MDC Lecture: When zombie cells attack, senolytics come to the rescue

Aging is a risk factor for human health. It is often accompanied by diseases such as Alzheimer’s, cancer, diabetes, arteriosclerosis, arthritis and cardiovascular disorders. “There appears to be a connection between age and the occurrence of these diseases,” says Dr. James L. Kirkland, director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic in Rochester, Minnesota, in the United States. “If we succeed in figuring out the cause – in other words, deciphering the aging process itself – we may be able prevent, alleviate, or cure many diseases.” For many years Kirkland has been investigating cellular aging. Scientists call this process senescence. Senescent cells stop dividing at some point. They are sometimes referred to in the press as “zombie cells,” because they are technically no longer alive but refuse to die. To protect themselves against the immune system, senescent cells secrete cytokines that promote inflammation, thus damaging or even killing nearby cells. This eventually leads to disease and frailty. The older a person gets, the more the senescent cells accumulate in tissue. The immune system does attack and kill these cells – but when such zombie cells accumulate in large numbers, the body’s immune defenses lose the battle against them.

Senolytic drugs aim to aid the immune system by clearing senescent cells out of the body. Kirkland will talk about what agents are involved, how they work and how far along the research is in his virtual lecture on “Aging, Chronic Disease, and Senolytic Agents: The Path to Translation” on September 21. In addition to cellular senescence, Kirkland’s research also focuses on age-related adipose tissue and metabolic dysfunction. He has received numerous awards for his research, including this year’s Irving S. Wright Award of Distinction from the American Federation for Aging Research.

There are some researchers who see aging as a disease that can be cured. Would you count yourself among them?

My goal is not to add years to life at all costs, but rather to extend health span.

I don’t get into that debate. I’m a geriatrician, I’m a clinician, I’m also a basic scientist. My goal is not to add years to life at all costs, but rather to extend health span – the period of life free of disease, disability, pain, cognitive impairment, and dependence.

How did you discover that senescent cells might be the key to eliminating age-related diseases?

Senescence was discovered a long time ago. The first study on the topic appeared back in 1961. Later in 2004, Norman Sharpless, now the director of the National Cancer Institute, published a paper in which he described how he was able to slow the pace of senescent cell accumulation in mice. Mice that underwent such a treatment were not only healthier than other mice of the same age, but also lived longer. So that’s what gave me and my team the idea that senescent cells are associated with health span. We asked, “What would happen if we got rid of them?” So we started trying to figure out ways to remove them from the body.

What did you find out?

Senescent cells develop defense mechanisms that enable them to survive despite the fact that they kill the cells around them. So we have developed senolytic drugs that temporarily turn off these defense strategies. During this time, the senescent cells kill themselves instead of the cells around them.

How have you tested the senolytics?

In 2018, we transplanted human senescent cells into mice. These mice aged very quickly and died of age-related diseases. With senolytics we were able to prevent such early death. Then, as part of a clinical trial, we administered senolytics to patients with idiopathic pulmonary fibrosis (IPF). IPF is a chronic, irreversible, progressive, often fatal disease in which the lungs become scarred and breathing becomes increasingly difficult. The therapy improved the patients’ condition, but the trial had few participants. In another clinical trial in patients with diabetes and kidney dysfunction we were able to reduce senescent cells in adipose tissue and their products in the blood.

Is it conceivable that at some point people will take senolytics prophylactically to get rid of senescent cells and ward off age-related diseases altogether?

Absolutely not – because senescent cells are not purely damaging. They play a role in various phases of development, remodel tissues, are important in wound repair, they occur in the placenta and are involved in childbirth and other important processes. So we only want to get rid of them when they cause dysfunction – for example after cancer treatment with radiation or chemotherapy. Such treatments kill cancer cells or make cancer cells become senescent. And then they can work like time bombs because sometimes they transform themselves into even more malignant, drug-resistant cancer cells.

How long it will take for senolytics to find their way into clinical practice?

That’s very hard to say. It depends on the results of the clinical trials that are currently under way. It’s far too early for people to take these drugs outside of clinical trials. With these substances, we are intervening in fundamental biological processes and don’t yet know enough about the potential effects.

Jana Ehrhardt-Joswig conducted the interview