T Cell Senescence Is Involved in the Disruption of Glucose Metabolism in Type 2 Diabetes

Cellular senescence is an important contributing cause of aging. Senescent cells accumulate with age and secrete a potent mix of molecules and vesicles, the senescence associated secretory phenotype. This disrupts tissue function in a range of ways, and produces chronic inflammation that accelerates the progression of all of the common age-related conditions. All forms of cell in the body appear to be capable of senescence, and the cells of the immune system are no exception. With advancing age, an increasing number of T cells of the adaptive immune system become senescent, producing the same damaging secretions.

Exactly what damage is done by senescent T cells? Firstly, it appears that they contribute to autoimmunity - which is very interesting in light of other work showing that senescent cells of other varieties also contribute to the autoimmune condition of type 1 diabetes. Secondly, senescent T cells, like other senescent cells, produce the outcome of chronic inflammation in tissues throughout the body. The harms done by inflammation sustained over the long term really can't be overstated: it degrades function and accelerates most of the aspects of degenerative aging.

Researchers here find that, interestingly, senescent T cells appear to be quite influential in the pathology of type 2 diabetes. This is near entirely a self-inflicted condition produced by the presence of excess visceral fat tissue and its distorting effect on metabolism. Type 2 diabetes appears to also result in larger numbers of senescent T cells - which fits with other evidence suggesting that the pathway of obesity, metabolic syndrome, and type 2 diabetes tends to produce more senescent cells in general, particularly in fat tissue, and leads to a shorter life expectancy and earlier onset of age-related disease.

T-cell senescence contributes to abnormal glucose homeostasis in humans and mice

Chronic inflammation is strongly associated with metabolic diseases, including diabetes and atherosclerosis. Patients with insulin resistance are considered to be at greater risk of cardiovascular disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, play essential roles in the pathogenesis of insulin resistance. Moreover, patients with prediabetes show significantly lower insulin sensitivity and higher levels of inflammatory markers than metabolically normal individuals. In addition, low-grade inflammation in prediabetes is thought to increase the risk of a cardiovascular event.

Aging of the immune system also contributes to the development of chronic inflammation and has an important effect on metabolic disease and immunologic disorders in humans. In addition, low-grade chronic inflammation is a driver of immunosenescence. The chronic inflammatory environment that is a characteristic of metabolic diseases may also be induced by augmented secretion of proinflammatory cytokines, including TNF-α and IL-6, reactive oxygen species (ROS), and acute-phase reactants released from senescent immune cells. In human studies, several lines of evidence indicate that a senescent T-cell-mediated inflammatory response is associated with the pathogenesis of acute coronary syndrome and hypertension. However, any relationship between the immunosenescence of T cells and abnormal glucose homeostasis remains to be elucidated.

In the present study, we investigate whether T-cell senescence contributes to the systemic inflammatory response in patients with prediabetes and mice with diet-induced obesity by immunologically characterizing senescent T cells. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity.

Human senescent (CD28-CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans.

Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

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