A study by scientists at Newcastle University Biosciences Institute suggests that a simple, one-off treatment using senolytic drugs can prevent long-term side effects associated with cancer radiotherapy. The research, in a mouse model, showed that treatment with senolytic drugs reduced frailty and improved muscle and liver function, as well as short-term memory. The study, they suggest, offers new hope that people who receive cancer therapies might have a better quality of life for the rest of their lives.
Research lead Satomi Miwa, PhD, Lecturer, Translational Biology of Ageing, Newcastle University, said: “Increasing number of people are now successfully treated from cancer, and the survival rates from many cancer types are high. The people who had beaten cancers can start looking forward to their new lives again—but only if the quality of life is not going to be affected. Sadly, this is the case for the moment. However, our new research shows that there is a way to prevent any long-term side effects occurring, and to reduce risks of cancer relapse.”
Miwa and colleagues reported on their findings in eLife, in a paper titled “Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice,” in which they concluded “Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.”
Cancer has become an increasingly survivable disease, and cancer-specific mortality in developed countries has dropped sharply over the last decades, the authors noted. There are about 2 million cancer survivors in the U.K., and many of them face premature memory loss and faster occurrence of various diseases resembling premature ageing, to which sadly, there is no cure, or approved treatment approach.
“Many cancer types have now high cure rates, and in some fields the emphasis has started to shift towards efforts to improve the quality of survivorship after successful cancer treatment,” the researchers continued. “This is necessary as long-term survivors of childhood and adult cancers undergo a wide-range of negative health and quality of life changes that lead to increased frailty, multi-morbidity and mortality compared to the general population.”
The cause of premature ageing in cancer survivors is thought to be driven by DNA-damaging cancer therapies, which, while eliminating cancer cells, can also damage normal cells. “Numerous biological processes have been proposed as drivers of this, with therapy-induced cell senescence prominent amongst them,” the team noted.
The researchers wanted to know whether they could prevent such consequences of cancer therapies, through the use of short treatment with senolytics, a class of drugs that specifically eliminate damaged cells due to cancer. Senolytics are an exciting development in the biology of ageing as the drugs kill senescent cells by targeting their survival mechanisms, which are absent in normal cells. They have been shown to postpone or in some cases, heal age-associated disease or disability in mice.
“Our core hypothesis was that therapy-induced senescence would greatly and persistently accelerate the accumulation of senescent cells by enhancing secondary senescence via bystander signaling, thus causing progressive worsening of ageing-associated symptoms with time following a single bout of DNA-damaging therapies,” they noted. “If this hypothesis is correct, eliminating therapy induced senescent cells by a one-off, short senolytic or senostatic intervention adjuvant to radiation or chemotherapy should be sufficient to prevent progressive premature ageing and to normalize the rate of frailty progression.”
For the newly reported studies, the researchers investigated the effects of some well recognized first generation senolytics (Navitoclax and dasatinib+quercetin), in a mouse model of premature ageing induced by whole-body irradiation. “We focused on frailty as a primary outcome because premature frailty is a well-documented, clinically important problem of long-term cancer survivors,” they explained. The team separately tested a 10-week course of metformin—a senostatic rather than a senolytic—in irradiated male mice. Treatment was started a month after they finished radiation treatment, after the mice had recovered from their therapy, but before there was much evidence of radiation-induced senescence in various tissues.
The study results showed that animals treated with senolytic drugs soon after radiotherapy did not develop premature ageing, and even animals treated after they started demonstrating signs of premature ageing also show improved health conditions subsequently. “These data show that a short-term senolytic intervention even if applied at an advanced age still has beneficial effect on irradiation-induced premature progression of frailty and cognitive decline,” the investigators noted. Results from studies using metformin were also encouraging. “Metformin was similarly effective as senolytics,” they noted. “.… these data indicate that a relatively short treatment with the senostatic metformin rescues multiple domains of irradiation-induced premature ageing in mice for at least 10 months after cessation of the intervention.”
While acknowledging several limitations of their studies, the investigators concluded, “ … we have shown that short senolytic or senostatic interventions can effectively rescue premature progressive frailty and accelerated ageing induced by whole body irradiation over a significant part of the life history in male mice. We believe these results warrant further efforts to translate senolytic and senostatic interventions towards an adjuvant therapy for long-term tumor survivors.”
Currently, a dozen clinical trials using different senolytic drugs in humans are underway, or being registered in the U.S., against such conditions as pulmonary fibrosis (lung fibrosis), diabetic kidney disease and osteoarthritis. The group intends to continue with their research. Miwa commented, “We want to test our approach in cancer types specifically, and move to clinical setting as fast as we can. We are particularly interested in childhood brain tumor survivors, as they are the worst affected group of people suffering from long term side effects from cancer therapies.”
