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Effects of Grape Skin Extract on Age-Related Mitochondrial Dysfunction, Memory and Life Span in C57BL/6J Mice

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Abstract

Dementia contributes substantially to the burden of disability experienced at old age, and mitochondrial dysfunction (MD) was identified as common final pathway in brain aging and Alzheimer’s disease. Due to its early appearance, MD is a promising target for nutritional prevention strategies and polyphenols as potential neurohormetic inducers may be strong neuroprotective candidates. This study aimed to investigate the effects of a polyphenol-rich grape skin extract (PGE) on age-related dysfunctions of brain mitochondria, memory, life span and potential hormetic pathways in C57BL/6J mice. PGE was administered at a dose of 200 mg/kg body weight/d in a 3-week short-term, 6-month long-term and life-long study. MD in the brains of aged mice (19–22 months old) compared to young mice (3 months old) was demonstrated by lower ATP levels and by impaired mitochondrial respiratory complex activity (except for mice treated with antioxidant-depleted food pellets). Long-term PGE feeding partly enhanced brain mitochondrial respiration with only minor beneficial effect on brain ATP levels and memory of aged mice. Life-long PGE feeding led to a transient but significant shift of survival curve toward higher survival rates but without effect on the overall survival. The moderate effects of PGE were associated with elevated SIRT1 but not SIRT3 mRNA expressions in brain and liver tissue. The beneficial effects of the grape extract may have been influenced by the profile of bioavailable polyphenols and the starting point of interventions.

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References

  • Afshordel, S., Hagl, S., Werner, D., Röhner, N., Kögel, D., Bazan, N. G., et al. (2015). Omega-3 polyunsaturated fatty acids improve mitochondrial dysfunction in brain aging-impact of Bcl-2 and NPD-1 like metabolites. Prostaglandins Leukotrienes and Essential Fatty Acids, 92, 23–31.

    Article  CAS  Google Scholar 

  • Allam, F., Dao, A. T., Chugh, G., Bohat, R., Jafri, F., Patki, G., et al. (2013). Grape powder supplementation prevents oxidative stress-induced anxiety-like behavior, memory impairment, and high blood pressure in rats. Journal of Nutrition, 143(6), 835–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arola-Arnal, A., Oms-Oliu, G., Crescenti, A., del Bas, J. M., Ras, M. R., Arola, L., et al. (2013). Distribution of grape seed flavanols and their metabolites in pregnant rats and their fetuses. Molecular Nutrition & Food Research, 57(10), 1741–1752.

    CAS  Google Scholar 

  • Arumugam, T. V., Gleichmann, M., Tang, S. C., & Mattson, M. P. (2006). Hormesis/preconditioning mechanisms, the nervous system and aging. Aging Research Reviews, 5(2), 165–178.

    Article  CAS  PubMed  Google Scholar 

  • Bell, E. L., & Guarente, L. (2011). The SirT3 divining rod points to oxidative stress. Molecular Cell, 42(5), 561–568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bohlen, Von, Halbach, O., Zacher, C., Gass, P., & Unsicker, K. (2006). Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. Journal of Neuroscience Research, 83(4), 525–531.

    Article  Google Scholar 

  • Bohn, T. (2014). Dietary factors affecting polyphenol bioavailability. Nutrition Reviews, 72(7), 429–452.

    Article  PubMed  Google Scholar 

  • Cardozo, M. G., Medeiros, N., Lacerda Ddos, S., de Almeida, D. C., Henriques, J. A., Dani, C., et al. (2013). Effect of chronic treatment with conventional and organic purple grape juices (Vitis labrusca) on rats fed with high-fat diet. Cellular and Molecular Neurobiology, 33(8), 1123–1133.

    Article  CAS  PubMed  Google Scholar 

  • Casadesus, G., Shukitt-Hale, B., Stellwagen, H. M., Zhu, X., Lee, H. G., Smith, M. A., et al. (2004). Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutritional Neuroscience, 7(5–6), 309–316.

