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 Ca²⁺ current (I_Ca) inactivates more slowly, and outwardly-directed K⁺ currents are reduced, and likely contribute to AP-prolongation. The rate of Ca²⁺ 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 Ca²⁺ pump, accounts in part for a decrease in the SR pump site density. The contractile response to both β₁-AR and β₂-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 β₁-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.