Edited by: Claire Williams, University of Reading, United Kingdom
Reviewed by: Maria Devita, University of Padua, Italy; Francisco Felix Caballero, Autonomous University of Madrid, Spain
This article was submitted to Nutrition, Psychology and Brain Health, a section of the journal Frontiers in Nutrition
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Physical frailty and cognitive aging have important influences on poor clinical outcomes in older adults. Many studies have investigated the association between frailty and cognitive function, but whether vitamin D mediates the association between frailty and cognitive function is unclear. We explored the mediating role of vitamin D on the cross-sectional association between physical frailty and cognitive function using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS).
We analyzed data from 1944 subjects aged 60 years and older from the 2011 CLHLS cohort. Frailty status was identified by the Osteoporotic Fracture Study (SOF) index. The Chinese version of the Mini-Mental State Examination (MMSE) was used to assess cognitive function. Linear regression models were used to examine the association between frailty, vitamin D, and cognition, adjusted for a range of covariates. Mediation analyses tested the indirect effects of vitamin D on physical frailty and cognitive function.
Physical frailty was negatively associated with vitamin D levels and scores on the MMSE, and vitamin D levels were positively associated with scores on the MMSE. Linear regression analysis showed that physical frailty and serum vitamin D concentration were significant predictors of cognitive function. Importantly, mediation analysis showed that serum vitamin D concentration significantly mediated the relationship between physical frailty and cognitive function.
The association between physical frailty and cognitive function appears to be mediated by vitamin D. Future studies should explore whether serum vitamin D concentrations may mediate the association between physical frailty and cognitive decline and whether this mediating role is moderated by other factors.
Population aging continues to accelerate globally, especially in China, due to advances in health-care, public health, and social and economic development leading to increased survival rates. Between 2018 and 2050, China's population of people aged 60 and older will increase from 249 million to 478 million and from 17.9 to 35.1% of the total population (
As aging is associated with physical frailty and cognitive decline, it is reasonable to understand the relationship between cognition and physical frailty. A large number of studies have verified that older adults with PF perform worse on global cognition (
Therefore, using nationally representative longitudinal survey data, the current study aimed to examine the relationship between vitamin levels, frailty status, and cognitive function among community-dwelling older adults, as well as to verify the mediating role of vitamin levels between PF and cognitive function.
Participants were recruited from the 6th (2011) wave of CLHLS, which was the first and largest national, community-based, longitudinal prospective cohort survey. The samples were randomly selected from half of the 22 counties and municipalities of the 31 provinces that make up approximately 85% of the population of China. The sampling characteristics were as follows: for each centenarian who voluntarily agreed to participate in the study, one octogenarian and one non-agenarian of predefined age and sex were randomly selected and interviewed by the CLHLS, and for every two centenarians, three nearby people aged approximately 65-79 were randomly selected. The CLHLS collected biomarkers in the longevity regions, including Xiayi County in Henan Province, Zhongxiang City in Hubei Province, Yongfu County in Guangxi Autonomous Area, Laizhou City in Shandong Province, Sanshui District in Guangdong Province, Mayang County in Hunan Province, Chengmai County in Hainan Province and Rudong County in Jiangsu Province. Therefore, it provides information on basic demographics, health status, socioeconomic characteristics, and lifestyle of the elderly (
More details of the CLHLS, such as the sampling design and assessment of data quality, are described at
A total of 2,429 participants were initially enrolled in the study. In the analysis, younger ages (<60 years,
The current study relied on the Study of Osteoporotic Fractures (SOF) frailty index to define physical frailty, which includes three simple self-reported components: underweight (defined as body mass index<18.5), low energy level (indicated by a positive response to the question “Over the last 6 months, have you been limited in activities because of a health problem?”), and muscle strength (inability to stand up from a chair without the assistance of arms) (
Cognitive function of the CLHLS participants was measured using the Chinese version of the Mini-Mental State Examination (MMSE), which measures four aspects of cognitive function: orientation, short memory, attention and computation, recall, and language, with scores ranging from 0 to 30 (
Because serum 25(OH)D reflects the source of vitamin D from sunlight exposure and diet, it is considered the best biomarker of vitamin D status. Therefore, we measured serum 25(OH)D concentrations to represent vitamin D levels(
The covariates adjusted for in this study, including sociodemographic variables, health condition information, and confounding biomarkers, were obtained through structured questionnaires, physical examinations, and biomarker collections.
