SPPB) score, which is the primary outcome of this trial.

Based on the results of previous randomized controlled trials [22,37], a multifaceted nutrition and exercise intervention is expected to yield a mean between-group difference of approximately 1.4 points in SPPB score change after 3 months, compared to the control group. The pooled standard deviation (SD) of the SPPB score change is estimated to be 2.5 points.

At α = 0.05, β = 0.1 and k = 3 were used. For a three-group superiority trial, the required sample size per group was calculated: n = ( − ) ( + × k 1 Z 1 2 − / α Z 1 − β ) 2 s 2 ∑ i = 1 k ( μ i − μ ) 2

Accounting for an anticipated 10% loss to follow-up, the sample size was increased to 105 participants per group, resulting in a total sample size of 315 participants.

This study will employ the Intention-to-Treat (ITT) and Per-Protocol (PP) analysis sets to ensure that all randomized study subjects remain in their assigned groups. The Intention-to-Treat population will include all randomized participants, analyzed according to their assigned group. The Per-Protocol population will include only those participants who completed the intervention as prescribed and had no major protocol deviations. For missing quantitative data, the last observation carried forward method will be used. When the results of the ITT and PP analyses are consistent, the ITT results will be presented. When the results differ, the differences will be discussed. The variables will be analyzed using SPSS V.23.0 software. All statistical tests will be two-sided at the 5% level of significance. Continuous variables with a normal distribution will be shown as the mean and SD and those with an abnormal distribution will be presented as the median and IQR. Categorical variables will be expressed as a percentage or constituent ratio. Baseline characteristics will be presented for each group using descriptive statistics (means and standard deviations for normally distributed continuous data, medians and interquartile ranges for non-normally distributed data, and frequencies and percentages for categorical data). Mixed-model repeated-measures analysis of variance with adjustment for baseline characteristics will be performed for different measurement time points between groups, and interaction between groups and measurement time. For continuous outcomes, we will report the pre- and post-intervention means for the intervention and control groups, as well as the model-adjusted mean differences between groups. For binary outcomes, we will report the pre- and post-intervention percentages for the intervention and control groups, along with the adjusted odds ratios (ORs) between groups. The 95% confidence intervals (CIs) and associated p-values will be calculated. We will use nontargeted metabolomics methods to examine the changes in serum differential metabolites in each group before and after the intervention and explore the mechanism of intervention. We will use 16S rRNA gene sequencing to detect changes in gut microbiota and differential bacterial genera among groups. To address the second primary hypothesis regarding the potential mechanisms, correlation analyses (Spearman’s or Pearson’s correlation) and mediation analysis will be performed to examine the relationships between changes in clinical outcomes (SPPB score and frailty) and changes in biomarker levels (inflammatory markers and microbial abundance). Subgroup analyses will be conducted to investigate whether the effects of the intervention vary across different demographic and clinical subgroups.