Study design

This will be a prospective, multicenter cohort study that adopts a multiple randomized controlled trial design [15] to clinically investigate markers associated with KM-based healthy aging. The baseline phase is scheduled from August 2023 to December 2024, aiming to recruit 1,000 participants. Each participant will undergo two follow-up assessments, the first occurring one year post-enrollment, extending the study period through 2025 (Fig 1).

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Fig 1. Schedule of assessments and procedures for aging cohort (KoMAC) study.

Screening: Initial assessment phase before baseline visit, including consent and eligibility checks. Visit 1 (Baseline): Baseline data collection, including demographic survey, physical measurements, health habits, and initial health assessments. Visit 2 (1-year follow-up ±  4 weeks): Follow-up assessments conducted 1 year after baseline to monitor health changes, excluding clinical lab tests. Visit 3 (2-year follow-up ±  4 weeks): Final follow-up assessments conducted 2 years after baseline, similar in scope to Visit 2.

https://doi.org/10.1371/journal.pone.0316986.g001

Study sample

This study will be conducted with a target group of 1000 participants who are entering old age and who are recruited from Wonkwang University Korean Medicine Hospital, a medium-sized city, and Jangheung Integrative Medical Hospital, a rural area in South Korea. The objective is to investigate potential cohort losses due to yearly mortality and other factors, with a target panel retention rate exceeding 80%. Despite limitations in achieving perfect representativeness of the population, practical feasibility will be considered by selecting research participants based on the demographic distribution of the population aged 50–65 years in Iksan and Jangheung, Jeonbuk, as of 2023 [16,17]. Considering the budget for this cohort project and the target population of individuals entering old age at Iksan and Jangheung in 2023 (for a total of 82,498 individuals), the goal is to recruit approximately 1% of this target population while factoring in a panel dropout rate of 20%. Therefore, the aim is to register a total of 1,000 adult participants, encompassing both sexes.

Study population

This study will be This proposal involves recruiting 1,000 individuals over a two-year period from August 2023 to December 2024 for the study of individuals entering old age. Eligible participants will be identified by Clinical Research Coordinators (CRCs) from each institution who receive thorough training regarding the inclusion/exclusion criteria and recruitment procedures.

The inclusion criteria are as follows: (1) adults aged 50 to 65 years; (2) adults residing in either a medium-sized city (Iksan city and nearby areas in Jeonbuk state) or a rural area (Jangheung County and nearby areas in Jeonnam state); (3) adults who can read and respond to the questionnaire; and (4) adults who understand the purpose of the study and provide written consent to participate. The exclusion criteria are as follows: (1) a history of major psychiatric disorders diagnosed by the DSM-5, such as psychotic symptoms, schizophrenia spectrum disorders, delusional disorders, bipolar disorders, alcohol or substance use disorders; (2) the inability to communicate effectively or limitations in reading and writing; and (3) determination by the research team or responsible personnel that the study cannot be completed due to a medical condition. Additionally, (1) participants for whom the selected or excluded criteria are violated following screening, (2) participants who withdraw consent during the study, and (3) participants who are not traceable will be considered premature withdrawals from this study.

After registration, follow-up examinations will be performed at 1-year intervals from August 2024 to December 2025. However, blood tests will be administered every two years: at baseline and during the final follow-up. A strategy for sustained participation will be adopted to keep participants engaged in the cohort study. This will include sending quarterly health management information through a webzine and providing free health consultation services to prevent dropout of participants. Additionally, substantial compensation will be provided every visit, along with immediate explanations of the health screening process, to minimize participant attrition.

Study procedures

After commencing the research, banners for participant recruitment will be displayed in local public health care institutions and health centers. Contact will be initiated with individuals who respond to the banners; their age will be verified and visit schedules will be coordinated. Participants will be asked to maintain fasting for eight hours before their scheduled institution visit and to bring photographs of any nutritional supplements or medications that they are currently taking.

At the first visit, a research nurse will provide an overall explanation of the study. Then, the specific tests scheduled for the day will be detailed using a worksheet, with the nurse providing thorough explanations and addressing any queries immediately. After completing the explanations, participants will sign the research consent form and the consent form for the use of human-derived materials.

