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Cardiovascular Disease and Aging

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Advances in Geroscience

Abstract

Cardiovascular diseases are the leading cause of death for population over 65 years of age. With the progressive increase of population in this age group, it is crucial to understand the interaction between aging and cardiovascular diseases. Aging results in structural changes and functional decline of the cardiovascular system and is a major risk factor for cardiovascular diseases. Aging not only increases the prevalence of cardiovascular diseases but is also associated with impaired responses to cardiovascular diseases. This supports the notion that age-related changes in the cardiovascular system superimpose and interact with the pathophysiological mechanisms that lead to cardiovascular disease. This chapter will provide an overview of cardiovascular aging in humans and mammalian models, and discuss the recent advances in understanding how different hallmarks of aging play their roles in the pathogenesis of cardiovascular aging.

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References

  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ et al (2014) Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 129(3):e28–e292. doi:10.1161/01.cir.0000441139.02102.80

    PubMed  Google Scholar 

  2. Hakuno D, Kimura N, Yoshioka M, Fukuda K (2009) Molecular mechanisms underlying the onset of degenerative aortic valve disease. J Mol Med (Berl) 87(1):17–24. doi:10.1007/s00109-008-0400-9

    CAS  Google Scholar 

  3. Connell PS, Han RI, Grande-Allen KJ (2012) Differentiating the aging of the mitral valve from human and canine myxomatous degeneration. J Vet Cardiol 14(1):31–45. doi:10.1016/j.jvc.2011.11.003, S1760-2734(12)00004-5 [pii]

    PubMed Central  PubMed  Google Scholar 

  4. Gerstenblith G, Frederiksen J, Yin FC, Fortuin NJ, Lakatta EG, Weisfeldt ML (1977) Echocardiographic assessment of a normal adult aging population. Circulation 56(2):273–278

    CAS  PubMed  Google Scholar 

  5. Vasan RS, Levy D (2000) Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 101(17):2118–2121

    CAS  PubMed  Google Scholar 

  6. Benjamin EJ, Levy D, Anderson KM, Wolf PA, Plehn JF, Evans JC et al (1992) Determinants of Doppler indexes of left ventricular diastolic function in normal subjects (the Framingham Heart Study). Am J Cardiol 70(4):508–515 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  7. Schulman SP, Lakatta EG, Fleg JL, Lakatta L, Becker LC, Gerstenblith G (1992) Age-related decline in left ventricular filling at rest and exercise. Am J Physiol 263(6 Pt 2):H1932–H1938 [Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  8. Swinne CJ, Shapiro EP, Lima SD, Fleg JL (1992) Age-associated changes in left ventricular diastolic performance during isometric exercise in normal subjects. Am J Cardiol 69(8):823–826

    CAS  PubMed  Google Scholar 

  9. Fleg JL, O’Connor F, Gerstenblith G, Becker LC, Clulow J, Schulman SP et al (1995) Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 78(3):890–900 [Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  10. Rodeheffer RJ, Gerstenblith G, Beard E, Fleg JL, Becker LC, Weisfeldt ML et al (1986) Postural changes in cardiac volumes in men in relation to adult age. Exp Gerontol 21(4–5):367–378 [Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  11. Najjar SS, LE, Gerstenblith G (2011) Cardiovascular aging: the next frontier in cardiovascular prevention. In: Foody JM, Blumenthal R, Wong NA (eds) Preventive cardiology: a companion to Braunwald’s heart disease. Elsevier/Saunders, Philadelphia, pp 415–432

    Google Scholar 

  12. Yin FC, Weisfeldt ML, Milnor WR (1981) Role of aortic input impedance in the decreased cardiovascular response to exercise with aging in dogs. J Clin Invest 68(1):28–38 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Tsuji H, Larson MG, Venditti FJ Jr, Manders ES, Evans JC, Feldman CL et al (1996) Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 94(11):2850–2855 [Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  14. Fleg JL, Kennedy HL (1992) Long-term prognostic significance of ambulatory electrocardiographic findings in apparently healthy subjects greater than or equal to 60 years of age. Am J Cardiol 70(7):748–751

    CAS  PubMed  Google Scholar 

  15. Fleg JL, Kennedy HL (1982) Cardiac arrhythmias in a healthy elderly population: detection by 24-hour ambulatory electrocardiography. Chest 81(3):302–307

    CAS  PubMed  Google Scholar 

  16. Asai K, Kudej RK, Shen YT, Yang GP, Takagi G, Kudej AB et al (2000) Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler Thromb Vasc Biol 20(6):1493–1499 [Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  17. Virmani R, Avolio AP, Mergner WJ, Robinowitz M, Herderick EE, Cornhill JF et al (1991) Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis. Comparison between occidental and Chinese communities. Am J Pathol 139(5):1119–1129 [Comparative Study Research Support, U.S. Gov’t, P.H.S.]

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Lakatta EG, Wang M, Najjar SS (2009) Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and molecular levels. Med Clin North Am 93(3):583–604. doi:10.1016/j.mcna.2009.02.008, [Research Support, N.I.H., Intramural Review] Table of Contents

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Najjar SS (2009) IMT as a risk marker: the plot thickens. J Am Soc Echocardiogr 22(5):505–507. doi:10.1016/j.echo.2009.03.019 [Comment Editorial Research Support, N.I.H., Intramural]

    PubMed Central  PubMed  Google Scholar 

  20. Adams MR, Nakagomi A, Keech A, Robinson J, McCredie R, Bailey BP et al (1995) Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation 92(8):2127–2134 [Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  21. Wildman RP, Farhat GN, Patel AS, Mackey RH, Brockwell S, Thompson T et al (2005) Weight change is associated with change in arterial stiffness among healthy young adults. Hypertension 45(2):187–192. doi:10.1161/01.HYP.0000152200.10578.5d [Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  22. Wilkinson IB, Franklin SS, Cockcroft JR (2004) Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology. Hypertension 44(2):112–116. doi:10.1161/01.HYP.0000138068.03893.40 [Review]

    CAS  PubMed  Google Scholar 

  23. Tarasov KV, Sanna S, Scuteri A, Strait JB, Orru M, Parsa A et al (2009) COL4A1 is associated with arterial stiffness by genome-wide association scan. Circ Cardiovasc Genet 2(2):151–158. doi:10.1161/CIRCGENETICS.108.823245 [Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov’t]

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D et al (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27(21):2588–2605. doi:10.1093/eurheartj/ehl254

    PubMed  Google Scholar 

  25. Franklin SS, Gustin WT, Wong ND, Larson MG, Weber MA, Kannel WB et al (1997) Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 96(1):308–315 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  26. AlGhatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P et al (2013) Longitudinal trajectories of arterial stiffness and the role of blood pressure: the Baltimore Longitudinal Study of Aging. Hypertension 62(5):934–941. doi:10.1161/HYPERTENSIONAHA.113.01445

