Senolytic treatment with dasatinib and quercetin selectively improves cardiac autonomic balance in obesity.

Abstract

Chronic sympathetic nerve activity (SNA) to end organs plays a crucial role in the pathophysiology of obesity-induced hypertension. Oxidative stress and neuroinflammation in the rostral ventrolateral medulla (RVLM), a key brainstem region regulating sympathetic outflow, have been implicated in the sympathetic overactivity in obesity. However, the upstream mechanisms driving RVLM neuroinflammation remain unknown. We hypothesized that obesity induces cellular senescence, a stress response characterized by irreversible cell cycle arrest, in the RVLM and contributes to sympathoexcitation. To test this, C57BL/6 J male mice were fed chow or a high-fat diet (HFD) for 16 weeks, followed by treatment with Dasatinib (5 mg/kg) and Quercetin (50 mg/kg) (D + Q) to selectively eliminate senescent cells. Blood pressure was assessed by radiotelemetry in conscious, freely moving mice. SNA was indirectly measured through heart rate variability (HRV) analysis, depressor response to hexamethonium, and serum norepinephrine levels. The RVLM was microdissected for gene expression and protein analysis of senescence markers and DNA damage. Our results showed that HFD mice had a significant increase in mean arterial pressure and SNA compared to chow-fed controls. Obesity was associated with increased DNA damage and upregulation of cellular senescence markers in the RVLM. Senolytic treatment with D + Q selectively improved cardiac autonomic balance as assessed by HRV, without altering indices of global SNA or blood pressure. Collectively, our findings identify cellular senescence in the RVLM as a novel contributor to obesity-induced sympathoexcitation, and senolytic therapy could be a potential therapeutic avenue for obesity-associated autonomic dysfunction.