Association of serum bilirubin with longevity: Evidence from a retrospective longitudinal study and cross-sectional data
DOI:
https://doi.org/10.1515/anre-2017-0024Keywords:
aging, antioxidant, bilirubin, inflammation, longevity, longitudinal study, sex differencesAbstract
Bilirubin is a potent antioxidant and an important anti-inflammatory factor. Therefore, there has been an increasing focus on serum bilirubin as a negative risk factor of cardiovascular mortality in men and an indicator of improved survival in both sexes, but the direct mechanisms of these links and the causes of sex differences are not well understood. Moreover, the evidence from longitudinal studies on effects of bilirubin on longevity is limited. In this study, we retrospectively analyzed two groups of older adults to explore age-dependent changes in serum bilirubin levels and their associations with long-term survival in both sexes. Longitudinal data from 142 individuals (68 men and 74 women) aged 45 to 70 years were compared with cross-sectional data from 225 individuals (113 men and 112 women). The latter group was divided into four categories of survival, i.e. 53, 63, 68, and 76+ based on data on lifespan. ANOVA, t-test, and regression analysis were run. The analysis of the longitudinal data showed an increase in serum total bilirubin levels in men (0.3038e0.093x, R2 = 0.667) and women (0.1838e0.0187x, R2 = 0.950), while the analysis of cross-sectional data revealed a U-shaped pattern of age-related changes in men (0.001x2 - 0.1263x + 4.4524, R2 = 0.999) but an inverted U-shaped pattern in women (0.0006x2 + 0.072x - 1.6924, R2 = 0.195). On balance, these results suggest that elevated but normal bilirubin levels might confer a survival advantage in older men but not women. Alternatively, the positive relationship between serum total bilirubin and lifespan was not causal but coincidental. Further studies are needed to elucidate the direct mechanisms of the association between serum bilirubin levels and longevity in elderly people of both sexes.
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Agrawal VV, Sharma R. 2015. To study inverse relationship between serum total bilirubin levels and severity of diseases in patients with stable coronary artery disease as assessed by coronary angiography and syntax score. J Ind Coll Cariol 5:209–13.
View in Google Scholar
Ajja R, Lee DC, Sui X, Church TS, Steven NB. 2011. Usefulness of serum bilirubin and cardiorespiratory fitness as predictors of mortality in men. Am J Cardiol 108:1438–42.
View in Google Scholar
Bakrania B, Du Toit EF, Ashton KJ, Kiessling CJ, Wagner KH, Headrick JP, Bulmer AC. 2014. Hyperbilirubinemia modulates myocardial function, aortic ejection, and ischemic stress resistance in the Gunn rat. Am J Physiol Heart Circ Physiol 307:H1142–9.
View in Google Scholar
Bakrania B, Du Toit EF, Ashton KJ, Wagner KH, Headrick JP, Bulmer AC. 2017. Chronically elevated bilirubin protects from cardiac reperfusion injury in the male Gunn rat. Acta Physiol 220:461–70.
View in Google Scholar
Baradaran A, Nasri H, Rafieian-Kopaei M. 2014. Oxidative stress and hypertension: possibility of hypertension therapy with antioxidants. J Res Med Sci 19:358–67.
View in Google Scholar
Boland BS, Dong MH, Bettencourt R, Barrett- Connor E, Loomba R. 2014. Association of serum bilirubin with aging and mortality. J Clin Exp Hepatol 4:1–7.
View in Google Scholar
Boon AC, Bulmer AC, Coombes JS, Fassett RG. 2014. Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations. Am J Physiol Renal Physiol 307:F123–36.
View in Google Scholar
Boon AC, Hawkins CL, Coombes JS, Wagner KH, Bulmer AC. 2015. Bilirubin scavenges chloramines and inhibits myeloperoxidase- induces protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum. Free Radic Biol Med 86:259–68.
View in Google Scholar
Borysławski K, Chmielewski P. 2012. Jak zdrowo się starzeć? In: J Gulanowski, editor. Uniwersytety Trzeciego Wieku. Wrocław: Agencja Wydawnicza „Argi”. 69–80.
View in Google Scholar
Bossard M, Aeschbacher S, Schoen T, Hochgruber T, von Rotz M, Blum J, Risch M, Risch L, Conen D. 2014. Serum bilirubin levels and risk or prediabetes in young and healthy adults. Int J Cardiol 171:e24-5.
