Neurobiology of diseaseSep 18, 2026

Early signs of cell aging and treatment targets in a mouse model of ALS with TDP-43 mutation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 19, 2026

Abstract

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.

Cellular senescence may be an early feature of ALS pathology.
Longitudinal treatment with dasatinib and quercetin improved motor behavior and neuromuscular function in ALS mice.
D&Q treatment reduced axonal damage as indicated by plasma neurofilament light chain levels.
Motor cortex excitability improved, and layer V neuron counts were preserved following D&Q treatment.
Cortical microglia may mediate the benefits of senolytic treatment by showing reduced TDP-43 burden and senescence markers.

Simplified

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-43^Q331K 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-43^Q331K 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.

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Early signs of cell aging and treatment targets in a mouse model of ALS with TDP-43 mutation

Abstract

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