From Healthy Aging to Frailty: In Search of the Underlying Mechanisms

Author(s): Paola Brivio , Maria Serena Paladini , Giorgio Racagni , Marco Andrea Riva , Francesca Calabrese* , Raffaella Molteni .

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 20 , 2019

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Abstract:

Population aging is accelerating rapidly worldwide, from 461 million people older than 65 years in 2004 to an estimated 2 billion people by 2050, leading to critical implications for the planning and delivery of health and social care.

The most problematic expression of population aging is the clinical condition of frailty, which is a state of increased vulnerability that develops as a consequence of the accumulation of microscopic damages in many physiological systems that lead to a striking and disproportionate change in health state, even after an apparently small insult.

Since little is known about the biology of frailty, an important perspective to understand this phenomenon is to establish how the alterations that physiologically occur during a condition of healthy aging may instead promote cumulative decline with subsequent depletion of homoeostatic reserve and increase the vulnerability also after minor stressor events.

In this context, the present review aims to provide a description of the molecular mechanisms that, by having a critical impact on behavior and neuronal function in aging, might be relevant for the development of frailty. Moreover, since these biological systems are also involved in the coping strategies set in motion to respond to environmental challenges, we propose a role for lifestyle stress as an important player to drive frailty in aging.

Keywords: Neuroplasticity, epigenetic, neuroinflammation, HPA axis, stress, aging.

[1]
Fried, L.P.; Tangen, C.M.; Walston, J.; Newman, A.B.; Hirsch, C.; Gottdiener, J.; Seeman, T.; Tracy, R.; Kop, W.J.; Burke, G.; McBurnie, M.A. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci., 2001, 56(3), M146-M156.
[http://dx.doi.org/10.1093/gerona/56.3.M146] [PMID: 11253156]
[2]
Azpurua, J.; Eaton, B.A. Neuronal epigenetics and the aging synapse. Front. Cell. Neurosci., 2015, 9(208), 208.
[http://dx.doi.org/10.3389/fncel.2015.00208] [PMID: 26074775]
[3]
Morrison, J.H.; Baxter, M.G. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci., 2012, 13(4), 240-250.
[http://dx.doi.org/10.1038/nrn3200] [PMID: 22395804]
[4]
Nakamura, S.; Akiguchi, I.; Kameyama, M.; Mizuno, N. Age-related changes of pyramidal cell basal dendrites in layers III and V of human motor cortex: a quantitative Golgi study. Acta Neuropathol., 1985, 65(3-4), 281-284.
[http://dx.doi.org/10.1007/BF00687009] [PMID: 3976364]
[5]
Barnes, C.A. Normal aging: regionally specific changes in hippocampal synaptic transmission. Trends Neurosci., 1994, 17(1), 13-18.
[http://dx.doi.org/10.1016/0166-2236(94)90029-9] [PMID: 7511843]
[6]
Jacobs, B.; Schall, M.; Prather, M.; Kapler, E.; Driscoll, L.; Baca, S.; Jacobs, J.; Ford, K.; Wainwright, M.; Treml, M. Regional dendritic and spine variation in human cerebral cortex: a quantitative golgi study. Cereb. Cortex, 2001, 11(6), 558-571.
[http://dx.doi.org/10.1093/cercor/11.6.558] [PMID: 11375917]
[7]
Hof, P.R.; Duan, H.; Page, T.L.; Einstein, M.; Wicinski, B.; He, Y.; Erwin, J.M.; Morrison, J.H. Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting neurons in macaque and patas monkeys. Brain Res., 2002, 928(1-2), 175-186.
[http://dx.doi.org/10.1016/S0006-8993(01)03345-5] [PMID: 11844485]
[8]
Duan, H.; Wearne, S.L.; Rocher, A.B.; Macedo, A.; Morrison, J.H.; Hof, P.R. Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys. Cereb. Cortex, 2003, 13(9), 950-961.
[http://dx.doi.org/10.1093/cercor/13.9.950] [PMID: 12902394]
[9]
Chang, Y.M.; Rosene, D.L.; Killiany, R.J.; Mangiamele, L.A.; Luebke, J.I. Increased action potential firing rates of layer 2/3 pyramidal cells in the prefrontal cortex are significantly related to cognitive performance in aged monkeys. Cereb. Cortex, 2005, 15(4), 409-418.
[http://dx.doi.org/10.1093/cercor/bhh144] [PMID: 15749985]
[10]
Burke, S.N.; Barnes, C.A. Neural plasticity in the ageing brain. Nat. Rev. Neurosci., 2006, 7(1), 30-40.
[http://dx.doi.org/10.1038/nrn1809] [PMID: 16371948]
[11]
Coggan, J.S.; Grutzendler, J.; Bishop, D.L.; Cook, M.R.; Gan, W.; Heym, J.; Lichtman, J.W. Age-associated synapse elimination in mouse parasympathetic ganglia. J. Neurobiol., 2004, 60(2), 214-226.
[http://dx.doi.org/10.1002/neu.20022] [PMID: 15266652]
[12]
Canas, P.M.; Duarte, J.M.; Rodrigues, R.J.; Köfalvi, A.; Cunha, R.A. Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol. Aging, 2009, 30(11), 1877-1884.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.01.003] [PMID: 18304697]
[13]
Richard, M.B.; Taylor, S.R.; Greer, C.A. Age-induced disruption of selective olfactory bulb synaptic circuits. Proc. Natl. Acad. Sci. USA, 2010, 107(35), 15613-15618.
[http://dx.doi.org/10.1073/pnas.1007931107] [PMID: 20679234]
[14]
Gonzales, R.A.; Brown, L.M.; Jones, T.W.; Trent, R.D.; Westbrook, S.L.; Leslie, S.W. N-methyl-D-aspartate mediated responses decrease with age in Fischer 344 rat brain. Neurobiol. Aging, 1991, 12(3), 219-225.
[http://dx.doi.org/10.1016/0197-4580(91)90100-X] [PMID: 1678878]
[15]
Pittaluga, A.; Fedele, E.; Risiglione, C.; Raiteri, M. Age-related decrease of the NMDA receptor-mediated noradrenaline release in rat hippocampus and partial restoration by D-cycloserine. Eur. J. Pharmacol., 1993, 231(1), 129-134.
[http://dx.doi.org/10.1016/0014-2999(93)90693-C] [PMID: 8444277]
[16]
Barnes, C.A.; Rao, G.; Shen, J. Age-related decrease in the N-methyl-D-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1. Neurobiol. Aging, 1997, 18(4), 445-452.
[http://dx.doi.org/10.1016/S0197-4580(97)00044-4] [PMID: 9330977]
[17]
Magnusson, K.R. The aging of the NMDA receptor complex. Front. Biosci., 1998, 3, e70-e80.
[http://dx.doi.org/10.2741/A368] [PMID: 9576682]
[18]
Eckles-Smith, K.; Clayton, D.; Bickford, P.; Browning, M.D. Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression. Brain Res. Mol. Brain Res., 2000, 78(1-2), 154-162.
[http://dx.doi.org/10.1016/S0169-328X(00)00088-7] [PMID: 10891595]
[19]
Gore, A.C.; Oung, T.; Woller, M.J. Age-related changes in hypothalamic gonadotropin-releasing hormone and N-methyl-D-aspartate receptor gene expression, and their regulation by oestrogen, in the female rat. J. Neuroendocrinol., 2002, 14(4), 300-309.
[http://dx.doi.org/10.1046/j.1365-2826.2002.00777.x] [PMID: 11963827]
[20]
Liu, P.; Smith, P.F.; Darlington, C.L. Glutamate receptor subunits expression in memory-associated brain structures: regional variations and effects of aging. Synapse, 2008, 62(11), 834-841.
