Associations between Specific Redox Biomarkers and Age in a Large European Cohort: The MARK-AGE Project

Daniela Weber, Wolfgang Stuetz, Olivier Toussaint, Florence Debacq-Chainiaux, Martijn E T Dollé, Eugène Jansen, Efstathios S Gonos, Claudio Franceschi, Ewa Sikora, Antti Hervonen, Nicolle Breusing, Thilo Sindlinger, María Moreno-Villanueva, Alexander Bürkle, Tilman Grune, Daniela Weber, Wolfgang Stuetz, Olivier Toussaint, Florence Debacq-Chainiaux, Martijn E T Dollé, Eugène Jansen, Efstathios S Gonos, Claudio Franceschi, Ewa Sikora, Antti Hervonen, Nicolle Breusing, Thilo Sindlinger, María Moreno-Villanueva, Alexander Bürkle, Tilman Grune

Abstract

Oxidative stress and antioxidants play a role in age-related diseases and in the aging process. We here present data on protein carbonyls, 3-nitrotyrosine, malondialdehyde, and cellular and plasma antioxidants (glutathione, cysteine, ascorbic acid, uric acid, α-tocopherol, and lycopene) and their relation with age in the European multicenter study MARK-AGE. To avoid confounding, only data from countries which recruited subjects from all three study groups (five of eight centers) and only participants aged ≥55 years were selected resulting in data from 1559 participants. These included subjects from (1) the general population, (2) members from long-living families, and (3) their spouses. In addition, 683 middle-aged reference participants (35-54 years) served as a control. After adjustment for age, BMI, smoking status, gender, and country, there were differences in protein carbonyls, malondialdehyde, 3-nitrotyrosine, α-tocopherol, cysteine, and glutathione between the 3 study groups. Protein carbonyls and 3-nitrotyrosine as well as cysteine, uric acid, and lycopene were identified as independent biomarkers with the highest correlation with age. Interestingly, from all antioxidants measured, only lycopene was lower in all aged groups and from the oxidative stress biomarkers, only 3-nitrotyrosine was increased in the descendants from long-living families compared to the middle-aged control group. We conclude that both lifestyle and genetics may be important contributors to redox biomarkers in an aging population.

Figures

Figure 1
Figure 1
Classical biomarkers of oxidative stress: protein carbonyls (a), 3-nitrotyrosine (b), and malondialdehyde (c). Biomarker concentrations are displayed according to study groups (A) and age groups (B), respectively. RASIG (n = 794); GO (n = 493); SGO (n = 272). Outliers and extreme values are included in the analyses but not shown in the figure. Statistically significant differences are indicated by asterisks: ∗P < 0.05 and ∗∗∗P < 0.001.
Figure 2
Figure 2
Cysteine concentration by study groups (a) and age groups (b). RASIG (n = 794); GO (n = 493); SGO (n = 272). Outliers and extreme values are included in the analyses but not shown in the figure. Statistically significant differences are indicated by asterisks: ∗∗P < 0.01 and ∗∗∗P < 0.001.
Figure 3
Figure 3
Lycopene concentration by study groups (a) and age groups (b). RASIG (n = 794); GO (n = 493); SGO (n = 272). Outliers and extreme values are included in the analyses but not shown in the figure. Statistically significant differences are indicated by asterisks: ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001.

