Fighting Father Time: The acceleration of aging research during the millenium
Number: 00S04. Issue: Spring 2000
Author[s]:
Grace Liao and Jane Lo
Keywords:
Abstract:
Milestones of Aging: sterility, osteoporosis, menopause,
Alzheimer?s, arthritis, hair color loss, loss of vision, and the ever-defining
wrinkles. Studying and/or controlling the aging process has both challenged and
baffled scientists for over 2000 years.
Before this century, the issue of aging centered more on political and
religious issues than the scientific and medical issues; aging was accepted as
an immutable and irreversible life process, and little time was devoted to the
possibility of eliminating these milestones.
However, as
life expectancies continue to increase, society?s concern with slowing the
destructive processes of aging has grown, stimulating the devotion of further
research in the scientific community to aging. Ranging a broad spectrum from
the hard evidence of medical research to the idealism of science fiction, the
world of science strives to uncover ways to redefine the nature of aging.
A variety of aging-related phenomena and
diseases, including cancer, atherosclerosis and immune defiencies, are
accounted for in a theory of aging in which these and other diseases associated
with aging are thought to be incurred by oxidative damage. During oxidative phosphorylation, the
biochemical pathway that allows for the usage of oxygen in energy production,
the mitochondria produce reactive oxygen species know as free radicals. Asserting that the modification and damage
to cellular molecules by free radicals may lead to alteration of genetic
programming and disrupt cell function, this theory proposes that free radicals
are capable of causing harm regardless of DNA damage.
The
increase in levels of ?oxidative stress? throughout the human lifespan, and
also the evidence of the correlation between lifespan and the ratio of oxygen
consumption to body weight in a number of species, seem to support this theory.
Recent experimentation with Drosophila has extended the lifespan of these fruit
flies by manipulating the biochemical pathway that metabolizes superoxide and
hydrogen peroxide. In light of these
findings, a method of preventing many of the degenerative diseases connected
with aging should be available via antioxidants such as carotenoids,
tocopherols and ascorbate naturally present in fruits and vegetables. The free radical theory has been popular
since Dr. Denham Harmon?s first proposal in the middle of the 20th century and
is still undergoing rigorous research.
Opponents
of the free radical theory have argued that the results produced through
experimentation have yielded no definite results connecting free radicals with
cellular aging. Also, some scientists
would agree with the German researcher Georg Duve in claiming that the free
radical theory has relegated oxygen to the role of an enemy rather than a
life-sustaining element, a possibly detrimental view.
Duve
provides the example of the long lifespans of birds as phenomena unexplained by
the free radical theory. Birds with a
much higher oxygen consumption and metabolic rate, and thus, with a higher
oxidative level, have actually been found to live longer than non-flying
anyimals with the same body size.
Although Duve agrees that this may be the result of a highly effective defense
system in birds, he also believes these findings indicate that an entirely
different view of oxygen is possible, and further research is necessary. The argument counter to the free radical
theory states that the correlation of free radicals with disease should not
lead to a conclusion that free radicals cause disease; they could, rather, be a
sign of the disease, an immune system defense responding to the presence of
disease.
In response
to the question of cellular aging, recent research on telomeres may provide the
key to slowing down the aging process through work that directly affects
cellular activity. Programmed cell
death is a well-documented occurrence. Hayflick?s Limit, the existence of a
finite number of cell divisions of certain somatic cells is the first recorded
discovery on these grounds. Another
prevalent theory, apoptosis, where infection of cells by a virus appears to
activate a special suicide mechanism which causes the cell to degrade its own
polymers, leads to death of the cell as it attempts to burrow the infecting
virus.
Apoptosis
is an essential part of the immune process, preventing the formation of
antibodies to autologous proteins, and possibly eliminating cells dangerous to
multicellular organisms. Recent
hypotheses have suggested that aging is nothing but programmed death at the
supracellular level that follows a mechanism similar to apoptosis, refered to
as phenoptosis.
The focus
on telomeres began in 1971 with the work of A.M. Olovnikov. Olovnikov formulated the problem of terminal
underreplication of linear DNA molecules at this time, theorizing that the
cause of this phenomenon was the inability of DNA polymerases to replicate
several nucleotides at 3? ends of DNA template strands. The suggestion was offered that there was a
specific biological mechanism which prevented this event in cells except for
gametes, cancer cells and the cells of vegetatively reproducing organisms.
Studies
over the past few years have uncovered the enzyme telomerase that compensates
for DNA shortening in the above mentioned cell types by adding a repeated
sequence (in humans, the hexamer TTAGGG), forming the ends of nuclear DNA, the
telomeres. The telomerase loses its
function over time, and thus, the telomere begins to shorten, impairing the
functioning of the chromosome, particularly since the telomere not only
provides protection for genetic data, but also has a structural role in the
spatial arrangement of the chromosomes in the nucleus. The close correlation between the shortening
of the telomeric DNA regions and Hayflick?s limit indicates that activating the
telomerase gene in the cell will cause it to surpass this limit and continue
reproducing.
However,
reenacting the telomerase gene may not lead to positive effects in terms of the
aging discussion. "We don?t want
to stop cellular aging," asserted Judith Campisi, senior staff scientist
at the Lawrence Berkeley National Laboratories, whose research focuses on the
connections between aging and cancer.
"That would be a disaster." According, to Campisi, aging of cells is really a way of
postponing cancer by allowing damaged cells to die and preventing cells from
dividing. Conversely, the way cancer is
formed in older persons is through the changing functions of the cells that no
longer divide; as the function of the cell changes, the possibility of mutation
increases.
