Insulin resistance is a common pathological state strongly associated with obesity and aging. Insulin resistance occurs when muscle, fat, and liver cells do not respond well to insulin and cannot use glucose for energy. This causes the pancreas to make more insulin, resulting in elevated blood sugar levels over time leading to various health problems.
Results from this work will also enable future testing of pharmacological interventions that eliminate these cells to treat not only metabolic dysfunction, but also a wide range of age-related diseases. — Ming Xu
Insulin resistance (IR) is a hallmark for prediabetes, which affects one third of Americans. It also presents a risk for type 2 diabetes, heart disease, stroke, and dementia. Besides exercise and weight loss, there are few mechanism-based strategies to improve insulin resistance and physical dysfunction.
Another feature of obesity and aging is the accumulation of p21high cells in various tissues. p21high cells are one major type of senescent cells, cells which do not divide, which have been found to cause various diseases associated with obesity or aging. However, little is known about the role and exact mechanisms of p21high influences IR in obesity and aging.
Ming Xu, a UConn Health assistant professor at the UConn Center on Aging and Department of Genetics and Genome Sciences has developed a mouse model to study the relationship between p21high cells and insulin resistance. The National Institutes of Health is providing $2.2 million in funding for this five-year study.
Xu and his team have generated and validated a novel transgenic mouse model. The model enables them to monitor, kill, or modulate p21high cells in vivo without affecting other cells.
In their preliminary studies, the researchers found that intermittently clearing p21high cells out of obese mice significantly alleviates insulin resistance. In this study, Xu’s team will see if targeting these cells will alleviate the metabolic and physical dysfunction associated with obesity. These findings could lead to the development of new strategies to target these cells to combat insulin resistance and metabolic dysfunction in humans.
The UConn research team will use single cell transcriptomics technology, a method that studies the complete set of RNA transcripts that are produced by the genome, to measure the level of gene expression of p21high cells in tissues with obesity. By revealing the genetic features of these cells, the researchers will develop a better understanding of the specific pathways in which they may be able to target these cells.
“Results from this work will also enable future testing of pharmacological interventions that eliminate these cells to treat not only metabolic dysfunction, but also a wide range of age-related diseases,” Xu says.
The UConn Center for Aging is committed to providing care for aging adults and conducting research dedicated to improving their quality of life. As people are living longer, it is becoming even more essential to increase our knowledge of the aging process and promote better health and quality of life for older adults.
Xu holds a Ph.D. from the University of Kansas Medical Center in rehabilitation science. His lab leverages novel mouse models and primary human cells as tools to examine the role and underlying mechanism of senescent cells in various conditions in mammals. Xu’s previous work found drugs which can kill senescent cells can extend healthy lifespan in aged mammals, and these drugs are currently under clinical trials. Xu’s current research works to find new drugs to target senescent cells in order to alleviate a range of age-related diseases as a group, and promote healthy aging.