, Volume 41, Issue 5, pp 609–617 | Cite as

Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice

  • Anna Csiszar
  • Andriy Yabluchanskiy
  • Anna Ungvari
  • Zoltan Ungvari
  • Stefano TarantiniEmail author
Original Article


Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via the homeostatic mechanism known as neurovascular coupling (NVC) has an essential role in maintenance of normal brain function. In advanced age cerebromicrovascular endothelial dysfunction impairs NVC responses, which contribute to age-related cognitive decline. Recently, we have shown that pharmacological treatments that attenuate mitochondrial production of reactive oxygen species (ROS) provide significant neurovascular protection, improving NVC responses in aged mice. Transgenic mice that overexpress human catalase localized to the mitochondria (mCAT) are protected from age-related mitochondrial oxidative stress and exhibit a longevity phenotype associated with resistance to several age-related pathologies. The present study was designed to test the hypothesis that mitochondria-targeted overexpression of catalase also confers protection against age-related impairment of NVC responses. To achieve this goal, NVC responses were assessed in aged (24 months old) mCAT mice and compared with those in age-matched wild-type mice and young control mice by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that mitochondrial overexpression of catalase resulted in improved NVC in aged mice due to preserved NO-mediated (L-NAME inhibitable) component of the response. Thus, our present and previous findings demonstrate that interventions that boost mitochondrial antioxidative defenses confer significant cerebromicrovascular protective effects, which preserve NVC responses in aged mice. Our findings provide additional proof-of-concept for the potential use of mitochondria-targeted antioxidants as therapy for prevention of vascular cognitive impairment associated with aging.


Oxidative stress Aging Mitochondria Cerebral circulation Vascular cognitive impairment Endothelial dysfunction 


Funding information

This work was financially 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 (NINDS; 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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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.


