Association between anemia and frailty in 13,175 community-dwelling older adults in China CURRENT STATUS:

Anemia and frailty contribute to poor health outcomes in older adults; however, most current research in lower income countries has concentrated on anemia or frailty alone rather than in combination. The aim of the present study was to investigate the association between anemia and frailty in community-dwelling adults aged 50 years and older in China. The study population was sourced from the 2007/10 SAGE China Wave 1. Anemia was defined as hemoglobin less than 13g/dL for men and less than 12g/dL for women. A frailty index (FI) was compiled to assess frailty. The association between anemia and frailty was evaluated using a 2-level hierarchical logistic model.

risk factors based on the WHO STEPwise approach to Surveillance (WHO STEPS, WHO 2005). Sociodemographic variables included age, sex, education, rural/urban residence, and household wealth.
Age was categorized into four groups: 50 to 59 years; 60 to 69 years; 70 to 79 years; and 80 years or older. Highest level of education completed was classified into six categories using an international classification scheme (No formal education; less than primary; primary school completed; secondary school completed; high school completed; college completed and above) for use in this analysis [13].
The household wealth was generated using an asset-based approach and included possession of assets and dwelling characteristics [14], with the resulting wealth quintiles ranging from quintile 1 (Q1, poorest) to quintile 5 (Q5, wealthiest) households.
Non-communicable disease risk factors included alcohol and tobacco consumption, poor diet and low physical activity levels. Tobacco use was classified into four groups: never smoker, not current smokers, current smokers (not daily) and current daily smokers. Alcohol consumption was categorized into four groups: never drinker, non-heavy drinkers, infrequent heavy drinkers and frequent heavy drinkers according to the number of standard drinks consumed in a given week. Physical activity was measured by the Global Physical Activity Questionnaire (GPAQ) and three categories were generated: low, moderate and high levels [15]. Diet was assessed through fruit and vegetable consumption and calculated by the number of daily servings eaten. Five or more servings were defined as sufficient daily intake (equivalent to at least 400 grams per day), fewer than five servings was categorized as insufficient [16].

Statistical methods
Statistic analyses were conducted using STATA SE version 14.1 (Stata Corp, College Station, TX). The population prevalence of anemia and frailty was calculated by using normalized weights. Weights were based on selection probability, non-response, and post-stratification adjustments. A 2-level hierarchical logistic model was used to evaluate the association between anemia and frailty using STATA command "melogit". We also included hemoglobin concentration as a continuous variable in the model (models 3 and 4) to see if there was an association between hemoglobin concentration and frailty. Covariates of interest included age, gender, education, smoking, nutrition, physical activity. P < 0.05 from two-sided statistical tests was considered statistically significant.

Results
The sociodemographic characteristics of samples are shown in Table 1. A total of 13,175 individuals aged 50 and older were included in the analysis. The proportion of women (50.2%) was higher than men (49.8%) in the study, with small sex differences by age groups. The overall mean age was 62.6 years (SE 0.2). The majority of the respondents were between 50 and 59 years old (44.9%), nearly half of all respondents (47.3%) lived in an urban area. Fifty-eight percent had completed primary school or higher. The prevalences of lowest and highest wealth quintile were 16.3% and 21.8% respectively.

