title: Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome: implications for normal aging and age-dependent neurodegenerative disorders.
abstract: While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogues of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Charlestown, MA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Graziotto
authors.forename: Kan
authors.initials: K
authors.lastname: Cao
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects*; D006801:Humans; D034904:Lamin Type A; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D011371:Progeria / Q000188:drug therapy / Q000473:pathology*; D011498:Protein Precursors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D020123:Sirolimus