A small but increasing fraction of the supporting glial cells of the brain become senescent in later life, and there is good evidence from animal studies for this to be an important contributing cause of neurodegeneration. Senescent cells secrete a mix of signals that provoke chronic inflammation, as well as detrimental changes to tissue structure and cell function. Inflammation in the brain is an important component of neurodegenerative disease, and researchers have proposed that the most common forms of dementia are driven in large part by cellular senescence and consequent inflammation in the brain.
Accumulating evidence suggests that the sympathetic nervous system (SNS) overactivity plays a crucial role in age-related increase in the risk for cardiovascular diseases such as hypertension, myocardial infarction, stroke, and heart diseases. Previous studies indicate that neuroinflammation in key brainstem regions that regulate sympathetic outflow plays a pathogenic role in aging-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. While senescent cells and their secretory phenotype (SASP) have been implicated in the pathogenesis of several age-related diseases, their role in age-related neuroinflammation in the brainstem and SNS overactivity has not been investigated.
To test this, we isolated brainstems from young (2-4 months) and aged (24 months) male C57BL/6J mice and assessed senescence using a combination of RNA-in situ hybridization, PCR analysis, multiplex assay, and SA-β gal staining. Our results show significant increases in p16Ink4a expression, increased activity of SA-β gal and increases in SASP levels in the aged brainstem, suggesting age-induced senescence in the brainstem. Further, analysis of senescence markers in glial cells enriched fraction from fresh brainstem samples demonstrated that glial cells are more susceptible to senesce with age in the brainstem. In conclusion, our study suggests that aging induces glial senescence in the brainstem which likely causes inflammation and SNS overactivity.