Journals of Gerontology: MEDICAL SCIENCES Cite journal as: J Gerontol A Biol Sci Med Sci. 2015 January;70(1):78–84 doi:10.1093/gerona/glu098

© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: [email protected]. Advance Access publication July 1, 2014

Effects of the Mediterranean Diet Supplemented With Coenzyme Q10 on Metabolomic Profiles in Elderly Men and Women

Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain. 2 Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, New York. 3 Nutrigenomics Research Group, UCD Conway Institute and School of Public Health, University College Dublin, Ireland. 4 Institute of Food and Health, University College Dublin, Ireland. 1

*The first two authors and the last two authors contributed equally to this work. Address correspondence to José López-Miranda, PhD, MD, Lipids and Atherosclerosis Unit at Reina Sofia University Hospital, Avda. Menendez Pidal, s/n. Córdoba 14004, Spain. Email: [email protected]

Background.  Characterization of the variations in the metabolomic profiles of elderly people is a necessary step to understand changes associated with aging. This study assessed whether diets with different fat quality and supplementation with coenzyme Q10 (CoQ) affect the metabolomic profile in urine analyzed by proton nuclear magnetic resonance spectroscopy from elderly people. Methods.  Ten participants received, in a cross-over design, four isocaloric diets for 4-week periods each: Mediterranean diet supplemented with CoQ (Med + CoQ diet); Mediterranean diet; Western diet rich in saturated fat diet; low-fat, high-carbohydrate diet enriched in n-3 polyunsaturated fat. Results.  Multivariate analysis showed differences between diets when comparing Med + CoQ diet and saturated fat diet, with greater hippurate urine levels after Med + CoQ diet and higher phenylacetylglycine levels after saturated fat diet in women. Following consumption of Med + CoQ, hippurate excretion was positively correlated with CoQ and β-carotene plasma levels and inversely related to Nrf2, thioredoxin, superoxide dismutase 1, and gp91phox subunit of NADPH oxidase gene expression. After saturated fat diet consumption, phenylacetylglycine excretion was inversely related to CoQ plasma level and positively correlated with isoprostanes urinary level. Conclusions.  The association between hippurate excretion and antioxidant biomarkers along with the relationship between phenylacetylglycine excretion and oxidant biomarkers suggests that the long-term consumption of a Med + CoQ diet could be beneficial for healthy aging and a promising challenge in the prevention of processes related to chronic oxidative stress, such as cardiovascular and neurodegenerative disease. Key Words:  Coenzyme Q10—Hippurate—Mediterranean diet—Oxidative stress—Phenylacetylglycine. Received March 7, 2014; Accepted May 22, 2014 Decision Editor: Stephen Kritchevsky, PhD

P

rospective studies suggest that a high degree of adherence to a Mediterranean diet is associated with a reduction of the incidence of major cardiovascular events,1 metabolic syndrome,2 and other agingrelated diseases.3 Some of the beneficial effects of this dietary pattern are related to its antioxidant capacity, derived from a high consumption of fruits, vegetables, and olive oil as the main source of fat (monounsaturared fatty acids [MUFA])4,5. Taking this into account, 78

we have recently demonstrated that consumption of a Mediterranean diet rich in olive oil and supplemented with coenzyme Q10 (Med + CoQ diet) (CoQ: 2,3-dimethoxy-5-methy-6-decaprenyl-1,4-benzoquinone) reduces postprandial oxidative stress (OxS) in elderly men and women, with respect to a Western diet rich in saturated fatty acid (SFA) diet.6,7 CoQ is part of the mammalian mitochondrial electron transport chain and a potent lipid soluble antioxidant that

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Lorena González-Guardia,1,* Elena María Yubero-Serrano,2,* Javier Delgado-Lista,1 Pablo Perez-Martinez,1 Antonio Garcia-Rios,1 Carmen Marin,1 Antonio Camargo,1 Nieves Delgado-Casado,1 Helen M. Roche,3,4 Francisco Perez-Jimenez,1 Lorraine Brennan,4,* and José López-Miranda1,*



