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Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment

Abstract

Age-related impairment of angiogenesis likely has a critical role in cerebromicrovascular rarefaction and development of vascular cognitive impairment and dementia (VCID) in the elderly. Recently, we demonstrated that aging is associated with NAD+ depletion in the vasculature and that administration of NAD+ precursors exerts potent anti-aging vascular effects, rescuing endothelium-mediated vasodilation in the cerebral circulation and improving cerebral blood supply. The present study was designed to elucidate how treatment with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, impacts age-related impairment of endothelial angiogenic processes. Using cerebromicrovascular endothelial cells (CMVECs) isolated from young and aged F344xBN rats, we demonstrated that compared with young cells, aged CMVECs exhibit impaired proliferation, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing [ECIS] technology), impaired ability to form capillary-like structures, and increased oxidative stress. NMN treatment in aged CMVECs significantly improved angiogenic processes and attenuated H2O2 production. We also found that pre-treatment with EX-527, a pharmacological inhibitor of SIRT1, prevented NMN-mediated restoration of angiogenic processes in aged CMVECs. Collectively, we find that normal cellular NAD+ levels are essential for normal endothelial angiogenic processes, suggesting that age-related cellular NAD+ depletion and consequential SIRT1 dysregulation may be a potentially reversible mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging. We recommend that pro-angiogenic effects of NAD+ boosters should be considered in both preclinical and clinical studies.

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References

  • Bach MH, Sadoun E, Reed MJ (2005) Defects in activation of nitric oxide synthases occur during delayed angiogenesis in aging. Mech Ageing Dev 126(4):467–473

    PubMed  CAS  Article  Google Scholar 

  • Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S, Tamas A, Helyes Z, Reglodi D, Sonntag WE, Csiszar A, Ungvari Z (2015) Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 70(6):665–674

    PubMed  CAS  Article  Google Scholar 

  • Bentourkia M, Bol A, Ivanoiu A, Labar D, Sibomana M, Coppens A, Michel C, Cosnard G, De Volder AG (2000) Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging. J Neurol Sci 181(1–2):19–28

    PubMed  CAS  Article  Google Scholar 

  • Bonkowski MS, Sinclair DA (2016) Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17(11):679–690

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • 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. Geroscience 40:337–346

    PubMed Central  CAS  Article  Google Scholar 

  • Csiszar A, Gautam T, Sosnowska D, Tarantini S, Banki E, Tucsek Z, Toth P, Losonczy G, Koller A, Reglodi D, Giles CB, Wren JD, Sonntag WE, Ungvari Z (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307(3):H292–H306

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Csiszar A, Sosnowska D, Tucsek Z, Gautam T, Toth P, Losonczy G, Colman RJ, Weindruch R, Anderson RM, Sonntag WE, Ungvari Z (2013) Circulating factors induced by caloric restriction in the nonhuman primate Macaca mulatta activate angiogenic processes in endothelial cells. J Gerontol A Biol Sci Med Sci 68(3):235–249

    PubMed  CAS  Article  Google Scholar 

  • 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 39:359–372

    PubMed  PubMed Central  Article  Google Scholar 

  • 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: in press 316:H1253–H1266

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Cunningham GM, Flores LC, Roman MG, Cheng C, Dube S, Allen C, Valentine JM, Hubbard GB, Bai Y, Saunders TL, Ikeno Y (2018) Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice. Geroscience 40:453–468

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne B, Joshi S, Lu Y, Trevino-Villarreal JH, Kang MJ, Hung TT, Lee B, Williams EO, Igarashi M, Mitchell JR, Wu LE, Turner N, Arany Z, Guarente L, Sinclair DA (2018) Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging. Cell 173(1):74–89 e20

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, Imai S, Seals DR (2016) Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell 15(3):522–530

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • 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(2):187–198

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • 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(3):347–356

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64(6):575–611

    PubMed  CAS  Article  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(5–6):513–521

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Garcia-Amado M, Prensa L (2012) Stereological analysis of neuron, glial and endothelial cell numbers in the human amygdaloid complex. PLoS One 7(6):e38692

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Garten A, Petzold S, Korner A, Imai S, Kiess W (2009) Nampt: linking NAD biology, metabolism and cancer. Trends Endocrinol Metab 20(3):130–138