    Article  CAS  PubMed  Google Scholar 

  • Chen, W., Müller, D., Richling, E., & Wink, M. (2013). Anthocyanin-rich purple wheat prolongs the life span of Caenorhabditis elegans probably by activating the DAF-16/FOXO transcription factor. Journal of Agricultural and Food Chemistry, 61(12), 3047–3053.

    Article  CAS  PubMed  Google Scholar 

  • Cheng, A., Hou, Y., & Mattson, M. P. (2010). Mitochondria and neuroplasticity. American Society for Neurochemistry Neuro, 2(5), e00045.

    PubMed  PubMed Central  Google Scholar 

  • Chung, S., Yao, H., Caito, S., Hwang, J. W., Arunachalam, G., & Rahman, I. (2010). Regulation of SIRT1 in cellular functions: role of polyphenols. Archives of Biochemistry and Biophysics, 501(1), 79–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Desquiret-Dumas, V., Gueguen, N., Leman, G., Baron, S., Nivet-Antoine, V., Chupin, S., et al. (2013). Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. The Journal of Biological Chemistry, 288(51), 36662–36675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diamanti, J., Mezzetti, B., Giampieri, F., Alvarez-Suarez, J. M., Quiles, J. L., Gonzalez-Alonso, A., et al. (2014). Doxorubicin-induced oxidative stress in rats is efficiently counteracted by dietary anthocyanin differently enriched strawberry (Fragaria × ananassa Duch.). Journal of Agricultural and Food Chemistry, 62(18), 3935–3943.

    Article  CAS  PubMed  Google Scholar 

  • Duffy, K. B., Spangler, E. L., Devan, B. D., Guo, Z., Bowker, J. L., Janas, A. M., et al. (2008). A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats. Neurobiology of Aging, 29(11), 1680–1689.

    Article  CAS  PubMed  Google Scholar 

  • Eckert, G. P., Renner, K., Eckert, S. H., Eckmann, J., Hagl, S., Abdel-Kader, R. M., et al. (2012). Mitochondrial dysfunction—A pharmacological target in Alzheimer’s disease. Molecular Neurobiology, 46(1), 136–150.

    Article  CAS  PubMed  Google Scholar 

  • Fisher-Wellman, K. H., Lin, C. T., Ryan, T. E., Reese, L. R., Gilliam, L. A., Cathey, B. L., et al. (2015). Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochemical Journal, 467(2), 271–280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghanim, H., Sia, C. L., Korzeniewski, K., Lohano, T., Abuaysheh, S., Marumganti, A., et al. (2011). A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. The Journal of Clinical Endocrinology and Metabolism, 96(5), 1409–1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodrick, C. L. (1975). Behavioral differences in young and aged mice: strain differences for activity measures, operant learning, sensory discrimination, and alcohol preference. Experimental Aging Research, 1(2), 191–207.

    Article  CAS  PubMed  Google Scholar 

  • Goyarzu, P., Malin, D. H., Lau, F. C., Taglialatela, G., Moon, W. D., Jennings, R., et al. (2004). Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutritional Neuroscience, 7(2), 75–83.

    Article  PubMed  Google Scholar 

  • Grimm, A., Friedland, K., & Eckert, A. (2016). Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease. Biogerontology, 17(2), 281–296.

    Article  CAS  PubMed  Google Scholar 

  • Gutierres, J. M., Carvalho, F. B., Schetinger, M. R. C., Rodrigues, M. V., Schmatz, R., Pimentel, V. C., et al. (2012). Protective effects of anthocyanins on the ectonucleotidase activity in the impairment of memory induced by scopolamine in adult rats. Life Sciences, 91(23–24), 1221–1228.

    Article  CAS  PubMed  Google Scholar 

  • Hagl, S., Asseburg, H., Heinrich, M., Sus, N., Blumrich, E. M., Dringen, R., et al. (2016a). Effects of long-term rice bran extract supplementation on survival, cognition and brain mitochondrial function in aged NMRI mice. Neuromolecular Medicine. doi:10.1007/s12017-016-8420-z.