Mediterranean Diet and CoQ10 in the Elderly MEN AND WOMEN

Participants and Recruitment A total of 63 persons were contacted among those willing to enter the study. Inclusion and exclusion criteria were fulfilled by 10 patients (age ≥65  years; five men and five women). The main cause of exclusion was existence of several diseases. Complete inclusion and exclusion criteria were described in previous publications7,16 and are shown in Supplementary Table 1. The study was carried out in the Lipid and Atherosclerosis Unit at the Reina Sofia University Hospital, from December 2004 to December 2007. The study protocol was approved by the Human Investigation Review Committee of the Reina Sofia University Hospital according to institutional and Good Clinical Practice guidelines (protocol number: 772).

follows: (i) Med + CoQ diet (200 mg/d in capsules), containing 15% of energy as protein, 47% of energy as carbohydrate, and 38% of total energy as fat (24% MUFA [provided by virgin olive oil], 10% SFA, 4% polyunsaturated fatty acid [PUFA]), (ii) Mediterranean diet not supplemented with CoQ (Med diet), with the same composition of the first diet but supplemented by placebo capsules, (iii) Western diet rich in SFA diet with 15% of energy as protein, 47% of energy as carbohydrate, and 38% of total energy as fat (12% MUFA, 22% SFA, 4% PUFA), and (iv) low-fat, high-carbohydrate diet enriched in n-3 PUFA (CHO-PUFA diet), with 15% of energy as protein, 55% as carbohydrate, and 30% as fat (10% SFA, 12% MUFA, and 8% PUFA with 2% a-linolenic acid) (see Supplementary Table 2). The cholesterol intake was kept constant (2 were considered important in discriminating between groups. Metabolites responsible for the peaks in these regions were assigned using in-house databases and the Chenomx Database. Assignments were confirmed using 2D TOCSY experiments. The Statistical Package for the Social Sciences (SPSS 17.0 for Windows Inc., Chicago, IL) was used for the statistical comparisons. The Kolmogorov–Smirnov test did not show a significant departure from normality in the distribution of variance values. Hippurate, phenylacetylglycine, glycerol results, and gender comparison were analyzed using Student’s t test in order to evaluate data variation after dietary intervention. A  study of the relationship among parameters was also carried out using Pearson’s linear correlation coefficient. Differences were considered to be significant when p < .05.



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Figure 1. (A) PCA score plot (R2 = .31, Q2 = 0.17) derived from 1H-NMR urine spectra collected pre- and post-dietary intervention. Open squares represent male samples and closed circles represent female samples. (B) PLS-DA score plot derived from 1H-NMR urine spectra collected from women after Med + CoQ diet (open circles) and after SFA diet intervention (close squares). R2 = .21, Q2 = 0.17. 1H-NMR, proton nuclear magnetic resonance spectroscopy; CoQ, coenzyme Q10; PCA, principal component analysis; PLS-DA, partial least squares discriminant analysis.

Table 1.  Metabolites Identified as Being Discriminant Between Med + CoQ and SFA Diet Metabolite Hippurate Hippurate Hippurate Hippurate Phenylacetylglycine Phenylacetylglycine Unassigned peak Unassigned peak Unassigned peak

Chemical Shift (ppm)

VIP Values

Med + CoQ

SFA

p Value

3.975 3.965 7.835 7.545 7.435 7.375 3.725 2.175 3.635

6.380 6.176 5.241 3.542 2.963 2.380 2.413 2.204 2.134

0.022 ± 0.006 0.021 ± 0.006 0.016 ± 0.005 0.006 ± 0.002 0.003 ± 0.002 0.003 ± 0.001 0.007 ± 0.001 0.002 ± 0.001 0.006 ± 0.001

0.014 ± 0.004 0.013 ± 0.004 0.009 ± 0.003 0.004 ± 0.001 0.005 ± 0.002 0.005 ± 0.001 0.008 ± 0.001 0.003 ± 0.002 0.007 ± 0.002

.037 .038 .041 .049 .045 .045 .084 .167 .160

Notes: Average intensities of metabolite bin regions fot the Med + CoQ diet and SFA diet are shown. Values are means ± SD and are presented as arbitrary units. p Values are reported for paired t test. CoQ, coenzyme Q10; SFA, saturated fat; VIP, variable importance in the projection.

