Association of anemia with all-cause mortality in Chinese centenarians: a prospective cohort study

Abstract

Objectives

This study aimed to examine the relationship between anemia and all-cause mortality in Chinese centenarians.

Design

Prospective cohort study.

Setting and participants

We included 1002 Chinese centenarians from the China Hainan Centenarian Cohort Study (CHCCS)

Measurements

Standard procedures were followed to perform blood analysis, home interviews, and physical examinations. Anemia was defined as a hemoglobin level of less than 130 g/L for men and less than 120 g/L for women.

Results

During the 9-year follow-up period, a total of 929 (92.7%) deaths were identified. Cox proportional hazards regression models revealed that anemia (hazard ratio [HR] 1.289, 95% confidence interval [CI]: 1.117–1.489) was significantly associated with all-cause mortality. There was an apparent dose-response relationship between anemia and all-cause mortality. Centenarians with severe anemia had approximately 1.6 times higher likelihood of all-cause mortality than those without anemia (HR 1.662; 95% CI: 1.154–2.394).

Conclusion

Anemia is associated with an increased risk of all-cause mortality in Chinese centenarians. Further research will be needed to collect more comprehensive data on the etiology of anemia and causes of death in centenarians.

1. Introduction

With the growing global concern of aging, promoting health among older people has become a prominent global concern [1,2]. Anemia is widely recognized as a significant global health problem and is particularly prevalent among older adults [3]. The prevalence of anemia increases with age, reaching 30.7% in individuals older than 80, 37% in those older than 90, and more than 50% in centenarians [[4], [5], [6]].

As a multifactorial condition often associated with nutritional deficiencies, chronic inflammation, and age-related physiological changes, anemia is a common but abnormal finding during the aging process [7]. Anemia is of significant clinical importance in older adults, as numerous studies have highlighted its association with adverse health outcomes, including prolonged hospitalization, cognitive impairment, insomnia, reduced health-related quality of life, and decreased physical functioning [[8], [9], [10], [11], [12], [13], [14]]. Moreover, several studies have suggested that anemia is associated with an increased risk of mortality [[15], [16], [17], [18], [19], [20]]. However, studies on the association between anemia and all-cause mortality in centenarians are scarce, and the sample sizes are minimal. For example, a study by Wieczorowska-Tobis et al. investigated the prevalence of anemia in a small sample of 57 Polish centenarians [5], while Haslam et al. examined the prevalence and predictors of anemia in 185 centenarians from Georgia, USA [6]. However, these studies did not specifically examine the association between anemia and all-cause mortality in centenarians.

Centenarians, previously considered rare, are now the fastest-growing age group globally. Their numbers have approximately doubled every decade since 1950 and are projected to quintuple between 2023 and 2050, particularly in China [21,22]. Analyzing the blood biomarker profiles in populations with exceptional longevity provides an opportunity to deepen our understanding of the mechanisms that contribute to remarkable lifespans. [23]. To date, no other studies have specifically examined the association between anemia and all-cause mortality in Chinese centenarians. Therefore, there is a need for a better understanding of anemia and all-cause mortality in the oldest age group, particularly in centenarians.

To address these knowledge gaps, this study aimed to investigate the association between anemia and all-cause mortality using a large centenarian cohort with nine years of follow-up. The findings of this study will provide essential data and scientific evidence to inform healthcare strategies, interventions, and future research priorities tailored to the unique needs of centenarian populations.

2. Methods

2.1. Study participants

This study utilized data from the China-Hainan Centenarian Cohort Study (CHCCS), one of the largest studies of centenarians in the Asia-Pacific region. The recruitment and sampling procedures of this complete sample study have been previously described [24]. Briefly, it was carried out in a complete sample study in June 2014, according to the household register provided by the Civil Affairs Bureau. Blood analysis, home interview, and physical examination were performed following standard procedures by the interdisciplinary research team. This prospective cohort study included 1,002 eligible centenarians aged over 100 years old residing in 18 county-level units in Hainan. Participants were subsequently contacted until March 31, 2023, to obtain follow-up information.

The ethics committee of the Hainan branch of the Chinese People's Liberation Army General Hospital approved this study (number 301HNLL-2016-01). Written informed consent was obtained from each participant and their legal guardians prior to the study's commencement. The study complied with the Declaration of Helsinki (seventh revision, 2013) on medical protocols and ethics.

2.2. Exposure and covariates

According to the World Health Organization (WHO) criteria, anemia is defined as a hemoglobin level less than 130 g/L for men and less than 120 g/L for women [25], and anemia is classified by severity into mild (110 g/L to normal), moderate (80 g/L to 110 g/L), and severe anemia (less than 80 g/L).

