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Cited by 191Barrier Structure and Function StudiesNeurological Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice

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Tucsek, Z., Toth, P., Tarantini, S., Sosnowska, D., Gautam, T., Warrington, J. P., Giles, C. B., Wren, J. D. +5 more·2014·The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
DOI 10.1093/gerona/glu080PMC PMC4204615
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Abstract

Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. 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 Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.

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  • Microvascular endothelial aging disrupts the blood-brain barrier, which promotes neuroinflammation and exacerbates cognitive decline.

    “In addition, microvascular endothelial aging also disrupts the blood-brain barrier, which promotes neuroinflammation, exacerbating cognitive decline”

    From Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain (2020) · cites this paper as Tucsek et al. 2014a

    The Discussion (page unavailable in our copy) says that cerebral microvascular impairment, together with blood-brain barrier disruption and neuroinflammation, likely contributes to cognitive decline in aged obese mice. It does not establish the claimed causal sequence in which endothelial aging disrupts the barrier, thereby promoting neuroinflammation; the citing sentence also states more definitively what the paper presents as likely. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Aging decreases capillary density (microvascular rarefaction) in the brain.

    “Aging decreases capillary density (known as ' microvascular rarefaction ' ) (Csiszar et al. 2017; Tarantini et al. 2016; Tucsek et al. 2014a; Ungvari et al. 2013a; Banki et al. 2015; Toth et al. 2017)”

    From Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain (2020) · cites this paper as Tucsek et al. 2014a

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Research works printed but not linked: 69

