At Undoing Aging 2019, we interviewed some of the best researchers who are involved in discovering therapies for the root causes of aging. Their research aims to ameliorate the damages of aging and may one day lead to a future without age-related diseases.
Dr. Judith Campisi, one of the speakers at this conference, is a professor at the Buck Institute for Research on Aging. We asked her about the capabilities and future of senolytic drugs, which remove senescent cells from the body, along with other, related topics.
There currently seems to be a growing sense of optimism among researchers regarding doing something about aging. What has changed in the last few years to encourage this?
The tools of cell and molecular biology. There are experiments that are being done now that, when I was a graduate student, and even a postdoc, were considered impossible. Now we have so many tools to explore our cells and their reactions and how they fit into tissues and organisms. It’s really made progress in aging research possible.
That’s fantastic. You are a renowned expert in the field of cellular senescence. Senolytic drugs are a proposed way to clear out senescent cells and seem to be beneficial in mice, but the question is, do senescent cells work the same way in humans as they do in mice?
It’s a good question. It’s an excellent question. I would say, chances are, the answer is yes, but we don’t know that definitively yet. For example, in my lab, we always start with human cells, and then we look at mouse cells. Then, if those two cell types behave the same way, we look at the mouse so we can hope to extrapolate to humans, but, in fact, it’s still very early days. As you know, the first senolytic drugs have just entered clinical trials for humans. We have a ways to go;
We will see, hopefully soon. What kinds of age-related diseases might be potentially addressed with senolytics?
Well, if you believe a mouse can predict what happens in a human, it’s an amazing array of age-related diseases: everything from neurodegeneration to cancer, late-life cancer. So, I think if we’re correct, and the mouse models are correct, they’re going to be a huge array of age-related diseases: everything from the brain, to kidneys, to your joints, to your heart, et cetera.
Speaking of senolytics, a lot of current-generation senolytics are repurposed cancer drugs, such as navitoclax and dasatinib. Why is it that cancer drugs have senolytic effects?
Well, think about what a cancer cell needs to do to survive. It needs to avoid death. We know that senescent cells are also somewhat stable; they usually use the same mechanisms to avoid cell death so that they’re stable in the body. Now, the difference between cancer and a senescent cell is if you want to cure cancer, you have to kill every cancer cell, because one cancer cell can go on and form a tumor. That’s not the case in the case of senescent cells. In the mouse models, we kill maybe between 60 and 80% of the senescent cells, and there’s already improvement in healthspan. It’s a different threshold between cancer and senescence, and those anti-cancer drugs failed because of the very, very high bar that’s needed to eradicate cancer.
Very fascinating. Some research also suggests that some naturally occurring plant flavonoids, such as quercetin, apigenin, piperlongumine, and fisetin, may also influence the SASP or are actually senolytics. What do you think of the potential of such compounds?
The data are mixed. For some of these compounds, the act of killing senescent cells looks pretty good. For others, it looks more like these compounds might suppress the SASP, the secretory phenotype; the advantage of killing a senescent cell is that it’s gone for some period of time until those senescent cells can build up again. Whereas if you suppress the SASP, as soon as you take away the compound, the cell starts secreting again.
Senescent cells use various pro-survival pathways to evade apoptosis, such as BCL2, p53, and FOXO4, which is why no single senolytic agent has yet been able to remove senescent cells across the board. What are your thoughts on a senolytic cocktail therapy that hits all these pathways at once?
It’s likely. I do want to point out, though, that I think where the research needs to go is to really understand the heterogeneity amongst senescent cells. It may be that we don’t need as much of a cocktail if the damaging senescent cells have something in common. As you know, there are good things that senescent cells do as well, and we don’t want to eliminate those good cells. Right now, there’s a big push in the field, certainly in my lab and many other labs, to understand the heterogeneity so that the drugs can be more specific. Eventually, there probably might be a cocktail. Even then, we’re going to have to exercise a little bit of caution. You don’t want to take a senolytic before you go to surgery.
Yes, I heard about that. That’s not a good idea. Senescent cells are not present in younger individuals for very long, so why does the immune system stop clearing out these problem cells beyond about age 50?
The short answer is we don’t know the answer to that. We don’t know whether senescent cells are made at a higher rate in older individuals, whether they’re cleared at a slower rate due to the immune system not catching up, or some combination of both, and it could easily be some combination of both. We’re also just beginning to understand how the immune system identifies and targets the cells and how those senescent cells can also evolve mechanisms, much like cancer cells, to avoid the immune system. These are very early days, and the whole immune component is something that we need to understand much better.
What do you think about the proposal of boosting or rejuvenating the immune system to help clear senescent cells?
Could work, but I will remind you that there are some anti-cancer therapies that have the same idea, and there have been some big surprises. For example, some patients on immunotherapy for cancer are developing Type 1 diabetes, Type 1 diabetes, autoimmune disease. The immune system is this very finely tuned system, and we don’t know as much about the immune system as we should. I would be very cautious about tweaking the immune system one way or the other.
You mentioned before that senolytics are currently in human trials; particularly, they are in human trials with Unity. Is there anything that you could tell us about how things are going with that?
I believe this is public knowledge; you can find it on your website. I believe they’re recruiting for phase 2. I think phase 1 went fine, meaning nobody dies, nobody’s leg fell off, so that’s good. As you know, phase 1 is more about safety. Phase 2, I think, will be starting soon.
I think that in the second quarter of 2019, they were hoping to release the information. As a last question, I would like to ask you if there is a question that you would like us to ask you, something that people never ask you, but you would really like to answer? Is there anything like that, and in that case, what is that question? We are happy to hear your answer to that.
Maybe the important question is, what is the distinction between aging and death? Because, as you know, there are some people who believe that aging is programmed, that it was selected to make room for the new generation. I think it’s definitely true that, in some cases, some species’ death is selected: salmon, they swim upstream, they spawn, they die, and that’s programmed. Aging is something else, and I cannot think of a way it could be programmed. For example, I can’t imagine how evolution would select for a deteriorating joint or a deteriorating brain or a deteriorating heart or whatever, that’s aging, and that’s what we’re hoping to avoid. Death, I think, is inevitable.
I have a hard time imagining that deterioration would be selected for as well. That’s about all I wanted to ask you. I’m very happy that you could find the time to talk to us.
It was great talking to you.
