关键词: 衰弱, 老年人, 慢性病, 25-羟维生素D, 维生素D, 白介素-6

Abstract:

【Abstract】Background  Frailty-related issue is increasingly prominent with the acceleration of aging in China.However, domestic research on frailty is still in its infancy characterized by non-objective diagnosis basis, unclear pathogenesis and imperfect interventions.Objective  To investigate the correlation of 25-hydroxyvitamin D and interleukin-6 with frailty in elderly patients with chronic disease in the stable phase，so asto explore objective diagnostic basis and new interventions for frailty. Methods  A total of 152 inpatients （≥ 60 years old） with chronic disease in the stable phase were recruited from Department of Geriatrics，the First People's Hospital of Yunnan Province（hereinafter referred to as “the department of the hospital”） from November 2020 to April 2021. Clinic and laboratory data were collected. Comprehensive geriatric assessment was conducted via an internet-based platform of the Comprehensive Geriatric Assessment（inpatient version） developed by the department of the hospital，among which frailty was assessed by the Chinese version of Fried Frailty Phenotype，a component of the assessment scale. Results  Among the 152 patients，47（30.9%） had no frailty，51（33.6%） had pre-frailty and 54（35.6%） had frailty. According to the binary Logistic regression analysis，disability〔OR=6.162，95%CI（1.091，34.789），P=0.039〕， 25-hydroxyvitamin D〔OR=0.901，95%CI（0.825，0.985），P=0.022〕 and interleukin-6〔OR=1.103，95%CI（1.012，1.201），P=0.025〕 were influencing factors for frailty in elderly patients with chronic disease in the stable phase. Conclusion  Sufficient 25-hydroxyvitamin D may be associated with decreased risk of frailty and elevated interleukin-6 may be associated with increased risk of frailty in elderly patients with chronic disease in the stable phase. So these two indicators may be potential targets for predicting and treating frailty.

【Key words】 Frailty；Aged；Chronic disease；25-hydroxy-vitamin D；Vitamin D；Interleukin-6

【Chinese Library Classification Number】R 151.1 【Document Identification Code】A

1.Introduction

Frailty is a special state in which the physical functions of the elderly gradually decline. It is characterized by weakened muscle strength and endurance, decreased physiological functions, increased vulnerability, decreased anti-stress ability with subsequent adverse consequences such as falls, disability, cognitive impairment, mental abnormalities, and even death^[1][2]. To identify high-risk older adults, Fried et al^.[3]roposed the use of a clinical phenotype to characterize frailty, which consisted of five body components, including decreased muscle strength, reduced walking speed, fatigue, reduced physical activity and unconscious weight loss. These criteria are now widely used in clinical research for the diagnosis of frailty.

With the aging of the Chinese population, the problem of frailty in old age is increasingly serious. However, frailty specific diagnosis is not objective, the pathogenesis is not clear, and the intervention is not sound, indicating that the current research on this matter is yet in its infancy. Although there are previous studies that have explored the possibility of symptoms related to the geriatric syndrome, such as cognitive function, daily activity ability, anxiety and depression and others, to diagnose frailty more confidently and precisely, data on the correlation between 25- hydroxyvitamin D (25(OH)D), interleukin (IL)-6 and frailty in elderly are still missing. Therefore, we aim to explore the correlation between senile frailty and 25(OH)D and IL-6, so asto lay a foundation for the objective diagnosis and intervention of senile frailty in the future.

2   Objects and Methods

2.1 Research objects   

152 patients at the age of 60 years and above, diagnosed with a chronic disease in the stable phase were recruited at the Department of Geriatrics, the First People's Hospital of Yunnan Province, China. The inclusion criteria were as follows: 1) previously hospitalized patients with no new disease, aged ≥ 60 years without new disease, 2) patients with no communication barriers and able to cooperate in the comprehensive geriatric assessment (CGA), and 3) patients who were voluntarily participating in the study and have signed the informed consent. The applied exclusion criteria were: 1) elderly people who have been supplemented with Vitamin D and anti-inflammatory drugs in the past one month, 2) patients, who were diagnosed with acute infectious diseases recently, 3) patients with serious physical and/or mental diseases with communication barriers, who were unable to complete the Fried scale assessment, 4) patients who were bedridden or unstable for a long time and 5) patientswho had insufficient information on the evaluation scale or laboratory data.

