Targeting senescent cells may fight insulin resistance

Investigators have identified a previously unrecognized population of senescent cells, called p21high cells, in fat tissue and demonstrated their contributory role in metabolic dysfunction, obesity, insulin resistance and type 2 diabetes.

Treatment with an anti-senescent cell drug combination was shown to reduce these p21high cells in human fat and to mitigate their harmful metabolic effects in immune deficient mice, suggesting that targeting them may represent a new therapeutic approach to metabolic diseases, including insulin resistance.

Insulin resistance is frequently associated with obesity, representing a major risk factor for type 2 diabetes, but limited mechanism-based strategies exist to alleviate insulin resistance.

"Although the exact mechanisms of action of metformin, one of the first-line antidiabetic medications, are not fully understood, one of them is to inhibit hepatic gluconeogenesis," noted study leader Ming Xu.

"Our new strategy targets adipose tissue, so theoretically these two interventions might be combined to achieve additive benefits in patients," said the assistant professor in the UConn Center on Aging and Department of Genetics and Genome Sciences at UConn Health in Farmington, Connecticut.

Besides obesity, insulin resistance has also been linked a sedentary lifestyle, poor diet and now, according to the new UConn Health study, senescent cells in patients' body fat.

Senescence

Senescence occurs in response to a range of cellular stresses. Senescent cells – cells that are not actively dying, but have ceased to go through the cell division cycle – accumulate in multiple tissues with high weight and aging, where they secrete deleterious proinflammatory cytokines, chemokines and proteases.

A role has also been recently been identified for cellular senescence in promoting metabolic dysfunction, although several major questions remain unanswered in this regard.

This was investigated in the new study led by Xu and his colleagues at UConn Health. They reported their results in the November 22, 2021, issue of Cell Metabolism.

Using single-cell transcriptomics, the researchers identified the important but previously unexamined p21high senescent cell population, which accumulate in adipose tissue in obesity.

In a mouse model of obesity, they demonstrated that intermittent monthly clearance of these p21high cells could both prevent and alleviate insulin resistance, as assessed using glucose and insulin tolerance tests (GTT/ITT).

"With p21high cells clearance, both GTT and ITT were improved by 50-70%, compared to nonobese mice," Xu told BioWorld Science.

Moreover, when Cre-Lox site-specific recombinase technology was used to achieve exclusive inactivation of the nuclear transcriptional activator NF-kappaB signaling pathway within p21high cells, this was shown to attenuate insulin resistance.

This is a significant finding, said Xu, "as it demonstrates for the first time the underlying mechanisms whereby p21high senescent cells cause insulin resistance in vivo."

Fat transplantation experiments were then used to establish that p21high cells within adipose tissue were sufficient to cause insulin resistance in vivo.

"We cleared p21high cells from the fat in obese mice, then transplanted these fat cells and control fat cells with p21high cells into lean recipient mice," Xu explained.

"We found that control fat from obese mice could cause insulin resistance in recipient mice compared to the sham mice, which had undergone the surgery but had no fat transplantation."

However, "fat without p21high cells could no longer induce insulin resistance in lean recipient mice, suggesting that adipose tissue-specific intervention might be possible for treating insulin resistance, which may reduce side effects in other tissues," said Xu.

He and his colleagues then tested the efficacy of a combination of the experimental senolytic drugs dasatinib and quercetin (D+Q), which have previously been used to extend both life- and health-span in aged mice.

Dasatinib (Sprycel; Bristol Myers Squibb) has been approved by the U.S. FDA for the treatment of certain leukemias, whereas quercetin is a widely used plant flavonoid dietary supplement.

"D+Q is currently being tested as a means of clearing senescent cells in various clinical trials, including for diabetic kidney disease, Alzheimer's disease, and for accelerated age-like state after bone marrow transplantation and in childhood cancer survivors," said Xu.

"In addition, a recent small phase I clinical trial of D+Q showed that its short-term intermittent oral administration was relatively safe and could improve physical function in older idiopathic pulmonary fibrosis patients." Importantly, in the present study, D+Q was shown to be able to kill p21high cells in human fat cells donated by obese individuals with metabolic problems, and to mitigate insulin resistance following xenotransplantation into immune deficient mice.

"Human fat from obese individuals induced insulin resistance in mice, while this harmful effect was almost fully prevented in human fat treated with D+Q," Xu told BioWorld Science.

Taken together, these findings establish the basis for pursuing the targeting of p21high cells as a new therapy aimed at alleviating insulin resistance.

"These drugs can make human fat healthy, which could be great; the results were very impressive and clear the route for potential clinical trials."

"We are currently in the process of preparing more clinical trials to assess the efficacy and safety of D+Q in type 2 diabetes patients," Xu said.

"While preclinical results have been very promising, large scale clinical trials are critical to examine the efficacy and safety of these drugs in humans before their clinical use." (Wang, L. et al. Cell Metab 2021, Advanced publication).

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