Vascular Aging and Free Radicals

  • Zoltan Ungvari
  • Akos Koller
  • Peter Toth
  • Anna Csiszar
Reference work entry

Abstract

Understanding common causes of late-life cardiovascular disease, stroke, peripheral artery disease, and vascular cognitive impairment is important as it enables the development of novel approaches to extend the healthspan of the elderly. This overview focuses on cellular mechanisms promoting vascular oxidative stress during aging, including NADPH oxidase activation and mitochondrial ROS production; describes the role of age-related GH/IGF-1 deficiency and dysregulation of Nrf2; and explores the links between mitochondrial oxidative stress, inflammation, endothelial dysfunction, endothelial apoptosis, and development of vascular diseases in the elderly.

Keywords

Nitric Oxide NADPH Oxidase Peripheral Artery Disease Vascular Cognitive Impairment Mitochondrial Oxidative Stress 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants from the American Heart Association (to ZU, AK, PT, and AC), American Federation for Aging Research (to AC), the Oklahoma Center for the Advancement of Science and Technology (to AC and ZU), the NIH (AG031085 to AC, AT006526 to ZU), the Hungarian National Science Research Funds (OTKA K71591), the Hungarian National Development Agency (TÁMOP/SROP-4.2.1/b-10/2/KONV-2010-0012), and the Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center (to AC). The authors would like to express their gratitude for the support of the Donald W. Reynolds Foundation, which funds aging research at the University of Oklahoma Health Sciences Center under its Aging and Quality of Life Program.

References

  1. (1999) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 354(9177):447–455Google Scholar
  2. Adler A, Messina E, Sherman B, Wang Z, Huang H, Linke A, Hintze TH (2003) NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. Am J Physiol Heart Circ Physiol 285(3):H1015–H1022PubMedGoogle Scholar
  3. Agarwal B, Campen MJ, Channell MM, Wherry SJ, Varamini B, Davis JG, Baur JA, Smoliga JM (2012) Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int J CardiolGoogle Scholar
  4. Anversa P, Li P, Sonnenblick EH, Olivetti G (1994) Effects of aging on quantitative structural properties of coronary vasculature and microvasculature in rats. Am J Physiol 267(3 Pt 2):H1062–H1073PubMedGoogle Scholar
  5. Arenas IA, Xu Y, Davidge ST (2006) Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-{alpha} antagonism. Am J Physiol Heart Circ Physiol 290(3):H1259–H1263PubMedGoogle Scholar
  6. Asai K, Kudej RK, Shen YT, Yang GP, Takagi G, Kudej AB, Geng YJ, Sato N, Nazareno JB, Vatner DE, Natividad F, Bishop SP, Vatner SF (2000) Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler Thromb Vasc Biol 20(6):1493–1499PubMedGoogle Scholar
  7. Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, Ballabh P, Koller A, Farley JA, Sonntag WE, Csiszar A, Ungvari Z (2011) Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol A Biol Sci Med Sci 67(6):553–564PubMedGoogle Scholar
  8. 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(4):313–329Google Scholar
  9. Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R (2012) Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 11(6):443–461PubMedGoogle Scholar
  10. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68(3):409–427PubMedCentralPubMedGoogle Scholar
  11. Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM (2003) Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 108(16):2000–2006PubMedGoogle Scholar
  12. Burns EM, Kruckeberg TW, Comerford LE, Buschmann MT (1979) Thinning of capillary walls and declining numbers of endothelial mitochondria in the cerebral cortex of the aging primate, Macaca nemestrina. J Gerontol 34(5):642–650PubMedGoogle Scholar
  13. Burns EM, Kruckeberg TW, Gaetano PK (1981) Changes with age in cerebral capillary morphology. Neurobiol Aging 2(4):283–291PubMedGoogle Scholar
  14. Cernadas MR, Sanchez de Miguel L, Garcia-Duran M, Gonzalez-Fernandez F, Millas I, Monton M, Rodrigo J, Rico L, Fernandez P, de Frutos T, Rodriguez-Feo JA, Guerra J, Caramelo C, Casado S, Lopez F (1998) Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Circ Res 83(3):279–286PubMedGoogle Scholar
  15. Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW (2012) Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation 9(1):179PubMedCentralPubMedGoogle Scholar
