Grant: Project Grant

The normal heartbeat is initiated in the pacemaker of the heart (the sinoatrial node). From the sinoatrial node the heartbeat is conducted to the surrounding atria (the upper chambers of the heart) and then to the rest of the heart. When this pattern is disrupted, arrhythmias, such as sinoatrial node arrhythmias and atrial fibrillation, can result. Aging is a major risk factor for these arrhythmias; however the mechanisms are not well understood. Furthermore, it is well known that not all individuals age at the same rate. Instead, some individuals age more successfully, showing fewer signs of aging-related declines in health, while others of the same chronological age are not so lucky. This has led to the concept of frailty, defined as a state of increased vulnerability to adverse health outcomes. My laboratory has pioneered the development of the 'mouse clinical frailty index' for measuring frailty in aging mice and shown that SAN disease and atrial fibrillation are strongly related to the degree of frailty. Caloric restriction (a modest reduction in caloric intake without malnutrition) has been shown to promote healthy aging and increase longevity in aging mammals, including humans. This suggests that caloric restriction could prevent frailty and improve cardiac function in aging individuals. Accordingly, we have begun to study the effects of caloric restriction on frailty, as well as sinoatrial node disease and atrial fibrillation, in aging mice. Our new data show that caloric restriction potently improves frailty index scores in aging mice. Moreover, caloric restriction prevents sinoatrial node disease and reduces the susceptibility to atrial fibrillation in aging mice. Strikingly, these improvements are strongly related the degree of frailty in aging mice. Our proposed studies will build on these new findings and fully explore the effects of caloric restriction on frailty, as well as sinoatrial node disease and atrial arrhythmias, in aging mice.