Senescence field has “completely exploded”

Aubrey de Grey expects senescence-targeting sector will see Phase 3 trials within “a couple of years”.

As one of the hallmarks of aging, cellular senescence is heavily linked to many chronic diseases, and senotherapeutics, which target senescence, have the potential to treat these diseases by addressing their root cause rather than their symptoms.

Fresh from raising a staggering $28 million for the SENS Research Foundation through a wildly successful crypto auction, longevity iconoclast Aubrey de Grey has shared his views on senolytics and alternative approaches to targeting senescence.

Longevity.Technology: With the ink barely dry on our recent market intelligence report on the emergence of senotherapeutics as a hot topic in biotech, we caught up with the SENS founder and Chief Science Officer to find out where he believes there is greatest potential for success in senescence.

With investment money flowing freely into start-ups developing senotherapeutics, and companies like Unity Biotechnology already conducting human trials, de Grey is bullish about the sector.

“The field of targeting senescent cells has completely exploded,” says de Grey. “And I would say that it’s now become the highest profile area across all the hallmarks of aging. But there’s definitely a spectrum of degrees of understanding – there are some people that understand the whole thing really well, and some people who don’t.”

A simplistic view of the field is that senescent cells are bad for us, and, because there are more of them in older people than there are in younger people, they are associated with aging, so we need to reduce them.

“I use the term “death-resistant cells”, which doesn’t have any connotations about what kind of behaviour the cell is engaging in that is somehow undesirable,” says de Grey. “It just emphasises the fact that the reason these cells are accumulating, is because the body is failing to get them to commit suicide (apoptosis), which is what normally happens with bad cells.”

Senolytics “barrelling forward”

And de Grey believes that there are “a whole bunch” of questions about how we might go about reducing the number of senescent cells in our bodies.

“The most simple way, and something I originally didn’t really believe would be possible, is to find drugs that are able to selectively make senescent cells unhappy, and cause them to commit suicide. And it turns out one can find those drugs,” he says, referring to the senolytic approach adopted by companies like Unity.

And, in general, de Grey feels that the development of senolytics has been going rather well, despite some setbacks.

“The field as a whole is barrelling forward with a wide variety of different synthetic drugs that can induce apoptosis selectively in senescent cells, by a variety of different mechanisms. And that’s wonderful,” he says. “However, pharmaceuticals are always going to have some limitations, they’re always going to have some degree of non-selectivity, some toxicity to the cells that we don’t want them to kill, and some cells that we do want to kill that they will fail to kill. So it still makes sense for us to consider alternative approaches.”

Looking beyond senolytics

The first alternative approach that de Grey talks about is actually the one that he originally felt held the most promise.

“People called it suicide gene therapy, where you create an engineered virus that goes into cells throughout the body, whether senescent or not,” he explains. “In the senescent cells, the cargo of the engineered virus is activated, and it makes a protein that rapidly causes the cell to kill itself.”

In principle, this approach is already used routinely in the lab to manipulate mice, for example, but using it clinically in humans is challenging.

“There is a company that’s trying to do that – Oisín Biotechnologies – and they’re definitely making good progress,” says de Grey. “They’ve got a very nice delivery vehicle for their engineered DNA.”

Another way to target senescence that interests de Grey is to use the human immune system itself.

“We have seen this enormous revolution in cancer therapy over the past decade as a result of enhancing the immune system’s ability to identify and to attack cancer cells – and the same kind of thing can be done for senescent cells,” he says, highlighting the work of SIWA Therapeutics in this area. “The goal is to identify why some senescent cells manage to resist the immune system, and then to break down that resistance in one way or another.”

De Grey also addresses the idea of modifying senescent cells without killing them – essentially reversing the process to make them non-senescent again.

“Some people have become quite excited about this, because it seems to be possible, but I’m personally not persuaded that this is a sensible thing to do,” he says, pointing out that there can be good physiological reasons why cells become senescent, and also that cells may become senescent because their DNA might be damaged. “In a situation like that, you don’t want to inactivate its senescence because that’s a way for the cell to protect the body from itself, so to speak.”

The final alternative approach to senolytics that de Grey highlights is all about finding a way to stop cells from becoming senescent in the first place. But, as Buck Institute professor Judy Campisi pointed out in a recent interview, there is reason for caution, with plenty of evidence to show that senescent cells also play a role in key biological processes. De Grey concurs that this approach to targeting senescence is “a really tricky thing to mess with”.

“If you inhibit a certain process, then wound healing doesn’t work so well, which is no good thing,” he says. “You need to be quite sophisticated and selective, and so that may not be the way to go.”

Phase 3 trials on the horizon

With so much work going on, and so many different ways to tackle the challenge of senescence, there are still no Phase 3 trials in this field. But de Grey believes we’re not far away.

“I think it’s close. Unity are still ahead of the field in terms of progress, the trial that failed last year with a Phase 2 trial, but they’ve got two other trials in Phase 2 for other indications – they’re covering a lot of bases,” he says. “They’re well-funded, they’re a really good company, they’ve got everything going for them, and I think we could be talking no more than a couple of years before we get things through the process.”

When it comes to targeting aging, there’s constant debate and discussion and development around the regulatory process for deciding how to regulate clinical trials, but de Grey is accepting of the fact that change takes time.

“The FDA and its counterparts around the world want to save lives just as much as the medical researchers do,” he says. “It’s just that we have to contend with the inherent risk aversion of the general public, who get much more upset when one person dies in a clinical trial than they do if 100,000 people die because they couldn’t get medicines that hadn’t been approved as quickly as they could have been.”

Read all about senotherapeutics in our report, to which Dr de Grey contributed the foreword, HERE, and check out our senotherapeutic company profiles HERE.

Image courtesy of Erin Ashford