The Correlation Between Nutrition and Frailty and the Predictive Value of Different Nutritional Indexes for Frailty

Background: Frailty is a kind of geriatric syndrome, which is very common in the elderly. Patients with malnutrition are at higher risk of frailty. This study analyzes the risk factors of frailty and the predictive value of different indicators for the occurrence of frailty through a cross-sectional study. Results: The study included 179 hospitalized patients aged 65 years and over. Patients were divided into non-frailty group and frailty group according to Fried Frailty Phenotype. Compared with the non-frailty group, the upper arm circumference, calf circumference, hemoglobin, albumin, prealbumin, cholesterol and low density lipoprotein in the frailty group were lower (P < 0.05). Comprehensive nutritional assessment, whether as a categorical variable or a continuous variable, was signicantly correlated with frailty (P < 0.05). Model1 showed that the risk of frailty in malnourished patients was 3.381 times higher than that in well nourished patients (P = 0.036). Model2 showed that the risk of frailty decreased by 13.8% for every 1 point increase in MNA score (P = 0.009). The area under the curves of albumin, prealbumin and hemoglobin was larger (AUC > 0.65), AUC was 0.718, 0.693 and 0.743, respectively. Conclusions: Malnutrition is closely related to frailty. Albumin, prealbumin and hemoglobin have predictive value for frailty. Further cohort studies are needed to verify their ability to screen for frailty.


Introduction
Frailty is undoubtedly one of the most serious global public health challenges we will confront in the coming century. The rapid expansion of the aging population has led to a corresponding increase in the number of frail elderly [1,2] . Frailty is de ned as a clinical state in which individuals are more likely to have health-related negative events when exposed to endogenous or exogenous stressors [3,4] . Frailty is a dynamic evolution process from health to weakness, in which the degree of weakness can develop to any direction with the passage of time [2] . Accordingly, frailty may be reversible, and its related functional decline is also a disease that may be prevented [5] . Nutrition is a crucial factor closely related to frailty syndrome [6] . Malnutrition can signi cantly aggravate the development of frailty, because long-term malnutrition, insu cient protein and energy intake can lead to weight loss (one of the ve criteria of frailty phenotype), fatigue, weakness, slow walking speed and low level of physical activity [7] . The pathophysiology of frailty is complex and multifactorial, and nutrition is an important mechanism of its pathogenesis and a speci c target of treatment [8,9] . Although people are more and more interested in the relationship between frailty and nutrition, we have not found any nutritional indicators that can predict the occurrence of frailty. The purpose of this study is to reveal for the rst time that albumin, prealbumin and hemoglobin have predictive value for the occurrence of frailty, and to explore the risk factors of frailty, so as to provide the basis for the possible effective prevention and treatment.

Study Design
This work is a cross-sectional study conducted in the cadre ward of the First Hospital of Jilin University from December 2020 to June 2021. Inpatients aged 65 years or above were recruited. Patients who were unable to walk for neuromusculoskeletal diseases such as Parkinson's disease, severe knee or hip osteoarthritis, lumbar spinal stenosis, and Participants with malignant tumors, severe cognitive impairment, autoimmune diseases, severe liver and kidney dysfunction were excluded from the study. The study was in line with the declaration of Helsinki Declaration and approved by the ethics committee of the First Hospital of Jilin University.

General information
Age, gender and exercise were evaluated by self-made face-to-face interview questionnaire.
Clinical information comes from electronic medical records, including smoking history, drinking history, types and diseases of chronic diseases, hemoglobin, albumin, prealbumin, cholesterol, triglyceride and low density lipoprotein Cholesterol.

Anthropometric measurements
(1) Height and weight were measured according to clinical standards.
(2) Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. (4) Handgrip strength of the dominant hand was measured by handgrip dynamometer(JAMAR@Plus)for 3 times, and the maximum handgrip strength was taken for analysis.
(5) Participants stood with their feet shoulder width apart and the calf circumference around the most prominent part of the gastrocnemius muscle was measured (accurate to 0.1 cm).
(6) Arm circumferenceat the level of the thickest part of biceps brachii muscle was measured with the upper limb sags naturally (accurate to 0.1 cm).