  1. Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges EL, Ungvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE (2017) IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience. 39:129–145PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarcel-Ares MN, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A (2012) Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol Biol Med Sci 67:313–329CrossRefGoogle Scholar
  3. Carlson BW, Craft MA, Carlson JR, Razaq W, Deardeuff KK, Benbrook DM (2018) Accelerated vascular aging and persistent cognitive impairment in older female breast cancer survivors. Geroscience. 40:325–336PubMedPubMedCentralCrossRefGoogle Scholar
  4. Chen BR, Kozberg MG, Bouchard MB, Shaik MA, Hillman EM (2014) A critical role for the vascular endothelium in functional neurovascular coupling in the brain. J Am Heart Assoc. 2014 Jun 12;3(3):e000787.
  5. Csipo T, Fulop GA, Lipecz A, Tarantini S, Kiss T, Balasubramanian P, Csiszar A, Ungvari Z, Yabluchanskiy A (2018) Short-term weight loss reverses obesity-induced microvascular endothelial dysfunction. GeroscienceGoogle Scholar
  6. Csipo T, Lipecz A, Fulop GA, Hand RA, Ngo BN, Dzialendzik M, Tarantini S, Balasubramanian P, Kiss T, Yabluchanska V, Silva-Palacios F, Courtney DL, Dasari TW, Sorond F, Sonntag WE, Csiszar A, Ungvari Z, Yabluchanskiy A (2019) Age-related decline in peripheral vascular health predicts cognitive impairment. Geroscience 41(2):125–136PubMedPubMedCentralCrossRefGoogle Scholar
  7. Csiszar A, Ungvari Z, Edwards JG, Kaminski PM, Wolin MS, Koller A, Kaley G (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90:1159–1166PubMedCrossRefGoogle Scholar
  8. Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z (2008) Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295:H1882–H1894PubMedPubMedCentralCrossRefGoogle Scholar
  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.Google Scholar
  10. Csiszar A, Tarantini S, Yabluchanskiy A, Balasubramanian P, Kiss T, Farkas E, Baur JA, Ungvari ZI (2019) Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Am J Physiol Heart Circ Physiol 316(6):H1253–H1266PubMedCrossRefGoogle Scholar
  11. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, Gollahon K, Martin GM, Loeb LA, Ladiges WC, Rabinovitch PS (2009) Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 119:2789–2797PubMedPubMedCentralCrossRefGoogle Scholar
  12. Dai DF, Chen T, Szeto H, Nieves-Cintron M, Kutyavin V, Santana LF, Rabinovitch PS (2011) Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 58:73–82PubMedPubMedCentralCrossRefGoogle Scholar
  13. Dai DF, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110:1109–1124PubMedCrossRefGoogle Scholar
  14. Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS (2014) Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan 3:6PubMedPubMedCentralCrossRefGoogle Scholar
  15. Dai DF, Chiao YA, Martin GM, Marcinek DJ, Basisty N, Quarles EK, Rabinovitch PS (2017) Mitochondrial-targeted catalase: extended longevity and the roles in various disease ,models. Prog Mol Biol Transl Sci 146:203–241PubMedCrossRefGoogle Scholar
  16. Deepa SS, Bhaskaran S, Espinoza S, Brooks SV, McArdle A, Jackson MJ, Van Remmen H, Richardson A (2017) A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse. Geroscience. 39:187–198PubMedPubMedCentralCrossRefGoogle Scholar
  17. Fabiani M, Gordon BA, Maclin EL, Pearson MA, Brumback-Peltz CR, Low KA, McAuley E, Sutton BP, Kramer AF, Gratton G (2013) Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study. NeuroimageGoogle Scholar
  18. Fang Y, McFadden S, Darcy J, Hill CM, Huber JA, Verhulst S, Kopchick JJ, Miller RA, Sun LY, Bartke A (2017) Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice. Geroscience. 39:347–356PubMedPubMedCentralCrossRefGoogle Scholar
  19. 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. 40:513–521PubMedPubMedCentralCrossRefGoogle Scholar
  20. Ge X, Pettan-Brewer C, Morton J, Carter K, Fatemi S, Rabinovitch P, Ladiges WC (2015) Mitochondrial catalase suppresses naturally occurring lung cancer in old mice. Pathobiol Aging Age Relat Dis. 2015 Sep 22;5:28776. eCollection 2015CrossRefGoogle Scholar
  21. Gillon A, Nielsen K, Steel C, Cornwall J, Sheard P (2018) Exercise attenuates age-associated changes in motoneuron number, nucleocytoplasmic transport proteins and neuromuscular health. Geroscience. 40:177–192PubMedPubMedCentralCrossRefGoogle Scholar
  22. Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR (2014) Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol 592:2549–2561PubMedPubMedCentralCrossRefGoogle Scholar
