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Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

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The aim of this study was to determine the outcomes of oestrogen and melatonin treatments following long-term ovarian hormone depletion on neuroinflammation and apoptotic processes in dentate gyrus of hippocampi. Forty-six female Wistar rats of 22 months of age were used. Twelve of them remained intact, and the other 34 were ovariectomized at 12 months of age. Ovariectomized animals were divided into three groups and treated for 10 weeks with oestrogens, melatonin or saline. All rats were killed by decapitation at 24 months of age, and dentate gyri were collected. A group of 2 month-old intact female rats was used as young control. The levels of pro-inflammatory cytokines and heat shock protein 70 (HSP 70) were analysed by ELISA. The expressions of TNFα, IL1β, GFAP, nNOS, iNOS, HO-1, NFκB, Bax, Bad, AIF, Bcl2 and SIRT1 genes were detected by real-time (RT)-PCR. Western blots were used to measure the protein expression of NFκB p65, NFκB p50/105, IκBα, IκBβ, p38 MAPK, MAP-2 and synapsin I. We have assessed the ability of 17β-oestradiol and melatonin administration to downregulate markers of neuroinflammation in the dentate gyrus of ovariectomized female rats. Results indicated that 17β-oestradiol and melatonin treatments were able to significantly decrease expression of pro-inflammatory cytokines, iNOS and HO-1 in the hippocampus when compared to non-treated animals. A similar age- and long-term ovarian hormone depletion- related increase in GFAP was also attenuated after both melatonin and oestradiol treatments. In a similar way to oestradiol, melatonin decreased the activation of p38 MAPK and NFκB pathways. The treatments enhanced the levels of synaptic molecules synapsin I and MAP-2 and have been shown to modulate the pro-antiapoptotic ratio favouring the second and to increase SIRT1 expression. These findings support the potential therapeutic role of melatonin and oestradiol as protective anti-inflammatory agents for the central nervous system during menopause.

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References

  • Amantea D, Russo R, Bagetta G, Corasaniti MT (2005) From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. Pharmacol Res 52:119–132

    Article  PubMed  CAS  Google Scholar 

  • Benedusi V, Meda C, Della Toree S, Monteleone G, Vegeto E, Maggi A (2012) A lack of ovarian function increases neuroinflammation in aged mice. Endocrinology 153:2777–2788

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bethea CL, Reddy AP, Tokuyama Y, Henderson JA, Lima FB (2009) Protective actions of ovarian hormones in the serotonin system of macaques. Front Neuroendocrinol 30(2):212–238

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18:1633–1641

    PubMed  CAS  Google Scholar 

  • Bhat NR, Feinstein DL, Shen Q, Bhat AN (2002) p38 MAPK mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating transcription factor-2. J Biol Chem 277:29584–29592

    Article  PubMed  CAS  Google Scholar 

  • Brinton RD (2009) Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci 30(4):212–222

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Buckler H (2005) The menopause transition: endocrine changes and clinical symptoms. J Br Menopause Soc 11:61–65

    Article  PubMed  Google Scholar 

  • Cerbai F, Lana D, Nosi D et al (2012) The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS ONE 7(9):e45250

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cerciat M, Unkila M, Garcia-Segura LM, Arevalo MA (2010) Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-gamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro. Glia 58:93–102

    Article  PubMed  CAS  Google Scholar 

  • Choi J-S, Kim SJ, Shin JA, Lee KE, Park EM (2008) Effects of estrogen on temporal expressions of IL-1β and IL-1ra in rat organotypic hippocampal slices exposed to oxygen–glucose deprivation. Neurosci Lett 438:233–237

    Article  PubMed  CAS  Google Scholar 

  • Ciortea R, Costin N, Braicu I, Haragâş D, Hudacsko A, Bondor C, Mihu D, Mihu CM (2011) Effect of melatonin on intra-abdominal fat in correlation with endometrial proliferation in ovariectomized rats. Anticancer Res 31(8):2637–2643

    PubMed  CAS  Google Scholar 

  • Clapp-Lilly KL, Smith MA, Perry G, Duffy LK (2001) Melatonin reduces interleukin secretion in amyloid-beta stressed mouse brain slices. Chem Biol Interact 134:101–107

    Article  PubMed  CAS  Google Scholar 

  • Cvoro A, Yuan C, Paruthiyil S, Miller OH, Yamamoto KR, Leitman DC (2011) Cross talk between glucocorticoid and estrogen receptors occurs at a subset of proinflammatory genes. J Immunol 186(7):4354–4360

    Article  PubMed  CAS  Google Scholar 

  • Diaz BL, Llaneza PC (2008) Endocrine regulation of the course of menopause by oral melatonin: first case report. Menopause 15(2):388–392