Frailty Assessment
Frailty was de ned as a major biological phenotype by Fried Frailty Phenotype [10] . Satisfying three or more of the ve followings were diagnosed as frailty syndrome, including weight loss of more than 4.5 kg or > 5%, fatigue, less physical activity, slow pace and weak handgrip in the past year. Fatigue refers to feeling that everything needs effort or can't move forward for three or more days. The decrease of handgrip strength was estimated by lower limit of handgrip strength which was determined according to the subjects' gender and body mass index. Male < 383 kcal / week or female < 270 kcal / week was judged as physical activity decrease. Walking speed was calculated by the time required to walk 4.57 meters, male with height ≤ 173 cm, walking speed ≥ 7 s or height > 173 cm, walking speed ≥ 6 s was identi ed as walking speed descent; while the standard of walking speed descent among female is height ≤ 159 cm, walking speed ≥ 7 s or height > 159 cm, walking speed ≥ 6 s.

Malnutrition
Mini Nutritional Assessment (MNA) is a nutritional assessment tool with 18 questions specially developed for the elderly. It consists of four parts: anthropometry (body mass index, calf circumference and arm circumference measurement), self reported health status, dietary problems (including weight loss) and clinical health status. MNA was used to comprehensively evaluate the nutritional status of elderly patients [11,12] . The total score of MNA is 30 points, if the score was < 17 points, patients were classi ed as malnutrition; if the score was between 17 to 23.5 points, subjects were at the risk of malnutrition; good nutrition, if the score was > 23.5 points.

Data Analysis
SPSS/WIN 23.0 software was used for statistical analysis (IBM Corp., Armonk, NY, USA). Continuous variables were analyzed using mean and standard deviation, and classi ed variables were analyzed using percentage. In order to determine the impact of malnutrition on senile frailty patients, after adjusting for confounding factors, multivariate Logistic regression analysis was used to observe the OR value and 95% con dence interval. The AUC value was calculated by drawing ROC curve to identify the predictive value of different nutritional indexes for senile frailty patients. Values of p ≤ 0.05 were considered statistically signi cant.

General baseline characteristics of patients
As shown in Table 1, a total of 179 participants participated in the study. There were 60 patients in the frailty group with an average age of 84.87 ± 7.79, and 119 patients in the non-frailty group with an average age of 77.37 ± 8.98. The age difference between the two groups was statistically signi cant (P < 0.001). In addition, there were signi cant differences in the proportion of smoking and exercise. The difference in the number of chronic diseases, activities of daily living score, MNA score and nutritional status between the two groups were also exhibit statistically signi cant (P < 0.05).
3.2 Comparison of the anthropometric parameters and the nutrition index of laboratory between the frailty group and the non-frailty group As shown in Table 2, compared with the non-frailty group, the upper arm circumference, calf circumference, hemoglobin, albumin, prealbumin, cholesterol and low density lipoprotein of patients in the frailty group were lower (P < 0.05).

Relationship between comprehensive nutritional assessment and frailty
As shown in Table 3, we incorporated the comprehensive assessment of nutrition into the Logistic regression model in the form of categorical variables and continuous variables to explore the relationship between nutrition and frailty. The results showed that nutrition was signi cantly correlated with weakness, whether as a categorical variable or a continuous variable (P < 0.05). Model1 showed that the risk of frailty in malnourished patients was 3.381 times higher than well-nourished patients (P = 0.036). Model2 showed that the risk of frailty decreased by 13.8% for every 1 point increase in MNA score (P = 0.009).
3.4 The predictive value of MNA score, anthropometric parameters and laboratory index to the occurrence of frailty.
The predictive value of different nutritional indexes on the occurrence of frailty in elderly was analyzed and compared. Results are shown in Table 4, the area under the curve of MNA score, albumin, prealbumin and hemoglobin was larger (AUC > 0.65), AUC was 0.773, 0.718, 0.693 and 0.743, respectively. However, through the comparison, it was found that MNA score did not exhibit obvious superiority for the prediction of frailty than albumin, prealbumin and hemoglobin. The relevant ROC curve is shown in Fig. 1.

