The
Genetic Connection
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IN
SEARCH OF
THE SECRETS OF AGING
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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.
Longevity
Genes
By demonstrating
that genes are linked to life span, the long-lived fruit flies
have set the stage for more questions.
A
few have been identified; more are on the horizon.
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What specific genes
are involved? What activates them? How do they influence aging
and longevity? In numerous laboratories, the search for answers
is on.
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, page 10). 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.
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.
Cell
Senescence
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.
Proliferative
Genes
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
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.
The
Genetic Connection: Selected Readings
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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