Skip to main content

Thank you for visiting 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:

Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation


Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope1,2,3. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process1,2,4,5. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes6,7,8,9,10. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing11.

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

Access options

Buy this article

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

Figure 1: Activation of a p53-induced pathway as a result of Zmpste24 or Lmna deficiencies.
Figure 2: Senescence in Zmpste24 -/- mice
Figure 3: Lmna heterozygosity rescues the Zmpste24 -/- phenotype.
Figure 4: Partial recovery of the Zmpste24 -/- phenotype in a p53-null background.

Similar content being viewed by others


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

    Article  Google Scholar 

  2. Bergo, M. O. et al. Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc. Natl Acad. Sci. USA 99, 13049–13054 (2002)

    Article  ADS  CAS  Google Scholar 

  3. Corrigan, D. P. et al. Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24. Biochem. J. 387, 129–138 (2005)

    Article  CAS  Google Scholar 

  4. 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 

  5. Mounkes, L. C., Kozlov, S., Hernandez, L., Sullivan, T. & Stewart, C. L. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 423, 298–301 (2003)

    Article  ADS  CAS  Google Scholar 

  6. Agarwal, A. K., Fryns, J. P., Auchus, R. J. & Garg, A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum. Mol. Genet. 12, 1995–2001 (2003)

    Article  CAS  Google Scholar 

  7. De Sandre-Giovannoli, A. et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 300, 2055 (2003)

    Article  CAS  Google Scholar 

  8. Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423, 293–298 (2003)

    Article  ADS  CAS  Google Scholar 

  9. Chen, L. et al. LMNA mutations in atypical Werner's syndrome. Lancet 362, 440–445 (2003)

    Article  CAS  Google Scholar 

  10. Navarro, C. L. et al. Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. Hum. Mol. Genet. 14, 1503–1513 (2005)

    Article  CAS  Google Scholar 

  11. Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002)

    Article  ADS  CAS  Google Scholar 

  12. Yu, J. et al. Identification and classification of p53-regulated genes. Proc. Natl Acad. Sci. USA 96, 14517–14522 (1999)

    Article  ADS  CAS  Google Scholar 

  13. Qiu, W. et al. Hypermethylation of growth arrest DNA damage-inducible gene 45 beta promoter in human hepatocellular carcinoma. Am. J. Pathol. 165, 1689–1699 (2004)

    Article  CAS  Google Scholar 

  14. Fei, P., Bernhard, E. J. & El-Deiry, W. S. Tissue-specific induction of p53 targets in vivo. Cancer Res. 62, 7316–7327 (2002)

    CAS  PubMed  Google Scholar 

  15. Wei, W., Hemmer, R. M. & Sedivy, J. M. Role of p14(ARF) in replicative and induced senescence of human fibroblasts. Mol. Cell. Biol. 21, 6748–6757 (2001)

    Article  CAS  Google Scholar 

  16. Bode, A. M. & Dong, Z. Post-translational modification of p53 in tumorigenesis. Nature Rev. Cancer 4, 793–805 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000)

    Article  ADS  CAS  Google Scholar 

  19. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995)

    Article  ADS  CAS  Google Scholar 

  20. Campisi, J. Cancer and ageing: rival demons? Nature Rev. Cancer 3, 339–349 (2003)

    Article  CAS  Google Scholar 

  21. Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001)

    Article  CAS  Google Scholar 

  22. Sharpless, N. E. & DePinho, R. A. Telomeres, stem cells, senescence, and cancer. J. Clin. Invest. 113, 160–168 (2004)

    Article  CAS  Google Scholar 

  23. Fong, L. G. et al. Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. Proc. Natl Acad. Sci. USA 101, 18111–18116 (2004)

    Article  ADS  CAS  Google Scholar 

  24. Johnson, B. R. et al. A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc. Natl Acad. Sci. USA 101, 9677–9682 (2004)

    Article  ADS  CAS  Google Scholar 

  25. Yan, T., Li, S., Jiang, X. & Oberley, L. W. Altered levels of primary antioxidant enzymes in progeria skin fibroblasts. Biochem. Biophys. Res. Commun. 257, 163–167 (1999)

    Article  CAS  Google Scholar 

  26. Petriv, O. I. & Rachubinski, R. A. Lack of peroxisomal catalase causes a progeric phenotype in Caenorhabditis elegans. J. Biol. Chem. 279, 19996–20001 (2004)

    Article  CAS  Google Scholar 

  27. Schriner, S. E. et al. Extension of murine lifespan by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005)

    Article  ADS  CAS  Google Scholar 

  28. Hutchison, C. J. & Worman, H. J. A-type lamins: guardians of the soma? Nature Cell Biol. 6, 1062–1067 (2004)

    Article  CAS  Google Scholar 

  29. Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004)

    Article  CAS  Google Scholar 

  30. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994)

    Article  CAS  Google Scholar 

Download references


We thank A. Astudillo for help with histopathological analysis; E. Fermiñán (CIC-Salamanca) for help with microarray experiments; X. S. Puente, A. Fueyo, J. Alvarez, P. Zuazua, G. Velasco, A. Bernad, S. Laín and M. Serrano for support and comments; T. Sánchez and L. Santos for help in animal care facilities; and M. Fernández, S. Alvarez and M. S. Pitiot for technical assistance. This work was supported by grants from Ministerio de Educación y Ciencia, Fundación “La Caixa”, the European Union, the Swedish Research Council, the Swedish Cancer Society and the Research Grant Council of Hong Kong. The Instituto Universitario de Oncología is supported by Obra Social Cajastur, and Red de Centros de Cancer Instituto Carlos III, Spain.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Carlos López-Otín.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Progeria in Zmpste24-deficient mice. (PDF 86 kb)

Supplementary Figure 2

p21 overexpression in tissues from Zmpste24-null mice. (PDF 75 kb)

Supplementary Figure 3

p21 overexpression in Zmpste24-deficient mice increases with age and phenotype severity. (PDF 47 kb)

Supplementary Figure 4

Heterochromatin alterations in Zmpste24-deficient mice. (PDF 92 kb)

Supplementary Figure 5

Lack of increased apoptosis in Zmpste24-null mice . (PDF 39 kb)

Supplementary Figure 6

Retinoblastoma protein levels (pRb) are decreased in liver from Zmpste24-deficient mice. (PDF 39 kb)

Supplementary Figure Legends

Full text to accompany the above Supplementary Figures. (DOC 30 kb)

Supplementary Table 1

Transcriptional alterations in tissues from Zmpste24- and Lmna- deficient mice. (PDF 49 kb)

Supplementary Table 2

Analysis of potential alternative splicing forms of mouse p53 mRNA in wild-type and Zmpste24-deficient mice. (PDF 24 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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