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Senolytic Treatment Minimizes the Contribution of Excess Fat Tissue to Insulin Resistance in Mice


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Posted 29 November 2021 - 08:20 PM


Senescent cells accumulate with age throughout the body, and contribute directly to the onset and progression of a wide range of age-related conditions. While never present in large numbers in comparison to normal somatic cells, senescent cells are metabolically active, secreting signals that provoke chronic inflammation, altered cell behavior, and numerous forms of tissue dysfunction. Senolytic therapies selectively target senescent cells for destruction, most by forcing these errant cells into the programmed cell death process of apoptosis. Senescent cells are primed to self-destruct, and suppressing anti-apoptosis mechanisms for a time can push them over the edge while leaving normal cells largely unaffected.

In recent years, researchers have shown that many of the detrimental effects of excess visceral fat tissue are mediated by the presence of senescent cells in that fat tissue. This isn't just age-related: excess visceral fat generates senescent cells even in youth, but it does become worse with age. Thus eliminating senescent cells on a periodic basis via the use of senolytic therapies may allow for some decoupling of excess visceral fat from poor health and accelerated aging. One of the more prominent consequences of gaining too much fat tissue is the onset of type 2 diabetes, a condition that can be reversed even at a comparatively late stage by low-calorie diets leading to weight loss. Senescent cells appear to play an important role here, causing the death and dysfunction of islet cells in the pancreas, cells that are necessary for the correct function of insulin metabolism.

Researchers here demonstrate that eliminating senescent cells in fat tissue causes a sizable improvement in the manifestations of type 2 diabetes in mice. This isn't the first time that results of this sort have been produced by the scientific community, and the data here can be added to that from similar studies conducted in last few years. Since most of these studies used the readily available senolytic treatment of dasatinib and quercetin, presently in human trials for other conditions, it is perhaps surprising to see little movement towards off-label use in humans, given the considerable size of the diabetic patient community.

Deleting Dysfunctional Cells Alleviates Diabetes

The cells in your body are constantly renewing themselves, with older cells aging and dying as new ones are being born. But sometimes that process goes awry. Occasionally damaged cells linger. Called senescent cells, they hang around, acting as a bad influence on other cells nearby. Their bad influence changes how the neighboring cells handle sugars or proteins and so causes metabolic problems. Type 2 diabetes is the most common metabolic disease in the US. Most people with diabetes have insulin resistance, which is associated with obesity, lack of exercise, and poor diet. But it also has a lot to do with senescent cells in people's body fat, according to new findings. And clearing away those senescent cells seems to stop diabetic behavior in obese mice.

Alleviating the negative effects of fat on metabolism was a dramatic result, the researchers said. If a therapy worked that well in humans, it would be a game-changing treatment for diabetes. Researchers tested the efficacy of a combination of experimental drugs, dasatinib and quercetin. Dasatinib and quercetin had already been shown to extend lifespan and good health in aged mice. In this study, they found these drugs can kill senescent cells from cultures of human fat tissue. The tissue was donated by individuals with obesity who were known to have metabolic troubles. 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.

Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity

Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice.

Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immunodeficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.


View the full article at FightAging




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