|
|
| |
|
2005
[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
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.
|
|
|
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
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.
|
|
|
|
|
|
