Association of Serum Total Bilirubin Concentration with Telomere Length: The National Health and Nutrition Examination Survey

Hao, Lu; Chen, Qiuyan; Chen, Xi; Zhou, Qing

doi:https://doi.org/10.1155/2021/4688900

Oxidative Medicine and Cellular Longevity

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Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2021 | Article ID 4688900 | https://doi.org/10.1155/2021/4688900

Association of Serum Total Bilirubin Concentration with Telomere Length: The National Health and Nutrition Examination Survey

Lu Hao,¹Qiuyan Chen,¹Xi Chen,²and Qing Zhou²

Academic Editor: Ilaria Peluso

Received13 May 2021

Revised09 Sept 2021

Accepted16 Sept 2021

Published24 Sept 2021

Abstract

Introduction. Mildly increased bilirubin concentration has a protective effect on oxidative stress–related diseases. However, it remains unknown whether elevated circulating bilirubin is associated with longer telomere length. The aim of this cross-sectional study was to examine the association between total bilirubin concentration and telomere length. Methods. We used the data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. The multivariable linear regression model was used to examine the association between total bilirubin concentration and telomere length. The nonlinear relationship was analyzed using a generalized additive model with the smoothing plot. Results. A total of 7818 participants with a mean age of years were included. Compared with the lowest concentration of total bilirubin (Q1), the highest quartile of total bilirubin concentration was associated with longer telomere length in male (, 95 CI%: 0.00, 0.07, ) and female (, 95 CI%: 0.02, 0.04, ). Furthermore, an inverted U-shaped relationship between total bilirubin and telomere length was found. On the left of turning points (), total bilirubin concentration was positively associated with telomere length (, 95 CI%: 0.14, 0.32, ). However, the association between total bilirubin concentration and telomere length was not significant (, 95% CI: -0.01, 0.04, ) above the turning point. Conclusion. This is the first evidence based on a nationally representative survey demonstrating a positive and nonlinear association between total bilirubin concentration and telomere length. Future large-scale prospective studies are warranted to confirm our findings.

1. Introduction

Telomeres are specialized structures at the ends of eukaryotic chromosomes, and they play a vital role in providing genomic stability and maintaining chromosomal structural integrity [1, 2]. Telomeres consist of repeated and species-specific noncoding DNA sequences and various specifically bound proteins [3]. Because telomeres are gradually shortened in each cell division by semiconservative DNA replication, telomeres are a potential biomarker for cell senescence and apoptosis and age-related diseases [4–6]. Short telomere lengths are associated with all-cause, cardiovascular, and cancer mortality [7, 8]. In addition, leukocyte telomere length may be a cancer prognosis biomarker [9].

Many epidemiologic studies have revealed that telomere length variability and attrition rate are not only determined by genetic background but also affected by environmental and dietary factors [10–12]. Factors that promote telomere shortening include obesity [13], consumption of sugary drinks [14], smoking [15], and decreased physical activity [16]. By contrast, intake of foods with antioxidant and anti-inflammatory properties is associated with longer telomere length [17, 18]. Bilirubin, the end product of heme catabolism in the intravascular compartment, is one of the most potent endogenous antioxidants [19]. For decades, bilirubin has been considered an ominous sign of liver diseases; however, recent evidence suggests that mildly increased bilirubin concentration has a protective effect on oxidative stress–related diseases, including metabolic syndrome [20] and cardiovascular diseases [21]. In addition, a negative correlation between bilirubin and cancer risk has been observed in breast cancer [22], lung cancer [23], and colorectal cancer [24]. High normal levels of total bilirubin are associated with lower cancer mortality [25]. Elevated serum bilirubin levels have also been associated with increased survival in cancer patients [26, 27]. More interestingly, a recent study showed that an occurrence of longer telomeres was observed in male individuals with Gilbert’s syndrome chronically exposed to increased unconjugated bilirubin [28]. However, the previous study is limited by retrospective nature and small sample size. It remains unknown whether elevated circulating total bilirubin is associated with longer telomere length among more representative population with a rigorous sampling design.

To fill this knowledge gap, we conducted a cross-sectional study using 1999 to 2002 data from the National Health and Nutrition Examination Survey (NHANES). We examined the association between total bilirubin concentration and telomere length. In addition, on the basis of existing evidence on bilirubin, we examined the nonlinear relation between total bilirubin concentration and telomere length by using a generalized additive model (GAM).

2. Materials and Methods

2.1. Study Population

The NHANES is designed to assess the health and nutritional status among the noninstitutional civilian United States population and adopted a stratified multistage probabilistic sampling method to select a representative sample in 15 counties across the country. We used NHANES data from 1999 to 2002 [29]. The procedures involving human subject were approved by the National Center for Health Statistics Research Ethics Review Board, and written informed consent was obtained from all participants.

In the NHANES 1999-2002, there were a total of 21004 individuals, and our analysis was limited to 7827 individuals who had data on mean telomere length. Among them, the individuals without total bilirubin concentrations were further excluded (). In the end, a total of 7818 participants aged more than 18 years were included in this cross-sectional study.

2.2. Laboratory Analyses

The concentration of total bilirubin was analyzed on Beckman Synchron LX20 by using the timed endpoint Diazo method. In the reaction, bilirubin reacts with diazo reagent in the presence of caffeine, benzoate, and acetate as accelerators to form azobilirubin. The LX20 monitors the change in absorbance at 520 nm at a fixed time interval. This change in absorbance is directly proportional to the concentration of total bilirubin in the sample.

The telomere length assay was performed in the laboratory of Dr. Elizabeth Blackburn at the University of California, San Francisco, using the quantitative polymerase chain reaction (PCR) method to measure telomere length relative to standard reference DNA (T/S ratio), as described in detail previously [30, 31]. Notably, due to the wide variance in telomere length measures across labs and types of assays, the base pair estimates are only comparable to the T/S ratio data generated by the same reference standards and the same laboratory procedures. The conversion from T/S ratio to base pairs was not used, and the primary outcome was mean telomere length (T/S ratio). Each sample was assayed 3 times on 3 days, and the samples were analyzed on duplicate wells, resulting in 6 data points. Each assay plate contained 96 control wells with 8 control DNA samples, which were used to normalize between run variability. The interassay coefficient of variation for telomere length was 6.5%.

2.3. Other Variables Analyzed

For all included participants in this study, demographic data on age, sex, race (non-Hispanic white, black, Mexican American, other Hispanic, and other race/ethnicity), and education level (less than high school, high school, and more than high school) were collected. Furthermore, the physical examination and lifestyle factors including body mass index (BMI), smoke status, physical activity, energy intake, alcohol use, diabetes, hypertension, and C-reactive protein were extracted. We categorized BMI as underweight (<18.5), normal (18.5- <25), overweight (25- <30), and obesity (≥30). The smoke status was classified into none, past, and current smoker. Physical activity was estimated by deriving metabolic equivalents for self-reported leisure and normal-time activities and was classified into no aerobic activity, low activity (fewer than 150 min/week), moderate activity (150 to 300 medium intensity min/week), and high activity (4300 medium intensive activity min/week or 4150 high intensity min/week).

2.4. Statistical Analysis

The continuous variables were presented as . Categorical variables were expressed as the numbers and percentages. The total bilirubin concentrations were categorized based on quintiles (Q1-Q5), and quintile 1 (Q1) was the referent category. The one-way ANOVA (continuous variables) test and chi-square tests (categorical variables) were used to assess the differences between groups. We used univariable and multivariable linear regression model to calculate the β-coefficient and 95% confidence intervals (CIs) to evaluate the association between total bilirubin concentration and mean telomere length. The adjusted model was adjusted for age (continuous), race (non-Hispanic white, black, Mexican American, other Hispanic, other race/ethnicity or missing), education (less than high school, high school, more than high school, or missing), body mass index (<18.5, 18.5- <25, 25- <30, ≥30, or missing), smoke status (none, past, current, or missing), alcohol (yes, no, or missing), physical activity (no aerobic activity, low activity, moderate activity, high activity, or missing), energy intake (Q1-Q4), diabetes (yes, no, or missing), and hypertension (yes, no, or missing). We used GAM to identify the nonlinear relationship between total bilirubin concentration and mean telomere length. If the nonlinear relationship was found, the piece-wise linear regression model calculates the threshold effect of total bilirubin concentration and mean telomere length by the smoothing plot. Furthermore, the subgroup analyses were conducted and stratified by age, sex, BMI, smoke status, alcohol, physical activity, energy intake, diabetes, and hypertension. All the statistical analyses were conducted using (http://www.R-project.org) and EmpowerStats software (http://www.empowerstats.com/, X&Y solutions, Inc. Boston MA)). Two-sided values <0.05 were considered as statistical significance.

3. Results

The baseline characteristics by quartile of total bilirubin concentration are shown in Table 1. A total of 7818 participants were ultimately included in this cross-sectional analysis. The average age was years, and 51.82% were female. There were 2418 (31.95%) obese participants, 870 (11.23%) diabetes participants, and 2393 (30.77%) hypertension participants. Furthermore, 1694 (21.71%) of the participants were current smokers, and 1952 (26.00%) of the participants have a history of drinking. Participants in the higher quartile of total bilirubin concentration (Q2-Q5) had higher relative telomere length (T/S ratio) compared to those with the lowest total bilirubin concentration (Q1) ().

The univariable linear regression for association between total bilirubin concentration and mean telomere length is presented in Table 2. The age, BMI, past smoker, diabetes, hypertension, and C-reactive protein were negatively associated with relative telomere length. In contrast, the female, education, energy intake, physical activity, and alcohol use were positively associated with the telomere length.

Table 3 shows the crude and fully adjusted association between total bilirubin concentrations and mean telomere length by sex. The result of univariate linear regression model showed a significant positive association between total bilirubin concentration and mean telomere length, with β of 0.06 (95 CI%: 0.02, 0.09, ) in male and 0.03 (95CI%: 0.00, 0.06, ) in female for the fifth vs. the first quartile of total bilirubin concentration. In the multiple linear regression model, compared with the lowest concentration of total bilirubin (Q1), the highest quartile of total bilirubin concentration was associated with increased level of telomere length in male (, 95CI%: 0.00, 0.07, ) and female (, 95CI%: 0.02, 0.07, ). Furthermore, sensitivity analysis results showed that participants tended to have increased level of telomere length as the quintile of serum selenium concentration increased (all for trend <0.01).

The GAM model with smoothing curve showed that the total bilirubin concentrations and telomere length were nonlinear after multivariable adjustment (Figure 1). According to the piece-wise linear regression analysis, there were threshold effects between total bilirubin concentrations and telomere length (Table 4), and we calculated that the turning points were 0.5 mg/dL in total bilirubin concentrations. On the left of turning points (), we observed a significant positive association between total bilirubin concentration and mean telomere length, with a β of 0.23 (95 CI%: 0.14, 0.32, ). However, the association between total bilirubin concentration and telomere length was not significant (, 95% CI: -0.01, 0.04, ) above the turning point ().

Figure 1

Nonlinear relationship between total bilirubin concentration and telomere length. Adjusted model adjust for age (continuous), race (non-Hispanic white, black, Mexican American, other Hispanic, other race/ethnicity or missing), education (less than high school, high school, more than high school, or missing), body mass index (<18.5, 18.5- <25, 25- <30, ≥30, or missing), smoke status (none, past, current, or missing), alcohol (yes, no, or missing), physical activity (no aerobic activity, low activity, moderate activity, high activity, or missing), energy intake (Q1-Q4), diabetes (yes, no, or missing), hypertension (yes, no, or missing), and C-reactive protein (Q1-Q3).

Table 5 shows the association between total bilirubin concentration and telomere length in different subgroups. The results showed that the effect sizes of total bilirubin on telomere length were not significant in participants aged ≥60 years. There were no significant interaction effects of BMI, smoke status, energy intake, alcohol use, physical activity, history of diabetes and hypertension, and C-reactive protein.

