Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation–induced impairment of neurovascular coupling responses protecting cognitive function in mice
Tóm tắt
Từ khóa
Tài liệu tham khảo
Abdul-Aziz AM, Sun Y, Hellmich C, Marlein CR, Mistry J, Forde E, Piddock RE, Shafat MS, Morfakis A, Mehta T, Di Palma F, Macaulay I, Ingham CJ, Haestier A, Collins A, Campisi J, Bowles KM, Rushworth SA (2019) Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Blood 133:446–456
Ashpole NM, Warrington JP, Mitschelen MC, Yan H, Sosnowska D, Gautam T, Farley JA, Csiszar A, Ungvari Z, Sonntag WE (2014) Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells. Am J Physiol Heart Circ Physiol 307:H858–H868
Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA (2010) Glial and neuronal control of brain blood flow. Nature. 468:232–243
Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, IWF v, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, JHJ H, Campisi J, de Keizer PLJ (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169:132–147 e16
Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189
Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C (2012) Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 7:e45069
Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562:578–582
Campisi J (2016) Cellular senescence and lung function during aging. Yin and Yang. Ann Am Thorac Soc 13:S402–S406
Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22:78–83
Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 354:472–477
Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK (2015) Cellular senescence and the aging brain. Exp Gerontol 68:3–7. https://doi.org/10.1016/j.exger.2014.09.018
Chinta SJ, Woods G, Demaria M, Rane A, Zou Y, McQuade A, Rajagopalan S, Limbad C, Madden DT, Campisi J, Andersen JK (2018) Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep 22:930–940
Coppe JP, Rodier F, Patil CK, Freund A, Desprez PY, Campisi J (2011) Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 286:36396–36403
Csipo T, Mukli P, Lipecz A, Tarantini S, Bahadli D, Abdulhussein O, Owens C, Kiss T, Balasubramanian P, Nyul-Toth A, Hand RA, Yabluchanska V, Sorond FA, Csiszar A, Ungvari Z, Yabluchanskiy A (2019a) Assessment of age-related decline of neurovascular coupling responses by functional near-infrared spectroscopy (fNIRS) in humans. Geroscience. 41:495–509
Csipo T, Lipecz A, Ashpole NM, Balasubramanian P, Tarantini S (2019) Astrocyte senescence contributes to cognitive decline. Geroscience. https://doi.org/10.1007/s11357-019-00140-9
Csiszar A, Tarantini S, Fulop GA, Kiss T, Valcarcel-Ares MN, Galvan V, Ungvari Z, Yabluchanskiy A (2017) Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. Geroscience 39(4):359–372. https://doi.org/10.1007/s11357-017-9991-9
Csiszar A, Yabluchanskiy A, Ungvari A, Ungvari Z, Tarantini S (2019) Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice. Geroscience. 41:609–617
Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dolle ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722–733
Demaria M, O'Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J (2017) Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov 7:165–176
Dunn KM, Hill-Eubanks DC, Liedtke WB, Nelson MT (2013) TRPV4 channels stimulate Ca2+−induced Ca2+ release in astrocytic endfeet and amplify neurovascular coupling responses. Proc Natl Acad Sci U S A 110:6157–6162
Farias Quipildor GE, Mao K, Hu Z, Novaj A, Cui MH, Gulinello M, Branch CA, Gubbi S, Patel K, Moellering DR, Tarantini S, Kiss T, Yabluchanskiy A, Ungvari Z, Sonntag WE, Huffman DM (2019) Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. Geroscience. 41:185–208
Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, Negley BA, Sfeir JG, Ogrodnik MB, Hachfeld CM, LeBrasseur NK, Drake MT, Pignolo RJ, Pirtskhalava T, Tchkonia T, Oursler MJ, Kirkland JL, Khosla S (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23:1072–1079
Febo M, Foster TC (2016) Preclinical magnetic resonance imaging and spectroscopy studies of memory, aging, and cognitive decline. Front Aging Neurosci 8:158
Filosa JA, Iddings JA (2013) Astrocyte regulation of cerebral vascular tone. Am J Physiol Heart Circ Physiol 305:H609–H619
Freund A, Orjalo AV, Desprez PY, Campisi J (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 16:238–246
Fulop GA, Kiss T, Tarantini S, Balasubramanian P, Yabluchanskiy A, Farkas E, Bari F, Ungvari Z, Csiszar A (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience. 40:513–521