    PubMed  CAS  Article  Google Scholar 

  • Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155(7):1624–1638

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • 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(5–6):475–489

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Habermehl TL, Parkinson KC, Hubbard GB, Ikeno Y, Engelmeyer JI, Schumacher B, Mason JB (2018) Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice. Geroscience 41(1):25–38. https://doi.org/10.1007/s11357-018-0049-4

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Hagstadius S, Risberg J (1989) Regional cerebral blood flow characteristics and variations with age in resting normal subjects. Brain Cogn 10(1):28–43

    PubMed  CAS  Article  Google Scholar 

  • Imai SI, Guarente L (2016) It takes two to tango: NAD(+) and sirtuins in aging/longevity control. NPJ Aging Mech Dis 2:16017

    PubMed  PubMed Central  Article  Google Scholar 

  • Ingraham JP, Forbes ME, Riddle DR, Sonntag WE (2008) Aging reduces hypoxia-induced microvascular growth in the rodent hippocampus. J Gerontol A Biol Sci Med Sci 63(1):12–20

    PubMed  Article  Google Scholar 

  • Johnson S, Wozniak DF, Imai S (2018) CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. NPJ Aging Mech Dis 4:10

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Kawamura J, Terayama Y, Takashima S, Obara K, Pavol MA, Meyer JS, Mortel KF, Weathers S (1993) Leuko-araiosis and cerebral perfusion in normal aging. Exp Aging Res 19(3):225–240

    PubMed  CAS  Article  Google Scholar 

  • Khan AS, Lynch CD, Sane DC, Willingham MC, Sonntag WE (2001) Growth hormone increases regional coronary blood flow and capillary density in aged rats. J Gerontol A Biol Sci Med Sci 56(8):B364–B371

    PubMed  CAS  Article  Google Scholar 

  • Kim S, Wyckoff J, Morris AT, Succop A, Avery A, Duncan GE, Jazwinski SM (2018) DNA methylation associated with healthy aging of elderly twins. Geroscience 40(5–6):469–484

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Koike T, Vernon RB, Gooden MD, Sadoun E, Reed MJ (2003) Inhibited angiogenesis in aging: a role for TIMP-2. J Gerontol A Biol Sci Med Sci 58(9):B798–B805

    PubMed  Article  Google Scholar 

  • Konopka AR, Laurin JL, Musci RV, Wolff CA, Reid JJ, Biela LM, Zhang Q, Peelor FF 3rd, Melby CL, Hamilton KL, Miller BF (2017) Influence of Nrf2 activators on subcellular skeletal muscle protein and DNA synthesis rates after 6 weeks of milk protein feeding in older adults. Geroscience 39(2):175–186

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Krejza J, Mariak Z, Walecki J, Szydlik P, Lewko J, Ustymowicz A (1999) Transcranial color Doppler sonography of basal cerebral arteries in 182 healthy subjects: age and sex variability and normal reference values for blood flow parameters. AJR Am J Roentgenol 172(1):213–218

    PubMed  CAS  Article  Google Scholar 

  • Lahteenvuo J, Rosenzweig A (2012) Effects of aging on angiogenesis. Circ Res 110(9):1252–1264

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • 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(2):163–176

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Lewis KN, Rubinstein ND, Buffenstein R (2018) A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence. Geroscience 40(2):105–121

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Lynch CD, Cooney PT, Bennett SA, Thornton PL, Khan AS, Ingram RL, Sonntag WE (1999) Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats. Neurobiol Aging 20(2):191–200

    PubMed  CAS  Article  Google Scholar 

  • Martin AJ, Friston KJ, Colebatch JG, Frackowiak RS (1991) Decreases in regional cerebral blood flow with normal aging. J Cereb Blood Flow Metab 11(4):684–689

    PubMed  CAS  Article  Google Scholar 

  • Masser DR, Hadad N, Porter H, Stout MB, Unnikrishnan A, Stanford DR, Freeman WM (2018) Analysis of DNA modifications in aging research. Geroscience 40(1):11–29

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ (2012) Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7(7):e42357

