Aging and TNF induce premature senescence of astrocytes after spinal cord injury via regulating YAP expression

Spinal cord injury (SCI) causes chronic functional impairment in patients. In addition, SCI is tormenting more and more older adults, and those who suffer from SCI often have shorter lifespans. Previous studies have confirmed that overexpression of p75 leads to neuroinflammation and motor dysfunction following spinal cord injury in adult mice.As TNF-α is upregulated after SCI, targeting TNF-mediated inflammation may be an attractive option to combat trauma, paving the way for new therapeutic insight. In this study, we evaluated behavioral testing, phenotype of senescent cells, reactive oxygen species (ROS), inflammation and mitochondrial damage in adult (2-month-old) and aged (20-month-old) female wild-type (WT) and p75 knockout (KO) mice.Herein, we hypothesized that aged mice were more prone to death after SCI, but p75 deletion could promote motor/sensory function recovery and improve survival in both adult and aged mice. Further exploration of the underlying mechanism revealed that the expression of p-YAP was reduced in vivo and in vitro, and p75 deletion partially rescued aging-induced astrocytes senescence.Taken together, our study have identified an unrecognized function of the p75-YAP pathway on preventing astrocytic aging in vitro and in vivo, which may provide further insights and new targets into slowing spinal cord aging and improving dysfunctional remission and longevity.