Senolytics Can Treat a Drug-Resistant Form of Epilepsy
As research into senescent cells continues to gather momentum over the years, links to specific conditions are spilling over from aging into other fields of medical research. Temporal lobe epilepsy isn't an age-related condition, but a number of the most unpleasant outcomes inflicted on the brain by aging, including stroke and brain cancer, can induce epilepsy in addition to all of the other attendant consequences. Interestingly, researchers have found that there is a clear correlation between an excessive burden of senescent cells in the brain and temporal lobe epilepsy. Senescent cells are by now well established to disrupt tissue structure and function via their inflammatory signaling when present in significant numbers over the long term. Typically this only happens in old age, but some other events such as infection, cancer therapies, and injury can result in a lasting excessive burden of senescent cells that emerges earlier in life.
Fortunately there is a low cost therapy that clears some fraction of lingering senescent cells, and has been shown to do so in early human trials, alongside a reasonable safety profile. This is the combination of dasatinib and quercetin. Unfortunately, there is little financial incentive for those organizations capable of conducting large scale clinical trials of dasatinib and quercetin to actually do so; low cost generic drugs and supplements are not a good source of revenue. Thus this approach to therapy remains stuck in the state of being available to the adventurous, prescribed by a small number of anti-aging physicians, and in much need of a far greater body of human clinical trial data than is likely to arrive any time soon.
Clearing the Brain of Aging Cells Could Aid Epilepsy and Reduce Seizures
Temporal lobe epilepsy (TLE) can be caused by several factors, including brain injuries from trauma or stroke, infections like meningitis, brain tumors, blood vessel malformations, and genetic syndromes. TLE is the most common type of drug-resistant epilepsy, affecting about 40% of patients with the condition. In one part of their study, the investigators looked at donated brain tissue in the lab that had been surgically removed from the temporal lobes of people. They found a five-fold elevation of senescent glia cells in human TLE cases compared to autopsy tissue from people without the disease. Glia cells support and protect neurons but do not produce electrical neuronal impulses.
Based on their human brain tissue investigation, the researchers suspected there could be an abundance of senescent cells in a mouse model that mimics TLE. Indeed, within two weeks of the initial injury that triggered TLE in the mice, the investigators found increases in cellular markers of senescence at both gene and protein levels. Treatment to remove the aging cells in mice resulted in a 50% reduction in these senescent cells, normalized their ability to navigate mazes, reduced seizures, and protected a third of animals from epilepsy altogether.
The drug treatment tested in the mice was a combination of dasatinib, a targeted therapy used to treat leukemia, and quercetin, a plant flavonoid found in fruits, vegetables, tea, and wine that can act as a powerful antioxidant and have anti-inflammatory properties. The combination of the two drugs has been widely used to kill senescent cells in a range of diseases modeled in animal studies.
The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied. We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In a mouse model of TLE, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following induction of TLE. Senolytic treatment in mice produced a 50% reduction in senescent cells, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.