[http://dx.doi.org/10.1002/syn.20563] [PMID: 18720514]
[21]
Zhao, X.; Rosenke, R.; Kronemann, D.; Brim, B.; Das, S.R.; Dunah, A.W.; Magnusson, K.R. The effects of aging on N-methyl-D-aspartate receptor subunits in the synaptic membrane and relationships to long-term spatial memory. Neuroscience, 2009, 162(4), 933-945.
[http://dx.doi.org/10.1016/j.neuroscience.2009.05.018] [PMID: 19446010]
[22]
Marín, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci., 2012, 13(2), 107-120.
[http://dx.doi.org/10.1038/nrn3155] [PMID: 22251963]
[23]
Peinemann, A.; Lehner, C.; Conrad, B.; Siebner, H.R. Age-related decrease in paired-pulse intracortical inhibition in the human primary motor cortex. Neurosci. Lett., 2001, 313(1-2), 33-36.
[http://dx.doi.org/10.1016/S0304-3940(01)02239-X] [PMID: 11684333]
[24]
Pellicciari, M.C.; Miniussi, C.; Rossini, P.M.; De Gennaro, L. Increased cortical plasticity in the elderly: changes in the somatosensory cortex after paired associative stimulation. Neuroscience, 2009, 163(1), 266-276.
[http://dx.doi.org/10.1016/j.neuroscience.2009.06.013] [PMID: 19524024]
[25]
Huttunen, J.; Wikström, H.; Salonen, O.; Ilmoniemi, R.J. Human somatosensory cortical activation strengths: comparison between males and females and age-related changes. Brain Res., 1999, 818(2), 196-203.
[http://dx.doi.org/10.1016/S0006-8993(98)01215-3] [PMID: 10082804]
[26]
Erlander, M.G.; Tillakaratne, N.J.; Feldblum, S.; Patel, N.; Tobin, A.J. Two genes encode distinct glutamate decarboxylases. Neuron, 1991, 7(1), 91-100.
[http://dx.doi.org/10.1016/0896-6273(91)90077-D] [PMID: 2069816]
[27]
Gold, J.R.; Bajo, V.M. Insult-induced adaptive plasticity of the auditory system. Front. Neurosci., 2014, 8, 110.
[http://dx.doi.org/10.3389/fnins.2014.00110] [PMID: 24904256]
[28]
Rissman, R.A.; Mobley, W.C. Implications for treatment: GABAA receptors in aging, Down syndrome and Alzheimer’s disease. J. Neurochem., 2011, 117(4), 613-622.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07237.x] [PMID: 21388375]
[29]
Gutiérrez, A.; Khan, Z.U.; Ruano, D.; Miralles, C.P.; Vitorica, J.; De Blas, A.L. Aging-related subunit expression changes of the GABAA receptor in the rat hippocampus. Neuroscience, 1996, 74(2), 341-348.
[http://dx.doi.org/10.1016/0306-4522(96)00137-6] [PMID: 8865187]
[30]
McQuail, J.A.; Bañuelos, C.; LaSarge, C.L.; Nicolle, M.M.; Bizon, J.L. GABA(B) receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats. Neurobiol. Aging, , 2012, 33(6), 1124- e1-1124. e12..
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.11.011] [PMID: 22169202]
[31]
Calabrese, F.; Riva, M.A.; Molteni, R. Synaptic alterations associated with depression and schizophrenia: potential as a therapeutic target. Expert Opin. Ther. Targets, 2016, 20(10), 1195-1207.
[http://dx.doi.org/10.1080/14728222.2016.1188080] [PMID: 27167520]
[32]
Ramón y Cajal, S. R. Estudios sobre la degeneración y regeneracion del sistema nervioso. Moya , 1913-1914.
[33]
Fuchs, E.; Flügge, G. Adult neuroplasticity: more than 40 years of research. Neural Plast., 2014, 2014, 541870.
[http://dx.doi.org/10.1155/2014/541870] [PMID: 24883212]
[34]
Raz, N.; Lindenberger, U.; Rodrigue, K.M.; Kennedy, K.M.; Head, D.; Williamson, A.; Dahle, C.; Gerstorf, D.; Acker, J.D. Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb. Cortex, 2005, 15(11), 1676-1689.
[http://dx.doi.org/10.1093/cercor/bhi044] [PMID: 15703252]
[35]
Brody, H. Organization of the cerebral cortex. III. A study of aging in the human cerebral cortex. J. Comp. Neurol., 1955, 102(2), 511-516.
[http://dx.doi.org/10.1002/cne.901020206] [PMID: 14381544]
[36]
Scheibel, A.B. Dendritic changes in senile and presenile dementias. Res. Publ. Assoc. Res. Nerv. Ment. Dis., 1979, 57, 107-124.
[PMID: 419330]
[37]
Hedden, T.; Gabrieli, J.D. Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci., 2004, 5(2), 87-96.
[http://dx.doi.org/10.1038/nrn1323] [PMID: 14735112]
[38]
Grill, J.D.; Riddle, D.R. Age-related and laminar-specific dendritic changes in the medial frontal cortex of the rat. Brain Res., 2002, 937(1-2), 8-21.
[http://dx.doi.org/10.1016/S0006-8993(02)02457-5] [PMID: 12020857]
[39]
Uylings, H.B.; de Brabander, J.M. Neuronal changes in normal human aging and Alzheimer’s disease. Brain Cogn., 2002, 49(3), 268-276.
[http://dx.doi.org/10.1006/brcg.2001.1500] [PMID: 12139954]
[40]
Burger, C. Region-specific genetic alterations in the aging hippocampus: implications for cognitive aging. Front. Aging Neurosci., 2010, 2, 140.
[http://dx.doi.org/10.3389/fnagi.2010.00140] [PMID: 21048902]
[41]
Olariu, A.; Cleaver, K.M.; Cameron, H.A. Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle. J. Comp. Neurol., 2007, 501(4), 659-667.
[http://dx.doi.org/10.1002/cne.21268] [PMID: 17278139]
[42]
Lister, J.P.; Barnes, C.A. Neurobiological changes in the hippocampus during normative aging. Arch. Neurol., 2009, 66(7), 829-833.
[http://dx.doi.org/10.1001/archneurol.2009.125] [PMID: 19597084]
[43]
Kapogiannis, D.; Mattson, M.P. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol., 2011, 10(2), 187-198.
[http://dx.doi.org/10.1016/S1474-4422(10)70277-5] [PMID: 21147038]
[44]
Poo, M.M. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci., 2001, 2(1), 24-32.
[http://dx.doi.org/10.1038/35049004] [PMID: 11253356]
[45]
Lu, B. Pro-region of neurotrophins: role in synaptic modulation. Neuron, 2003, 39(5), 735-738.
[http://dx.doi.org/10.1016/S0896-6273(03)00538-5] [PMID: 12948441]
[46]
Oliveira, S.L.; Pillat, M.M.; Cheffer, A.; Lameu, C.; Schwindt, T.T.; Ulrich, H. Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytometry A, 2013, 83(1), 76-89.
[http://dx.doi.org/10.1002/cyto.a.22161] [PMID: 23044513]
[47]
Chao, M.V.; Hempstead, B.L. p75 and Trk: a two-receptor system. Trends Neurosci., 1995, 18(7), 321-326.
[http://dx.doi.org/10.1016/0166-2236(95)93922-K] [PMID: 7571013]
[48]
Mitre, M.; Mariga, A.; Chao, M.V. Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin. Sci. (Lond.), 2017, 131(1), 13-23.
[http://dx.doi.org/10.1042/CS20160044] [PMID: 27908981]
[49]
Esposito, D.; Patel, P.; Stephens, R.M.; Perez, P.; Chao, M.V.; Kaplan, D.R.; Hempstead, B.L. The cytoplasmic and transmembrane domains of the p75 and Trk A receptors regulate high affinity binding to nerve growth factor. J. Biol. Chem., 2001, 276(35), 32687-32695.
