November 18, 2005
Researchers Uncover New Genes that Control Longevity
An effort to understand the molecular mechanisms that control aging
has led Howard Hughes Medical Institute researchers and their
colleagues to 10 new genes that regulate longevity in yeast. The
studies also suggest a new model for how aging is slowed when caloric
intake is restricted.
Molecular biologists Matt Kaeberlein, Brian Kennedy, Stanley Fields,
and colleagues at the University of Washington, reported in the
November 18, 2005, issue of the journal Science that by
decreasing the function of nutrient-responsive pathways such as TOR and
Sch9, the life span of yeast is extended. Fields is a Howard Hughes
Medical Institute investigator at the University of Washington.
“Even though yeast is a simple, single-cell organism, it’s still capable of revealing mechanisms in the aging process. Similar genes may control aging in higher organisms, too.”
Stanley Fields
The results of the studies are important because they begin to
provide an explanation for the “life extension” effect seen
in laboratory animals when food is restricted. So the studies could
offer new clues about the molecular mechanisms that living organisms
employ when food is scarce, said Fields.
Although it seems counterintuitive, experiments showed long ago that
severely restricting food intake leads to an increase in longevity - by
as much as 40 percent — in some animals. Although the longevity
phenomenon was well documented in laboratory animals, researchers
remained unsure about how it happened.
Now, the experiments by Kaeberlein, Kennedy, Fields and their
colleagues are uncovering some of the molecular pathways that are
involved in controlling longevity in yeast, and thus probably in more
complex organisms.
“Through a large-scale screening process we have identified a
set of genes that slows aging in yeast.” Kaeberlein explained. He
and his colleagues are hoping to use that model to expand their
understanding of longevity higher up the evolutionary ladder, even into
humans. “We speculate that it is important in higher
organisms,” Fields added, since very similar genes are found in
most other species, from worms to fruit flies, mice and humans.
The next step, Kaeberlein said, is to begin similar work in the
nematode worm, Caenorhabditis elegans. After that, they hope to
study the process in mice, and eventually in humans — all with the
goal of understanding the aging process.
Although it is unlikely to happen soon, the discoveries may
eventually identify targets that can be manipulated — perhaps by drug
treatments — to alter the aging process, Fields said. One drug,
rapamycin, is already known to impact one of these genetic pathways,
but it has the dangerous side effect of disabling the immune
system.
“We'd like to understand how aging occurs in yeast,”
Fields added, because “even though yeast is a simple, single-cell
organism, it's still capable of revealing mechanisms in the aging
process. Similar genes may control aging in higher organisms,
too.”
The two years of laboratory work, much of it done by Kaeberlein and
Kennedy, were extraordinarily tedious, involving complex genetic and
biochemical tests on a special collection of 4,800 strains of yeast
cells developed by other scientists. Each yeast strain was engineered
to be special, and different, by lacking a different gene.
One of the group's most challenging tasks involved segregating 564
yeast strains into three categories: short-lived, not long-lived, and
long-lived. Such work involved careful examination of tens of thousands
of individual yeast cells under the microscope, separating
“daughter cells” from “mother cells,” and
segregating strains according to longevity.
In yeast, aging is measured by counting “replicative life
span,” the number of daughter cells produced by a given mother
cell before senescence. In the experiments published in Science,
researchers categorized cells as not long-lived if the mean life span
was less than 26 generations. If the mean life span was less than 20
generations, those yeast strains were put in the short-lived category.
Finally, if the mean life span was greater than 36 generations, then
those strains were called long-lived.
In time, the researchers gradually sorted out some gene mutations
that altered the life span of the cells. As a result, “ten new
genes were identified that are connected to longevity, and six of them
are implicated in a single pathway” in the cell's response to
nutrition, Fields explained.
For example, one gene they identified, called TOR1, seems to
regulate yeast's response to nutritional conditions. When the gene is
mutated, and not working properly, the yeast undergo a starvation
response similar to that of calorie-restricted cells - even when
nutrients are abundant. The acronym TOR stands for “target of
rapamycin.”
What's also clear is that these genes don't work alone. TOR and its
relatives are active in networks. Fields and his colleagues are trying
to identify and analyze other parts of such systems.
“Our hope is that this will lead us to the mechanisms involved
in caloric restriction and life extension,” Kaeberlein said.
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Jennifer Michalowski
