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Originally published in Science Express on 27 April 2006
Science 19 May 2006:
Vol. 312. no. 5776, pp. 1059 - 1063
DOI: 10.1126/science.1127168
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Reports

Lamin A-Dependent Nuclear Defects in Human Aging

Paola Scaffidi and Tom Misteli*

Mutations in the nuclear structural protein lamin A cause the premature aging syndrome Hutchinson-Gilford progeria (HGPS). Whether lamin A plays any role in normal aging is unknown. We show that the same molecular mechanism responsible for HGPS is active in healthy cells. Cell nuclei from old individuals acquire defects similar to those of 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.

National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA.

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

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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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