At St Jude children’s research hospital in Memphis, Tennessee, an unusual clinical trial is under way that, if successful, could have wider ramifications for the vast field of age-related chronic diseases. At first glance, childhood cancer survivors may seem like an unusual population in which to study ageing, but as Greg Armstrong, principal investigator of St Jude’s Childhood Cancer Survivorship Study, explains, we now know they represent a group of individuals who are ageing unusually quickly.
For while modern chemotherapies and radiotherapies have become increasingly efficient at curing childhood cancers, this comes at a great cost, owing to the corrosive impact of such treatment on these children’s bodies, something that becomes more apparent when they reach middle age.
“Of these children, 85% are going to beat their cancer, but it’s a win at a cost,” says Armstrong. “We know that these kids will have shortened lifespans. They often die young of chronic diseases like heart disease, stroke or secondary cancers which present much earlier. And we discovered about a decade ago that this is because they’re ageing much faster than their chronological age.”
In particular, this is reflected not just in their biology, but in physical frailty. When Kirsten Ness, a physical therapist and clinical epidemiologist at St Jude, assessed a group of childhood cancer survivors aged 24-41, she noted that when it came to heart function, flexibility, respiratory capacity and range of motion, they resembled people decades older. “We showed that at 30, they have physiological frailty that resembles people in their 70s and 80s, and it’s getting worse over time,” says Ness.
The underlying cause of this is senescence, a state in which cells cease to continue dividing as normal, but instead simply linger, refusing to die. Because of this quality, senescent cells have sometimes been described as “zombie cells” and they are now regarded as a driving force and a reflection of ageing. Over the course of a lifetime, our bodies incur increasing amounts of damage which in turn makes many of our cells, distributed throughout our body, more likely to become senescent.
For childhood cancer survivors, it appears that the consequence of undergoing such radical treatments at a young age leaves them with abnormally large populations of senescent cells, which would normally take decades to accrue. Ness explains that this drives loss of function and disease risk, and not only because senescent cells cease to function as they normally would. Senescent cells also generate a stream of inflammatory molecules, something known as the senescence-associated secretory phenotype (SASP). “If we look at data from our childhood cancer survivors, we can see that they have this low-grade inflammation,” says Ness. “And so they don’t feel great, they don’t move great.”
Over the past decade, interest has steadily grown in a class of drugs known as senolytics, so called because they have been shown to be capable of eliminating senescent cells in mice by disabling certain pathways, causing them to self-destruct. One of the most well-studied senolytics is actually a chemotherapy drug called dasatinib, while others include the natural chemicals quercetin and fisetin, which are found in various fruits and vegetables.
Now, Armstrong is leading a trial of 50-60 childhood cancer survivors with signs of frailty, along with blood-based markers that indicate a significant amount of senescence. Aged about 40, on average, the participants will receive oral doses of either dasatinib and quercetin, or fisetin, to see whether it can improve their physical function over the course of six months. These individuals will then be tracked every five years to assess whether this treatment can help extend their life expectancy.
For researchers into ageing around the world, such data represents a first tentative step towards indicating whether senolytics could one day be used as a way of extending healthy lifespan in all older adults.
At September’s British Society for Research on Ageing conference, Johannes Grillari, director of the Ludwig Boltzmann Institute for Traumatology in Vienna, discussed the future of senolytics in front of an intrigued audience of gerontologists.
As Grillari explained, while scientists continue to assess the long-term safety profile of these drugs, they will mostly be used in trials of patients with advanced illnesses, where the accumulation of senescent cells is thought to be a significant contributing factor.
“It’s all about the risk-benefit ratio, and if you’re considering giving them to healthy individuals then the risk must be close to zero,” Grillari later told the Observer. “But the promise is that these cells seem to be a common denominator in every age-associated disease that has ever been looked at: cardiovascular diseases, neurodegenerative diseases, musculoskeletal diseases, lung fibrosis, chronic kidney disease, you name it. And if we use senolytics, we see that the inflammation goes away and the regenerative capacity of the surrounding tissue is restored – well, at least if you’re a mouse.”
Based on dozens of preclinical studies in which rodents have been manipulated to develop various chronic diseases before being cured, senolytics are now starting to reach humans. The data so far is limited but clinical trials are under way to see whether dasatinib and quercetin can modulate disease progression in patients in the early stages of Alzheimer’s disease, while this same combination has previously been shown to alleviate some physical dysfunction in people with chronic lung disease.