View in Google Scholar
Bulmer AC, Verkade HJ, Wagner KH. 2013. Bilirubin and beyond: a review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 52:193–205.
View in Google Scholar
Chen YH, Chau LY, Chen JW, Lin SJ. 2008. Serum bilirubin and ferritin levels link heme oxygenase-1 gene promoter polymorphism and susceptibility to coronary artery disease in diabetic patients. Diabetes Care 31:1615–20.
View in Google Scholar
Chmielewski P. 2012. Pochodzenie rodziny u Homo sapiens. Kosmos 61:351–62.
View in Google Scholar
Chmielewski P. 2016. Teoria sezonowego programowania długowieczności. Kosmos 65:323-37.
View in Google Scholar
Chmielewski P. 2017. Rethinking modern theories of ageing and their classification: the proximate mechanisms and the ultimate explanations. Anthropol Rev 80: 259–272.
View in Google Scholar
Chmielewski P, Borysławski K, Chmielowiec K, Chmielowiec J. 2015a. Height loss with advancing age in a hospitalized population of Polish men and women: magnitude, pattern and associations with mortality. Anthropol Rev 78:157–68.
View in Google Scholar
Chmielewski P, Borysławski K, Chmielowiec K, Chmielowiec J. 2015b. Longitudinal and cross-sectional changes with age in selected anthropometric and physiological traits in hospitalized adults: an insight from the Polish Longitudinal Study of Aging (PLSA). Anthropol Rev 78:317–36.
View in Google Scholar
Chmielewski P, Borysławski K. 2016. Proksymalne przyczyny starzenia się człowieka: przypadkowe uszkodzenia molekularne czy hiperfunkcja programów rozwojowych? Kosmos 65:339–49.
View in Google Scholar
Chmielewski PP, Borysławski K, Chmielowiec K, Chmielowiec J, Strzelec B. 2016a. The association between total leukocyte count and longevity: Evidence from longitudinal and cross-sectional data. Ann Anat 204:1–10.
View in Google Scholar
Chmielewski P, Borysławski K, Strzelec B. 2016b. Contemporary views on human aging and longevity. Anthropol Rev 79:115–42.
View in Google Scholar
Chmielewski P, Strzelec B, Borysławski K, Chmielowiec K, Chmielowiec J, Dąbrowski P. 2016c. Effects of aging on the function of the urinary system: longitudinal changes with age in selected urine parameters in a hospitalized population of older adults. Anthropol Rev 79:331–45.
View in Google Scholar
Chmielewski P, Strzelec B, Chmielowiec J, Chmielowiec K, Borysławski K. 2017. Association between body size and selected hematological parameters in men and women aged 45 and above from a hospitalized population of older adults: an insight from the Polish Longitudinal Study of Aging (1960-2000). Anthropol Rev 80:171–90.
View in Google Scholar
Chmielewski PP, Strzelec B. 2017. Elevated leukocyte count as a harbinger of systemic inflammation, disease progression, and poor prognosis: a review. Folia Morphol available at: https://journals.viamedica.pl/folia_morphologica
View in Google Scholar
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr., Jones DW, Materson BJ, Oparil S, Wright JT Jr., Roccella EJ. 2003. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42:1206–52.
View in Google Scholar
Choi SH, Yun KE, Choi HJ. 2013. Relationships between serum total bilirubin levels and metabolic syndrome in Korean adults. Nutr Metab Cardiovasc Dis 23:31–7.
View in Google Scholar
De la Fuente M, Miquel J. 2009. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 15: 3003–26.
View in Google Scholar
Demir M, Demir C, Keçeoğlu S .2014. Relationship between serum bilirubin concentration and nondipper hypertension. Int J Clin Exp Med 7:1454–8.
View in Google Scholar
Djousse L, Levy D, Cupples LA, Evans JC, D’Agostino RB, Ellison RC. 2001. Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol 87:1196–200.
View in Google Scholar
Erdogan D, Gullu H, Yildirim E, Tok D, Kirbs I, Ciftci O, Baycan ST, Muderrisoglu H. 2006. Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women. Atherosclerosis 184:431–7.
View in Google Scholar
Franceschi C, Campisi J. 2014. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69:S4–9.
View in Google Scholar
Franco OH, Peeters A, Bonneux L, de Laet C. 2005. Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women. Hypertension 46:280–6.
View in Google Scholar
Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. 1996. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol 16:250–5.
View in Google Scholar
Idelman G, Smith DL, Zucker SD. 2015. Bilirubin inhibits the up-regulation of inducible nitric oxide synthase by scavenging reactive oxygen species generated by the toll-like receptor 4-dependent activation of NADPH oxidase. Redox Biol 5:398–408.
View in Google Scholar
Jiang H, Ju Z, Rudolph KL. 2007. Telomere shortening and ageing. Z Gerontol Geriatr 40:314–24.
View in Google Scholar
Jørgensen ME, Torp-Pedersen C, Finer N, Caterson I, James WP, Legler UF, Andersson C. 2014. Association between serum bilirubin and cardiovascular disease in an overweight high risk population from the SCOUT trial. Nutr Metab Cardiovasc Dis 24:656–62.
View in Google Scholar
Jung CH, Lee MJ, Kang YM, Hwang JY, Jang JE, Leem J, Park JY, Kim HK, Lee WJ. 2014. Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: A 4 year retrospective longitudinal study. Metabolism 63:87–93.
View in Google Scholar
Kapitulnik J, Maines MD. 2012. The role of bile pigments in health and disease: Effects on cell signaling, cytotoxicity, and cytoprotection. Front Pharmacol 3:136.
View in Google Scholar
Kimm H, Yun JE, Jo J, Jee SH. 2009. Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke 40:3422–7.
View in Google Scholar
Kirkwood T. 2010. Why women live longer. Stress alone does not explain the longevity gap. Sci Am 303:34–5.
View in Google Scholar
Kundur AR, Singh I, Bulmer AC. 2015. Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert’s syndrome? Atherosclerosis 239:73–84.
View in Google Scholar
Kunutsor SK. 2015. Serum total bilirubin levels and coronary heart disease - Causal association or epiphenomenon? Exp Gerontol 72:63–6.
View in Google Scholar
Li Y, Meng SY, Meng CC, Yu WG, Wang RT. 2013. Decreased serum bilirubin is associated with arterial stiffness in men. Nutr Metab Cardiovasc Dis 23:375–81.
View in Google Scholar
Li N, Xu M, Cai MY, Zhou F, Li CF, Wang BX, Ou W, Wang SY. 2015. Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer. Cancer Epidemiol 39:763–8.
View in Google Scholar
Lima LM, Carvalho MG, Sousa MO. 2007. Apo B/apo A-I ratio and cardiovascular risk prediction. Arq Bras Cardiol 88:e187-90.
View in Google Scholar
Lin JP, O’Donnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S, Kronenberg F. 2006. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation 114:1476–81.
View in Google Scholar
Lin LY, Kuo HK, Hwang JJ, Lai LP, Chiang FT, Tseng CD, Lin JL. 2009. Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents. Atherosclerosis 203:563–8.
View in Google Scholar
Lin JP, Vitek L, Schwertner HA. 2010. Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem 56:1535–43.
View in Google Scholar
Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Kihara Y, Chayama K, Noma K, Nakashima A, Tomiyama H, Takase B, Yamashina A, Higashi Y. 2012. Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation 126:598–603.
View in Google Scholar
Nano J, Muka T, Cepeda M, Voortman T, Dhana K, Brahimaj A, Dehghan A, Franco OH. 2016. Associations of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: A systematic review and meta-analysis of observational evidence. Diabetes Metab 42:389–97.
View in Google Scholar
Novotny L, Vitek L. 2003. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med 228:568–71.
View in Google Scholar
Oda E. 2014. A decrease in total bilirubin predicted hyper-LDL cholesterolemia in a health screening population. Atherosclerosis 235:334–8.
View in Google Scholar
Oda E. 2016. Cross-sectional and longitudinal associations between serum bilirubin and prediabetes in a health screening population. Can J Diabetes 40:270–5.
View in Google Scholar
Ohnaka K, Kono S, Inoguchi T, Yin G, Morita M, Adachi M, Kawate H, Takayanagi R. 2010. Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res Clin Pract 88:103–10.
View in Google Scholar
Ong KL, Allison MA, Cheung BM, Wu BJ, Barter PJ, Rye KA. 2014. The relationship between total bilirubin levels and total mortality in older adults: the United States National Health and Nutrition Examination Survey (NHANES) 1999–2004. PLoS One 9:e94479.
View in Google Scholar
Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA. 2008. Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999-2004. Am J Med 121:781–8.
View in Google Scholar
Peyton KJ, Shebib AR, Azam MA, Liu XM, Tulis DA, Durante W. 2012. Bilirubin inhibits neointima formation and vascular smooth muscle cell proliferation and migration. Front Pharmacol 3:48.
View in Google Scholar
Regan JC, Partridge L. 2013. Gender and longevity: why do men die earlier than women? Comparative and experimental evidence. Best Pract Res Clin Endocrinol Metab 27:467–79.
View in Google Scholar
Rincon M, Rudin E, Barzilai N. 2005. The insulin/IGF-1 signaling in mammals and its relevance to human longevity. Exp Gerontol 40:873–7.
View in Google Scholar
Rodwell VW, Bender DA, Botham KM, Kennelly PJ, Weil PA. 2015. Harper’s illustrated biochemistry. 30th ed. New York: McGraw Hill.
View in Google Scholar
Ryter SW. 2012. Bile pigments in pulmonary and vascular disease. Front Pharmacol 3:39.
View in Google Scholar
Santangelo R, Mancuso C, Marchetti S, Di Stasio E, Pani G, Fadda G. 2012. Bilirubin: an endogenous molecule with antiviral activity in vitro. Front Pharmacol 3:36.
View in Google Scholar
Schmidt WN, Mathahs MM, Zhu Z. 2012. Heme and HO-1 inhibition of HCV, HBV, and HIV. Front Pharmacol 3:129.
View in Google Scholar
Schwertner HA. 1998. Association of smoking and low serum bilirubin antioxidant concentrations. Atherosclerosis 136:383–7.
View in Google Scholar
Schwertner HA, Jackson WG, Tolan G. 1994. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem 40:18–23 .
View in Google Scholar
Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, Snyder SH. 2009. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc Natl Acad Sci USA 106:5171–6.
View in Google Scholar
Sniderman AD, Jungner I, Holme I, Aastveit A, Walldius G. 2006. Errors that result from the TC/HDL C ratio rather than the apo B/apo A-I ratio to identify the lipoprotein-related risk of vascular disease. J Intern Med 259:455–61.
View in Google Scholar
Stec DE, Hosick PA, Granger JP. 2012. Bilirubin, renal hemodynamics, and blood pressure. Front Pharmacol 3:18.
View in Google Scholar
Tanaka M, Fukui M, Tomiyasu K, Akabame S, Nakano K, Hasegawa G, Oda Y, Nakamura N. 2009. Low serum bilirubin concentration is associated with coronary artery calcification (CAC). Atherosclerosis 206:287–91.
View in Google Scholar
Tatami Y, Suzuki S, Ishii H, Shibata Y, Osugi N, Ota T, Kawamura Y, Tanaka A, Takeshita S, Murohara T. 2014. Impact of serum bilirubin levels on carotid atherosclerosis in patients with coronary artery disease. IJC Metab Endocr 5:24–7.
View in Google Scholar
Temme EH, Zhang J, Schouten EG, Kesteloot H. 2001. Serum bilirubin and 10-year mortality risk in a Belgian population. Cancer Causes Control 12:887–94.
View in Google Scholar
Vitek L. 2012. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol 3:55.
View in Google Scholar
Vitek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P. 2002. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 160:449–56.
View in Google Scholar
Vitek L, Schwertner HA. 2007. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem 43:1-57.
View in Google Scholar
Walldius G, Jungner I, Aastveit AH, Holme I, Furberg CD, Sniderman AD. 2004. The apoB/apoA-I ratio is better than the cholesterol rations to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk. Clin Chem Lab Med 42:1355–63.
View in Google Scholar
Wallner M, Marculescu R, Doberer D, Wolzt M, Wagner O, Vitek L, Bulmer AC, Wagner KH. 2013. Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert’s syndrome. Clin Sci 125:257–64.
View in Google Scholar
Wegiel B, Otterbein LE. 2012. Go green: the anti-inflammatory effects of biliverdin reductase. Front Pharmacol 3:47.
View in Google Scholar
Wu TW, Fung KP, Yang CC. 1994. Unconjugated bilirubin inhibits the oxidation of human low-density lipoprotein better than Trolox. Life Sci 54:477–81.
View in Google Scholar
Wu TW, Fung KP, Wu J Yang CC, Weisel RD. 1996. Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol 51:859-62.
View in Google Scholar
Zhang ZY, Bian LQ, Kim SJ Zhou CC, Choi YH. 2012. Inverse relation of total serum bilirubin to coronary artery calcification score detected by multidetector computed tomography in males. Clin Cardiol 35:301–6.
View in Google Scholar
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