Demographic details (age, marital status, education, ethnicity, smoking habits, drinking habits, and living situation) of the participants were collected during home interviews. Body mass index (BMI) was calculated using the standard formula of weight in kilograms divided by height in square meters. BMI < 18.5 kg/m² was recognized as underweight. C-reactive protein (CRP) >0.8 mg/dl was defined as inflammation. Chronic conditions (hypertension, diabetes mellitus, heart disease, chronic obstructive pulmonary disease (COPD)/asthma, and stroke) were identified based on self-reports combined with the medical records of the participants. Hypertension was defined as systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg, or normal BP with concomitant use of antihypertensive medications [26]. Diabetes mellitus was defined as a fasting blood glucose (FBG) level ≥7.0 mmol/L or taking hypoglycemic drugs/insulin [27].

2.3. Main outcome

The primary outcome of this study was all-cause mortality. The survival status and date of death of participants were collected through linkage to the death registration system of the public security department and the registration system of the Hainan Provincial Committee on Aging and were subsequently verified by telephone. After the survival status was confirmed, the study came to an end. There was no missing follow-up until March 31, 2023.

2.4. Statistical analyses

The data are presented as means ± standard deviations or medians for continuous variables and as counts (%) for categorical variables. The differences in the continuous variables of the two groups were compared using Student’s t-tests and Mann–Whitney U test. The differences in categorical variables were explored using Chi-square tests or Fisher’s exact test. The association of anemia with all-cause mortality was examined using Cox proportional hazard models. To ensure the validity of our analysis, we evaluated the proportional hazards assumption through the Schoenfeld residuals technique and found no evidence of violation. The survival curve was estimated using the Kaplan–Meier and the log-rank test. All of the analyses were performed with SPSS software (Version 19.0 for Windows, serial number 5087722; IBM Corporation, Armonk, NY, USA). A 2-tailed p < 0.05 was considered statistically significant.

3. Results

Table 1 presents the general characteristics of the 1002 Chinese centenarians by anemia. Our analysis included 1002 participants, of which 82.0% (822) were females. The prevalence of anemia was 68.5%, with higher rates among men (76.1%) and slightly lower rates among women (66.8%). Participants with anemia exhibited significantly lower hemoglobin levels (105 ± 13.2 g/L) than those without anemia (129.7 ± 7.9 g/L). Gender and BMI showed significant differences between participants with and without anemia.

Table 1.

General characteristics of the 1002 in centenarians with and without anemia.

Characteristic	With Anemia	Without Anemia	P value
No. of participants	686	316
Mean ± SD
Age	102.8 ± 2.7	102.7 ± 2.7	0.734
Hemoglobin, g/L	105.2 ± 13.2	129.7 ± 7.9	<0.001**
BMI, kg/m2	17.9 ± 3.1	18.7 ± 3.4	<0.001**
N (%)
Female	549 (80.0)	273 (86.4)	0.015*
Married	69 (10.1)	31 (9.8)	0.903
Illiterate	621 (90.5)	294 (93.0)	0.189
Han ethnicity	603 (87.9)	280 (88.6)	0.748
Current smoker	27 (3.9)	8 (2.5)	0.261
Current alcohol user	65 (9.5)	34 (10.8)	0.527
Live with Family	598 (87.2)	265 (83.9)	0.159
Inflammation (CRP > 0.8 mg/dl)	120 (17.5)	43 (13.6)	0.122
Chronic conditions
Hypertension	519 (75.7)	238 (75.3)	0.908
Diabetes mellitus	65 (9.5)	31 (9.8)	0.867
Heart diseases	29 (4.2)	12 (3.8)	0.750
COPD/Asthma	32 (4.7)	20 (6.3)	0.270
Stroke	14 (2.0)	8 (2.5)	0.622

Note: (1) Abbreviations: BMI, body mass index; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease. (2) *p < 0.05; **p < 0.001.

During the 9-year follow-up period, a total of 929 (92.7%) deaths were identified. The Kaplan-Meier survival curves are shown in Fig. 1. Multivariable Cox proportional hazard model analysis results indicated a significant association between anemia and all-cause mortality (adjusted HR = 1.289, 95% CI: 1.117–1.489) (Table 2). The adjusted hazard ratio (HR) of all-cause mortality when comparing participants with mild and moderate anemia with participants without anemia were 1.207(95% CI: 1.037–1.405) and 1.542(95% CI: 1.260–1.887), respectively.

Fig. 1.

Kaplan–Meier survival curves for centenarians by the anemia categories.

Table 2.

The association between anemia and all-cause mortality in Chinese centenarians.