    CAS  PubMed  Google Scholar 

  27. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D et al (2012) Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 308(9):875–881. doi:10.1001/2012.jama.10503

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Weisbrod RM, Shiang T, Al Sayah L, Fry JL, Bajpai S, Reinhart-King CA et al (2013) Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension 62(6):1105–1110. doi:10.1161/HYPERTENSIONAHA.113.01744

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Feridooni HA, Dibb KM, Howlett SE (2014) How cardiomyocyte excitation, calcium release and contraction become altered with age. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2014.12.004 [Review]

    PubMed  Google Scholar 

  30. Wang M, Jiang L, Monticone RE, Lakatta EG (2014) Proinflammation: the key to arterial aging. Trends Endocrinol Metab 25(2):72–79. doi:10.1016/j.tem.2013.10.002 [Research Support, N.I.H., Intramural Review]

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Lakatta EG, Levy D (2003) Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 107(1):139–146

    PubMed  Google Scholar 

  32. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emonds 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(21):2789–2797. doi:10.1161/CIRCULATIONAHA.108.822403 [Research Support, N.I.H., Extramural]

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Khouri SJ, Maly GT, Suh DD, Walsh TE (2004) A practical approach to the echocardiographic evaluation of diastolic function. J Am Soc Echocardiogr 17(3):290–297

    PubMed  Google Scholar 

  34. Lin J, Lopez EF, Jin Y, Van Remmen H, Bauch T, Han HC et al (2008) Age-related cardiac muscle sarcopenia: combining experimental and mathematical modeling to identify mechanisms. Exp Gerontol 43(4):296–306

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Lindsey ML, Goshorn DK, Squires CE, Escobar GP, Hendrick JW, Mingoia JT et al (2005) Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function. Cardiovasc Res 66(2):410–419. doi:10.1016/j.cardiores.2004.11.029 [Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, Non-P.H.S. Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  36. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA et al (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3(6), e2264

    PubMed Central  PubMed  Google Scholar 

  37. Tei C, Nishimura RA, Seward JB, Tajik AJ (1997) Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 10(2):169–178

    CAS  PubMed  Google Scholar 

  38. Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, Capasso JM (1990) Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res 67(4):871–885 [Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  39. Burgess ML, McCrea JC, Hedrick HL (2001) Age-associated changes in cardiac matrix and integrins. Mech Ageing Dev 122(15):1739–1756

    CAS  PubMed  Google Scholar 

  40. Treuting PM, Linford NJ, Knoblaugh SE, Emond MJ, Morton JF, Martin GM et al (2008) Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci Med Sci 63(8):813–822

    PubMed  Google Scholar 

  41. Zheng F, Plati AR, Potier M, Schulman Y, Berho M, Banerjee A et al (2003) Resistance to glomerulosclerosis in B6 mice disappears after menopause. Am J Pathol 162(4):1339–1348

    PubMed Central  PubMed  Google Scholar 

  42. Csiszar A, Ungvari Z, Edwards JG, Kaminski PM, Wolin MS, Koller A et al (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90(11):1159–1166

    CAS  PubMed  Google Scholar 

  43. Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010) Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci 65(10):1028–1041. doi:10.1093/gerona/glq113, glq113 [pii]

    PubMed  Google Scholar 

  44. Riddle DR, Sonntag WE, Lichtenwalner RJ (2003) Microvascular plasticity in aging. Ageing Res Rev 2(2):149–168, S1568163702000648 [pii]

    PubMed  Google Scholar 

  45. Toth P, Csiszar A, Tucsek Z, Sosnowska D, Gautam T, Koller A et al (2013) Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice. Am J Physiol Heart Circ Physiol 305(12):H1698–H1708. doi:10.1152/ajpheart.00377.2013, ajpheart.00377.2013 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S et al (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33(11):1732–1742. doi:10.1038/jcbfm.2013.143, jcbfm2013143 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T et al (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(3):H299–H308. doi:10.1152/ajpheart.00744.2013, ajpheart.00744.2013 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G et al (2011) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301(2):H363–H372

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Ungvari ZI, Labinskyy N, Gupte SA, Chander PN, Edwards JG, Csiszar A (2008) Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. Am J Physiol Heart Circ Physiol 294(5):H2121–H2128

    CAS  PubMed  Google Scholar 

  50. Ungvari ZI, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith KE et al (2007) Increased mitochondrial H2O2 production promotes endothelial NF-kB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293(1):H37–H47

    CAS  PubMed  Google Scholar 

  51. Han J, Hosokawa M, Umezawa M, Yagi H, Matsushita T, Higuchi K et al (1998) Age-related changes in blood pressure in the senescence-accelerated mouse (SAM): aged SAMP1 mice manifest hypertensive vascular disease. Lab Anim Sci 48(3):256–263

    CAS  PubMed  Google Scholar 

  52. Qiu H, Zhu Y, Sun Z, Trzeciakowski JP, Gansner M, Depre C et al (2010) Short communication: vascular smooth muscle cell stiffness as a mechanism for increased aortic stiffness with aging. Circ Res 107(5):615–619. doi:10.1161/CIRCRESAHA.110.221846, CIRCRESAHA.110.221846 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Eichberg JW, Shade RE (1987) “Normal” blood pressure in chimpanzees. J Med Primatol 16(5):317–321

    CAS  PubMed  Google Scholar 

  54. Strong JP (1976) Atherosclerosis in primates. Introduction and overview. Primates Med 9:1–15

    CAS  PubMed  Google Scholar 

  55. Zarins CK, Glagov S, Vesselinovitch D, Wissler RW (1990) Aneurysm formation in experimental atherosclerosis: relationship to plaque evolution. J Vasc Surg 12(3):246–256, 0741-5214(90)90144-Y [pii]

    CAS  PubMed  Google Scholar 

  56. Csiszar A, Sosnowska D, Wang M, Lakatta EG, Sonntag WE, Ungvari Z (2012) Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J Gerontol A Biol Sci Med Sci 67(8):811–820. doi:10.1093/gerona/glr228, glr228 [pii]

    PubMed Central  PubMed  Google Scholar 

  57. Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, Monticone RE et al (2011) 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(8):866–875

    PubMed  Google Scholar 

  58. Mackic JB, Bading J, Ghiso J, Walker L, Wisniewski T, Frangione B et al (2002) Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer’s disease lesions. Vascul Pharmacol 38(6):303–313, S1537189102001982 [pii]

    CAS  PubMed  Google Scholar 

  59. 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):642–650

    CAS  PubMed  Google Scholar 

  60. Mammucari C, Rizzuto R (2010) Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev 131(7–8):536–543. doi:10.1016/j.mad.2010.07.003, S0047-6374(10)00135-1 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Trifunovic A, Larsson NG (2008) Mitochondrial dysfunction as a cause of ageing. J Intern Med 263(2):167–178. doi:10.1111/j.1365-2796.2007.01905.x, JIM1905 [pii]

