Research Agenda for Cardiovascular Aging: Humans to Molecules
Edward G. Lakatta MD
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging; and the Intramural Research Program, National Institute of Health, Baltimore, MD 21224
Search for more papers by this authorEdward G. Lakatta MD
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging; and the Intramural Research Program, National Institute of Health, Baltimore, MD 21224
Search for more papers by this authorAbstract
Clinical manifestations of specific cardiovascular diseases, e.g., atherosclerosis and hypertension, that lead to heart failure and stroke likely become altered in older persons of advanced age because interactions occur between age-associated cardiovascular changes in health and specific pathophysiologic mechanisms that underlie cardiovascular diseases. The interactions result in a lower threshold for clinical symptoms, and greater severity and poorer prognosis of these diseases in older vs. younger persons. In this regard, cardiovascular changes that occur during aging in health ought not to be considered to reflect a “normal process”; rather these specific age-associated changes must be construed as specific “risk factors” for the aforementioned cardiovascular diseases and ought to become targets of interventions designed to prevent the epidemic of cardiovascular disease in later life. Such a strategy would thus advocate preventive treatment for what is now considered to be “normal cardiovascular aging.” Effective and efficient prevention of the “risks” associated with cardiovascular aging in apparent health requires a fundamental understanding of these changes ranging in scope from humans to molecules. An opinion regarding specific directions for research aimed toward the achievement of this understanding is provided.
References
- 1 Rowe J, Kahn RL. Successful aging. Gerontologist. 1997; 37: 433–440.
- 2 Celermajer DS, Sorensen KE, Spiegelhalter DJ, et al. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol. 1994; 24: 471–476.
- 3 Michel JB, Heudes D, Michel O, et al. Effect of chronic ANG I-converting enzyme inhibition on aging processes. II. Large arteries. Am J Physiol. 1994; 267: R124–R135.
- 4 Fornieri C, Quaglino D, Mori G. Role of the extracellular matrix in age-related modifications of the rat aorta. Arterioscler Thromb. 1992; 12: 1008–1016.
- 5 Haudenschild CC, Prescott MF, Chobanian AV. Aortic endothelial and subendothelial cells in experimental hypertension and aging. Hypertension. 1981; 3(suppl I): I148–I153.
- 6 Wolinsky H. Long-term effects of hypertension on the rat aortic wall and their relation to concurrent aging changes: Morphological and chemical studies. Circ Res. 1972; 30: 301–309.
- 7 Guyton JR, Lindsay KL, Dao DT. Comparison of aortic intima and inner media in young adult versus aging rats. Am J Pathol. 1983; 111: 234–246.
- 8 Jenkins GM, Crow MT, Bilato C, et al. The role of MMP-2 in neointima formation following balloon injury in the rat. Circulation. 1998; 97: 82–90.
- 9 Galis ZS, Suknova GK, Libby P. Microscopic localization of active proteases by in situ zymography: Detection of matrix metalloproteinase activity in vascular tissue. FASEB J. 1995; 9: 874–980.
- 10 Majesky MW, Lindner V, Twardzik DR, et al. Production of transforming growth factor β 1 during repair of arterial injury. J Clin Invest. 1991; 88: 904–910.
- 11 Li Z, Froehlich J, Galis Z, et al. Age-associated accumulation of matrix metalloproteinase-2 (MMP-2) within the rat aortic wall and increased MMP-2 production by vascular smooth muscle cells. AHA 70th Session: Circ Suppl. 1997; 96(8): I172.
- 12 Hariri RJ, Alonso DR, Hajjar DP, et al. Aging and atherosclerosis. I. Development of myointimal hyperplasmia after endothelial cell injury. J Exp Med. 1986; 164: 1171–1178.
- 13 Pauly RR, Passaniti A, Bilato C, et al. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation. Circ Res. 1994; 75: 41–54.
- 14 Pauly RR, Passaniti A, Crow M, et al. Experimental models which mimic the differentiation and dedifferentiation of vascular cells. Circulation. 1992; 86 (suppl 6): III68–III73.
- 15 Sarazani R, Arnaldi G, Takasaki I, et al. Effects of hypertension and aging on platelet-derived growth factor and platelet-derived growth factor receptor expression in rat aorta and heart. Hypertension. 1991; 18(suppl III): III93–III99.
