After spinal cord injury (SCI), initial mechanical damage is followed by a secondary injury that exacerbates tissue destruction and functional deficits. In contusive thoracic SCI, white matter damage, which progresses for weeks post-injury, is the critical anatomical determinant of locomotor dysfunction. Few targets have been identified whose manipulation reduces SCI-associated secondary injury with a therapeutic window of <12-24 h. Although locomotor recovery is observed in SCI rodents, it is usually incomplete. The limits to recovery involve neuron and oligodendrocyte loss, prolonged inflammatory responses, vascular dysfunction, lack of efficient regeneration, and/or a finite capacity of synaptic plasticity. Breaking the ceiling of locomotor recovery in rodents remains a major challenge. Proliferating cells that accumulate DNA damage may undergo cellular senescence. Senescence-associated induction of the cyclin-dependent kinases (CDK) inhibitors p21 and p16 triggers permanent exit from the cell cycle. The senescence-associated secretory phenotype (SASP) involves secretion of multiple cytotoxic pro-inflammatory mediators. Elimination of senescent cells (senolysis) improves many age-dependent pathologies and reduces neurodegeneration in mouse models of fronto-temporal dementia or β-amyloidosis. In those cases, improved outcomes were associated with elimination of senescent microglia/astrocytes or oligodendrocyte precursor cells (OPCs). As those glial cells proliferate in response to CNS injury, their senescence is a likely by-product of trauma-induced gliosis. Our preliminary data reveal increased expression of cellular senescence markers at dpi 3 and 42 following T9 contusive SCI. Hence, by promoting neuroinflammation and tissue scarring, senescent cells may increase white matter loss and compromise neurorepair/neuroplasticity after contusive SCI. We hypothesize that accumulation of senescent cells after SCI contributes to progressive white matter loss and reduces recovery of locomotor function. In aim 1 we will determine the identity and spatio-temporal distribution of senescent cells in the spinal cord of SCI mice. In aim 2 we will test effects of pharmacological (2a) or pharmacogenetic (2b) senolysis on white matter sparing and hindlimb locomotor function after moderate T9 contusive SCI. Effects of senolysis will be evaluated by analyzing senescence markers, neuroinflammation, reactive gliosis, apoptosis, white matter sparing, and hindlimb locomotion. These studies will conclusively evaluate the pathogenic significance of SCI- associated cellular senescence. As senolytic drugs are already in use in clinical trials for other diseases, these studies may define a novel and readily translatable therapeutic treatment for both acute and chronic SCI- induced pathologies. Although it has been proposed that organismal aging may modify outcome of SCI, this application is focused on an entirely distinct issue that has not been previously addressed: the ...