Sociodemographic variables included age, sex (female/male), marital status (married/other), place of residence (rural/other), and years of schooling.
Health status information is obtained through self-reporting and includes lifestyle and chronic disease status. The former included smoking (yes/no), alcohol consumption (yes/no), and exercise (yes/no), and the latter consisted of hypertension (yes/no), diabetes (yes/no), heart disease (yes/no), cerebrovascular disease (yes/no), and respiratory disease (yes/no). Hypertension was diagnosed by systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥90 mmHg (
The confounding biomarkers included indicators from both routine blood tests and blood biochemical tests and were performed by the central clinical laboratory at Capital Medical University in Beijing. The assessment of blood samples analysis was determined by using a commercial diagnostic kit (Roche Diagnostics, Germany) on an automated biochemistry machine (Hitachi 7180, Japan). Specifically, the Immunoturbidimetric assay method was used to measure C-reactive proteins (CRPS), the Cholesterol oxidase method was used to measure total cholesterol (CHO), and the picric acid method was used to test serum creatinine (CREA). The glycerol phosphate oxidase-peroxidase method was used to measure triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) by the direct method, and low-density lipoprotein cholesterol (LDL-C) by the Friedewald formula [LDL-C= TC-HDL-C-TG/2.17 (in mmol/L)]. Furthermore, the thiobarbituric acid method was used to measure malondialdehyde (MDA) and the xanthine/xanthine oxidase method was used to assay superoxide dismutase (SOD).
First, numbers and percentages were used to describe categorical variables, while means (standard deviation, SD) or medians (interquartile range, IQR) were used to describe continuous data. ANOVA, Kruskal–Wallis test, or χ2 test were used to compare characteristics among groups.
Second, Spearman's coefficient was used to test the correlation between the variables.
Third, to determine the possible mediator role of vitamin D between physical frailty and cognitive function, we designed a mediation analysis (see
The diagram of the mediation analysis of physical frailty on cognitive function. *
Sample characteristics according to periodontal status.
Age,M (SD) | 85.06 (12.75) | 82.00 (12.04) | 95.39 (9.14) | <0.001 |
Gender(male) | 913 (46.8) | 795 (52.9) | 118 (26.5) | <0.001 |
Married | 818 (42.0) | 745 (49.6) | 73 (16.4) | <0.001 |
Years of school | 0 (0, 4) | 0 (0, 5) | 0 (0,0) | <0.001 |
Rural | 1640 (84.4) | 1266 (84.4) | 374 (84.2) | 0.933 |
Current smoking | 342 (17.5) | 301 (20.0) | 41 (9.2) | <0.001 |
Current drinking | 327 (16.8) | 295 (19.6) | 32 (7.2) | <0.001 |
Current regular exercise | 321 (16.5) | 275 (18.3) | 46 (10.3) | <0.001 |
Hypertension | 518 (26.6) | 419 (27.9) | 99 (22.2) | 0.058 |
Diabetes | 43 (2.2) | 35 (2.3) | 8 (1.8) | 0.028 |
Heart diseases | 142 (7.3) | 112 (7.5) | 30 (6.7) | 0.055 |
Cerebrovascular diseases | 147 (7.5) | 103 (6.9) | 44 (9.9) | 0.001 |
Respiratory diseases | 172 (8.8) | 128 (8.5) | 44 (9.9) | 0.012 |
25 (OH) D (nmol/L) | 39.55 (28.48, 54.10) | 42.20 (30.89,56.47) | 31.13 (23.30, 43.22) | <0.001 |
CRPS (mg/L) | 0.89 (0.39, 2.45) | 0.87 (0.39,2.25) | 1.09 (0.41, 3.59) | 0.004 |
Vitamin B12 (pmol/L) | 346.50 (249.25, 500.00) | 350.00 (256.00,503.00) | 324.00 (229.50, 494.25) | 0.237 |
CHO (mmol/L) | 4.25 (3.60, 4.92) | 4.27 (3.64,4.94) | 4.10 (3.49, 4.76) | 0.004 |
CREA (mmol/L) | 77.00 (64.25, 92.00) | 77.00 (65.25,92.00) | 75.00 (61.00, 92.75) | 0.739 |
HDLC (mmol/L) | 1.24 (1.03, 1.50) | 1.25 (1.03,1.50) | 1.23 (1.04, 1.48) | 0.900 |
LDLC (mmol/L) | 2.5 (1.98, 3.04) | 2.52 (2.00,3.06) | 2.44 (1.89, 2.95) | 0.039 |
TG (mmol/L) | 0.82 (0.60, 1.17) | 0.83 (0.60,1.21) | 0.77 (0.59, 1.07) | <0.001 |
SOD (IU/mL) | 57.77 (52.56, 62.56) | 57.43 (52.11,62.22) | 59.11 (53.96,63.54) | <0.001 |
MDA (umol/L) | 4.80 (3.83, 5.86) | 4.81 (3.87,5.89) | 4.78 (3.68, 5.70) | 0.757 |
Baseline MMSE score | 28 (21,29) | 28 (25, 29) | 19.00 (6, 27) | <0.001 |
The associations between physical frailty and serum levels of 25(OH) D3 (nmol/L).
