Project Summary/Abstract (30 lines) Regardless of family history, site of onset, and sequence of symptoms and progression, all Amyotrophic Lateral Sclerosis (ALS) patients lose muscle mass as the cells (motor neurons; MNs) that connect to muscle in limbs to control movement stop working and eventually die. However, the complexity of the structure and function of the nervous system is achieved through extensive developmental processes and is maintained in part due to the resiliency of the cells to maintain function and resist activating cell death processes. Therefore, there appears to be an extensive delay between initial neuronal dysfunction and physical degeneration. Experiments in this proposal will investigate a novel hypothesis: motoneurons in ALS enter cellular senescence following neuromuscular (NMJ) denervation as part of a complicated stress response to avoid active degeneration and cell death. Nonetheless, while this protective mechanism may preserve the physical presence of the cell, senescent cell dysfunction and potentially toxic secretome promotes chronic tissue degeneration over time that facilitates disease progression. We will further investigate if pharmacological administration of well-characterized senolytics can effectively clear senescent motoneurons and reduced neurotoxicity in the SOD1 mouse model of ALS. Successful outcome of these experiments will open a novel avenue of investigation in ALS and develop new therapeutic targets. An area desperately in need of development for the majority of ALS patients that die on average 2-4 years after diagnosis.