X-Message-Number: 30092
Date: Fri, 30 Nov 2007 23:23:34 -0800 (PST)
From: 
Subject: Scientists find gene key to giving mice young-looking skin

Scientists find gene key to giving mice young-looking skin

Study raises hope of faster recovery from injuries
Team warns long-term use might trigger cancer

James Randerson
The Guardian
Friday November 30 2007
Scientists have found a way to reverse the aging process in skin, restoring
thinning tissue to a thicker, more youthful state in two weeks.
The advance, which works by manipulating a master control gene in cells that
changes the level of activity of other genes, has so far been demonstrated
only in mice. Researchers say that if it can be translated to people it
might help older people recover more quickly from injury or boost organ
function during illness.
But they played down suggestions that the technique could be used as a
"fountain of youth", as the targeted gene also plays a role in the immune
system and cancer. They fear that manipulating it could have longer-term and
potentially disastrous side effects. "You might get a longer life span, but
at the expense of something else," said Howard Chang, assistant professor of
dermatology at Stanford University in California, who led the study. "Here
we show that ageing in mouse skin can be reversed by blocking a single gene
... we found a pretty striking reversal to that of the young skin."
The discovery adds weight to the notion that the ageing process is more than
simply the accumulation of life's knocks. Previous studies have shown ageing
is a genetically programmed process that can be slowed in mammals by a
calorie-restricted diet or exercise. In more invasive studies young mice had
their circulatory systems surgically connected to older animals. The result
was that the aging organs of the older animals were rejuvenated.
"Ageing is not just a result of wear and tear, but is also the consequence
of a continually active genetic program that might be blocked for improving
human health," said Chang. "The finding that aged skin can be 'rejuvenated'
by a genetic intervention late in life implies that the ageing program is
plastic, and therefore can be potentially manipulated to decrease the
deleterious effects of aging."
His team identified genes involved in the ageing process by looking for
those which were expressed at different levels in young and old animals.
They also did the same exercise for human genes, to try to ensure that the
finding would be relevant to people. This exercise threw up 14 candidates,
of which the strongest was a master control gene called NF-kappa-B. It
controls other target genes involved in the immune system, inflammation and
cell death.
The team blocked the action of NF-kappa-B in skin cells in two-year-old
mice. After two weeks they examined the genes active in the animals' skin
and found that the genetic profile was very similar to the skin of newborn
mice: it was thicker, and more cells appeared to be dividing.
The team cannot be sure that NF-kappa-B has the same effect in humans. But
the human version lies in a part of our genome that has been shown in
previous studies to be associated with human longevity. The results are
published in the journal Genes and Development.
A similar short-term intervention to switch off NF-kappa-B might be possible
to speed up recovery from injury, but the team warns that altering it for
longer periods might have unexpected consequences. Because it controls genes
in many locations with various functions the researchers worry it could lead
to cancer.
Nina Goad, for the British Association of Dermatologists, welcomed the
research. "This research looks very interesting. Targeting of gene therapy
to skin is still very difficult, but this may provide some new avenues of
research that will be of value to wound healing following skin trauma, or
disfiguring skin cancer surgery. However, the researchers' caveats about the
unforeseen consequences of manipulating genes that play a role in many cells
are most important and add a strong element of caution."

____________________________________________________
Published online before print November 30, 2007
Genes and Development, DOI: 10.1101/gad.1588507
OPEN ACCESS ARTICLE


http://www.genesdev.org/cgi/reprint/gad.1588507v1?ijkey=4e285d31ca7a6b6d31fc478aa42f96d3ad18c6b3

Motif module map reveals enforcement of aging by continual NF-B activity
  Adam S. Adler1, Saurabh Sinha2, Tiara L.A. Kawahara1, Jennifer
Y. Zhang3, Eran Segal4,6, and Howard Y. Chang1,5
1 Program in Epithelial Biology and Cancer Biology Program, Stanford
University School of Medicine, Stanford, California 94305, USA; 2 Department
of Computer Science, University of Illinois at Urbana Champaign, Urbana,
Illinois 61801, USA; 3 Department of Medicine/Dermatology, Duke University
Medical Center, Durham, North Carolina 27710, USA; 4 Department of Computer
Science and Applied Mathematics, Weizmann Institute of Science, Rehovot
76100, Israel
  Aging is characterized by specific alterations in gene expression, but
their underlying mechanisms and functional consequences are not well
understood. Here we develop a systematic approach to identify
combinatorial cis-regulatory motifs that drive age-dependent gene
expression across different tissues and organisms. Integrated analysis of
365 microarrays spanning nine tissue types predicted fourteen motifs as
major regulators of age-dependent gene expression in human and mouse. The
motif most strongly associated with aging was that of the transcription
factor NF-B. Inducible genetic blockade of NF-B for 2 wk in the epidermis
of chronologically aged mice reverted the tissue characteristics and
global gene expression programs to those of young mice. Age-specific NF-B
blockade and orthogonal cell cycle interventions revealed that NF-B
controls cell cycle exit and gene expression signature of aging in
parallel but not sequential pathways. These results identify a conserved
network of regulatory pathways underlying mammalian aging and show that
NF-B is continually required to enforce many features of aging in a
tissue-specific manner.
[Keywords: Aging; NF-B; epidermis; functional genomics; computational
biology]]
Received June 29, 2007; revised version accepted October 16, 2007.