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24(6):795–806

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Mitschelen M, Garteiser P, Carnes BA, Farley JA, Doblas S, Demoe JH, Warrington JP, Yan H, Nicolle MM, Towner R, Sonntag WE (2009) Basal and hypercapnia-altered cerebrovascular perfusion predict mild cognitive impairment in aging rodents. Neuroscience 164(3):918–928

    PubMed  CAS  Article  Google Scholar 

  • Miura S, Saitoh SI, Kokubun T, Owada T, Yamauchi H, Machii H, Takeishi Y (2017) Mitochondrial-targeted antioxidant maintains blood flow, mitochondrial function, and redox balance in old mice following prolonged limb ischemia. Int J Mol Sci 18(9). https://doi.org/10.3390/ijms18091897

  • Moeller JR, Ishikawa T, Dhawan V, Spetsieris P, Mandel F, Alexander GE, Grady C, Pietrini P, Eidelberg D (1996) The metabolic topography of normal aging. J Cereb Blood Flow Metab 16(3):385–398

    PubMed  CAS  Article  Google Scholar 

  • Murugesan N, Demarest TG, Madri JA, Pachter JS (2012) Brain regional angiogenic potential at the neurovascular unit during normal aging. Neurobiol Aging 33(5):1004 e1001–1004 e1016

    Article  CAS  Google Scholar 

  • Nacarelli T, Azar A, Altinok O, Orynbayeva Z, Sell C (2018) Rapamycin increases oxidative metabolism and enhances metabolic flexibility in human cardiac fibroblasts. Geroscience 40:243–256

    CAS  Article  PubMed Central  Google Scholar 

  • Olecka M, Huse K, Platzer M (2018) The high degree of cystathionine beta-synthase (CBS) activation by S-adenosylmethionine (SAM) may explain naked mole-rat’s distinct methionine metabolite profile compared to mouse. Geroscience 40(4):359–360

    PubMed  PubMed Central  Article  Google Scholar 

  • 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

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Pagani M, Salmaso D, Jonsson C, Hatherly R, Jacobsson H, Larsson SA, Wagner A (2002) Regional cerebral blood flow as assessed by principal component analysis and (99m)Tc-HMPAO SPET in healthy subjects at rest: normal distribution and effect of age and gender. Eur J Nucl Med Mol Imaging 29(1):67–75

    PubMed  CAS  Article  Google Scholar 

  • 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(2):147–160

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Reed MJ, Bradshaw AD, Shaw M, Sadoun E, Han N, Ferara N, Funk S, Puolakkainen P, Sage EH (2005) Enhanced angiogenesis characteristic of SPARC-null mice disappears with age. J Cell Physiol 204(3):800–807

    PubMed  CAS  Article  Google Scholar 

  • 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(5–6):437–452

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2(2):149–168

    PubMed  Article  Google Scholar 

  • Sadoun E, Reed MJ (2003) Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J Histochem Cytochem 51(9):1119–1130

    PubMed  CAS  Article  Google Scholar 

  • Schultz MB, Sinclair DA (2016) Why NAD(+) declines during aging: it’s destroyed. Cell Metab 23(6):965–966

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Schultz SK, O’Leary DS, Boles Ponto LL, Watkins GL, Hichwa RD, Andreasen NC (1999) Age-related changes in regional cerebral blood flow among young to mid-life adults. Neuroreport 10(12):2493–2496

    PubMed  CAS  Article  Google Scholar 

  • Sonntag WE, Csiszar A, Decabo R, Ferrucci L, Ungvari Z (2012) Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 67A:587–598

    PubMed Central  CAS  Article  Google Scholar 

  • Sonntag WE, Lynch C, Thornton P, Khan A, Bennett S, Ingram R (2000) The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing. J Anat 197(Pt 4):575–585

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Sonntag WE, Lynch CD, Cooney PT, Hutchins PM (1997) Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1. Endocrinology 138(8):3515–3520

    PubMed  CAS  Article  Google Scholar 

  • Sure VN, Sakamuri S, Sperling JA, Evans WR, Merdzo I, Mostany R, Murfee WL, Busija DW, Katakam PVG (2018) A novel high-throughput assay for respiration in isolated brain microvessels reveals impaired mitochondrial function in the aged mice. Geroscience 40(4):365–375

