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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Finkelstein, David B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Medicine
United States
Zip Code
Peng, Yajing; Shapiro, Samantha L; Banduseela, Varuna C et al. (2018) Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging Cell 17:e12820
Yu, Deyang; Yang, Shany E; Miller, Blake R et al. (2018) Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J 32:3471-3482
Cummings, Nicole E; Williams, Elizabeth M; Kasza, Ildiko et al. (2018) Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol 596:623-645
Cummings, Nicole E; Lamming, Dudley W (2017) Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Mol Cell Endocrinol 455:13-22
Moretti, Julien; Roy, Soumit; Bozec, Dominique et al. (2017) STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum. Cell 171:809-823.e13
Linnemann, Amelia K; Blumer, Joseph; Marasco, Michelle R et al. (2017) Interleukin 6 protects pancreatic ? cells from apoptosis by stimulation of autophagy. FASEB J 31:4140-4152
Lamming, Dudley W; Baar, Emma L; Arriola Apelo, Sebastian I et al. (2017) Short-term consumption of a plant protein diet does not improve glucose homeostasis of young C57BL/6J mice. Nutr Healthy Aging 4:239-245
Knoll, Marko; Winther, Sally; Natarajan, Anirudh et al. (2017) SYK kinase mediates brown fat differentiation and activation. Nat Commun 8:2115
Beyaz, Semir; Mana, Miyeko D; Roper, Jatin et al. (2016) High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531:53-8
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

Showing the most recent 10 out of 29 publications