    Article  PubMed  Google Scholar 

  • Dimayuga FO, Reed JL, Carnero GA, Wang C, Dimayuga ER, Dimayuga VM, Perger A, Wilson ME, Keller JN, Bruce-Keller AJ (2005) Estrogen and brain inflammation: effects on microglial expression of MHC, costimulatory molecules and cytokines. J Neuroimmunol 161:123–136

    Article  PubMed  CAS  Google Scholar 

  • Eijo G, Zarate S, Jaita G, Ferraris J, Magri ML, Zaldivar V, Radl D, Boti V, Pisera D, Seilicovich A (2011) Inhibition of nuclear factor-kappa B sensitises anterior pituitary cells to tumor necrosis factor-α- and lipopolysaccharide-induced apoptosis. J Neuroendocrinol 23(8):651–659

    Article  PubMed  CAS  Google Scholar 

  • Farinas C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28:138–145

    Article  Google Scholar 

  • Feldman I, Feldman GM, Mobarak C, Dunkelberg JC, Leslie KK (2007) Identification of proteins within the nuclear factor-kappa B transcriptional complex including estrogen receptor-alpha. Am J Obstet Gynecol 196(4):394–e1-11

    PubMed  PubMed Central  Google Scholar 

  • Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    Article  PubMed  CAS  Google Scholar 

  • Frankel D, Mehindate K, Schipper HM (2000) Role of heme oxygenase-1 in the regulation of manganese superoxide dismutase gene expression in oxidatively-challenged astroglia. J Cell Physiol 185:80–86

    Article  PubMed  CAS  Google Scholar 

  • Gabai VL, Meriin AB, Mosser DD, Caron AW, Rits S, Shifrin VI, Sherman MY (1997) Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 272(29):18033–18037

    Article  PubMed  CAS  Google Scholar 

  • Gollapudi L, Oblinger MM (1999) Stable transfection of PC12 cells with estrogen receptor (ERalpha): protective effects of estrogen on cell survival after serum deprivation. J Neurosci Res 56:99–108

    Article  PubMed  CAS  Google Scholar 

  • Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256

    Article  PubMed  CAS  Google Scholar 

  • Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D et al (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 95:10896–10901

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Harrod CG, Bendok BR, Batjer H (2005) Interactions between melatonin and estrogen may regulate cerebrovascular function in women: clinical implications for the effective use of HRT during menopause and aging. Med Hypotheses 64:725–735

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa N, Kato H, Araki T (2007) Age-related changes of astrocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. Mech Ageing Dev 128:311–316

    Article  PubMed  CAS  Google Scholar 

  • Hou Y, Wei H, Luo Y, Liu G (2010) Modulating expression of brain heat shock proteins by estrogen in ovariectomized mice model of aging. Exp Gerontol 45:323–330

    Article  PubMed  CAS  Google Scholar 

  • Kajta M, Trotter A, Lasoń W, Beyer C (2006) Impact of 17β-estradiol on cytokine-mediated apoptotic effects in primary hippocampal and neocortical cell cultures. Brain Res 1116:64–74

    Article  PubMed  CAS  Google Scholar 

  • Kalaitzidis D, Gilmore TD (2005) Transcription factor cross-talk: the estrogen receptor and NF-κB. Trends Endocrinol Metab 16:46–52

    Article  PubMed  CAS  Google Scholar 

  • Kolthur-Seetharam U, Dantzer F, McBurney MW, de Murcia G, Sassone-Corsi P (2006) Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle 5:873–877

    Article  PubMed  CAS  Google Scholar 

  • Kozuka N, Itofusa R, Kudo Y, Morita M (2005) Lipopolysaccharide and proinflammatory cytokines require different astrocyte states to induce nitric oxide production. J Neurosci Res 82:717–728

    Article  PubMed  CAS  Google Scholar 

  • Lee YM, Cheng PY, Hong SF, Chen SY, Lam KK, Sheu JR, Yen MH (2005) Oxidative stress induces vascular heme oxygenase-1 expression in ovariectomized rats. Free Radic Biol Med 39:108–117

    Article  PubMed  CAS  Google Scholar 

  • Lei DL, Long JM, Hengemihle J, O’Neill J, Manaye KF, Ingram DK, Mouton PR (2003) Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice. Neuroscience 121:659–666

    Article  PubMed  CAS  Google Scholar 

  • Liang YL, Zhang ZH, Liu XJ, Liu XQ, Tao L, Zhang YF, Wang H, Zhang C, Chen X, Xu DX (2012) Melatonin protects against apoptosis-inducing factor (AIF)-dependent cell death during acetaminophen-induced acute liver failure. PLoS ONE 7(12):e51911

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lynch MA (2010) Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci 1:6

    Article  PubMed  PubMed Central  Google Scholar 

  • Lyons A, McQuillan K, Deighan BF, O’Reilly JA, Downer EJ, Murphy AC, Watson M, Piazza A, O’Connell F, Griffin R, Mills KH, Lynch MA (2009) Decreased neuronal CD200 expression in IL-4-deficient mice results in increased neuroinflammation in response to lipopolysaccharide. Brain Behav Immun 23:1020–1027

    Article  PubMed  CAS  Google Scholar 

  • Mahmoodzadeh S, Fritschka S, Dworatzek E, Pham TH, Becher E, Kuehne A, Davidson MM, Regitz-Zagrosek V (2009) Nuclear factor-kappaB regulates estrogen receptor-alpha transcription in the human heart. J Biol Chem 284:24705–24714

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Manthey D, Behl C (2006) From structural biochemistry to expression profiling: neuroprotective activities of estrogen. Neuroscience 138:845–850

    Article  PubMed  CAS  Google Scholar 

  • Marcus JS, Karackattu SL, Fleegal MA, Sumners C (2003) Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk mitogen-activated protein kinase and NF-kappaB. Glia 41:152–160

    Article  PubMed  Google Scholar 

  • Martins DB, Mazzanti CM, França RT, Pagnoncelli M, Costa MM, Martins de Souza E, Gonçalves J et al (2012) 17-β estradiol in the acetylcholinesterase activity and lipid peroxidation in the brain and blood of ovariectomized adult and middle-aged rats. Life Sci 90:351–359

    Article  PubMed  CAS  Google Scholar 

  • McAsey ME, Cady C, Jackson LM, Li M, Randall S, Nathan BP, Struble RG (2006) Time course of response to estradiol replacement in ovariectomized mice: brain apolipoprotein E and synaptophysin transiently increase and glial fibrillary acidic protein is suppressed. Exp Neurol 197(1):197–205

    Article  PubMed  CAS  Google Scholar 

  • McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45

    Article  PubMed  PubMed Central  Google Scholar 

  • Meda C, Vegeto E, Pollio G, Ciana P, Patrone C, Pellicciari C, Maggi A (2000) Oestrogen prevention of neural cell death correlates with decreased expression of mRNA for the pro-apoptotic protein nip-2. J Neuroendocrinol 12:1051–1059

    Article  PubMed  CAS  Google Scholar 

  • Meng Y, Wang R, Yang F, Ji Z, Fang L, Sheng S (2010) Amyloid precursor protein 17-mer peptide ameliorates hippocampal neurodegeneration in ovariectomized rats. Neurosci Lett 468:173–177

    Article  PubMed  CAS  Google Scholar 

  • Michan S, Li Y, Meng-Hsiu Chou M, Parrella E, Ge H, Long JM et al (2010) SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci 30(29):9695–9707

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C (2008) CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 28:4018–4025

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Murphy N, Cowley TR, Blau CW, Dempsey CN, Noonan J, Gowran A, Tanveer R, Olango WM, Finn DP, Campbell VA, Lynch MA (2012) The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation. J Neuroinflammation 9:79

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Noda M, Doi Y, Liang J, Kawanokuchi J, Sonobe Y et al (2011) Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem 286:2308–2319

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Nopparat C, Porter JE, Ebadi M, Govitrapong P (2010) The mechanisms for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. J Pineal Res 49(4):382–389

    Article  PubMed  CAS  Google Scholar 

  • O’neill L (2006) Targeting signal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov 5:549–563

    Article  PubMed  Google Scholar 

  • Okatani Y, Morioka N, Wakatsuki A (2000) Changes in nocturnal melatonin secretion in perimenopausal women: correlation with endogenous estrogen concentrations. J Pineal Res 28(2):111–118

    Article  PubMed  CAS  Google Scholar 

  • Pawluski JL, Brummelte S, Barha CK, Crozier TM, Galea LAM (2009) Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging. Front Neuroendocrinol 30(3):343–357

    Article  PubMed  CAS  Google Scholar 

  • Perez-Martin M, Salazar V, Castillo C, Ariznavarreta C, Azcoitia I, Garcia-Segura LM, Tresguerres JAF (2005) Estradiol and soy extract increase the production of new cells in the dentate gyrus of old rats. Exp Gerontol 40:450–453

    Article  PubMed  CAS  Google Scholar 

  • Rastogi M, Ojha RP, Prabu PC, Devi BP, Agrawal A, Dubey GP (2012) Prevention of age-associated neurodegeneration and promotion of healthy brain ageing in female Wistar rats by long term use of bacosides. Biogerontology 13:183–195

    Article  PubMed  CAS  Google Scholar 

  • Reiter RJ, Craft CM, Johnson JE, King TS, Richardson BA, Vaughan GM, Vaughan MK (1981) Age-associated reduction in nocturnal pineal melatonin levels in female rats. Endocrinology 109:1295–1297