[http://dx.doi.org/10.1074/jbc.M011674200] [PMID: 11435417]
[50]
Ziegenhorn, A.A.; Schulte-Herbrüggen, O.; Danker-Hopfe, H.; Malbranc, M.; Hartung, H.D.; Anders, D.; Lang, U.E.; Steinhagen-Thiessen, E.; Schaub, R.T.; Hellweg, R. Serum neurotrophins--a study on the time course and influencing factors in a large old age sample. Neurobiol. Aging, 2007, 28(9), 1436-1445.
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.06.011] [PMID: 16879899]
[51]
Calabrese, F.; Guidotti, G.; Racagni, G.; Riva, M.A. Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor. Neurobiol. Aging, 2013, 34(12), 2768-2776.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.06.014] [PMID: 23870838]
[52]
Chapman, T.R.; Barrientos, R.M.; Ahrendsen, J.T.; Hoover, J.M.; Maier, S.F.; Patterson, S.L. Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol. Aging, 2012, 33(4), 832.e1-832.e14.
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.07.015] [PMID: 21907460]
[53]
Erickson, K.I.; Prakash, R.S.; Voss, M.W.; Chaddock, L.; Heo, S.; McLaren, M.; Pence, B.D.; Martin, S.A.; Vieira, V.J.; Woods, J.A.; McAuley, E.; Kramer, A.F. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J. Neurosci., 2010, 30(15), 5368-5375.
[http://dx.doi.org/10.1523/JNEUROSCI.6251-09.2010] [PMID: 20392958]
[54]
Mattson, M.P.; Magnus, T. Ageing and neuronal vulnerability. Nat. Rev. Neurosci., 2006, 7(4), 278-294.
[http://dx.doi.org/10.1038/nrn1886] [PMID: 16552414]
[55]
Monti, B.; Berteotti, C.; Contestabile, A. Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment. Hippocampus, 2005, 15(8), 1041-1049.
[http://dx.doi.org/10.1002/hipo.20099] [PMID: 16086428]
[56]
Adlard, P.A.; Perreau, V.M.; Cotman, C.W. The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol. Aging, 2005, 26(4), 511-520.
[http://dx.doi.org/10.1016/j.neurobiolaging.2004.05.006] [PMID: 15653179]
[57]
Yurek, D.M.; Fletcher-Turner, A. Lesion-induced increase of BDNF is greater in the striatum of young versus old rat brain. Exp. Neurol., 2000, 161(1), 392-396.
[http://dx.doi.org/10.1006/exnr.1999.7274] [PMID: 10683304]
[58]
Nakai, S.; Matsunaga, W.; Ishida, Y.; Isobe, K.; Shirokawa, T. Effects of BDNF infusion on the axon terminals of locus coeruleus neurons of aging rats. Neurosci. Res., 2006, 54(3), 213-219.
[http://dx.doi.org/10.1016/j.neures.2005.12.001] [PMID: 16406148]
[59]
Kennedy, K.M.; Reese, E.D.; Horn, M.M.; Sizemore, A.N.; Unni, A.K.; Meerbrey, M.E.; Kalich, A.G., Jr; Rodrigue, K.M. BDNF val66met polymorphism affects aging of multiple types of memory. Brain Res., 2015, 1612, 104-117.
[http://dx.doi.org/10.1016/j.brainres.2014.09.044] [PMID: 25264352]
[60]
Shimizu, E.; Hashimoto, K.; Iyo, M. Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am. J. Med. Genet. B. Neuropsychiatr. Genet., 2004, 126B(1), 122-123.
[http://dx.doi.org/10.1002/ajmg.b.20118] [PMID: 15048661]
[61]
Chen, Z.Y.; Jing, D.; Bath, K.G.; Ieraci, A.; Khan, T.; Siao, C.J.; Herrera, D.G.; Toth, M.; Yang, C.; McEwen, B.S.; Hempstead, B.L.; Lee, F.S. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science, 2006, 314(5796), 140-143.
[http://dx.doi.org/10.1126/science.1129663] [PMID: 17023662]
[62]
Yu, H.; Wang, D.D.; Wang, Y.; Liu, T.; Lee, F.S.; Chen, Z.Y. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J. Neurosci., 2012, 32(12), 4092-4101.
[http://dx.doi.org/10.1523/JNEUROSCI.5048-11.2012] [PMID: 22442074]
[63]
Phillips, H.S.; Hains, J.M.; Armanini, M.; Laramee, G.R.; Johnson, S.A.; Winslow, J.W. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron, 1991, 7(5), 695-702.
[http://dx.doi.org/10.1016/0896-6273(91)90273-3] [PMID: 1742020]
[64]
Peng, S.; Wuu, J.; Mufson, E.J.; Fahnestock, M. Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J. Neurochem., 2005, 93(6), 1412-1421.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03135.x] [PMID: 15935057]
[65]
Lee, J.; Fukumoto, H.; Orne, J.; Klucken, J.; Raju, S.; Vanderburg, C.R.; Irizarry, M.C.; Hyman, B.T.; Ingelsson, M. Decreased levels of BDNF protein in Alzheimer temporal cortex are independent of BDNF polymorphisms. Exp. Neurol., 2005, 194(1), 91-96.
[http://dx.doi.org/10.1016/j.expneurol.2005.01.026] [PMID: 15899246]
[66]
Murer, M.G.; Yan, Q.; Raisman-Vozari, R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog. Neurobiol., 2001, 63(1), 71-124.
[http://dx.doi.org/10.1016/S0301-0082(00)00014-9] [PMID: 11040419]
[67]
Joëls, M. Functional actions of corticosteroids in the hippocampus. Eur. J. Pharmacol., 2008, 583(2-3), 312-321.
[http://dx.doi.org/10.1016/j.ejphar.2007.11.064] [PMID: 18275953]
[68]
Lu, N.Z.; Wardell, S.E.; Burnstein, K.L.; Defranco, D.; Fuller, P.J.; Giguere, V.; Hochberg, R.B.; McKay, L.; Renoir, J.M.; Weigel, N.L.; Wilson, E.M.; McDonnell, D.P.; Cidlowski, J.A. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol. Rev., 2006, 58(4), 782-797.
[http://dx.doi.org/10.1124/pr.58.4.9] [PMID: 17132855]
[69]
Revest, J.M.; Kaouane, N.; Mondin, M.; Le Roux, A.; Rougé-Pont, F.; Vallée, M.; Barik, J.; Tronche, F.; Desmedt, A.; Piazza, P.V. The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib. Mol.Psychiatry,, 2010, 15(12), 1125-1140-1151..
[http://dx.doi.org/10.1038/mp.2010.118] [PMID: 20368707]
[70]
Chrousos, G.P. Stress and disorders of the stress system. Nat. Rev. Endocrinol., 2009, 5(7), 374-381.
[http://dx.doi.org/10.1038/nrendo.2009.106] [PMID: 19488073]
[71]
Chrousos, G.P.; Kino, T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic. Sci. STKE, 2005, 2005(304), pe48.
[PMID: 16204701]
[72]
McEwen, B.S.; Bowles, N.P.; Gray, J.D.; Hill, M.N.; Hunter, R.G.; Karatsoreos, I.N.; Nasca, C. Mechanisms of stress in the brain. Nat. Neurosci., 2015, 18(10), 1353-1363.
[http://dx.doi.org/10.1038/nn.4086] [PMID: 26404710]
[73]
Nicolaides, N.C.; Kyratzi, E.; Lamprokostopoulou, A.; Chrousos, G.P.; Charmandari, E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation, 2015, 22(1-2), 6-19.
[http://dx.doi.org/10.1159/000362736] [PMID: 25227402]
[74]
Ferrari, E.; Magri, F. Role of neuroendocrine pathways in cognitive decline during aging. Ageing Res. Rev., 2008, 7(3), 225-233.
[http://dx.doi.org/10.1016/j.arr.2008.07.001] [PMID: 18672097]
[75]
Sapolsky, R.M. Glucocorticoids, stress, and their adverse neurological effects: relevance to aging. Exp. Gerontol., 1999, 34(6), 721-732.
