Perspectives on mammalian cardiovascular aging: humans to molecules.
Age-related changes in cardiovascular function and structure in healthy adult volunteer community dwelling subjects (from 20 to 85 years) is remarkable for changes in pump function [impaired left ventricular (LV) ejection reserve capacity manifest by a reduced ejection fraction and accompanied by diminished cardioacceleration, LV dilation at end diastole and an altered diastolic filling pattern] and increased vascular afterloading. There is also evidence for a reduction in the number of cardiac myocytes with advancing age. Subcellular changes with aging (best understood in rodents) include certain regulatory factors of excitation-contraction-relaxation coupling (i.e. calcium handling), modulation by adrenergic receptor (AR) stimulation, and changes in the generation and sensitivity to the damaging effects of ROS. Coordinated changes in gene expression and/or protein function with aging result in a prolonged action potential (AP), Ca(i) transient, and contraction. L-type Ca(2+) current (I(Ca)) inactivates more slowly, and outwardly-directed K(+) currents are reduced, and likely contribute to AP-prolongation. The rate of Ca(2+) sequestration by the sarcoplasmic reticulum (SR) decreases in the senescent myocardium, in part underlying the prolonged Ca(i) transient. An age-associated reduction in transcription of the SERCA2 gene, coding for the SR Ca(2+) pump, accounts in part for a decrease in the SR pump site density. The contractile response to both beta(1)-AR and beta(2)-AR stimulation diminishes with aging due to decreased adrenergic augmentation of I(Ca), and thus the Ca(i) transient, in senescent vs. young hearts. The age-associated reduction in the postsynaptic response of myocardial cells to beta(1)-AR stimulation appears to be due to multiple changes in molecular and biochemical receptor coupling and post-receptor mechanisms. An increased basal production of ROS is paralleled by increased ROS-sensitivity, markers of chronic ROS damage and mitochondrial functional decline. Overall, these changes lead to a diminished (but not necessarily exhausted) capacity of the heart to adapt to physiological or pathological stress with advancing age.
Lakatta
Edward G
EG
Laboratory of Cardiovascular Science, NIA Intramural Research Program, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. lakattae@grc.nia.nih.gov
Sollott
Steven J
SJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation; D008563:Membrane Lipids / Q000378:metabolism; D008875:Middle Aged; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D013312:Stress, Physiological / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology
D008563:Membrane Lipids; D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta