What Might Survivors Of Childhood Cancer Teach Us About Ageing?

We know that one of the primary drivers of ageing and age-related disease is cellular senescence. This is when cells are unable to divide, either because they have reached their replicative limit or because they have sustained significant damage. In young people, such cells either self-destruct or are removed by the immune system, but in old age, senescent cells accumulate faster than they can be removed.

Senescent cells are the bad apples that spoil the barrel. They release molecular signals that mark them for destruction by the immune system, but when these cells accumulate in large numbers, those same signals trigger inflammation in surrounding tissues, turning more cells senescent and promoting age-related diseases.

We do know of some drugs that are capable of clearing at least a proportion of these senescent cells. These drugs, called senolytics, are still in the early phases of human clinical trials, but have shown some promise for the treatment of age-related diseases. For example, a 20-week course of dasatinib and quercetin (D+Q), a common combination of senolytic drugs, was associated with significantly improved markers of bone health in 60+ year-old women. 

Though encouraging, these trials have a lot of limitations. They typically study groups of people who already have some form of age related condition, a significant burden of senescent cells, and the studies don’t usually last long enough to determine if participants taking senolytics lived longer on average. What we would really like to know is whether taking senolytics earlier in life, before significant age-related frailty and disease sets in, can delay ageing and extend lifespan.

That’s why this clinical trial, estimated to complete in 2027, is quite interesting. The trial will test senolytics D+Q and fisetin not in the elderly, but in a relatively small sample of around 50-60 survivors of childhood cancer who are now around the age of 40. Why childhood cancer? Childhood cancer survivors represent a group of people who are ageing unusually quickly. This is because radiotherapy and most chemotherapy damages all cells, not just cancer cells, thereby triggering senescence. This leaves survivors of childhood cancer with a higher burden of senescent cells than normal for their age, and results in them showing signs of age-related frailty and disease earlier than their peers.

The participants, who will include those with signs of frailty but no age-related disease, will take either D+Q or fisetin for a month, and will then be followed up after 60 days and 150 days. The main goals of the study are to see whether the treatment reduces markers of senescent cell burden and improves walking speed, as well as other indicators of frailty such as markers of bone loss and impaired cognitive function. The study will also check on participants every 5 years to see whether the treatment reduces mortality.

Since childhood cancer survivors appear to be ageing at a faster rate, this trial may provide us with some insight into whether senolytics can delay ageing in people who have not yet developed age related diseases, and over a shorter time period than a similar trial in naturally ageing populations. Of course, this also means that the results might not translate well to normally ageing people in which cellular damage and senescence is accumulated slowly over time. Just as we wouldn’t assume that a treatment for heart disease would improve heart health in already healthy people, we can’t assume that senolytics would work in normally ageing people just because they work in abnormally ageing people. Still, data from trials like this may help point us in the right direction as we slowly move towards larger trials of senescence-targeting treatments.