[http://dx.doi.org/10.1016/S0531-5565(99)00047-9] [PMID: 10579633]
[76]
Swaab, D.F.; Bao, A.M.; Lucassen, P.J. The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev., 2005, 4(2), 141-194.
[http://dx.doi.org/10.1016/j.arr.2005.03.003] [PMID: 15996533]
[77]
Sapolsky, R.M.; Altmann, J. Incidence of hypercortisolism and dexamethasone resistance increases with age among wild baboons. Biol. Psychiatry, 1991, 30(10), 1008-1016.
[http://dx.doi.org/10.1016/0006-3223(91)90121-2] [PMID: 1756195]
[78]
Otte, C.; Hart, S.; Neylan, T.C.; Marmar, C.R.; Yaffe, K.; Mohr, D.C. A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology, 2005, 30(1), 80-91.
[http://dx.doi.org/10.1016/j.psyneuen.2004.06.002] [PMID: 15358445]
[79]
Fries, E.; Dettenborn, L.; Kirschbaum, C. The cortisol awakening response (CAR): facts and future directions. Int. J. Psychophysiol., 2009, 72(1), 67-73.
[http://dx.doi.org/10.1016/j.ijpsycho.2008.03.014] [PMID: 18854200]
[80]
Van Cauter, E. Diurnal and ultradian rhythms in human endocrine function: a minireview. Horm. Res., 1990, 34(2), 45-53.
[http://dx.doi.org/10.1159/000181794] [PMID: 1965834]
[81]
Almeida, D.M.; McGonagle, K.; King, H. Assessing daily stress processes in social surveys by combining stressor exposure and salivary cortisol. Biodemogr. Soc. Biol., 2009, 55(2), 219-237.
[http://dx.doi.org/10.1080/19485560903382338] [PMID: 20183906]
[82]
Lightman, S.L.; Windle, R.J.; Julian, M.D.; Harbuz, M.S.; Shanks, N.; Wood, S.A.; Kershaw, Y.M.; Ingram, C.D. Significance of pulsatility in the HPA axis. Novartis Found. Symp., 2000, 227, 244-257.
[http://dx.doi.org/10.1002/0470870796.ch14] [PMID: 10752074]
[83]
Lupien, S.J.; de Leon, M.; de Santi, S.; Convit, A.; Tarshish, C.; Nair, N.P.; Thakur, M.; McEwen, B.S.; Hauger, R.L.; Meaney, M.J. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat. Neurosci., 1998, 1(1), 69-73.
[http://dx.doi.org/10.1038/271] [PMID: 10195112]
[84]
Tizabi, Y.; Aguilera, G.; Gilad, G.M. Age-related reduction in pituitary corticotropin-releasing hormone receptors in two rat strains. Neurobiol. Aging, 1992, 13(2), 227-230.
[http://dx.doi.org/10.1016/0197-4580(92)90034-U] [PMID: 1326090]
[85]
Purnell, J.Q.; Brandon, D.D.; Isabelle, L.M.; Loriaux, D.L.; Samuels, M.H. Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women. J. Clin. Endocrinol. Metab., 2004, 89(1), 281-287.
[http://dx.doi.org/10.1210/jc.2003-030440] [PMID: 14715862]
[86]
Seeman, T.E.; Singer, B.; Wilkinson, C.W.; McEwen, B. Gender differences in age-related changes in HPA axis reactivity. Psychoneuroendocrinology, 2001, 26(3), 225-240.
[http://dx.doi.org/10.1016/S0306-4530(00)00043-3] [PMID: 11166486]
[87]
Adam, E.K.; Hawkley, L.C.; Kudielka, B.M.; Cacioppo, J.T. Day-to-day dynamics of experience--cortisol associations in a population-based sample of older adults. Proc. Natl. Acad. Sci. USA, 2006, 103(45), 17058-17063.
[http://dx.doi.org/10.1073/pnas.0605053103] [PMID: 17075058]
[88]
Dmitrieva, N.O.; Almeida, D.M.; Dmitrieva, J.; Loken, E.; Pieper, C.F. A day-centered approach to modeling cortisol: diurnal cortisol profiles and their associations among U.S. adults. Psychoneuroendocrinology, 2013, 38(10), 2354-2365.
[http://dx.doi.org/10.1016/j.psyneuen.2013.05.003] [PMID: 23770247]
[89]
Karlamangla, A.S.; Friedman, E.M.; Seeman, T.E.; Stawksi, R.S.; Almeida, D.M. Daytime trajectories of cortisol: demographic and socioeconomic differences--findings from the National Study of Daily Experiences. Psychoneuroendocrinology, 2013, 38(11), 2585-2597.
[http://dx.doi.org/10.1016/j.psyneuen.2013.06.010] [PMID: 23831263]
[90]
Nater, U.M.; Hoppmann, C.A.; Scott, S.B. Diurnal profiles of salivary cortisol and alpha-amylase change across the adult lifespan: evidence from repeated daily life assessments. Psychoneuroendocrinology, 2013, 38(12), 3167-3171.
[http://dx.doi.org/10.1016/j.psyneuen.2013.09.008] [PMID: 24099860]
[91]
Johar, H.; Emeny, R.T.; Bidlingmaier, M.; Reincke, M.; Thorand, B.; Peters, A.; Heier, M.; Ladwig, K.H. Blunted diurnal cortisol pattern is associated with frailty: a cross-sectional study of 745 participants aged 65 to 90 years. J. Clin. Endocrinol. Metab., 2014, 99(3), E464-E468.
[http://dx.doi.org/10.1210/jc.2013-3079] [PMID: 24564322]
[92]
Varadhan, R.; Walston, J.; Cappola, A.R.; Carlson, M.C.; Wand, G.S.; Fried, L.P. Higher levels and blunted diurnal variation of cortisol in frail older women. J. Gerontol. A Biol. Sci. Med. Sci., 2008, 63(2), 190-195.
[http://dx.doi.org/10.1093/gerona/63.2.190] [PMID: 18314456]
[93]
Noordam, R.; Jansen, S.W.; Akintola, A.A.; Oei, N.Y.; Maier, A.B.; Pijl, H.; Slagboom, P.E.; Westendorp, R.G.; van der Grond, J.; de Craen, A.J.; van Heemst, D. Leiden Longevity Study group.Familial longevity is marked by lower diurnal salivary cortisol levels: the Leiden Longevity Study. PLoS One, 2012, 7(2), e31166.
[http://dx.doi.org/10.1371/journal.pone.0031166] [PMID: 22348049]
[94]
Bélanger, A.; Candas, B.; Dupont, A.; Cusan, L.; Diamond, P.; Gomez, J.L.; Labrie, F. Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J. Clin. Endocrinol. Metab., 1994, 79(4), 1086-1090.
[PMID: 7962278]
[95]
Murakami, K.; Nakagawa, T.; Shozu, M.; Uchide, K.; Koike, K.; Inoue, M. Changes with aging of steroidal levels in the cerebrospinal fluid of women. Maturitas, 1999, 33(1), 71-80.
[http://dx.doi.org/10.1016/S0378-5122(99)00040-7] [PMID: 10585175]
[96]
Linkowski, P.; Van Onderbergen, A.; Kerkhofs, M.; Bosson, D.; Mendlewicz, J.; Van Cauter, E. Twin study of the 24-h cortisol profile: evidence for genetic control of the human circadian clock. Am. J. Physiol., 1993, 264(2 Pt 1), E173-E181.
[PMID: 8447383]
[97]
Sapolsky, R.M.; Krey, L.C.; McEwen, B.S. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev., 1986, 7(3), 284-301.
[http://dx.doi.org/10.1210/edrv-7-3-284] [PMID: 3527687]
[98]
Issa, A.M.; Rowe, W.; Gauthier, S.; Meaney, M.J. Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J. Neurosci., 1990, 10(10), 3247-3254.
