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Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging

Abstract

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 aging1,2. 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/LAΔ50 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.

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Figure 1: Prelamin A accumulation in the presence of farnesyltransferase and geranylgeranyl transferase inhibitors.
Figure 2: Mass spectrometry analysis of prelamin A alternative geranylgeranylation in the presence of farnesyltransferase inhibitors.
Figure 3: Synergistic effect of pravastatin and zoledronate on prelamin A accumulation in normal and HGPS fibroblast nuclei.
Figure 4: Combined treatment with statins and aminobisphosphonates ameliorates Zmpste24−/− mouse progeroid phenotypes.

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Acknowledgements

We thank G. Morris (Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital) for antibody 4A7. We thank X.S. Puente, C.L. Ramírez, A.F. Braña, P. Bourgeois, C. Massart, F. Canals, M. Barbacid, C. Guerra, K. Tryggvason, C. Stewart and G. Velasco for helpful comments and advice and F. Rodríguez, S. Alvarez, E. Francezon, L. Espinosa and I. Bocaccio for excellent technical assistance. This work was supported by grants from Ministerio de Educación y Ciencia-Spain, Fundación La Caixa, Fundación M. Botín, Institut National de la Santé et de la Recherche Médicale-France, Agence Nationale de la Recherche-France, Association Française contre les Myopathies and the European Union (FP6 CancerDegradome and FP6 Eurolaminopathies). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias.

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I.V., A.P.U., J. Cadiñanos, F.G.O. and J.M.P.F. carried out animal experiments. S.P., C.L.N., P.C., N.F., I.V. and A.P.U. performed cell-culture based studies. I.V., J. Cadiñanos, J.M.P.F. and M.F.S. carried out mass spectrometry experiments. F.d.C. and J. Cobo conducted micro-CT analysis. C.L.-O., J.M.P.F., P.C. and N.L. were responsible for designing and supervising the project and writing the manuscript.

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Correspondence to Carlos López-Otín.

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Varela, I., Pereira, S., Ugalde, A. et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med 14, 767–772 (2008). https://doi.org/10.1038/nm1786

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