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Seeking Senescence - the search for the cause of a
Seeking Senescence: specific genes may control how many times a cell can
divide.
by Deborah Erickson
Normal cells don't live forever. But some do continue dividing longer
than others, seemingly controlled by a predetermined counting
mechanism. Cells taken from humans or horses outlast those from mice,
for instance. Cells from younger donors will double more often than
those from older ones, as if they know they had more time allotted.
The ability to divide slows as cells age.
One popular notion is that cellular aging is the cumulative result of
small random changes, a breakdown provoked by a torrent of unintended
insults. Others argue that senescence in normal cells is probably
controlled by specific genes. "If you think that normal cells age
because they are damaged, then immortal cells must have something that
lets them escape," says Olivia M. Pereira-Smith, a geneticist at the
Huffington Center on Aging at the Baylor College of Medicine in
Houston.
Pereira-Smith and her colleague Yi Ning began examining cells that
divide indefinitely, searching for a gene to induce aging and so stop
proliferation. Their results, which will be published in the
Proceedings of the National Academy of Sciences, indicate that one
such gene involved in aging may be located on chromosome 4 in humans.
The Texas researchers first fused normal cells with immortal ones that
were cancerous or virally infected, to see whether the hybrid
offspring would also divide indefinitely. Most did not. The tendency
to be normal--and thus of limited life span--is apparently the
dominant inherited trait, whether cells originate in skin, muscle,
veins or blood. Therefore, the few cells that do manage to become
immortal must have a recessive gene for that trait, Pereira-Smith
concluded.
Next the team began fusing immortal cells with other immortal cells,
assuming that whatever recessive defect was responsible for each
parent's longevity would be passed on to the hybrid. If parents
shared the same genetic defect, the hybrid would also be immortal.
But if parents were immortal and lacked the defect, their capacity for
division would not be passed on to the hybrid. These parent cell
lines would be assigned to different groups for indefinite division,
depending on the other traits their hybrids inherited.
After fusing 30 cell lines from assorted tissues in all possible
combinations, Pereira-Smith and her collaborators found that any given
immortal cell line would fit into just one of four possible groups.
This limited assignment indicates that a small number of highly
specific genes are involved in senescence, she declares: "You need to
turn on a certain set of genes to become senescent, so you have to
lose any one of the set to become immortal."
Having firmly established which cells could be expected to live
forever, Pereira-Smith decided to see whether they could be stopped
from proliferating. "We decided to look at the chromosomes that have
been implicated in tumor suppression," she notes, explaining that
senescence could be involved in tumor suppression because it prevents
cells from growing without control. Perhaps a gene sitting somewhere
on one of those chromosomes would stop cells from dividing.
A procedure known as microcell fusion enabled the researchers to
transfer a normal single human chromosome into an immortal cell line.
The technique entails treating cells so that the nuclei break up into
little bags of nuclear membrane, each one of which contains only one
or two chromosomes. The microsacs are blown out of the cell cytoplasm
and fused into the nucleus of another cell.
The first try was disappointing. When chromosome 11, which has been
implicated in tumor suppression, was introduced to immortal cell
lines, "they proliferated just fine," Pereira-Smith recalls. It may
stop tumors but is apparently not involved in cell aging, she
observes. The team chose to repeat the microcell experiment with
chromosome 4. "We got lucky," the laboratory chief says with obvious
delight. This chromosome was able to induce senescence in a line of
cervical carcinoma cells but not in the other groups. Her laboratory
continues examining other cell lines within the group to see if the
effect can be replicated.
The next step is to find where on the chromosome the gene is located
and figure out how it is regulated. Gene hunting is never an easy
task, however. The classic example of the frustrating process is
Huntington's disease. Researchers have known for more than 10 years
that the gene for the inherited disorder lies somewhere on chromosome
4, but no one has yet been able to pinpoint it. But technology is
getting better every day, the geneticist declares. Once the gene is
in hand, scientists will be able to study its involvement in the
senescence of various normal cells. Pereira-Smith muses that "maybe
then we will be able to intervene not just in the laboratory but in
aging people."
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