Table 2.   Correlations Between Urinary Levels of Hippurate, Phenylacetylglycine, and Other Factorsa After Med + CoQ Diet Intervention

Hippurate

Pearson correlation p value

Phenylacetylglycine

Pearson correlation p value

CoQ

β-Carotene

Nrf2

Trx

SOD1

gp91phox

.899* .038 CoQ −.897* .039

.928* .023 Isoprostanes .952* .013

−.978** .004

−.976** .004

−.913* .030

−.898* .039

Notes: β-Carotene plasma levels; CoQ, coenzyme Q10 plasma levels; gp91phox, subunit of NADPH oxidase gene expression; isoprostanes urinary levels; Nrf2, transcription factor Nrf2 gene expression; SOD1, superoxide dismutase 1 gene expression; Trx, Thioredoxin gene expression. a Pearson’s correlation: *p < .05; **p < .01.

of hippurate and Nrf2 gene expression and antioxidant enzymes gene expression as Trx, SOD1, and gp91phox subunit of NADPH oxidase (Table 2). Similarly, after consumption of SFA diet, we observed a strong negative correlation between urinary levels of phenylacetylglycine and CoQ plasma levels and a great positive correlation between urinary levels of phenylacetylglycine and urinary isoprostanes (Table 2). Data from these parameters used for the correlations were previously analyzed and published.6,7

Gender Comparison of Oxidative Stress Biomarkers Gender-related differences after Med + CoQ diet intervention were studied. We observed that the increment of plasma levels of the antioxidants CoQ and β-carotene were significantly greater (p = .04 and p < .05, respectively) in women (CoQ: 1.02 μmol/L; β-carotene: 0.08 μmol/L) compared with men (CoQ: 0.64 μmol/L; β-carotene: 0.04 μmol/L). By contrast, we found that OxS biomarkers such as oxidized low-density lipoprotein or lipid peroxides after

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Med + CoQ were higher in men (oxidized low-density lipoprotein: 59.60 μmol/L, lipid peroxides: 0.57 μmol/L) than in women (oxidized low-density lipoprotein: 47.40 μmol/L, lipid peroxides: 0.35 μmol/L; p = .01 and p < .01, respectively). Data from these parameters used for the correlations were previously analyzed and published.6,7

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Discussion The process of aging has been attributed partly to cellular free radical damage as well as to decreased exogenous antioxidants. Thus, the present study demonstrates that the consumption of a Med diet supplemented with CoQ is associated with increased levels of excreted hippurate and decreased levels of phenylacetylglycine compared to a SFA-rich diet in postmenopausal women (≥65 years). We also observed that hippurate urine levels are strongly correlated with plasma antioxidant biomarkers and urine phenylacetylglycine levels are highly related to urinary oxidant biomarkers. In the same population, we have previously demonstrated that Med + CoQ diet ameliorates postprandial OxS with improved endothelial function and decreased plasma lipid peroxidation products, protein carbonyl levels, DNA damage, and antioxidant enzyme activities.6,24 Moreover, we have proved that this diet exerts a greater postprandial decrease in gene expression of genes related to OxS (Nrf2, GPx1, SOD),7 inflammatory response (p65, IKK-β, interleukin-1β), and endoplasmic reticulum stress (sXBP1, CRT, Bip)25 in peripheral blood mononuclear cells with respect to SFA diet in elderly people. The combination between dietary interventions with different fat quality and supplementation in CoQ has also yielded interesting outcomes in rat models, in which it modifies the proteomic profile of the cytosolic and microsomal fractions from hepatocytes.26 Moreover, it has been demonstrated that MUFA can protect mitochondria from age-related changes, and the addition of CoQ to n-6 PUFA partially resembles those MUFA antioxidant benefits.27,28 Hippuric acid (N-benzoylglycine) is known to be catabolically synthesized by conjugation of benzoic acid with glycine from its precursor quinic acid, via the shikimate pathway in the gastrointestinal tract.29 This metabolite is considered as one of the final products of gut microbial metabolism in urine after intake of dietary polyphenols. In fact, several intervention studies have indicated that consumption of polyphenol-rich extracts30 or tea31 enhances its excretion. In this connection, it has been proposed that hippurate is not directly beneficial by itself but it could be considered as an indicator of antioxidant molecules synthesis by gut microflora,32 DNA repair enhancement and nuclear factor-κB inhibition.33 In accordance with these studies, our strong correlation results suggest that hippurate is positively related to antioxidant compounds such as CoQ and β-carotene, and negatively associated with the gene

