Microglia and astrocytes are essential regulators of central nervous system homeostasis; however, during ageing and chronic disease these glial populations undergo maladaptive phenotypic transitions characterised by loss of homeostatic function, heightened reactivity, and acquisition of pro-inflammatory and senescent features. Such changes are increasingly implicated in sustained neuroinflammation and the process of inflammaging. The paraventricular nucleus (PVN) of the hypothalamus serves as a critical integrative centre for autonomic and neuroendocrine control, exerting powerful influence over sympathetic outflow through projections to cardiovascular regulatory nuclei. Disruption of glial homeostasis within the PVN therefore represents a plausible mechanism linking neuroinflammation to autonomic dysregulation in cardiovascular disease. 

Using immunohistochemistry, we examined glial activation and cellular senescence within the PVN in an isoproterenol (ISO; 150 mg/kg)-induced mouse model of heart failure across age groups. All experimental procedures were conducted in accordance with the regulations for animal testing, directed by the Home Office and stipulated under the under the Animal (Scientific Procedures) Act 1986. ISO treatment resulted in robust microglial activation in the PVN of both young (n = 9; 12-week-old; 429.00 ± 85.10) and aged (n =6; 23-month-old; 766.83 ± 76.28) mice, accompanied by marked astrocytic reactivity in young (109.47 ± 14.20) and aged animals (815.39 ± 205.37). Notably, ageing significantly amplified the magnitude of glial activation, indicating an age-dependent vulnerability of the PVN to inflammatory remodelling. Consistent with this, expression of the senescence marker p16^INK4a was elevated in the PVN following ISO treatment in young (3.09 ± 1.81) and aged mice (18.24 ± 5.11), suggesting that cellular senescence contributes to the pro-inflammatory glial milieu. 

Importantly, post-ISO administration of the senolytic combination dasatinib (5 mg/kg) and quercetin (50 mg/kg) in aged mice significantly attenuated PVN glial reactivity, reducing microglial (502.62 ± 97.44) and astrocytic activation (533.37 ± 31.24), alongside a marked decrease in p16^INK4a expression (15.58 ± 3.32 vs. 3.09 ± 1.81). These findings indicate that senescent cells actively contribute to PVN centred neuroinflammation and that their selective clearance can partially restore glial homeostasis. 

Collectively, our data demonstrate that heart failure and biological ageing synergistically drive a reactive and pathological glial phenotype within the PVN, implicating glial senescence as a key mechanistic link between neuroinflammation and maladaptive sympathetic regulation. This study provides proof-of-concept evidence that region specific targeting of senescent and over activated glial cells may represent a novel therapeutic strategy for mitigating neurogenic contributions to cardiovascular disease.