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In laboratories around the country, scientists are isolating
specific genes, cloning them, mapping them to chromosomes, and studying
their products to learn what they do and how they influence aging
and longevity. |
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Humans seem
to have a maximum life span of about 120 years, but for tortoises
it's 150 and for dogs, about 20. What underlies these differences
among species are genes, the coded segments of DNA (deoxyribonucleic
acid) strung like beads along the chromosomes of nearly every living
cell. In humans, the nucleus of each cell holds 23 pairs of chromosomes,
and together these chromosomes contain about 100,000 genes.
The link between
genes and life span is unquestioned. The simple observation that
some species live longer than others -- humans longer than dogs,
tortoises longer than mice -- is one convincing piece of evidence.
Another comes from recent, dramatic laboratory studies in which
researchers, through selective breeding or genetic engineering,
have been able to raise animals with extended life spans. For example,
fruit flies bred selectively have lived nearly twice as long as
average (see In the Lab of the Long-Lived
Fruit Flies).
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Longevity
Genes
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By demonstrating
that genes are linked to life span, the long-lived fruit flies have
set the stage for more questions. What specific genes are involved?
What activates them? How do they influence aging and longevity? In
numerous laboratories, the search for answers is on.
A
few have been identified; more are on the horizon.
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Some leads are
coming from yeast cells in which researchers have found evidence of
14 genes that seem to be related to aging (see Tracking
Down a Longevity Gene). Longevity-related genes have also been
found in tiny worms called nematodes and in fruit flies. Like yeast,
nematodes and fruit flies have short life spans and their genes, which
are known and do not vary greatly, are relatively easy to study.
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| In
the Lab of the Long-Lived Fruit Flies
A
laboratory at the University of California, Irvine, is the
home of thousands of Drosophila melanogaster or fruit
flies that routinely live for 70 or 80 days, nearly twice
the average Drosophila life span. Here evolutionary
biologist Michael Rose has bred the long-lived stocks by
selecting and mating flies late in life.
To
begin the process of genetic selection, Rose first collected
eggs laid by middle-aged fruit flies and let them hatch
in isolation. The progeny were then transferred to a communal
plexiglass cage to eat, grow, and breed under conditions
ideal for mating. Once they had reached advanced ages, the
eggs laid by older females (and fertilized by older males)
were again collected and removed to individual hatching
vials. The cycle was repeated, but with succeeding generations,
the day on which the eggs were collected was progressively
postponed. After two years and 15 generations, the laboratory
had stocks of Drosophila with longer life spans.
The
next question is what genes and what gene products are involved?
Since the first experiments, Rose has bred longer life spans
into fruit flies by selecting for other characteristics,
such as ability to resist starvation, so the flies' long
life spans are not necessarily tied to their fertility late
in life.
One
possibility is that the anti-oxidant enzyme, superoxide
dismutase (SOD), is involved. In another laboratory at Irvine,
the late Robert Tyler discovered that the longer-lived flies
had a somewhat different form of the SOD gene, which was
more active than its counterpart in the flies with average
life spans. This finding has given a boost to the hypothesis
that anti-oxidant enzymes like SOD are linked to aging or
longevity.
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Some of the
genes found in yeast and fruit flies seem to promote longevity.
But others may shorten life span. One such "death gene" has been
isolated in nematodes by researchers at the University of Colorado
in Boulder, who found that mutation of a certain gene more than
doubles the nematode's normal 3-week life span. Thomas Johnson's
laboratory in Boulder has also uncovered evidence that the mutant
may extend life span by overproducing superoxide dismutase (SOD)
and catalase, two anti-oxidant enzymes that have been linked to
longevity in other studies (see Oxygen Radicals).
The genes
isolated so far are only a few of what scientists think may be dozens,
perhaps hundreds, of longevity- and aging-related genes. Tracking
them down in organisms like nematodes and yeast is just the beginning.
The next big question for many gerontologists is whether there are
counterparts in people -- human homologs -- of the genes found in
laboratory animals.
Other unanswered
questions concern the roles played by these genes. What exactly
do they do? On one level, all genes function by transcribing their
"codes" -- actually DNA base sequences -- into another nucleic acid
called messenger ribonucleic acid or mRNA. Messenger RNA is then
translated into proteins. Transcription and translation together
constitute the process known as gene expression.
