Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging.
Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.
Varela
Ignacio
I
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, calle Fernando, Bongera s/n, 33006-Oviedo, Spain.
Pereira
Sandrine
S
Ugalde
Alejandro P
AP
Navarro
Claire L
CL
Suárez
María F
MF
Cau
Pierre
P
Cadiñanos
Juan
J
Osorio
Fernando G
FG
Foray
Nicolas
N
Cobo
Juan
J
de Carlos
Félix
F
Lévy
Nicolas
N
Freije
José M P
JM
López-Otín
Carlos
C
D019588:Aging, Premature / Q000188:drug therapy*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use; D054876:Prenylation / Q000187:drug effects; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D000077211:Zoledronic Acid; D051231:Farnesyltranstransferase; D017035:Pravastatin