‘Zombified’ cells in blood vessels may play a key role in the development of age-related metabolic diseases such as diabetes, a new study has found. And killing these zombie cells could be a promising approach for future treatments.
Cells normally respond to stress by becoming senescent, a state in which cells remain in the body in which they permanently stop dividing. These senescent cells may have several useful functions. For example, some play an important role in wound healing. However, as senescent cells accumulate in the body over time, they are also known to be the cause of age-related diseases.
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In a new study published Thursday (November 20) in the journal Cell Metabolism, the research team focused on endothelial cells (meaning the cells lining blood vessels) to identify specific cases in which aging can negatively impact metabolism. The study also suggests strategies for treating many aspects of aging, not just age-related metabolic problems, experts told Live Science.
“Finding a unifying target, such as blood vessels, opens up the possibility of targeting very different aspects of aging at the same time,” said Dr. Cristina Aguayo Mazzucato, an assistant professor at Harvard Medical School who was not involved in the study.
Identifying harmful senescent cells
Senescent cells are increasingly recognized to contribute to the development of age-related metabolic diseases. But researchers are still trying to pinpoint the specific cells in which aging is harmful rather than beneficial.
In this study, the researchers chose to focus on vascular cells, which have been shown to be important for the function of most organs and help control metabolism in many tissues, study co-author Dr. Nicholas Musi, a professor of medicine at Cedars-Sinai Medical Center, told Live Science.
To determine whether these cells were the main cause of metabolic abnormalities, the researchers fed a pair of laboratory mice a high-fat diet to gain weight and induce cellular senescence. Senescent endothelial cells were then removed for further study. The researchers then exposed a different set of endothelial cells to radiation to induce senescence and transplanted the cells into lean, metabolically normal laboratory mice.
Removal of senescent endothelial cells from obese mice was associated with reduced fat mass, improved blood sugar levels, and an overall reduction in metabolic dysfunction. Conversely, transplanting senescent cells into lean mice was associated with increased blood sugar levels and insulin resistance.
“As these cells enter the dormant state of senescence, they begin producing inflammatory substances called senescence-associated secretory phenotype (SASP),” Musi said. This mechanism helps explain why removal of senescent cells is associated with increased metabolic rate. Cells normally take nutrients, such as fats and glucose, from the bloodstream to produce the energy they need to function properly. But that process goes haywire when it encounters an onslaught of inflammatory molecules from SASP cells, he explained.
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“The metabolism of the cells changes, which leads to tissue abnormalities and then to systemic metabolic abnormalities,” Mushi told Live Science.
‘Senolytic destruction’ is a potential treatment
In the second phase of the study, the researchers treated both groups of mice with fisetin. Fisetin is a drug the team previously discovered could eliminate senescent cells. This type of drug is known as a senolytic agent. In both groups, treatment with fisetin was associated with a reduction in senescent vascular cells and improved glucose tolerance.
The researchers also tested the drug in tissue samples from six obese adults in their 40s and 50s. They observed a similar reduction in senescent vascular cells within the treated tissues.
Dr. Aguayo Mazzucato believes this research could pave the way for new treatments targeting senescent cells in the cardiovascular system. “Metabolic dysfunction is a systemic problem, with changes in nutrient utilization in many tissues,” she says. Aged vascular cells are present throughout the body, so targeting senescent vascular cells in different organs could help doctors address a variety of diseases, she added.
“Instead of saying we’re going to cure cancer or cure diabetes or Alzheimer’s disease, [or] “The idea is that all defined forms of Parkinson’s disease are age-related, and that there is a common pathway for all age-related diseases,” said Aguayo-Mazzucato.
Future research should include clinical studies investigating whether aging has the same effects on human blood vessels as observed in laboratory mice, Suda said.
This article is for informational purposes only and does not provide medical advice.
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