- 16 McCaffrey TA, Nichlson AC, Szabo PE, et al. Aging and atherosclerosis: The increased proliferation of arterial smooth muscle cells isolated from old rats is associated with increased platelet derived growth factor-like activity. J Exp Med. 1988; 167: 163–174.
- 17 Stemerman MB, Weinstein R, Rowe JW, et al. Vascular smooth muscle cell growth kinetics in vivo in aged rats. Proc Natl Acad Sci USA. 1982; 79: 3863–3866.
- 18 Senior RM, Griffin GL, Fliszar CJ, et al. Human 92- and 72-kilodalton type IV collagenase are elastases. J Biol Chem. 1991; 266: 7870–7875.
- 19 Hornebeek W, Adnet JJ, Robert L. Age dependent variation of elastin and elastase in aorta and human breast cancers. Exp Gerontol. 1978; 13: 293–298.
- 20 Robert L. Aging of the vascular wall and atherogenesis: Role of the elastin-laminin receptor. Atherosclerosis. 1996; 123: 169–179.
- 21 Shapiro SD, Griffin GL, Gilbert DJ, et al. Molecular cloning, chromosomal localization, and bacterial expression of a murine macrophage metallelastase. J Biol Chem. 1992; 267: 4664–4671.
- 22 McCaffrey TA, Nichlson AC, Szabo PE, et al. Aging and atherosclerosis: The increased proliferation of arterial smooth muscle cells isolated from old rats is associated with increased platelet derived growth factor-like activity. J Exp Med. 1988; 67: 163–174.
- 23 Nagai J, Metter EJ, Earley CJ, et al. Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation. 1998; 98: 1504–1509.
- 24 O'Leary DH, Polak JF, Kronmal RA, et al, for the Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and medial thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999; 340: 14–22.
- 25 Vaitkevicius PV, Fleg JL, Engel JH. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation. 1993; 88: 1456–1462.
- 26 Gerstenblith G, Fredricksen J, Yin FCP, et al. Echocardiographic assessment of a normal adult ageing population. Circulation. 1977; 56: 273–278.
- 27 Olivetti G, Melissari M, Capasso JM, et al. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991; 68: 1560–1568.
- 28 Lakatta EG. Deficient neuroendocrine regulation of the cardiovascular system with advancing age in healthy humans (point of view). Circulation. 1993; 87: 631–636.
- 29 Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev. 1993; 73: 413–467.
- 30 Anversa P, Palackal T, Sonnenblick EH, et al. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart Circ Res. 1990; 67: 671.
- 31 Fraticelli A, Josephson R, Danziger R, et al. Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence. Am J Physiol. 1989; 257: H259.
- 32 Wei JY, Spurgeon HA, Lakatta EG. Excitation-contraction in rat myocardium: Alterations with adult aging. Am J Physiol. 1984; 246: H784.
- 33 Capasso JM, Malhotra A, Remily RM, et al. Effects of age on mechanical and electrical performance of rat myocardium. Am J Physiol. 1983; 245: H72.
- 34 Esler MD, Turner AG, Kaye DM, et al. Ageing effects on human sympathetic neuronal function. Am. J. Physiol. 1995; 268: R278–R285.
- 35 Fleg JL, Tzankoff SP, Lakatta EG. Age-related augmentation of plasma catecholamines during dynamic exercise in healthy males. J Appl Physiol. 1985; 59: 1033–1039.
- 36 Kajstura J, Cheng W, Sarangarajan R, et al. Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol. 1996; 271: H1215–H1228.
- 37 Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death. J Clin Invest. 1995; 96: 2247–2259.
- 38 Cigola E, Kastura J, Li B, et al. Angiotensin II activates programmed myocyte cell death in vitro. Exp Cell Res. 1997; 231: 363–371.
- 39 Walker KE, Lakatta EG, Houser SR. Age associated changes in membrane currents in rat ventricular myocytes. Cardiovasc Res. 1993; 27: 1968.
- 40 Froehlich JP, Lakatta EG, Beard E, et al. Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium. J Molec Cell Cardiol. 1978; 10: 427.
- 41 Orchard CH, Lakatta EG. Intracellular calcium transients and developed tensions in rat heart muscle. A mechanism for the negative interval-strength relationship. J Gen Physiol. 1985; 86: 637.