expression of Nrf2 and several molecules related to OxS processes (Trx, SOD1, gp91phox). Little is known about the excretion of phenylacetylglycine in humans following dietary intervention. Herein, we show that phenylacetylglycine levels are inversely associated with CoQ levels and in contrast, highly positive correlated to urinary levels of isoprostanes, which are considered as biomarkers for monitoring oxidative status.34 Phenylacetylglycine is generated from phenylacetate via phase II detoxification mechanisms or from microbiota metabolism35 and is often overexpressed in disease. It is one of the major metabolites excreted in spontaneous hypertensive rats35 and it may act as a putative biomarker of phospholipidosis in rats, a disorder characterized by the excess accumulation of phospholipids in tissues.36 In humans, urinary acylglycines are often used as diagnostic tool for mitochondrial fatty acid oxidation disorders37 and phenylacetylglycine levels are significantly higher in heart failure patients than in healthy controls.38,39 Due to the important role of OxS in cardiovascular disease40 and considering these studies, greater phenylacetylglycine excretion could be linked to an increase of OxS-related process. Indeed, our correlation results show a great association between this metabolite and isoprostanes (urinary OxS biomarker). Our present data suggest that the benefit caused by Med + CoQ consumption is greater in elderly women compared with men. In this regard, the antioxidant compounds CoQ and β-carotene are higher in women than men, while lipid peroxides and oxidized low-density lipoprotein plasma levels in men are greater than women. This gender difference is interesting and should be retested in other studies since these women are postmenopausal and therefore, they do not have the additional antioxidant benefits attributed to estrogen levels. Moreover, hippurate and phenylacetylglycine are microbial metabolites and differences in its levels could be due to gut microbial diversity between men and women. On the other hand, the fact that we only found differences when comparing Med + CoQ and SFA diet, may indicate that the antioxidant compounds present in Mediterranean diet, together with CoQ may produce a synergic antioxidant effect (the most antioxidant diet) when is compared to SFA diet (the most oxidant diet). The present study has the advantage of a randomized cross-over design in which all the participants have experienced the four diet periods, each individual acting as his/ her own control and strengthening the fact that the effects observed are due to the influence of the type of diet. Multiple studies have shown that a 3-week dietary period is enough for assessing its effects, and in longer periods, there is not influence of previous diets.41,42 In our study, and to avoid any doubt, we extended the dietary periods to 4 weeks each, thus securing that the effects found were not provided by previous diets. We are aware that the main limitations of the study are the low number of individuals and the subtle results



Mediterranean Diet and CoQ10 in the Elderly MEN AND WOMEN

Supplementary Material Supplementary material can be found at: http://biomedgerontology. oxfordjournals.org/. Funding This work was supported in part by research grants from the Ministerio de Ciencia e Innovación (AGL2004-07907, AGL2006-01979, AGL200912270 to J.L.-M.  and FIS PI10/01041 to P.P.-M.); Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P06-CTS-01425 to J.L.-M., CTS5015 to F.P.-J.); Consejería de Salud, Junta de Andalucía (06/128, 07/43, PI0193/2009 to J.L.-M., 06/129 to F.P.-J., PI-0252/09 to J.D.-L., and PI-0058/10 to P.P.-M.). Acknowledgments We thank Kaneka Corporation (Japan) for the production of CoQ and placebo capsules. The CIBEROBN is an initiative of the Instituto de Salud Carlos III, Madrid, Spain. Conflict of Interest statement The authors declare no conflict of interest. References 1. Estruch R, Ros E, Salas-Salvado J, et  al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–1290. doi:10.1056/NEJMoa1200303 2. Kesse-Guyot E, Ahluwalia N, Lassale C, Hercberg S, Fezeu L, Lairon D. Adherence to Mediterranean diet reduces the risk of metabolic syndrome: a 6-year prospective study. Nutr Metab Cardiovasc Dis. 2013;23:677–683. doi:10.1016/j.numecd.2012.02.005 3. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003;348:2599–2608. doi:10.1056/NEJMoa025039 4. Bach-Faig A, Berry EM, Lairon D, et  al. Mediterranean diet pyramid today. Science and cultural updates. Public Health Nutr. 2011;14:2274–2284. doi:10.1017/S1368980011002515 5. Zamora-Ros R, Serafini M, Estruch R, et al. Mediterranean diet and non enzymatic antioxidant capacity in the PREDIMED study: evidence for a mechanism of antioxidant tuning. Nutr Metab Cardiovasc Dis. 2013. doi:10.1016/j.numecd.2012.12.008 6. Yubero-Serrano EM, Delgado-Casado N, Delgado-Lista J, et  al. Postprandial antioxidant effect of the Mediterranean diet supplemented with coenzyme Q10 in elderly men and women. Age (Dordr). 2011;33:579–590. doi:10.1007/s11357-010-9199-8 7. Yubero-Serrano EM, Gonzalez-Guardia L, Rangel-Zuniga O, et  al. Postprandial antioxidant gene expression is modified by Mediterranean