[http://dx.doi.org/10.1523/JNEUROSCI.10-10-03247.1990] [PMID: 2170594]
[99]
Ferrari, E.; Magri, F.; Dori, D.; Migliorati, G.; Nescis, T.; Molla, G.; Fioravanti, M.; Solerte, S.B. Neuroendocrine correlates of the aging brain in humans. Neuroendocrinology, 1995, 61(4), 464-470.
[http://dx.doi.org/10.1159/000126869] [PMID: 7783860]
[100]
Bizon, J.L.; Helm, K.A.; Han, J.S.; Chun, H.J.; Pucilowska, J.; Lund, P.K.; Gallagher, M. Hypothalamic-pituitary-adrenal axis function and corticosterone receptor expression in behaviourally characterized young and aged Long-Evans rats. Eur. J. Neurosci., 2001, 14(10), 1739-1751.
[http://dx.doi.org/10.1046/j.0953-816x.2001.01781.x] [PMID: 11860468]
[101]
Lund, P.K.; Hoyt, E.C.; Bizon, J.; Smith, D.R.; Haberman, R.; Helm, K.; Gallagher, M. Transcriptional mechanisms of hippocampal aging. Exp. Gerontol., 2004, 39(11-12), 1613-1622.
[http://dx.doi.org/10.1016/j.exger.2004.06.018] [PMID: 15582277]
[102]
Lee, S.Y.; Hwang, Y.K.; Yun, H.S.; Han, J.S. Decreased levels of nuclear glucocorticoid receptor protein in the hippocampus of aged Long-Evans rats with cognitive impairment. Brain Res., 2012, 1478, 48-54.
[http://dx.doi.org/10.1016/j.brainres.2012.08.035] [PMID: 22971526]
[103]
Sapolsky, R. Sick of poverty. Sci. Am., 2005, 293(6), 92-99.
[http://dx.doi.org/10.1038/scientificamerican1205-92] [PMID: 16323696]
[104]
Hibberd, C.; Yau, J.L.; Seckl, J.R. Glucocorticoids and the ageing hippocampus. J. Anat., 2000, 197(Pt 4), 553-562.
[http://dx.doi.org/10.1046/j.1469-7580.2000.19740553.x] [PMID: 11197528]
[105]
Cizza, G.; Calogero, A.E.; Brady, L.S.; Bagdy, G.; Bergamini, E.; Blackman, M.R.; Chrousos, G.P.; Gold, P.W. Male Fischer 344/N rats show a progressive central impairment of the hypothalamic-pituitary-adrenal axis with advancing age. Endocrinology, 1994, 134(4), 1611-1620.
[http://dx.doi.org/10.1210/endo.134.4.8137722] [PMID: 8137722]
[106]
Kasckow, J.W.; Regmi, A.; Mulchahey, J.J.; Plotsky, P.M.; Hauger, R.L. Changes in brain corticotropin-releasing factor messenger RNA expression in aged Fischer 344 rats. Brain Res., 1999, 822(1-2), 228-230.
[http://dx.doi.org/10.1016/S0006-8993(98)01365-1] [PMID: 10082900]
[107]
Hauger, R.L.; Thrivikraman, K.V.; Plotsky, P.M. Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats. Endocrinology, 1994, 134(3), 1528-1536.
[http://dx.doi.org/10.1210/endo.134.3.8119195] [PMID: 8119195]
[108]
Ceccatelli, S.; Calzá, L.; Giardino, L. Age-related changes in the expression of corticotropin-releasing hormone receptor mRNA in the rat pituitary. Brain Res. Mol. Brain Res., 1996, 37(1-2), 175-180.
[http://dx.doi.org/10.1016/0169-328X(95)00304-B] [PMID: 8738149]
[109]
Meijer, O.C.; Topic, B.; Steenbergen, P.J.; Jocham, G.; Huston, J.P.; Oitzl, M.S. Correlations between hypothalamus-pituitary-adrenal axis parameters depend on age and learning capacity. Endocrinology, 2005, 146(3), 1372-1381.
[http://dx.doi.org/10.1210/en.2004-0416] [PMID: 15564338]
[110]
Aguilera, G. HPA axis responsiveness to stress: implications for healthy aging. Exp. Gerontol., 2011, 46(2-3), 90-95.
[http://dx.doi.org/10.1016/j.exger.2010.08.023] [PMID: 20833240]
[111]
Cooper, M.S. 11beta-Hydroxysteroid dehydrogenase: a regulator of glucocorticoid response in osteoporosis. J. Endocrinol. Invest., 2008, 31(7)(Suppl.), 16-21.
[PMID: 18791346]
[112]
Holmes, M.C.; Carter, R.N.; Noble, J.; Chitnis, S.; Dutia, A.; Paterson, J.M.; Mullins, J.J.; Seckl, J.R.; Yau, J.L. 11beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments. J. Neurosci., 2010, 30(20), 6916-6920.
[http://dx.doi.org/10.1523/JNEUROSCI.0731-10.2010] [PMID: 20484633]
[113]
Sapolsky, R.M.; Krey, L.C.; McEwen, B.S. Corticosterone receptors decline in a site-specific manner in the aged rat brain. Brain Res., 1983, 289(1-2), 235-240.
[http://dx.doi.org/10.1016/0006-8993(83)90024-0] [PMID: 6661643]
[114]
Murphy, E.K.; Spencer, R.L.; Sipe, K.J.; Herman, J.P. Decrements in nuclear glucocorticoid receptor (GR) protein levels and DNA binding in aged rat hippocampus. Endocrinology, 2002, 143(4), 1362-1370.
[http://dx.doi.org/10.1210/endo.143.4.8740] [PMID: 11897693]
[115]
Landfield, P.W.; Baskin, R.K.; Pitler, T.A. Brain aging correlates: retardation by hormonal-pharmacological treatments. Science, 1981, 214(4520), 581-584.
[http://dx.doi.org/10.1126/science.6270791] [PMID: 6270791]
[116]
Landfield, P.W.; Waymire, J.C.; Lynch, G. Hippocampal aging and adrenocorticoids: quantitative correlations. Science, 1978, 202(4372), 1098-1102.
[http://dx.doi.org/10.1126/science.715460] [PMID: 715460]
[117]
Li, G.; Cherrier, M.M.; Tsuang, D.W.; Petrie, E.C.; Colasurdo, E.A.; Craft, S.; Schellenberg, G.D.; Peskind, E.R.; Raskind, M.A.; Wilkinson, C.W. Salivary cortisol and memory function in human aging. Neurobiol. Aging, 2006, 27(11), 1705-1714.
[http://dx.doi.org/10.1016/j.neurobiolaging.2005.09.031] [PMID: 16274857]
[118]
Gage, F.H.; Dunnett, S.B.; Björklund, A. Spatial learning and motor deficits in aged rats. Neurobiol. Aging, 1984, 5(1), 43-48.
[http://dx.doi.org/10.1016/0197-4580(84)90084-8] [PMID: 6738785]
[119]
Gallagher, M.; Pelleymounter, M.A. An age-related spatial learning deficit: choline uptake distinguishes “impaired” and “unimpaired” rats. Neurobiol. Aging, 1988, 9(4), 363-369.
[http://dx.doi.org/10.1016/S0197-4580(88)80082-4] [PMID: 3185855]
[120]
Markowska, A.L.; Stone, W.S.; Ingram, D.K.; Reynolds, J.; Gold, P.E.; Conti, L.H.; Pontecorvo, M.J.; Wenk, G.L.; Olton, D.S. Individual differences in aging: behavioral and neurobiological correlates. Neurobiol. Aging, 1989, 10(1), 31-43.
[http://dx.doi.org/10.1016/S0197-4580(89)80008-9] [PMID: 2569170]
[121]
Matzel, L.D.; Grossman, H.; Light, K.; Townsend, D.; Kolata, S. Age-related declines in general cognitive abilities of Balb/C mice are associated with disparities in working memory, body weight, and general activity. Learn. Mem., 2008, 15(10), 733-746.