- 42 Lompre AM, Lambert F, Lakatta EG, et al. Expression of sarcoplasmic reticulum Ca 2+– ATPase and calsequestrin genes in rat heart during ontogenic development and aging. Circ Res. 1991; 69: 1380.
- 43 Maciel LMZ, Polikar R, Rohrer D, et al. Age-induced decreases in the messenger RNA coding for the sarcoplasmic reticulum Ca2+–ATPase of the rat heart. Circ Res. 1990; 67: 230.
- 44 Tate CA, Taffet GE, Hudson EK, et al. Enhanced calcium uptake of cardiac sarcoplasmic reticulum in exercise-trained old rats. Am J Physiol. 1990; 258: H431.
- 45 Effron MB, Bhatnagar GM, Spurgeon HA, et al. Changes in myosin isoenzymes, ATPase activity and contraction duration in rat cardiac muscle with aging can be modulated by thyroxine. Circ Res. 1987; 60: 238–245.
- 46 O'Neill L, Holbrook NJ, Fargnoli J, et al. Progressive changes from young adult age to senescence in mRNA for rat cardiac myosin heavy chain genes. Cardioscience. 1991; 2: 1–5.
- 47 Bhatnagar GM, Walford GD, Beard ES, et al. ATPase activity and force production in myofibrils and twitch characteristics in intact muscle from neonatal, adult, and senescent rat myocardium. J Molec Cell Cardiol. 1984; 16: 203.
- 48 Koban MU, Moorman AFM, Holtz J, et al. Expressional analysis of the cardiac Na-Ca exchanger in rat development and senescence. Cardiovasc Res. 1998; 37: 405–423.
- 49 Hano O, Bogdanov KY, Sakai M, et al. Reduced threshold for myocardial cell calcium intolerance in the rat heart with aging. Am J Physiol. 1995; 269: H1607.
- 50 Lakatta EG. Chaotic behavior of myocardial cells: Possible implications regarding the pathophysiology of heart failure. Perspect Biol Med. 1989; 32: 421–433.
- 51 Schulman SP, Lakatta EG, Fleg JL, et al. Age-related decline in left ventricular filling at rest and exercise. Am J Physiol. 1992; 263: H1932–H1938.
- 52 Swinne CJ, Shapiro EP, Lima SD, et al. Age-associated changes in left ventricular diastolic performance during isometric exercise in normal subjects. Am. J Cardiol. 1992; 69: 823–826.
- 53 Fleg JL, Lakatta EG. Role of muscle loss in the age-associated reduction in VO2 max. J Appl Physiol. 1988; 65(3): 1147–1151.
- 54 Fleg JL, O'Connor FC, Gerstenblith G, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol. 1995; 78: 890–900.
- 55 Iwase S, Mano T, Watanabe T, et al. Age-related changes of sympathetic outflow to muscles in humans. J Gerontol. 1991; 46: M1–M5.
- 56 Hogikyan RV, Supiano MA. Arterial α-adrenergic responsiveness is decreased and SNS activity is increased in older humans. Am J Physiol. 1994; 266: E717–E724.
- 57 Sudhir K, Esler MD, Jennings GL, et al. Estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover in perimenopausal women. Hypertension. 1997; 30: 1538–1543.
- 58 Xiao R-P, Spurgeon HA, O'Connor F, et al. Age-associated changes in β adrenergic modulation on rat cardiac excitation-contraction coupling. J Clin Invest. 1994; 94: 2051.
- 59 Scarpace PJ. Forskolin activation of adenylate cyclase in rat myocardium with age: Effects of guanine nucleotide analogs. Mech Ageing Dev. 1990; 52: 169.
- 60 Xiao R-P, Tomhave ED, Xiangwu J, et al. Age-associated reductions in cardiac β1- and β2-adrenoceptor responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest. 1998; 101: 1273–1282.
- 61 Jiang MT, Moffat MP, Narayanan N. Age-related alterations in the phosphorylation of sarcoplasmic reticulum and myofibrillar proteins and diminished contractile response to isoproterenol in intact rat ventricle. Circ Res. 1993; 72: 102.
- 62 Sakai M, Danzinger RS, Staddon JM, et al. Decrease with senescence in the norepinephrine-induced phosphorylation of myofilament proteins in isolated rat cardiac myocytes. J Molec Cell Cardiol. 1989; 21: 1327–1336.