Syntaxin 4 Overexpression Ameliorates Effects of Aging and High-Fat Diet on Glucose Control and Extends Lifespan

• Syntaxin 4 abundance is inversely related to aging
• Aged Syntaxin-4-enriched mice retain youthful glucose and insulin tolerances
• Syntaxin 4 enrichment protects from high-fat-induced muscle and islet derangements

SummaryIndirect evidence suggests that improved insulin sensitivity may contribute to improved lifespan of mice in which aging has been slowed by mutations, drugs, or dietary means, even in stocks of mice that do not show signs of late-life diabetes. Peripheral responses to insulin can be augmented by overexpression of Syntaxin 4 (Syn4), a plasma-membrane-localized SNARE protein. We show here that Syn4 transgenic (Tg) mice with high level expression of Syn4 had a significant extension of lifespan (33% increase in median) and showed increased peripheral insulin sensitivity, even at ages where controls exhibited age-related insulin resistance. Moreover, skeletal muscle GLUT4 and islet insulin granule exocytosis processes were fully protected in Syn4 Tg mice challenged with a high-fat diet. Hence, high-level expressing Syn4 Tg mice may exert better glycemic control, which slows multiple aspects of aging and extends lifespan, even in non-diabetic mice.

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