Editor’s summary
Changes in innervation of the heart can contribute to arrhythmias, and the risk of arrhythmias greatly increases with age. Wagner et al. uncovered a mechanism connecting these two phenomena. The authors studied young and aging mice and demonstrated that innervation of the heart decreases with age. Age-related accumulation of senescent cells promotes the release of semaphorin-3A, which reduces the density of neuronal axons in the heart. At the same time, aging is associated with a decrease in a microRNA that counteracts the effects of semaphorin-3A, further tipping the balance toward decreased innervation. These age-related losses in innervation could be reversed by treating the mice with senolytic drugs, suggesting a potential therapeutic approach.
—Yevgeniya Nusinovich
Abstract
Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes. Aging down-regulates microRNA 145 (miR-145) and derepresses the neurorepulsive factor semaphorin-3A. miR-145 deletion, which increased Sema3a expression or endothelial Sema3a overexpression, reduced axon density, mimicking the aged-heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reversed Sema3a expression, preserved heart rate patterns, and reduced electrical instability. These data suggest that senescence-mediated regulation of nerve density contributes to age-associated cardiac dysfunction.
Permalink
https://doi.org/10.1126/science.ade4961
https://pubmed.ncbi.nlm.nih.gov/37616346
Cite this article:
Wagner JUG, Tombor LS, Malacarne PF, Kettenhausen LM, Panthel J, Kujundzic H, Manickam N, Schmitz K, Cipca M, Stilz KA, Fischer A, Muhly-Reinholz M, Abplanalp WT, John D, Mohanta SK, Weber C, Habenicht AJR, Buchmann GK, Angendohr S, Amin E, Scherschel K, Klöcker N, Kelm M, Schüttler D, Clauss S, Günther S, Boettger T, Braun T, Bär C, Pham MD, Krishnan J, Hille S, Müller OJ, Bozoglu T, Kupatt C, Nardini E, Osmanagic-Myers S, Meyer C, Zeiher AM, Brandes RP, Luxán G, Dimmeler S. Aging impairs the neurovascular interface in the heart. Science. 2023 Aug 25;381(6660):897-906. doi: 10.1126/science.ade4961. Epub 2023 Aug 24. PMID: 37616346.