    Google Scholar 

  • Hagl, S., Berressem, D., Grewal, R., Sus, N., Frank, J., & Eckert, G. P. (2016b). Rice bran extract improves mitochondrial dysfunction in brains of aged NMRI mice. Nutritional Neuroscience, 19(1), 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Hagl, S., Kocher, A., Schiborr, C., Eckert, S. H., Ciobanu, I., Birringer, M., et al. (2013). Rice bran extract protects from mitochondrial dysfunction in guinea pig brains. Pharmacological Research, 76, 17–27.

    Article  CAS  PubMed  Google Scholar 

  • Hauptmann, S., Scherping, I., Dröse, S., Brandt, U., Schulz, K. L., Jendrach, M., et al. (2009). Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiology of Aging, 30(10), 1574–1586.

    Article  CAS  PubMed  Google Scholar 

  • Hector, K. L., Lagisz, M., & Nakagawa, S. (2012). The effect of resveratrol on longevity across species: a meta-analysis. Biology Letters, 8(5), 790–793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hokayem, M., Blond, E., Vidal, H., Lambert, K., Meugnier, E., Feillet-Coudray, C., et al. (2013). Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. Diabetes Care, 36(6), 1454–1461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones, E., & Hughes, R. E. (1982). Quercetin, flavonoids and the life-span of mice. Experimental Gerontology, 17, 213–217.

    Article  CAS  PubMed  Google Scholar 

  • Kann, O. (2015). The interneuron energy hypothesis: Implications for brain disease. Neurobiology of Disease, 90, 75–85.

    Article  PubMed  Google Scholar 

  • Krikorian, R., Boespflug, E. L., Fleck, D. E., Stein, A. L., Wightman, J. D., Shidler, M. D., et al. (2012). Concord grape juice supplementation and neurocognitive function in human aging. Journal of Agricultural and Food Chemistry, 60(23), 5736–5742.

    Article  CAS  PubMed  Google Scholar 

  • Krikorian, R., Nash, T. A., Shidler, M. D., Shukitt-Hale, B., & Joseph, J. A. (2010). Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. British Journal of Nutrition, 103(5), 730–734.

    Article  CAS  PubMed  Google Scholar 

  • Lamport, D. J., Lawton, C. L., Merat, N., Jamson, H., Myrissa, K., Hofman, D., et al. (2016). Concord grape juice, cognitive function, and driving performance: a 12-wk, placebo-controlled, randomized crossover trial in mothers of preteen children. American Journal of Clinical Nutrition, 103(3), 775–783.

    Article  PubMed  Google Scholar 

  • Larsen, S., Nielsen, J., Hansen, C. N., Nielsen, L. B., Wibrand, F., Stride, N., et al. (2012). Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. The Journal of Physiology, 590(14), 3349–3360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laslo, M., Sun, X., Hsiao, C. T., Wu, W. W., Shen, R. F., & Zou, S. (2013). A botanical containing freeze dried açai pulp promotes healthy aging and reduces oxidative damage in sod1 knockdown flies. Age (Dordr), 35(4), 1117–1132.

    Article  CAS  Google Scholar 

  • Lee, Y., & Oh, S. (2015). Administration of red ginseng ameliorates memory decline in aged mice. Journal of Ginseng Research, 39(3), 250–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, Q., Zhao, H., Zhao, M., Zhang, Z., & Li, Y. (2010). Chronic green tea catechins administration prevents oxidative stress-related brain aging in C57BL/6J mice. Brain Research, 1353, 28–35.

    Article  CAS  PubMed  Google Scholar 

  • Long, J., Gao, H., Sun, L., Liu, J., & Zhao-Wilson, X. (2009). Grape extract protects mitochondria from oxidative damage and improves locomotor dysfunction and extends lifespan in a Drosophila Parkinson’s disease model. Rejuvenation Research, 12(5), 321–331.

    Article  CAS  PubMed  Google Scholar 

  • Lu, J., Wu, D. M., Zheng, Y. L., Hu, B., Cheng, W., & Zhang, Z. F. (2012). Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice. Free Radical Biology and Medicine, 52(3), 646–659.