4. Discussion

In this study, we demonstrated a significant positive association between total bilirubin concentration and telomere length in a nationally representative US population. Multivariable regression analysis revealed that higher total bilirubin concentrations (Q1-Q4) were associated with longer telomeres than the lowest total bilirubin concentration. In addition, an inverted U-shaped relationship was observed, indicating that mildly increased bilirubin concentration is protective against telomere shortening. When we added multiple potential confounding factors, including sociodemographics and lifestyle factors and C-reactive protein level, the results were consistent in both crude and fully adjusted models. Sensitivity and stratification analysis of the association between total bilirubin concentration and telomere length was relatively stable and revealed similar results across all subgroups without any indication of interaction. Although unmeasured confounding such as genetic factors and drug therapy may have persisted, the current evidence was sufficiently strong to support robust conclusions.

To our knowledge, our study is the first to indicate a significant positive association between mildly increased total bilirubin concentration and telomere length. Interestingly, similar to our findings, a previous case-control study suggested that Gilbert’s syndrome characterized by elevated unconjugated bilirubin in serum was associated with longer telomeres [28]. One possible explanation for this positive association is that unconjugated bilirubin might affect the immune response by downregulating intracellular production of cytokines, as evident from the decreased IL-6 and IL-1β level in monocytes from individuals with Gilbert’s Syndrome [28]. Previous study has demonstrated that IL-1β may be driving telomere attrition due to the faster cell turnover influenced by increased baseline inflammation [32]. Meanwhile, higher expression levels of proinflammatory genes such as IL-6, IL-1β, and IL-8 were associated with shorter telomere length in peripheral blood mononuclear cells [33]. Furthermore, DNA protection was found in the epithelial tissues of older Gilbert’s syndrome patients with mildly elevated circulating unconjugated bilirubin [34].

In addition to the widely reported immune response that affects telomere length, increased oxidative stress is believed to play a crucial role in telomere attrition. Animal experiments have demonstrated that chronic oxidative stress can cause telomere shortening in testes, fat, tail, and skin [35]. In addition, high-intensity stress can directly shorten telomere length by inducing telomere double-strand breaks [36]. Human studies have also indicated that dietary and blood-derived antioxidants can delay telomere shortening [37, 38]. Therefore, given the aforementioned direct and indirect evidence, another potential explanation for protective effect of increased total bilirubin concentration on telomere shortening might be attributable to the antioxidant property of bilirubin. Bilirubin belongs to the superfamily of tetrapyrrolic compounds; these compounds can scavenge excess reactive oxygen species, have anti-inflammatory effects, or directly affect cell signaling [39]. Early in vitro studies have indicated that bilirubin is an effective antioxidant under physiological conditions, perhaps having an anti-inflammatory effect [40]. Bilirubin inhibits low-density lipoprotein and lipid oxidation, which can prevent atherosclerotic plaques and, consequently, the development of cardiovascular disease [41]. Observational cohort studies have suggested that a slight increase in bilirubin levels is associated with a reduced risk of cardiovascular disease, supporting the concept of bilirubin as a protective antioxidant [42]. More importantly, bilirubin is the main contributor of the total antioxidant capacity in plasma, and it is more effective than water-soluble antioxidants such as glutathione and vitamin E analogs that are in protecting lipids from oxidation [40, 43].

Notably, our data revealed an inverted U-shaped relationship between total bilirubin concentration and telomere length. Thus, the telomere length increased with increased bilirubin concentration up to 0.5 mg/dL, beyond which this association was not significant. Similar findings were also observed in other observational studies. A large cohort study that included 130 052 patients demonstrated that the association between bilirubin and risk of cardiovascular disease was nonlinear (L shaped). At bilirubin levels <10 to 15 μmol/L, myocardial infarction decreases by 3% to 5% for every 1 μmol/L increase in bilirubin levels [44]. A prospective study revealed a U-shaped relationship between bilirubin concentration and coronary heart disease [45]. Taken together, these results confirm that bilirubin may protect against telomere shortening under normal physiological conditions.

