Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation.
Statins such as simvastatin are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and standard therapy for the prevention and treatment of cardiovascular diseases in mammals. Here we show that simvastatin significantly increased the mean and maximum lifespan of Drosophila melanogaster (Drosophila) and enhanced cardiac function in aging flies by significantly reducing heart arrhythmias and increasing the contraction proportion of the contraction/relaxation cycle. These results appeared independent of internal changes in ubiquinone or juvenile hormone levels. Rather, they appeared to involve decreased protein prenylation. Simvastatin decreased the membrane association (prenylation) of specific small Ras GTPases in mice. Both farnesyl (L744832) and type 1 geranylgeranyl transferase (GGTI-298) inhibitors increased Drosophila lifespan. These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan species, and may explain the pleiotropic (non-cholesterol related) health effects of statins.
Department of Biochemistry, University of California Riverside, Riverside, California, United States of America. spindler@ucr.edu
Stephen R
SR
Spindler
Rui
R
Li
Joseph M
JM
Dhahbi
Amy
A
Yamakawa
Patricia
P
Mote
Rolf
R
Bodmer
Karen
K
Ocorr
Renee T
RT
Williams
Yinsheng
Y
Wang
Kenneth P
KP
Ablao
D000375:Aging / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal; D001549:Benzamides / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy; D004331:Drosophila melanogaster; D005247:Feeding Behavior; D006321:Heart / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008136:Longevity; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D019821:Simvastatin / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
D001549:Benzamides; C102521:GGTI 298; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096898:L 744832; D014451:Ubiquinone; D008715:Methionine; D019821:Simvastatin; C024989:coenzyme Q10