The Role of the TORC1 Complex in Aging

Project Summary

The Target of Rapamycin Complex I has been implicated in the regulation of aging and lifespan in many eukaryotic organisms ranging from yeast to humans. We are interested in how aberrant nutrient sensing, and TORC1 in specific, causes delayed or accelerated aging in model organisms.

To test this we are using mice, flies and yeast, we are studying how this complex is regulated during aging, and how manipulation of this complex alters lifespan and aging-related phenotypes. We generate genetically modified or pharmacological approaches using these animals where these pathways are activated or repressed. We can then test for changes in lifespan and normal function in these organisms. We are particularly interested in determining the molecular mechanisms and potential reversibility of these changes associated with aging.

Several studies have suggested that mTORC1 inhibition promotes longevity, and we have been interested in the role of muscle in this process. In one example of this work, we generated flies lacking mTORC1 signaling in their muscles via knockdown of Raptor an essential component of the mTORC1 complex. Surprisingly these mice had shortened lifespans, likely due to an inability to build and repair muscle (see Hatfield et al. 2012). Another study, using mice, evaluated what happened of mTORC1 is constitutively activated in muscle (via removal of its negative regulator TSC1) showed that these mice also have shortened lifespan (see the pre-print Stephenson et al., 2019.

Who is Working on This?

Dave Bridges

Dave Bridges
Associate Professor, Department of Nutritional Sciences, University of Michigan since 2022-09-01

Publications

What have we published on this topic?

  1. Cody Cousineau, Detrick Snyder, JeAnna Redd, Sophia Turner, Treyton Carr and Dave Bridges. Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice 2024. bioRxiv Full Text Details. Preprint
  2. Michael Saul, Elizabeth Litkowski, Niran Hadad, Amy Dunn, Stephanie Boas, Jon Wilcox, Julia Robbins, Yiyang Wu, Vivek Philip, Gennefer Merrihew, Jea Park, Philip De Jager, Dave Bridges, Vilas Menon, David Bennett, Timothy Hohman, Michael MacCoss and Catherine Kaczorowski. Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the AD-BXD Mouse Population 2024. bioRxiv Full Text Details. Preprint
  3. Laura Gunder, Innocence Harvey, JeAnna Redd, Carol Davis, Ayat AL-Tamimi, Susan Brooks and Dave Bridges. Obesity Augments Glucocorticoid-Dependent Muscle Atrophy in Male C57BL/6J Mice 2020. Biomedicines 8(10):420 Full Text Details.
  4. Erin Stephenson, JeAnna Redd, Detrick Snyder, Quynh Tran, Binbin Lu, Matthew Peloquin, Molly Mulcahy, Innocence Harvey, Kaleigh Fisher, Joan Han, Nathan Qi, Alan Saltiel and Dave Bridges. Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice 2019. bioRxiv Full Text Details. Preprint
  5. Dubek Kazyken, Brian Magnuson, Cagri Bodur, Hugo Acosta-Jaquez, Deqiang Zhang, Xin Tong, Tammy Barnes, Gabrielle Steinl, Nicole Patterson, Christopher Altheim, Naveen Sharma, Ken Inoki, Gregory Cartee, Dave Bridges, Lei Yin and Diane Fingar. AMPK directly activates mTORC2 to promote cell survival during acute energetic stress 2019. Science Signaling 11(12):585 Full Text Details.
  6. John Bissler, Fahad Zadjali, Dave Bridges, Aristotelis Astrindis, Sharon Barone, Ying Yao, JeAnna Redd, Brian Siroky, Yanqing Wang, Joel Finley, Michael Rusniak, Heinz Baumann, Kamyar Zahedi, Kenneth Gross and Manoocher Soleimani. Tuberous sclerosis complex exhibits a new renal cystogenic mechanism. 2019. Physiological Reports 7(2):e13983 Full Text Details.
  7. Suriyan Ponnusamy, Ryan Sullivan, Dahui You, Nadeem Zafar, Chuan He Yang, Thirumagal Thiyagarajan, Daniel Johnson, Maron Barrett, Nikki Koehler, Mayra Star, Erin Stephenson, Dave Bridges, Stephania Cormier, Lawrence Pfeffer and Ramesh Narayanan. Androgen Receptor Agonists Increase Lean Mass, Improve Cardiopulmonary Functions, and Extend Survival in Preclinical Models of Duchenne Muscular Dystrophy 2017. Human Molecular Genetics Full Text Details.
  8. Izzy Hatfield, Innocence Harvey, Erika Yates, JeAnna Redd, Lawrence Reiter and Dave Bridges. The role of TORC1 in muscle development in Drosophila. 2015. Scientific Reports 5:9676 Full Text Details.

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