The proteins
expressed by genes carry out a multitude of functions in each cell
and tissue in the body, and some of these functions are related
to aging. So when we ask what longevity- or aging-related genes
do, we are actually asking what their protein products do at the
cellular and tissue levels. Increasingly, gerontologists are also
asking how alterations in the process of gene expression itself
may affect aging.
Some proteins,
such as anti-oxidants, appear to prevent damage to cells, and others
may repair damaged DNA or help cells respond to stress; more about
these comes later. Other gene products are thought to control cell
senescence, a process that could prove to be a key piece in the
puzzle of aging and longevity.
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Cell Senescence
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Picture a
cell: the threadlike pairs of chromosomes inhabit a nucleus that floats
in a sea of cytoplasm along with other tiny organelles that do the
cell's work, the whole 
surrounded by a membrane at the surface of which the cell sends and
receives messages from other cells. Then picture the chromosomes,
condensing into rod-like structures that divide in two, the nucleus
disappearing, the chromosomes migrating to opposite sides of the cell
where other nuclei are formed, and after that the entire cell following
the chromosomes' lead, pulling apart and forming two identical daughter
cells.
This, the
process of mitosis, or asexual cell division, takes place in nearly
all of the 100 trillion or so cells that make up the human body.
But it does not go on indefinitely. About the middle of this century,
researchers learned that cells have finite life spans, at least
when studied in test tubes -- in vitro.
A
built-in limit on cell division may help explain the aging
process.
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After a certain
number of divisions, they enter a state of cell senescence,
in which they do not divide or proliferate and DNA synthesis is blocked.
For example, young human fibroblasts -- collagen-producing cells frequently
used in this branch of aging research -- divide about 50 times and
then stop. This phenomenon has become known as the Hayflick limit,
after Leonard Hayflick, who with Paul Moorhead first described it
while at the Wistar Institute in Philadelphia.
Intrigued
by the possibility that the Hayflick limit might help explain some
aspects of bodily aging, gerontologists have looked for and found
links between senescence and human life spans. Fibroblasts taken
from 75-year-olds, for example, have fewer divisions remaining than
cells from a child. Moreover, the longer a species' life span, the
higher its Hayflick limit; human fibroblasts have higher Hayflick
limits than mice fibroblasts.
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Proliferative
Genes
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Searching
for explanations of proliferation and senescence, scientists have
found certain genes that appear to trigger cell proliferation. One
example of such a proliferative gene is c-fos, which
encodes a short-lived protein that is thought to regulate the expression
of other genes important in cell division.
But c-fos
and others of its kind are countered by anti-proliferative genes,
which seem to interfere with division. The first evidence of an
anti-proliferative gene came from an eye tumor called retinoblastoma.
When one of
the genes from retinoblastoma cells -- later called the RB gene
-- became inactive, the cells went on dividing indefinitely and
produced a tumor. But when the RB gene product was activated, the
cells stopped dividing. This gene's product, in other words, appeared
to suppress proliferation.
Senescence
is the norm in the world of cells. In some cases, however, a cell
somehow escapes this control mechanism and goes on dividing, becoming,
in the terms of cell biology, immortal. And because immortal cells
eventually form tumors, this is one area in which aging research
and cancer research intersect. Investigators theorize that a failure
of anti-proliferative genes (also known as tumor suppressor genes)
is the first step in a complex process that leads to development
of a tumor. Senescence, according to this view, may have evolved
because it protected against cancer,.
Still a mystery
is how these genes' products function to promote and suppress cell
proliferation. There are indications that a multilayer control system
is at work, involving probably a host of intricate mechanisms that
interact to maintain a balance between the two kinds of genes. Many
gerontologists are now involved in unraveling these intricacies,
studying both the genes and their products to learn which ones influence
senescence and how.
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| Tracking
Down a Longevity Gene
Investigators
are finding clues to aging and longevity in yeast, one-celled
organisms that have some intriguing genetic similarities
to human cells. In a laboratory at Louisiana State University
Medical Center in New Orleans, Michal Jazwinski has found
genes that seem to promote longevity in these rapidly dividing,
easy-to-study organisms.
Yeast
normally have about 21 cell divisions or generations. Jazwinski
observed that over the course of that "life span," certain
genes in the yeast are more active or less active as the
cells age; in the language of molecular biology, they are
differentially expressed. So far, Jazwinski has found 14
such genes in yeast.
