Heart rate is finely tuned through neural control to maintain body homeostasis in constantly changing conditions. Although some of the mechanisms behind the pacemaker slowdown are being elucidated, there are still many unanswered questions. Hence, aging is the leading risk factor for heart pacemaker dysfunction, which justifies the urgency of understanding the pacemaker’s age-dependent decline. This syndrome is the main cause for more than 600,000 artificial pacemaker implantations carried out annually in the world. In pathological cases, this slowdown results in arrhythmia and sometimes sudden death as part of a group of idiopathic disorders known as Sick Sinus Syndrome. The slowdown of the intrinsic pacemaker rate is the main cause for the accompanying decline in maximum heart rate, playing a significant role in the loss of aerobic capacity in older adults. The intrinsic pacemaker rate declines linearly from birth at a rate of ~ 0.8 bpm/year in humans and ~ 4 bpm/month in mice. Mammals, including humans and mice, experience a natural and continuous decrease in the intrinsic pacemaker rate throughout their entire lifespan (Fig. Despite the remarkable reliability of this tissue, the pacemaker is not exempt from the detrimental effects of aging. The automaticity of the cardiac pacemaker relies on the unique ability of its cells to continuously generate action potentials, starting very early during embryonic development and working non-stop until the moment we die. ![]() Every heartbeat starts with a subtle electrical spark inside the sinoatrial node, a small and highly specialized tissue located next to the right atrium also known as the cardiac pacemaker. On average, the human heart beats 100,000 times a day. In this review, we revisit the main evidence on the neural control of the pacemaker at the tissue and cellular level and the effects of aging on shaping this neural control. Such evidence includes remodeling of pacemaker tissue architecture, alterations in the innervation, changes in the sympathetic acceleration and the parasympathetic deceleration, and alterations in the responsiveness of pacemaker cells to adrenergic and cholinergic modulation. ![]() Neural control of the pacemaker is remodeled from birth to adulthood, with strong evidence of age-related dysfunction that leads to a downshift of the pacemaker. ![]() Why the pacemaker rhythm slows with age is poorly understood. Mammals experience a natural and continuous decrease in the pacemaker rate throughout the entire lifespan. Sympathetic and parasympathetic terminals act over the pacemaker cells as the accelerator and the brake pedals, increasing or reducing the firing rate of pacemaker cells to match physiological demands. Pacemaker rate is constantly tuned by the autonomous nervous system to maintain body homeostasis. The cardiac pacemaker ignites and coordinates the contraction of the whole heart, uninterruptedly, throughout our entire life.
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