This study was implemented after approval of the Medical Ethics Committee of the First People's Hospital of Yunnan Province (No. KHLL2021-KY034).

2.2   Data Collection

2.2.1 General information   

Patients’ general information, including age, gender, height, body mass, body mass index (BMI), educational level, allergyhistory, vision or hearing loss, presence or absence of dentures, marital status, eating habits, sleep time, sleep aids supplementation, current smoking (referring to smoking in the last 30 days before the survey), current drinking (referring to the alcohol consumption in the last 30 days before the survey) were collected.

2.2.2    Comprehensive Geriatric Assessment (CGA) 

The internet-based platform of the Comprehensive Geriatric Assessment (inpatient version) is a software independently developed by the Department of Geriatrics, First People's Hospital of Yunnan Province, China and was applied in the current study. It consists of several national general assessment scales and has certain intelligence. The calculated scores and evaluation results were given automatically according to each assessment option following the criteria and reference scope formulated by various general scales. The researchers collected patients’ data through a WeChat mini-program or computer, and Excel forms were automatically generated for data summary later. The assessors were geriatricians who have received the "Comprehensive Geriatric Assessment System" software training. The assessment included mainly nutritional status assessment and the Micronutrient Assessment Scale (MNA-SF) was used. Values ≥ 24 were considered as indicators of good nutrition, betwen17 and 24 were designated as potential malnutrition, while between 0 and 17 were classified as malnutrition. The cognitive function assessment was according to the Simple Mental State Examination Scale (MMSE), where values between 0 and 9 were classified as a severe impairment, between 10 and 20 - as moderate impairment, between 21 and 26 were classified as mild impairment, while scores between 27 and 30 were designated as cognitive normal functions. Evaluation of anxiety and depression followed the Geriatric Depression Scale (GDS-15), where scores ≥ 6 indicated anxiety and depression. Evaluation of depression following the Self-rating Depression Scale (SDS) was used and the T scores <50 indicated no presence of depression, whereas T ≥ 50 was classified as a depressive mental state. The evaluation of anxiety was according to the Self-rating Anxiety Scale (SAS), where scores <50 indicated lack of anxiety, while equal and above 50 was categorized as anxiety. Daily living ability assessment was according to the basic Living activity ability (BADL) scale, where scores between 91 and 100 were indicators of good daily living function, between 61 and 90 were regarded as mild functional impairment, between 41 and 60 was labeled as moderate functional impairment, between 21 and 40 were considered as severe functional impairment, whereas patients with scores between 0 and 20 were grouped as completely disabled. Instrumental living ability assessment was according to the Instrumental Ability of Daily Living (IADL) scale was used to assess whether patients were able to go shopping, go out for activities, cook food, maintain household chores and wash clothes. Those who need assistance in 3 or more of these criteria were considered disabled. The sleep status assessment was done according to the Assens Insomnia Scale (AIS), where scores between 0 and 3 indicated good sleep, between 4 and 6 spoke for potential insomnia, whereas between 7 and 24 indicated insomnia. Fall risk assessment was according to the Morse Fall Risk Assessment Scale, where scores between 0 and 24 classified the patients at low risk of fall, between 25 and 44 categorized the patients at moderate risk, whereas scores equal and above ≥ 45 categorized the elderly people at severe risk. The balance function evaluation was agreeing with the Tinetti balance and gait scale, where scores less than 15 indicated the risk of falling, between 15 and 24 designated balance dysfunction, whereas scores ≥ 24 indicated good physical function. The visual simulation method was used for pain evaluation. Scores equal to 0 indicated lack of pain, between 1 and 3 designated mild pain, between 4 and 6 showed the presence of moderate pain, whereas between 7 and 10 indicated presence of severe pain. The evaluation of urinary incontinence was in harmony with the Incontinence Questionnaire Simple Form (ICI-Q-SF), where scores equal to 0 classified the patients into the group of asymptomaticurinary incontinence, between 1 and 7 determined the elderly people with mildurinary incontinence, between 8 and 14 indicated moderateurinary incontinence, whereas the scores between 15 and 21 indicated that the patients had severe urinary incontinence. Constipation was assessed using the Roma  = 3 \* ROMAN III Scale (≥2). Other parameters that were taken into account included falls (within the last 1 year), the number of chronic diseases, the coexistence of multiple diseases (≥ 2 diseases), multiple medications (≥ 5 oral medications), the number of medications and others. All these allowed to assess and diagnose frailty and evaluating scores are presented in Table 1.

