Journals of Gerontology Series A: Biological Sciences and Medical Sciences Large Type Edition
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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:115-124 (2006)
© 2006 The Gerontological Society of America

Aging in Heterozygous Dnmt1-Deficient Mice: Effects on Survival, the DNA Methylation Genes, and the Development of Amyloidosis

Donna Ray, Ailing Wu, J. Erby Wilkinson, Hedwig S. Murphy2,3, Qianjin Lu1,5, Barbara Kluve-Beckerman, Juris J. Liepnieks, Merrill Benson, Raymond Yung1,4 and Bruce Richardson1,4,

Departments of 1 Medicine and 2 Pathology, University of Michigan, Ann Arbor.
Departments of 3 Pathology and Laboratory Medicine and 4 Medicine, Ann Arbor Veterans Administration Health Service, Michigan.
5 Second Xiangya Hospital, Central South University, Changsha, China.
6 Department of Pathology and Laboratory Medicine at the Indiana University School of Medicine, Indianapolis.

Address correspondence to Bruce Richardson, MD, PhD, 5310 Cancer Center and Geriatrics Center Bldg., Ann Arbor, MI 48109-0940. E-mail: brichard{at}umich.edu

We previously reported that heterozygous DNA methyltransferase 1-deficient (Dnmt1+/–) mice maintain T-cell immune function and DNA methylation levels with aging, whereas controls develop autoimmunity, immune senescence, and DNA hypomethylation. We therefore compared survival, cause of death, and T-cell DNA methylation gene expression during aging in Dnmt1+/– mice and controls. No difference in longevity was observed, but greater numbers of Dnmt1+/– mice developed jejunal apolipoprotein AII amyloidosis. Both groups showed decreased Dnmt1 expression with aging. However, expression of the de novo methyltransferases Dnmt3a and Dnmt3b increased with aging in stimulated T cells from control mice. MeCP2, a methylcytosine binding protein that participates in maintenance DNA methylation, increased with age in Dnmt1+/– mice, suggesting a mechanism for the sustained DNA methylation levels. This model thus provides potential mechanisms for DNA methylation changes of aging, and suggests that changes in DNA methylation may contribute to some forms of amyloidosis that develop with aging.






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