Farnesylated prelamin A is a processing intermediate produced in the lamin A 
maturation pathway. Accumulation of a truncated farnesylated prelamin A form, 
called progerin, is a hallmark of the severe premature ageing syndrome, 
Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to 
chromatin damage and cellular senescence and ultimately causes skin and 
endothelial defects, bone resorption, lipodystrophy and accelerated ageing. 
Knowledge of the mechanism underlying prelamin A turnover is critical for the 
development of clinically effective protein inhibitors that can avoid 
accumulation to toxic levels without impairing lamin A/C expression, which is 
essential for normal biological functions. Little is known about specific 
molecules that may target farnesylated prelamin A to elicit protein degradation. 
Here, we report the discovery of rapamycin as a novel inhibitor of progerin, 
which dramatically and selectively decreases protein levels through a mechanism 
involving autophagic degradation. Rapamycin treatment of progeria cells lowers 
progerin, as well as wild-type prelamin A levels, and rescues the chromatin 
phenotype of cultured fibroblasts, including histone methylation status and BAF 
and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not 
affect lamin C protein levels, but increases the relative expression of the 
prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to 
the class of macrolides, previously found to increase longevity in mouse models, 
can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated 
prelamin A accumulation, and restore chromatin dynamics in progeroid 
laminopathies.