UConn Health scientists have discovered that eliminating old, dysfunctional—senescent—cells in human fat can alleviate characteristic signs of diabetes. Their studies showed that using two experimental drugs, dasatinib and quercetin, as a treatment to target a particular population of senescent cells in immunodeficient mice carrying human fat implants almost completely eliminated the adverse effects of the fat tissue.
The team claims the discovery could lead to new treatments for type 2 diabetes and other metabolic diseases. “These drugs can make human fat healthy, and that could be great,” said research lead Ming Xu, PhD, assistant professor in the UConn Center on Aging and the department of genetics and genome sciences at UConn Health. “The results were very impressive and cleared the route for potential clinical trials.”
Xu and colleagues reported on their findings in Cell Metabolism, in a paper titled, “Targeting p21Cip1-highly-expressing cells in adipose tissue alleviates insulin resistance in obesity,” in which they concluded, “Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.”
CDC figures indicate that more than 93 million U.S. adults are obese, the authors wrote. “Obesity accelerates the aging processes and is among the most significant risk factors for the development of type 2 diabetes (T2D), one of the leading causes of death for older adults,” the authors wrote. In fact, T2D is the most common metabolic disease in the United States, and affects about 34 million people, or one out of every 10 U.S. inhabitants, according to additional CDC figures cited by UConn Health. Most people with diabetes have insulin resistance, which is associated with obesity, lack of exercise, and poor diet.
The cells in our bodies are constantly renewing themselves, with older cells aging and dying as new ones are generated. But sometimes that process goes awry, and damaged cells can linger. These senescent cells act as a bad influence on other cells nearby, which changes how the neighboring cells handle sugars or proteins, and so causes metabolic problems. “Cellular senescence refers to the cell fate that occurs in response to a range of cellular stresses and that involves, in essence, an irreversible proliferative arrest,” the team continued. “Senescent cells accumulate in multiple tissues with obesity and aging, and they secrete a variety of pro-inflammatory cytokines, chemokines, and proteases, termed the senescence-associated secretory phenotype (SASP).”
The research team used single-cell transcriptomic techniques to focus on a previously unexplored senescent cell population, p21Cip1-highly-expressing (p21high) cells, which express high levels of p21, a cyclin-dependent kinase inhibitor, and one of the key markers for cellular senescence. “While p21 is one of the two major regulators and cellular markers for senescent cells, the role of p21high cells remains largely unknown in various pathological conditions in vivo,” they wrote.
For their study, Xu and colleagues investigated the effects of targeting P21high cells in mouse models, and tested the two drugs, dasatinib and quercetin, in animals carrying human adipose tissue transplants. Dasatinib and quercetin have previously been shown to extend lifespan and good health in aged mice. Moreover, the team noted, “Dasatinib plus quercetin (D+Q) has been shown to specifically kill senescent cells.” The fat tissue was donated by individuals with obesity, who were known to have metabolic problems.
The team first confirmed that obese animals fed a high-fat diet accumulated p21high cells in adipose tissue. Using their newly developed mouse model, the researchers then demonstrated that clearance of the senescent cells once every month was effective for both slowing down the development of diabetes and also alleviating developed diabetic symptoms in obese mice. “Our study implicates p21high cells as a new and potentially translatable target for T2D interventions,” they wrote. “Monthly clearance of p21high cells can provide long-term protective effects on IR in obese mice.” They claimed that their combined data “… provide evidence that intermittent clearance of p21high cells can confer long-term protection against obesity-induced metabolic dysfunction, and the timing of clearance can be quite flexible, enhancing potential clinical applicability.”
The studies also showed that the dasatinib plus quercetin can kill senescent cells from cultures of human fat tissue (visceral adipose tissue; VAT). Without treatment, the human fat tissues induced metabolic problems in immune-deficient mice. After treatment with dasatinib and quercetin, the harmful effects of the fat tissue were almost eliminated. “D+Q treatment in these VAT samples fully mitigated the harmful metabolic effect of the transplanted VAT,” they stated. Xu noted that previous research has focused on different cell markers, but that clearing away cells highly expressing p21 had such a marked effect on alleviating diabetes that this marker should get more attention. “Our study implicates p21high cells as a new and potentially translatable target for T2D interventions.”
They say the finding that the ability to alleviate the negative effects of fat on metabolism was a dramatic result, and if a therapy worked that well in humans, it would be a game-changing treatment for diabetes. Xu, together with UConn Health scientists Lichao Wang, PhD, Binsheng Wang, PhD, and colleagues at UConn Health and the Mayo Clinic are now pursuing the use of the dasatinib and quercetin combination in clinical trials to see if the drugs can improve T2D in human patients. “Although these preclinical results were very promising, large-scale clinical trials are absolutely critical to examine the efficacy and safety of these drugs in humans before clinical use,” emphasized Xu.
The team also pointed out that their human fat tissue transplantation model could have broader applications in the search for other drugs that might reduce insulin resistance. “… human adipose tissue transplantation model we developed here can be leveraged to screen a range of senolytic drugs or other agents on human individuals’ adipose tissues to alleviate IR in vivo, which has potential to be an invaluable tool for future precision medicine.”