Slaying 'zombie cells' in blood vessels could be key to treating diabetes, early study finds

"Zombified" cells in blood vessels may play a key role in the development of metabolic diseases, like diabetes, with age, a new study finds. And slaying these zombie cells could be a promising approach for future treatments.

Cells usually become senescent — a state in which they permanently stop dividing but linger in the body — as a stress response. These senescent cells may have some useful functions; for example, some play a key role in wound healing. But senescent cells are also known to contribute to age-related diseases, as more and more build up in the body over time.

In previous research with mice, scientists found that targeting senescent cells with drugs can alleviate various signs of aging and extend the animals' healthy life span, lead study author Dr. Mayasoshi Suda, an assistant professor at Cedars-Sinai Medical Center in Los Angeles, told Live Science.

In the new study, published Thursday (Nov. 20) in the journal Cell Metabolism, the team focused on endothelial cells, meaning the cells that line blood vessels, and identified a specific case in which senescence can be harmful to the metabolism. The study also hints at a strategy for treating not only age-related metabolic issues but many aspects of aging, an expert told Live Science.

"By finding a unifying target, such as blood vessels, you open up the possibility that you might be able to, at the same time, target very different aspects of aging," said Dr. Christina Aguayo-Mazzucato, an assistant professor of medicine at Harvard Medical School who was not involved in the study.

Identifying harmful senescent cells

Senescent cells are increasingly recognized as contributors to the development of age-related metabolic diseases. But researchers are still trying to identify specific cells in which senescence is harmful, as opposed to beneficial.

In this study, researchers chose to focus on blood vessel cells, which are critical for the function of most organs and have been shown to help control metabolism in many tissues, study co-author Dr. Nicolas Musi, a professor of medicine at Cedars-Sinai Medical Center, told Live Science.

To identify whether these cells were key drivers of metabolic disorders, the researchers fed one set of lab mice a high-fat diet to raise their body weights and induce senescence in their cells; they then removed their senescent endothelial cells for further study. In addition, the team exposed a different set of endothelial cells to radiation to induce senescence and then transplanted those cells into lean lab mice with normal metabolisms.

Removing senescent endothelial cells from the obese mice was associated with reduced fat mass, improved blood sugar levels and an overall reduction of metabolic dysfunction. Conversely, transplanting senescent cells into lean mice was associated with higher blood sugar levels and insulin resistance.

"When these cells go into this dormant state of senescence, they start producing inflammatory substances that are called Senescence-Associated Secretory Phenotype (SASP)," Musi said. This mechanism helps explain why removing senescent cells was associated with an improved metabolic rate. Cells usually take nutrients from the bloodstream, such as fat and glucose, to create the energy they need to function properly. But when they encounter the onslaught of inflammatory molecules from SASP cells, that process gets derailed, he explained.

"Cellular metabolism gets altered, and that translates into abnormal tissue and then abnormal whole-body metabolism," Musi told Live Science.

'Senolytics' are potential treatments

In a second phase of the study, the researchers treated both groups of mice with fisetin, a drug that the team previously found could eliminate senescent cells. This type of drug is known as a senolytic. In both groups, treatment with fisetin was associated with fewer senescent blood-vessel cells and improved glucose tolerance.

The researchers also tested the drug on tissue samples from six adults with obesity who were in their 40s and 50s. They observed a similar decline in senescent blood vessel cells in the treated tissue.

Aguayo-Mazzucato thinks this study could pave the way for new treatments targeting senescent cells in the cardiovascular system. "Metabolic dysfunction is a whole-body problem. You have nutrient utilization alterations in a lot of tissues," she said. Because senescent vascular cells are present throughout the entire body, targeting them in different organs could help doctors address a range of diseases, she added.

"Rather than say we're going to treat cancer or we're going to treat diabetes, Alzheimer's [or] Parkinson's as defined entities, the idea is saying they're all age-related and there are pathways that are common to all age-related diseases," Aguayo-Mazzucato said.

Future research should include clinical studies that investigate whether senescence has the same effects in human blood vessels that were observed in lab mice, Suda said.