    Article  PubMed  CAS  Google Scholar 

  • Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577

    Article  PubMed  CAS  Google Scholar 

  • Rumora L, Lovric J, Sairam MR, Maysinger D (2007) Impairments of heat shock protein expression and MAPK translocation in the central nervous system of follitropin receptor knockout mice. Exp Gerontol 42:619–628

    Article  PubMed  CAS  Google Scholar 

  • Sales S, Ureshino RP, dos Tavares do Santos Pereira R et al (2010) Effects of 17β-estradiol replacement on the apoptotic effects caused by ovariectomy in the rat hippocampus. Life Sci 86:832–838

    Article  PubMed  CAS  Google Scholar 

  • Santizo R, Pelligrino DA (1999) Estrogen reduces leukocyte adhesion in the cerebral circulation of female rats. J Cereb Blood Flow Metab 19:1061–1065

    Article  PubMed  CAS  Google Scholar 

  • Schipper HM, Bennett DA, Liberman A, Bienias JL, Schneider JA, Kelly J, Arvanitakis Z (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27:252–261

    Article  PubMed  CAS  Google Scholar 

  • Sharma K, Mehra RD (2008) Long-term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprotection to hippocampal neurons by modulating the expression of Bcl-2 and Bax. Brain Res 1204:1–15

    Article  PubMed  CAS  Google Scholar 

  • Sherwin BB, Henry JF (2008) Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: a critical review. Front Neuroendocrinol 29:88–113

    Article  PubMed  CAS  Google Scholar 

  • Shetha DS, Tajuddin NF, Druse MJ (2009) Antioxidant neuroprotection against ethanol-induced apoptosis in HN2-5 cells. Brain Res 1285:14–21

    Article  Google Scholar 

  • Shuster LT, Gostout BS, Grossardt BR, Rocca WA (2008) Prophylactic oophorectomy in premenopausal women and long-term health. Menopause Int 14:111–116

    PubMed  PubMed Central  Google Scholar 

  • Tamura H, Nakamura Y, Narimatsu A, Yamagata Y, Takasaki A, Reiter RJ, Sugino N (2008) Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels. J Pineal Res 45(1):101–105

    Article  PubMed  CAS  Google Scholar 

  • Tan J, Town T, Paris D, Placzek A, Parker T, Crawford F, Yu H, Humphrey J, Mullan M (1999) Activation of microglial cells by the CD40 pathway: relevance to multiple sclerosis. J Neuroimmunol 97:77–85

    Article  PubMed  CAS  Google Scholar 

  • Tyagi E, Agrawal R, Nath C, Shukla R (2010) Effect of melatonin on neuroinflammation and acetylcholinesterase activity induced by LPS in rat brain. Eur J Pharmacol 640:206–210

    Article  PubMed  CAS  Google Scholar 

  • Valles SL, Borras C, Gambini J, Furriol J, Ortega A, Sastre J, Pallardo FV, Viña J (2008) Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell 7(1):112–118

    Article  PubMed  CAS  Google Scholar 

  • Veneroso C, Tuñón MJ, González-Gallego J, Collado PS (2009) Melatonin reduces cardiac inflammatory injury induced by acute exercise. J Pineal Res 47(2):184–191

    Article  PubMed  CAS  Google Scholar 

  • Wen Y, Yang S, Liu R, Perez E, Yi KD, Koulen P, Simpkins JW (2004) Estrogen attenuates nuclear factor-κB activation induced by transient cerebral ischemia. Brain Res 1008:147–154

    Article  PubMed  CAS  Google Scholar 

  • Xu Z, Wang BR, Wang X, Kuang F, Duan XL, Jiao XY, Ju G (2006) Erk1/2 and p38 mitogen activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury. Life Sci 79:1895–1905

    Article  PubMed  CAS  Google Scholar 

  • Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA et al (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zhang J, Piantadosi CA (1992) Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Investig 90:1193–1199

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgment

Thanks are given to D. Campon for his technical support.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Instituto de Investigación Biomédica de Vigo (IBIV), Xerencia de Xestión Integrada de Vigo, SERGAS, Biomedical Research Unit, Hospital Rebullón (CHUVI), Puxeiros s/n, 36415, MOS Pontevedra, Spain

    Roman A. Kireev

  2. Department Physiology, Medical School, University Complutense of Madrid, Madrid, Spain

    Roman A. Kireev & Jesus A. F. Tresguerres

  3. Department Biochemistry and Molecular Biology, Medical School, University Complutense of Madrid, Madrid, Spain

    Elena Vara

  4. Department Physiology, Medical School, University of Valencia, Valencia, Spain

    Jose Viña

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  1. Roman A. Kireev
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Correspondence to Roman A. Kireev.

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Kireev, R.A., Vara, E., Viña, J. et al. Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats. AGE 36, 9707 (2014). https://doi.org/10.1007/s11357-014-9707-3

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