Intervention in Progeria by Alterations in dietary macronutrient Composition

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Project Summary Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic progeria – a disease of rapid aging. Treatment with rapamycin, an inhibitor of the mTOR (mechanistic Target Of Rapamycin) protein kinase, reverses HGPS phenotypes at the cellular level in HGPS fibroblasts and extends the health and lifespan of mice lacking Lmna. Unfortunately, rapamycin has serious side effects in humans, including both metabolic effects and immunosuppression, which may preclude its long-term use for HGPS patients. While many of the beneficial effects of rapamycin are due to its inhibition of mTOR complex 1 (mTORC1), we have found that many of negative side effects are mediated by “off-target” inhibition of a second mTOR complex, mTORC2. In this proposal, we propose to develop a dietary technique to specifically decrease mTORC1 signaling by decreasing the dietary abundance of specific amino acids. We will then test this intervention and compare to rapamycin in a newly developed HGPS mouse model with the same splicing defect found in humans HGPS patients, and which is unique in reproducing both the progeroid external phenotypes and internal lethal vascular defects found in humans with HGPS. This study will identify new avenues for promoting healthy aging and suppressing disease in the context of HGPS, and may be broadly applicable to other laminopathies as well as normal aging. This proposal will serve as a platform for an R01 application that will not only investigate the molecular mechanisms by which mTOR inhibition can slow the progression of HGPS, but examine the efficacy and mechanisms of similar interventions in normal aging.