[http://dx.doi.org/10.1101/lm.954808] [PMID: 18832560]
[122]
McEwen, B.S. Allostasis, allostatic load, and the aging nervous system: role of excitatory amino acids and excitotoxicity. Neurochem. Res., 2000, 25(9-10), 1219-1231.
[http://dx.doi.org/10.1023/A:1007687911139] [PMID: 11059796]
[123]
Stewart, J.A. The detrimental effects of allostasis: allostatic load as a measure of cumulative stress. J. Physiol. Anthropol., 2006, 25(1), 133-145.
[http://dx.doi.org/10.2114/jpa2.25.133] [PMID: 16617218]
[124]
Banks, W.A. The blood-brain barrier in neuroimmunology: tales of separation and assimilation. Brain Behav. Immun., 2015, 44, 1-8.
[http://dx.doi.org/10.1016/j.bbi.2014.08.007] [PMID: 25172555]
[125]
Ellwardt, E.; Walsh, J.T.; Kipnis, J.; Zipp, F. Understanding the role of T cells in CNS homeostasis. Trends Immunol., 2016, 37(2), 154-165.
[http://dx.doi.org/10.1016/j.it.2015.12.008] [PMID: 26775912]
[126]
Maier, S.F.; Watkins, L.R. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol. Rev., 1998, 105(1), 83-107.
[http://dx.doi.org/10.1037/0033-295X.105.1.83] [PMID: 9450372]
[127]
Maier, S.F. Bi-directional immune-brain communication: Implications for understanding stress, pain, and cognition. Brain Behav. Immun., 2003, 17(2), 69-85.
[http://dx.doi.org/10.1016/S0889-1591(03)00032-1] [PMID: 12676570]
[128]
Turrin, N.P.; Gayle, D.; Ilyin, S.E.; Flynn, M.C.; Langhans, W.; Schwartz, G.J.; Plata-Salamán, C.R. Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide. Brain Res. Bull., 2001, 54(4), 443-453.
[http://dx.doi.org/10.1016/S0361-9230(01)00445-2] [PMID: 11306198]
[129]
Louveau, A.; Smirnov, I.; Keyes, T.J.; Eccles, J.D.; Rouhani, S.J.; Peske, J.D.; Derecki, N.C.; Castle, D.; Mandell, J.W.; Lee, K.S.; Harris, T.H.; Kipnis, J. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015, 523(7560), 337-341.
[http://dx.doi.org/10.1038/nature14432] [PMID: 26030524]
[130]
Raper, D.; Louveau, A.; Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci., 2016, 39(9), 581-586.
[http://dx.doi.org/10.1016/j.tins.2016.07.001] [PMID: 27460561]
[131]
Xia, S.; Zhang, X.; Zheng, S.; Khanabdali, R.; Kalionis, B.; Wu, J.; Wan, W.; Tai, X. An update on inflamm-aging: mechanisms, prevention, and treatment. J. Immunol. Res., 2016, •••, 20168426874.
[http://dx.doi.org/10.1155/2016/8426874] [PMID: 27493973]
[132]
Franceschi, C.; Bonafè, M.; Valensin, S.; Olivieri, F.; De Luca, M.; Ottaviani, E.; De Benedictis, G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci., 2000, 908, 244-254.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb06651.x] [PMID: 10911963]
[133]
Franceschi, C.; Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(Suppl. 1), S4-S9.
[http://dx.doi.org/10.1093/gerona/glu057] [PMID: 24833586]
[134]
Pawelec, G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun. Ageing, 2012, 9(1), 15.
[http://dx.doi.org/10.1186/1742-4933-9-15] [PMID: 22830639]
[135]
Fagiolo, U.; Cossarizza, A.; Scala, E.; Fanales-Belasio, E.; Ortolani, C.; Cozzi, E.; Monti, D.; Franceschi, C.; Paganelli, R. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol., 1993, 23(9), 2375-2378.
[http://dx.doi.org/10.1002/eji.1830230950] [PMID: 8370415]
[136]
Effros, R.B.; Dagarag, M.; Spaulding, C.; Man, J. The role of CD8+ T-cell replicative senescence in human aging. Immunol. Rev., 2005, 205, 147-157.
[http://dx.doi.org/10.1111/j.0105-2896.2005.00259.x] [PMID: 15882351]
[137]
Vescovini, R.; Biasini, C.; Fagnoni, F.F.; Telera, A.R.; Zanlari, L.; Pedrazzoni, M.; Bucci, L.; Monti, D.; Medici, M.C.; Chezzi, C.; Franceschi, C.; Sansoni, P. Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects. J. Immunol., 2007, 179(6), 4283-4291.
[http://dx.doi.org/10.4049/jimmunol.179.6.4283] [PMID: 17785869]
[138]
Baylis, D.; Bartlett, D.B.; Patel, H.P.; Roberts, H.C. Understanding how we age: insights into inflammaging. Longev. Healthspan, 2013, 2(1), 8.
[http://dx.doi.org/10.1186/2046-2395-2-8] [PMID: 24472098]
[139]
De Martinis, M.; Franceschi, C.; Monti, D.; Ginaldi, L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett., 2005, 579(10), 2035-2039.
[http://dx.doi.org/10.1016/j.febslet.2005.02.055] [PMID: 15811314]
[140]
Cannizzo, E.S.; Clement, C.C.; Sahu, R.; Follo, C.; Santambrogio, L. Oxidative stress, inflamm-aging and immunosenescence. J. Proteomics, 2011, 74(11), 2313-2323.
[http://dx.doi.org/10.1016/j.jprot.2011.06.005] [PMID: 21718814]
[141]
Kreutzberg, G.W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci., 1996, 19(8), 312-318.
[http://dx.doi.org/10.1016/0166-2236(96)10049-7] [PMID: 8843599]
[142]
Colton, C.A. Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune Pharmacol., 2009, 4(4), 399-418.
[http://dx.doi.org/10.1007/s11481-009-9164-4] [PMID: 19655259]
[143]
Parkhurst, C.N.; Yang, G.; Ninan, I.; Savas, J.N.; Yates, J.R., III; Lafaille, J.J.; Hempstead, B.L.; Littman, D.R.; Gan, W.B. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 2013, 155(7), 1596-1609.
[http://dx.doi.org/10.1016/j.cell.2013.11.030] [PMID: 24360280]
[144]
Flanary, B.E.; Streit, W.J. Telomeres shorten with age in rat cerebellum and cortex in vivo. J. Anti Aging Med., 2003, 6(4), 299-308.
[http://dx.doi.org/10.1089/109454503323028894] [PMID: 15142431]
[145]
Flanary, B.E.; Sammons, N.W.; Nguyen, C.; Walker, D.; Streit, W.J. Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res., 2007, 10(1), 61-74.
[http://dx.doi.org/10.1089/rej.2006.9096] [PMID: 17378753]
[146]
Hefendehl, J.K.; Neher, J.J.; Sühs, R.B.; Kohsaka, S.; Skodras, A.; Jucker, M. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell, 2014, 13(1), 60-69.
[http://dx.doi.org/10.1111/acel.12149] [PMID: 23953759]
[147]
Sierra, A.; Gottfried-Blackmore, A.C.; McEwen, B.S.; Bulloch, K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia, 2007, 55(4), 412-424.
[http://dx.doi.org/10.1002/glia.20468] [PMID: 17203473]
[148]
Tremblay, M.E.; Zettel, M.L.; Ison, J.R.; Allen, P.D.; Majewska, A.K. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia, 2012, 60(4), 541-558.
[http://dx.doi.org/10.1002/glia.22287] [PMID: 22223464]
[149]
Sheng, J.G.; Mrak, R.E.; Griffin, W.S. Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain. Acta Neuropathol., 1998, 95(3), 229-234.