    Article  CAS  PubMed  Google Scholar 

  • Manczak, M., Anekonda, T. S., Henson, E., Park, B. S., Quinn, J., & Reddy, P. H. (2006). Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics, 15(9), 1437–1449.

    Article  CAS  PubMed  Google Scholar 

  • Manczak, M., Jung, Y., Park, B. S., Partovi, D., & Reddy, P. H. (2005). Time-course of mitochondrial gene expressions in mice brains: implications for mitochondrial dysfunction, oxidative damage, and cytochrome c in aging. Journal of Neurochemistry, 92(3), 494–504.

    Article  CAS  PubMed  Google Scholar 

  • Manczak, M., Park, B. S., Jung, Y., & Reddy, P. H. (2004). Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: Implications for early mitochondrial dysfunction and oxidative damage. NeuroMolecular Medicine, 5(2), 147–162.

    Article  CAS  PubMed  Google Scholar 

  • Margalef, M., Pons, Z., Bravo, F. I., Muguerza, B., & Arola-Arnal, A. (2015). Tissue distribution of rat flavanol metabolites at different doses. The Journal of Nutritional Biochemistry, 26(10), 987–995.

    Article  CAS  PubMed  Google Scholar 

  • Mattson, M. P., Gleichmann, M., & Cheng, A. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron, 60(5), 748–766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattson, M. P., & Magnus, T. (2006). Aging and neuronal vulnerability. Nature Reviews Neuroscience, 7(4), 278–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moreno-Ulloa, A., Nogueira, L., Rodriguez, A., Barboza, J., Hogan, M. C., Ceballos, G., et al. (2015). Recovery of indicators of mitochondrial biogenesis, oxidative stress, and aging with (-)-epicatechin in senile mice. The Journals of Gerontology Series A Biological Sciences and Medical Sciences, 70(11), 1370–1378.

    Article  Google Scholar 

  • Murugaiyah, V., & Mattson, M. P. (2015). Neurohormetic phytochemicals: An evolutionary-bioenergetic perspective. Neurochemistry International, 89, 271–280.

    Article  CAS  PubMed  Google Scholar 

  • Müller, W. E., Eckert, A., Kurz, C., Eckert, G. P., & Leuner, K. (2010). Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer’s disease-therapeutic aspects. Molecular Neurobiology, 41(2–3), 159–171.

    Article  PubMed  Google Scholar 

  • Navarro, A., Gomez, C., López-Cepero, J. M., & Boveris, A. (2004). Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. The American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 286(3), 505–511.

    Article  Google Scholar 

  • Navarro, A., Sánchez Del Pino, M. J., Gómez, C., Peralta, J. L., & Boveris, A. (2002). Behavioral dysfunction, brain oxidative stress, and impaired mitochondrial electron transfer in aging mice. The American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 282(4), R985–R992.

    Article  CAS  PubMed  Google Scholar 

  • Pajuelo, D., Quesada, H., Díaz, S., Fernández-Iglesias, A., Arola-Arnal, A., Bladé, C., et al. (2012). Chronic dietary supplementation of proanthocyanidins corrects the mitochondrial dysfunction of brown adipose tissue caused by diet-induced obesity in Wistar rats. British Journal of Nutrition, 107(2), 170–178.

    Article  CAS  PubMed  Google Scholar 

  • Patki, G., Ali, Q., Pokkunuri, I., Asghar, M., & Salim, S. (2015). Grape powder treatment prevents anxiety-like behavior in a rat model of aging. Nutrition Research, 35(6), 504–511.

    Article  CAS  PubMed  Google Scholar 

  • Patki, G., Allam, F. H., Atrooz, F., Dao, A. T., Solanki, N., Chugh, G., et al. (2013). Grape powder intake prevents ovariectomy-induced anxiety-like behavior, memory impairment and high blood pressure in female Wistar rats. PLoS One, 8(9), e74522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., et al. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism, 8(2), 157–168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng, C., Zuo, Y., Kwan, K. M., Liang, Y., Ma, K. Y., Chan, H. Y., et al. (2012). Blueberry extract prolongs lifespan of Drosophila melanogaster. Experimental Gerontology, 47(2), 170–178.