Variable	Crude Model		Model 1		Model 2
	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value
Continuous, per 10 unit	0.909 (0.873,0.946)	<0.001	0.903 (0.868,0.940)	<0.001	0.916 (0.879,0.955)	<0.001
Anemia
No	1		1		1
Yes	1.356 (1.179,1.560)	<0.001	1.332 (1.156,1.535)	<0.001	1.289 (1.117,1.489)	<0.001
Severity of anemia
No anemia	1		1		1
Mild anemia	1.264 (1.090,1.467)	0.002	1.232 (1.060,1.431)	0.007	1.207 (1.037,1.405)	0.015
Moderate anemia	1.638 (1.346,1.993)	<0.001	1.641 (1.346,1.999)	<0.001	1.542 (1.260,1.887)	<0.001
Severe anemia	1.721 (1.199,2.470)	0.003	1.719 (1.196,2.472)	0.003	1.662 (1.154,2.394)	0.006
P for trend	<0.001		<0.001		0.005

Note: (1) HR: hazard ratio; CI: confidence interval. (2) Model 1: Adjusted for age, sex, illiterate, marital status, ethnicity, current smoker, current drinker, and living situation; Model 2: Adjusted for variables in Model 2 plus BMI, CRP, and chronic conditions (hypertension, diabetes mellitus, heart disease, stroke, chronic obstructive pulmonary disease/asthma).

There was an apparent dose-response relationship between anemia and all-cause mortality in all models (p for trend<0.01). Centenarians with severe anemia had approximately 1.6 times higher likelihood of all-cause mortality than those without anemia (adjusted HR = 1.662; 95% CI 1.154–2.394). Furthermore, when included as a continuous variable, the hemoglobin levels were also associated with all-cause mortality (adjusted HR per 10-unit increase in the hemoglobin levels, 0.916; 95% CI: 0.879−0.955).

Stratified analysis by gender is presented in Table 3. The relationship between anemia and all-cause mortality remained statistically significant in women but not men. The mortality risk increased by 36.1% for participants with anemia in Chinese female centenarians (adjusted HR = 1.361; 95% CI: 1.163–1.593).

Table 3.

Gender stratified analyses between anemia and all-cause mortality in Chinese centenarians.

Variable	Crude Model		Model 1		Model 2
	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value
Female
Continuous, per 10 unit	0.886 (0.847,0.927)	<0.001	0.882 (0.843,0.923)	<0.001	0.894 (0.853,0.937)	<0.001
Nonanemic	1		1		1
Anemic	1.393 (1.195,1.624)	<0.001	1.406 (1.206,1.640)	<0.001	1.361 (1.163,1.593)	<0.001
Male
Continuous, per 10 unit	0.977 (0.896,1.064)	0.592	0.996 (0.907,1.093)	0.927	1.014 (0.921,1.117)	0.771
Nonanemic	1		1		1
Anemic	1.061 (0.746,1.509)	0.741	0.917 (0.636,1.320)	0.640	0.912 (0.626,1.329)	0.633

Note: (1) HR: hazard ratio; CI: confidence interval. (2) Model 1: Adjusted for age, sex, illiterate, marital status, ethnicity, current smoker, current drinker, and living situation; Model 2: Adjusted for variables in Model 2 plus BMI, CRP, and chronic conditions (hypertension, diabetes mellitus, heart disease, stroke, chronic obstructive pulmonary disease/asthma).

4. Discussion

Based on a large cohort study of 1,002 Chinese centenarians, we found that anemia was significantly associated with an increased risk of all-cause mortality. We observed a dose-response relationship between anemia severity and mortality risk, with severe anemia being associated with the highest likelihood of all-cause mortality compared to those without anemia. Moreover, we found a significant gender difference in the association between anemia and mortality, with the mortality risk increased by 36.1% for female centenarians with anemia, even after adjusting for potential confounders. These findings underscore the importance of screening, managing, and treating anemia in centenarians, especially in women, to improve health outcomes and reduce mortality risk in this rapidly growing age group.

The prevalence of anemia in our study was 68.5%, with higher rates in men (76.1%) and slightly lower rates in women (66.8%). These findings are consistent with previous studies on anemia prevalence in centenarians. For example, in a study of 57 Chinese centenarians, 66.7% of participants were found to have anemia, while in another study of 185 Georgian centenarians, the prevalence was 50.3%. Additionally, among 89 Polish centenarians, anemia was found in 57% of men and 29% of women [5,6,28]. These findings underscore the commonality of anemia among centenarians and highlight the significance of screening and managing it in this population.

Our study confirms that baseline anemia is an independent risk factor for all-cause mortality in centenarians, which is consistent with the findings of most previous studies in older individuals [[29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]]. For instance, in another study involving 17,030 community-dwelling subjects aged 66 years and older, anemia (defined as hemoglobin < 110 g/L) was found to be associated with an increased risk of death, with an HR of 4.29 (95% CI: 3.55–5.12) [29]. Similarly, a cohort study of 8,935 subjects aged ≥60 years, based on the Thai National Health Examination Survey (NHES-IV), showed that the presence of anemia was associated with an increased risk of mortality, with an HR of 1.66 (95% CI: 1.50–1.84) [31]. However, most studies that have examined the relationship between anemia or hemoglobin levels and mortality have relied on a single measurement of hemoglobin. Further studies need to explore the association between changes in hemoglobin concentration and mortality.