Discussion
This study reported the prevalences of anemia and frailty and the two conditions combined in a large population of older Chinese adults. The prevalence of both conditions were higher at older ages and in individuals with lower education levels. In addition, anemia was significantly associated with frailty, where each 1 g/dL increase in hemoglobin concentration was related with 4% decrease in the odds of frailty after adjusting for several variables. As far as we know, this was the first paper addressing the association between anemia and frailty among community-dwelling adults aged 50 years and older in China.
Estimates of anemia prevalence differ considerably, with reported prevalence ranging from 2.9% to 61% in older men and from 3.3% to 41% in older women [17]. Anemia prevalence was 14.1% for men and 10.2% for women aged 65 and older in the US National Health and Nutrition Examination Survey (NHANES 2013-2016) [18]. An Australian epidemiologic study had anemia estimates of 14.6% among men aged 70+ years [19]. Thirty-eight percent of community-dwelling people aged 60 years and older had anemia in a small study in India [20]. Likewise, 38.1% of older adults had anemia in the Singapore Longitudinal Ageing Studies (SLAS) [21]. Our analyses indicated that the prevalence of anemia was 31.0% (95%CI: 28.4-33.8%) in China. The different population, sampling programs and hemoglobin test methods may contribute to the difference between these studies.
Attention to the measurement and impact of frailty in older age has increasing substantially over the past decade. The deficit accumulation approach has been well tested in different populations. For example, the overall weighted prevalence of frailty was 9.9% in the community-dwelling older population (60+ years) derived from the China Comprehensive Geriatric Assessment Study (CCGAS), based on the Comprehensive Geriatric Assessment Frailty Index [22]. The physical frailty phenotype approach was used in an analysis of the China Health and Retirement Longitudinal Study (CHARLS), resulting in 7% of adults aged 60 years or older being classified as frail [23]. In our study, the frailty index resulted in 14.7% (95%CI: 13.5-16.0%) of community-dwelling residents aged 50 + years being classified as frail, higher than the two studies mentioned which use somewhat different frailty criteria.
Anemia reduces the oxygen-carrying capacity, which can result in tissue hypoxia and lead to a number of poor outcomes, including reduced submaximal and maximal aerobic capacity, failing muscle strength, cognitive impairment and development of frailty [24][25][26], which related to vulnerability and some negative outcomes . Several previous studies have examined the interaction between anemia and frailty among older people in high income countries. A case-control study in Baltimore (USA) firstly explored the relationship between anemia and frailty, showing an inverse correlation between interleukin-6 (IL-6) and hemoglobin or hematocrit in the frail group, suggesting that frail subjects have evidence of inflammation and lower hemoglobin and hematocrit levels [27].
Data from the Women´s Health and Aging Studies (WHAS) I and II found mildly low and low-normal hemoglobin levels were associated with increased frailty, and the risk of frailty increased at statistically significant levels for anemia adjusted for age, race, and education [28][29]. Another crosssectional and longitudinal study in older Australian men also suggested that anemia may contribute to the development of frailty [19]. Recent studies including older men and women indicated that older anemic adults were more likely to be frail, with the association between lower levels of hemoglobin and number of frailty criteria showing dose-response effect [30][31][32]. However, another contrasting result suggested having anemia contributed to a weak but significantly lower chance of worsening frailty [33]. In our study, we used 40 variables to construct a Frailty Index and observed that both anemia and lower concentrations of hemoglobin were associated with frailty.
Some studies have suggested that age-associated chronic inflammation is an explanatory factor in the relationship between anemia and frailty. In older adults, anemia and frailty may share a pathophysiological pathway with chronic inflammatory processes, resulting from immunosenescenceassociated changes and increased oxidative stress [34][35][36]. Gabriele [37] described a close connection between inflammaging, anemia, and frailty, where comorbidities and inflammaging contribute to anemia of chronic inflammation(ACI), which was the most frequent type of anemia in older adults.
Considering the etiopathogenetic mechanisms of inflammation, some interventions such as dietetic approach and physical exercise that can moderate oxidative stress and chronic inflammation may prevent anemia, frailty and their negative impact on functional performance and quality of life. Our results also indicated sufficient intake of vegetables and fruit and moderate to high levels of physical exercise had protective effects.
There were a few limitations in our study. Firstly, we used cross-sectional data from SAGE China Wave 1, it cannot provide causal direction in the relationship between anemia and frailty. Results from SAGE China Waves 2 and 3 may provide an opportunity to examine the direction of this relationship we identified. Secondly, we used self-report for some items to construct Frailty Index, which may be influenced by recall bias, although self-reported health questions are widely applied in population studies. Thirdly, the missing data for hemoglobin may have also contributed to bias. However, our study was based on a large, national probability sample of older adults of both genders in China. We do not expect these missing values to have impacted the results or interpretations. Furthermore, the results indicated a quantitative relationship between hemoglobin concentration and frailty.

Conclusions
In conclusion, anemia and frailty were prevalent in China dwelling adults aged 50 years and older, and we also found that anemia and low-normal hemoglobin concentrations were significantly associated with frailty. Therefore, health care professionals caring for older adults may want to improve their recognition and treatment of anemia in their patient populations. Attention at the primary care level may reduce this risk for frailty, disability, hospitalization and mortality. This way, effective policies, early screening and health interventions can be employed for avoiding, delaying or