    CAS  PubMed  Google Scholar 

  62. Terzioglu M, Larsson NG (2007) Mitochondrial dysfunction in mammalian ageing. Novartis Found Symp 287:197–208; discussion 208–113

    CAS  PubMed  Google Scholar 

  63. Judge S, Jang YM, Smith A, Hagen T, Leeuwenburgh C (2005) Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J 19(3):419–421

    CAS  PubMed  Google Scholar 

  64. Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292(2):C670–C686

    CAS  PubMed  Google Scholar 

  65. Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308(5730):1909–1911

    CAS  PubMed  Google Scholar 

  66. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE et al (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429(6990):417–423

    CAS  PubMed  Google Scholar 

  67. Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE et al (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309(5733):481–484

    CAS  PubMed  Google Scholar 

  68. Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ et al (2010) Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9(4):536–544. doi:10.1111/j.1474-9726.2010.00581.x, ACE581 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Isoyama S, Nitta-Komatsubara Y (2002) Acute and chronic adaptation to hemodynamic overload and ischemia in the aged heart. Heart Fail Rev 7(1):63–69

    PubMed  Google Scholar 

  70. Juhaszova M, Rabuel C, Zorov DB, Lakatta EG, Sollott SJ (2005) Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res 66(2):233–244

    CAS  PubMed  Google Scholar 

  71. Nitta Y, Abe K, Aoki M, Ohno I, Isoyama S (1994) Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Am J Physiol 267(5 Pt 2):H1795–H1803

    CAS  PubMed  Google Scholar 

  72. Chou TC, Yen MH, Li CY, Ding YA (1998) Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension 31(2):643–648

    CAS  PubMed  Google Scholar 

  73. Korzick DH, Holiman DA, Boluyt MO, Laughlin MH, Lakatta EG (2001) Diminished alpha1-adrenergic-mediated contraction and translocation of PKC in senescent rat heart. Am J Physiol Heart Circ Physiol 281(2):H581–H589

    CAS  PubMed  Google Scholar 

  74. Tani M, Honma Y, Hasegawa H, Tamaki K (2001) Direct activation of mitochondrial K(ATP) channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts. Cardiovasc Res 49(1):56–68

    CAS  PubMed  Google Scholar 

  75. Kennedy BK, Steffen KK, Kaeberlein M (2007) Ruminations on dietary restriction and aging. Cell Mol Life Sci 64(11):1323–1328. doi:10.1007/s00018-007-6470-y

    CAS  PubMed  Google Scholar 

  76. Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493(7432):338–345. doi:10.1038/nature11861, nature11861 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R et al (2006) Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 4(2):133–142. doi:10.1016/j.cmet.2006.05.013

    CAS  PubMed  Google Scholar 

  78. Wessells R, Fitzgerald E, Piazza N, Ocorr K, Morley S, Davies C et al (2009) d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila. Aging Cell 8(5):542–552. doi:10.1111/j.1474-9726.2009.00504.x

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Meikle L, McMullen JR, Sherwood MC, Lader AS, Walker V, Chan JA et al (2005) A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes. Hum Mol Genet 14(3):429–435. doi:10.1093/hmg/ddi039 [Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  80. Blagosklonny MV (2010) Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 9(4):683–688

    CAS  PubMed  Google Scholar 

  81. Mattson MP, Wan R (2005) Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem 16(3):129–137. doi:10.1016/j.jnutbio.2004.12.007 [Review]

    CAS  PubMed  Google Scholar 

  82. Taffet GE, Pham TT, Hartley CJ (1997) The age-associated alterations in late diastolic function in mice are improved by caloric restriction. J Gerontol A Biol Sci Med Sci 52(6):B285–B290 [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]

    CAS  PubMed  Google Scholar 

  83. Meyer TE, Kovacs SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L (2006) Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 47(2):398–402. doi:10.1016/j.jacc.2005.08.069 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  84. Seymour EM, Parikh RV, Singer AA, Bolling SF (2006) Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat. J Mol Cell Cardiol 41(4):661–668. doi:10.1016/j.yjmcc.2006.07.012 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  85. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A et al (2010) Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11(1):35–46. doi:10.1016/j.cmet.2009.11.010

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395. doi:10.1038/nature08221

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20(2):174–184. doi:10.1101/gad.1381406

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schroder S, Adler T et al (2013) Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest 123(8):3272–3291. doi:10.1172/JCI67674, 67674 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  89. Flynn JM, O’Leary MN, Zambataro CA, Academia EC, Presley MP, Garrett BJ et al (2013) Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. doi:10.1111/acel.12109

    Google Scholar 

  90. Dai DF, Karunadharma PP, Chiao YA, Basisty N, Crispin D, Hsieh EJ et al (2014) Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 13(3):529–539. doi:10.1111/acel.12203

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Bedford L, Hay D, Devoy A, Paine S, Powe DG, Seth R et al (2008) Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci 28(33):8189–8198. doi:10.1523/JNEUROSCI.2218-08.2008

    CAS  PubMed  Google Scholar 

  92. Douglas PM, Dillin A (2010) Protein homeostasis and aging in neurodegeneration. J Cell Biol 190(5):719–729. doi:10.1083/jcb.201005144

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Christians ES, Benjamin IJ (2012) Proteostasis and REDOX state in the heart. Am J Physiol Heart Circ Physiol 302(1):H24–H37. doi:10.1152/ajpheart.00903.2011

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Hedhli N, Pelat M, Depre C (2005) Protein turnover in cardiac cell growth and survival. Cardiovasc Res 68(2):186–196. doi:10.1016/j.cardiores.2005.06.025

    CAS  PubMed  Google Scholar 

  95. Surguchev A, Surguchov A (2010) Conformational diseases: looking into the eyes. Brain Res Bull 81(1):12–24. doi:10.1016/j.brainresbull.2009.09.015

    CAS  PubMed  Google Scholar 

  96. Vinciguerra M, Musaro A, Rosenthal N (2010) Regulation of muscle atrophy in aging and disease. Adv Exp Med Biol 694:211–233

    CAS  PubMed  Google Scholar 

  97. Marzetti E, Calvani R, Bernabei R, Leeuwenburgh C (2012) Apoptosis in skeletal myocytes: a potential target for interventions against sarcopenia and physical frailty – a mini-review. Gerontology 58(2):99–106. doi:10.1159/000330064

    CAS  PubMed  Google Scholar 

  98. de Magalhães JP (2004) From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. Exp Cell Res 300(1):1–10. doi:10.1016/j.yexcr.2004.07.006

    PubMed  Google Scholar 

  99. Gray DA, Woulfe J (2005) Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowledge Environ 2005(5):re1. doi:10.1126/sageke.2005.5.re1, 2005/5/re1 [pii]

    PubMed  Google Scholar 

  100. Morimoto RI, Cuervo AM (2009) Protein homeostasis and aging: taking care of proteins from the cradle to the grave. J Gerontol A Biol Sci Med Sci 64(2):167–170. doi:10.1093/gerona/gln071

