European Journal of Nutrition

, Volume 58, Issue 2, pp 653–663 | Cite as

Xanthohumol exerts protective effects in liver alterations associated with aging

  • Cristina Fernández-García
  • Lisa RancanEmail author
  • Sergio D. Paredes
  • César Montero
  • Mónica de la Fuente
  • Elena Vara
  • Jesús A. F. Tresguerres
Original Contribution


Background and aims

Aging is associated with a deregulation of biological systems that lead to an increase in oxidative stress, inflammation, and apoptosis, among other effects. Xanthohumol is the main preylated chalcone present in hops (Humulus lupulus L.) whose antioxidant, anti-inflammatory and chemopreventive properties have been shown in recent years. In the present study, the possible protective effects of xanthohumol on liver alterations associated with aging were evaluated.


Male young and old senescence-accelerated prone mice (SAMP8), aged 2 and 10 months, respectively, were divided into four groups: non-treated young, non-treated old, old treated with 1 mg/kg/day xanthohumol, and old treated with 5 mg/kg/day xanthohumol. Male senescence-accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed and livers were collected. mRNA (AIF, BAD, BAX, Bcl-2, eNOS, HO-1, IL-1β, NF-κB2, PCNA, sirtuin 1 and TNF-α) and protein expressions (BAD, BAX, AIF, caspase-3, Blc-2, eNOS, iNOS, TNF-α, IL1β, NF-κB2, and IL10) were measured by RT-PCR and Western blotting, respectively. Mean values were analyzed using ANOVA.


A significant increase in mRNA and protein levels of oxidative stress, pro-inflammatory and proliferative markers, as well as pro-apoptotic parameters was shown in old non-treated SAMP8 mice compared to the young SAMP8 group and SAMR1 mice. In general, age-related oxidative stress, inflammation and apoptosis were significantly decreased (p < 0.05) after XN treatment. In most cases, this effect was dose-dependent.


XN was shown to modulate inflammation, apoptosis, and oxidative stress in aged livers, exerting a protective effect in hepatic alterations.


Liver Aging Inflammation Senescence-accelerated mouse Xanthohumol 



The authors would like to thank Medicine students Paula Corral, Bryan Hyacinthe, and Mario Calvo-Soto (School of Medicine, Complutense University of Madrid, Spain) for their continued interest and cooperation in our work. The skillful technical assistance of Rocío Campón (Dept. of Physiology, School of Medicine, Complutense University of Madrid, Spain) is also gratefully acknowledged.

Author contributions

EV, JAFT designed the research; CFG, LR, SDP, CM conducted the research; EV, MF analyzed the data; CFG, LR, SDP, EV wrote the paper. All authors read and approved the final manuscript.