To improve our interpretation of findings and produce more robust results, we adjusted for multiple potential confounding factors, including age, ethnicity, education, BMI, smoking status, alcohol, physical activity, energy intake, diabetes, hypertension, and C-reactive protein. Stratification of the association between total bilirubin concentration and telomere length by sex, BMI, smoking status, energy intake, alcohol use, physical activity, and history of diabetes and hypertension revealed similar results across all subgroups. Meanwhile, our results revealed that the association between total bilirubin and telomere length was not significant in participants aged ≥60 years. Because telomere length is generally considered a reliable biomarker of aging, telomere shortening is associated with a shorter healthy life span [46]. In other words, the older participants in this study may have already had shorter telomeres, leading to the lack of a significant association.

Given telomere length has been investigated as a potential biomarker for cardiovascular disease [47], diabetes mellitus [48], Alzheimer and Parkinson disease [49], chronic obstructive pulmonary disease (COPD) [50], and cancer incidence and mortality [8]. Therefore, identifying the key factors affecting telomere attrition helps prevent and control these chronic diseases and elucidate their pathophysiological mechanisms. Our study’s main strength is that it provides the first evidence on the association between total bilirubin concentration and telomere length based on a nationally representative survey. Our findings have critical clinical and public health implications. In addition, we used a GAM with a spline curve to examine the nonlinear relationship between total bilirubin and telomere length. However, this study also has several limitations. First, its cross-sectional design precluded the determination of a causal relationship. Second, the NHANES database does not collect data on unconjugated bilirubin, Gilbert’s Syndrome, and cytokines level, such as IL-6 and IL-1β. Therefore, we cannot determine the further link between mild unconjugated hyperbilirubinaemia in Gilbert syndrome individuals and increased telomere length, and whether this association is mediated by immune response. However, only limited data are available regarding the association between Gilbert syndrome and telomere length. Future studies using a prospective and large sample size data could further elucidate these issues. Thirdly, although we adjusted carefully for multiple confounders, our findings might still be affected by residual confounders, such as genetic factors and drug therapy. Finally, data on telomere length are limited in the NHANES; large-scale prospective studies are warranted to verify our conclusions.

5. Conclusion

In conclusion, our study based on a nationally representative survey demonstrates a positive and nonlinear association between total bilirubin concentration and telomere length. Future large-scale prospective studies are warranted to confirm our findings.

Data Availability

The data that support the findings of this study are available in the DRYAD repository [Patel, Chirag J. et al. (2016), data from a database of human exposomes and phenomes from the US National Health and Nutrition Examination Survey, Dryad, Dataset, doi:10.5061/dryad.d5h62].

Conflicts of Interest

The authors declare that they have no conflict of interests.

Authors’ Contributions

The study design was performed by L H and Q Z. Data analysis was carried out by Q C and X C. drafting of manuscript was performed by L H. Lu Hao and Qiuyan Chen contributed to this work equally.

Acknowledgments

This work was supported by Shenzhen Baoan Shiyan People’s Hospital Fund (2020SY07).

