Mice Cleared of Senescent Cells Shown to Die Healthier—Not Just Live Longer

By Deborah Borfitz 

August 20, 2024 | By treating a particular brand of senescent cells, it is now possible to live healthier for longer—at least in mice. If the findings can be translated to humans, that could mean an extra decade of healthiness. Plenty of medicines are already available to help people live longer, but not necessarily with vitality, according to gerontologist Ming Xu, Ph.D., assistant professor in the University of Connecticut’s Center on Aging and the department of genetics and genome sciences.  

For the most part, anti-aging researchers have been measuring physical functioning only at certain time point and “not comprehensively to assess the dynamic of the healthspan over the post-treatment lifespan,” says Xu. That deficiency was uniquely addressed with a time-consuming study, published in Cell Metabolism (DOI: 10.1016/j.cmet.2024.07.006), where the health of individual mice was assessed monthly from the time they were 20 months old (equivalent to 60-year-old humans) until death. 

Mice in the group receiving monthly treatments to remove a small number of cells highly expressing p21, an established senescence marker, were found to not only live an average of 9% longer (about 79 days) than the control mice but to also walk faster and have better grip strength during their added lifespan. They also were shown to have improved cardiac, metabolic, and liver function as measured at a single time point by, respectively, echo ultrasound, glucose and insulin tolerance tests, and circulating levels of alanine transaminase. 

The choice of the two longitudinal metrics (walking speed and grip strength) was based on a balance of what was clinically relevant as well as not overly stressing the mice, Xu says. “Some mice live up to two years after treatment, which means we have to measure them at least 24 times, so the measurements had to be very mild and non-invasive.” Frailty was additionally assessed by the animals’ visual appearance. 

Reasons to Hope

The long-term possibility here is that people will be living longer without the burden of chronic conditions such as heart disease, diabetes, and cancer. This is a higher bar than simply extending biological age, which appears to have a hard limit, says Xu. 

One 15th century Englishman reportedly lived to be 152 years old, but the oldest person verified by modern standards was a French woman who made it just past her 122nd birthday. In experimental mice, Xu says, the oldest recorded age is about 1,400 days—roughly equivalent to 140 human years. In his latest study, the oldest treated mice lived to be 43 months (1,300 days), comparable to a 130-year-old human. 

Clinical trials have many potential complications that can make a medicine’s journey to market expensive, lengthy, and uncertain, says Xu, who advises against getting “over-optimistic” about the latest breakthrough study findings. Which is not to say he is not hopeful, he adds. 

Despite the well-known difficulties encountered when moving out of the preclinical setting, mice like humans are mammals, he notes. Additionally, “the fundamental aging process theoretically should be conserved between species, so if we can find a way to slow down the aging process in one species it is very likely we may be able to do the same thing in other species.” 

Perhaps most importantly, Xu and his team have had a few positive experiences to reference. “Some of our findings in mice have been partially repeated in humans, so this boosts my confidence.” 

One of these prior studies confirmed that the combination senolytic drug D+Q (dasatinib plus quercetin) that improved physical function in aged mice (Nature Medicine, DOI: 10.1038/s41591-018-0092-9) also did so in older humans (EBioMedicine, DOI: 10.1016/j.ebiom.2018.12.052). Similarly, another earlier study in aged mice finding that D+Q can improve bone formation (Nature Medicine, DOI:  10.1038/nm.4385) was partially confirmed in older women (Nature Medicine, DOI: 10.1038/s41591-024-03096-2).  

Intriguing Findings 

In the latest study, treatment of mice was accomplished by leveraging “genetic tricks” whereby the animals were bred to express p21 so that an injectable drug (tamoxifen) could induce its clearance, says Xu. In the future, this might be translated to humans by developing or screening drugs or making chimeric antigen receptor (CAR) T-cell therapies targeting the culprit pro-inflammatory cells.  

Xu reports that in the treated transgenic mice inflammatory cytokine levels, both in circulation and in various tissues, were reduced. Importantly, however, no such reduction in the immune cell population was seen in the spleen—"the largest reservoir for all immune cells in the body.” This means investigators were not suppressing the immune system itself, which would be dangerous for aged people who are more susceptible to infectious diseases, autoimmune disorders, and cancer. 

For some reason, in mice anyway, p21 cells do not accumulate in middle age but only later, he adds. His best guess is that the p21 cells cannot effectively be cleared once the aging process impairs the immune system. The intriguing suggestion here is that fewer treatments of shorter durations could do the trick. 

Closing the Gap

Among anti-aging researchers, p16 senescent cells have often been the focus of attention, says Xu. But “more and more evidence show that senescent cells are highly heterogenous,” with p16 representing just one of those cell populations and p21 another. Disagreement about the senescent cells that matter has been a “big problem in the field,” he adds, in terms of the senolytic drugs being tested and the potential overlap in the cells they’re annihilating. 

Nonetheless, a longstanding goal has been to close the average nine-year gap between lifespan and healthy lifespan (healthspan). Efforts to increase lifespan do not necessarily result in people living out those added years with normal function and without morbidity, he notes. 

That won’t change so long as preclinical studies fail to consider the health of mice when they’re close to death, regardless of when individual animals happen to die. “Most studies in the aging field measure lifespan as we do, but they only measure [health and physical] function at one or two time points,” generally between the ages of 18 and 24 months, says Xu. His approach, in contrast, demonstrated that the biologically older mice cleared of p21 both lived longer and healthier than their untreated counterparts.   

Next steps for Xu and his colleagues include both identifying drugs that can specifically target p21-highly-expressing cells, as well as developing technology allowing them to study its safety and effectiveness in wild type mice in lieu of using transgenes. The longer-term objective is to perform clinical trials, which could easily be another five to 10 years, he says.