Abstract:

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.

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Lamin A-Dependent Nuclear Defects in Human Aging

Paola Scaffidi

Tom Misteli

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

^{To whom correspondence should be addressed. E-mail:}vog.hin.liam@tiletsim

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Abstract

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. Agerelated 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.

Abstract

References and Notes

References

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16. We thank D. Donato for help with statistical analysis, C. Baker for design of specific primer pairs, M. Sinensky for advice on metabolic labeling of farnesylated lamin A, and K. Wilson and T. Jenuwein for providing reagents. Fluorescence imaging was performed at the NCI Fluorescence Imaging Facility. This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research.

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