References

T. de Lange, “How telomeres solve the end-protection problem,” Science, vol. 326, no. 5955, pp. 948–952, 2009.
View at: Publisher Site | Google Scholar
E. H. Blackburn, “Switching and signaling at the telomere,” Cell, vol. 106, no. 6, pp. 661–673, 2001.
View at: Publisher Site | Google Scholar
U. Mons, A. Müezzinler, B. Schöttker et al., “Leukocyte telomere length and all-cause, cardiovascular disease, and cancer mortality: results from individual-participant-data meta-analysis of 2 large prospective cohort studies,” American journal of epidemiology., vol. 185, no. 12, pp. 1317–1326, 2017.
View at: Publisher Site | Google Scholar
K. Okamoto and H. Seimiya, “Revisiting telomere shortening in cancer,” Cell, vol. 8, no. 2, p. 107, 2019.
View at: Publisher Site | Google Scholar
A. Muezzinler, A. K. Zaineddin, and H. Brenner, “A systematic review of leukocyte telomere length and age in adults,” Ageing research reviews., vol. 12, no. 2, pp. 509–519, 2013.
View at: Publisher Site | Google Scholar
E. H. Blackburn, E. S. Epel, and J. Lin, “Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection,” Science, vol. 350, no. 6265, pp. 1193–1198, 2015.
View at: Publisher Site | Google Scholar
L. Rode, B. G. Nordestgaard, and S. E. Bojesen, “Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population,” Journal of the National Cancer Institute, vol. 107, no. 6, article djv074, 2015.
View at: Publisher Site | Google Scholar
P. Willeit, J. Willeit, A. Mayr et al., “Telomere length and risk of incident cancer and cancer mortality,” Journal of the American Medical Association, vol. 304, no. 1, pp. 69–75, 2010.
View at: Publisher Site | Google Scholar
C. Zhang, X. Chen, L. Li, Y. Zhou, C. Wang, and S. Hou, “The association between telomere length and cancer prognosis: evidence from a meta-analysis,” PLoS One, vol. 10, no. 7, article e0133174, 2015.
View at: Publisher Site | Google Scholar
M. Asghar, S. Bensch, M. Tarka, B. Hansson, and D. Hasselquist, “Maternal and genetic factors determine early life telomere length,” Proceedings Biological sciences., vol. 282, no. 1799, p. 20142263, 2015.
View at: Publisher Site | Google Scholar
B. Liu, Y. Sun, G. Xu et al., “Association between body iron status and leukocyte telomere length, a biomarker of biological aging, in a nationally representative sample of US adults,” Journal of the Academy of Nutrition and Dietetics., vol. 119, no. 4, pp. 617–625, 2019.
View at: Publisher Site | Google Scholar
M. Mazidi, E. D. Michos, and M. Banach, “The association of telomere length and serum 25-hydroxyvitamin D levels in US adults: the National Health and Nutrition Examination Survey,” Archives of medical science: AMS., vol. 1, pp. 61–65, 2017.
View at: Publisher Site | Google Scholar
M. Lee, H. Martin, M. A. Firpo, and E. W. Demerath, “Inverse association between adiposity and telomere length: the Fels longitudinal study,” American journal of human biology: the official journal of the Human Biology Council., vol. 23, no. 1, pp. 100–106, 2011.
View at: Publisher Site | Google Scholar
C. W. Leung, B. A. Laraia, B. L. Needham et al., “Soda and cell aging: associations between sugar-sweetened beverage consumption and leukocyte telomere length in healthy adults from the National Health and Nutrition Examination Surveys,” American journal of public health., vol. 104, no. 12, pp. 2425–2431, 2014.
View at: Publisher Site | Google Scholar
L. Mirabello, W. Y. Huang, J. Y. Wong et al., “The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer,” Aging Cell, vol. 8, no. 4, pp. 405–413, 2009.
View at: Publisher Site | Google Scholar
L. A. Tucker, “Physical activity and telomere length in U.S. men and women: an NHANES investigation,” Preventive medicine, vol. 100, pp. 145–151, 2017.
View at: Publisher Site | Google Scholar
S. García-Calzón, A. Moleres, M. A. Martínez-González, J. A. Martínez, G. Zalba, and A. Marti, “Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population,” Clinical nutrition., vol. 34, no. 4, pp. 694–699, 2015.