PF | reference | reference | reference | reference |
Non-PF | 10.488 (8.477,12.499) | 5.138 (2.988,7.287) | 5.029 (2.878,7.179) | 4.989 (2.855,7.122) |
The associations between physical frailty and cognitive function.
PF | reference | reference | reference | reference |
Non-PF | 8.728 (7.867, 9.590) | 4.270 (3.419, 5.120) | 4.235 (3.387, 5.082) | 4.171 (3.329, 5.013) |
We subsequently examined whether 25(OH) D mediated the relationship between frailty and cognitive function using the PROCESS macro for SPSS. As shown in the mediation model (see
This is the first study to examine the possible mediating role of vitamin D on the relationship between physical frailty and cognitive function in a community elderly population in a long-lived region of China. We found a significant negative association between physical frailty and both vitamin D and cognitive function. In addition, our results suggest that the effect of frailty on cognitive function was partially mediated by vitamin D among the elderly community.
Although a number of studies have investigated the relationship between 25(OH) D levels and frailty, both cross-sectional surveys and longitudinal studies appear to have reached inconsistent conclusions. However, relevant meta-analyses have confirmed this association. One meta-analysis showed a significant association between low levels of 25(OH) D and the risk of frailty compared to high levels of 25(OH) D (
In addition, certain factors have been identified in the literature as potential risk factors for frailty, such as chronic diseases, lifestyle, and some biomarkers (
However, after adjusting for these covariates in our study model, the association between 25(OH) D and frailty was not significantly confounded. This suggests that 25(OH) D is independently associated with the risk of frailty. Nevertheless, there are unknown factors that were not included in this study and whether these factors influence this relationship, so more comprehensive research is needed in the future.
The negative association between frailty and cognitive function has been well studied. A recent systematic review and meta-analysis of cross-sectional studies examining the relationship between physical frailty and cognitive function in older adults showed that frailty status had a significant negative effect on cognitive function, both in terms of overall cognitive function and in terms of individual cognitive domains. Furthermore, even after adjusting for age, the frailty assessment tool used and cognitive functioning status, the effect was not significantly reduced (
In this study, we found a positive association between the level of vitamin D and cognitive function, i.e., older adults with high levels of vitamin D concentrations in China were more likely to report higher MMSE scores than those with low levels of vitamin D concentrations. There is evidence of a protective effect of high levels of vitamin D concentrations on cognitive decline, dementia, and Alzheimer's disease in older adults (
The strength of the current study is that plasma blood samples were collected from participants from multiple communities in multiple regions of China, which allowed us to increase the credibility of the samples and enable our study to produce reliable results. In addition, to our knowledge, this is the first time that the relationship between vitamin D in physical frailty and cognitive function has been explored nationally in older Chinese adults.
This study also has limitations that may affect our interpretation of the findings. First, the cross-sectional study design did not allow for an examination of the causal relationship between physical frailty and cognitive decline because of the lack of temporality. Specifically, the exposure and the outcome are measured at the same point in time, rather than before the outcome occurs. Second, cognitive function was assessed
In a cohort of older Chinese adults with representative longevity, frailty was found to be associated with significantly poorer cognitive performance, and frail older adults reported lower vitamin D levels. Furthermore, the association between frailty and impaired cognitive function appears to be mediated by vitamin D deficiency. Future studies should explore whether low vitamin D levels may mediate the association between physical frailty and cognitive decline and whether this mediating effect is regulated by oxidative stress, inflammation, and energy metabolism.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Writing—original draft preparation and writing—review and editing: JX. Project administration: W-XX. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.