Garcia V, Cheng J, Weidenhammer A, Ding Y, Wu CC, Zhang F, Gotlinger K, Falck JR, Schwartzman ML (2015) Androgen-induced hypertension in angiotensinogen deficient mice: role of 20-HETE and EETS. Prostaglandins Other Lipid Mediat 116–117:124–130
Gaspar LE, Mehta MP, Patchell RA, Burri SH, Robinson PD, Morris RE, Ammirati M, Andrews DW, Asher AL, Cobbs CS, Kondziolka D, Linskey ME, Loeffler JS, McDermott M, Mikkelsen T, Olson JJ, Paleologos NA, Ryken TC, Kalkanis SN (2010) The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neuro-Oncol 96:17–32
Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol (1985) 100:328–335
Girouard H, Bonev AD, Hannah RM, Meredith A, Aldrich RW, Nelson MT (2010) Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. Proc Natl Acad Sci U S A 107:3811–3816
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713
Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775–781
Jungblut M, Tiveron MC, Barral S, Abrahamsen B, Knobel S, Pennartz S, Schmitz J, Perraut M, Pfrieger FW, Stoffel W, Cremer H, Bosio A (2012) Isolation and characterization of living primary astroglial cells using the new GLAST-specific monoclonal antibody ACSA-1. Glia 60:894–907
Justice JN, Gregory H, Tchkonia T, LeBrasseur NK, Kirkland JL, Kritchevsky SB, Nicklas BJ (2018) Cellular senescence biomarker p16INK4a+ cell burden in thigh adipose is associated with poor physical function in older women. J Gerontol A Biol Sci Med Sci 73:939–945
Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C (2004) Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95:1019–1026
Keller D, Ero C, Markram H (2018) Cell densities in the mouse brain: a systematic review. Front Neuroanat 12:83
Khuntia D, Brown P, Li J, Mehta MP (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24:1295–1304
Kim HN, Chang J, Iyer S, Han L, Campisi J, Manolagas SC, Zhou D, Almeida M (2019) Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice. Aging Cell 18:e12923
Lamproglou I, Martin S, Diserbo M, Multon E, Petiet A, Colas-Linhart N, Bok B, Martin C (2001) Total body 4.5 Gy gamma irradiation-induced early delayed learning and memory dysfunction in the rat. Cell Mol Biol (Noisy-le-grand) 47:453–457
Lee YW, Cho HJ, Lee WH, Sonntag WE (2012) Whole brain radiation-induced cognitive impairment: pathophysiological mechanisms and therapeutic targets. Biomol Ther (Seoul) 20:357–370
Lipecz A, Csipo T, Tarantini S, Hand RA, Ngo BN, Conley S, Nemeth G, Tsorbatzoglou A, Courtney DL, Yabluchanska V, Csiszar A, Ungvari ZI, Yabluchanskiy A (2019) Age-related impairment of neurovascular coupling responses: a dynamic vessel analysis (DVA)-based approach to measure decreased flicker light stimulus-induced retinal arteriolar dilation in healthy older adults. Geroscience 41(3):341–349. https://doi.org/10.1007/s11357-019-00078-y
Lye JJ, Latorre E, Lee BP, Bandinelli S, Holley JE, Gutowski NJ, Ferrucci L, Harries LW (2019) Astrocyte senescence may drive alterations in GFAPalpha, CDKN2A p14(ARF), and TAU3 transcript expression and contribute to cognitive decline. Geroscience 41:561–573
Mehina EMF, Murphy-Royal C, Gordon GR (2017) Steady-state free Ca(2+) in astrocytes is decreased by experience and impacts arteriole tone. J Neurosci 37:8150–8165
Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Kruger P, Fielder E, Victorelli S, Ruswhandi RA, Giorgadze N, Pirtskhalava T, Podgorni O, Enikolopov G, Johnson KO, Xu M, Inman C, Schafer M, Weigl M, Ikeno Y, Burns TC, Passos JF, von Zglinicki T, Kirkland JL, Jurk D (2019) Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab 29(5):1233. https://doi.org/10.1016/j.cmet.2019.01.013
Oomen CA, Farkas E, Roman V, van der Beek EM, Luiten PG, Meerlo P (2009) Resveratrol preserves cerebrovascular density and cognitive function in aging mice. Front Aging Neurosci 1:4
Patil CG, Pricola K, Sarmiento JM, Garg SK, Bryant A, Black KL (2012) Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev 9:CD006121
Patil P, Dong Q, Wang D, Chang J, Wiley C, Demaria M, Lee J, Kang J, Niedernhofer LJ, Robbins PD, Sowa G, Campisi J, Zhou D, Vo N (2019) Systemic clearance of p16(INK4a) -positive senescent cells mitigates age-associated intervertebral disc degeneration. Aging Cell 18:e12927
Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979
Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15:973–977
Rosenegger DG, Gordon GR (2015) A slow or modulatory role of astrocytes in neurovascular coupling. Microcirculation 22:197–203
Sato K, Chino D, Nishioka N, Kanai K, Aoki M, Obara K, Miyauchi S, Tanaka Y (2014) Pharmacological evidence showing significant roles for potassium channels and CYP epoxygenase metabolites in the relaxant effects of docosahexaenoic acid on the rat aorta contracted with U46619. Biol Pharm Bull 37:394–403
Shi L, Adams MM, Long A, Carter CC, Bennett C, Sonntag WE, Nicolle MM, Robbins M, D'Agostino R, Brunso-Bechtold JK (2006) Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat Res 166:892–899
Sorond FA, Kiely DK, Galica A, Moscufo N, Serrador JM, Iloputaife I, Egorova S, Dell’Oglio E, Meier DS, Newton E, Milberg WP, Guttmann CR, Lipsitz LA (2011) Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston study. Ann Neurol 70:213–220
Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND (2013) Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology 81(10):904–909. https://doi.org/10.1212/WNL.0b013e3182a351aa
Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY (2009) CNS complications of radiotherapy and chemotherapy. Lancet. 374:1639–1651
Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges E, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P (2015) Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35(11):1871–1881. https://doi.org/10.1038/jcbfm.2015.162
Tarantini S, Tran CH, Gordon GR, Ungvari Z, Csiszar A (2016) Impaired neurovascular coupling in aging and Alzheimer's disease: Contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol. https://doi.org/10.1016/j.exger.2016.11.004
Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017a) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58. https://doi.org/10.1016/j.exger.2016.11.004
Tarantini S, Yabluchanksiy A, Fulop GA, Hertelendy P, Valcarcel-Ares MN, Kiss T, Bagwell JM, O'Connor D, Farkas E, Sorond F, Csiszar A, Ungvari Z (2017b) Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. GeroScience 39(5–6):601–614. https://doi.org/10.1007/s11357-017-0003-x
Tarantini S, Fulop GA, Kiss T, Farkas E, Zolei-Szenasi D, Galvan V, Toth P, Csiszar A, Ungvari Z, Yabluchanskiy A (2017c) Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging. Geroscience 39(4):465–473. https://doi.org/10.1007/s11357-017-9980-z
Tarantini S, Valcarcel-Ares MN, Yabluchanskiy A, Tucsek Z, Hertelendy P, Kiss T, Gautam T, Zhang XA, Sonntag WE, de Cabo R, Farkas E, Elliott ME, Kinter MT, Deak F, Ungvari Z, Csiszar A 2018a) Nrf2 deficiency exacerbates obesity-induced oxidative stress, neurovascular dysfunction, blood brain barrier disruption, neuroinflammation, amyloidogenic gene expression and cognitive decline in mice, mimicking the aging phenotype. J Gerontol A Biol Sci Med Sci. in press
Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Fulop GA, Hertelendy P, Gautam T, Farkas E, Perz A, Rabinovitch PS, Sonntag WE, Csiszar A, Ungvari Z (2018b) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell 17
Tarantini S, Yabluchanskiy A, Csipo T, Fulop G, Kiss T, Balasubramanian P, DelFavero J, Ahire C, Ungvari A, Nyul-Toth A, Farkas E, Benyo Z, Toth A, Csiszar A, Ungvari Z (2019a) Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging. Geroscience. 41:533–542
Tarantini S, Valcarcel-Ares MN, Toth P, Yabluchanskiy A, Tucsek Z, Kiss T, Hertelendy P, Kinter M, Ballabh P, Sule Z, Farkas E, Baur JA, Sinclair DA, Csiszar A, Ungvari Z (2019b) Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol 24:101192
Tchkonia T, Kirkland JL (2018) Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA 320:1319–1320
Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972
Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari ZI (2014) Resveratrol treatment rescues neurovascular coupling in aged mice:role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidas. Am J Physiol Heart Circ Physiol 306:H299–H308
Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015a) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14:1034–1044
Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z (2015b) Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 309:H1837–H1845
Toth P, Szarka N, Farkas E, Ezer E, Czeiter E, Amrein K, Ungvari Z, Hartings JA, Buki A, Koller A (2016) Traumatic brain injury-induced autoregulatory dysfunction and spreading depression-related neurovascular uncoupling: Pathomechanisms, perspectives, and therapeutic implications. Am J Physiol Heart Circ Physiol 311:H1118–H1131
Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312:H1–H20
Tran CH, Gordon GR (2015) Astrocyte and microvascular imaging in awake animals using two-photon microscopy. Microcirculation 22:219–227
Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352
Tucsek Z, Noa Valcarcel-Ares M, Tarantini S, Yabluchanskiy A, Fulop G, Gautam T, Orock A, Csiszar A, Deak F, Ungvari Z (2017) Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. Geroscience 39(4):385–406. https://doi.org/10.1007/s11357-017-9981-y
Turnquist C, Beck JA, Horikawa I, Obiorah IE, Von Muhlinen N, Vojtesek B, Lane DP, Grunseich C, Chahine JJ, Ames HM, Smart DD, Harris BT, Harris CC (2019) Radiation-induced astrocyte senescence is rescued by Delta133p53. Neuro-Oncology 21:474–485
Ulu A, Harris TR, Morisseau C, Miyabe C, Inoue H, Schuster G, Dong H, Iosif AM, Liu JY, Weiss RH, Chiamvimonvat N, Imig JD, Hammock BD (2013) Anti-inflammatory effects of omega-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. J Cardiovasc Pharmacol 62:285–297
Ungvari Z, Podlutsky A, Sosnowska D, Tucsek Z, Toth P, Deak F, Gautam T, Csiszar A, Sonntag WE (2013) Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J Gerontol A Biol Sci Med Sci 68:1443–1457
Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fulop GA, Logan S, Kiss T, Farkas E, Csiszar A, Yabluchanskiy A (2017) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience. 39:33–42
Valcarcel-Ares MN, Tucsek Z, Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, Balasubramanian P, Gautam T, Galvan V, Ballabh P, Richardson A, Freeman WM, Wren JD, Deak F, Ungvari Z, Csiszar A (2019) Obesity in aging exacerbates neuroinflammation, dysregulating synaptic function-related genes and altering eicosanoid synthesis in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline. J Gerontol A Biol Sci Med Sci 74(3):290–298. https://doi.org/10.1093/gerona/gly127
Wang RX, Chai Q, Lu T, Lee HC (2011) Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity. Cardiovasc Res 90:344–352
Wang Y, Armando AM, Quehenberger O, Yan C, Dennis EA (2014) Comprehensive ultra-performance liquid chromatographic separation and mass spectrometric analysis of eicosanoid metabolites in human samples. J Chromatogr A 1359:60–69
Warrington JP, Csiszar A, Johnson DA, Herman TS, Ahmad S, Lee YW, Sonntag WE (2011) Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice. Am J Physiol Heart Circ Physiol 300:H736–H744
Warrington JP, Csiszar A, Mitschelen M, Lee YW, Sonntag WE (2012) Whole brain radiation-induced impairments in learning and memory are time-sensitive and reversible by systemic hypoxia. PLoS One 7:e30444
Warrington JP, Ashpole N, Csiszar A, Lee YW, Ungvari Z, Sonntag WE (2013) Whole brain radiation-induced vascular cognitive impairment: mechanisms and implications. J Vasc Res 50:445–457
Welzel G, Fleckenstein K, Mai SK, Hermann B, Kraus-Tiefenbacher U, Wenz F (2008a) Acute neurocognitive impairment during cranial radiation therapy in patients with intracranial tumors. Strahlenther Onkol 184:647–654
Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenbacher U, Mai SK, Wenz F (2008b) Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys 72:1311–1318
Wiedenhoeft T, Tarantini S, Nyul-Toth A, Yabluchanskiy A, Csipo T, Balasubramanian P, Lipecz A, Kiss T, Csiszar A, Csiszar A, Ungvari Z (2019) Fusogenic liposomes effectively deliver resveratrol to the cerebral microcirculation and improve endothelium-dependent neurovascular coupling responses in aged mice. Geroscience. 41:711–725
Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL (2015) Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4:e12997. https://doi.org/10.7554/eLife.12997
Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL, Johnson KO, Verzosa GC, Langhi LGP, Weigl M, Giorgadze N, LeBrasseur NK, Miller JD, Jurk D, Singh RJ, Allison DB, Ejima K, Hubbard GB, Ikeno Y, Cubro H, Garovic VD, Hou X, Weroha SJ, Robbins PD, Niedernhofer LJ, Khosla S, Tchkonia T, Kirkland JL (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246–1256
Zhang G, Panigrahy D, Mahakian LM, Yang J, Liu JY, Stephen Lee KS, Wettersten HI, Ulu A, Hu X, Tam S, Hwang SH, Ingham ES, Kieran MW, Weiss RH, Ferrara KW, Hammock BD (2013) Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci U S A 110:6530–6535
Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL (2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15:428–435