[biomed] [tt] universal mechanism of aging

Thu Nov 27 13:41:12 CET 2008

On Thu, 2008-11-27 at 13:21 +0100, Eugen Leitl wrote:
> http://flyinghigh.org/2008/11/universal-mechanism-of-aging-discovered/

(
http://www.technologyreview.com/printer_friendly_article.aspx?id=21719&channel=biomedicine&section=
)

Wednesday, November 26, 2008
How Cells Age
Parallels between mice and yeast uncover a potentially universal aging
mechanism.
By Jocelyn Rice

Elderly mice and aging yeast have more in common than scientists ever
suspected. A new study by Harvard Medical School researchers reveals
that the biochemical mechanism that makes yeast grow old has a
surprising parallel in mice, suggesting it may be a universal cause of
aging in all organisms.

"It was very exciting when we made the discovery, because it was so
unexpected," says David Sinclair, a Harvard Medical School professor of
pathology and senior author of the study, published today in Cell.

In yeast, aging--marked by an inability to continue replicating--is
modulated by a protein called Sir2, which has counterparts, called
sirtuins, in nearly every known organism. Normally, yeast Sir2 attaches
to repeating DNA sequences to keep them stable. It also doubles as a DNA
repairer, migrating to damaged spots on the genome and helping to patch
them up. When a yeast cell is young, DNA damage is minimal, and Sir2 can
keep up both these roles. But as the cell ages and accumulates more and
more DNA damage, Sir2 becomes too busy with repairs to consistently
stabilize those volatile repeating sequences. Left unsupervised, the
repeats recombine into little extrachromosomal loops of DNA that build
up and prevent the cell from reproducing.

This mechanism was discovered a decade ago in the MIT lab of Leonard
Guarente, where Sinclair was then a postdoctoral researcher. For years,
says Sinclair, few scientists suspected it had any relevance for
understanding the process of aging in humans or other mammals. Although
sirtuins have been linked to aging in a wide variety of organisms, their
mechanism of action was understood only in yeast. But now it seems a
remarkably similar process may underlie aging in mice as well.

One function of the mouse version of Sir2, called SIRT1, is to regulate
how genes are expressed in various tissues. Patterns of expression
differ among organs--many genes that need to be active in the liver, for
instance, must remain silent in the brain. By binding to regulatory
regions alongside certain genes, SIRT1 helps dictate those patterns.
Because SIRT1 has also been shown to participate in DNA repair, Sinclair
and his colleagues wondered whether increasing DNA damage would
compromise the protein's normal regulatory role, as is the case with
Sir2 in yeast.

Sure enough, when the researchers treated mouse embryonic stem cells
with DNA-damaging hydrogen peroxide, SIRT1 migrated away from regulatory
regions of the genome and toward the many areas where DNA strands had
broken. As a result, genes that were normally shut off suddenly became
active. Gene expression patterns, once exquisitely fine-tuned, went
haywire.

"This is something that's eerily parallel to what we know in yeast,"
says Jan Vijg, chair of genetics at Albert Einstein College of Medicine,
who was not involved in the study.

Yeast are the only organism in which the mechanism of aging is well
understood, says Sinclair. "We only know for sure why yeast age," he
says. "[With] all the other organisms, it's still a black box. But we're
hoping that this is an explanation for all organisms."

Guarente agrees that the resemblance to yeast is surprising. "It was
interesting to see this commonality," he says. "The degree to which it
recapitulates yeast is pretty striking." But he is more skeptical that
this particular mechanism will turn out to be universal, cautioning that
the process of aging is so chaotic and haphazard that the notion of a
universal may not be useful.

Sinclair says the finding also provides a plausible explanation for two
well-known phenomena: that DNA damage accelerates aging, and that
patterns of gene expression tend to go awry as an animal gets older.

The sirtuins have received considerable attention in recent years for
their apparent role in aging. An overabundance of sirtuins extends the
life spans of yeast, nematodes, and flies. In addition, molecules that
seem to activate sirtuins--such as resveratrol, found in red wine--have
a protective effect against some age-related diseases in mice. Sinclair
cofounded Sirtris Pharmaceuticals in Cambridge, MA, to investigate the
therapeutic possibilities of highly potent resveratrol-like molecules.
The company is testing a series of products, including a treatment for
treating type 2 diabetes.

The new study adds to this growing body of evidence for the many ways
sirtuins contribute to aging and age-related disease. "SIRT1 is reported
to do so many different things now; the challenge is going to be
figuring out which of those it really does, and which of those are
really important for diseases," says Brian Kennedy, another former
member of Guarente's lab. Kennedy, now an associate professor of
biochemistry at the University of Washington, was not involved in the
study.

Guarente also emphasizes the broad importance of sirtuins, beyond the
newly discovered SIRT1 mechanism. "The universal in aging we already
know is sirtuins; they do so many things," he says. "The best way to
approach this is to be able to trigger sirtuins so that you get all of
the outputs and all of the benefits that they can bestow," he adds,
noting that many of those outputs are unrelated to the new mechanism.

Sinclair and his colleagues also found evidence of a link between the
SIRT1 mechanism and cancer, a disease strongly associated with old age.
When dosed with resveratrol or beefed up with an extra copy of the SIRT1
gene, mice normally prone to cancer developed fewer tumors. Both of
these interventions increased the available amount of SIRT1, likely
enhancing the protein's ability to repair the DNA damage that leads to
cancer without compromising its function as a gene regulator.

SIRT1 was already known to regulate a handful of mouse genes, but the
new study revealed hundreds more. Many of these genes were found to be
overexpressed in the brains of aging mice, underlining the potential
importance of SIRT1-based gene deregulation in the aging process.

While the striking parallel between mice and yeast suggests that
sirtuins' competing dual roles may be relevant in a wide variety of
organisms, it remains to be seen just how that mechanism fits into the
larger picture of mammalian aging, says Vijg. Nonetheless, Sinclair is
confident that his group has uncovered a potentially universal
mechanism. "Life, in general, has an Achilles heel," says Sinclair, "and
this is it."