Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence - a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype - has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43Q331K ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43Q331K mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.