This study was supported by Grants from Red de Fragilidad y Envejecimiento RETICEF (RD12/0043/0032) and GRUPOS UCM-BSCH (GR35/10-A).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Sanz A, Stefanatos RK (2008) The mitochondrial free radical theory of aging: a critical view. Curr Aging Sci 1(1):10–21CrossRefGoogle Scholar
  2. 2.
    Schmucker D (2005) Age-related changes in liver structure and function: implications for disease? Exp Gerontol 40(8–9):650–659CrossRefGoogle Scholar
  3. 3.
    Preedy V (2014) Aging. Chapter 1. Oxidative stress and frailty: a closer look at the origin of a human aging phenotypeGoogle Scholar
  4. 4.
    Aikata H, Takaishi H, Kawakami Y, Takahashi S, Kitamoto M, Nakanishi T et al (2000) Telomere reduction in human liver tissues with age and chronic inflammation. Exp Cell Res 256(2):578–582CrossRefGoogle Scholar
  5. 5.
    Jaskelioff M, Muller F, Paik J, Thomas E, Jiang S, Adams A, Sahin E, Kost-Alimova M, Protopopov A, Cadiñanos J, Horner J, Maratos-Flier E, DePinho R (2010) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469(7328):102–106CrossRefGoogle Scholar
  6. 6.
    Aravinthan A, Alexander G (2016) Senescence in chronic liver disease: is the future in ageing? J Hepatol 65:825–834CrossRefGoogle Scholar
  7. 7.
    Pinto C, Cestero J, Rodríguez-Galdón B, Macías P (2014) Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus L.), protects rat tissues against oxidative damage after acute ethanol administration. Toxicol Rep 1:726–733CrossRefGoogle Scholar
  8. 8.
    Vanhoecke B, Derycke L, Van Marck V, Depypere H, De Keukeleire D, Bracke M (2005) Antiinvasive effect of xanthohumol, a prenylated chalcone present in hops (Humulus lupulus L.) and beer. Int J Cancer 117(6):889–895CrossRefGoogle Scholar
  9. 9.
    Zhang B, Chu W, Wei P, Liu Y, Wei T (2015) Xanthohumol induces generation of reactive oxygen species and triggers apoptosis through inhibition of mitochondrial electron transfer chain complex I. Free Radical Biol Med 89:486–497CrossRefGoogle Scholar
  10. 10.
    Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010) Mechanisms of vascular aging: new perspectives. J Gerontol Ser A Biol Sci Med Sci 65(10):1028–1041CrossRefGoogle Scholar
  11. 11.
    Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T et al (1981) A new murine model of accelerated senescence. Mech Ageing Dev 17(2):183–194CrossRefGoogle Scholar
  12. 12.
    Yagi H, Katoh S, Akiguchi I, Takeda T (1988) Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAM-P/8 as an animal model of disturbances in recent memory. Brain Res 474(1):86–93CrossRefGoogle Scholar
  13. 13.
    Tresguerres JA, Kireev R, Forman K, Cuesta S, Tresguerres AF, Vara E (2012) Effect of chronic melatonin administration on several physiological parameters from old wistar rats and SAMP8 mice. Curr Aging Sci 5(3):242–253CrossRefGoogle Scholar
  14. 14.
    Paredes SD, Forman KA, Garcia C, Vara E, Escames G, Tresguerres JA (2014) Protective actions of melatonin and growth hormone on the aged cardiovascular system. Hormone Mol Biol Clin Investig 18(2):79–88CrossRefGoogle Scholar
  15. 15.
    Puig A, Rancan L, Paredes SD, Carrasco A, Escames G, Vara E et al (2016) Melatonin decreases the expression of inflammation and apoptosis markers in the lung of a senescence-accelerated mice model. Exp Gerontol 75:1–7CrossRefGoogle Scholar
  16. 16.
    Rancan L, Paredes SD, García I, Muñoz P, García C, López de Hontanar G, de la Fuente M, Vara E, Tresguerres JAF (2017) Protective effect of xanthohumol against age-related brain damage. J Nutr Biochem 49:133–140CrossRefGoogle Scholar
  17. 17.
    Montoliu C, Vallés S, Renau-Piqueras J, Guerri C (2002) Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J Neurochem 63(5):1855–1862CrossRefGoogle Scholar
  18. 18.
    Chomcznyski P, Sacchi N (2006) The single-step method of RNA isolation by acid guanidinium thiocynate-phenol-chloroform extraction: twenty something years on. Nat Protoc 1:581–585CrossRefGoogle Scholar
  19. 19.
    Shmittgen DT, Livak KJ (2001) Analysis of relative gene expression data using real-time quantitive PCR and the 2-∆∆CT method. Methods 25:402–408CrossRefGoogle Scholar
  20. 20.
    Pasparakis M, Alexopoulou L, Episkopou V, Kollias G (1996) Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184(4):1397–1411CrossRefGoogle Scholar
  21. 21.
    Lee IS, Lim J, Gal J, Kang JC, Kim HJ, Kang BY et al (2011) Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int 58(2):153–160CrossRefGoogle Scholar
  22. 22.
    Gieling R, Wallace K, Han Y (2009) Interleukin-1 participates in the progression from liver injury to fibrosis. Am J Physiol Gastrointest Liver Physiol 296(6):G1324-G1331CrossRefGoogle Scholar
  23. 23.
    Tak P, Firestein G (2001) NF-κB: a key role in inflammatory diseases. J Clin Investig 107(1):7–11CrossRefGoogle Scholar
  24. 24.
    Peluso I, Raguzzini A, Serafini M (2013) Effect of flavonoids on circulating levels of TNF-alpha and IL-6 in humans: a systematic review and meta-analysis. Mol Nutr Food Res 57(5):784–801CrossRefGoogle Scholar
  25. 25.
    Garcia-Lafuente A, Guillamon E, Villares A, Rostagno MA, Martinez JA (2009) Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm Res 58(9):537–552CrossRefGoogle Scholar
  26. 26.
    Paredes SD, Rancan L, Kireev R, González A, Louzao P, González P, Rodríguez-Bobada C, García C, Vara E, Tresguerres J (2015) Melatonin counteracts at a transcriptional level the inflammatory and apoptotic response secondary to ischemic brain injury induced by middle cerebral artery blockade in aging rats. BioRes Open Access 4(1):407–416CrossRefGoogle Scholar
  27. 27.
    Meador BM, Krzyszton CP, Johnson RW, Huey KA (2008) Effects of IL-10 and age on IL-6, IL-1beta, and TNF-alpha responses in mouse skeletal and cardiac muscle to an acute inflammatory insult. J Appl Physiol 104(4):991–997CrossRefGoogle Scholar
  28. 28.
    Lu B, Chen H, Lu HG (2012) The relationship between apoptosis and aging. Adv Biosci Biotechnol 3:705–711CrossRefGoogle Scholar
  29. 29.
    Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N et al (2000) Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 476(3):118–123CrossRefGoogle Scholar
  30. 30.
    Cau SB, Carneiro FS, Tostes RC (2012) Differential modulation of nitric oxide synthases in aging: therapeutic opportunities. Front Physiol 3:218Google Scholar
  31. 31.
    Schipper HM (2000) Heme oxygenase-1: role in brain aging and neurodegeneration. Exp Gerontol 35(6–7):821–830CrossRefGoogle Scholar
  32. 32.
    Kelman Z (1997) PCNA: structure, functions and interactions. Oncogene 14(6):629–640CrossRefGoogle Scholar
  33. 33.
    Guarente L (2007) Sirtuins in aging and disease. Cold Spring Harb Symp Quant Biol:483–488Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Cristina Fernández-García
    • 1
  • Lisa Rancan
    • 1
    Email author
  • Sergio D. Paredes
    • 2
  • César Montero
    • 1
  • Mónica de la Fuente
    • 3
  • Elena Vara
    • 1
  • Jesús A. F. Tresguerres
    • 2
  1. 1.Department of Biochemistry and Molecular Biology, School of MedicineUniversity Complutense of MadridMadridSpain
  2. 2.Department Physiology, School of MedicineComplutense University of MadridMadridSpain
  3. 3.Department of Physiology, Genetics and Microbiology, School of BiologyComplutense University of MadridMadridSpain

Personalised recommendations