A medical registration form will be provided only to participants who sign both forms. For fasting patients, blood tests will be conducted first, and a light snack will be provided for those who complete the blood draw. Subsequently, participants will complete the all surveys and examinations. The entire examination process will take approximately 1 hour and 30 minutes. Upon completion, participants will be provided with information regarding their next examination date. Recruitment began on August 16, 2023, at Wonkwang University Korean Medicine Hospital and on August 22, 2023, at Jangheung Integrative Medical Hospital. It is expected to be completed by December 31, 2025.

Outcome measures

Various outcomes will be examined to assess the health profiles of individuals entering old age in rural and urban areas and to investigate the meaningful associations between healthy aging and the following four factors: biological factors, psychological factors, social factors, and KM-based phenotype factors [18–38]. Biological factors include sex, age, weight, height, BMI, blood pressure, pulse rate, body temperature, overall wellness, smoking and alcohol history, physical activity, nutritional status, dietary habits, appetite, supplement intake, constipation degree, comorbidities, daily living activities, physical resilience, oral and gynecological health, medical, surgical, and medication histories, family medical history, physical performance, knee and lumbar joint range of motion, core and grip strength, hearing, vision, pulmonary function, pulsometry, brain wave examination, bone density, body composition, and clinical lab tests, including biochemical, hormonal, hematological markers, urine tests, and omics profiles (metabolomics/lipidomics, proteomics). Psychological factors include assessments of overall wellness, sleep quality, quality of life, fear of falling, depression levels, and cognitive function. Social factors include education level, family and social relationships, pregnancy and lactation history, overall wellness, smoking and alcohol history, healthcare access, and quality of life. KM-based phenotype factors such as kidney deficiency, five organ deficiency, blood stasis, and core seven-emotions status will also be evaluated. Table 1 provides details of the measurements and instruments used in this study to be acquired.

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Table 1. Measurement and instruments used in the Korean Medicine for Aging Cohort (KoMAC) study.

https://doi.org/10.1371/journal.pone.0316986.t001

Data management and monitoring

All the data collected in this cohort study will be reported in an electronic case report form and managed on a web-based platform (iCReaT; Korea National Institute of Health, Cheongju, Republic of Korea). CRCs will be trained in using this system before initiating data entry and will enter the data according to standardized data entry guidelines. The data management will be coordinated by the Korea Institute of Oriental Medicine. Initially, a monitoring agent will be dispatched to each institution once per week for the first month, followed by monthly visits to ensure a seamless research process.

Statistical analysis

We will conduct various analyses within the cohort. The results of the participants’ demographic data, the questionnaire-based prevalence of age-related symptoms and KM-based phenotype, physical function, and other outcome variables will be summarized using descriptive summary measures. For continuous outcomes, both univariate and multivariate linear regression analyses will be employed, while logistic regression will be used for dichotomous outcomes. Specifically, group differences (between KM-based phenotypes or between rural and urban areas) will be analyzed using Student’s t test and analysis of variance. The relationships between KM-based phenotypes and physical and psychological health, as well as demographic variables, will be analyzed using multiple regression.

Additionally, missing data patterns will be examined, and appropriate methods for handling missing data, such as Last Observation Carried Forward (LOCF) or Multiple Imputation, will be applied. Mixture models will be utilized to identify subgroups of subjects based on their biological and psychological characteristics. To estimate the cumulative risk of outcomes, Kaplan‒Meier analysis will be employed. Adjustments for covariates will be made before the follow-up period, during which Cox proportional hazard models will be used to estimate the risk of experiencing any of the outcomes. In addition, prediction modeling will be attempted by incorporating new covariates under investigation. P values less than 0.05 will be considered to indicate statistical significance. All statistical analyses will be conducted using SAS® version 9.4.

Patient and public involvement

Patients and/or the public were not involved in this research’s design, conduct, reporting, or dissemination plans as it describes a protocol.

Ethics and dissemination

This study received approval from the Institutional Review Board (IRB) of Wonkwang University Korean Medicine Hospital, Iksan, Republic of Korea (approval number: WKUIOMH-IRB-2023-05) on August 16, 2023 and Jangheung Integrative Medical Hospital (approval number: WKUJIM-202307-001) on August 21, 2023. Written informed consent will be obtained from all participants prior to their enrollment in the study. This study is registered with the Clinical Research Information Service (https://cris.nih.go.kr/cris/en/) (KCT0008863), and the current protocol version is 1.3. The results from this cohort study will be disseminated through the publication of peer-reviewed manuscripts, presentations at scientific meetings, and/or conferences.