#413 Longevity Scientist Breaks Down What Causes Aging of Cells - Matt Kaeberlein PhD

Siim Land (0:30)

One of the world's leading experts in my opinion and others, when it comes to longevity, and we can make a podcast pretty much about all the hallmarks of aging and different topics. So yeah, I decided that maybe it's nice to have you back and discuss one of more like a popular topic in longevity space over the last few years, which is sales in essence.

Matt Kaeberlein (0:51)

Sure.

Siim Land (0:52)

Yeah, it's quite interesting. So maybe we can start. So what is sales in essence and how does it relate to aging?

Matt Kaeberlein (1:01)

Sure. So I think maybe it's useful to start from a very high level, and then we can drill a little bit deeper. So one way to think about senescent cells is to start from thinking about what happens when cells in our body stop functioning the way they're supposed to or stop doing their job. So every cell in our body, just like in every organism, has a job to do and different cell types have different jobs. But just like human beings, sometimes our cells stop doing what they're supposed to. And there are then multiple paths that those cells can go down. Probably the most common path that a dysfunctional cell will go down is something called apoptosis, which is cell death. So the cell will die, it'll go away. While that might seem like over time, that could create problems. In general, apoptotic cell death is a productive path for a dysfunctional cell to go down because we have stem cells that can replace the cells that die. Another path cells can go down is cancer. And obviously, that's a bad path that creates all sorts of problems. And we have some mechanisms in place that protect us against cells becoming cancerous. So apoptosis is one, they can die. Another very potent anti-cancer mechanism is this process of senescence, which you've alluded to. So that's kind of the third path that dysfunctional cells can go down. And senescent cells are cells that stop dividing. So they exit the cell cycle, at least we think permanently, but they don't die. And so they just kind of hang out. And that wouldn't really be a problem except these cells don't only hang out, they start giving off signals that cause surrounding cells to become dysfunctional. And these are primarily thought of as inflammatory signals, although not exclusively inflammatory signals. So people may have heard of the SASP or senescence-associated secretory phenotype. That's the signals that I'm talking about, these secreted factors that are given off by senescent cells that largely are pro-inflammatory, although not exclusively pro-inflammatory. Okay. So how does this tie into aging? Well, it turns out that as we get older, we have more and more of these cells that go down the senescence pathway. And that's happening at the same time that our immune system becomes less able to clear senescent cells. So when we're young, our immune system is quite effective at clearing these senescent cells so we don't accumulate too many of them. As we get older, it seems as though the immune system becomes less able to clear the senescent cells, and we have more cells becoming senescent.

So we have this gradually growing burden of senescent cells within our bodies that are giving off these chronic inflammatory signals, and that's thought to contribute to some significant extent to the process that people call inflammation. So you mentioned the hallmarks of aging. Chronic inflammation is another hallmark of aging that can be caused by senescent cells along with several other hallmarks of aging. So the extent to which senescent cells are driving inflammation versus other potential causes of inflammation, like DNA damage, mitochondrial dysfunction, things like that, is a little bit unclear, but they seem to be a contributing factor. And I think the best evidence to suggest that targeting senescent cells may be a useful strategy come from studies where people have caused mice to genetically remove their senescent cells. And we can see when we do that, you get increased lifespan and improvement in several healthspan measures. So it seems as though getting rid of senescent cells, at least in mice, can have beneficial effects in the context of healthy longevity.

Siim Land (4:52)

And this is obviously like a natural process that happens as well. So like, you know, if you're 100 years old, then you will have more senescent cells presumably than if you're like 20 or 30 years old.

Matt Kaeberlein (5:05)

Yeah, I mean, again, that is certainly the dominant paradigm in the field, and I think there's lots of data to back that up. We don't have, there's a couple of things to say that make it a little bit hard to have 100% confidence to what extent senescent cell burden increases with age. One is there's still a little bit of a lack of consensus in the field about how you measure senescent cells or even how you define senescent cells.