We have completed the first part of the study (as published by Wagner et al in Science 2023). The publication investigates the relationship between aging and cardiovascular health, particularly focusing on the neurovascular interface in the heart. In particular, the research demonstrated the decline of nerve density in the heart and how this impacts overall cardiac health and includes work performed by all four work packages as follows.
Key findings
1. Dysregulation of innervation of the aging heart (WP 1): We observed significant alterations in the aging heart. We found that the density of sympathetic, parasympathetic and sensory nerves in the left ventricle of aging hearts significantly declines. Interestingly, there was no change in the right heart and even an augmented innervation in the atria, a finding which we are currently further exploring. Moreover, we have finalized histologic studies to elucidate the alignment of nerves with vessels, including lymphatics (unpublished).
2. Dysregulation of Neurovascular Genes (WP2): Aging was shown to dysregulate the expression of several genes involved in neuroregulation, particularly produced by the vasculature. We showed that the expression of the repulsive cue Semaphorin 3a (Sema3a) in endothelial cells can cause cardiac denervation showing that the disruption in endothelial gene regulation plays a critical role in the degradation of the neurovascular network, further contributing to cardiac dysfunction.
3. Role of MicroRNA 145 (miR-145) (WP2): The study identifies microRNA 145 (miR-145) as a crucial factor in maintaining nerve density within the heart. In aging hearts, miR-145 is downregulated, which leads to the derepression of semaphorin-3A (Sema3a), a neurorepulsive factor that inhibits nerve growth. Deletion of miR-145, which leads to increased Sema3a expression, or overexpression of Sema3a in endothelial cells, results in reduced axon density and altered heart rate variability in the heart. This reduction mirrors the nerve density loss and decreased heart rate variability seen in aged hearts, reinforcing the idea that miR-145 and Sema3a play a pivotal role in age-related neurovascular dysfunction.
4. Senescence and Cardiac Denervation (WP4): The study also identifies the accumulation of senescent cells as a key factor in age-related cardiac denervation. Senescent cells increase in number as the heart ages, coinciding with the reduction in nerve density. This accumulation appears to be a significant contributor to the overall decline in cardiac function with age.
5. Reversing Age-Related Effects (WP4): In a promising discovery, the removal of senescent cells in aged models rescues the heart from denervation. By eliminating these cells, we were able to reverse the increase in Sema3a expression, restore nerve density, and improve heart rate patterns. Additionally, the elimination of senescent cells reduced electrical instability in the heart, which is important for preventing arrhythmias and maintaining healthy cardiac rhythms.