  23. Grant CD, Jafari N, Hou L, Li Y, Stewart JD, Zhang G, Lamichhane A, Manson JE, Baccarelli AA, Whitsel EA, Conneely KN (2017) A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk. Geroscience. 39:475–489PubMedPubMedCentralCrossRefGoogle Scholar
  24. Katsyuba E, Mottis A, Zietak M, De Franco F, van der Velpen V, Gariani K, Ryu D, Cialabrini L, Matilainen O, Liscio P, Giacche N, Stokar-Regenscheit N, Legouis D, de Seigneux S, Ivanisevic J, Raffaelli N, Schoonjans K, Pellicciari R, Auwerx J (2018) De novo NAD(+) synthesis enhances mitochondrial function and improves health. Nature. 563:354–359PubMedPubMedCentralCrossRefGoogle Scholar
  25. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, Wyss-Coray T, Sierra F (2014) Geroscience: linking aging to chronic disease. Cell. 159:709–713PubMedPubMedCentralCrossRefGoogle Scholar
  26. Kiss T, Balasubramanian P, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Csipo T, Lipecz A, Reglodi D, Zhang XA, Bari F, Farkas E, Csiszar A, Ungvari Z (2019) Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for prevention of vascular cognitive impairment. GeroScience in pressGoogle Scholar
  27. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI (2010) Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 12:668–674PubMedPubMedCentralCrossRefGoogle Scholar
  28. Lee HJ, Feliers D, Barnes JL, Oh S, Choudhury GG, Diaz V, Galvan V, Strong R, Nelson J, Salmon A, Kevil CG, Kasinath BS (2018) Hydrogen sulfide ameliorates aging-associated changes in the kidney. Geroscience. 40:163–176PubMedPubMedCentralCrossRefGoogle Scholar
  29. 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. (3):41, 341–349PubMedPubMedCentralCrossRefGoogle Scholar
  30. Nacarelli T, Azar A, Altinok O, Orynbayeva Z, Sell C (2018) Rapamycin increases oxidative metabolism and enhances metabolic flexibility in human cardiac fibroblasts. GeroscienceGoogle Scholar
  31. Ng LF, Gruber J, Cheah IK, Goo CK, Cheong WF, Shui G, Sit KP, Wenk MR, Halliwell B (2014) The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease. Free Radic Biol Med 71:390–401PubMedCrossRefGoogle Scholar
  32. Olsen RH, Johnson LA, Zuloaga DG, Limoli CL, Raber J (2013) Enhanced hippocampus-dependent memory and reduced anxiety in mice over-expressing human catalase in mitochondria. J Neurochem 125:303–313PubMedPubMedCentralCrossRefGoogle Scholar
  33. Park L, Anrather J, Girouard H, Zhou P, Iadecola C (2007) Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J Cereb Blood Flow Metab 27:1908–1918PubMedCrossRefGoogle Scholar
  34. Podlutsky A, Valcarcel-Ares MN, Yancey K, Podlutskaya V, Nagykaldi E, Gautam T, Miller RA, Sonntag WE, Csiszar A, Ungvari Z (2017) The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. Geroscience. 39:147–160PubMedPubMedCentralCrossRefGoogle Scholar
  35. Reglodi D, Atlasz T, Szabo E, Jungling A, Tamas A, Juhasz T, Fulop BD, Bardosi A (2018) PACAP deficiency as a model of aging. Geroscience. 40:437–452PubMedPubMedCentralCrossRefGoogle Scholar
  36. Rossman MJ, Santos-Parker JR, Steward CAC, Bispham NZ, Cuevas LM, Rosenberg HL, Woodward KA, Chonchol M, Gioscia-Ryan RA, Murphy MP, Seals DR (2018) Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension. 71:1056–1063PubMedPubMedCentralCrossRefGoogle Scholar
  37. Schriner SE, Linford NJ (2006) Extension of mouse lifespan by overexpression of catalase. Age (Dordr). 2006 Jun;28(2):209–18. Epub 2006 Jun 22PubMedPubMedCentralCrossRefGoogle Scholar
  38. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 308:1909–1911PubMedCrossRefGoogle Scholar
  39. Selvaratnam J, Robaire B (2016) Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production. Exp Gerontol 84:12–20PubMedCrossRefGoogle Scholar
  40. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, Rabinovitch PS, Marcinek DJ (2013) Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell 12:763–771PubMedPubMedCentralCrossRefGoogle Scholar
  41. Sierra F, Kohanski R (2017) Geroscience and the trans-NIH geroscience interest group, GSIG. Geroscience 39:1–5PubMedPubMedCentralCrossRefGoogle Scholar
  42. 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 70:213–220PubMedPubMedCentralCrossRefGoogle Scholar
  43. 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):904–909PubMedPubMedCentralCrossRefGoogle Scholar
  44. Stefanova I, Stephan T, Becker-Bense S, Dera T, Brandt T, Dieterich M (2013) Age-related changes of blood-oxygen-level-dependent signal dynamics during optokinetic stimulation. Neurobiol Aging 34:2277–2286PubMedCrossRefGoogle Scholar
  45. 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 35:1871–1881PubMedPubMedCentralCrossRefGoogle Scholar
  46. 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. 2017 Aug;94:52–58. Epub 2016 Nov 12PubMedCrossRefGoogle Scholar
  47. 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 94:52–58PubMedCrossRefGoogle Scholar
  48. 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. 39:601–614PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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):465–473PubMedPubMedCentralCrossRefGoogle Scholar
  50. 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 73(7):853–863PubMedCrossRefGoogle Scholar
  51. 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 17PubMedCentralCrossRefGoogle Scholar
  52. 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 (2019) Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol 24:101192PubMedPubMedCentralCrossRefGoogle Scholar
  53. Topcuoglu MA, Aydin H, Saka E (2009) Occipital cortex activation studied with simultaneous recordings of functional transcranial Doppler ultrasound (fTCD) and visual evoked potential (VEP) in cognitively normal human subjects: effect of healthy aging. Neurosci Lett 452:17–22PubMedCrossRefGoogle Scholar
  54. 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–H308PubMedCrossRefGoogle Scholar
  55. Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z (2015a) 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–H1845PubMedPubMedCentralCrossRefGoogle Scholar
  56. Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015b) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14:1034–1044PubMedPubMedCentralCrossRefGoogle Scholar
  57. 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–H20CrossRefPubMedGoogle Scholar
  58. Treuting PM, Linford NJ, Knoblaugh SE, Emond MJ, Morton JF, Martin GM, Rabinovitch PS, Ladiges WC (2008) Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci Med Sci 63:813–822PubMedCrossRefGoogle Scholar
  59. 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.Google Scholar
  60. Ungvari ZI, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith KE, Csiszar A (2007) Increased mitochondrial H2O2 production promotes endothelial NF-kB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293:H37–H47PubMedCrossRefGoogle Scholar
  61. Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, Zhang C, Pacher P, Csiszar A (2009) Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol 297:H1876–H1881PubMedPubMedCentralCrossRefGoogle Scholar
  62. Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE, Telljohann R, Pinto JT, de Cabo R, Sonntag WE, Lakatta E, Csiszar A (2011a) Age-associated vascular oxidative stress, Nrf2 dysfunction and NF-kB activation in the non-human primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66:866–875PubMedCrossRefGoogle Scholar
  63. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, Ballabh P, de Cabo R, Sonntag WE, Csiszar A (2011b) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301:H363–H372PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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. 39:33–42PubMedPubMedCentralCrossRefGoogle Scholar
  65. Ungvari Z, Yabluchanskiy A, Tarantini S, Toth P, Kirkpatrick AC, Csiszar A, Prodan CI (2018a) Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience. 40:485–496PubMedPubMedCentralCrossRefGoogle Scholar
  66. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018b) Mechanisms of vascular aging. Circ Res 123:849–867PubMedPubMedCentralCrossRefGoogle Scholar
  67. Unnikrishnan A, Jackson J, Matyi SA, Hadad N, Wronowski B, Georgescu C, Garrett KP, Wren JD, Freeman WM, Richardson A (2017) Role of DNA methylation in the dietary restriction mediated cellular memory. Geroscience. 39:331–345PubMedPubMedCentralCrossRefGoogle Scholar
  68. Wang Y, Wang W, Wang N, Tall AR, Tabas I (2017) Mitochondrial oxidative stress promotes atherosclerosis and neutrophil extracellular traps in aged mice. Arterioscler Thromb Vasc Biol 37:e99–e107PubMedPubMedCentralGoogle Scholar
  69. Zaletel M, Strucl M, Pretnar-Oblak J, Zvan B (2005) Age-related changes in the relationship between visual evoked potentials and visually evoked cerebral blood flow velocity response. Funct Neurol 20:115–120PubMedGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience, Department of BiochemistryUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.International Training Program in Geroscience, Theoretical Medicine Doctoral School, Department of Medical Physics and InformaticsUniversity of SzegedSzegedHungary
  3. 3.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Institute of Clinical Experimental ResearchSemmelweis UniversityBudapestHungary
  4. 4.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public HealthSemmelweis UniversityBudapestHungary
  5. 5.Department of Health Promotion Sciences, College of Public HealthUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations