Age-associated deficient pacemaker function. (A) Age-associated reduction in basal beating interval and sensitivity to PDE inhibition by IBMX and β-AR stimulation by ISO. Note that the maximal beating rate is restored in response to maximal IBMX or ISO concentration (adapted from Yaniv et al. [2016]). Data are presented as mean ± SD. (B) Age-associated reduction in L-type, T-type, and HCN current conductance (adapted from Larson et al. [2013]) shown for sinoatrial node myocytes in mice aged 2–3 mo (black), 21–24 mo (green), and 28 mo (red) in the absence (filled circles) and presence (open circles) of 1 µM ISO. Data are presented as average ± SEM. (C) Age-associated reduced LCR ensemble, SERCA, and RyR2 presence (adapted from Liu et al. [2014]). From top to bottom: mean amplitudes of Ca²⁺ signals of the LCR ensemble (integrated Ca²⁺ signal produced by each LCR); representative Western blots of SAN (protein expression), atrial and ventricular tissues from adult (2–4 mo) and aged (24–27 mo) mice normalized to sarcomeric actin levels; RyR protein levels. Data are presented as mean ± SD. (top) *, P < 0.05 versus adult, mixed effects model for repeated measure ANOVA; (middle) *, P < 0.05 versus adult, two-tailed t test; (bottom) **, P < 0.01 versus adult; and *, P < 0.05, two-tailed t test.