When cells become irreversibly damaged, this may lead to various age-related diseases, such as dementia, organ failure, and cancer. UMC Utrecht’s molecular biologist Peter de Keizer has discovered a way to clear out these so-called ‘senescent’ cells. This is a very promising step toward preventing and curing cancer and other diseases in the near future.

Throughout our lives, the cells in our bodies sustain damage. This DNA damage can result from ‘normal’ aging, but also from external factors, such as excessive sunlight, our diet, or smoking. Our bodies repair most of this damage, but sometimes a small amount remains. At a certain point, there is simply too much damage to be repaired. Cells can then become ‘senescent’ (from the Latin word for aging).

These senescent cells are thus irreparably damaged, but they do not die. In a sense, they form a kind of rust in our organs. They often still function quite well on their own. The problem, however, is that they chronically release all kinds of substances into their surroundings. And these, in turn, cause mini-inflammations and disrupt communication with and within neighboring cells. Think of it as sand getting into an engine.

In this way, senescent cells accelerate aging and contribute to the progression of various diseases. Results in laboratory animals have shown that these irreparably damaged cells contribute to conditions such as cancer, loss of muscle mass and strength, liver damage, cardiovascular disease, and forms of neurodegeneration (diseases of the nervous system).

Peter de Keizer is an associate professor at UMC Utrecht. He has dedicated his career to the study of senescent cells. After more than 15 years of research and testing in the lab – including studies on laboratory animals – the time is near to test if his findings also work in humans. Clinical trials involving his research are therefore set to begin at UMC Utrecht in 2027, focusing on people with cancer. An interview with a tenacious researcher.

What drew you to those senescent cells?

“I’m extremely fascinated by the molecular biology of aging: what exactly causes us to age? We can see on the outside that we’re aging, but what’s happening at the smallest level inside us, in our cells and molecules? Just by living, cells in our bodies are constantly getting damaged, losing their function, and can eventually cause cancer and all kinds of age-related diseases.”

“I’ve always been incredibly curious about how this process works and how we can stop it. How is it that one cell goes into hibernation, while another doesn’t?  And how can I, as a molecular biologist, find innovative ways – and ultimately drugs – to destroy those senescent cells?”

What is the connection between senescence and cancer?

“Senescence is a stress response in cells after they have been severely or irreparably damaged. This can occur in normal cells, but also in cancer cells. And senescent cells can also contribute to the development of cancer in other ways. For example, they secrete pro-inflammatory proteins, which stimulate cancer and can lead to metastasis. Furthermore, senescent cells can themselves develop into cancer if their DNA mutates in a certain way.”

Are all senescent cells the same?

“No, there are an enormous number of types, and that is precisely what makes them so difficult to combat.  We now know that one type has developed specific scars in the DNA. We refer to this as scarred senescence or scarred cancer. This involves irreversible damage. We now understand this type much better, and we believe it could have a major impact if we target and destroy those specific cells.”

“We encounter these severe scars in the DNA, for example, in one-quarter to one-third of patients with metastatic colorectal, ovarian, or breast cancer. And precisely to destroy that type of cancer cell, we have developed a special so-called ‘CPP’ (cell-penetrating peptide – ed.) in the lab.”

What exactly is a CPP?

“It’s a molecule that can pass through the cell membrane and transport substances inside to do their job. In this case, their mission is to clear out the scar cells. How do they do that? In scar cells, the p53 protein is negatively charged at various sites. This means that the environment around the protein has a lower acidity level, or pH value, at those sites. Scar cells remain alive because the negatively charged p53 protein is chemically bound to another protein: FOXO4. We have created a CPP that separates the two proteins. As a result, the scar cells die.”

Have you tested the treatment yet?

“Our approach proved successful in mice: it extended the lifespan of mice, which age rapidly. Following further research, we now have a CPP version that targets scar cells even more specifically: in 800-day-old mice, healthy lifespan was extended by 27 percent.”

Has it also been tested for cancer?

“Yes, we already observed in mice with cancer that the number of metastases from colorectal and breast cancer to the liver decreased. This is particularly effective when the p53 protein is mutated, which is a major challenge in treating many types of cancer.”

“In addition, we observed that the CPP prevented breast cancer cells from spreading further throughout the mice’s bodies. All of this is still being studied in depth, including dosing regimens, dosing frequencies, and the solvents to be used. Ultimately, we want to test this thoroughly in clinical trials, but it certainly looks promising so far.”

When do you plan to test the drug in humans?

“Safety studies in animals have now been completed. We are currently evaluating which treatment regimens might be most effective.  Depending on sufficient funding and further evidence of efficacy in mice, clinical trials in humans are expected to begin in 2027. These trials will involve patients with mutant p53 breast and colorectal cancer.”

Why focus specifically on those types of cancer?

“It is precisely with these types of cancer that a great deal of scarring occurs, especially in more advanced stages. We could have chosen other types of cancer, but precisely because of the high degree of scarring associated with breast and colorectal cancer, we hope to achieve positive results more quickly during our first clinical trials.”

Why is there more scarring in these types of cancer?

“The p53 protein is often mutated in these types of cancer and therefore takes on a different form. Our CPP also works on these mutated p53 variants—and perhaps even better. That’s exciting, because these cancers are generally more difficult to treat with immunotherapy and conventional chemotherapy and radiation therapy.

“Our research therefore hopefully offers new treatment options for cancers with mutated forms of p53. If the initial results from the clinical trials are positive, we will also investigate whether it works for other types of cancer.”

The clinical trials focus on curing or reducing cancer. But can cancer (and its spread) also be prevented by clearing out senescent or scar cells?

“That’s exactly what we’re hoping to achieve. Senescent cells secrete substances that damage their surroundings. This affects the surrounding cells, causing the cancer to worsen. By destroying the most problematic senescent cells – the scar cells, we believe – we may be able to slow down the progression of the cancer or prevent it from metastasizing.”

“Metastases are often difficult to treat, but we’ve already seen them significantly reduced in mouse studies. This is an important development, because we often find that while the primary tumor can be treated effectively, the metastases that arise from it cannot. We hope to see in clinical trials that the cancer recurs or metastasizes less frequently in humans as well.”

Apart from the clinical trials, what other ‘senescence-related questions’ are you currently working on?

“We’re also trying to identify other types of senescent cells. For example, we want to determine which subtype of senescence is active in which disease. We also want to investigate why surrounding cells are disrupted by senescent cells. What exactly happens to these cells, and what does that mean for the development of cancer and other age-related diseases?”

“Senescent cells play a broad role in aging in general. That’s why, in our clinical studies with cancer patients, we’ll also examine various factors that measure aging. Here at UMC Utrecht, we work within a vast hub of knowledge, data, and new techniques. And doctors are always nearby and willing to collaborate with us. We are now also working together within UMC Utrecht on projects related to neurodegeneration and cardiovascular diseases.”

Where do you hope to be in five years?

“By then, I hope we’ve completed a successful clinical trial and, through our CPP, contributed to better cancer treatment. After that, I might dive back into the lab. On to the next CPP drug we can use to treat people. For cancer or another disease, such as Alzheimer’s or ALS. And, of course, for cardiovascular diseases, such as aneurysms (weak spots in arteries – ed.)”

“This is exactly why I find the elimination of senescent cells so interesting: it could offer a solution for so many diseases. We’re seeing a 27 percent increase in lifespan in mice, with cognitive and motor functions remaining intact until the very end. These are indications that eliminating senescent cells could also be effective against conditions such as dementia. I find it incredibly challenging to investigate this further.”