The mammalian target of rapamycin (mTOR) signaling pathway is a highly conserved pathway that regulates growth and metabolism in response to the availability of nutrients. mTOR signaling is inhibited by rapamycin, an FDA-approved compound widely used during transplantation surgery as an immunosuppressant, as well as in clinical trials for the treatment of cancer. Treatment with rapamycin extends the lifespan of many model organisms, including mice, and is beneficial for the treatment of diseases of aging, including Alzheimer's disease, in mouse models. Treatment with rapamycin, and inhibition of mTOR complex 1 (mTORC1), is proposed to promote longevity by a mechanism similar to that of calorie restricted (CR) diet, in which caloric intake is reduced while maintaining adequate nutrition. However, we have found that rapamycin also inhibits mTOR complex 2 (mTORC2), disrupting glucose homeostasis and increasing hepatic insulin resistance. While studies in C. elegans have shown increased longevity when mTORC2 signaling is disrupted, the effect of disrupting mTORC2 in mammals is unknown. The work proposed herein will use a genetic approach to determine the effects of decreased mTORC2 signaling on lifespan, and furthermore will examine the contribution of mTORC2 signaling to the effects of a CR diet. Using mice engineered to overexpress Rictor, a key component of mTORC2, we will examine the ability of increased mTORC2 to promote longevity and increase resistance to the negative effects of a high-fat diet on glucose homeostasis. We will use a mass spectrometry based approach to understand the role played by mTORC2 in vivo, and identify pathways regulated by mTORC2 as well as characterize novel mTORC2 substrates. Finally, we will characterize mTORC2 signaling during normal aging.
These aims will significantly increase our understanding of how the mTOR signaling pathway functions during pro-longevity interventions, and potentially increase our ability to treat diseases of aging without undesirable side effects. We will also determine if increased mTORC2 signaling can ameliorate the negative consequences of obesity on glucose homeostasis, determining if mTORC2 signaling might be of therapeutic use for the treatment of type 2 diabetes. Our mass spectrometry-based approach will help us to learn more about the in vivo consequences of modulating the mTORC2 pathway, and help us learn about how this pathway changes during the aging process.

Public Health Relevance

Age-related diseases, including cancer, neurodegenerative disorders, cardiovascular disease, and type II diabetes, are the major contributors to morbidity and mortality in Western society today. The work in this proposal aims to understand the mechanism by which pro- longevity interventions regulate lifespan as well as glucose levels and insulin sensitivity. This work also seeks to identify novel targets and cellular pathways involved in the aging process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
4R00AG041765-03
Application #
8779807
Study Section
Special Emphasis Panel (NSS)
Program Officer
Finkelstein, David B
Project Start
2014-01-01
Project End
2016-12-13
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$249,000
Indirect Cost
$83,551
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Strong, Randy; Miller, Richard A; Antebi, Adam et al. (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872-84
Kennedy, Brian K; Lamming, Dudley W (2016) The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab 23:990-1003
Gregg, Trillian; Poudel, Chetan; Schmidt, Brian A et al. (2016) Pancreatic β-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity. Diabetes 65:2700-10
Arriola Apelo, Sebastian I; Lamming, Dudley W (2016) Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island. J Gerontol A Biol Sci Med Sci 71:841-9
Tran, Cassie M; Mukherjee, Sarmistha; Ye, Lan et al. (2016) Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue. Diabetes 65:927-41
Fontana, Luigi; Cummings, Nicole E; Arriola Apelo, Sebastian I et al. (2016) Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Rep 16:520-30
Cummings, Nicole E; Lamming, Dudley W (2016) Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Mol Cell Endocrinol :
Arriola Apelo, Sebastian I; Neuman, Joshua C; Baar, Emma L et al. (2016) Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15:28-38

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