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."

Link: https://www.theguardian.com/science/2018/jan/23/flushing-out-zombie-cells-could-help-stave-off-parkinsons-study-suggests

Comments

Is there any disease of aging that senescent cells have yet to be shown to contribute to?

Posted by: Jim at January 24th, 2018 5:59 AM

@Jim - did you mean "shown not to contribute to".

Posted by: The Rage at January 24th, 2018 6:29 AM

The only thing new here is the specific focus on senolytics as a treatment; we've known for some time that glial cells may be central to various forms of dementia. The only question mark is in the order of events: do these immune cells become worn out because of the exertions of clearing out damaged neurons and their amyloid deposits etc., or do worn out immune cells' insufficiency in clearing out waste then lead to the harmful build ups that cause dementia. I'll make an educated guess and say it's the latter.

Posted by: Mark at January 24th, 2018 7:50 AM

I should say as well that senolytics to clear out senescent glial cells caused by poisoning (once that poisoning has ceased), is a different prospect to clearing out glial cells that have senesced due to say, replicative senescence; the latter are unlikely to be replaced.

Posted by: Mark at January 24th, 2018 7:54 AM

So what did they learn here?

- Dead Parkinson's patients had more senescent astrocytes in comparison to those without a chronic neuro-degenerative disease - Kind of obvious

- Exposing human astrocytes to a potent, restricted herbicide / poison made healthy astrocytes senescent - Kind of very obvious

- Control mice injected with said poison did a lot worse than those injected with it along with a senescent cell removing agent - ok respectable lab finding, but this is still a "chicken or the egg dynamic" as per above

This research is much more relevant to say a short term, chemical warfare counter-measure program than anything that would mimic what happens in the real world with progressive Parkinson's

Posted by: Jim Defilice at January 24th, 2018 9:06 AM

@Jim Defilice:

-I actually don't think it's obvious - though it's certainly becoming increasingly expected (see the other Jim's question) - that you'd find senescent cells in the brains of people with a chronic neurodegenerative disease. The focus is, of course, usually on the neurons.

-Similarly, the herbicide: the particular agent is paraquat, exposure to which* has been consistently linked to Parkinson's disease in humans, and the careful low-dose, long-term studies they did here in several model systems are a quite relevant model and are not just a matter of carpet-bombing the brain with something generically toxic. Notably, they chose mice in an age range where blood-brain barrier resistance to paraquat entry is relatively high, and injected them intraperitoneally, thereby slowing and lowering brain exposure to the neurotoxin, whereas many studies use either neonatal mice (whose BBB is still developing and provides little protection) or much older ones (whose BBBs are becoming leaky), or inject it directly into the brain.

Researchers have been trying for many years to understand the mechanism underlying the not only the epidemiological association, but even the mouse models, in terms of direct effects on the neurons, and have come up with contradictory and unconvincing findings. Here, Chinta, Woods, Andersen, Campisi, and others have revealed something few others would have guessed: that it was instead an indirect effect on the astrocytes. In combination with the substantial rescue afforded by ablating senescent cells, and the additional data they have using an inducible MAO-B model of PD (still unpublished - but see Andersen's Rejuvenation Biotechnology 2014 conference presentation), this is an elegant, novel, and convincing experiment, even considered in pure science terms; when you add in the translational potential for preventing neurodegenerative disease in humans, it is positively thrilling.

-"Chicken and egg dynamic:" no, this is exactly the demonstration of causation. They didn't do anything to block the toxin from inducing senescence in the mice's astrocytes: they allowed it to attack the brain, ablated the senescent cells directly, and rescued the model.

* To be clear, the data linking paraquat to PD are on farm workers exposed to the neurotoxin during field work, not to consumer exposure to paraquat residues on produce.

Posted by: Michael at January 25th, 2018 1:02 PM

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