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Researchers identify a potentially universal
mechanism of aging
Newswise — Like our current financial
crisis, the aging process might also be a
product excessive deregulation.
Researchers have discovered that DNA damage
decreases a cell’s ability to regulate which
genes are turned on and off in particular
settings. This mechanism, which applies both
to fungus and to us, might represent a
universal culprit for aging.
“This is the first potentially fundamental,
root cause of aging that we’ve found,” says
Harvard Medical School professor of
pathology David Sinclair. “There may very
well be others, but our finding that aging
in a simple yeast cell is directly relevant
to aging in mammals comes as a surprise.”
These findings appear in the November 28
issue of the journal Cell.
For some time, scientists have know that a
group of genes called sirtuins are involved
in the aging process. These genes, when
stimulated by either the red-wine chemical
resveratrol
Nearly a decade ago, Sinclair and colleagues
in the Massachusetts Institute of Technology
lab of Leonard Guarente found that a
particular sirtuin in yeast affected the
aging process in two specific ways—it helped
regulate gene activity in cells and repair
breaks in DNA. As DNA damage accumulated
over time, however, the sirtuin became too
distracted to properly regulate gene
activity, and as a result, characteristics
of aging set in.
“For ten years, this entire phenomenon in
yeast was considered to be relevant only to
yeast,” says Sinclair. “But we decided to
test of this same process occurs in
mammals.”
Philipp Oberdoerffer, a postdoctoral
scientist in Sinclair’s Harvard Medical
School lab, used a sophisticated microarray
platform to probe the mammalian version of
the yeast sirtuin gene in mouse cells. The
results in mice corroborated what Sinclair,
Guarente, and colleagues had found in yeast
ten years earlier.
Oberdoerffer found that a primary function
of sirtuin in the mammalian system was to
oversee patterns of gene expression (which
genes are switch on and which are switch
off). While all genes are present in all
cells, only a select few need to be active
at any given time.
If the wrong genes are switched on, this can
harm the cell. (In a kidney cell, for
example, all liver genes are present, but
switched off.
If these genes were to become active, that
could damage the kidney.) As a protective
measure, sirtuins guard genes that should be
off and ensure that they remain silent.
To do this, they help preserve the molecular
packaging—called chromatin—that shrink-wraps
these genes tight and keeps them idle.
The problem for the cell, however, is that
the sirtuin has another important job. When
DNA is damaged by UV light or free radicals,
sirtuins act as volunteer emergency
responders.
They leave their genomic guardian posts and
aid the DNA repair mechanism at the site of
damage.
During this unguarded interval, the
chromatin wrapping may start to unravel, and
the genes that are meant to stay silent may
in fact come to life.
For the most part, sirtuins are able to
return to their post and wrap the genes back
in their packaging, before they cause
permanent damage. As mice age, however,
rates of DNA damage (typically caused by
degrading mitochondria) increase.
The authors found that this damage pulls
sirtuins away from their posts more
frequently. As a result, deregulation of
gene expression becomes chronic. Chromatin
unwraps in places where it shouldn’t, as
sirtuin guardians work overtime putting out
fires around the genome, and the unwrapped
genes never return to their silent state.
In fact, many of these haplessly activated
genes are directly linked with aging
phenotypes. The researchers found that a
number of such unregulated mouse genes were
persistently active in older mice.
“We then began wondering what would happen
if we put more of the sirtuin back into the
mice,” says Oberdoerffer. “Our hypothesis
was that with more sirtuins, DNA repair
would be more efficient, and the mouse would
maintain a youthful pattern gene expression
into old age.”
That’s precisely what happened. Using a
mouse genetically altered to model lymphoma,
Oberdoerffer administered extra copies of
the sirtuin gene, or fed them the sirtuin
activator resveratrol, which in turn
extended their mean lifespan by 24 to 46
percent.
“It is remarkable that an aging mechanism
found in yeast a decade ago, in which
sirtuins redistribute with damage or aging,
is also applicable to mammals,” says Leonard
Guarente, Novartis Professor of Biology at
MIT, who is not an author on the paper.
“This should lead to new approaches to
protect cells against the ravages of aging
by finding drugs that can stabilize this
redistribution of sirtuins over time.”
Both Sinclair and Oberdoerffer agree with
Guarente’s sentiment that these findings may
have therapeutic relevance.
“According to this specific mechanism, while
DNA damage exacerbates aging, the actual
cause is not the DNA damage itself but the
lack of gene regulation that results,” says
Oberdoerffer.
“Lots of research has shown that this
particular process of regulating gene
activity, otherwise known as epigenetics,
can be reversed—unlike actual mutations in
DNA. We see here, through a
proof-of-principal demonstration, that
elements of aging can be reversed.”
Recent findings by Chu-Xia Deng of the
National Institute of Diabetes, Digestive
and Kidney Diseases, has also found that
mice that lack sirtuin are susceptible to
DNA damage and cancer, reinforcing
Sinclair’s and Oberdoerffer’s data.
This research was funded by the National
Institutes of Health, and the Glenn
Foundation for Medical Research. David
Sinclair is a consultant to Genocea, Shaklee
and Sirtris, a GSK company developing
sirtuin based drugs.
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