  1. Wang YC, Colditz GA, Kuntz KM. Forecasting the obesity epi- demic in the aging U.S. population. obesity (Silver Spring). 2007;15:2855-2865.
  2. Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. obes Rev. 2008;9:204-218.
  3. Alosco ML, Spitznagel MB, Raz N, et al. Obesity interacts with cere- bral hypoperfusion to exacerbate cognitive impairment in older adults with heart failure. cerebrovasc Dis extra. 2012;2:88-98.
  4. Bruce-Keller AJ, White CL, Gupta S, et al. NOX activity in brain aging: exacerbation by high fat diet. Free Radic Biol Med. 2010;49:22-30.
  5. Morrison CD, Pistell PJ, Ingram DK, et al. High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J neurochem. 2010;114:1581-1589.
  6. Tucsek Z, Toth P, Sosnowska D, et al. 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 Biol Med Sci. 2013. doi:10.1093/gerona/glt177 · DOI
  7. Beavers KM, Hsu FC, Houston DK, et al.; Health ABC Study. The role of metabolic syndrome, adiposity, and inflammation in physical performance in the Health ABC Study. J Gerontol a Biol Sci Med Sci. 2013;68:617-623.
  8. Scuteri A, Najjar SS, Muller DC, et al. Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness. J am coll cardiol. 2004;43:1388-1395.
  9. Brinkley TE, Hsu FC, Beavers KM, et al. Total and abdominal adipos- ity are associated with inflammation in older adults using a factor anal- ysis approach. J Gerontol a Biol Sci Med Sci. 2012;67:1099-1106.
  10. Sloboda N, Fève B, Thornton SN, et al. Fatty acids impair endothelium- dependent vasorelaxation: a link between obesity and arterial stiffness in very old Zucker rats. J Gerontol a Biol Sci Med Sci. 2012;67:927-938.
  11. Lin AL, Zheng W, Halloran JJ, et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's dis- ease. J cereb Blood Flow Metab. 2013;33:1412-1421.
  12. García-Amado M, Prensa L. Stereological analysis of neuron, glial and endothelial cell numbers in the human amygdaloid complex. PloS one. 2012;7:e38692.
  13. Ingraham JP, Forbes ME, Riddle DR, Sonntag WE. Aging reduces hypoxia-induced microvascular growth in the rodent hippocampus. J Gerontol a Biol Sci Med Sci. 2008;63:12-20.
  14. Khan AS, Lynch CD, Sane DC, Willingham MC, Sonntag WE. Growth hormone increases regional coronary blood flow and capillary density in aged rats. J Gerontol a Biol Sci Med Sci. 2001;56:B364-B371.
  15. Sonntag WE, Lynch CD, Cooney PT, Hutchins PM. Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1. endocrinology. 1997;138:3515-3520.
  16. Warrington JP, Csiszar A, Johnson DA, et al. Cerebral micro- vascular rarefaction induced by whole brain radiation is revers- ible by systemic hypoxia in mice. am J Physiol Heart circ Physiol. 2011;300:H736-H744.
  17. Warrington JP, Csiszar A, Mitschelen M, Lee YW, Sonntag WE. Whole brain radiation-induced impairments in learning and memory are time-sensitive and reversible by systemic hypoxia. PloS one. 2012;7:e30444.
  18. Li W, Prakash R, Chawla D, et al. Early effects of high-fat diet on neurovascular function and focal ischemic brain injury. am J Physiol Regul integr comp Physiol. 2013;304:R1001-R1008.
  19. Bailey-Downs LC, Tucsek Z, Toth P, et al. Aging exacerbates obe- sity-induced oxidative stress and inflammation in perivascular adi- pose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation. J Gerontol a Biol Sci Med Sci. 2013;68:780-792.
  20. Carrié I, Debray M, Bourre JM, Francès H. Age-induced cognitive alterations in OF1 mice. Physiol Behav. 1999;66:651-656.
  21. Toth P, Tucsek Z, Sosnowska D, et al. Age-related autoregula- tory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J cereb Blood Flow Metab. 2013;33:1732-1742.
  22. Toth P, Tarantini S, Tucsek Z, et al. Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicro- vascular endothelial function and downregulation of NADPH oxidase. am J Physiol Heart circ Physiol. 2014;306:H299-H308.
  23. Csiszar A, Smith K, Labinskyy N, Orosz Z, Rivera A, Ungvari Z. Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. am J Physiol Heart circ Physiol. 2006;291:H1694-H1699.
  24. Zhang H, Zhang J, Ungvari Z, Zhang C. Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress. arterioscler Thromb Vasc Biol. 2009;29:1164-1171.
  25. Kazama K, Anrather J, Zhou P, et al. Angiotensin II impairs neuro- vascular coupling in neocortex through NADPH oxidase-derived radi- cals. circ Res. 2004;95:1019-1026.
  26. Hof PR, Young WC, Bloom FE, Belichenko PV, Celio MR. comparative cytoachitectonic atlas of the c57Bl/6 and 129/Sv Mouse Brains. New York, NY: Elsevier; 2000.
  27. Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. nat neurosci. 2011;14:1398-1405.
  28. Csiszar A, Tucsek Z, Toth P, et al. Synergistic effects of hyperten- sion and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease. am J Physiol Heart circ Physiol. 2013;305:H1120-H1130.
  29. Bailey-Downs LC, Mitschelen M, Sosnowska D, et al. 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 a Biol Sci Med Sci. 2012;67:313-329.
  30. Dvinge H, Bertone P. HTqPCR: high-throughput analysis and visu- alization of quantitative real-time PCR data in R. Bioinformatics. 2009;25:3325-3326.
  31. Ungvari Z, Tucsek Z, Sosnowska D, et al. Aging-induced dysregula- tion of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol a Biol Sci Med Sci. 2013;68:877-891.
  32. Csiszar A, Sosnowska D, Tucsek Z, et al. Circulating factors induced by caloric restriction in the nonhuman primate Macaca mulatta acti- vate angiogenic processes in endothelial cells. J Gerontol a Biol Sci Med Sci. 2013;68:235-249.
  33. Valcarcel-Ares MN, Gautam T, Warrington JP, et al. Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol a Biol Sci Med Sci. 2012;67:821-829.
  34. Tucsek Z, Gautam T, Sonntag WE, et al. Aging exacerbates micro- vascular endothelial damage induced by circulating factors pre- sent in the serum of septic patients. J Gerontol a Biol Sci Med Sci. 2013;68:652-660.
