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Researcher
Knows Why We Age: A Critical Gene "Retires"
Dec. 27, 2002 - With
age, the body deteriorates. Muscles atrophy. Bones grow thin. The skin
loses its elasticity. Wounds are slow to heal. Our tissues don't
regenerate the way they did in youth.
University of Illinois
at Chicago researcher Robert Costa believes he knows why - our FoxM1B
gene retires.
In a paper to be
published in the Dec. 24 issue of the Proceedings of the National
Academy of Sciences, Costa's research group has shown that the FoxM1B
gene, found on human chromosome number 12, is critical for tissues to
heal and replenish themselves.
If the gene is
defective or just tired out (as in old age and rare genetic disorders
causing premature aging), DNA can't duplicate itself, and cells can't
divide and multiply the way they normally do. The result: a flood of
activity in genes associated with aging.
Costa has been working
on the FoxM1B gene since he discovered the whole family of Fox genes
in 1993. Research has since shown that Fox family genes, found in
animals from insects on up through mammals, are involved in the entire
life cycle of a cell -- its proliferation, maturation and death.
Fox is short for
Forkhead Box, a name referring to a mutation in the gene in the fruit
fly that causes a duplication in the head structure.
One key finding came
last year: Costa's research group was studying the FoxM1B gene in
mice; in particular how it affects growth of the liver after a portion
of the organ is removed. One of the few adult organs capable in
mammals of completely regenerating itself, the liver is also the only
organ that regenerates from fully mature cells. Others, like blood,
form new tissue from immature cells.
The experiment showed
that the liver grew back at a rate typical of young mice -- a
discovery that led Costa to dub FoxM1B the "fountain-of-youth gene."
In the new study,
Costa's team set out to understand how FoxM1B directs the busy
molecular traffic inside a cell to make it proliferate. In a feat of
genetic engineering, the team created mice with liver cells lacking
the FoxM1B gene. Rates of regeneration were measured in these mice and
in mice whose FoxM1B gene was intact. Without FoxM1B, regeneration was
slow.
Cell division requires
two basic steps: first a doubling of DNA, the genetic instructions
inside a cell, and then a process called mitosis, in which the
duplicated DNA is separated into two new daughter cells.
Like a traffic cop,
FoxM1B controls both steps, Costa says. "If the cells had no FoxM1B
gene," he said, "their DNA often failed to make a copy of itself, and
they had trouble dividing."
The DNA failed to
duplicate due to a pileup of a protein called p21Cip1.
According to Costa,
FoxM1B probably unleashes the enzyme that normally digests this
protein to prevent it from building up in the cell.
When the p21Cip1
protein accumulates, Costa says, it sets in motion a series of
molecular events, like falling dominoes, that prevents DNA from
doubling and gives a green light to genes linked with the diseases of
old age.
"We know from earlier
research by others that abnormal accumulation of p21Cip1 protein
occurs during aging, turning on a host of genes associated with
diseases found in the elderly, like Alzheimer's and cancer," Costa
said.
Costa's team also
found that FoxM1B controls a key enzyme needed to help cells pull
apart at the end of mitosis, the final step in cell division.
"These results clearly
link FoxM1B with the failure of tissues to mend," Costa said. "And in
old age, when the FoxM1B gene is essentially out of action, we see the
results."
The study was
supported by a grant from the National Institute of Diabetes and
Digestive and Kidney Diseases, one of the National Institutes of
Health.
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