References

    1. Atkuri K. R., Mantovani J. J., Herzenberg L. A., Herzenberg L. A. N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology. 2007;7:355–359. doi: 10.1016/j.coph.2007.04.005.
    1. Greilberger J., Koidl C., Greilberger M., et al. Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer’s disease. Free Radical Research. 2008;42:633–638.
    1. Gil L., Siems W., Mazurek B., et al. Age-associated analysis of oxidative stress parameters in human plasma and erythrocytes. Free Radical Research. 2006;40:495–505.
    1. Mutlu-Turkoglu U., Ilhan E., Oztezcan S., Kuru A., Aykac-Toker G., Uysal M. Age-related increases in plasma malondialdehyde and protein carbonyl levels and lymphocyte DNA damage in elderly subjects. Clinical Biochemistry. 2003;36:397–400. doi: 10.1016/S0009-9120(03)00035-3.
    1. Mehdi M. M., Rizvi S. I. Plasma protein hydroperoxides during aging in humans: correlation with paraoxonase 1 (PON1) arylesterase activity and plasma total thiols. Archives of Medical Research. 2013;44:136–141. doi: 10.1016/j.arcmed.2013.01.003.
    1. Pandey K. B., Mehdi M. M., Maurya P. K., Rizvi S. I. Plasma protein oxidation and its correlation with antioxidant potential during human aging. Disease Markers. 2010;29:31–36. doi: 10.3233/DMA-2010-0723.
    1. Schottker B., Brenner H., Jansen E. H., et al. Evidence for the free radical/oxidative stress theory of ageing from the CHANCES consortium: a meta-analysis of individual participant data. BMC Medicine. 2015;13:p. 300.
    1. Saum K. U., Dieffenbach A. K., Jansen E. H., et al. Association between oxidative stress and frailty in an elderly German population: results from the ESTHER cohort study. Gerontology. 2015;61:407–415. doi: 10.1159/000380881.
    1. Schottker B., Saum K. U., Jansen E. H., et al. Oxidative stress markers and all-cause mortality at older age: a population-based cohort study. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. 2015;70:518–524. doi: 10.1093/gerona/glu111.
    1. Semba R. D., Ferrucci L., Sun K., et al. Oxidative stress is associated with greater mortality in older women living in the community. Journal of the American Geriatrics Society. 2007;55:1421–1425. doi: 10.1111/j.1532-5415.2007.01308.x.
    1. Breusing N., Grune T. Biomarkers of protein oxidation from a chemical, biological and medical point of view. Experimental Gerontology. 2010;45:733–737. doi: 10.1016/j.exger.2010.04.004.
    1. Burkle A., Moreno-Villanueva M., Bernhard J., et al. MARK-AGE biomarkers of ageing. Mechanisms of Ageing and Development. 2015;151:2–12. doi: 10.1016/j.mad.2015.03.006.
    1. Capri M., Moreno-Villanueva M., Cevenini E., et al. MARK-AGE population: from the human model to new insights. Mechanisms of Ageing and Development. 2015;151:13–17. doi: 10.1016/j.mad.2015.03.010.
    1. Moreno-Villanueva M., Capri M., Breusing N., et al. MARK-AGE standard operating procedures (SOPs): a successful effort. Mechanisms of Ageing and Development. 2015;151:18–25. doi: 10.1016/j.mad.2015.03.007.
    1. Moreno-Villanueva M., Kotter T., Sindlinger T., et al. The MARK-AGE phenotypic database: structure and strategy. Mechanisms of Ageing and Development. 2015;151:26–30. doi: 10.1016/j.mad.2015.03.005.
    1. Franceschi C., Bezrukov V., Blanche H., et al. Genetics of healthy aging in Europe: the EU-integrated project GEHA (Genetics of healthy aging) Annals of the New York Academy of Sciences. 2007;1100:21–45. doi: 10.1196/annals.1395.003.
    1. Chen W., Zhao Y., Seefeldt T., Guan X. Determination of thiols and disulfides via HPLC quantification of 5-thio-2-nitrobenzoic acid. Journal of Pharmaceutical and Biomedical Analysis. 2008;48(5):1375–1380. doi: 10.1016/j.jpba.2008.08.033.
    1. Hongsibsong S., Stuetz W., Sus N., Prapamontol T., Grune T., Frank J. Dietary exposure to continuous small doses of α-cypermethrin in the presence or absence of dietary curcumin does not induce oxidative stress in male Wistar rats. Toxicology Reports. 2014;1:1106–1114. doi: 10.1016/j.toxrep.2014.10.025.
    1. Wong S. H., Knight J. A., Hopfer S. M., Zaharia O., Leach C. N., Jr., Sunderman F. W., Jr. Lipoperoxides in plasma as measured by liquid-chromatographic separation of malondialdehyde-thiobarbituric acid adduct. Clinical Chemistry. 1987;33:214–220.
    1. Weber D., Stuetz W., Bernhard W., et al. Oxidative stress markers and micronutrients in maternal and cord blood in relation to neonatal outcome. European Journal of Clinical Nutrition. 2014;68:215–222.
    1. Buss H., Chan T. P., Sluis K. B., Domigan N. M., Winterbourn C. C. Protein carbonyl measurement by a sensitive ELISA method. Free Radical Biology and Medicine. 1997;23:361–366. doi: 10.1016/S0891-5849(97)00104-4.
    1. Stuetz W., Weber D., Dolle M. E., et al. Plasma carotenoids, tocopherols, and retinol in the age-stratified (35–74 years) general population: a cross-sectional study in six European countries. Nutrients. 2016;8(10):p. 64.
    1. Dalle-Donne I., Rossi R., Giustarini D., Milzani A., Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clinica Chimica Acta. 2003;329:23–38. doi: 10.1016/S0009-8981(03)00003-2.
    1. Levine R. L., Garland D., Oliver C. N., et al. Determination of carbonyl content in oxidatively modified proteins. Methods in Enzymology. 1990;186:464–478.
    1. Komosinska-Vassev K., Olczyk P., Winsz-Szczotka K., Klimek K., Olczyk K. Plasma biomarkers of oxidative and AGE-mediated damage of proteins and glycosaminoglycans during healthy ageing: a possible association with ECM metabolism. Mechanisms of Ageing and Development. 2012;133:538–548. doi: 10.1016/j.mad.2012.07.001.
    1. Cakatay U., Kayali R., Uzun H. Relation of plasma protein oxidation parameters and paraoxonase activity in the ageing population. Clinical and Experimental Medicine. 2008;8:51–57. doi: 10.1007/s10238-008-0156-0.
    1. Herce-Pagliai C., Kotecha S., Shuker D. E. Analytical methods for 3-nitrotyrosine as a marker of exposure to reactive nitrogen species: a review. Nitric Oxide : Biology and Chemistry. 1998;2:324–336. doi: 10.1006/niox.1998.0192.
    1. Van Der Vliet A., Eiserich J. P., Halliwell B., Cross C. E. Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional mechanism of nitric oxide-dependent toxicity. Journal of Biological Chemistry. 1997;272:7617–7625.
    1. Frijhoff J., Winyard P. G., Zarkovic N., et al. Clinical relevance of biomarkers of oxidative stress. Antioxidants & Redox Signaling. 2015;23:1144–1170. doi: 10.1089/ars.2015.6317.
    1. von Haehling S., Bode-Boger S. M., Martens-Lobenhoffer J., et al. Elevated levels of asymmetric dimethylarginine in chronic heart failure: a pathophysiologic link between oxygen radical load and impaired vasodilator capacity and the therapeutic effect of allopurinol. Clinical Pharmacology and Therapeutics. 2010;88:506–512. doi: 10.1038/clpt.2010.116.
    1. Itabe H., Yamamoto H., Suzuki M., et al. Oxidized phosphatidylcholines that modify proteins. Analysis by monoclonal antibody against oxidized low density lipoprotein. Journal of Biological Chemistry. 1996;271:33208–33217.
    1. Yamakura F., Taka H., Fujimura T., Murayama K. Inactivation of human manganese-superoxide dismutase by peroxynitrite is caused by exclusive nitration of tyrosine 34 to 3-nitrotyrosine. The Journal of Biological Chemistry. 1998;273:14085–14089. doi: 10.1074/jbc.273.23.14085.
