Many signaling pathways linked to aging are linked to the regulation of metabolic signaling and stress response pathways. For instance, the target of rapamycin (TOR) pathway is an evolutionarily-conserved nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Two complexes, mTORC1 and 2, have overlapping upstream regulators and downstream effectors. Reduced mTOR signaling, either by genetic intervention or with the clinically approved drug rapamycin, extends longevity in mice (as well as yeast, worms and flies) or delays many pathologies of aging. Rapamycin, which acutely inhibits mTORC1 but also inhibits mTORC2 after long-term exposure, has also been proposed as a drug for type II diabetes since it has beneficial effects in peripheral tissues. However, chronic rapamycin exposure leads to pre-diabetic phenotypes, including hyperglycemia, glucose intolerance, insulin resistance, and hyperlipidemia, making it an unlikely drug candidate in diseases linked to metabolism. Given its central role in aging and metabolism, it is critical to understand how different perturbations of the mTOR pathway impact aging and metabolism. Here, we use mouse models and cell culture studies to dissect and improve rapamycin function, as well as to test one of the major downstream targets of mTORC1, 4E-BP1. Justifying the emphasis on 4E-BP1, enhanced 4E- BP activity is associated with lifespan extension in worms and flies, and we find that transgenic mice overexpressing 4E-BP1 are resistant to high fat diet-induced metabolic dysfunction. We will (1) employ variants of rapamycin that are more specific to the mTORC1 complex, testing the hypothesis that specific inhibition of mTORC1 will be protective in the context of high fat diet-induced diabetes. We will also (2) use multiple mouse models of 4E-BP1 overexpression in both over nutrition and aging studies. Preliminary data indicates that an inflammation-induced loss of 4E-BP1 expression in the context of a high fat diet underlies the specific propensity of males to become glucose intolerant and insulin resistant. We will determine the mechanisms underlying this gender dimorphism and its impact on the mTOR pathway. In addition, we will determine why muscle specific activation of 4E-BP1 preserves both skeletal muscle function and brown fat content during over nutrition and aging. Together, these studies will yield several new insights regarding the specifics of mTOR signaling in the context of aging and metabolism, and lead to the further development of novel rapamycin derivatives that are predicted to maintain efficacy against age-related disease indications while having reduced metabolic side effects.
The mTOR pathway is at the center of mammalian aging studies and is a target for drug intervention by the clinically approved drug, rapamycin, and novel derivatives that are being developed. Reduced mTOR signaling leads to increased lifespan as well as protection from a range of age-related diseases. mTOR is also tightly linked to metabolism and diabetes. This proposal seeks to understand the relationship between metabolism and aging with respect to the mTOR pathway, identifying key mechanisms underpinning the beneficial effects of reduced mTOR signaling and developing novel therapeutics to prevent disease and/or extend human healthspan.
| Kennedy, Brian K; Lamming, Dudley W (2016) The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging. Cell Metab 23:990-1003 |