  35. Ungvari Z, Labinskyy N, Mukhopadhyay P, et al. Resveratrol attenu- ates mitochondrial oxidative stress in coronary arterial endothelial cells. am J Physiol Heart circ Physiol. 2009;297:H1876-H1881.
  36. Ungvari Z, Bagi Z, Feher A, et al. Resveratrol confers endothelial pro- tection via activation of the antioxidant transcription factor Nrf2. am J Physiol Heart circ Physiol. 2010;299:H18-H24.
  37. Ungvari Z, Bailey-Downs L, Gautam T, et al. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. am J Physiol Heart circ Physiol. 2011;300:H1133-H1140.
  38. Csiszar A, Labinskyy N, Perez V, et al. Endothelial function and vas- cular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. am J Physiol Heart circ Physiol. 2008;295:H1882-H1894.
  39. Bailey-Downs LC, Sosnowska D, Toth P, et al. Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impair- ment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol a Biol Sci Med Sci. 2012;67:553-564.
  40. Csiszar A, Podlutsky A, Podlutskaya N, et al. Testing the oxidative stress hypothesis of aging in primate fibroblasts: is there a correlation between species longevity and cellular ROS production? J Gerontol a Biol Sci Med Sci. 2012;67:841-852.
  41. Ungvari Z, Sosnowska D, Podlutsky A, Koncz P, Sonntag WE, Csiszar A. Free radical production, antioxidant capacity, and oxidative stress response signatures in fibroblasts from Lewis Dwarf rats: effects of life span-extending peripubertal GH treatment. J Gerontol a Biol Sci Med Sci. 2011;66:501-510. doi:10.1093/gerona/glr004 · DOI
  42. Stenholm S, Sallinen J, Koster A, et al. Association between obesity history and hand grip strength in older adults-exploring the roles of inflammation and insulin resistance as mediating factors. J Gerontol a Biol Sci Med Sci. 2011;66:341-348.
  43. Bell RD, Winkler EA, Sagare AP, et al. Pericytes control key neu- rovascular functions and neuronal phenotype in the adult brain and during brain aging. neuron. 2010;68:409-427.
  44. Park L, Anrather J, Girouard H, Zhou P, Iadecola C. Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. J cereb Blood Flow Metab. 2007;27:1908-1918.
  45. Surmi BK, Hasty AH. Macrophage infiltration into adipose tissue: ini- tiation, propagation and remodeling. Future lipidol. 2008;3:545-556.
  46. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm. 2006;74:443-477.
  47. Hocking SL, Wu LE, Guilhaus M, Chisholm DJ, James DE. Intrinsic depot-specific differences in the secretome of adipose tissue, preadi- pocytes, and adipose tissue-derived microvascular endothelial cells. Diabetes. 2010;59:3008-3016.
  48. Cartier A, Côté M, Lemieux I, et al. Age-related differences in inflammatory markers in men: contribution of visceral adiposity. Metabolism. 2009;58:1452-1458.
  49. Wu D, Ren Z, Pae M, et al. Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J immunol. 2007;179:4829-4839.
  50. Troen AM, Shea-Budgell M, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH. B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proc natl acad Sci u S a. 2008;105:12474-12479.
  51. Khan AS, Sane DC, Wannenburg T, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. cardiovasc Res. 2002;54:25-35.
  52. Riddle DR, Sonntag WE, Lichtenwalner RJ. Microvascular plasticity in aging. ageing Res Rev. 2003;2:149-168.
  53. Zhu Y, Sun Y, Xie L, Jin K, Sheibani N, Greenberg DA. Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells. Stroke. 2003;34:2483-2488.
  54. Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A. Mechanisms of vascular aging: new perspectives. J Gerontol a Biol Sci Med Sci. 2010;65:1028-1041.
  55. Ungvari Z, Bailey-Downs L, Gautam T, et al. Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol a Biol Sci Med Sci. 2011;66:866-875.
  56. Ungvari Z, Bailey-Downs L, Sosnowska D, et al. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2- mediated antioxidant response. am J Physiol Heart circ Physiol. 2011;301:H363-H372.
  57. Oomen CA, Farkas E, Roman V, van der Beek EM, Luiten PG, Meerlo P. Resveratrol preserves cerebrovascular density and cognitive func- tion in aging mice. Front aging neurosci. 2009;1:4.
  58. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. cell Metab. 2008;8:157-168.
  59. Zaletel M, Strucl M, Pretnar-Oblak J, Zvan B. Age-related changes in the relationship between visual evoked potentials and visu- ally evoked cerebral blood flow velocity response. Funct neurol. 2005;20:115-120.
  60. Topcuoglu MA, Aydin H, Saka E. Occipital cortex activation stud- ied with simultaneous recordings of functional transcranial Doppler ultrasound (fTCD) and visual evoked potential (VEP) in cogni- tively normal human subjects: effect of healthy aging. neurosci lett. 2009;452:17-22.
  61. Stefanova I, Stephan T, Becker-Bense S, Dera T, Brandt T, Dieterich M. Age-related changes of blood-oxygen-level-dependent sig- nal dynamics during optokinetic stimulation. neurobiol aging. 2013;34:2277-2286.
  62. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. neurology. 2013;81:904-909.
  63. Sorond FA, Kiely DK, Galica A, et al. Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston Study. ann neurol. 2011;70:213-220.
  64. Girouard H, Park L, Anrather J, Zhou P, Iadecola C. Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunc- tion induced by angiotensin II. arterioscler Thromb Vasc Biol. 2007;27:303-309.
  65. Stobart JL, Lu L, Anderson HD, Mori H, Anderson CM. Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase. Proc natl acad Sci u S a. 2013;110:3149-3154.
  66. Longden T, Nelson M. Recruitment of the vascular endothelium into neurovascular coupling. Proceedings of the British Pharmacological Society. The FaSeB Journal. 2012;26:842.4.
  67. Csiszar A, Ungvari Z, Edwards JG, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. circ Res. 2002;90:1159-1166.
  68. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315-424.
  69. Lynch CM, Kinzenbaw DA, Chen X, et al. Nox2-derived superoxide contributes to cerebral vascular dysfunction in diet-induced obesity. Stroke. 2013;44:3195-3201.

