Ageing is an important risk factor for impaired cardiovascular health. The ageing myocardium is characterised by microcirculatory dysfunction and nerves are connected to vessels. However, the impact of aging on the interaction of the nervous system with the vasculature and a possible contribution towards cardiac pathologies has not been the focus of research yet.
In a recent elegant and comprehensive study in Science, Stefanie Dimmeler, Julian Wagner, and colleagues have investigated how aging effects the neurovascular interface of the heart.
They compared the nervous system in the heart of old (>16 months) and young (3 months) mice and showed that innervation of sympathetic, parasympathetic, and sensory neurons in specific areas of the heart declines in an age-dependent manner, which is associated with ventricular tachycardia. The authors then showed that the decline in innervation is mediated by ageing endothelial cells (EC). and sequencing demonstrated that aging dysregulates vascular-derived neuroregulatory genes associated with derepressed expression of semaphorin-3a (Sema3a). The authors subsequently verified this causal relationship by various knockdown and supernatant-treatment experiments. This suggests that EC senescence comes first, and cardiac denervation follows. Gavage of senolytics to aged mice resulted in the removal of senescent cells, interfered with age-induced cardiac denervation, reduced Sema3a expression and rescued cardiac electrophysiological function.
This study identifies a novel mechanism of the EC-secreted semaphorin-3a as a factor in the "senescence-associated secretory phenotype". The potential of senolytics for clinical applications to improve the health of the ageing heart needs further investigation but is undoubtedly a valuable contribution to reducing the burden of senescence.
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