    Article  CAS  PubMed  Google Scholar 

  • Pervin, M., Hasnat, M. A., Lee, Y. M., da Kim, H., Jo, J. E., & Lim, B. O. (2014). Antioxidant activity and acetylcholinesterase inhibition of grape skin anthocyanin (GSA). Molecules, 19(7), 9403–9418.

    Article  PubMed  Google Scholar 

  • Picard, M., & McEwen, B. S. (2014). Mitochondria impact brain function and cognition. Proceedings of the National Academy of Sciences of the United States of America, 111(1), 7–8.

    Article  CAS  PubMed  Google Scholar 

  • Pistell, P. J., Spangler, E. L., Kelly-Bell, B., Miller, M. G., de Cabo, R., & Ingram, D. K. (2012). Age-associated learning and memory deficits in two mouse versions of the Stone T-maze. Neurobiology of Aging, 33(10), 2431–2439.

    Article  PubMed  PubMed Central  Google Scholar 

  • Porquet, D., Casadesús, G., Bayod, S., Vicente, A., Canudas, A. M., Vilaplana, J., et al. (2013). Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8. Age (Dordr), 35(5), 1851–1865.

    Article  CAS  Google Scholar 

  • Rabøl, R., Larsen, S., Højberg, P. M. V., Almdal, T., Boushel, R., Haugaard, S. B., et al. (2010). Regional Anatomic Differences in Skeletal Muscle Mitochondrial Respiration in Type 2 Diabetes and Obesity. Journal of Clinical Endocrinology and Metabolism, 95(2), 857–863.

    Article  PubMed  Google Scholar 

  • Radak, Z., Koltai, E., Taylor, A. W., Higuchi, M., Kumagai, S., Ohno, H., et al. (2013). Redox-regulating sirtuins in aging, caloric restriction, and exercise. Free Radical Biology and Medicine, 58, 87–97.

    Article  CAS  PubMed  Google Scholar 

  • Rendeiro, C., Vauzour, D., Rattray, M., Waffo-Téguo, P., Mérillon, J. M., Butler, L. T., et al. (2013). Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One, 8(5), e63535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Del Rio, D., Rodriguez-Mateos, A., Spencer, J. P., Tognolini, M., Borges, G., & Crozier, A. (2013). Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxidants and Redox Signaling, 18(14), 1818–1892.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rodgers, J. T., Lerin, C., Gerhart-Hines, Z., & Puigserver, P. (2008). Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Letters, 582(1), 46–53.

    Article  CAS  PubMed  Google Scholar 

  • Ronchi, J. A., Figueira, T. R., Ravagnani, F. G., Oliveira, H. C., Vercesi, A. E., & Castilho, R. F. (2013). A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities. Free Radical Biology and Medicine, 63, 446–456.

    Article  CAS  PubMed  Google Scholar 

  • Rothman, S. M., Griffioen, K. J., Wan, R., & Mattson, M. P. (2012). Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. Annals of the New York Academy of Sciences, 1264, 49–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaffer, S., Asseburg, H., Kuntz, S., Mueller, W. E., & Eckert, G. P. (2012). Effects of polyphenols on brain aging and Alzheimer’s disease: Focus on mitochondria. Molecular Neurobiology, 46(1), 161–178.

    Article  CAS  PubMed  Google Scholar 

  • Schaffer, S., & Halliwell, B. (2012). Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations. Genes and Nutrition, 7(2), 99–109.

    Article  CAS  PubMed  Google Scholar 

  • Serradj, N., & Jamon, M. (2007). Age-related changes in the motricity of the inbred mice strains 129/sv and C57BL/6j. Behavioural Brain Research, 177(1), 80–89.

    Article  PubMed  Google Scholar 

  • Shukitt-Hale, B., Carey, A. N., Jenkins, D., Rabin, B. M., & Joseph, J. A. (2007). Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging. Neurobiology of Aging, 28(8), 1187–1194.

    Article  CAS  PubMed  Google Scholar 

  • Shukitt-Hale, B., Carey, A., Simon, L., Mark, D. A., & Joseph, J. A. (2006). Effects of Concord grape juice on cognitive and motor deficits in aging. Nutrition, 22(3), 295–302.

    Article  CAS  PubMed  Google Scholar 

  • Skemiene, K., Liobikas, J., & Borutaite, V. (2015). Anthocyanins as substrates for mitochondrial complex I - protective effect against heart ischemic injury. FEBS Journal, 282(5), 963–971.

    Article  CAS  PubMed  Google Scholar 

  • Stauch, K. L., Purnell, P. R., Villeneuve, L. M., & Fox, H. S. (2015). Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism. Proteomics, 15(9), 1574–1586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strathearn, K. E., Yousef, G. G., Grace, M. H., Roy, S. L., Tambe, M. A., Ferruzzi, M. G., et al. (2014). Neuroprotective effects of anthocyanin- and proanthocyanidin-rich extracts in cellular models of Parkinson′s disease. Brain Research, 1555, 60–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strong, R., Miller, R. A., Astle, C. M., Baur, J. A., de Cabo, R., Fernandez, E., et al. (2013). Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. The Journals of Gerontology Series A Biological Sciences and Medical Sciences, 68(1), 6–16.

    Article  CAS  Google Scholar 

  • Tang, X., Shen, T., Jiang, X., Xia, M., Sun, X., Guo, H., et al. (2015). Purified anthocyanins from bilberry and black currant attenuate hepatic mitochondrial dysfunction and steatohepatitis in mice with methionine and choline deficiency. Journal of Agricultural and Food Chemistry, 63(2), 552–561.

    Article  CAS  PubMed  Google Scholar 

  • The Jackson Laboratory. (2015a). Life span as a biomarker. https://www.jax.org/research-and-faculty/research-labs/the-harrison-lab/gerontology/life-span-as-a-biomarker#. Assessed 15 December 2015.

  • The Jackson Laboratory. (2015b). Baseline life span data. https://www.jax.org/research-and-faculty/research-labs/the-harrison-lab/gerontology/available-data. Assessed 15 December 2015.

  • The Jackson Laboratory. (2016). Nomenclature of inbred mice. Nnt mutation and function. https://www.jax.org/jax-mice-and-services/customer-support/technical-support/genetics-and-nomenclature/inbred-mice. Assessed 20 January 2016.

  • Wang, J., Bi, W., Cheng, A., Freire, D., Vempati, P., Zhao, W., et al. (2014). Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer’s disease-experimental approach and therapeutic implications. Frontiers in Aging Neuroscience, 6, 42.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, L., Li, Y. M., Lei, L., Liu, Y., Wang, X., Ma, K. Y., et al. (2015). Cranberry anthocyanin extract prolongs lifespan of fruit flies. Experimental Gerontology, 69, 189–195.

    Article  CAS  PubMed  Google Scholar 

  • Wang, J., Tang, C., Ferruzzi, M. G., Gong, B., Song, B. J., Janle, E. M., et al. (2013). Role of standardized grape polyphenol preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model. Molecular Nutrition & Food Research, 57(12), 2091–2102.

    Article  CAS  Google Scholar 

  • Webster, B. R., Lu, Z., Sack, M. N., & Scott, I. (2012). The role of sirtuins in modulating redox stressors. Free Radical Biology and Medicine, 52, 281–290.

    Article  CAS  PubMed  Google Scholar 

  • Wiese, S., Esatbeyoglu, T., Winterhalter, P., Kruse, H. P., Winkler, S., Bub, A., et al. (2015). Comparative biokinetics and metabolism of pure monomeric, dimeric, and polymeric flavan-3-ols: a randomized cross-over study in humans. Molecular Nutrition & Food Research, 59(4), 610–621.

    Article  CAS  Google Scholar 

  • Wilson, M. A., Shukitt-Hale, B., Kalt, W., Ingram, D. K., Joseph, J. A., & Wolkow, C. A. (2006). Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell, 5(1), 59–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • World Health Organization. (2015). World report on ageing and health. http://apps.who.int/iris/bitstream/10665/186463/1/9789240694811_eng.pdf?ua=1. Assessed 04 December 2015.

