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^{1, 2}. 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 syndrome³. We show herein that both prelamin A and its truncated form progerin/LA50 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.

1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, calle Fernando. Bongera s/n, 33006-Oviedo, Spain.
2. Institut National de la Sante et de la Recherche Medicale UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Université de la Méditerranée, Faculté de Médecine, 13385 Marseille Cedex 05, France.
3. Institut National de la Sante et de la Recherche Medicale U647, ID17, European Synchrotron Research Facility, 6 rue Jules Horowitz, 38043-Grenoble, France.
4. Departamento de Cirugía y Especialidades Médico-Quirúrgicas, and Instituto Asturiano de Odontología, calle Julián Clavería 6, Universidad de Oviedo, 33006-Oviedo, Spain.

Correspondence to: Carlos López-Otín¹ e-mail: clo@uniovi.es

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