diet supplemented with coenzyme Q(10) in elderly men and women. Age (Dordr). 2013;35:159–170. doi:10.1007/s11357-011-9331-4 8. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660:171–199. doi:10.1016/j. bbamem.2003.11.012 9. Bour S, Carmona MC, Galinier A, et al. Coenzyme Q as an antiadipogenic factor. Antioxid Redox Signal. 2011;14:403–413. doi:10.1089/ ars.2010.3350 10. Fotino AD, Thompson-Paul AM, Bazzano LA. Effect of coenzyme Q10 supplementation on heart failure: a meta-analysis. Am J Clin Nutr. 2013;97:268–275. doi:10.3945/ajcn.112.040741 11. Gao L, Mao Q, Cao J, Wang Y, Zhou X, Fan L. Effects of coenzyme Q10 on vascular endothelial function in humans: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;221:311–316. doi:10.1016/j.atherosclerosis.2011.10.027 12. Safarinejad MR, Shafiei N, Safarinejad S. Effects of EPA, gammalinolenic acid or coenzyme Q10 on serum prostate-specific antigen levels: a randomised, double-blind trial. Br J Nutr. 2013;110:164– 171. doi:10.1017/S0007114512004783 13. Mancuso M, Orsucci D, Volpi L, Calsolaro V, Siciliano G. Coenzyme Q10 in neuromuscular and neurodegenerative disorders. Curr Drug Targets. 2010;11:111–121. doi:10.2174/138945010790031018 14. Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012;22:R741–R752. doi:10.1016/j.cub.2012.07.024 15. Kirkwood TB, Kowald A. The free-radical theory of ageing–older, wiser and still alive: modelling positional effects of the primary targets of ROS reveals new support. Bioessays. 2012;34:692–700. doi:10.1002/bies.201200014 16. Gutierrez-Mariscal FM, Perez-Martinez P, Delgado-Lista J, et  al. Mediterranean diet supplemented with coenzyme Q10 induces postprandial changes in p53 in response to oxidative DNA damage in elderly subjects. Age (Dordr). 2011;34:389–403. doi:10.1007/ s11357-011-9229-1 17. Gariballa S, Afandi B, Abuhaltem M, Yassin J, Habib H, Ibrahim W. Oxidative damage and inflammation in obese diabetic Emirati subjects supplemented with antioxidants and B-vitamins: a randomized placebo-controlled trail. Nutr Metab (Lond). 2013;10:21. doi:10.1186/1743-7075-10-21 18. Gibney MJ, Walsh M, Brennan L, Roche HM, German B, van Ommen B. Metabolomics in human nutrition: opportunities and challenges. Am J Clin Nutr. 2005;82:497–503. 19. Lenz EM, Bright J, Wilson ID, et al. Metabonomics, dietary influences and cultural differences: a 1H NMR-based study of urine samples obtained from healthy British and Swedish subjects. J Pharm Biomed Anal. 2004;36:841–849. doi:10.1016/j.jpba.2004.08.002 20. Psihogios NG, Gazi IF, Elisaf MS, Seferiadis KI, Bairaktari ET. Genderrelated and age-related urinalysis of healthy subjects by NMR-based metabonomics. NMR Biomed. 2008;21:195–207. doi:10.1002/nbm.1176 21. Human Nutrition Information Service DoA. Composition of Foods. Washington, DC: US Government Printing Office; 1987. 22. Varela G. Tablas de composición de alimentos. (Food Composition Tables). Madrid: Instituto de Nutrición CSIC; 1980. 23. Marin C, Ramirez R, Delgado-Lista J, et  al. Mediterranean diet reduces endothelial damage and improves the regenerative capacity of endothelium. Am J Clin Nutr. 2011;93:267–274. doi:10.3945/ ajcn.110.006866 24. Gutierrez-Mariscal FM, Yubero-Serrano EM, Rangel-Zuniga OA, et al. Postprandial activation of P53-dependent DNA repair is modified by Mediterranean diet supplemented with coenzyme Q10 in elderly subjects. J Gerontol A  Biol Sci Med Sci. 2014;69:886–893. doi:10.1093/gerona/glt174 25. Yubero-Serrano EM, Gonzalez-Guardia L, Rangel-Zuniga O, et  al. Mediterranean diet supplemented with coenzyme Q10 modifies the expression of proinflammatory and endoplasmic reticulum stressrelated genes in elderly men and women. J Gerontol A Biol Sci Med Sci. 2012;67:3–10. doi:10.1093/gerona/glr167

