2005

Oncogene. 2005 May 16
Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome.
Kyng KJ, May A, Stevnsner T, Becker KG, Kolvra S, Bohr VA.
[1] 1Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA [2] 2Danish Center for Molecular Gerontology, Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus C, Denmark.

The accumulation of DNA damage and mutations is considered a major cause of cancer and aging. While it is known that DNA damage can affect changes in gene expression, transcriptional regulation after DNA damage is poorly understood. We characterized the expression of 6912 genes in human primary fibroblasts after exposure to three different kinds of cellular stress that introduces DNA damage: 4-nitroquinoline-1-oxide (4NQO), gamma-irradiation, or UV-irradiation. Each type of stress elicited damage specific gene expression changes of up to 10-fold. A total of 85 genes had similar changes in expression of 3-40-fold after all three kinds of stress. We examined transcription in cells from young and old individuals and from patients with Werner syndrome (WS), a segmental progeroid condition with a high incidence of cancer, and found various age-associated transcriptional changes depending upon the type of cellular stress. Compared to young individuals, both WS and old individuals had similarly aberrant transcriptional responses to gamma- and UV-irradiation, suggesting a role for Werner protein in stress-induced gene expression. Our results suggest that aberrant DNA damage-induced gene regulation may contribute to the aging process and the premature aging in WS.Oncogene advance online publication, 16 May 2005; doi:10.1038/sj.onc.1208692.

2002

Mech Ageing Dev 2002 Jan;123(2-3):177-93
Gene expression profiling of aging using DNA microarrays.
Weindruch R, Kayo T, Lee CK, Prolla TA.
Department of Medicine, University of Wisconsin-Madison and Veterans Administration Hospital, Geriatric Research, Education and Clinical Center, Madison, WI 53705, USA.

We have previously employed high density oligonucleotide arrays representing thousands of genes to determine the gene expression profile of the aging process in skeletal muscle (gastrocnemius) and brain (cerebellum and neocortex) of male C57BL/6 mice. Specific gene expression profiles are associated with the aging process of individual organs, and caloric restriction can prevent or retard the establishment of these gene expression alterations. The use of DNA microarrays may provide a new tool to measure biological age on a tissue-specific basis and to evaluate at the molecular level the efficacy of interventions designed to retard the aging process.

Chem Senses 2002 Mar;27(3):299-306
DNA microarray analysis of the aging brain.
Prolla TA.
Departments of Genetics and Medical Genetics, University of Wisconsin, 445 Henry Mall, Madison, WI 53706, USA.

To examine molecular events associated with brain aging and its retardation by caloric restriction (CR), we have employed high-density oligonucleotide arrays providing data on 6347 genes to define transcriptional patterns in two brain regions (cerebellum and neocortex). Male C57BL/6 mice were either fed normally or subjected to CR. To investigate aging, 5 month (young adult) and 30 month-old normally fed mice were compared. To study CR, 30 month-old control and CR mice were compared. In both brain regions, aging resulted in a gene expression profile suggestive of a marked inflammatory response, oxidative stress and reduced neuronal plasticity and neurotrophic support. In the brain, CR selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses. In addition to providing an improved understanding of the aging process, the use of DNA microarrays generates panels of hundreds of transcriptional biomarkers of molecular aging, providing a new tool to measure biological age on a tissue-specific basis. These studies suggest that genomic approaches may be useful in understanding the molecular basis of the aging process in experimental animals.

1997

Exp Gerontol 1997 Jul;32(4-5):383-394
The heterochromatin loss model of aging.
Villeponteau B.
Geron Corporation, Menlo Park, CA 94025, USA.

There are significant changes in gene expression that occur with cellular senescence and organismic aging. Genes residing in compacted heterochromatin domains are typically silenced due to an altered accessibility to transcription factors. Heterochromatin domains and gene silencing are set up in early development and were initially believed to be maintained for the remainder of the lifespan. Recent data suggest that there may be a net loss of heterochromatin with advancing age in both yeast and mice. The gradual loss of heterochromatin-induced gene silencing could explain the changes in gene expression that are closely linked with aging. A general model is proposed for heterochromatin loss as a major factor in generating alterations in gene expression with age. The heterochromatin loss model is supported by several lines of evidence and suggests that a fundamental genetic mechanism underlies most of the changes in gene expression observed with senescence.