The combined influences of sinoatrial nodal (SAN) pacemaker cell automaticity and its response to autonomic input determine the heart’s beating interval variability and mean beating rate. To determine the intrinsic SAN and autonomic signatures buried within EKG RR interval time series change in advanced age, we measured RR interval variability before and during double autonomic blockade at 3-month intervals from 6 months of age until the end of life in long-lived (those that achieved the total cohort median life span of 24 months and beyond) C57/BL6 mice. Prior to 21 months of age, time-dependent changes in intrinsic RR interval variability and mean RR interval were relatively minor. Between 21 and 30 months of age, however, marked changes emerged in intrinsic SAN RR interval variability signatures, pointing to a reduction in the kinetics of pacemaker clock mechanisms, leading to reduced synchronization of molecular functions within and among SAN cells. This loss of high-frequency signal processing within intrinsic SAN signatures resulted in a marked increase in the mean intrinsic RR interval. The impact of autonomic signatures on RR interval variability were net sympathetic and partially compensated for the reduced kinetics of the intrinsic SAN RR interval variability signatures, and partially, but not completely, shifted the EKG RR time series intervals to a more youthful pattern. Cross-sectional analyses of other subsets of C57/BL6 ages indicated that at or beyond the median life span of our longitudinal cohort, noncardiac, constitutional, whole-body frailty was increased, energetic efficiency was reduced, and the respiratory exchange ratio increased. We interpret the progressive reduction in kinetics in intrinsic SAN RR interval variability signatures in this context of whole-body frailty beyond 21 months of age to be a manifestation of “heartbeat frailty.”

窦房结 (SAN) 起搏器细胞自动性及其对自主输入的响应的综合影响决定了心脏的搏动间隔变异性和平均搏动率。为了确定高龄时 EKG RR 间隔时间序列变化中隐藏的内在 SAN 和自主特征，我们在双自主神经封锁之前和期间以 3 个月的间隔测量了长寿者从 6 个月大到生命结束的 RR 间隔变异性。 （总队列中位寿命达到 24 个月及以上的小鼠）C57/BL6 小鼠。在 21 月龄之前，内在 RR 间隔变异性和平均 RR 间隔随时间的变化相对较小。然而，在 21 至 30 个月龄之间，内在 SAN RR 间隔变异性特征出现显着变化，表明起搏器时钟机制的动力学降低，导致 SAN 细胞内和之间分子功能的同步性降低。固有 SAN 特征中高频信号处理的损失导致平均固有 RR 间隔显着增加。自主信号对 RR 间隔变异性的影响是净同情的，并且部分补偿了内在 SAN RR 间隔变异性特征的动力学降低，并且部分但不完全地将 EKG RR 时间序列间隔转变为更年轻的模式。对 C57/BL6 年龄其他子集的横断面分析表明，在我们纵向队列的中位寿命或超过中位寿命时，非心脏、体质、全身虚弱程度增加，能量效率降低，呼吸交换比增加。我们将 21 个月以上全身虚弱的背景下内在 SAN RR 间隔变异性特征的动力学逐渐降低解释为“心跳虚弱”的表现。