View at: Publisher Site | Google Scholar
N. Shivappa, M. D. Wirth, T. G. Hurley, and J. R. Hebert, “Association between the dietary inflammatory index (DII) and telomere length and C-reactive protein from the National Health and nutrition examination Survey-1999-2002,” Molecular nutrition & food research., vol. 61, no. 4, 2017.
View at: Publisher Site | Google Scholar
L. Vitek, J. A. Hubacek, A. Pajak et al., “Association between plasma bilirubin and mortality,” Annals of hepatology., vol. 18, no. 2, pp. 379–385, 2019.
View at: Publisher Site | Google Scholar
L. Y. Lin, H. K. Kuo, J. J. Hwang et al., “Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents,” Atherosclerosis, vol. 203, no. 2, pp. 563–568, 2009.
View at: Publisher Site | Google Scholar
J. P. Lin, L. Vitek, and H. A. Schwertner, “Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease,” Clinical chemistry., vol. 56, no. 10, pp. 1535–1543, 2010.
View at: Publisher Site | Google Scholar
S. Ching, D. Ingram, R. Hahnel, J. Beilby, and E. Rossi, “Serum levels of micronutrients, antioxidants and total antioxidant status predict risk of breast cancer in a case control study,” The Journal of nutrition., vol. 132, no. 2, pp. 303–306, 2002.
View at: Publisher Site | Google Scholar
L. J. Horsfall, G. Rait, K. Walters, D. M. Swallow, S. P. Pereira, and I. Nazareth, “Serum bilirubin and risk of respiratory disease and death,” Journal of the American Medical Association, vol. 305, no. 7, pp. 691–697, 2011.
View at: Publisher Site | Google Scholar
A. Jirásková, J. Novotný, L. Novotný et al., “Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer,” International journal of cancer., vol. 131, no. 7, pp. 1549–1555, 2012.
View at: Publisher Site | Google Scholar
E. H. Temme, J. Zhang, E. G. Schouten, and H. Kesteloot, “Serum bilirubin and 10-year mortality risk in a Belgian population,” Cancer causes & control: CCC., vol. 12, no. 10, pp. 887–894, 2001.
View at: Publisher Site | Google Scholar
N. Li, M. Xu, M. Y. Cai et al., “Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer,” Cancer epidemiology., vol. 39, no. 5, pp. 763–768, 2015.
View at: Publisher Site | Google Scholar
X. Liu, Q. H. Meng, Y. Ye, M. A. Hildebrandt, J. Gu, and X. Wu, “Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer,” Carcinogenesis, vol. 36, no. 2, pp. 243–248, 2015.
View at: Publisher Site | Google Scholar
A. Tosevska, C. Moelzer, M. Wallner et al., “Longer telomeres in chronic, moderate, unconjugated hyperbilirubinaemia: insights from a human study on Gilbert's syndrome,” Scientific Reports, vol. 6, no. 1, 2016.
View at: Publisher Site | Google Scholar
C. J. Patel, N. Pho, M. McDuffie et al., “A database of human exposomes and phenomes from the US National Health and Nutrition Examination Survey,” Scientific data., vol. 3, no. 1, 2016.
View at: Publisher Site | Google Scholar
R. M. Cawthon, “Telomere measurement by quantitative PCR,” Nucleic acids research., vol. 30, no. 10, article e47, pp. 47e–447, 2002.
View at: Publisher Site | Google Scholar
B. L. Needham, N. Adler, S. Gregorich et al., “Socioeconomic status, health behavior, and leukocyte telomere length in the National Health and nutrition examination survey, 1999-2002,” Social science & medicine., vol. 85, pp. 1–8, 2013.
View at: Publisher Site | Google Scholar
D. Baylis, G. Ntani, M. H. Edwards et al., “Inflammation, telomere length, and grip strength: a 10-year longitudinal study,” Calcified Tissue International, vol. 95, no. 1, pp. 54–63, 2014.
View at: Publisher Site | Google Scholar
J. Lin, J. Sun, S. Wang et al., “_In vitro_ proinflammatory gene expression predicts _in vivo_ telomere shortening: A preliminary study,” Psychoneuroendocrinology, vol. 96, pp. 179–187, 2018.
View at: Publisher Site | Google Scholar
M. Wallner, S. M. Blassnigg, K. Marisch et al., “Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilbert's syndrome measured with the micronucleus cytome assay,” Mutagenesis, vol. 27, no. 6, pp. 731–735, 2012.