Table 1  Contents of the Chinese version of Fried method for evaluation and classification of frailty among elderly people

Note: The lack of compliance with any of the items listed in Table 1 indicated a lack of frailty. The compliance with 1 and/or 2 items indicated a pre-frailty condition, while the compliance with 3 items was firmly diagnosed as frailty; IPAQ = International Physical Activity Scale

2.2.3   Laboratory examination  

30 ml of fasting venous blood was collected from the hospitalized elderly patients from 6:00 to 8:00 am and sent to the clinical laboratory of our hospital for testing. The automatic analyzer Xiang Instrument L1550 was used for blood samples analyse. The blood was centrifuged at 3 500 r/min for 5 min. The detected parameters included the white blood cells (WBC) and red blood cells count (RBC), haemoglobin (Hb), platelets (PLT) and neutrophils count (NEUT), as well as the C-reactive protein (CRP). The aspartate (AST) and alanine aminotransferase (ALT) were detected by the rate method. Triacylglycerols (TG) were detected by the deionization glycerol method, the total protein (TP) was detected by the biuret method, albumin (ALB) was detected by the bromocresol green method, while the total cholesterol (TC) was detected by the cholesterol oxidase method. High density (HDL) and low-density lipoproteins (LDL) were detected by the elimination method. Blood sodium (Na⁺), blood potassium (K⁺) and blood chlorine (Cl^-) were detected by the ion-selective electrode method. Creatinine (Cr) and glycosylated haemoglobin (HbA1c) were assayed by enzyme reactions. Urea nitrogen (BUN) was assayed by the urease UV rate method. Uric acid (UA) was assayed by enzyme calorimetry. Blood calcium (Ca²⁺) was assessed by the arsenazo ⅲ method. The Hexokinase method was used for assessing the amount of fasting blood glucose. Fructosamine was detected by the tetrazolium blue method. Thyroid-stimulating hormone (TSH), triiodothyronine (T₃), thyroid hormone (T₄), free triiodothyronine (FT3), free thyroid hormone (FT₄), ferritin, vitamin B12, folic acid, 25(OH)D, estradiol, testosterone, homocysteine (Hcy), fasting insulin (FINS) were detected by electrochemiluminescence. Activated partial thrombin time (APTT), prothrombin time (PT), thrombin time (TT) and D-dimer (DD₂) were detected by the magnetic bead method or by immunoturbidimetry. Tumour necrosis factor (TNF), IL-10, IL-6, IL-12P70, IL-1 and IL-8 were detected by chemiluminescence.

2.2.4   Data quality control  

To assure the gathered data quality all assessment physicians passed the training programme for assessment of the Comprehensive Geriatric Assessment System Software Platform (Inpatient version). All incomplete or inconsistent data were regarded as invalid data and thus excluded from the study.

2.3  Statistical Methods  

SPSS 23.0 software was used for statistical analysis. The measurement data (

3   Results

152 elderly patients were included in the study, among them, 47 (30.9%) had no frailty, 51 (33.6%) had early frailty and 54 (35.6%) had frailty.

3.1   Comparison of general data and geriatric syndrome of patients with different degrees of frailty   

There were no significant differences in gender, height, body mass, BMI, education level, food or drug allergy, denture, marital status, eating habits, sleep time, use of sleeping supplementation, current smoking and alcohol consumption, present anxiety, fall, pain, urinary incontinence, constipation and multiple diseases among patients with different degrees of frailty (P > 0.05). There were statistically significant differences in age, visual impairment, hearing impairment, nutritional status, cognitive function, presence of anxiety and depression, presence of anxiety, daily living ability, disability, sleep status, fall risk, balance function, number of chronic diseases, multiple medications, number of medications（P <0.05). These data are shown in Table 2.

