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Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation–induced impairment of neurovascular coupling responses protecting cognitive function in mice

  • ORIGINAL ARTICLE/Understanding Senescence in Brain Aging and Alzheimer’s Disease
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Abstract

Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~ 50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI-treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte-dependent NVC responses (whisker-stimulation-induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC-related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post-irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI-induced senescence and NVC dysfunction, senescent cells were depleted from WBI-treated animals (at 3 months post-WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL-2/BCL-xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI-treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses, and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.

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References

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705

    CAS  PubMed  Google Scholar 

  • Campisi J (2016) Cellular senescence and lung function during aging. Yin and Yang. Ann Am Thorac Soc 13:S402–S406

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen J, Torres C (2019) Astrocyte senescence: evidence and significance. Aging Cell 18:e12937

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Febo M, Foster TC (2016) Preclinical magnetic resonance imaging and spectroscopy studies of memory, aging, and cognitive decline. Front Aging Neurosci 8:158

    PubMed  PubMed Central  Google Scholar 

  • Filosa JA, Iddings JA (2013) Astrocyte regulation of cerebral vascular tone. Am J Physiol Heart Circ Physiol 305:H609–H619

    CAS  PubMed  PubMed Central  Google Scholar 

  • Freund A, Orjalo AV, Desprez PY, Campisi J (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 16:238–246

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Keller D, Ero C, Markram H (2018) Cell densities in the mouse brain: a systematic review. Front Neuroanat 12:83

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khuntia D, Brown P, Li J, Mehta MP (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24:1295–1304

    CAS  PubMed  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenegger DG, Gordon GR (2015) A slow or modulatory role of astrocytes in neurovascular coupling. Microcirculation 22:197–203

    PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tchkonia T, Kirkland JL (2018) Aging, cell senescence, and chronic disease: emerging therapeutic strategies. JAMA 320:1319–1320

    PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Tran CH, Gordon GR (2015) Astrocyte and microvascular imaging in awake animals using two-photon microscopy. Microcirculation 22:219–227

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors express their gratitude to Signe Dahlberg-Wright (University of California) for the expert help with the eicosanoid measurements and for Unity Biotechnology, Inc. for providing the p163MR mice model.

Funding

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (R01-NS056218 to AC, R01-NS100782 to ZU), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to AY), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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Author notes

  1. Andriy Yabluchanskiy, Stefano Tarantini and Priya Balasubramanian contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK, 731042, USA

    Andriy Yabluchanskiy, Stefano Tarantini, Priya Balasubramanian, Tamas Kiss, Tamas Csipo, Gábor A. Fülöp, Agnes Lipecz, Chetan Ahire, Jordan DelFavero, Adam Nyul-Toth, William E. Sonntag, Anna Csiszar & Zoltan Ungvari

  2. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Andriy Yabluchanskiy, Stefano Tarantini, Tamas Csipo, Agnes Lipecz, Adam Nyul-Toth & Zoltan Ungvari

  3. International Training Program in Geroscience, Theoretical Medicine Doctoral School/Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Tamas Kiss & Zoltan Ungvari

  4. International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology/ Kalman Laki Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tamas Csipo & Gábor A. Fülöp

  5. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Gábor A. Fülöp

  6. Institute of Biophysics, Biological Research Centre, Szeged, Hungary

    Adam Nyul-Toth

  7. Department of Pharmacology, New York Medical College School of Medicine, Valhalla, NY, USA

    Michal L. Schwartzman

  8. Buck Institute for Research on Aging, Novato, CA, USA

    Judith Campisi & Anna Csiszar

  9. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary

    Anna Csiszar

  10. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

Authors
  1. Andriy Yabluchanskiy
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  2. Stefano Tarantini
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  3. Priya Balasubramanian
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  6. Gábor A. Fülöp
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  9. Jordan DelFavero
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  10. Adam Nyul-Toth
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  14. Anna Csiszar
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  15. Zoltan Ungvari
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Corresponding author

Correspondence to Zoltan Ungvari.

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Yabluchanskiy, A., Tarantini, S., Balasubramanian, P. et al. Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation–induced impairment of neurovascular coupling responses protecting cognitive function in mice. GeroScience 42, 409–428 (2020). https://doi.org/10.1007/s11357-020-00154-8

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