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Too much mTOR is Linked to Diabetes and Aging

A new study takes a look at the relationship between metabolism, aging, and type 2 diabetes and in particular the mTORC1 protein complex, part of the mTOR pathway.

The mTOR pathway

The mechanistic target of rapamycin (mTOR) pathway is a major part of metabolism and is one of four major pathways that control it; collectively, the four pathways are part of deregulated nutrient sensing, which is one of the aging processes.

The mTOR pathway includes two distinct protein complexes: mTORC1 and mTORC2. The pathway senses amino acids and is associated with nutrient abundance. It is a kinase, which means that it adds phosphates to molecules. mTOR is a master regulator of anabolic metabolism, the process of creating new proteins and tissues.

Studies show that less mTOR activity increases lifespan in various species, including mice, yeast, worms, and flies. Think of high mTOR activity being an analog of the phrase “Live fast, die young”, because too much activity is good for growth but bad for lifespan. However, too little mTOR activity is not beneficial either and can disrupt healing and insulin sensitivity and can cause cataracts in mouse models [1].

mTOR has been well studied in the last few years, particularly for its role in caloric restriction. Inhibiting mTOR has been tried as an approach to emulate some of the positives of caloric restriction, particularly the mTORC1 pathway, which appears to be the better of the two complexes to target. Targeting mTORC1 increases healthy lifespan in mice due to the activation of stress response mechanisms and enhanced autophagy (the recycling of unwanted cellular components).

The study sees researchers looking at mTORC1 and its role as a regulator of metabolism and its relationship to aging and type 2 diabetes [2].

Abstract

Type 2 Diabetes Mellitus (T2DM), a worldwide epidemics, is a progressive disease initially developing an insulin resistant state, with manifest pancreatic beta islet overwork and hyperinsulinemia. As the disease progresses, pancreatic β cells are overwhelmed and fails in their capacity to compensate insulin resistance. In addition, it is usually associated with other metabolic diseases such as hyperlipidemia, obesity and the metabolic syndrome. During the progression to T2DM there is a chronic activation of mTORC1 signaling pathway, which induces aging and acts as an endogenous inhibitor of autophagy. The complex 1 of mTOR (mTORC1) controls cell proliferation, cell growth as well as metabolism in a variety of cell types through a complex signaling network. Autophagy is involved in the recycling of cellular components for energy generation under nutrient deprivation, and serves as a complementary degradation system to the ubiquitin-proteasome pathway. Autophagy represents a protective mechanism for different cell types, including pancreatic β cells, and potentiates β cell survival across the progression to T2DM. Here, we focus our attention on the chronic overactivation of mTORC1 signaling pathway in β islets from pre-diabetics patients, making these cells more prone to trigger apoptosis upon several cellular stressors and allowing the progression from prediabetes to type 2 diabetes status.

Conclusion

In both aging and type 2 diabetes, the level of mTORC1 activity is elevated and drives both the disease and one of the aging processes. This suggests that approaches that reduce excessive mTORC1 activity may be beneficial for healthy longevity and for combating metabolic diseases such as type 2 diabetes.

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Guillén, C., & Benito, M. (2018). mTORC1 overactivation as a key aging factor in the progression to type 2 Diabetes Mellitus. Frontiers in endocrinology, 9, 621.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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