Reversing ageing in the brain

20 August 2019

Interview with 

Robin Franklin & Robin Chalut, Wellcome-MRC Cambridge Stem Cell Institute

BRAIN

Brain schematic

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As we get older, our muscles and joints start to stiffen, making us move a bit slower. This week, a study reveals the same is true for our brains, and this affects how well the brain’s stem cells can keep the nervous system in good working order. The good news is that this aspect of ageing it might be reversible. To explain how, Robin Franklin and Kevin Chalut from the Wellcome-MRC Cambridge Stem Cell Institute. First up, Kevin explained the stem cells they were looking at.

Robin - These are stem cells in the brain. Turns out actually our brain is full of stem cells, they're all over the place, but they're rather unusual sorts of stem cells in that they don't make all of the cells of the brain. So our brain consists of a variety of different types of cell: there are nerve cells which have these long extensions of nerve fibers, but there are also other types of cells called oligodendrocytes and they make the insulation around the nerve fibres. Now the stem cells in our brain are very good at making oligodendrocytes but they're not very good at making the nerve cells.

Chris - And because they can make these supporting cells that surround nerve cells and help them to function, they therefore are contributing, are they, to the ongoing function of the nervous system throughout 60/70/80 years of life?

Robin - Well the real significance of these cells is in the context of disease. So if you lose nerve cells - if you have a disease in nerve cells like Alzheimer's - they're gone forever because the stem cells don't replace them. The diseases of the support cells, the oligodendrocytes - such as MS - do at least in the early stages have the capacity to be regenerated, so your stem cells can make lost oligodendrocytes. The problem of course is that these cells become less and less effective at doing that as you get older, and so in diseases like MS of many decades’ duration there's a big problem of how you deal with the ageing phenomenon in the adult stem cell.

Chris - And Kevin what insights have you now got into why the older brain is less good at fixing itself with these sorts of stem cells than the younger brain?

Kevin - Well I think there is a lot of ideas about why that would be the case, but the finding that we made in this paper that was new is that we found that the brain is stiffening with age. And at the same time we found that if we could take these old stem cells and put them into a young animal, we found that they could be entirely rejuvenated. It’s as if they always knew what they could do but they just didn't know they were supposed to do it. So what we did was we put these two facts together - the fact that it wasn't irreversible, and the fact that the brain stiffens with age - and we made the hypothesis that perhaps it's about stiffness.

Chris - How do we know it's the stiffness that's important?

Kevin - So we have these synthetic scaffolds that we invented so that we could put cells onto a stiff or a soft synthetic scaffold, and nothing else was different except for the stiffness.

Chris - Right.

Kevin - And so what we were able to do is put these old cells onto the very soft scaffold and know that the only thing that was changing was the stiffness.

Chris - And do we know how the cells are doing the cellular equivalent of the Princess and the Pea experiment? How they know they're in a stiff or a soft environment?

Kevin - We have a lot of ideas, and I suppose that one could expand on it, but one of the things that I suppose that we do know is that there's this thing called “mechanical signalling”: how cells are getting signals about how stiff their environment is. And one of the main proteins that's responsible for this is a protein called Piezo1, which is sort of a channel that sits on the surface of these cells and that basically tells the cell, “am I in a stiff environment or am I in a soft environment?”

Chris - And as the cell... because these cells start in one place, they're born in one place, they've got to migrate or move to where they're needed; and I presume as they move they're encountering this environment, they're sensing it, via the signalling from this Piezo1 signal...

Kevin - Yes.

Chris - And that has some effect on the cells telling them to either grow more or less, according to how much signalling is there?

Kevin - Yes, exactly. It's a combination of the environment stiffening, and they encounter all sorts of environment, but then they also have these signals that tell them how stiff that environment is.

Chris - Robin, why have we got a system in our brains then - that can stop the brain repairing itself as well as it could do when we get older - in the first place?

Robin - Yeah, that's a great question and I'm not sure we know the answer to that. I sort of think that once an organism has got beyond the age of being reproductively useful it doesn't matter what happens, and so this is just a function of wear and tear that, the brain starts getting stiffer, our stem cells don't work so well. Of course that's a problem for humans with chronic diseases.

Chris - Sure. And talking of chronic diseases, could you use your learning between the two of you to get these cells to perform better? If you know this signal exists, is it possible to blindfold the cells to the stiffness of the environment in which they find themselves, so they're fooled into thinking they're back in a young brain and they can repair better?

Robin - Well that's exactly what we intend to do. I mean I think that there are two very interesting implications of this study in terms of therapies. One is that if you transplant a fit, vibrant cell into an old environment it ain't going to work, because the old environment will make that into an old cell. But secondly what we found is that actually if you dissociate an old cell from its stiff environment it now works as if it's a young cell, so actually the translation implications of that, of perking up these old cells - that you really haven't clapped out at all, they’re just in the wrong environment - and reinvigorate them, then the therapeutic opportunities are really very exciting.

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