A Deep Dive On Fisetin | Dr Juliette Tavenier

Benjamin Hopkins (0:01)

Okay, hi everyone, welcome back. If you are liking and subscribing, you're a legend. If you're not, please do, because it helps us keep doing what we're doing and making these episodes. We have the wonderful Juliette Taverner here with us today.

Juliette, welcome to the podcast.

Juliette Taverner (0:17)

Yeah, thank you for having me.

Benjamin Hopkins (0:18)

It's a pleasure. Could you explain what your research is all about to someone who's unfamiliar with it?

Juliette Taverner (0:26)

So we're working with senolytics and cellular senescence. So a bit of background. So throughout your life, your cells are exposed to different stressors, oxidative stress, mechanical wear and tear, DNA damage from radiation. And so when a healthy cell has sustained too much damage, it usually takes one or two path. It can either try to repair itself, regain its normal biological function. If the damage is way beyond fixing, the cells will usually try to undergo apoptosis or programmed cell death. But some cells are unable to repair themselves, and they also resist this apoptosis or cell death.

And so rather than continuing to divide and risk becoming cancerous, they enter this state of permanent arrest, which we call cellular senescence. So they still refuse to die, but they stop dividing. They're technically still alive, but they don't perform their normal biological function anymore. That's why they're sometimes called these zombie cells. And they are actually metabolically hyperactive, and they secrete this really toxic cocktail of inflammatory factors that is known as the SASP, or the Senescence Associated Secretory Phenotype. And this SASP is spreading chronic inflammation in the tissue around the senescence cells. It can also subject the neighboring cells to so much stress that they in turn become senescent, so it's like spreading senescence. And eventually when you have too many of these senescent cells, this SASP can go in the circulation and spread senescence in other organs throughout the body.

So what we're trying to do is prevent the senescent cells from causing all this damage in your organs. Now I should say that cellular senescence is not always a bad thing. As I mentioned, it's a protective alternative to cancer and it also plays a really important role in wound healing and development when it is localized and limited. So normally, senescent cells are removed by the immune system when you're young. You have a well-functioning immune system and you have macrophages and natural kill cells that will patrol and try to clear these senescent cells. But as we age, we face this decline in immune function that's known as immunosenescence, where the immune system becomes sluggish and less effective at identifying and removing these senescent cells.

So when the rate of generation of new senescent cells exceeds the rate at which your immune system can clear them, you cross this threshold where you start to have an accumulation of senescent cells and their saps that really drives systemic chronic inflammation throughout your organs, throughout your body, and that directly drives many of the age-related chronic diseases.

Benjamin Hopkins (3:05)

Let these go.

Juliette Taverner (3:06)

Yeah. So what we're trying to test is whether we can pharmacologically reduce this burden of senescent cell or maybe prevent getting to the point where you have crossed this threshold and have way too many senescent cells that your immune system cannot deal with them anymore.

And we're doing that.

Benjamin Hopkins (3:26)

I wanted to ask, it's almost, my understanding is this, it's almost like cellular clear clear up. And I guess where I get confused is where does autophagy work in the same way where senolytics work or do they work in different ways?

Juliette Taverner (3:40)

I'm not an expert in autophagy, so I.

Benjamin Hopkins (3:43)

Fair enough.

It's broad. It's a weird question to be honest. My understanding is senolytics as a group will help this cellular clear up. But I know one specific senolytic is facetin you spent a lot of work on. Could you speak to facetin as a senolytic, as a compound and where we find it? And then how have you been dealing with it?

Juliette Taverner (4:06)

Yeah, sure. So, facetin is a naturally occurring flavonoid. It's found in a lot of fruits and vegetables like strawberries, apples and onions. And as a flavonoid, it's long been known to have anti-inflammatory antioxidant effects. But more recently it was identified to be one of those that we call synomorphics, synotherapeutics, sorry, actually.

And there are two kinds of synotherapeutics. There are synomorphics.

They don't eliminate senescent cells. And they work by inhibiting these pathways that produce the SASP. So they lower this chronic inflammation and potentially can help limit the spread of senescence. And so, for therapeutic synomorphics to be effective, you would likely have to take it every day to keep suppressing, like dampening this inflammation. And then you have synolytics, which selectively triggers cell death in the senescent cells. So senescent cells are quite stubborn. You know, they're surrounded by their own very toxic SASP, but still they're able to survive it. And the way to do that is because they upregulate some survival networks that are known as SCAPs or senescent cells and see apoptotic pathways. And so, FICEDEN and other synolytics, they work by inhibiting some of the proteins in these survival pathways that allow the cells to undergo acoptosis eventually. And so, in contrast to the sedomorphics that you maybe need to take every day, because senescent cells do not divide, senolytics can be taken in a hit and run manner where you just have a high dose for maybe two days per month and then repeat every month.