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obtained since changes in metabolomic profiles resulting from dietary intervention are not easy to detect because of the strong intraindividual variation.43 An adequate nutritional status may be central to improve the health of elderly people. Therefore, our results show that the consumption of a Med diet supplemented with exogenous CoQ produces the excretion of urinary metabolites associated with an improvement of OxS, while endproducts excreted after the intake of a SFA diet are related to increased OxS process in elderly people. Therefore, the consumption of a Med + CoQ diet could be beneficial for healthy aging of individuals and specific dietary intervention might be a promising challenge in the prevention and treatment of processes that lead to a rise in chronic OxS, such as cardiovascular, neurodegenerative diseases, and aging.

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26. Sharanova NE, Kulakova SN, Baturina VA, et al. Effect of coenzyme Q10 on the proteomic profile of the cytosolic and microsomal fractions from rat hepatocytes upon dietary consumption of various lipid components during ontogeny. Bull Exp Biol Med. 2013;154:320–325. doi:10.1007/s10517-013-1941-7 27. Quiles JL, Pamplona R, Ramirez-Tortosa MC, et al. Coenzyme Q addition to an n-6 PUFA-rich diet resembles benefits on age-related mitochondrial DNA deletion and oxidative stress of a MUFA-rich diet in rat heart. Mech Ageing Dev. 2010;131:38–47. doi:10.1016/j.mad.2009.11.004 28. Ochoa JJ, Pamplona R, Ramirez-Tortosa MC, et  al. Age-related changes in brain mitochondrial DNA deletion and oxidative stress are differentially modulated by dietary fat type and coenzyme Q(1) (0). Free Radical Bio Med. 2011;50:1053–1064. doi:10.1016/j. freeradbiomed.2011.02.004 29. Pero RW. Health consequences of catabolic synthesis of hip puric acid in humans. Curr Clin Pharmacol. 2010;5:67–73. doi:10.2174/157488410790410588 30. van Dorsten FA, Grün CH, van Velzen EJ, Jacobs DM, Draijer R, van Duynhoven JP. The metabolic fate of red wine and grape juice polyphenols in humans assessed by metabolomics. Mol Nutr Food Res. 2010;54:897–908. doi:10.1002/mnfr.200900212 31. Mulder TP, Rietveld AG, van Amelsvoort JM. Consumption of both black tea and green tea results in an increase in the excretion of hippuric acid into urine. Am J Clin Nutr. 2005;81(suppl 1):256S–260S. 32. Valentova K, Stejskal D, Bednar P, et al. Biosafety, antioxidant status, and metabolites in urine after consumption of dried cranberry juice in healthy women: a pilot double-blind placebo-controlled trial. J Agric Food Chem. 2007;55:3217–3224. doi:10.1021/jf0636014 33. Pero RW, Lund H, Leanderson T. Antioxidant metabolism induced by quinic acid. Increased urinary excretion of tryptophan and nicotinamide. Phytother Res. 2009;23:335–346. doi:10.1002/ptr.2628 34. Il’yasova D, Scarbrough P, Spasojevic I. Urinary biomarkers of oxidative status. Clin Chim Acta. 2012;413:1446–1453. doi:10.1016/j. cca.2012.06.012