Table 2 Comparison of clinical data and geriatric syndromes in participants by level of frailty

Note: Pain = mild pain + moderate pain + severe pain; urinary incontinence = mild urinary incontinence + moderate urinary incontinence + severe urinary incontinence; ^a represents F value; BMI = body mass index

3.2   Comparison of the laboratory examination indexes of the elderly patients with different degrees of frailty   

There were no significant differences in the WBC, RBC, PLT, NEUT, CRP, AST, TG, TP, TC, HDL, LDL, K+, Cr, HbA1c, BUN, UA, Ca2+, fasting blood glucose, glucosamine, TSH, T₃, T₄, FT₃, FT₄, ferritin, vitamin B₁₂, folic acid, testosterone, FINS, TT, TNF, IL-10, IL-12P70, IL-1 among the studied patients with different degrees of frailty (P>0.05). Statistically significant differences were found in the Hb, ALT, ALB, Na⁺, Cl^-, (25(OH)D, estradiol,  Hcy,, APTT, PT, DD₂, IL-6 and IL-8 (P<0.05). These parameters and interactions are shown in Table 3.

Table 3 Comparison of the laboratory indicators in the elderly participants by the level of frailty

Note: WBC=white blood cell count, RBC=red blood cell count, Hb=hemoglobin, PLT=platelet count, NEUT=neutrophil fraction, CRP=C reactive protein, AST=aspartate aminotransferase, ALT=alanine aminotransferase, TG=triacylglycerol, TP=total protein, ALB=albumin, TC=total cholesterol, HDL=high-density lipoprotein, LDL=low-density lipoprotein, Na⁺=serum sodium, K⁺=serum potassium, Cl^-= blood chlorine, Cr= creatinine, HbA1c= glycosylated hemoglobin, BUN= urea nitrogen, UA= uric acid, Ca²⁺=blood calcium, TSH= thyroid stimulating hormone, T₃= triiodothyronine, T4= thyroid hormone, FT₃= Free triiodothyronine, FT₄ = free thyroid hormone, 25 (OH) D = 25 hydroxyvitamin D, Hcy = homocysteine, FINS = fasting insulin, APTT = activated partial thromboplastin time, PT = coagulation proenzyme time, TT = thrombin time, DD₂ = D-dimer, TNF = tumor necrosis factor, IL = interleukin; ^a represents F value

3.3   Binary Logistic regression analysis   

Taking frailty of elderly patients with stable chronic diseases as a dependent variable, where 1 indicated lack of frailty and 2 designated pre-frailty and frailty, all variables with statistically significant differences (P<0.05) demonstrated in Tables 1 and 2 were taken as independent variables. These included the age (assigned: measured value), vision (where 0 was normal and 1 was decreased), hearing (where 0 was normal and 1 was accepted as decreased), nutritional status (where 0 indicated good nutrition, 1 - potential malnutrition and 2 - malnutrition), cognitive function (where 0 was normal cognition and 1 was cognitive impairment), anxiety and depression states (where 0 was accepted as no anxiety and depression state, whereas 1 was classified with anxiety and depression state, depression state (where 0 indicated no depression state, whereas 1 indicated presence of such), daily living ability (where 0 was indicative of good daily life function, while 1signified dysfunction of daily life), disability (where 0 indicated not disabled and 1 - complete disability), sleep status (with 0 equal to good sleep, 1equal to potential insomnia, whereas 2 represented insomnia), risk of fall (where 0 indicated low risk, 1- moderate risk, while 2 indicated severe risk), balance function (where 0 stood for good physical function, 1 for balance dysfunction, whereas 2 indicated risk of fall), number of chronic diseases (measured value), multiple medications (where 0 indicated none and 1 indicated presence), number of medications (measured value), Hb (measured value), ALT (measured value), ALB (measured value), Na+ (measured value), Cl- (measured value), 25- (OH) D (measured value), estradiol (measured value), Hcy (measured value), APTT (measured value), PT (measured value), DD2 (measured value), IL-6 (measured value), IL-8 (measured value). Binary Logistic regression analysis showed that the disability, 25-(OH)D and IL-6 were the independent influencing factors in elderly patients with stable chronic diseases (P<0.05), as shown in Table 4.