Cited by

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Authors
Tucsek, Z., Toth, P., Tarantini, S., Sosnowska, D., Gautam, T., Warrington, J. P., Giles, C. B., Wren, J. D., Koller, A., Ballabh, P., Sonntag, W. E., Ungvari, Z., & Csiszar, A.
Affiliations
  • University of Oklahoma Health Sciences Center (US)
  • University of Mississippi Medical Center (US)
  • Oklahoma Medical Research Foundation (US)
  • Westchester Medical Center (US)
ORCID
Venue
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
Publisher
Oxford University Press (OUP)
Published
2014-06-03
Volume
69
Issue
11
Pages
1339-1352
ISSN
  • 1079-5006 (ISSN-L)
  • 1758-535X
DOI
10.1093/gerona/glu080
PMC
PMC4204615
OpenAlex
W2132985113
Cited by
191
References
10
Citations by year
2026: 7 · 2025: 20 · 2024: 17 · 2023: 25 · 2022: 18 · 2021: 14 · 2020: 20 · 2019: 17 · 2018: 16 · 2017: 13 · 2016: 9 · 2015: 11 · 2014: 4
FWCI
6.42
Type
journal article
Language
en
Open access
Locations
  • The Journals of Gerontology Series A (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Touro Scholar (Touro College) (submittedVersion)
Funders
  • Ellison Medical Foundation (AG038747, AG031085, R01-AT006526)
  • American Heart Association (R01-AT006526, AG038747, AG031085)
  • Oklahoma Center for the Advancement of Science and Technology (AG031085, R01-AT006526, AG038747)
  • Hungarian Scientific Research Fund (K‐108444, 4.2.2.A-11/1/KONV-2012-0017, 4.2.2.A-11/1/KONV-2012-0024)
  • National Institutes of Health (5r01ag038747-05)
  • National Institute on Aging (AG038747, AG031085, K08AG031085)
  • National Institute of General Medical Sciences (U54GM104938)
  • National Center for Complementary and Alternative Medicine (AG038747, R01‐AT006526, AG031085, AT006526)
  • National Institute of Neurological Disorders and Stroke (R01NS056218)
  • National Center for Complementary and Integrative Health (R01AT006526)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
obesity, aging, neurovascular uncoupling, cognitive decline, hippocampus, cerebral microvasculature, pericyte coverage, angiogenic gene expression, oxidative stress, NADPH oxidase, cerebral blood flow, whisker stimulation, blood-brain barrier disruption, neuroinflammation, high-fat diet, Alzheimer's disease
MeSH terms
Aging, Animals, Blood-Brain Barrier, Brain, Cerebrovascular Circulation, Cognition Disorders, Disease Models, Animal, Hippocampus, Male, Mice, Inbred C57BL, Obesity, Oxidative Stress, Hand Strength, Maze Learning, Neovascularization, Physiologic, Pericytes, Mice, Microvessels, Diet, High-Fat, Transcriptome

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