  • Yokozawa, T., Lee, Y. A., Zhao, Q., Matsumoto, K., & Cho, E. J. (2009). Persimmon oligomeric proanthocyanidins extend life span of senescence-accelerated mice. Journal of Medicinal Food, 12(6), 1199–1205.

    Article  CAS  PubMed  Google Scholar 

  • Yokozawa, T., Park, C. H., Noh, J. S., & Roh, S. S. (2014). Role of oligomeric proanthocyanidins derived from an extract of persimmon fruits in the oxidative stress-related aging process. Molecules, 19(5), 6707–6726.

    Article  PubMed  Google Scholar 

  • Yousuf, S., Atif, F., Ahmad, M., Hoda, N., Ishrat, T., Khan, B., et al. (2009). Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia. Brain Research, 1250, 242–253.

    Article  CAS  PubMed  Google Scholar 

  • Yuan, R., Ackert-Bicknell, C., Paigen, B., Peters, L. L. (2014). Aging study: Lifespan and survival curves for 31 inbred strains of mice. Mouse Phenome Database at the Jackson Laboratory. http://phenome.jax.org/db/qp?rtn=views/measplot&brieflook=23401&projhint=Yuan2. Assessed 15 Dec 2015.

  • Zhu, W., Chen, S., Li, Z., Zhao, X., Li, W., Sun, Y., et al. (2014). Effects and mechanisms of resveratrol on the amelioration of oxidative stress and hepatic steatosis in KKAy mice. Nutrition and Metabolism, 11, 35.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zuo, Y., Peng, C., Liang, Y., Ma, K. Y., Yu, H., Edwin Chan, H. Y., et al. (2012). Black rice extract extends the lifespan of fruit flies. Food and Function, 3(12), 1271–1279.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The polyphenol-rich grape skin extract was kindly provided by Breko GmbH, Bremen, Germany, and was analyzed by the group of Prof. P. Winterhalter, Institute of Food Chemistry, Braunschweig University of Technology, Germany. This work was funded by the Alzheimer Forschung Initiative e.V. (Grant No. #14838).

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Authors and Affiliations

  1. Department of Pharmacology, Biocenter Campus Riedberg, Goethe-University of Frankfurt, 60438, Frankfurt, Germany

    Heike Asseburg, Carmina Schäfer, Stephanie Hagl, Maximilian Pohland, Dirk Berressem, Christina Plank & Gunter P. Eckert

  2. Institute of Nutritional Sciences, University of Giessen, Wilhelmstraße 20, 35392, Giessen, Germany

    Heike Asseburg & Gunter P. Eckert

  3. Provadis School of International Management and Technology AG, 65929, Frankfurt, Germany

    Madeleine Müller

  4. Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy

    Marta Borchiellini

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  1. Heike Asseburg
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  2. Carmina Schäfer
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  3. Madeleine Müller
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  4. Stephanie Hagl
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  8. Christina Plank
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  9. Gunter P. Eckert
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Correspondence to Gunter P. Eckert.

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Animal Rights

All animal studies were approved by the local authorities for animal welfare, and all experiments were carried out according to the European Communities Council Directive (86/609/EEC) by individuals with appropriate training.

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12017_2016_8428_MOESM1_ESM.eps

Relative normalized mRNA expression of antioxidant enzymes in brain (a-c) and liver (d-f) tissue from mice of the long-term (LT) study determined using quantitative real-time PCR. For more information on the design of the studies please refer to Fig. 1. Data represent mean ± SEM normalized on mean mRNA expression of young mice (100 %), n = 10, SOD2: super dismutase 2, CAT: catalase, GPx1: glutathione peroxidase 1 (EPS 512 kb)

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Asseburg, H., Schäfer, C., Müller, M. et al. Effects of Grape Skin Extract on Age-Related Mitochondrial Dysfunction, Memory and Life Span in C57BL/6J Mice. Neuromol Med 18, 378–395 (2016). https://doi.org/10.1007/s12017-016-8428-4

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  • DOI: https://doi.org/10.1007/s12017-016-8428-4

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