Can targeting 'zombie' cells really slow down ageing?

Researchers believe that targeting these cells could ultimately provide a new way of tackling age-related diseases, addressing the waning of the immune system that occurs as we age, and perhaps eventually allowing all of us to live healthier for longer.

“Senescent cells accumulate as we age,” says Luke O’Neill, a biochemistry professor at Trinity College Dublin. “There’s evidence that it’s to do with an inability to clear damaged cells from our bodies, and so they remain, releasing inflammatory factors that link to diseases. They’ve been associated with cancer, diabetes, heart disease, and Alzheimer’s disease, to name a few.”

A number of scientists in Ireland are attempting to understand the involvement of senescent cells in osteoarthritis, a degenerative joint disease which impacts 13% of all people over the age of 50, most notably women. 

According to Katarzyna Whysall, an associate professor at the University of Galway, it is thought that this is caused by cells called chondrocytes — which make up the cartilage that glues together bones and cushions joints like the knees and ankles — becoming senescent, perhaps contributing to increased inflammation and tissue degeneration.

As well as osteoarthritis, Whysall’s research group is particularly interested in the connection between senescence and the loss of muscle function and quality, shown to begin in our 30s and progressively worsen throughout our lives. Their work has found that, with time, growing numbers of muscle stem cells, which enable muscle tissue to repair itself and regenerate, become senescent, contributing to muscle loss.

“Muscle contains its own population of stem cells, satellite cells which have been shown to undergo senescence, and other cell types that contribute to muscle function and have also been shown to undergo senescence and turn into bad guys,” she says. “Instead of supporting muscle, they contribute to its decline.”

Whysall is looking to develop better diagnostic tools based on the degree of cellular senescence in muscles. These tools could detect whether an older person is at heightened risk of developing frailty.

She explains that small pieces of genetic materials called microRNAs are found in various tissues and bodily fluids associated with cellular senescence and could be used as part of a blood test. “In a small ongoing study, we’ve found that levels of certain blood microRNAs that are different between healthy older adults and those with chronic obstructive pulmonary disorder [a lung condition also linked to muscle mass loss or atrophy in the limbs] are associated with cell senescence,” she says.

“We’re interested in whether these blood microRNAs could be used to predict frailty in older adults, for example, following a stressful event such as a surgery or serious illness.”

Eliminating senescent cells

Identifying whether someone has an abnormally large number of senescent cells in a particular tissue could make them a candidate for certain interventions. For example, O’Neill points to studies that have shown exercise and intermittent fasting can help to reduce levels of senescence in the body, which may be one of the reasons why both are associated with health benefits.

However, at medical conferences around the world, most of the excitement relates to an emerging class of drugs known as senolytics, capable of removing senescent cells from the body. In the past decade, Mayo Clinic professor James Kirkland has pioneered studies on a series of compounds, which include the chemotherapy drug dasatinib and natural plant chemicals quercetin and fisetin, found in fruits and vegetables, which show they can eliminate senescent cells by disabling biological pathways, causing them to self-destruct.

“This is already showing great promise for ageing-related disorders,” says Whysall. “A seminal trial by professor Kirkland and his team showed that in people with idiopathic pulmonary fibrosis [a chronic disease causing lung scarring], three weeks of senolytic treatment with dasatinib and quercetin improved various physical performance scores, including walking endurance and gait speed. Another small study found encouraging results for senolytics use in Alzheimer’s disease, although more research is still needed.”

Scientists have also launched clinical trials testing senolytics in relatively young people with illnesses associated with abnormal numbers of senescent cells. In the Netherlands, the government is funding a clinical trial where dasatinib and quercetin will be offered to patients aged 18 to 65 with a diagnosis of non-alcoholic fatty liver disease, a chronic condition caused by unhealthy dietary and lifestyle patterns. 

According to Stijn Meijnikman, a gastroenterology and hepatology doctor running the trial, one of the major theories is that the disease is driven by the formation of senescent cells in the liver, which causes widespread scarring and inhibits the liver’s ability to repair itself.

“We’ve been planning this trial for more than four years,” says Meijnikman. “In patients with this liver scarring, we see skyrocketing rates of senescence in hepatocytes [the primary, functional cells of the liver], so the idea is that senolytics could represent a low-cost intervention that targets these cells.”

This is just one of numerous clinical trials of senolytic drugs now taking place worldwide. Some are investigating their use in osteoarthritis and sarcopenia, while others are already being planned for chronic kidney disease, cardiovascular diseases and various neurodegenerative diseases.

Necessary caution

A growing community of longevity enthusiasts and biohackers are even questioning whether they can be used to extend lifespan but Whysall urges caution.

“Some questions remain around the use of senolytics, for example, the potential side effects, but it is encouraging to see many clinical trials happening around the world,” she says.

Scientists urge a dose of caution when it comes to senolytics because senescent cells also play specific positive roles in our body, even if too many of them can damage our health. Researchers such as O’Neill say we still need to learn about appropriate doses of senolytics which can help patients without resulting in unnecessary harm, as well as the longer-term consequences of removing these cells.

“Cellular senescence plays a role in wound healing, for example, so any effect on that would mean they would be too dangerous to use,” says O’Neill. “They’re also involved in how embryos grow and represent a way to suppress [the growth of] tumours.”

Because of this, researchers in Japan are investigating more precise senolytic treatments designed to identify specific populations of senescent cells contributing to inflammation and selectively remove them.

One research group at Juntendo University in Japan is pursuing an ‘ageing vaccine’ which uses a protein called GPNMB to target inflammatory senescent cells and train the immune system to detect them.

Project lead professor Tohru Minamino says the GPNMB protein acts as a marker for especially malignant senescent cells, which produce a lot of inflammation. He hopes that directing the immune system to remove only the most damaging senescent cells and leaving those that might be needed for beneficial purposes like wound healing could represent a form of precision medicine.

Whysall says that therapeutic approaches using RNA, a strategy pioneered through the ground-breaking mRNA covid vaccines, could also potentially be used to train the immune system to attack senescent cells, particularly in muscle tissue. “The more precise the medicine, the less chance of side effects. For tissues such as muscle, detailed cellular atlases now exist which can help identify cells senolytics need to be delivered to.”

The results of clinical trials could lead to treatments targeting senescent cells being used for many age-related disorders.

Whysall would like to see Ireland participate in some of these trials: “We have the infrastructure and a lot of expertise in clinical trials. It is my hope and ambition to take some of the molecules we are researching into trials for sarcopenia and other conditions related to ageing.”