Discussion
This study con rms and extends previous reports, demonstrating the close relationship between malnutrition and frailty. A review on frailty and malnutrition in 2016 supports this conclusion and points out that both malnutrition and frailty are reversible and the incorrectly identi cation can lead to the onset of disability. Nutritional therapy, protein rich diet, correction of vitamin D de ciency and physical activity are all basic aspects of multidisciplinary treatment of senile frailty [7] . A recent review has also shown the importance of quantitative (energy intake) and qualitative (nutritional quality) factors of nutrition in the development of senile frailty syndrome [13] . Nutritional research on the prevention and management of frailty shows that a healthier diet, such as the Mediterranean diet, is mainly to improve physical activity and walking speed and reduce the risk of falls [14] .
Our study also found that there were signi cant differences in the proportion of smoking and exercise, the number of chronic diseases, the ADL score, MNA score and nutritional status between the frailty group and the non -frailty group (P < 0.05). Smoking is a risk factor for atherosclerosis [15] , and atherosclerosis is a common mechanism of frailty [16] . So our study found that people who smoke for a long time were more prone to frailty. Myasthenia is a major component of the frailty syndrome, both are considered as a powerful predictor of incidence rate, disability and death in the elderly. Exercise intervention and nutritional supplements are the strategies for preventing and treating muscle wasting and frailty [17] .
Chronic diseases are considered to be the main determinant of physical weakness [18] . According to the widely used construction of frailty phenotype proposed by Fried et al. [19] , chronic diseases play a central role in the beginning or deterioration of frailty. This study also found that weakness is related to the number of chronic diseases [20] . Studies nd that the decrease of hemoglobin [21][22][23] and albumin [23,24] levels in circular blood is associated with the incidence of frailty, which also supports our study. We further studied the predictive value of serum markers for the occurrence of senile frailty. We found that albumin, prealbumin and hemoglobin had predictive value for the occurrence of frailty. In a recent systematic review, nutrition is identi ed as a means of delaying the occurrence of negative consequences of frailty in the elderly [25] and a method of slowing the development and progress of frailty in the age [13] .
High quality diet matching is very important. Diet rich in antioxidants is an important factor in preventing and delaying the onset of frailty of old people [13] . Another study has found that there is a correlation between insu cient energy, nutrition intake and frailty of the elderly, energy intake ≤ 21 kcal / kg / day is associated with frailty, and intake of more than three nutrients (poor nutritional score) is signi cantly related to the frailty [26] .
The occurrence of frailty may involve a variety of pathophysiological pathways. Age related changes (mitochondrial dysfunction, neuronal degeneration, cell senescence, stem cell degeneration, DNA methylation and injury, autophagy), gene and environment (cognition, nutrition, activity), energy metabolism changes caused by chronic diseases (cardiovascular disease, hypertension, diabetes, arthritis, obesity), stress response injury (chronic in ammation, HPA axis, autonomic nervous system), chronic in ammation, HPA axis, autonomic nervous system, decreased neural function, decrease of anabolic hormones, eventually leading to physical weakness [2] . The acceleration of low-grade in ammatory activity may be a potential cause of frailty syndrome. Studies have proved that the increased of cytokines IL6, CRP and TNF α levels are associated with frailty [27][28][29] . Changes in the endocrine system provide a basis for frailty. The endocrine hormones associated with frailty are testosterone and its precursor DHEA, parathyroid hormone (PTH), vitamin D and insulin-like growth factor [30] . Increased HbA1c levels have been repeatedly shown to be associated with a higher incidence rate of frailty syndrome [31,32] . A series of commonly used serum markers have been evaluated as potentially associated with frailty, and glomerular ltration rate and albumin level are particularly noteworthy as potential indicators of frailty [30] . It was found in our study that albumin, prealbumin and hemoglobin have predictive value for the occurrence of frailty. It has also been found that elderly people at risk of malnutrition are more likely to develop geriatric syndrome (such as frailty syndrome or sarcopenia) than well nourished elderly people [33] . Therefore, early recognition of patients' albumin, prealbumin and hemoglobin results can reduce the incidence of senile frailty.
There are several limitations in current study. The main limitation is that this study is a cross-sectional design, so there is no statement of causality. Another limitation is the study samples are from one medical center, so the results are limited in universality. In conclusion, more prospective cohort studies in the elderly are needed to further understand the potential role of nutrition in preventing, delaying or reversing frailty syndrome.

Conclusions
Our study con rmed a signi cant correlation between malnutrition and frailty. Prospective cohort studies will be conducted on a large scale in the future to explore the effectiveness of nutritional intervention on frailty syndrome.   Table 3 Comprehensive assessment of nutrition and frailty.

Abbreviations
Variates OR (95% CI) P   Figure 1 The predictive value of albumin, prealbumin and hemoglobin for frailty