[http://dx.doi.org/10.1007/s004010050792] [PMID: 9542587]
[150]
Henry, C.J.; Huang, Y.; Wynne, A.M.; Godbout, J.P. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav. Immun., 2009, 23(3), 309-317.
[http://dx.doi.org/10.1016/j.bbi.2008.09.002] [PMID: 18814846]
[151]
Koellhoffer, E.C.; McCullough, L.D.; Ritzel, R.M. Old maids: aging and its impact on microglia function. Int. J. Mol. Sci., 2017, 18(4), E769.
[http://dx.doi.org/10.3390/ijms18040769] [PMID: 28379162]
[152]
Bisht, K.; Sharma, K.P.; Lecours, C.; Sánchez, M.G.; El Hajj, H.; Milior, G.; Olmos-Alonso, A.; Gómez-Nicola, D.; Luheshi, G.; Vallières, L.; Branchi, I.; Maggi, L.; Limatola, C.; Butovsky, O.; Tremblay, M.E. Dark microglia: a new phenotype predominantly associated with pathological states. Glia, 2016, 64(5), 826-839.
[http://dx.doi.org/10.1002/glia.22966] [PMID: 26847266]
[153]
Schönthal, A.H. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica (Cairo), 2012, •••, 2012857516.
[http://dx.doi.org/10.6064/2012/857516] [PMID: 24278747]
[154]
Boyd-Kirkup, J.D.; Green, C.D.; Wu, G.; Wang, D.; Han, J.D. Epigenomics and the regulation of aging. Epigenomics, 2013, 5(2), 205-227.
[http://dx.doi.org/10.2217/epi.13.5] [PMID: 23566097]
[155]
Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol., 2013, 14(10), R115.
[http://dx.doi.org/10.1186/gb-2013-14-10-r115] [PMID: 24138928]
[156]
Horvath, S.; Zhang, Y.; Langfelder, P.; Kahn, R.S.; Boks, M.P.; van Eijk, K.; van den Berg, L.H.; Ophoff, R.A. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol., 2012, 13(10), R97.
[http://dx.doi.org/10.1186/gb-2012-13-10-r97] [PMID: 23034122]
[157]
Florath, I.; Butterbach, K.; Müller, H.; Bewerunge-Hudler, M.; Brenner, H. Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Hum. Mol. Genet., 2014, 23(5), 1186-1201.
[http://dx.doi.org/10.1093/hmg/ddt531] [PMID: 24163245]
[158]
Heyn, H.; Li, N.; Ferreira, H.J.; Moran, S.; Pisano, D.G.; Gomez, A.; Diez, J.; Sanchez-Mut, J.V.; Setien, F.; Carmona, F.J.; Puca, A.A.; Sayols, S.; Pujana, M.A.; Serra-Musach, J.; Iglesias-Platas, I.; Formiga, F.; Fernandez, A.F.; Fraga, M.F.; Heath, S.C.; Valencia, A.; Gut, I.G.; Wang, J.; Esteller, M. Distinct DNA methylomes of newborns and centenarians. Proc. Natl. Acad. Sci. USA, 2012, 109(26), 10522-10527.
[http://dx.doi.org/10.1073/pnas.1120658109] [PMID: 22689993]
[159]
Issa, J.P.; Ottaviano, Y.L.; Celano, P.; Hamilton, S.R.; Davidson, N.E.; Baylin, S.B. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat. Genet., 1994, 7(4), 536-540.
[http://dx.doi.org/10.1038/ng0894-536] [PMID: 7951326]
[160]
Choi, E.K.; Uyeno, S.; Nishida, N.; Okumoto, T.; Fujimura, S.; Aoki, Y.; Nata, M.; Sagisaka, K.; Fukuda, Y.; Nakao, K.; Yoshimoto, T.; Kim, Y.S.; Ono, T. Alterations of c-fos gene methylation in the processes of aging and tumorigenesis in human liver. Mutat. Res., 1996, 354(1), 123-128.
[http://dx.doi.org/10.1016/0027-5107(96)00056-5] [PMID: 8692198]
[161]
Casillas, M.A., Jr; Lopatina, N.; Andrews, L.G.; Tollefsbol, T.O. Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol. Cell. Biochem., 2003, 252(1-2), 33-43.
[http://dx.doi.org/10.1023/A:1025548623524] [PMID: 14577574]
[162]
Zhang, Z.; Deng, C.; Lu, Q.; Richardson, B. Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter. Mech. Ageing Dev., 2002, 123(9), 1257-1268.
[http://dx.doi.org/10.1016/S0047-6374(02)00014-3] [PMID: 12020947]
[163]
Li, Y.; Liu, Y.; Strickland, F.M.; Richardson, B. Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp. Gerontol., 2010, 45(4), 312-322.
[http://dx.doi.org/10.1016/j.exger.2009.12.008] [PMID: 20035856]
[164]
Calvanese, V.; Lara, E.; Kahn, A.; Fraga, M.F. The role of epigenetics in aging and age-related diseases. Ageing Res. Rev., 2009, 8(4), 268-276.
[http://dx.doi.org/10.1016/j.arr.2009.03.004] [PMID: 19716530]
[165]
McQuown, S.C.; Barrett, R.M.; Matheos, D.P.; Post, R.J.; Rogge, G.A.; Alenghat, T.; Mullican, S.E.; Jones, S.; Rusche, J.R.; Lazar, M.A.; Wood, M.A. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci., 2011, 31(2), 764-774.
[http://dx.doi.org/10.1523/JNEUROSCI.5052-10.2011] [PMID: 21228185]
[166]
Russell, S.J.; Kahn, C.R. Endocrine regulation of ageing. Nat. Rev. Mol. Cell Biol., 2007, 8(9), 681-691.
[http://dx.doi.org/10.1038/nrm2234] [PMID: 17684529]
[167]
Mostoslavsky, R.; Chua, K.F.; Lombard, D.B.; Pang, W.W.; Fischer, M.R.; Gellon, L.; Liu, P.; Mostoslavsky, G.; Franco, S.; Murphy, M.M.; Mills, K.D.; Patel, P.; Hsu, J.T.; Hong, A.L.; Ford, E.; Cheng, H.L.; Kennedy, C.; Nunez, N.; Bronson, R.; Frendewey, D.; Auerbach, W.; Valenzuela, D.; Karow, M.; Hottiger, M.O.; Hursting, S.; Barrett, J.C.; Guarente, L.; Mulligan, R.; Demple, B.; Yancopoulos, G.D.; Alt, F.W. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 2006, 124(2), 315-329.
[http://dx.doi.org/10.1016/j.cell.2005.11.044] [PMID: 16439206]
[168]
McClay, J.L.; Aberg, K.A.; Clark, S.L.; Nerella, S.; Kumar, G.; Xie, L.Y.; Hudson, A.D.; Harada, A.; Hultman, C.M.; Magnusson, P.K.; Sullivan, P.F.; Van Den Oord, E.J. A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects. Hum. Mol. Genet., 2014, 23(5), 1175-1185.
[http://dx.doi.org/10.1093/hmg/ddt511] [PMID: 24135035]
[169]
Luoni, A.; Berry, A.; Calabrese, F.; Capoccia, S.; Bellisario, V.; Gass, P.; Cirulli, F.; Riva, M.A. Delayed BDNF alterations in the prefrontal cortex of rats exposed to prenatal stress: preventive effect of lurasidone treatment during adolescence. Eur. Neuropsychopharmacol., 2014, 24(6), 986-995.
[http://dx.doi.org/10.1016/j.euroneuro.2013.12.010] [PMID: 24440552]
[170]
Luoni, A.; Macchi, F.; Papp, M.; Molteni, R.; Riva, M.A. Lurasidone exerts antidepressant properties in the chronic mild stress model through the regulation of synaptic and neuroplastic mechanisms in the rat prefrontal cortex. Int. J. Neuropsychopharmacol., 2014, 18(4), pyu061.