Selecting
one of these genes, Jazwinski tried two different experiments.
First, he introduced the gene into yeast cells in a form
that allowed him to control its activity. When the gene
was activated to a greater degree than normal, or overexpressed,
some of the yeast cells went on dividing for 27 or 28 generations;
their period of activity was extended by 30 percent.
In
his second experiment, Jazwinski mutated the gene. When
he introduced this non-working version into a group of yeast
cells, they had only about 12 divisions.
The
two experiments made it clear that the gene, now called
LAG-1, influences the number of divisions in yeast
or, according to some researchers' ways of thinking, its
longevity. (LAG-1 is short for longevity assurance
gene.) But how it works is still a mystery. One small clue
lies in its sequence of DNA bases -- its genetic code --
which suggests that it produces a protein found in cell
membranes. One next step is to study the function of that
protein. Similar sequences have been found in human DNA,
so a second investigative path is to clone the human gene
and study its function. If there turns out to be a human
LAG-1 counterpart, new insights into aging may be
uncovered.
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Telomeres
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In the meantime,
scientists are finding more clues to senescence in the architecture
of DNA. Every chromosome, they have discovered, has tails at the ends
that get shorter as a cell divides. Named telomeres, the tails
all have the same, short sequence of DNA bases repeated thousands
of times. The repetitive structure stabilizes the chromosomes, forming
a tight bond between the two strands of the DNA.
Each time
a cell divides, the telomeres shed a number of bases, so telomere
length gives some indication of how many divisions the cell has
already undergone and how many remain before it becomes senescent.
This apparent
counting mechanism, almost like an abacus keeping track of the cell's
age, has led to speculation that telomeres do serve as molecular
meters of cell division. But they may play a more active role, and
telomere researchers are exploring the possibility that these chromosome
ends regulate cellular life span in some way.
The
repeated DNA bases in telomeres form tight bonds that help
stabilize chromosomes. About 50 bases are lost from each telomere
every time a normal cell divides.
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Telomere research
is another territory where cancer and aging research merge. In immortal
cancer cells, telomeres act abnormally -- they stop shrinking with
each cell division. In the search for clues to this phenomenon, researchers
have zeroed in on an enzyme called telomerase. Normally absent in
adult cells, telomerase seems to swing into action in advanced cancers,
enabling the telomeres to replace lost sequences and divide indefinitely.
This finding has led to speculation that if a drug could be developed
to block telomerase activity, it might aid in cancer treatment.
Whether cell
senescence is explained by abnormal gene products, telomere shortening,
or other factors, the question of what senescence has to do with
the aging of organisms remains and continues to be the focus of
intense study.
In the meantime,
gerontologists are also studying proteins in the body that may play
a role in aging and longevity. Genes hold the codes to these proteins,
but what substances turn the genes on and off? And once activated,
how do their products interact with the products of other genes?
What is their effect on cells and tissues? The biochemistry of aging
holds some of the answers.
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The Genetic
Connection: Selected Readings
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Goldstein,
S., "Replicative Senescence: The Human Fibroblast Comes of Age," Science
240:1129-1133, 1990.
Harley, C.B.,
Futcher, A.B., Greider, C.W., "Telomeres Shorten During Aging of
Human Fibroblasts," Nature 345:458-460, 1990.
Hayflick,
L., and Moorhead, P.S., "The Serial Cultivation of Human Diploid
Cell Strains," Experimental Cell Research 25:585-621, 1961.
Jazwinski,
S.M., "Genes of Youth: Genetics of Aging in Baker's Yeast," ASM
News 59:172-178, 1993.
Johnson, T.E.,
"Aging Can Be Genetically Dissected into Component Processes Using
Long-Lived Lines of Caenorhabditis elegans," Proceedings of the
National Academy of Sciences" 84:3777-3781, 1987.
McCormick,
A.M., and Campisi, J., "Cellular Aging and Senescence," Current
Opinion in Cell Biology 3:230-234, 1991.
Pereira-Smith,
O.M., and Smith, J.R., "Genetic Analysis of Indefinite Division
in Human Cells: Identification of Four Complementation Groups,"
Proceedings of the National Academy of Sciences 85:6042-6046,
1988.
Rose, M.R.,
"Laboratory Evolution of Postponed Senescence in Drosophila melanogaster,"
Evolution 38:1004-1010, 1984.
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