Rapamycin as an antiaging therapeutic?: targeting mammalian target of rapamycin to treat Hutchinson-Gilford progeria and neurodegenerative diseases.

摘要

Mammalian target of rapamycin (mTOR), a serine/threonine kinase and component of the mTORC1 signaling complex, acts as an energy, nutrient, growth factor, stress, and redox sensor to increase protein synthesis and decrease macroautophagy. mTORC1 plays a central role in the maintenance of homeostasis and its deterioration, seen in aging. The Food and Drug Administration (FDA)-approved immunosuppressive macrolide rapamycin binds immunophilin FKBP12 (FK506-binding protein) to inhibit mTORC1. Unlike most other interventions tested to date, inhibition of mTORC1 by rapamycin extends life span in old mice, likely by a combination of increased autophagy and decreased mRNA translation. Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder affecting children that is characterized by symptoms of premature aging, such as atherosclerosis. Increased autophagy induced by rapamycin reduces accumulation of progerin, an alternate spliced form of lamin A/C, that forms insoluble toxic aggregates, resulting in reduced HGPS-associated nuclear blebbing, growth inhibition, epigenetic dysregulation, and genomic instability. Rapamycin-induced autophagy also suppresses symptoms in mouse models of Alzheimer, Parkinson, and Huntington diseases, where toxic insoluble protein aggregates accumulate. On the basis of these results, modulation of mTORC1 function is a promising target for the development of therapeutics for neurodegenerative diseases and HGPS. Rapamycin is the obvious candidate for near-term evaluation in the treatment of these diseases. However, the substantial set of rapamycin-associated adverse effects, as well as the lack of aging-specific human data, should caution the routine use of rapamycin as an antiaging agent. The use of safer, but perhaps weaker, indirect mTORC1 inhibitors, such as metformin and resveratrol, may prove useful. Further study will ascertain whether such compounds extend human health or life span.