Table 4 Binary logistic regression analysis of frailty in elderly patients with chronic disease

4 Discussion

4.1   Occurrence of senile frailty and independent related factors  

Our results showed that the overall incidence of frailty in the studied hospitalized elderly patients was 35.6% (54/152), which was similar to the results of Lai Xiaoxing et al.^[4], Wei Yin et al.^[5]and others^[6], where the estimated incidence rate was 31.3%, 34.4% and 35.4%, respectively, which was higher than that estimated one by Wang Wanwan et al.^[7], whose calculations showed an incidence of the frailty of 25.1%. Interestingly, these estimations were lower than that by Jin Qiulu et al.^[8], who found that the frailty rate of elderly patients (≥ 80 years old) was 41.6%. These differences in the prevalence and incidence rate of frailty among elderly people may be due to different assessment tools, age, and study subjects.However,overall, the prevalence of frailty in China is not optimistic.Considering that is often followed by a variety of adverse consequences^[1-2], early screening, prevention and intervention can greatly reduce the prevalence and hospitalization rate of elderly people with frailty.

Other authors’ studies in the United States, Mexico, Australia and other countries have shown that Vitamin D (25(OH)D) is an independent factor affecting frailty^[9][11]. In addition, another analysis involving that 20 355 subjects from 13 studies demonstrated a significant inverse relationship between the 25(OH)D levels in patients’ blood results and increased frailty severity (following Fried's phenotypic definition) in both the original analysis and sensitivity analysis^[12]. The results of our study are consistent with those of the above. However, according to a cross-sectional study of community women aged ≥ 75 years in Belgium, there no relationship between low vitamin D levels and lower limb muscle strength and grip strength was estimated^[13]. The reason for this variance may be that the study from Belgium only targeted community women ≥ 75 years. Moreover, the levels of 25(OH)D in the blood are influenced by multiple factors, such as gender, age, geography and others, therefore these results may be somewhat limited.

According to multiple other meta-analyses, frailty and early frailty were associated with higher levels of CRP and IL-6^[14][15]. This was confirmed by a recent meta-analysis of 23 910 older adults, where the authors proved that frailty and pre-frailty were associated with higher levels of inflammatory factors, especially CRP and IL-6^[16]. Our research results were similar to the above studies. Although CRP was not an independent risk factor for frailty in our study, the single factor comparison was still statistically significant (P<0.05). The reason for this difference may be that the sample size of this study, which we understand that is relatively small. Second, the subjects were elderly patients with stable chronic diseases, and CRP was an acute phase reactant^[17], therefore it was possible to rise under a variety of pathophysiological conditions. Therefore, this non-specific inflammatory marker was not considered as necessarily related to frailty^[18].

4.2   25(OH)D, IL-6 and senile frailty are interrelated in elderly patients   

25(OH)D is the major circulating metabolite of Vitamin D which is a globally recognized marker reflecting the Vitamin D status. Vitamin D deficiency is often associated with muscle weakness^[19]. Vitamin D receptors (VDRs) are distributed in multiple target organs such as skin and muscles^[20].VDRs act as nuclear receptor-mediated gene effects. VDRs bind to  (1,25-(OH)2D) to induce the proliferation and differentiation of muscle fiber, and also affect the synthesis of related proteins. On the other hand, VDRs can also activate signal transduction pathways that can induce MAP kinase and phospholipase C through non-nuclear receptor-mediated non-genetic effects, so that a large number of calcium ions can rapidly flow into cells and affect muscle contraction^[21][22]. Therefore, the possible mechanisms of 25(OH)D deficiency leading to frailty are due to affected muscle strength, resulting in decreased grip strength ^[23][24] and because of reduced development of muscle cells, ultimately leading to unconscious weight loss^[25]. In addition, Vitamin D deficiency can also cause osteolysis secondary to hyperparathyroidism, leading to osteoporosis and even fracture, which can aggravate the progression of frailty and osteoporosis, leading to disability and other adverse events.

IL-6 levels increase with age^[14], and high IL-6 can be used as a predictor of both the occurrence of sarcopenia and the adverse outcomes of frailty and sarcopenia, such as disability, functional decline and even death^[26]. IL-6 can inhibit TNF-α and IL-1β and induce the production of CRP, fibrinogen and other acute-phase reactants^[14], it can also indirectly reduce growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, reduce protein synthesis and lead to sarcopenia. In addition, increased serum IL-6 and CRP levels were also associated with decreased grip strength^[27]. The study of Maet al.^[28]included 130 elderly patients and showed that IL-6 was negatively correlated with the strength and gait speed of the frailty elderly. IL-6 levels were also inversely associated with exercise tolerance in older adults after adjustment for age and gender. Therefore, we suggested that IL-6 could be applied as a biomarker for functional decline and frailty.

