Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. Additionally, we assessed whether rapamycin, an anti-aging treatment, reverses the age-related changes in sympathetic motor neurons. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of KCNQ channel currents emerged as a major contributor to age-related hyperexcitability. The administration of rapamycin in food for 12 weeks in middle-aged mice partially reverted the KCNQ current reduction and hyperexcitability associated with age. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity. Further, our data suggest that rapamycin’s beneficial anti-aging effects may be partly attributed to its potential to impact sympathetic nervous system components, providing novel insights into therapeutic strategies for age-related conditions.