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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.


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