Extending lifespan based on insulin sensitivity: Role of Syntaxin 4

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Extending lifespan by slowing the process of aging has always been a penchant desire of humanity. Slow aging and long life has been previously associated with higher insulin sensitivity, however, there has not been any established molecular event linking the two.

Recently, researchers at Indiana University School of Medicine (IU) reported a relationship between insulin sensitivity and aging. The group demonstrated a previously unrecognized role of Syntaxin 4 (Syn4) protein in promoting lifespan extension, which is a novel finding.

The process of glucose uptake

Let us try to understand the process of insulin-mediated glucose uptake in cells and the role of Syn4 in the same.

To clear the circulating glucose from blood, hormone ‘insulin’ from β cells of islets of Langerhans in our pancreas stimulates ‘Glucose transporter type 4 (GLUT4)’, stored in the intracellular vesicles in muscle and fat cells, to get fused with the plasma membrane of cells, which then leads to ‘glucose uptake’.

Now Syn4, a plasma membrane localized protein, is required for pancreatic β cell insulin secretion in response to elevated blood glucose. It is noteworthy that changes in Syn4 level affect important processes for maintaining homeostasis for glucose.

Levels of Syn4 are significantly reduced in case of type 2 diabetes (T2D) where cells exhibit insulin resistance (inability of cells to respond to insulin) causing high blood glucose level.

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The experiment

Based on the role of Syn4 in insulin secretion, Oh et al hypothesized that Syn4 deficiency might be associated with increased aging.

The study conducted by the group established that overexpression of Syn4 increased insulin sensitivity and exhibited marked extension in lifespan of mice.

To start with, the group created a transgenic mice overexpressing Syn4 protein (Syn4 Tg mice). For control (Con mice), wild-type littermates were chosen. Both the mice were assessed for the insulin secretion, glucose uptake, islets function and GLUT4 translocation.

In the study, it was found that the overexpression of Syn4 lead to high insulin secretion in Tg mice, thereby accelerating the glucose uptake. The islets function was also assessed and indicated better functioning in Syn4 Tg mice in comparison to Con mice.

Syn4 abundance was found to be inversely related to aging and extended lifespan of about 33% was observed in Syn4 enriched mice. These long-lived mice were protected from age or diet-induced insulin resistance.

The two mice strains were also compared in terms of dietary fat and triglycerides level and it was seen that although the level of body fat was similar in both strains, there was a marked reduction in the triglyceride levels due to increased skeletal muscle GLUT4 expression in Syn4 Tg mice.

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In a nutshell, high-level expressing Syn4 may exert better glycemic control (control of glucose level in blood and maintain glucose homeostasis), which slows multiple aspects of aging and extends lifespan (summarized in the graphical abstract below).

The group is highly optimistic that findings from this study can help in developing strategies to target Syn4 expression and activation in order to extend lifespan and longevity phenotype.

The original paper can be accessed here.

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