Senolytic potential: from organ transplants to space travel

James Kirkland highlights the range of potential applications of senolytics but warns against taking them before trial results are known.

Following last week’s article with Dr James L Kirkland of Mayo Clinic, today we bring you the second part of that conversation, which offers a fascinating insight into some of the applications currently being explored for senolytic drugs.

Longevity.Technology: From Alzheimer’s and mild cognitive impairment to frailty and diabetes, human trials of senolytics are already underway for a broad range of diseases and conditions. But, as Dr Kirkland explains, there are several other interesting areas of human health in which senolytics will soon be entering clinical trials.

Kirkland says that the Translational Geroscience Network expects to commence several interesting senolytics trials in the near future, including one looking at whether senolytics can boost the cancer-killing effects of chemotherapy.

“Cancer cells that aren’t killed outright by chemo and radiation are often induced to become senescent and then you’ve got a remission,” he says. “But senescent cells have a lot of mutational events going on – they can escape senescence and come back as worse tumours. The notion is to give chemo and radiation then senolytics, then chemo and radiation – a one-two punch approach.”

James Kirkland: Senolytics have a 20% chance of success
Dr James L Kirkland, Mayo Clinic.

Organ rehabilitation for transplants

Another planned trial will explore the potential of senolytics in organ transplantation. Kirkland says that surgeons have known for a long time that transplanting organs from older donors to younger recipients doesn’t usually work out well for the recipient.

“In the US at least, it’s rare for surgeons to ever transplant a kidney from a person who dies in a car accident if they’re over the age of 50,” he says. “Currently, 35,000 kidneys a year are being thrown away. If those organs could be rehabilitated, that would pretty much solve the entire kidney shortage in the US.”

The reasons why those transplants don’t usually work out may be down to senescence.

“We know senescence spreads,” says Kirkland. “If we transplant small numbers of senescent cells into a mouse, above a threshold, it’ll cause frailty and cause early death from all diseases that animal dies from naturally, not just one disease.”

“Senolytics start working very quickly – it only takes a couple of hours of exposure to senolytics to start killing senescent cells. So we’re working on trying to rehabilitate kidneys after they’re taken from the person who has died and before they are given to the recipient.”

Senolytics and space

Based on work being conducted in collaboration with Axion Space and SpaceX, the wide-ranging potential of senolytics may even extend beyond our planet. In the lab, Kirkland says that “very, very low doses” of the equivalent of solar and cosmic radiation have been shown to induce cells to become senescent.

Some of Dr Kirkland’s lab in collaboration with the SpaceX team.

“It’s known that astronauts are dying earlier of age-related diseases than other groups,” says Kirkland. “So we’re looking at markers of senescence in some of the astronauts on the International Space Station before launch and after coming back to Earth. They also took cells up with them that were pre-senescent, and we’re trying to see if they became senescent in the space environment versus cells on earth.”

Don’t take senolytics yet

One thing Kirkland is very concerned about is people deciding to take senolytics (such as dasatinib and quercetin) before the results of clinical trials are known.

“People should not be taking these drugs until the clinical trials are done,” he says. “And physicians should not be prescribing them. You see them on the internet and that’s worrisome to me.”

“Senolytics might prove to be beneficial or dangerous at different times in our lives. For example, you would not want to give a senolytic to a younger, healthy person who has no senescent cells, you’d only be exposing them to side-effects.”

Kirkland points out that the trials he is involved in are all FDA-controlled with ethical review boards, data safety and monitoring committees. And it’s vital to wait for the results of those trials before putting senolytics to work.

“We don’t know what the downside of these kinds of agents will be,” he says. “And anything that sounds too good to be true, is too good to be true. There will be downsides, and we don’t know what they are yet. We do know that in these trials so far, there have been no serious adverse events that are clearly study drug related. But it doesn’t mean they won’t happen.”

While some study data are showing target engagement (senescent cell clearance) as well as some degree of safety and tolerability, the key question is whether they are effective or not.

“Phase 2a clinical trials have anywhere from a 90 to 95% chance of failing, no matter how well designed they are, so many or most of these trials will fail,” says Kirkland. “And that’s why we’re trying to do multiple trials with multiple agents for multiple indications in parallel instead of in series – to try to move things forward quickly.”

READ MORE: Senolytics have a 20% chance of success