Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
AAAS Store

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Published Online April 27, 2006
Science DOI: 10.1126/science.1127168

Reports

Submitted on March 8, 2006
Accepted on April 12, 2006

Lamin A-Dependent Nuclear Defects in Human Aging

Paola Scaffidi 1 and Tom Misteli 1*

1 National Cancer Institute, NIH, Bethesda, MD 20892 USA.

* To whom correspondence should be addressed.
Tom Misteli , E-mail: mistelit{at}mail.nih.gov

Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford Progeria (HGPS). Whether lamin A plays any role in the normal aging process is unknown. Here we show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire similar defects as HGPS patient cells including changes in histone modifications and increased DNA damage. Age-related nuclear defects are caused by sporadic use in healthy individuals of the same cryptic splice site in lamin A whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging. These observations implicate lamin A in physiological aging.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging.
E. Meshorer and Y. Gruenbaum (2008)
J. Cell Biol. 181, 9-13
   Abstract »    Full Text »    PDF »
Nuclear envelope defects cause stem cell dysfunction in premature-aging mice.
J. Espada, I. Varela, I. Flores, A. P. Ugalde, J. Cadinanos, A. M. Pendas, C. L. Stewart, K. Tryggvason, M. A. Blasco, J. M.P. Freije, et al. (2008)
J. Cell Biol. 181, 27-35
   Abstract »    Full Text »    PDF »
Telomeres and Aging.
G. Aubert and P. M. Lansdorp (2008)
Physiol Rev 88, 557-579
   Abstract »    Full Text »    PDF »
Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin.
T. Dechat, K. Pfleghaar, K. Sengupta, T. Shimi, D. K. Shumaker, L. Solimando, and R. D. Goldman (2008)
Genes & Dev. 22, 832-853
   Abstract »    Full Text »    PDF »
Targeted transgenic expression of the mutation causing Hutchinson-Gilford progeria syndrome leads to proliferative and degenerative epidermal disease.
H. Sagelius, Y. Rosengardten, M. Hanif, M. R. Erdos, B. Rozell, F. S. Collins, and M. Eriksson (2008)
J. Cell Sci. 121, 969-978
   Abstract »    Full Text »    PDF »
Hutchinson-Gilford Progeria Syndrome, Aging, and the Nuclear Lamina.
B. Korf (2008)
N. Engl. J. Med. 358, 552-555
   Full Text »    PDF »
Phenotype and Course of Hutchinson-Gilford Progeria Syndrome.
M. A. Merideth, L. B. Gordon, S. Clauss, V. Sachdev, A. C.M. Smith, M. B. Perry, C. C. Brewer, C. Zalewski, H. J. Kim, B. Solomon, et al. (2008)
N. Engl. J. Med. 358, 592-604
   Abstract »    Full Text »    PDF »
Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A.
Y. Liu, Y. Wang, A. E. Rusinol, M. S. Sinensky, J. Liu, S. M. Shell, and Y. Zou (2008)
FASEB J 22, 603-611
   Abstract »    Full Text »    PDF »
Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development.
L. B. Gordon, K. M. McCarten, A. Giobbie-Hurder, J. T. Machan, S. E. Campbell, S. D. Berns, and M. W. Kieran (2007)
Pediatrics 120, 824-833
   Abstract »    Full Text »    PDF »
New Approaches to Progeria.
M. W. Kieran, L. Gordon, and M. Kleinman (2007)
Pediatrics 120, 834-841
   Abstract »    Full Text »    PDF »
Age-related changes in lamin A/C expression in cardiomyocytes.
J. Afilalo, I. A. Sebag, L. E. Chalifour, D. Rivas, R. Akter, K. Sharma, and G. Duque (2007)
Am J Physiol Heart Circ Physiol 293, H1451-H1456
   Abstract »    Full Text »    PDF »
Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes.
B. C. Capell, F. S. Collins, and E. G. Nabel (2007)
Circ. Res. 101, 13-26
   Abstract »    Full Text »    PDF »
Alterations to Nuclear Architecture and Genome Behavior in Senescent Cells.
I. S. MEHTA, M. FIGGITT, C. S. CLEMENTS, I. R. KILL, and J. M. BRIDGER (2007)
Ann. N.Y. Acad. Sci. 1100, 250-263
   Abstract »    Full Text »    PDF »
Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging.
T. Dechat, T. Shimi, S. A. Adam, A. E. Rusinol, D. A. Andres, H. P. Spielmann, M. S. Sinensky, and R. D. Goldman (2007)
PNAS 104, 4955-4960
   Abstract »    Full Text »    PDF »
Progeria of Stem Cells: Stem Cell Exhaustion in Hutchinson-Gilford Progeria Syndrome.
J. Halaschek-Wiener and A. Brooks-Wilson (2007)
J. Gerontol. A Biol. Sci. Med. Sci. 62, 3-8
   Abstract »    Full Text »    PDF »
UVA irradiation induces relocalisation of the DNA repair protein hOGG1 to nuclear speckles.
A. Campalans, R. Amouroux, A. Bravard, B. Epe, and J. P. Radicella (2007)
J. Cell Sci. 120, 23-32
   Abstract »    Full Text »    PDF »
LONGEVITY REGULATION AND AGING IN ANIMAL MODELS.
H. R. Warner (2006)
Gerontologist 46, 844-847
   Full Text »    PDF »
DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.
Y. Liu, A. Rusinol, M. Sinensky, Y. Wang, and Y. Zou (2006)
J. Cell Sci. 119, 4644-4649
   Abstract »    Full Text »    PDF »
Molecular bases of progeroid syndromes.
C. L. Navarro, P. Cau, and N. Levy (2006)
Hum. Mol. Genet. 15, R151-R161
   Abstract »    Full Text »    PDF »
Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors..
A. E. Rusinol and M. S. Sinensky (2006)
J. Cell Sci. 119, 3265-3272
   Abstract »    Full Text »    PDF »
Lamins as youth elixir.
W. A. Wells (2006)
J. Cell Biol. 173, 457b
   Full Text »    PDF »
A shared splice site?.
M. Leslie (2006)
Sci. Aging Knowl. Environ. 2006, nf13
   Abstract »    Full Text »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products