Why Eradicating ‘Zombie Cells’ Could Be the Key to Anti-Aging
- Senescent cells stop dividing and roam the body like zombies. As we age, they accumulate and cause inflammation and disease.
- The National Institute of Health recently spearheaded a large project that hopes to map senescent cells throughout the body.
- Clinical trials are already underway for drugs with the potential to rid the body of senescent cells and stave off aging as long as possible.
Aging could be the equivalent of a zombie apocalypse for your cells, scientists say.
As we age, our bodies fill up with a type of dysfunctional cell that permanently stops dividing, called a “senescent cell.” They don’t function like normal healthy cells, nor do they die off. Instead, these so-called “zombie cells” linger in our tissues, emit inflammatory signals, and increase the risk of age-related diseases. And just like zombies that spread their living-dead condition through a bite or scratch, senescent cells can also convert their healthy counterparts through chemicals they emit.
“They are the kind of bad apple that ruins the kart,” aging researcher at the Mayo Clinic, Nathan LeBrasseur, tells Popular Mechanics.
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Senescent cells were first discovered 60 years ago when scientists at the University of California San Francisco showed that human stem cells had a limit to how many times they could replicate. Their discovery overturned a long-held scientific belief that stem cells could churn out daughter cells endlessly. At first many did not believe them, and for years it was regarded as a strange phenomenon that only occurs in lab-grown cells.
But in 2012, a research group from the Mayo Clinic genetically engineered mice to have no senescent cells, and showed the mice were healthier. They did not develop cataracts, muscle weakness, or other signs of aging. The same group repeated the experiment in 2016 and showed mice without senescent cells stay healthier for longer. They could increase their “healthspan,” living disease-free into old age, according to LeBrasseur.
Since then, efforts to understand these cells have accelerated. In 2021, the National Institute of Health (NIH) launched the Cellular Senescence Network (SenNet), a $190 million program that aims to map the cells throughout the body in mice and humans. The program supports scientists in detailing the cells and the chemicals they emit throughout the body’s various organs and tissues. Their aim is to learn how to identify them using genetic markers, find new drug targets against them, and ultimately develop drugs to clear them from the body.
“The mapping of the cells is something that we really need in order to understand better how to target them,” Paul Robbins, molecular biologist at the University of Minnesota tells Popular Mechanics.
Mapping the Unknowns
“It’s hard to define what a senescent cell is,” leading senescent cell researcher, James Kirkland, tells Popular Mechanics. Kirkland leads a group at the Mayo Clinic that showed mice without senescent cells live healthier into old age. He explains that senescent cells become that way for a wide range of reasons. DNA damage can trigger senescence, but so can mechanical or physical stress—which is the basis for senescent cells accumulating in the knee joint. Senescent cells can develop in response to viruses like coronavirus, herpes, and HIV; and even to bacterial changes in the gut microbiome.
Kirkland says there are no good markers right now to find senescent cells, which is the reason researchers are mapping the tissues. “We are trying to reliably detect these senescent cells in tissues and understand just how heterogeneous or diverse they can be,” Matt Yousefzadeh, an aging researcher at Columbia University, tells Popular Mechanics. That is why the NIH has invested in these senescence tissue-mapping centers.”
Researchers are looking at every organ system in the body, including the liver, blood, kidneys, lungs, and, most recently, the brain.
“Instead of just studying senescent cells in cell cultures in the lab, we are trying to translate the technology,” Nicola Neretti, aging researcher at Brown University, tells Popular Mechanics. “We still don’t know how many senescent cells are in different tissues and cell types, or what the difference is between senescent cells in different cell types because there is no map of senescent cells in tissues yet,” he says.
Neretti focuses on the epigenome, looking for changes in DNA organization in the nucleus and which genes are turned on or off in senescent and normal cells. He is currently researching the specific cell types at the highest risk of becoming senescent in the blood and the liver.
LeBrasseur and his colleagues at the Mayo Clinic are looking at senescent cells in skeletal muscle. As muscles age they suffer from issues like atrophy, sarcopenia, weakness, and fibrosis. In a paper published in Nature Aging in 2022, his group identified two specific cell subsets in muscle that tend to senesce. Muscle tissue is composed of roughly 12 different cell types including stem cells, satellite cells, macrophages, and more. Two types in particular were found to be in senescent states in older mice: one is a type of stem cell, and the other is a myocyte or muscle fiber cell. Going forward, this knowledge will further help identify markers of aging. It will also allow researchers and companies to develop precision therapeutics that go after the specific cell types that cause inflammation without harming other cells.
Researchers are also looking for ways to detect the levels of senescence in the body. LeBrasseur has identified specific mixtures of chemicals that are excreted from senescent cells that can be detected in the bloodstream and provide an accessible way of measuring health. He thinks that some day these advances will help doctors measure the level of senescence and deliver medicines to clear the cells.
“If we understand this fundamental biology of aging, and what drives the aging process, we have the potential to delay age-related diseases as a group,” he says.
Treating Old Age as a Disease
The tantalizing prospect of ridding the body of zombie senescent cells would not just stave off old age, but also the range of diseases it brings with it. “Instead of treating one disease at a time and dealing with the complications of being on multiple medicines, we can treat aging and improve multiple conditions at once,” says Yousefzadeh.
Right now, it may seem like doctors are playing the equivalent of Whac-A-Mole with their aging patients. They might get a handle on heart disease only to have diabetes pop up a year later, or bring down high blood pressure just as arthritis kicks in. But researchers and biotech companies are investing heavily in drugs that promise to tackle the gamut of issues aging brings.
There are currently three leading anti-senescence drug candidates, collectively called “senolytics.” One is a drug combo that combines dasatinib, a drug used in leukemia therapy, and quercetin, a naturally occurring pigment found in foods such as grapes and red wine. The two are given together as a cocktail called D + Q. In a small pilot study in humans in 2019, the drug combo significantly improved a fatal lung disease called idiopathic pulmonary fibrosis, a condition marked by lung scarring and difficulty breathing that affects people 70 years and older. Today, there are multiple clinical trials testing the drug on a range of diseases including Alzheimer’s, fatty liver disease, chronic kidney disease, and more.
The next candidate is another naturally occurring compound called Fisetin, which is derived from a class of chemicals called polyphenol flavonoids, like those found in fruits, vegetables, tea, and wine. In 2018, a team of researchers at the University of Minnesota, including Yousafzadeh, tested a panel of 10 different flavonoids and found Fisetin to be the most potent at clearing senescent cells from mice, increasing lifespan and healthspan, and reducing age-related disease.
Researchers imagine that these types of drugs will be used intermittently in aging patients when their inflammation levels get high. Just like antibiotics are given in two-week courses to clear bacterial cells that infect the body, senolytics will be given in courses to clear the inflammation-boosting cells.
Last, and possibly closest to FDA approval, is a drug called UBX1325 from San Francisco-based Unity Biotechnology. The drug is derived from an experimental anti-cancer drug, and it is injected into the eye to treat age-related diseases of the eye including macular degeneration. UBX1325 just entered into a phase two clinical trial for the treatment of macular degeneration, and positive data has been reported from the study.
“I’m very optimistic about the future of senolytics,” aging researcher Paul Robbins, from the University of Minnesota, tells Popular Mechanics. “But, it is going to take much larger studies to prove the results,” he cautions. Robbins thinks that senolytics will be entering the clinic, but much work is needed to validate and test the drugs on large populations. He also warns that more research is needed to understand the difference between senescent cells. There is a wide range of senescent cells. Some are even beneficial, involved in wound healing and cancer prevention. “A lot of interesting questions that still have to be addressed,” he says.
Fight Senescent Cells Naturally
Even though senolytic drugs aren’t yet available, there’s still something people can do about it in the meantime. There is evidence that various lifestyle changes can reduce senescent cells naturally.
A study in 2021, coauthored by LeBrasseur, found that older adults showed a significant reduction in known markers of senescence after participating in a 12-week structured exercise program. The participants also reported improvements in body composition, like a reduction in BMI, and increased muscle strength and physical function.
In addition, there is ample evidence showing that diet can also affect aging and senescence. Caloric-restriction diets have been shown to be the most effective, non-genetic mechanism of clearing the cells, and researchers are actively researching the popular trend of intermittent fasting.
Monique Brouillette is a freelance contributor who writes about biology.