    1. Vadseth C., Souza J. M., Thomson L., et al. Pro-thrombotic state induced by post-translational modification of fibrinogen by reactive nitrogen species. The Journal of Biological Chemistry. 2004;279:8820–8826. doi: 10.1074/jbc.M306101200.
    1. Block G., Dietrich M., Norkus E., et al. Intraindividual variability of plasma antioxidants, markers of oxidative stress, C-reactive protein, cotinine, and other biomarkers. Epidemiology. 2006;17:404–412. doi: 10.1097/01.ede.0000220655.53323.e9.
    1. Block G., Dietrich M., Norkus E. P., et al. Factors associated with oxidative stress in human populations. American Journal of Epidemiology. 2002;156:274–285. doi: 10.1093/aje/kwf029.
    1. Samiec P. S., Drews-Botsch C., Flagg E. W., et al. Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radical Biology and Medicine. 1998;24:699–704. doi: 10.1016/S0891-5849(97)00286-4.
    1. Sekhar R. V., Patel S. G., Guthikonda A. P., et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. The American Journal of Clinical Nutrition. 2011;94:847–853. doi: 10.3945/ajcn.110.003483.
    1. Giustarini D., Dalle-Donne I., Lorenzini S., Milzani A., Rossi R. Age-related influence on thiol, disulfide, and protein-mixed disulfide levels in human plasma. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. 2006;61:1030–1038. doi: 10.1093/gerona/61.10.1030.
    1. Jones D. P., Mody V. C., Jr., Carlson J. L., Lynn M. J., Sternberg P., Jr. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radical Biology & Medicine. 2002;33:1290–1300. doi: 10.1016/S0891-5849(02)01040-7.
    1. Jones D. P., Carlson J. L., Mody V. C., Cai J., Lynn M. J., Sternberg P. Redox state of glutathione in human plasma. Free Radical Biology & Medicine. 2000;28:625–635. doi: 10.1016/S0891-5849(99)00275-0.
    1. Moriarty-Craige S. E., Jones D. P. Extracellular thiols and thiol/disulfide redox in metabolism. Annual Review of Nutrition. 2004;24:481–509. doi: 10.1146/annurev.nutr.24.012003.132208.
    1. Droge W. Oxidative stress and ageing: is ageing a cysteine deficiency syndrome? Philosophical Transactions of the Royal Society of London Series B, Biological Sciences. 2005;360:2355–2372. doi: 10.1098/rstb.2005.1770.
    1. Yin J., Ren W., Yang G., et al. L-cysteine metabolism and its nutritional implications. Molecular Nutrition & Food Research. 2016;60:134–146. doi: 10.1002/mnfr.201500031.
    1. Lippi G., Montagnana M., Franchini M., Favaloro E. J., Targher G. The paradoxical relationship between serum uric acid and cardiovascular disease. Clinica Chimica Acta. 2008;392:1–7. doi: 10.1016/j.cca.2008.02.024.
    1. Block G., Norkus E., Hudes M., Mandel S., Helzlsouer K. Which plasma antioxidants are most related to fruit and vegetable consumption? American Journal of Epidemiology. 2001;154:1113–1118. doi: 10.1093/aje/154.12.1113.
    1. Wang X., Ouyang Y., Liu J., et al. Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014;349, article g4490 doi: 10.1136/bmj.g4490.
    1. Sies H., Stahl W. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. The American Journal of Clinical Nutrition. 1995;62:1315S–1321S.
    1. Weber D., Kneschke N., Grimm S., Bergheim I., Breusing N., Grune T. Rapid and sensitive determination of protein-nitrotyrosine by ELISA: application to human plasma. Free Radical Research. 2012;46:276–285. doi: 10.3109/10715762.2011.652627.
    1. Augustyniak E., Adam A., Wojdyla K., et al. Validation of protein carbonyl measurement: a multi-centre study. Redox Biology. 2015;4:149–157. doi: 10.1016/j.redox.2014.12.014.
    1. Giustarini D., Dalle-Donne I., Tsikas D., Rossi R. Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Critical Reviews in Clinical Laboratory Sciences. 2009;46:241–281. doi: 10.3109/10408360903142326.

Source: PubMed

3
Subscribe