    PubMed  Google Scholar 

  101. Muscari C, Caldarera CM, Guarnieri C (1990) Age-dependent production of mitochondrial hydrogen peroxide, lipid peroxides and fluorescent pigments in the rat heart. Basic Res Cardiol 85(2):172–178

    CAS  PubMed  Google Scholar 

  102. Sohal RS, Sohal BH (1991) Hydrogen peroxide release by mitochondria increases during aging. Mech Ageing Dev 57(2):187–202, 0047-6374(91)90034-W [pii]

    CAS  PubMed  Google Scholar 

  103. Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269(8):1996–2002, 2869 [pii]

    CAS  PubMed  Google Scholar 

  104. Lewis SE, Goldspink DF, Phillips JG, Merry BJ, Holehan AM (1985) The effects of aging and chronic dietary restriction on whole body growth and protein turnover in the rat. Exp Gerontol 20(5):253–263 [Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  105. Merry BJ, Holehan AM, Lewis SE, Goldspink DF (1987) The effects of ageing and chronic dietary restriction on in vivo hepatic protein synthesis in the rat. Mech Ageing Dev 39(2):189–199 [Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  106. Karunadharma PP, Basisty N, Dai D-F, Chiao YA, Quarles EK, Hsieh EJ et al (2015) Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell. doi:10.1111/acel.12317

    PubMed Central  Google Scholar 

  107. Hsieh EJ, Shulman NJ, Dai DF, Vincow ES, Karunadharma PP, Pallanck L et al (2012) Topograph, a software platform for precursor enrichment corrected global protein turnover measurements. Mol Cell Proteomics 11(11):1468–1474. doi:10.1074/mcp.O112.017699

    PubMed Central  PubMed  Google Scholar 

  108. Miller BF, Robinson MM, Bruss MD, Hellerstein M, Hamilton KL (2012) A comprehensive assessment of mitochondrial protein synthesis and cellular proliferation with age and caloric restriction. Aging Cell 11(1):150–161. doi:10.1111/j.1474-9726.2011.00769.x

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Price JC, Guan S, Burlingame A, Prusiner SB, Ghaemmaghami S (2010) Analysis of proteome dynamics in the mouse brain. Proc Natl Acad Sci U S A 107(32):14508–14513. doi:10.1073/pnas.1006551107

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y et al (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 100(21):12313–12318

    PubMed Central  CAS  PubMed  Google Scholar 

  111. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114(6):763–776, S0092867403006871 [pii]

    CAS  PubMed  Google Scholar 

  112. van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC et al (2014) c-kit + cells minimally contribute cardiomyocytes to the heart. Nature 509(7500):337–341. doi:10.1038/nature13309, nature13309 [pii]

    PubMed Central  PubMed  Google Scholar 

  113. Anversa P, Rota M, Urbanek K, Hosoda T, Sonnenblick EH, Leri A et al (2005) Myocardial aging--a stem cell problem. Basic Res Cardiol 100(6):482–493

    CAS  PubMed  Google Scholar 

  114. Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME et al (2006) Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res 99(1):42–52

    CAS  PubMed  Google Scholar 

  115. Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D et al (2004) The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem 279(24):25689–25695

    CAS  PubMed  Google Scholar 

  116. Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C et al (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122(2):221–233. doi:10.1016/j.cell.2005.05.011 [Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  117. Hsiao LC, Perbellini F, Gomes RS, Tan JJ, Vieira S, Faggian G et al (2014) Murine cardiosphere-derived cells are impaired by age but not by cardiac dystrophic dysfunction. Stem Cells Dev 23(9):1027–1036. doi:10.1089/scd.2013.0388

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324(5923):98–102. doi:10.1126/science.1164680, 324/5923/98 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M et al (2013) Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493(7432):433–436. doi:10.1038/nature11682, nature11682 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Senyo SE, Lee RT, Kuhn B (2014) Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. Stem Cell Res 13(3 Pt B):532–541. doi:10.1016/j.scr.2014.09.003

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Ouzounian M, Lee DS, Liu PP (2008) Diastolic heart failure: mechanisms and controversies. Nat Clin Pract Cardiovasc Med 5(7):375–386. doi:10.1038/ncpcardio1245 [Research Support, Non-U.S. Gov’t Review]

    PubMed  Google Scholar 

  122. Cieslik KA, Trial J, Crawford JR, Taffet GE, Entman ML (2014) Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J Mol Cell Cardiol 70:56–63. doi:10.1016/j.yjmcc.2013.10.017

    CAS  PubMed  Google Scholar 

  123. Cieslik KA, Trial J, Entman ML (2011) Defective myofibroblast formation from mesenchymal stem cells in the aging murine heart rescue by activation of the AMPK pathway. Am J Pathol 179(4):1792–1806. doi:10.1016/j.ajpath.2011.06.022

    PubMed Central  CAS  PubMed  Google Scholar 

  124. Cieslik KA, Taffet GE, Carlson S, Hermosillo J, Trial J, Entman ML (2011) Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol 50(1):248–256. doi:10.1016/j.yjmcc.2010.10.019

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Cieslik KA, Trial J, Carlson S, Taffet GE, Entman ML (2013) Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart: role of elevated circulating insulin levels. FASEB J 27(4):1761–1771. doi:10.1096/fj.12-220145

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74(2):184–195. doi:10.1016/j.cardiores.2006.10.002 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review]

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Brooks WW, Conrad CH (2000) Myocardial fibrosis in transforming growth factor beta(1)heterozygous mice. J Mol Cell Cardiol 32(2):187–195. doi:10.1006/jmcc.1999.1065 [Research Support, U.S. Gov’t, Non-P.H.S.]

    CAS  PubMed  Google Scholar 

  128. Wang M, Zhang J, Walker SJ, Dworakowski R, Lakatta EG, Shah AM (2010) Involvement of NADPH oxidase in age-associated cardiac remodeling. J Mol Cell Cardiol 48(4):765–772. doi:10.1016/j.yjmcc.2010.01.006 [Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov’t]

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Panek AN, Posch MG, Alenina N, Ghadge SK, Erdmann B, Popova E et al (2009) Connective tissue growth factor overexpression in cardiomyocytes promotes cardiac hypertrophy and protection against pressure overload. PLoS One 4(8):e6743. doi:10.1371/journal.pone.0006743 [Research Support, Non-U.S. Gov’t]

    PubMed Central  PubMed  Google Scholar 

  130. Reed AL, Tanaka A, Sorescu D, Liu H, Jeong EM, Sturdy M et al (2011) Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse. Am J Physiol Heart Circ Physiol 301(3):H824–H831. doi:10.1152/ajpheart.00407.2010

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Bonnema DD, Zile MR (2010) Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298(2):H614–H622. doi:10.1152/ajpheart.00474.2009 [Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, Non-P.H.S.]