________________________________________________
Eur J Pharmacol. 2007 Jun 22;565(1-3):212-9. Epub 2007 Feb 17.
Magnolia ovovata extract and its active component magnolol prevent skin
photoaging via inhibition of nuclear factor kappaB.
    Tanaka K, Hasegawa J, Asamitsu K, Okamoto T. Department of Molecular and
Cellular Biology, Nagoya City University Graduate School of Medical
Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan.
    Transcriptional activity of nuclear factor kappaB (NF-kappaB) is induced
by environmental signals including inflammation, UV irradiation and
oxidative stress. It was shown that the NF-kappaB activity greatly
contributes to the skin photoaging process. Thus, it is plausible that
NF-kappaB inhibitors could directly prevent skin photoaging. In this study,
we found that Magnolia ovovata extract inhibited NF-kappaB-mediated gene
expression and demonstrated that external swabbing with Magnolia extract
preventing skin photoaging processes through keratinocyte hyperproliferation
and degradation of collagen fibers in mice skin. We have identified magnolol
as the solely responsible active compound in Magnolia extract. Magnolol
effectively inhibited the NF-kappaB-dependent transcription, but no effect
was observed with other inducible transcription factors such as activator
protein-1 (AP-1) and cyclic-AMP responsive element-binding protein (CREB).
In addition, magnolol was effective in inhibiting the production of basic
fibroblast growth factor (bFGF) and matrix metalloprotease-1 (MMP-1) from
the cells overexpressing p65, a major subunit of NF-kappaB. Although
magnolol did not affect the phosphorylation and degradation of IkappaBalpha,
it inhibited the nuclear translocation of the activated NF-kappaB. These
findings suggest that Magnolia extract and its active component magnolol can
be used to prevent the skin photoaging via inhibiting NF-kappaB by external
topical application.
PMID: 17346696

Mini Rev Med Chem. 2006 Aug;6(8):945-51.
Naturally occurring NF-kappaB inhibitors.
    Nam NH. University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Vietnam.
NF-kappaB is a ubiquitous and well-characterised protein responsible for the
regulation of complex phenomena, with a pivotal role in controlling cell
signalling in the body under certain physiological and pathological
conditions. Among other functions, NF-kappaB controls the expression of
genes encoding the pro-inflammatory cytokines (e. g., IL-1, IL-2, IL-6,
TNF-alpha, etc.), chemokines (e. g., IL-8, MIP-1alpha, MCP1, RANTES,
eotaxin, etc.), adhesion molecules (e. g., ICAM, VCAM, E-selectin),
inducible enzymes (COX-2 and iNOS), growth factors, some of the acute phase
proteins, and immune receptors, all of which play critical roles in
controlling most inflammatory processes. Since NF-kappaB represents an
important and very attractive therapeutic target for drugs to treat many
inflammatory diseases, including arthritis, asthma, and the auto-immune
diseases, most attention has been paid in the last decade to the
identification of compounds that selectively interfere with this pathway.
Recently, a great number of plant-derived substances have been evaluated as
possible inhibitors of the NF-kappaB pathway. These include a wide range of
compound classess, such as lignans (manassantins, (+)-saucernetin,
(-)-saucerneol methyl ether), sesquiterpenes (costunolide, parthenolide,
celastrol, celaphanol A), diterpenes (excisanin, kamebakaurin), triterpenes
(avicin, oleandrin), polyphenols (resveratrol, epigallocatechin gallate,
quercetin), etc. In this mini-review we will discuss the medicinal chemistry
of these compounds with regards to the NF-kappaB inhibition.
PMID: 16918500

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