Ageing impairs the neuro-vascular interface in the heart

Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by electrophysiological dysfunctions such as a reduced heart rate variability. These alterations can be intrinsic within cardiomyocytes, but might be modulated by the cardiac autonomic nervous system, as well[1][1]. It is known that nerves align with vessels during development[2][2], but the impact of aging on the cardiac neuro-vascular interface is unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads further to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion increased Sema3a expression and reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age while nerve density declined, rescued from age-induced dennervation, reduced Sema3a expression and preserved heart rate variability. These data suggest that senescence-associated regulation of neuro-regulatory genes contributes to a declined nerve density of the aging heart and thereby to a reduced heart rate variability. ### Competing Interest Statement The study is supported by non-profit organisations: the German Research Foundation (SFB1366, Project B4; TRR267, Project B3 and the Cluster of Excellence Cardiopulmonary Institute Exc2026/1), the German Center for Cardiovascular Research (DZHK Shared Expertise (B22-014 SE)), the Dr. Rolf-M.-Schwiete Foundation (2021-002) and the European Research Council. [1]: #ref-1 [2]: #ref-2