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Tarantini S, Fulop GA, Kiss T, Farkas E, Zolei-Szenasi D, Galvan V, Toth P, Csiszar A, Ungvari Z, Yabluchanskiy A (2017a) 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

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Tarantini S, Tucsek Z, Valcarcel-Ares MN, Toth P, Gautam T, Giles CB, Ballabh P, Wei JY, Wren JD, Ashpole NM, Sonntag WE, Ungvari Z, Csiszar A (2016) Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. Age (Dordr) 38(4):273–289

    CAS  Article  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 (2019) Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol 24:101192

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • 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 (2018) 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(2):e12731

    PubMed Central  Article  CAS  Google Scholar 

  • 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

    PubMed  PubMed Central  CAS  Article  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(1):H1–H20

    Article  PubMed  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 oxidase. Am J Physiol Heart Circ Physiol 306(3):H299–H308

    CAS  Article  PubMed  Google Scholar 

  • Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33(11):1732–1742

    PubMed  PubMed Central  CAS  Article  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 39:385–406

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Tucsek Z, Toth P, Sosnowsk D, Gautam T, Mitschelen M, Koller A, Szalai G, Sonntag WE, Ungvari Z, Csiszar A (2014a) Obesity in aging exacerbates blood brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 69(10):1212–1226

    PubMed  CAS  Article  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 (2014b) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69(11):1339–1352

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Ungvari Z, Csiszar A (2012) The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci 67A:599–610

    PubMed Central  CAS  Article  Google Scholar 

  • 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(5):H1876–H1881

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018a) Mechanisms of vascular aging. Circ Res 123(7):849–867

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fulop GA, Logan S, Kiss T, Farkas E, Csiszar A, Yabluchanskiy A (2017a) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience 39(1):33–42

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Ungvari Z, Tarantini S, Kiss T, Wren JD, Giles CB, Griffin CT, Murfee WL, Pacher P, Csiszar A (2018b) Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol 15(9):555–565

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A, Csiszar A, Losonczy G, Valcarcel-Ares MN, Sonntag WE (2013) Aging-induced dysregulation of Dicer1-dependent MicroRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68(8):877–891

    PubMed  CAS  Article  Google Scholar 

  • Ungvari Z, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Fulop GA, Kiss T, Csiszar A (2017b) Connective tissue growth factor (CTGF) in age-related vascular pathologies. Geroscience 39(5–6):491–498

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Ungvari Z, Yabluchanskiy A, Tarantini S, Toth P, Kirkpatrick AC, Csiszar A, Prodan CI (2018c) Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience 40(5–6):485–496

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, Losonczy G, Sonntag WE, Ungvari Z, Csiszar A (2012a) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 67(8):821–829

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, Losonczy G, Sonntag WE, Ungvari Z, Csiszar A (2012b) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 67(8):821–829

    PubMed  PubMed Central  Article  CAS  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(3):H736–H744

    PubMed  CAS  Article  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(1):e30444

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ, Lamming DW, Souza-Pinto NC, Bohr VA, Rosenzweig A, de Cabo R, Sauve AA, Sinclair DA (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130(6):1095–1107

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  • Yoshino J, Baur JA, Imai SI (2018) NAD(+) intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 27(3):513–528

    PubMed  CAS  Article  Google Scholar 

  • Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D’Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J (2016) NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352(6292):1436–1443

    PubMed  CAS  Article  Google Scholar 

  • Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12(12):723–738

    PubMed  PubMed Central  CAS  Article  Google Scholar 

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Funding

This work was supported by grants from the American Heart Association (ST, MNVA), 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), and the Presbyterian Health Foundation (to ZU, AC, AY).

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Correspondence to Zoltan Ungvari.

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Kiss, T., Balasubramanian, P., Valcarcel-Ares, M.N. et al. Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment. GeroScience 41, 619–630 (2019). https://doi.org/10.1007/s11357-019-00074-2

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  • DOI: https://doi.org/10.1007/s11357-019-00074-2

Keywords

  • Senescence
  • Endothelial dysfunction
  • Vascular contributions to cognitive impairment and dementia
  • Microcirculation
  • NAD+ precursor