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Tayebjee MH, Lip GYH, Blann AD, MacFadyen RJ (2005) Effects of age, gender, ethnicity, diurnal variation and exercise on circulating levels of matrix metalloproteinases (MMP)-2 and −9, and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMP)-1 and −2. Thromb Res 115(3):205–210

    CAS  PubMed  Google Scholar 

  133. Bonnema DD, Webb CS, Pennington WR, Stroud RE, Leonardi AE, Clark LL et al (2007) Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). J Card Fail 13(7):530–540. doi:10.1016/j.cardfail.2007.04.010 [Research Support, N.I.H., Extramural]

    PubMed Central  CAS  PubMed  Google Scholar 

  134. Spinale FG, Escobar GP, Mukherjee R, Zavadzkas JA, Saunders SM, Jeffords LB et al (2009) Cardiac-restricted overexpression of membrane type-1 matrix metalloproteinase in mice: effects on myocardial remodeling with aging. Circ Heart Fail 2(4):351–360. doi:10.1161/CIRCHEARTFAILURE.108.844845 [Research Support, N.I.H., Extramural Research Support, U.S. Gov’t, Non-P.H.S.]

    PubMed Central  CAS  PubMed  Google Scholar 

  135. Chiao YA, Dai Q, Zhang J, Lin J, Lopez EF, Ahuja SS et al (2011) Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging. Circ Cardiovasc Genet 4(4):455–462. doi:10.1161/CIRCGENETICS.111.959981 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J et al (2012) Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 96(3):444–455. doi:10.1093/cvr/cvs275 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Groban L, Pailes NA, Bennett CD, Carter CS, Chappell MC, Kitzman DW et al (2006) Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J Gerontol A Biol Sci Med Sci 61(1):28–35

    PubMed  Google Scholar 

  138. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F (2007) Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293(3):H1351–H1358. doi:10.1152/ajpheart.00393.2007, 00393.2007 [pii]

    CAS  PubMed  Google Scholar 

  139. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M et al (2009) Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119(3):524–530

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Stein M, Boulaksil M, Jansen JA, Herold E, Noorman M, Joles JA et al (2010) Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosterone system inhibitors in an aged mouse model. Am J Physiol Heart Circ Physiol 299(2):H310–H321. doi:10.1152/ajpheart.01137.2009, ajpheart.01137.2009 [pii]

    CAS  PubMed  Google Scholar 

  141. Inserra F, Basso N, Ferder M, Userpater M, Stella I, Paglia N et al (2009) Changes seen in the aging kidney and the effect of blocking the renin-angiotensin system. Ther Adv Cardiovasc Dis 3(5):341–346. doi:10.1177/1753944709339195, 1753944709339195 [pii]

    PubMed  Google Scholar 

  142. Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M et al (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90(4):E58–E65

    PubMed  Google Scholar 

  143. Doughan AK, Harrison DG, Dikalov SI (2008) Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102(4):488–496. doi:10.1161/CIRCRESAHA.107.162800, CIRCRESAHA.107.162800 [pii]

    CAS  PubMed  Google Scholar 

  144. Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY et al (2005) Mitochondria-derived reactive oxygen species and vascular MAP kinases: comparison of angiotensin II and diazoxide. Hypertension 45(3):438–444

    CAS  PubMed  Google Scholar 

  145. Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintron M, Chen T et al (2011) Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and G{alpha}q overexpression-induced heart failure. Circ Res 108(7):837–846. doi:10.1161/CIRCRESAHA.110.232306, CIRCRESAHA.110.232306 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Dai DF, Chen T, Szeto H, Nieves-Cintron M, Kutyavin V, Santana LF et al (2011) Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 58(1):73–82. doi:10.1016/j.jacc.2010.12.044, S0735-1097(11)01177-6 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT et al (2012) Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 93(1):79–88. doi:10.1093/cvr/cvr274 [Research Support, N.I.H., Extramural]

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X et al (2007) Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 100(10):1512–1521. doi:10.1161/01.RES.0000267723.65696.4a [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  149. Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A et al (2010) Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY) 2(12):914–923, 100252 [pii]

    CAS  Google Scholar 

  150. Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P et al (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153(4):828–839. doi:10.1016/j.cell.2013.04.015 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE et al (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. doi:10.1016/j.cmet.2015.05.010

    PubMed  Google Scholar 

  152. Quiat D, Olson EN (2013) MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J Clin Invest 123(1):11–18. doi:10.1172/JCI62876 [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review]

    PubMed Central  CAS  PubMed  Google Scholar 

  153. Smith-Vikos T, Slack FJ (2012) MicroRNAs and their roles in aging. J Cell Sci 125(Pt 1):7–17. doi:10.1242/jcs.099200 [Research Support, N.I.H., Extramural Review]

    PubMed Central  CAS  PubMed  Google Scholar 

  154. van Almen GC, Verhesen W, van Leeuwen RE, van de Vrie M, Eurlings C, Schellings MW et al (2011) MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure. Aging Cell 10(5):769–779. doi:10.1111/j.1474-9726.2011.00714.x [Research Support, Non-U.S. Gov’t]

    PubMed Central  PubMed  Google Scholar 

  155. Jazbutyte V, Fiedler J, Kneitz S, Galuppo P, Just A, Holzmann A et al (2013) MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age 35(3):747–762. doi:10.1007/s11357-012-9407-9 [Comparative Study Research Support, Non-U.S. Gov’t]

    PubMed Central  CAS  PubMed  Google Scholar 

  156. Boon RA, Iekushi K, Lechner S, Seeger T, Fischer A, Heydt S et al (2013) MicroRNA-34a regulates cardiac ageing and function. Nature 495(7439):107–110. doi:10.1038/nature11919 [Research Support, Non-U.S. Gov’t]

    CAS  PubMed  Google Scholar 

  157. Sun D, Huang A, Yan EH, Wu Z, Yan C, Kaminski PM et al (2004) Reduced release of nitric oxide to shear stress in mesenteric arteries of aged rats. Am J Physiol Heart Circ Physiol 286(6):H2249–H2256

    PubMed Central  CAS  PubMed  Google Scholar 

  158. Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF (2001) Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 37(2):529–534

    CAS  PubMed  Google Scholar 

  159. van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM et al (2000) Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192(12):1731–1744

    PubMed Central  PubMed  Google Scholar 

  160. Francia P, Delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E et al (2004) Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation 110(18):2889–2895

    CAS  PubMed  Google Scholar 

  161. Csiszar A, Labinskyy N, Orosz Z, Xiangmin Z, Buffenstein R, Ungvari Z (2007) Vascular aging in the longest-living rodent, the naked mole-rat. Am J Physiol 293:H919–H927

    CAS  Google Scholar 

  162. 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 103:1715–1721

    CAS  PubMed  Google Scholar 

  163. Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE et al (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):1659–1666

    CAS  PubMed  Google Scholar 

  164. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C et al (2003) Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299(5608):896–899

    CAS  PubMed  Google Scholar 

  165. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L et al (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310(5746):314–317

