Evidence for Clearance of Senescent Glial Cells to Slow Parkinson's Disease
Senescent cells accumulate with age and are one of the root causes of degenerative aging. Since senescent cells generate chronic inflammation, removing the accumulation of such cells in old tissues should improve matters for all age-related conditions with an inflammatory component. Of course that will vary greatly from condition to condition and between tissue types - there are other contributing causes for the chronic inflammation that characterizes old age, and in any specific case senescent cells may or may not be the most important cause.
Here researchers look at senescent astrocytes in the brain in the context of Parkinson's disease, finding that removing them in a mouse model of astrocyte senescence is beneficial. This line of research has been underway for a few years now, ever since the start of increased interest in cellular senescence in aging. The Alzheimer's research community is paying attention as well. The animal model used here is fairly artificial, disconnected from the real state of affairs in the aging brain, but the evidence gathered at least makes the point that senescent astrocytes are harmful, and that harm can be reversed by destroying them.
One concerning item in all of this research is that the signs of senescence, in terms of the usual marker proteins expressed, such as p16 and SA-β-gal, appear in a sizable fraction of astrocytes in old people. This may or may not reflect actual senescence, but it is a much higher proportion of cells in comparison to other aged tissues examined to date - sufficiently high to raise doubt over whether this is in fact the same phenomenon observed in better characterized types of senescent cells. It may be just as well that early senolytic therapies do not pass through the blood-brain barrier, as if all of those astrocytes are indeed senescent then removing a quarter to a half of them all at once would likely be dangerous at the very least, and possibly fatal.
In work that could open a new front in the war on Parkinson's disease, scientists have shown that they can stave off some of the effects of the neurodegenerative disease by flushing "zombie cells" from the brain. The approach may have benefits far beyond Parkinson's, with other neurodegenerative diseases - and the ageing process more broadly - all being linked to the ill effects of these "senescent" cells, which linger in tissues. "It's a completely new way of looking at neurodegenerative disease and finding potential drugs. For most of these conditions, we don't have any way to counteract them."
Parkinson's disease usually takes hold when certain types of neurons in the brain become impaired or die off completely. The neurons in question produce a substance called dopamine. Scientists suspected that other cells in the brain - the astrocytes which support the dopamine-generating neurons - may be involved in Parkinson's disease. Specifically, they thought astrocytes might cause problems when they became senescent, a state where cells stop dividing but release chemicals that drive up inflammation. This local inflammation could be harming nearby neurons.
Scientists described how brain tissue taken from dead Parkinson's patients had more senescent astrocytes than healthy brain tissue. They also found that exposing human astrocytes to the herbicide paraquat flipped the cells from a healthy state into senescence. The transformation into the zombie-like state forms part of the body's natural defences against cancer: when cells are in danger of uncontrolled growth, the switch to senescence keeps them in check.
To test whether senescent astrocytes might have a downside - and play a role in Parkinson's disease - the scientists exposed six-month-old mice to paraquat, a weedkiller that has been linked to Parkinson's disease in humans. The herbicide produced senescent astrocytes in the animals' brains and tests showed they had physical difficulties moving around. The scientists next looked at what happened when mice exposed to paraquat were injected with a drug that destroys senescent cells. The drug appeared to protect the mice and kept their movement problems at bay. "They are able to move around their cages well. They are almost indistinguishable from the healthy mice."