Brain cell senescence proved an early and reversible factor in ALS progression in mice: drugs that clear senescent cells nearly restored normal cortical function
Brain cell senescence proved an early and reversible factor in ALS progression in mice: drugs that clear senescent cells nearly restored normal cortical function
On September 18, Neurobiology of Disease published a study on mice carrying a model of amyotrophic lateral sclerosis (ALS). Researchers at the University of Missouri showed that signs of cellular senescence appear in the brain early, before the disease is fully established. Senolytics, a combination of dasatinib and quercetin already tested in humans, selectively clear senescent cells. In these mice the treatment nearly normalized the most severe deficit measured: motor cortex excitability. This is the first time such a therapy has been tested in an ALS model.
ALS destroys the neurons that control muscle movement. The disease begins with localized weakness, then spreads through the body and on average kills within three years. Nearly all damaged cells in ALS contain the protein TDP-43, which normally helps the cell process RNA inside the nucleus but in disease accumulates in toxic aggregates outside it. The strongest risk factor for ALS is age, and an increasingly recognized contributor to that age dependence is cellular senescence: a state in which cells stop dividing, resist death, and secrete inflammatory molecules that poison their neighbors. Whether this link was causal had never been tested directly. Only a year earlier, the same laboratory published a theoretical review connecting senescence markers to ALS and naming the clearance of senescent cells as a promising therapeutic direction.
To test the hypothesis, the authors used mice carrying the TDP-43 Q331K mutation, which reproduces the same type of TDP-43 pathology seen in most human ALS cases. For fifteen weeks, a subset of the mice received dasatinib and quercetin (D&Q), a combination first tested in humans in 2019 for pulmonary fibrosis. A pilot trial in older adults at risk of dementia showed that courses of D&Q are safely tolerated and reduce the inflammatory marker TNF-α.
Muscle strength recovered only temporarily, while coordination improved durably. Neuromuscular signals strengthened but did not reach the level of healthy mice. The authors then moved higher along the neural pathway, to the motor cortex. Earlier evidence suggests that ALS pathology often originates there and spreads downward to the spinal cord and muscles. In untreated mice, the electrical response of the cortex to stimulation dropped nearly to zero, making it the most severe impairment measured in this model. Under D&Q treatment, that response returned almost entirely to normal, and the number of neurons in that cortical layer did not decline as it did in untreated animals. Treated mice also showed lower blood levels of neurofilament light chain, a marker of nerve fiber damage already used in humans to track the effect of tofersen, an approved genetic therapy for ALS with mutations in the SOD1 gene.
The key cellular role appears to have been played by microglia, the brain's immune cells, which can themselves become senescent after injury and spread toxic TDP-43 between cells. In untreated mice, senescent microglia proliferated and accumulated pathological protein. Senolytics restored microglial density and morphology to normal and reduced this protein burden, although they did not eliminate it entirely. At the same time, the amount of TDP-43 mRNA in the cortex increased. The authors' explanation is compensatory: cells ramp up production of the protein to replace what the senolytics have already cleared. The precise mechanism by which senolytics remove toxic protein from the cortex (whether microglia themselves clear it or simply stop shuttling it between neurons) is, as the authors note, a question for further experiments.