[http://dx.doi.org/10.1093/ijnp/pyu061] [PMID: 25522402]
[171]
Roceri, M.; Cirulli, F.; Pessina, C.; Peretto, P.; Racagni, G.; Riva, M.A. Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions. Biol. Psychiatry, 2004, 55(7), 708-714.
[http://dx.doi.org/10.1016/j.biopsych.2003.12.011] [PMID: 15038999]
[172]
Roceri, M.; Hendriks, W.; Racagni, G.; Ellenbroek, B.A.; Riva, M.A. Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol. Psychiatry, 2002, 7(6), 609-616.
[http://dx.doi.org/10.1038/sj.mp.4001036] [PMID: 12140784]
[173]
Taliaz, D.; Loya, A.; Gersner, R.; Haramati, S.; Chen, A.; Zangen, A. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J. Neurosci., 2011, 31(12), 4475-4483.
[http://dx.doi.org/10.1523/JNEUROSCI.5725-10.2011] [PMID: 21430148]
[174]
Pardon, M.C. Stress and ageing interactions: a paradox in the context of shared etiological and physiopathological processes. Brain Res. Brain Res. Rev., 2007, 54(2), 251-273.
[http://dx.doi.org/10.1016/j.brainresrev.2007.02.007] [PMID: 17408561]
[175]
Gaffey, A.E.; Bergeman, C.S.; Clark, L.A.; Wirth, M.M. Aging and the HPA axis: Stress and resilience in older adults. Neurosci. Biobehav. Rev., 2016, 68, 928-945.
[http://dx.doi.org/10.1016/j.neubiorev.2016.05.036] [PMID: 27377692]
[176]
Van Cauter, E.; Leproult, R.; Kupfer, D.J. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J. Clin. Endocrinol. Metab., 1996, 81(7), 2468-2473.
[PMID: 8675562]
[177]
Seeman, T.E.; Robbins, R.J. Aging and hypothalamic-pituitary-adrenal response to challenge in humans. Endocr. Rev., 1994, 15(2), 233-260.
[PMID: 8026389]
[178]
Wilkinson, C.W.; Peskind, E.R.; Raskind, M.A. Decreased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology, 1997, 65(1), 79-90.
[http://dx.doi.org/10.1159/000127167] [PMID: 9032777]
[179]
Hildon, Z.; Smith, G.; Netuveli, G.; Blane, D. Understanding adversity and resilience at older ages. Sociol. Health Illn., 2008, 30(5), 726-740.
[http://dx.doi.org/10.1111/j.1467-9566.2008.01087.x] [PMID: 18444953]
[180]
Lupien, S.J.; Fiocco, A.; Wan, N.; Maheu, F.; Lord, C.; Schramek, T.; Tu, M.T. Stress hormones and human memory function across the lifespan. Psychoneuroendocrinology, 2005, 30(3), 225-242.
[http://dx.doi.org/10.1016/j.psyneuen.2004.08.003] [PMID: 15511597]
[181]
Meaney, M.J.; O’Donnell, D.; Rowe, W.; Tannenbaum, B.; Steverman, A.; Walker, M.; Nair, N.P.; Lupien, S. Individual differences in hypothalamic-pituitary-adrenal activity in later life and hippocampal aging. Exp. Gerontol., 1995, 30(3-4), 229-251.
[http://dx.doi.org/10.1016/0531-5565(94)00065-B] [PMID: 7556505]
[182]
Pardon, M.C.; Rattray, I. What do we know about the long-term consequences of stress on ageing and the progression of age-related neurodegenerative disorders? Neurosci. Biobehav. Rev., 2008, 32(6), 1103-1120.
[http://dx.doi.org/10.1016/j.neubiorev.2008.03.005] [PMID: 18436304]
[183]
Pedersen, W.A.; Wan, R.; Mattson, M.P. Impact of aging on stress-responsive neuroendocrine systems. Mech. Ageing Dev., 2001, 122(9), 963-983.
[http://dx.doi.org/10.1016/S0047-6374(01)00250-0] [PMID: 11348661]
[184]
Fraga, M.F.; Ballestar, E.; Paz, M.F.; Ropero, S.; Setien, F.; Ballestar, M.L.; Heine-Suñer, D.; Cigudosa, J.C.; Urioste, M.; Benitez, J.; Boix-Chornet, M.; Sanchez-Aguilera, A.; Ling, C.; Carlsson, E.; Poulsen, P.; Vaag, A.; Stephan, Z.; Spector, T.D.; Wu, Y.Z.; Plass, C.; Esteller, M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA, 2005, 102(30), 10604-10609.
[http://dx.doi.org/10.1073/pnas.0500398102] [PMID: 16009939]
[185]
Grönniger, E.; Weber, B.; Heil, O.; Peters, N.; Stäb, F.; Wenck, H.; Korn, B.; Winnefeld, M.; Lyko, F. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genet., 2010, 6(5), e1000971.
[http://dx.doi.org/10.1371/journal.pgen.1000971] [PMID: 20523906]
[186]
Hannum, G.; Guinney, J.; Zhao, L.; Zhang, L.; Hughes, G.; Sadda, S.; Klotzle, B.; Bibikova, M.; Fan, J.B.; Gao, Y.; Deconde, R.; Chen, M.; Rajapakse, I.; Friend, S.; Ideker, T.; Zhang, K. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell, 2013, 49(2), 359-367.
[http://dx.doi.org/10.1016/j.molcel.2012.10.016] [PMID: 23177740]
[187]
Zannas, A.S.; Arloth, J.; Carrillo-Roa, T.; Iurato, S.; Röh, S.; Ressler, K.J.; Nemeroff, C.B.; Smith, A.K.; Bradley, B.; Heim, C.; Menke, A.; Lange, J.F.; Brückl, T.; Ising, M.; Wray, N.R.; Erhardt, A.; Binder, E.B.; Mehta, D. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol., 2015, 16, 266.
[http://dx.doi.org/10.1186/s13059-015-0828-5] [PMID: 26673150]
[188]
Zannas, A.S.; Chrousos, G.P. Epigenetic programming by stress and glucocorticoids along the human lifespan. Mol. Psychiatry, 2017, 22(5), 640-646.
[http://dx.doi.org/10.1038/mp.2017.35] [PMID: 28289275]
[189]
Calcia, M.A.; Bonsall, D.R.; Bloomfield, P.S.; Selvaraj, S.; Barichello, T.; Howes, O.D. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl.), 2016, 233(9), 1637-1650.
[http://dx.doi.org/10.1007/s00213-016-4218-9] [PMID: 26847047]
[190]
Liu, Y.Z.; Wang, Y.X.; Jiang, C.L. Inflammation: the common pathway of stress-related diseases. Front. Hum. Neurosci., 2017, 11, 316.
[http://dx.doi.org/10.3389/fnhum.2017.00316] [PMID: 28676747]
[191]
Godbout, J.P.; Chen, J.; Abraham, J.; Richwine, A.F.; Berg, B.M.; Kelley, K.W.; Johnson, R.W. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J., 2005, 19(10), 1329-1331.
[http://dx.doi.org/10.1096/fj.05-3776fje] [PMID: 15919760]
[192]
Barrientos, R.M.; Watkins, L.R.; Rudy, J.W.; Maier, S.F. Characterization of the sickness response in young and aging rats following E. coli infection. Brain Behav. Immun., 2009, 23(4), 450-454.
[http://dx.doi.org/10.1016/j.bbi.2009.01.016] [PMID: 19486645]
[193]
Frank, M.G.; Barrientos, R.M.; Watkins, L.R.; Maier, S.F. Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo. J. Neuroimmunol., 2010, 226(1-2), 181-184.
[http://dx.doi.org/10.1016/j.jneuroim.2010.05.022] [PMID: 20537730]
[194]
Norden, D. M.; Muccigrosso, M. M.; Godbout, J. P. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacol,, 2015, 96(Pt A), 29-41.
[http://dx.doi.org/10.1016/j.neuropharm.2014.10.028]


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VOLUME: 26
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