View at: Publisher Site | Google Scholar
V. Cattan, N. Mercier, J. P. Gardner et al., “Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice,” Free Radical Biology and Medicine, vol. 44, no. 8, pp. 1592–1598, 2008.
View at: Publisher Site | Google Scholar
D. Bar-Or, G. W. Thomas, L. T. Rael, E. P. Lau, and J. V. Winkler, “Asp-ala-his-Lys (DAHK) inhibits copper-induced oxidative DNA double strand breaks and telomere shortening,” Biochemical and biophysical research communications., vol. 282, no. 1, pp. 356–360, 2001.
View at: Publisher Site | Google Scholar
Q. Xu, C. G. Parks, L. A. DeRoo, R. M. Cawthon, D. P. Sandler, and H. Chen, “Multivitamin use and telomere length in women,” The American journal of clinical nutrition., vol. 89, pp. 1857–1863, 2009.
View at: Google Scholar
K. B. Min and J. Y. Min, “Association between leukocyte telomere length and serum carotenoid in US adults,” European journal of nutrition., vol. 56, no. 3, pp. 1045–1052, 2017.
View at: Publisher Site | Google Scholar
L. Vitek, “The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases,” Frontiers in pharmacology., vol. 3, p. 55, 2012.
View at: Publisher Site | Google Scholar
R. Stocker, Y. Yamamoto, A. F. McDonagh, A. N. Glazer, and B. N. Ames, “Bilirubin is an antioxidant of possible physiological importance,” Science, vol. 235, no. 4792, pp. 1043–1046, 1987.
View at: Publisher Site | Google Scholar
B. S. Boland, M. H. Dong, R. Bettencourt, E. Barrett-Connor, and R. Loomba, “Association of serum bilirubin with aging and mortality,” Journal of clinical and experimental hepatology., vol. 4, no. 1, pp. 1–7, 2014.
View at: Publisher Site | Google Scholar
A. C. Bulmer, J. T. Blanchfield, I. Toth, R. G. Fassett, and J. S. Coombes, “Improved resistance to serum oxidation in Gilbert's syndrome: a mechanism for cardiovascular protection,” Atherosclerosis, vol. 199, no. 2, pp. 390–396, 2008.
View at: Publisher Site | Google Scholar
T. W. Wu, K. P. Fung, and C. C. Yang, “Unconjugated bilirubin inhibits the oxidation of human low density lipoprotein better than Trolox,” Life sciences., vol. 54, no. 25, pp. PL477–PL481, 1994.
View at: Publisher Site | Google Scholar
L. J. Horsfall, I. Nazareth, and I. Petersen, “Cardiovascular events as a function of serum bilirubin levels in a large, statin-treated cohort,” Circulation, vol. 126, no. 22, pp. 2556–2564, 2012.
View at: Publisher Site | Google Scholar
J. A. Troughton, J. V. Woodside, I. S. Young et al., “Bilirubin and coronary heart disease risk in the prospective epidemiological study of myocardial infarction (PRIME),” European Journal of Cardiovascular Prevention & Rehabilitation, vol. 14, no. 1, pp. 79–84, 2007.
View at: Publisher Site | Google Scholar
C. Lopez-Otin, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, pp. 1194–1217, 2013.
View at: Publisher Site | Google Scholar
P. C. Haycock, E. E. Heydon, S. Kaptoge, A. S. Butterworth, A. Thompson, and P. Willeit, “Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis,” BMJ, vol. 349, no. jul08 3, article g4227, 2014.
View at: Publisher Site | Google Scholar
J. Zhao, Y. Zhu, J. Lin et al., “Short leukocyte telomere length predicts risk of diabetes in american indians: the strong heart family study,” Diabetes, vol. 63, no. 1, pp. 354–362, 2014.
View at: Publisher Site | Google Scholar
M. A. Shammas, “Telomeres, lifestyle, cancer, and aging,” Current opinion in clinical nutrition and metabolic care., vol. 14, no. 1, pp. 28–34, 2011.
View at: Publisher Site | Google Scholar
L. Rode, S. E. Bojesen, M. Weischer, J. Vestbo, and B. G. Nordestgaard, “Short telomere length, lung function and chronic obstructive pulmonary disease in 46,396 individuals,” Thorax, vol. 68, no. 5, pp. 429–435, 2013.
View at: Publisher Site | Google Scholar

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Copyright © 2021 Lu Hao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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