All the above studies suggest that high IL-6 levels are associated with senile frailty, and Vitamin D deficiency may be involved in inflammation and immune system activation^[29]. Moreover, data are suggesting that Vitamin D supplementation reduced the levels of IL-6 in peripheral blood, inhibiting the production of IL-6 by peripheral blood monocytes, macrophages and T cells^[30][31], and thus upregulating the expression of anti-inflammatory factors (such as IL-10) and inflammatory suppressor molecules^[32].

4.3 Vitamin D supplementation as an intervention for reducing senile frailty   

Some relevant epidemiological studies suggested that Vitamin D had a potential role in maintaining and improving muscle strength, function and physical performance, thus maintaining the independence of elderly people^[33]. Other authors’ results demonstrated that the combined supplementation of elderly people with calcium and Vitamin D reduced the incidence of fractures and the risk of falls among them^[34][36]. In addition, a randomized controlled trial of 5,615 participants showed only a slight improvement in the overall muscle strength after baseline Vitamin D supplementation^[37]. Some data show that Vitamin D supplementation in elderly people may take longer or larger doses are needed before its beneficial effect on the muscles is present^[38], to slow the progression of frailty^[39]. Nonetheless, Cummingset al.^[40]confirmed that the high-dose Vitamin D supplementation increased the risk of falls. Therefore, the ideal supplementation threshold for Vitamin D is a major question that needs special attention. According to the American Institute of Medicine, concentrations of 25(OH)D above 50 nmol/L are fully sufficient for human needs ^[41], while the American Endocrine Society sets the sufficient threshold above 72.5 nmol/L, the insufficiency threshold between 52.5 and 72.5 nmol/L, while the deficiency threshold is set at daily uptake concentrations less than 50 nmol/L^[42]. Thus it can be seen that the dose critical value of vitamin D supplementation in the intervention of senile frailty needs further investigation.

5 Conclusion

The detected prevalence of senile frailty in hospitalized patients is not optimistic at all and is a burden to the medical and social systems in China. Therefore, the early screening, diagnosis and intervention of frailty are particularly essential. In this study, 25(OH)D and IL-6 were found to be independently correlated with frailty in elderly patients with stable chronic diseases. This indicates that 25(OH)D played as a protective factor of frailty in elderly patients with stable chronic diseases, while IL-6 was a risk factor. Therefore, 25(OH)D and IL-6 are expected to be predictors or objective biological indicators for the diagnosis of frailty in elderly patients with stable chronic diseases. In addition, Vitamin D supplementation may help prevent or delay senile frailty, though its dosage needs to be further discussed.

The innovativeness of this study can be summarized as follows:

1. The mobile software platform was successfully used to replace the traditional paper version for the evaluation of the senile frailty and related symptoms, which greatly reduced data collection time and statistical errors, thus increasing the reliability of the data.

2. The study of the senile frailty from the direction of the objective biomarkers in haematology and the mechanism of their action was described, which covered the lack of domestic research in this area.

3. This study proposed that 25-hydroxyvitamin D and interleukin-6 may be predictive or diagnostic factors of frailty in elderly patients with stable chronic diseases. Moreover, the hypothesis that Vitamin D supplementation of elderly patients may be a potential target for interventions is raised.

Like any other study, ours has some limitations too. The study was cross-sectional with a small sample size, which could not directly explore the causal relationship between the 25-hydroxyvitamin D, interleukin-6 and frailty. Second. it was a single-centre study with certain regional limitations. Finally, the subjects of this study were hospitalized elderly patients with stable chronic diseases, which could not represent the whole elderly population.

Author contribution: Dai Jingrong was responsible for the conception and design of the paper, the analysis and interpretation of the results, as well as the writing of the paper; Li Yan carried out the implementation and feasibility analysis of the research and was responsible for the quality control and review of the paper. Data collection was done by Li Jie, He Xu and Li Yang; He Xu and Li Yang, whosorted out and input data; Li Jie conducted the statistical processing and revised the paper; Dai Jingrong and Li Yan were responsible for the supervision and management of the article.

No conflict of interest is declared.

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Key words: Frailty, Aged, Chronic disease, 25-hydroxy-vitamin D, Vitamin D, Interleukin-6