A key finding of our study is the significant gender difference in the association between anemia and mortality among centenarians. The mortality risk increased by 36.1% for female centenarians with anemia (adjusted HR = 1.361; 95% CI: 1.163–1.593) even after adjusting for potential confounders. This finding suggests that the impact of anemia on mortality risk is more pronounced in women than in men. A study based on the Brazilian Longitudinal Study of Adult Health found that the prevalence of anemia was higher in women compared to men and that iron deficiency anemia was more common in women, while anemia of chronic kidney disease, and chronic inflammation was more prevalent in men [41]. Understanding these gender-specific pathways is crucial for developing targeted interventions to manage anemia effectively in the oldest old, particularly in women. Future studies should explore the potential role of hormonal changes, nutritional factors, and comorbidities in contributing to the observed gender differences.

It is crucial to consider whether the potential mechanisms linking anemia to increased mortality risk differ in centenarians. Unfortunately, anemia could not be readily classified in this uniquely aged population due to a limited battery of laboratory assessments and lack of clinical diagnoses [6]. Anemia may be a marker of underlying chronic diseases, inflammation, or nutritional deficiencies, which could independently contribute to mortality risk [3]. Numerous causes and underlying diseases can contribute to anemia in older adults, which include four main aspects: nutritional deficiencies such as iron, folate, and/or vitamin B12 deficiency, inflammation, clonal hematopoiesis, and unexplained anemia [[42], [43], [44]]. Chronic diseases such as diabetes, cardiovascular disease, and chronic kidney disease are well-established risk factors for anemia in older adults [45]. However, our results indicate that chronic diseases or inflammatory are not more prevalent in the anemic group, suggesting that other factors may be the primary drivers of anemia in this population. Age-related changes in hematopoiesis, nutritional deficiencies, or undiagnosed conditions could be potential contributors to anemia in centenarians. Given that anemia in older adults can result from various causes, it is crucial to identify and treat the underlying conditions promptly to manage anemia effectively in this population [46]. Our findings highlight the need for a comprehensive approach to anemia management in the oldest old, taking into account not only chronic diseases and inflammation but also other potential factors specific to this age group.

To our knowledge, this is the first study to specifically examine the association between anemia and all-cause mortality in a large cohort of Chinese centenarians. Our study possesses several strengths, including substantial sample size, a comprehensive long-term follow-up, a representative population, and access to high-quality register data that enables a thorough tracking of all participants. Additionally, the hemoglobin was analyzed in the same laboratory using a consistently applied and well-documented methodology. However, several limitations need to be considered in future studies. First, we acknowledge the potential for residual confounding. We did not have detailed information on the specific causes of anemia, such as iron deficiency, vitamin B12 or folate deficiency, or chronic diseases, and the causes of death for each participant, which prevented us from analyzing the association between anemia and cause-specific mortality. Future studies should aim to collect more comprehensive data on the etiology of anemia and causes of death in centenarians. Second, the exclusion of centenarians who were too ill to participate may have introduced a potential selection bias, which could have influenced the observed associations between anemia and mortality. Third, due to the limited sample sizes in men, the association between anemia and all-cause mortality among male centenarians needs to be further explored. Finally, our study was confined to community-based Chinese centenarians. Therefore, the generalization should be interpreted with caution.

5. Conclusion

In this study, anemia is associated with an increased risk of all-cause mortality in Chinese centenarians, suggesting that proper management of anemia can enhance overall well-being and increase lifespan. Further research will be needed to determine the underlying cause of anemia and to assess the potential benefits of correcting it, if possible, which could result in improved outcomes.

Author contributions

All authors contributed to the conception and design of the work, performed the acquisition, analysis, and interpretation of data for the work, and drafted and revised the article. All authors read and approved the final manuscript.

Funding

This work was supported by grants from National Key R&D Program of China (Grant No. 2022YFC2503605), National Natural Science Foundation of China (Grant No. 82173589,82173590), Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau (Grant No. 2023QNXM003)), General project of Chongqing Natural Science Foundation (Grant No. CSTB2022NSCQ-MSX1082) and medical technology innovation project of Shijiazhuang Science and Technology Bureau (Grant No. 211201253). The sponsors had no role in the design, conduct, interpretation, review, approval, or control of this article.

Ethics approval and consent to participate

This study has been approved by the ethics committee of Hainan Hospital of Chinese People’s Liberation Army General Hospital (301HNLL-2016-01). The informed consents were obtained from all the participants and their legal guardians.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGPT 3.5 in order to enhance proficiency in the English language. After using this tool/service, the authors reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.