Do Tiny Cellular Clocks Govern Human Aging?
The Wall Street Journal Interactive Edition -- February 17, 2000
By LAURA JOHANNES /
For more than a decade, scientists have debated, theorized and even
fantasized about the role of tiny cellular clocks called telomeres
in triggering the human aging process.
Now, new research is beginning to shed light on what the mysterious
microscopic bodies actually do. The findings are not likely to grant
humans immortality but could lead to treatments for diseases ranging
from liver cirrhosis to AIDS.
"We won't be making people live 200 years" via telomere research,
says Rita B. Effros, a researcher at University of California at
Los Angeles. "However, we'll probably be able to correct lots of
diseases and allow people to live longer and stay healthier
throughout their lives."
First seen under the microscope in the 1930s, telomeres are located
at the tips of chromosomes, the gene-bearing parts of a cell that
convey hereditary characteristics. In 1985, scientists discovered
a naturally occurring protein, dubbed telomerase, that the body uses
to repair telomeres. Telomerase is always present in some cells, but
in others it is mysteriously present only sometimes.
Interest in the field exploded a decade ago, when scientists
discovered that each time a cell divides, its telomeres grow shorter
-- so short, ultimately, that cells can no longer divide. Scientists
also noticed that in humans, successive generations of telomeres
appear to shorten with age. In some cell types, they are less than
half as long in elderly people as they are in newborns.
These discoveries gave rise to a theory that telomeres are like a
fuse that, when burned down, causes the human body to age. That idea
gained credence after scientists at Geron Corp. and elsewhere used
telomerase to repair telomeres and create cells that are, in effect,
"immortal." In other words, they could divide forever provided they
get normal nourishment. Normal cells divide only several dozen times,
then stop reproducing and die.
But making cells immortal is a far cry from making humans so. Some
critics say that telomere-shortening could be merely a symptom of
aging, not a cause. "I've got gray hair, and most people when they
get old get gray hair. Yet you wouldn't say gray hair causes aging,"
says Leonard Guarante, 47, a biology professor at the Massachusetts
Institute of Technology.
Even Ron DePinho, one of the foremost researchers in the field,
counts himself as something of a skeptic. Last year he reported
that mice genetically engineered to lack telomerase showed signs
of premature aging. They got gray earlier, were less able to heal
from wounds and ultimately died younger than normal mice.
His findings, published in the journal Cell in March, set an already
hot field on fire. But Dr. DePinho, of Boston's Dana-Farber Cancer
Center, points out that not every infirmity of age was apparent in
the telomerase-deprived mice. For instance, they didn't get the liver,
kidney and brain function problems that usually come with age.
Telomere shortening "is not the cause of organismal aging," he
concludes, but merely "a contributing factor."
Even so, the race is on to find medical applications for telomerase
therapy. Early research has shown that liver cells in people with
cirrhosis, a fatal disease caused by hepatitis, alcoholism or other
long-term abuse of the liver, have extraordinarily short telomeres.
Dr. DePinho, in mouse experiments, is exploring whether telomerase
therapy could be used to treat, or prevent, cirrhosis.
Another promising research area is AIDS. "Immune cells fighting the
virus are constantly asked to divide more and more, so their
telomeres shorten and they reach the limit," says the University
of California's Dr. Effros. She is now altering immune cells to make
large quantities of telomerase. If the therapy allows them to keep
regenerating indefinitely, such cells could ultimately be injected
into AIDS patients to boost their failing immune systems.
At Geron, scientists are working to see whether patches of human
skin, some in a dish and some grafted onto mice, can be made to
resist the ravages of aging by boosting their telomerase levels.
"Our primary focus is on these significant problems in elderly
skin," says company scientist Cal Harley. "Whether telomerase
therapy is going to help wrinkling, hair loss or hair graying,
we don't know yet."
What scientists do know is that cancer cells, known for their
ability to divide again and again, produce large amounts of
telomerase. Thus some researchers are studying whether
switching off telomerase production can stifle cancer growth.
Last year, researchers at the Massachusetts Institute of
Technology used gene therapy to turn off telomerase in cancer
cells in lab dishes and managed to stop them from dividing.
Such a gene therapy approach would be difficult in humans,
so the next step is to find a drug that interferes with
telomerase, which is present in about 85% to 90% of cancer
cells.
"Over the next three to five years a telomerase inhibitor will
be found and tested in the clinic," predicts MIT researcher
Robert Weinberg. "In conjunction with other drugs, I believe
we will really get very effective killing of tumors."
Many scientists have wondered: Would an animal engineered with
lots of telomerase be eternally young, or more prone to cancer?
Dr. DePinho has bred several hundred mice to make excess amounts
of the protein to find out.
The animals, now about middle-aged, so far look no different from
normal mice. But Carol Greider, one of the scientists who discovered
telomerase in 1985, has bet a colleague a six-pack of beer that they
will get cancer. If so, it will force scientists to think even more
seriously about the safety of telomerase therapy.
Write to Laura Johannes at laura.johannes@wsj.com |
