Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Medicine volume 14, pages 767–772 (2008)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Navarro, C.L., Cau, P. & Levy, N. Molecular bases of progeroid syndromes. Hum. Mol. Genet. 15 Suppl 2, R151–R161 (2006).

    Article  CAS  Google Scholar 

  2. Scaffidi, P. & Misteli, T. Lamin A–dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

    Article  CAS  Google Scholar 

  3. Young, S.G., Meta, M., Yang, S.H. & Fong, L.G. Prelamin A farnesylation and progeroid syndromes. J. Biol. Chem. 281, 39741–39745 (2006).

    Article  CAS  Google Scholar 

  4. Kipling, D., Davis, T., Ostler, E.L. & Faragher, R.G. What can progeroid syndromes tell us about human aging? Science 305, 1426–1431 (2004).

    Article  CAS  Google Scholar 

  5. Hennekam, R.C. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. A. 140, 2603–2624 (2006).

    Article  Google Scholar 

  6. Pendás, A.M. et al. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice. Nat. Genet. 31, 94–99 (2002).

    Article  Google Scholar 

  7. Ramirez, C.L., Cadinanos, J., Varela, I., Freije, J.M. & López-Otín, C. Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions. Cell. Mol. Life Sci. 64, 155–170 (2007).

    Article  CAS  Google Scholar 

  8. Varela, I. et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437, 564–568 (2005).

    Article  CAS  Google Scholar 

  9. Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nat. Med. 11, 780–785 (2005).

    Article  CAS  Google Scholar 

  10. Liu, Y., Rusinol, A., Sinensky, M., Wang, Y. & Zou, Y. DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A. J. Cell Sci. 119, 4644–4649 (2006).

    Article  CAS  Google Scholar 

  11. Espada, J. et al. Nuclear envelope defects cause stem cell dysfunction in premature-aging mice. J. Cell Biol. 181, 27–35 (2008).

    Article  CAS  Google Scholar 

  12. Cadiñanos, J., Varela, I., López-Otín, C. & Freije, J.M. From immature lamin to premature aging: molecular pathways and therapeutic opportunities. Cell Cycle 4, 1732–1735 (2005).

    Article  Google Scholar 

  13. Toth, J.I. et al. Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc. Natl. Acad. Sci. USA 102, 12873–12878 (2005).

    Article  CAS  Google Scholar 

  14. Capell, B.C. et al. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA 102, 12879–12884 (2005).

    Article  CAS  Google Scholar 

  15. Mallampalli, M.P., Huyer, G., Bendale, P., Gelb, M.H. & Michaelis, S. Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA 102, 14416–14421 (2005).

    Article  CAS  Google Scholar 

  16. Glynn, M.W. & Glover, T.W. Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Mol. Genet. 14, 2959–2969 (2005).

    Article  CAS  Google Scholar 

  17. Fong, L.G. et al. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311, 1621–1623 (2006).

    Article  CAS  Google Scholar 

  18. Yang, S.H. et al. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J. Clin. Invest. 116, 2115–2121 (2006).

    Article  CAS  Google Scholar 

  19. Whyte, D.B. et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459–14464 (1997).

    Article  CAS  Google Scholar 

  20. Rusinol, A.E. & Sinensky, M.S. Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. J. Cell Sci. 119, 3265–3272 (2006).

    Article  CAS  Google Scholar 

  21. Konstantinopoulos, P.A. & Papavassiliou, A.G. Multilevel modulation of the mevalonate and protein-prenylation circuitries as a novel strategy for anticancer therapy. Trends Pharmacol. Sci. 28, 6–13 (2007).

    Article  CAS  Google Scholar 

  22. Giraudo, E., Inoue, M. & Hanahan, D. An amino-bisphosphonate targets MMP-9–expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. 114, 623–633 (2004).

    Article  CAS  Google Scholar 

  23. Yamagata, T. et al. Effects of pravastatin in murine collagen-induced arthritis. Rheumatol. Int. 27, 631–639 (2007).

    Article  CAS  Google Scholar 

  24. Sullivan, T. et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J. Cell Biol. 147, 913–920 (1999).

    Article  CAS  Google Scholar 

  25. Demierre, M.F., Higgins, P.D., Gruber, S.B., Hawk, E. & Lippman, S.M. Statins and cancer prevention. Nat. Rev. Cancer 5, 930–942 (2005).

    Article  CAS  Google Scholar 

  26. Greenwood, J., Steinman, L. & Zamvil, S.S. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat. Rev. Immunol. 6, 358–370 (2006).

    Article  CAS  Google Scholar 

  27. Roelofs, A.J., Thompson, K., Gordon, S. & Rogers, M.J. Molecular mechanisms of action of bisphosphonates: current status. Clin. Cancer Res. 12, 6222s–6230s (2006).

    Article  CAS  Google Scholar 

  28. Issat, T. et al. Potentiated antitumor effects of the combination treatment with statins and pamidronate in vitro and in vivo. Int. J. Oncol. 30, 1413–1425 (2007).

    CAS  PubMed  Google Scholar 

  29. Schmidmaier, R., Simsek, M., Baumann, P., Emmerich, B. & Meinhardt, G. Synergistic antimyeloma effects of zoledronate and simvastatin. Anticancer Drugs 17, 621–629 (2006).

    Article  CAS  Google Scholar 

  30. Blobel, G. & Potter, V.R. Nuclei from rat liver: isolation method that combines purity with high yield. Science 154, 1662–1665 (1966).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  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

    Ignacio Varela, Alejandro P Ugalde, María F Suárez, Juan Cadiñanos, Fernando G Osorio, José M P Freije & Carlos López-Otín

  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, Marseille Cedex 05, 13385, France

    Sandrine Pereira, Claire L Navarro, Pierre Cau & Nicolas Lévy

  3. Institut National de la Sante et de la Recherche Medicale U647, ID17, European Synchrotron Research Facility, 6 rue Jules Horowitz, 38043-Grenoble, France

    Nicolas Foray

  4. Departamento de Cirugía y Especialidades Médico-Quirúrgicas, and Instituto Asturiano de Odontología, calle Julián Clavería 6, Universidad de Oviedo, 33006-Oviedo, Spain

    Juan Cobo & Félix de Carlos

Authors
  1. Ignacio Varela
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandrine Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alejandro P Ugalde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire L Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. María F Suárez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pierre Cau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Cadiñanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fernando G Osorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nicolas Foray
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Juan Cobo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Félix de Carlos
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nicolas Lévy
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. José M P Freije
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Carlos López-Otín
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Carlos López-Otín.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–7 (PDF 4377 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1786

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing