© 2017 Elsevier B.V. Dysregulation of autonomic control often develops with advancing age, favoring a chronic state of heightened sympathetic outflow with parasympathetic withdrawal. However, the mechanisms of this age-related autonomic impairment are not known. This study tested the hypothesis that inter-individual differences in autonomic outflow across the adult age-span are related to cerebral cortex thickness. A total of 55 healthy, active individuals participated in this study (21–73 years; 18 female). Physical fitness was treated as a possible covariate (VO2peak: 26–81 mL/kg/min). Cardiovagal baroreflex sensitivity, heart rate variability, and muscle sympathetic nerve activity (MSNA) were assessed during a laboratory session. T1-weighted images acquired at 3 T facilitated measures of cortical thickness (Brain Voyager 2.8.4). A priori cortical regions of interest included the medial prefrontal cortex (MPFC) and insula cortex. Cortical thickness at the MPFC correlated strongly with markers of autonomic outflow including heart rate variability (ln-high frequency power (slope: − 16, r2 = 0.65), SDNN (slope: 22, r2 = 0.22), total power (slope: 2872, r2 = 0.24)), and MSNA variables (burst frequency (slope: 1, r2 = 0.16), burst incidence (slope: − 26, r2 = 0.62) and total MSNA (slope: − 847, r2 = 0.56)). Further associations with burst incidence were observed within the left insula (p < 0.05). Importantly, the strength of the relationship between autonomic variables and cortical thickness was determined by age, and was not altered following adjustments for cardiorespiratory fitness. The current results implicate cortical atrophy in the frontal lobe as a contributor to both the sympathetic and parasympathetic changes that occur with age.