How the maturation of the immune response is linked to the ageing process...
31 July 2023

Interview with 

Yoni Savir, Technion, Israel


Graphic of the ovary with maturing follicles


Inflammation, and how the maturation of the immune response is linked to the ageing process is a key area of study. One place where this really matters is in the ovary, which goes through repeated cycles of inflammatory changes with each ovulation. And, as he explains to Chris Smith, that’s what Yoni Savir, from Israel’s Technion has been looking at…

Yoni -  What we wanted to understand is whether the ageing of the immune system is different in the period where the female is fertile compared to the period where she's not. And in mammals, in female mammals, we have a good system that actually divides the life of the female to a fertile period and non fertile period. There are some general ageing processes in all the organs, but we wanted to zoom in on the ovaries because they play a critical role in the fertility process in particular. While the female is fertile, it undergoes cycles that are actually periods of inflammation. So, therefore, looking at this may help understanding whether there is a failure of the immune system within this particular organ, this is crucial for fertility is extremely important.

Chris -  Let's just expand on that briefly because it may sound a bit counterintuitive to some that you have an organ that you want to make inflamed, but when an ovary goes through a cycle of maturing eggs and then ovulating them, there is inevitably this inflammation that happens. When that occurs, are you arguing then that we don't really know whether that inflammation is good or bad or how it changes and it's those factors solving those unknowns that we really need to get to the bottom of, to understand the ageing process in the ovary?

Yoni -  What we want to understand is how does the immune system respond to these continuous cycles? So what happens in ageing in general is as the organism is getting older, the ability of the immune system to regulate itself goes down, and as a result there is an overshoot and excessive response to inflammation. So if we have some inflammatory challenge when we are young, the immune system can regulate it very, very easily. But in old people, when you have an inflammatory challenge, the immune system responds without regulation. And what we asked ourselves, do we see the same process, which is called inflammaging in the ovary? Because if we do see inflammation there, if this hypothesis is right, this is bad news for the ovaries because there's a lot of inflammation there.

Chris -  So it's your point then that if we see in the same way that peripherally around the body, we get this increasingly exuberant immune response happening as we get older, if that also is happening in the ovary, it could affect the rate at which the ovary ages and therefore could affect the ability of the ovary to ovulate.

Yoni -  Exactly. That's the puzzle here. So we know that very old females, if we look at the ovaries, we'll see hallmarks of inflammaging. But when you ask yourself, does it really make sense to have inflammaging while the female is still fertile? So that's why we decided we wanted to concentrate on characterising the immune milieu, the cell types of the immune systems and their function on the single cell level.

Chris -  So tell us how you did that then. What did you use as in, did you look at humans or animals and what did you actually measure and over what time?

Yoni -  We took a female mouse at different ages. The lifespan of the mouse is around two years and they are fertile for about 9 to 11 months. So we looked at this 9 to 11 months and we took time points, isolated the single cells of the immune system within the ovary. And then for each one of these cells, we are able to measure the copies of the RNA molecules of each gene. And once we have that, we can learn the identity of the cell and how the levels of RNAs are changing as a function of age.

Chris -  And do you see a consistent picture and is there a difference between a young fertile ovulating mouse and one that's gone over that time point where they're going to turn the corner and stop being fertile?

Yoni -  First of all, there is a significant change in the immune system in the fertile period as well. And by looking at the types of cells and their genetic expression, we can actually see they are getting less inflammatory with age.

Chris -  That sounds counterintuitive because we began this conversation talking about the possibility that they could be a more exuberant immune response, but you are arguing that the opposite is happening.

Yoni -  Exactly. And in a way it actually does make sense. It suggests that the ageing phenomena is different for the fertile organism and the non fertile organism. And when you think about it, that actually makes a lot of sense. Once the organism is not fertile anymore, the evolutionary pressure to keep it alive goes down. So what we actually see is why the mouse feeling is still fertile. The immune system is ageing, there are changes, but these changes are actually under regulation to avoid inflammation.

Chris -  Would the consequence of that not occurring be that there would be premature failure of the ovary, it would become too inflamed too often, too quickly, and that would wipe out fertility sooner than you would want?

Yoni -  Exactly. Exactly. What we actually say is something very deep on the entire process of ageing. So it's very easy to go to a very old organism and to say, okay, there's inflammaging there. The broad question is, why do we have inflammation? Do we have inflammation because it's an inevitable consequence or because the organism's immune system lets go and say, ah, okay, I don't have to worry about that anymore. Our results show inflammaging is not an inevitable outcome of ageing because the female is fertile and there are inflammation cycles. The immune system is changing, it's ageing, but it still keeps its inflammatory markers down and does not develop inflammaging.


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