    CAS  PubMed  Google Scholar 

  166. Tschudi MR, Barton M, Bersinger NA, Moreau P, Cosentino F, Noll G et al (1996) Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery. J Clin Invest 98(4):899–905

    PubMed Central  CAS  PubMed  Google Scholar 

  167. Tanabe T, Maeda S, Miyauchi T, Iemitsu M, Takanashi M, Irukayama-Tomobe Y et al (2003) Exercise training improves ageing-induced decrease in eNOS expression of the aorta. Acta Physiol Scand 178(1):3–10

    CAS  PubMed  Google Scholar 

  168. 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):1685–1690

    PubMed  Google Scholar 

  169. 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):793–798

    CAS  PubMed  Google Scholar 

  170. Hoffmann J, Haendeler J, Aicher A, Rossig L, Vasa M, Zeiher AM et al (2001) Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ Res 89(8):709–715

    CAS  PubMed  Google Scholar 

  171. 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. doi:10.1113/jphysiol.2009.172221, jphysiol.2009.172221 [pii]

    PubMed Central  PubMed  Google Scholar 

  172. 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):671–680

    CAS  PubMed  Google Scholar 

  173. 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):21–30

    CAS  PubMed  Google Scholar 

  174. Csiszar A, Wang M, Lakatta EG, Ungvari ZI (2008) Inflammation and endothelial dysfunction during aging: role of NF-{kappa}B. J Appl Physiol 105(4):1333–1341. doi:10.1152/japplphysiol.90470.2008, 90470.2008 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Dai DF, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110(8):1109–1124. doi:10.1161/CIRCRESAHA.111.246140, 110/8/1109 [pii]

    CAS  PubMed  Google Scholar 

  176. Csiszar A, Podlutsky A, Wolin MS, Losonczy G, Pacher P, Ungvari Z (2009) Oxidative stress and accelerated vascular aging: implications for cigarette smoking. Front Biosci 14:3128–3144, 3440 [pii]

    CAS  Google Scholar 

  177. Adler A, Messina E, Sherman B, Wang Z, Huang H, Linke A et al (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–H1022

    CAS  PubMed  Google Scholar 

  178. Jacobson A, Yan C, Gao Q, Rincon-Skinner T, Rivera A, Edwards J et al (2007) Aging enhances pressure-induced arterial superoxide formation. Am J Physiol Heart Circ Physiol 293(3):H1344–H1350. doi:10.1152/ajpheart.00413.2007, 00413.2007 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  179. 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(12):1908–1918. doi:10.1038/sj.jcbfm.9600491, 9600491 [pii]

    CAS  PubMed  Google Scholar 

  180. Silva FH, Monica FZ, Bau FR, Brugnerotto AF, Priviero FB, Toque HA et al (2013) Superoxide anion production by NADPH oxidase plays a major role in erectile dysfunction in middle-aged rats: prevention by antioxidant therapy. J Sex Med 10(4):960–971. doi:10.1111/jsm.12063

    CAS  PubMed  Google Scholar 

  181. Kinkade K, Streeter J, Miller FJ (2013) Inhibition of NADPH oxidase by apocynin attenuates progression of atherosclerosis. Int J Mol Sci 14(8):17017–17028. doi:10.3390/ijms140817017, ijms140817017 [pii]

    PubMed Central  PubMed  Google Scholar 

  182. 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):388–698

    PubMed Central  CAS  PubMed  Google Scholar 

  183. Oudot A, Martin C, Busseuil D, Vergely C, Demaison L, Rochette L (2006) NADPH oxidases are in part responsible for increased cardiovascular superoxide production during aging. Free Radic Biol Med 40(12):2214–2222. doi:10.1016/j.freeradbiomed.2006.02.020, S0891-5849(06)00157-2 [pii]

    CAS  PubMed  Google Scholar 

  184. Dikalov SI, Ungvari Z (2013) Role of mitochondrial oxidative stress in hypertension. Am J Physiol Heart Circ Physiol 305(10):H1417–H1427. doi:10.1152/ajpheart.00089.2013, ajpheart.00089.2013 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  185. Springo Z, Tarantini S, Toth P, Tucsek Z, Tarantini S, Koller A, et al (2015) Aging exacerbates pressureinduced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol Biol Med Sci. doi:10.1093/gerona/glu244

    Google Scholar 

  186. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci U S A 107(35):15565–15570. doi:10.1073/pnas.1002178107, 1002178107 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Briones AM, Tabet F, Callera GE, Montezano AC, Yogi A, He Y et al (2011) Differential regulation of Nox1, Nox2 and Nox4 in vascular smooth muscle cells from WKY and SHR. J Am Soc Hypertens 5(3):137–153. doi:10.1016/j.jash.2011.02.001, S1933-1711(11)00041-6 [pii]

    CAS  PubMed  Google Scholar 

  188. Roos CM, Hagler M, Zhang B, Oehler EA, Arghami A, Miller JD (2013) Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice. Am J Physiol Heart Circ Physiol 305(10):H1428–H1439. doi:10.1152/ajpheart.00735.2012, ajpheart.00735.2012 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  189. 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):443–461. doi:10.1038/nrd3738, nrd3738 [pii]

    CAS  PubMed  Google Scholar 

  190. Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S et al (2014) Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab 20(1):183–190. doi:10.1016/j.cmet.2014.04.018, S1550-4131(14)00208-3 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  191. 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. doi:10.3389/neuro.24.004.2009

    PubMed Central  CAS  PubMed  Google Scholar 

  192. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N et al (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8(2):157–168

    PubMed Central  CAS  PubMed  Google Scholar 

  193. Carrizzo A, Puca A, Damato A, Marino M, Franco E, Pompeo F et al (2013) Resveratrol improves vascular function in patients with hypertension and dyslipidemia by modulating NO metabolism. Hypertension 62(2):359–366. doi:10.1161/HYPERTENSIONAHA.111.01009, HYPERTENSIONAHA.111.01009 [pii]

    CAS  PubMed  Google Scholar 

  194. Gao P, Xu TT, Lu J, Li L, Xu J, Hao DL et al (2014) Overexpression of SIRT1 in vascular smooth muscle cells attenuates angiotensin II-induced vascular remodeling and hypertension in mice. J Mol Med (Berl) 92(4):347–357. doi:10.1007/s00109-013-1111-4

    CAS  Google Scholar 

  195. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K et al (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299(1):H18–H24

    PubMed Central  CAS  PubMed  Google Scholar 

  196. Gano LB, Donato AJ, Pasha HM, Hearon CM Jr, Sindler AL, Seals DR (2014) The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am J Physiol Heart Circ Physiol 307(12):H1754–H1763. doi:10.1152/ajpheart.00377.2014, ajpheart.00377.2014 [pii]

    CAS  PubMed  Google Scholar 

  197. Kedenko L, Lamina C, Kedenko I, Kollerits B, Kiesslich T, Iglseder B et al (2014) Genetic polymorphisms at SIRT1 and FOXO1 are associated with carotid atherosclerosis in the SAPHIR cohort. BMC Med Genet 15(1):112. doi:10.1186/s12881-014-0112-7, s12881-014-0112-7 [pii]

    PubMed Central  PubMed  Google Scholar 

  198. Gorenne I, Kumar S, Gray K, Figg N, Yu H, Mercer J et al (2013) Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation 127(3):386–396. doi:10.1161/CIRCULATIONAHA.112.124404, CIRCULATIONAHA.112.124404 [pii]

    CAS  PubMed  Google Scholar 

  199. Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A et al (2014) The Sirt1 activator SRT3025 provides atheroprotection in Apoe−/− mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur Heart J. doi:10.1093/eurheartj/ehu095, ehu095 [pii]

    PubMed Central  PubMed  Google Scholar 

  200. Winnik S, Gaul DS, Preitner F, Lohmann C, Weber J, Miranda MX et al (2014) Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development. Basic Res Cardiol 109(1):399. doi:10.1007/s00395-013-0399-0

    PubMed Central  PubMed  Google Scholar 

  201. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E et al (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    CAS  PubMed  Google Scholar 

  202. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G (2003) Aging-induced proinflammatory shift in cytokine expression profile in rat coronary arteries. FASEB J 17(9):1183–1185

    CAS  PubMed  Google Scholar 

  203. Cernadas MR, Sanchez de Miguel L, Garcia-Duran M, Gonzalez-Fernandez F, Millas I, Monton M et al (1998) Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Circ Res 83(3):279–286

    CAS  PubMed  Google Scholar 

  204. Wang M, Zhang J, Jiang LQ, Spinetti G, Pintus G, Monticone R et al (2007) Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 50(1):219–227

    CAS  PubMed  Google Scholar 

  205. 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–H1263

    CAS  PubMed  Google Scholar 

  206. Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM, Goderie SK et al (2008) Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3(3):289–300. doi:10.1016/j.stem.2008.07.026, S1934-5909(08)00397-4 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  207. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201. doi:10.1016/j.neuron.2008.01.003, S0896-6273(08)00034-2 [pii]

    CAS  PubMed  Google Scholar 

  208. Fernandez-Vizarra P, Lopez-Franco O, Mallavia B, Higuera-Matas A, Lopez-Parra V, Ortiz-Munoz G et al (2012) Immunoglobulin G Fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice. Brain 135(Pt 9):2826–2837. doi:10.1093/brain/aws195, aws195 [pii]

    PubMed  Google Scholar 

  209. Zou Y, Yoon S, Jung KJ, Kim CH, Son TG, Kim MS et al (2006) Upregulation of aortic adhesion molecules during aging. J Gerontol A Biol Sci Med Sci 61(3):232–244

    PubMed  Google Scholar 

  210. Donato AJ, Black AD, Jablonski KL, Gano LB, Seals DR (2008) Aging is associated with greater nuclear NFkappaB, reduced IkappaBalpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans. Aging Cell 7(6):805–812. doi:10.1111/j.1474-9726.2008.00438.x, ACE438 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  211. 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):1397–1402

    CAS  PubMed  Google Scholar 

  212. Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE et al (2003) Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 41(6):1308–1316

    CAS  PubMed  Google Scholar 

  213. Wang M, Zhang J, Spinetti G, Jiang LQ, Monticone R, Zhao D et al (2005) Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats. Am J Pathol 167(5):1429–1442

    PubMed Central  CAS  PubMed  Google Scholar 

  214. Csiszar A, Gautam T, Sosnowska D, Tarantini S, Banki E, Tucsek Z et al (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. doi:10.1152/ajpheart.00307.2014, ajpheart.00307.2014 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  215. Erusalimsky JD (2009) Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol 106(1):326–332. doi:10.1152/japplphysiol.91353.2008, 91353.2008 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  216. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6(12):2853–2868. doi:10.1371/journal.pbio.0060301, 08-PLBI-RA-2566 [pii]

    CAS  PubMed  Google Scholar 

  217. Kajstura J, Cheng W, Sarangarajan R, Li P, Li B, Nitahara JA et al (1996) Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol 271(3 Pt 2):H1215–H1228

    CAS  PubMed  Google Scholar 

  218. Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P et al (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):313–329

    Google Scholar 

  219. Gardner AW, Parker DE, Montgomery PS, Sosnowska D, Casanegra AI, Ungvari Z et al (2014) Greater endothelial apoptosis and oxidative stress in patients with peripheral artery disease. Int J Vasc Med 2014:160534. doi:10.1155/2014/160534

    PubMed Central  PubMed  Google Scholar 

  220. Boddaert J, Mallat Z, Fornes P, Esposito B, Lecomte D, Verny M et al (2005) Age and gender effects on apoptosis in the human coronary arterial wall. Mech Ageing Dev 126(6–7):678–684. doi:10.1016/j.mad.2005.01.001, S0047-6374(05)00017-5 [pii]

    CAS  PubMed  Google Scholar 

  221. Wang H, Listrat A, Meunier B, Gueugneau M, Coudy-Gandilhon C, Combaret L et al (2014) Apoptosis in capillary endothelial cells in ageing skeletal muscle. Aging Cell 13(2):254–262. doi:10.1111/acel.12169

    PubMed Central  CAS  PubMed  Google Scholar 

  222. Tarnawski AS, Pai R, Tanigawa T, Matysiak-Budnik T, Ahluwalia A (2010) PTEN silencing reverses aging-related impairment of angiogenesis in microvascular endothelial cells. Biochem Biophys Res Commun 394(2):291–296. doi:10.1016/j.bbrc.2010.02.161, S0006-291X(10)00402-X [pii]

    CAS  PubMed  Google Scholar 

  223. 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. doi:10.1016/j.mad.2004.10.005, S0047-6374(04)00256-8 [pii]

    CAS  PubMed  Google Scholar 

  224. 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

    CAS  PubMed  Google Scholar 

  225. Ahluwalia A, Tarnawski AS (2011) Activation of the metabolic sensor – AMP activated protein kinase reverses impairment of angiogenesis in aging myocardial microvascular endothelial cells. Implications for the aging heart. J Physiol Pharmacol 62(5):583–587

    CAS  PubMed  Google Scholar 

  226. Ungvari Z, Tucsek Z, Sosnowska D, Toth P, Gautam T, Podlutsky A et al (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. doi:10.1093/gerona/gls242, gls242 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  227. Ungvari Z, Csiszar A (2012) The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci. doi:10.1093/gerona/gls072, gls072 [pii]

    Google Scholar 

  228. 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–H1073

    CAS  PubMed  Google Scholar 

  229. Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA et al (2001) Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 37(3):601–611, S0272638601863678 [pii]

    CAS  PubMed  Google Scholar 

  230. Montagna W, Carlisle K (1979) Structural changes in aging human skin. J Invest Dermatol 73(1):47–53

    CAS  PubMed  Google Scholar 

  231. Murugesan N, Demarest TG, Madri JA, Pachter JS (2011) Brain regional angiogenic potential at the neurovascular unit during normal aging. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2011.09.022, S0197-4580(11)00374-5 [pii]

    PubMed Central  PubMed  Google Scholar 

  232. Benderro GF, Lamanna JC (2011) Hypoxia-induced angiogenesis is delayed in aging mouse brain. Brain Res 1389:50–60. doi:10.1016/j.brainres.2011.03.016, S0006-8993(11)00513-0 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  233. 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, 63/1/12 [pii]

    PubMed  Google Scholar 

  234. 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

    CAS  PubMed  Google Scholar 

  235. 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):25–35, S0008636301005338 [pii]

    CAS  PubMed  Google Scholar 

  236. Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W et al (2013) Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5:27. doi:10.3389/fnagi.2013.00027

    PubMed Central  CAS  PubMed  Google Scholar 

  237. Tripathy D, Sanchez A, Yin X, Martinez J, Grammas P (2012) Age-related decrease in cerebrovascular-derived neuroprotective proteins: effect of acetaminophen. Microvasc Res 84(3):278–285. doi:10.1016/j.mvr.2012.08.004, S0026-2862(12)00153-7 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  238. Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S et al (2014) Age-related decline of autocrine PACAP impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol Biol Med Sci. doi:10.1093/gerona/glu1116

    Google Scholar 

  239. Csiszar A, Sosnowska D, Tucsek Z, Gautam T, Toth P, Losonczy G et al (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. doi:10.1093/gerona/gls158, gls158 [pii]

    PubMed Central  CAS  PubMed  Google Scholar 

  240. Lynch CD, Cooney PT, Bennett SA, Thornton PL, Khan AS, Ingram RL et al (1999) Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats. Neurobiol Aging 20(2):191–200, S0197458099000329 [pii]

    CAS  PubMed  Google Scholar 

  241. Maizel J, Xavier S, Chen J, Lin CH, Vasko R, Goligorsky MS (2014) Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction. Am J Physiol Heart Circ Physiol 307(12):H1691–H1704. doi:10.1152/ajpheart.00281.2014, ajpheart.00281.2014 [pii]

    CAS  PubMed  Google Scholar 

  242. Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R et al (2012) 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 Central  PubMed  Google Scholar 

  243. Chang EI, Loh SA, Ceradini DJ, Chang EI, Lin SE, Bastidas N et al (2007) Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation 116(24):2818–2829. doi:10.1161/CIRCULATIONAHA.107.715847, CIRCULATIONAHA.107.715847 [pii]

    CAS  PubMed  Google Scholar 

  244. Heiss C, Keymel S, Niesler U, Ziemann J, Kelm M, Kalka C (2005) Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol 45(9):1441–1448. doi:10.1016/j.jacc.2004.12.074, S0735-1097(05)00357-8 [pii]

    CAS  PubMed  Google Scholar 

  245. Thijssen DH, Vos JB, Verseyden C, van Zonneveld AJ, Smits P, Sweep FC et al (2006) Haematopoietic stem cells and endothelial progenitor cells in healthy men: effect of aging and training. Aging Cell 5(6):495–503. doi:10.1111/j.1474-9726.2006.00242.x, ACE242 [pii]

    CAS  PubMed  Google Scholar 

  246. Keymel S, Kalka C, Rassaf T, Yeghiazarians Y, Kelm M, Heiss C (2008) Impaired endothelial progenitor cell function predicts age-dependent carotid intimal thickening. Basic Res Cardiol 103(6):582–586. doi:10.1007/s00395-008-0742-z

    PubMed  Google Scholar 

  247. Zhu G, Song M, Wang H, Zhao G, Yu Z, Yin Y et al (2009) Young environment reverses the declined activity of aged rat-derived endothelial progenitor cells: involvement of the phosphatidylinositol 3-kinase/Akt signaling pathway. Ann Vasc Surg 23(4):519–534. doi:10.1016/j.avsg.2008.11.013, S0890-5096(09)00039-9 [pii]

    PubMed  Google Scholar 

  248. Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I et al (2004) Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94(4):514–524

    CAS  PubMed  Google Scholar 

  249. Humpert PM, Djuric Z, Zeuge U, Oikonomou D, Seregin Y, Laine K et al (2008) Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling. Mol Med 14(5–6):301–308. doi:10.2119/2007-00052.Humpert

    PubMed Central  CAS  PubMed  Google Scholar 

  250. Thum T, Hoeber S, Froese S, Klink I, Stichtenoth DO, Galuppo P et al (2007) Age-dependent impairment of endothelial progenitor cells is corrected by growth-hormone-mediated increase of insulin-like growth-factor-1. Circ Res 100(3):434–443

    CAS  PubMed  Google Scholar 

  251. Hoetzer GL, Van Guilder GP, Irmiger HM, Keith RS, Stauffer BL, DeSouza CA (2007) Aging, exercise, and endothelial progenitor cell clonogenic and migratory capacity in men. J Appl Physiol 102(3):847–852. doi:10.1152/japplphysiol.01183.2006, 01183.2006 [pii]

    PubMed  Google Scholar 

  252. Lakatta EG (1993) Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 73(2):413–467

    CAS  PubMed  Google Scholar 

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Acknowledgments

Y.A.C is a Glenn/AFAR postdoctoral fellow for Translational Research on Aging. We acknowledge support from NIH intramural funding for E.G.L., and the Ellison Medical Foundation and the American Federation for Aging Research, as well as NIH grants AG001751, AG038550 and HL101186 for P.S.R.

Editor: Youngsuk Oh, National Heart, Lung and Blood Institute (NHLBI), NIH.

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Authors and Affiliations

  1. Department of Pathology, University of Washington, Seattle, WA, 98195, USA

    Ying Ann Chiao Ph.D., Dao-Fu Dai M.D., Ph.D. & Peter Rabinovitch M.D., Ph.D.

  2. Laboratory of Cardiovascular Science, Biomedical Research Center, National Institute of Aging, Baltimore, MD, USA

    Edward Lakatta M.D.

  3. Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    Zoltan Ungvari M.D., Ph.D.

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  1. Ying Ann Chiao Ph.D.
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Correspondence to Peter Rabinovitch M.D., Ph.D. .

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  1. National Inst. of Aging Division of Aging Biology, National Institutes of Health, Bethesda, Maryland, USA

    Felipe Sierra

  2. National Inst on Aging/ National Inst of Health, Division of Aging Biology, Bethesda, Maryland, USA

    Ronald Kohanski

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Chiao, Y.A., Lakatta, E., Ungvari, Z., Dai, DF., Rabinovitch, P. (2016). Cardiovascular Disease and Aging. In: Sierra, F., Kohanski, R. (eds) Advances in Geroscience. Springer, Cham. https://doi.org/10.1007/978-3-319-23246-1_5

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