Grillari – who is also co-founder of Rockfish Bio, a company that has developed its own senolytic – is now hoping to launch trials in other disease states, as well as using the company’s senolytic to try to rejuvenate organs from older donors. While the NHS says there is no age limit for becoming an organ donor, research has previously shown that recipients of organs donated by the over-60s tend to have poorer outcomes because the organ is more likely to have existing damage, while the rejection rate is also much higher.
“There was a study in the 2000s that showed that the more senescent cells you have in a human transplant organ, the worse the outcome of the transplantation,” says Grillari. “Because the senescent cells are pro-inflammatory, they attack the recipients’ immune system, and seem to attack the donor organ more frequently. The hope is that senolytics can help, because kidney transplant organs, for example, are so rare.”
All of this will provide more data on the safety and efficacy of various senolytics, while many studies are continuing to focus on their potential benefit in relatively young people with advanced disease. Dutch government agencies are funding a trial where dasatinib and quercetin will be offered to patients aged 18-65 with a diagnosis of non-alcoholic fatty liver disease, a diet-related chronic illness where senescent cells are believed to be driving fibrosis, or scarring, throughout the organ, impairing its ability to function. According to Stijn Meijnikman, a gastroenterology and hepatology doctor leading the trial, the hope is that removing these cells will enable the liver to repair itself.
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“In mice, you see that if you get rid of the senescent cells, you get rid of the fibrosis,” says Meijnikman. “So we’re looking to see indications of that in humans. It’s a very short trial, but we’re hoping that briefly disrupting the pathways that allow senescent cells to persist will enable them to be cleaned up by the immune system.”
The wider community of longevity scientists and investors remain intrigued as to whether these drugs can ultimately help reverse some of the signs of ageing in mid to later life, and perhaps even extend human lifespan.
“More people are becoming familiar with the concept of senescent cells and how you can maybe positively influence this,” says Marc Bernegger, founder of Longevity Investors, a funding network.
Glancing at a photo that Grillari pulls up on our Teams call, it’s easy to understand the excitement. It shows an elderly mouse of 34 months – equivalent to 90 in human years – its fur thinning and grey. “Just like us, they get bald patches as they age,” laughs Grillari.
In another picture, after being treated with a senolytic, the same mouse appears visibly younger. Its fur has grown back and regained its original pigmentation. If such a drug were to achieve similar results in humans, it would undoubtedly be a blockbuster.
But many are urging caution. Prof Tohru Minamino of Juntendo University in Japan, who has studied cellular senescence for two decades, points out that some senescent cells are beneficial to our body, playing important roles in key physiological functions such as wound healing. Simply clearing away everything could have negative long-term consequences.
Minamino believes that he may have the answer. In 2021, he and his colleagues unveiled an “ageing vaccine” that uses a protein called GPNMB to selectively remove senescent cells that contribute to inflammation. “We’re trying to specifically target the bad guys,” he says.
Once again, this has been shown to work remarkably well in mice, with older rodents showing fewer functional impairments after receiving the vaccine and living substantially longer. Minamino is now hoping to develop this as an RNA-style vaccine, similar to the Covid jab, which trains the immune system to remove inflammatory senescent cells and could be used in patients with Alzheimer’s, chronic lung disease or frailty.
“One of the challenges at the moment is that we don’t have particularly good tools to estimate the number of senescent cells in the human body and the extent to which this changes with treatment,” says Minamino. “But if we can develop better imaging systems for measuring how these cells are accumulating, you can envision a future where this could be part of an annual medical check.”
Ultimately though, researchers caution that senescent cells are still only one piece of the ageing puzzle. As Meijnikman points out when I ask whether senolytics could be used to revive the livers of 80-year-olds, which have been weathered by decades of heavy drinking or a bad diet, this isn’t only about clearing senescence.
“Your body still needs to have the capacity to regenerate,” he says. “There’s still an open question about what would happen if we get rid of the senescent cells, but there’s no reservoir of new cells to replace them any more because your stem cells are no longer working. We are going to move this way in the future, treating more and more older people, but for now we first need to gather more evidence that senolytics can really work in humans.”
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