  16. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G (2004) Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging. Physiol Genomics 17(1):21–30PubMedGoogle Scholar
  17. Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z (2007) Vasculoprotective effects of anti-TNFalfa treatment in aging. Am J Pathol 170(1):388–698PubMedCentralPubMedGoogle Scholar
  18. Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z (2008a) Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295(5):H1882–H1894PubMedCentralPubMedGoogle Scholar
  19. 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(11):1159–1166PubMedGoogle Scholar
  20. Csiszar A, Wang M, Lakatta EG, Ungvari ZI (2008b) Inflammation and endothelial dysfunction during aging: role of NF-{kappa}B. J Appl Physiol 105(4):1333–1341PubMedCentralPubMedGoogle Scholar
  21. Csiszar A, Labinskyy N, Jimenez R, Pinto JT, Ballabh P, Losonczy G, Pearson KJ, de Cabo R, Ungvari Z (2009) Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. Mech Ageing Dev 130(8):518–527PubMedCentralPubMedGoogle Scholar
  22. Dai DF, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110(8):1109–1124PubMedGoogle Scholar
  23. Donato AJ, Black AD, Jablonski KL, Gano LB, Seals DR (2008) Aging is associated with greater nuclear NF kappa B, reduced I kappa B alpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans. Aging Cell 7(6):805–812PubMedCentralPubMedGoogle Scholar
  24. Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, Seals DR (2007) Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 100(11):1659–1666PubMedGoogle Scholar
  25. Durrant JR, Seals DR, Connell ML, Russell MJ, Lawson BR, Folian BJ, Donato AJ, Lesniewski LA (2009) Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol 587(Pt 13):3271–3285PubMedCentralPubMedGoogle Scholar
  26. Elhadd TA, Abdu TA, Oxtoby J, Kennedy G, McLaren M, Neary R, Belch JJ, Clayton RN (2001) Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency. J Clin Endocrinol Metab 86(9):4223–4232PubMedGoogle Scholar
  27. Fain JN (2006) Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 74:443–477PubMedGoogle Scholar
  28. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254PubMedGoogle Scholar
  29. Francia P, delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E, Pelicci PG, Schiavoni M, Luscher TF, Volpe M, Cosentino F (2004) Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation 110(18):2889–2895PubMedGoogle Scholar
  30. Fukao H, Ijiri Y, Miura M, Hashimoto M, Yamashita T, Fukunaga C, Oiwa K, Kawai Y, Suwa M, Yamamoto J (2004) Effect of trans-resveratrol on the thrombogenicity and atherogenicity in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Blood Coagul Fibrinolysis 15(6):441–446PubMedGoogle Scholar
  31. Greenwald SE (2007) Ageing of the conduit arteries. J Pathol 211(2):157–172PubMedGoogle Scholar
  32. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI (2000) The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci USA 97(16):9052–9057PubMedCentralPubMedGoogle Scholar
  33. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300PubMedGoogle Scholar
  34. Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20(4):145–147PubMedGoogle Scholar
  35. Hasegawa Y, Saito T, Ogihara T, Ishigaki Y, Yamada T, Imai J, Uno K, Gao J, Kaneko K, Shimosawa T, Asano T, Fujita T, Oka Y, Katagiri H (2012) Blockade of the nuclear factor-kappaB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation 125(9):1122–1133PubMedGoogle Scholar
  36. Hayashi K, Miyagawa K, Sato K, Ueda R, Dohi Y (2006) Temocapril, an angiotensin converting enzyme inhibitor, ameliorates age-related increase in carotid arterial stiffness in normotensive subjects. Cardiology 106(3):190–194PubMedGoogle Scholar
  37. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R (1996) Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334(18):1145–1149PubMedGoogle Scholar
  38. Henrichot E, Juge-Aubry CE, Pernin A, Pache JC, Velebit V, Dayer JM, Meda P, Chizzolini C, Meier CA (2005) Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? Arterioscler Thromb Vasc Biol 25(12):2594–2599PubMedGoogle Scholar
  39. Higashi Y, Sukhanov S, Shai SY, Delafontaine P (2012) Aging, atherosclerosis, and IGF-1. J Gerontol Biol Med Sci 67(6):626–639Google Scholar
  40. Hocking SL, Wu LE, Guilhaus M, Chisholm DJ, James DE (2010) Intrinsic depot-specific differences in the secretome of adipose tissue, preadipocytes, and adipose tissue-derived microvascular endothelial cells. Diabetes 59(12):3008–3016PubMedCentralPubMedGoogle Scholar
  41. Hoffmann J, Haendeler J, Aicher A, Rossig L, Vasa M, Zeiher AM, Dimmeler S (2001) Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ Res 89(8):709–715PubMedGoogle Scholar
  42. Jablonski KL, Seals DR, Eskurza I, Monahan KD, Donato AJ (2007) High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men. J Appl Physiol 103(5):1715–1721PubMedGoogle Scholar
  43. Jacobson A, Yan C, Gao Q, Rincon-Skinner T, Rivera A, Edwards J, Huang A, Kaley G, Sun D (2007) Aging enhances pressure-induced arterial superoxide formation. Am J Physiol Heart Circ Physiol 293(3):H1344–H1350PubMedGoogle Scholar
  44. Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS (2012) Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes 61(6):1444–1454PubMedCentralPubMedGoogle Scholar
  45. Jiang Y, Wang M, Huang K, Zhang Z, Shao N, Zhang Y, Wang W, Wang S (2012) Oxidized low-density lipoprotein induces secretion of interleukin-1beta by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun 425(2):121–126PubMedGoogle Scholar
  46. Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA, Gordon KL, Oyama TT, Hughes J, Hugo C, Kerjaschki D, Schreiner GF, Johnson RJ (2001) Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 37(3):601–611PubMedGoogle Scholar
  47. Khan AS, Sane DC, Wannenburg T, Sonntag WE (2002) Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system. Cardiovasc Res 54(1):25–35PubMedGoogle Scholar
  48. Labinskyy N, Mukhopadhyay P, Toth J, Szalai G, Veres M, Losonczy G, Pinto JT, Pacher P, Ballabh P, Podlutsky A, Austad SN, Csiszar A, Ungvari Z (2009) Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296(4):H946–H956PubMedCentralPubMedGoogle Scholar
  49. Landmesser U, Harrison DG (2001) Oxidant stress as a marker for cardiovascular events: ox marks the spot. Circulation 104(22):2638–2640PubMedGoogle Scholar
  50. Leri A, Liu Y, Wang X, Kajstura J, Malhotra A, Meggs LG, Anversa P (1999) Overexpression of insulin-like growth factor-1 attenuates the myocyte renin-angiotensin system in transgenic mice. Circ Res 84(7):752–762PubMedGoogle Scholar
  51. Li Q, Li B, Wang X, Leri A, Jana KP, Liu Y, Kajstura J, Baserga R, Anversa P (1997) Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 100(8):1991–1999PubMedCentralPubMedGoogle Scholar
  52. Li B, Setoguchi M, Wang X, Andreoli AM, Leri A, Malhotra A, Kajstura J, Anversa P (1999) Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart. Circ Res 84(9):1007–1019PubMedGoogle Scholar
  53. Li W, Mital S, Ojaimi C, Csiszar A, Kaley G, Hintze TH (2004) Premature death and age-related cardiac dysfunction in male eNOS-knockout mice. J Mol Cell Cardiol 37(3):671–680PubMedGoogle Scholar
  54. Marchesi C, Ebrahimian T, Angulo O, Paradis P, Schiffrin EL (2009) Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension 54(6):1384–1392PubMedGoogle Scholar
  55. Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS (2001) eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ Res 89(9):793–798PubMedGoogle Scholar
  56. Mayhan WG, Arrick DM, Sharpe GM, Sun H (2008) Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation 15(3):225–236PubMedGoogle Scholar
  57. Meagher EA, Barry OP, Lawson JA, Rokach J, FitzGerald GA (2001) Effects of vitamin E on lipid peroxidation in healthy persons. JAMA 285(9):1178–1182PubMedGoogle Scholar
  58. Michel JB, Heudes D, Michel O, Poitevin P, Philippe M, Scalbert E, Corman B, Levy BI (1994) Effect of chronic ANG I-converting enzyme inhibition on aging processes. II. Large arteries. Am J Physiol 267(1 Pt 2):R124–R135PubMedGoogle Scholar
  59. Montagna W, Carlisle K (1979) Structural changes in aging human skin. J Invest Dermatol 73(1):47–53PubMedGoogle Scholar
  60. Nakayama T, Sato W, Yoshimura A, Zhang L, Kosugi T, Campbell-Thompson M, Kojima H, Croker BP, Nakagawa T (2010) Endothelial von Willebrand factor release due to eNOS deficiency predisposes to thrombotic microangiopathy in mouse aging kidney. Am J Pathol 176(5):2198–2208PubMedCentralPubMedGoogle Scholar
  61. Nishimura S, Manabe I, Nagasaki M, Seo K, Yamashita H, Hosoya Y, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S (2008) In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue. J Clin Invest 118(2):710–721PubMedCentralPubMedGoogle Scholar
  62. Nisoli E, Falcone S, Tonello C, Cozzi V, Palomba L, Fiorani M, Pisconti A, Brunelli S, Cardile A, Francolini M, Cantoni O, Carruba MO, Moncada S, Clementi E (2004) Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc Natl Acad Sci USA 101(47):16507–16512PubMedCentralPubMedGoogle Scholar
  63. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310(5746):314–317PubMedGoogle Scholar
  64. O’Rourke MF (2007) Arterial aging: pathophysiological principles. Vasc Med 12(4):329–341PubMedGoogle Scholar
  65. Ohman MK, Luo W, Wang H, Guo C, Abdallah W, Russo HM, Eitzman DT (2011) Perivascular visceral adipose tissue induces atherosclerosis in apolipoprotein E deficient mice. Atherosclerosis 219(1):33–39PubMedCentralPubMedGoogle Scholar
  66. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Hammar S (1996) Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334(18):1150–1155PubMedGoogle Scholar
  67. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424PubMedCentralPubMedGoogle Scholar
  68. Papp D, Lenti K, Modos D, Fazekas D, Dul Z, Turei D, Foldvari-Nagy L, Nussinov R, Csermely P, Korcsmaros T (2012) The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops. FEBS Lett 586(13):1795–1802PubMedGoogle Scholar
  69. Payne GA, Borbouse L, Bratz IN, Roell WC, Bohlen HG, Dick GM, Tune JD (2008) Endogenous adipose-derived factors diminish coronary endothelial function via inhibition of nitric oxide synthase. Microcirculation 15(5):417–426PubMedCentralPubMedGoogle Scholar
  70. Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M, Tune JD (2010) Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol 30(9):1711–1717PubMedCentralPubMedGoogle Scholar
  71. Payne GA, Kohr MC, Tune JD (2012) Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol 165(3):659–669PubMedCentralPubMedGoogle Scholar
  72. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008a) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8(2):157–168PubMedCentralPubMedGoogle Scholar
  73. Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z, Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram DK, Navas P, de Cabo R (2008b) Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci USA 105(7):2325–2330PubMedCentralPubMedGoogle Scholar
  74. Police SB, Thatcher SE, Charnigo R, Daugherty A, Cassis LA (2009) Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 29(10):1458–1464PubMedCentralPubMedGoogle Scholar
  75. Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2(2):149–168PubMedGoogle Scholar
  76. Rippe C, Lesniewski L, Connell M, LaRocca T, Donato A, Seals D (2010) Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress. Aging Cell 9(3):304–312PubMedCentralPubMedGoogle Scholar
  77. Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB (2003) Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Am J Med 115(6):429–435PubMedGoogle Scholar
  78. Sindler AL, Delp MD, Reyes R, Wu G, Muller-Delp JM (2009) Effects of aging and exercise training on eNOS uncoupling in skeletal muscle resistance arterioles. J Physiol 107(2):389–398Google Scholar
  79. 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 67(6):587–598PubMedGoogle Scholar
  80. 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):3515–3520PubMedGoogle Scholar
  81. 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):575–585PubMedCentralPubMedGoogle Scholar
  82. Sonntag WE, Ramsey M, Carter CS (2005) Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res Rev 4(2):195–212PubMedGoogle Scholar
  83. Spinetti G, Wang M, Monticone R, Zhang J, Zhao D, Lakatta EG (2004) Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler Thromb Vasc Biol 24(8):1397–1402PubMedGoogle Scholar
  84. Steinberg D, Witztum JL (2002) Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation 105(17):2107–2111PubMedGoogle Scholar
  85. Sun D, Huang A, Yan EH, Wu Z, Yan C, Kaminski PM, Oury TD, Wolin MS, Kaley G (2004) Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats. Am J Physiol Heart Circ Physiol 286(6):H2249–H2256PubMedGoogle Scholar
  86. Surmi BK, Hasty AH (2008) Macrophage infiltration into adipose tissue: initiation, propagation and remodeling. Future Lipidol 3(5):545–556PubMedCentralPubMedGoogle Scholar
  87. Tanabe T, Maeda S, Miyauchi T, Iemitsu M, Takanashi M, Irukayama-Tomobe Y, Yokota T, Ohmori H, Matsuda M (2003) Exercise training improves ageing-induced decrease in eNOS expression of the aorta. Acta Physiol Scand 178(1):3–10PubMedGoogle Scholar
  88. Trott DW, Seawright JW, Luttrell MJ, Woodman CR (2011) NAD(P)H oxidase-derived reactive oxygen species contribute to age-related impairments of endothelium-dependent dilation in rat soleus feed arteries. J Appl Physiol 110(5):1171–1180PubMedCentralPubMedGoogle Scholar
  89. Tschudi MR, Barton M, Bersinger NA, Moreau P, Cosentino F, Noll G, Malinski T, Luscher TF (1996) Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery. J Clin Invest 98(4):899–905PubMedCentralPubMedGoogle Scholar
  90. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, de Cabo R, Csiszar A (2010a) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299(1):H18–H24PubMedCentralPubMedGoogle Scholar
  91. Ungvari Z, Bailey-Downs L, Gautam T, Koncz P, Losonczy G, Ballabh P, de Cabo R, Sonntag WE, Csiszar A (2011a) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2-mediated antioxidant response. Am J Physiol 301(2):H363–H372Google Scholar
  92. Ungvari ZI, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, Ballabh P, Recchia FA, Wilkerson DC, Sonntag WE, Pearson KJ, de Cabo R, Csiszar A (2011c) Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 300(4):H1133–H1140PubMedCentralPubMedGoogle Scholar
  93. 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 (2011b) Age-associated vascular oxidative stress, Nrf2 dysfunction and NF-kB activation in the non-human primate Macaca mulatta. J Gerontol Biol Med Sci 66(8):866–875Google Scholar
  94. Ungvari Z, Buffenstein R, Austad SN, Podlutsky A, Kaley G, Csiszar A (2008a) Oxidative stress in vascular senescence: lessons from successfully aging species. Front Biosci 13:5056–5070PubMedGoogle Scholar
  95. Ungvari Z, Csiszar A (2012) The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci 67(6):599–610PubMedGoogle Scholar
  96. Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010b) Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci 65(10):1028–1041PubMedGoogle Scholar
  97. Ungvari ZI, Labinskyy N, Gupte SA, Chander PN, Edwards JG, Csiszar A (2008c) Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. Am J Physiol Heart Circ Physiol 294(5):H2121–H2128PubMedGoogle Scholar
  98. van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Lüscher TF (2000) Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192(12):1731–1744PubMedCentralPubMedGoogle Scholar
  99. 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(1):H37–H47PubMedGoogle Scholar
  100. Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R (2008b) Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging. Circ Res 102(5):519–528PubMedCentralPubMedGoogle Scholar
  101. Verhagen SN, Visseren FL (2011) Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis 214(1):3–10PubMedGoogle Scholar
  102. Verhoye E, Langlois MR (2009) Circulating oxidized low-density lipoprotein: a biomarker of atherosclerosis and cardiovascular risk? Clin Chem Lab Med 47(2):128–137PubMedGoogle Scholar
  103. Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG (2003) Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 41(6):1308–1316PubMedGoogle Scholar
  104. Wang M, Zhang J, Spinetti G, Jiang LQ, Monticone R, Zhao D, Cheng L, Krawczyk M, Talan M, Pintus G, Lakatta EG (2005a) Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats. Am J Pathol 167(5):1429–1442PubMedCentralPubMedGoogle Scholar
  105. Wang Z, Zou J, Cao K, Hsieh TC, Huang Y, Wu JM (2005b) Dealcoholized red wine containing known amounts of resveratrol suppresses atherosclerosis in hypercholesterolemic rabbits without affecting plasma lipid levels. Int J Mol Med 16(4):533–540PubMedGoogle Scholar
  106. Wang M, Zhang J, Jiang LQ, Spinetti G, Pintus G, Monticone R, Kolodgie FD, Virmani R, Lakatta EG (2007) Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 50(1):219–227PubMedGoogle Scholar
  107. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14(11):1398–1405PubMedCentralPubMedGoogle Scholar
  108. Woodman CR, Price EM, Laughlin MH (2002) Aging induces muscle-specific impairment of endothelium-dependent dilation in skeletal muscle feed arteries. J Appl Physiol 93(5):1685–1690PubMedGoogle Scholar
  109. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med 342(3):154–160PubMedGoogle Scholar
  110. Zou Y, Yoon S, Jung KJ, Kim CH, Son TG, Kim MS, Kim YJ, Lee J, Yu BP, Chung HY (2006) Upregulation of aortic adhesion molecules during aging. J Gerontol 61(3):232–244Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Zoltan Ungvari
    • 1
    • 2
  • Akos Koller
    • 2
  • Peter Toth
    • 1
  • Anna Csiszar
    • 1
    • 2
  1. 1.Department of Geriatric Medicine, Reynolds Oklahoma Center on AgingUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Department of Pathophysiology and Gerontology and Szentágothai János Tudományos és KutatóközpontUniversity of PécsPécsHungary

Personalised recommendations