Tissue-specific pharmacology to enhance healthspan

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Aging-related diseases are among the greatest public health challenges. To allow a healthier aging society, healthspan-extending drugs are critically needed. Development of such drugs will likely be vastly more effective for an aging population than attempting to treat aging-related diseases individually. Inhibition of mechanistic Target Of Rapamycin (mTOR) is an evolutionarily conserved strategy for slowing aging and extending lifespan. Perhaps the most promising and clinically translatable approach for healthspan extension is mTOR inhibition caused by the small molecule Rapamycin. But understanding of the role of mTOR in age-related cellular deterioration at the systems level is lacking, which prevents development of safer and more effective Rapamycin analogs (Rapalogs). Specifically, because of the lack of methods to target Rapamycin to specific cell types, it is not known how Rapamycin’s activity in particular cell types contributes to anti-aging effects at the organismal level. The broad implication for this fundamental gap in knowledge is that crucial opportunities for development of therapeutics for safe and effective healthspan extension may be missed. This provides a strong rationale for elucidating how specific cell types affect net outcomes of pharmacological healthspan and lifespan extension caused by Rapamycin. Our long-term goal is to determine which cell types are responsible for Rapamycin's effects on healthspan extension, develop targeted mTOR inhibition pharmacology, and thus enable effective and safe healthspan extension in humans in the longer term. The central hypothesis of the proposed project is that pro-longevity effects of Rapamycin can be enhanced by targeting the drug only to the specific tissues that are responsible for these effects. To test this hypothesis and to advance toward our long-term goal, we propose the following specific aims: (1) Develop a chemical-genetic approach for programmable, cell-type-specific targeting of Rapamycin; (2) Establish a chemical-genetic, in vivo platform for cell-type-specific pharmacological mTOR inhibition; and, (3) Determine if healthspan and lifespan benefits of systemic, pharmacological mTOR inhibition can be improved by selective sparing of Rapamycin's inhibition of mTOR in skeletal muscle. The proposed project is significant because it will use innovative, multidisciplinary approaches to address a major area of unmet medical need. The proposed study is expected to yield new chemical-genetic tools and Rapalogs enabling tissue-specific, pharmacological mTOR inhibition, and comprehensive analysis of healthspan metrics and lifespan. We expect the proposed study will open the door to more effective approaches for pharmacological extension of healthspan via generation of tissue-specific mTOR inhibitors with improved clinical efficacy and safety.