In addition
to these findings and in spite of the general acceptance of the shortening of
telomeres involvement in the aging process, there has been some evidence to the
contrary. Telomere shortening in yeast
has led to cell death, not the phenotype seen in mammalian cell senescence, and
although mice cells senesce faster than human cells in culture, mice telomeres
are actually up to ten times as long as human telomeres and do not shorten over
the lifetime.
A recent
breakthrough hints at the possibility of tremendous work being done with
telomeres in the future. In November of
1999, a team of Italian scientists reported the discovery of a gene that
allegedly exerts major control over the lifespan of mice. Although it remains uncertain what the
effects of the corresponding gene in humans may be, the prosepctive
implications of the discovery are mind-boggling. At the time of discovery, Dr. Steven N. Austed of the University
of Oregon told the New York Times, ?This is a fascinating start on what could
prove an incredibly exciting pathway for research.?
The gene
was discovered by Dr. Pier Giuseppe Pelicci of the European Institute of
Oncology in Milan, in conjunction with scientists from the Institute of
Pathology in Perugia, Italy and the Memorial Sloan-Kettering Cancer Center in
New York. As first reported to the
journal Nature, the discovered gene produces the protein that triggers the
self-destruct process of damaged cells as explained by Campisi. The most surprising factor is that as of
yet, no negative effects have been observed when blocking the manufacture of
the trigger protein. Further research
is needed to investigate issues surrounding the utility of this discovery in
extending or improving human life, but the absence of downfalls is astounding
in a life-extending technique that has seen results as successful as those
witnessed in the extensive research of dietary restriction.
In contrast
with most aging research, one of the few successful techniques involving
manipulation of the environment or the use of drugs and vitamins that has been
successful, is dietary restriction.
Dietary restriction has been seen to significantly extend the lifespan
of experimental animals, notably rodents.
In addition, dietary restriction also appears to slow down the rate of
increase in age-specific mortality and of age-associated disease
processes. It has also been shown to
delay the decline of some anti-oxidant defenses with age. The positive effects of dietary restriction
rely on reduced caloric intake rather than on specific dietary components.
Although
calorie restriction is perhaps the most widely studied method for retarding the
deleterious effect of aging, its biological mechanisms and applicability to
humans have, unfortunately, thus far eluded gerontologists and
geriatricians. Calorie restriction
regimens have been seen to maintain the vitality of organisms ranging from protozoa
to monkeys, but its effects on humans have yet to be seen. If calorie restriction does prove to be an
effective method of slowing aging in humans in addition to short-lived mammals,
this research will have great significance in a society such as ours, which is
prone to overeating and remaining inactive.
The work on
aging research extends beyond the possibility of extending the human
lifespan. As seen by numerous examples
in current times, it has also devoted considerable effort to improving the
final decades of life. Research into
the causes of the symptoms of old age has produced many positive results,
particularly in hormonal research.
After
menopause, estrogen levels in women plunge as much as 90 percent from their
lifetime high, producing many of the symptoms associated with old age, such as
brittle bones, thinning skin, diminished circulation and vaginal dryness. Current research is attempting to explore
the effectiveness of replacing estrogen with hormones such as progesterone in
order to eliminate these dreaded symptoms.
If estrogen is successfully replaced, such problems as osteoporosis and
cardiovascular disease (the leading killer of American women), and maybe even
age-related memory loss can be prevented.
However, estrogen replacement may also have negative effects. In a 1997 study of 40,000 post-menopausal
women who had taken estrogen for five years, the prevalence of breast cancer
was 40 percent higher than in nonusers.
Estrogen may not actually cause greast cancer, but it may accelerate the
growth of existing cancers.
Research on
treating impotence in aging men has already taken a revolutionary turn. Viagra (sildenafil) may not restore youthful
vitality, but it has shown moderate success in treating erectile dysfunction. Unlike past treatments, Viagra is fairly
easy to use. One pill is taken an hour
before sexual activity; no injections or insertions directly into the penis are
necessary as they were with past treatments.
Viagra became a top-selling drug within a few weeks of its approval by
the U.S. Food and Drug Administration in March of 1998.
Menopause,
what we consider to be one of the milestones of aging and an event experienced
by a considerable percentage of the population, has been reversed using
cryotechnology. This discovery, announced September 24, 1999 by the National
Post, has far-reaching consequences with female fertility being extended into
old age. The process of achieving this breakthrough was done through
cryogenically preserving an ovary that was surgically removed from a sterile,
menopausal woman. Margaret Lloyd-Hart, the patient, then had segments of the
reconstructed ovary transplanted into her pelvic wall where it was stimulated
with hormones and eventually produced an egg. This is one example of how
cryogenics, the science that deals with the production of very low temperatures
and their effect on the properties of matter, and related fields might apply to
the aging process either by slowing it down or reversing it entirely.
BioTime,
Inc. located in Berkeley, California, is currently on the cutting-edge of such
cryotechnology. Their main purpose has been to develop synthetic solutions,
such as Hextend, to be used to replace blood volume or for organ preservation
solutions during low temperature surgery. In addition, they are in the process
of developing solutions which would allow total replacement of fluids in the
body during operations.
Financial
assistance for such programs, however, has been slow in cumulating, slowing
down the progress of research in this field. BioTime, Inc., has felt the reverberations
of such cautious, hesitant funding. If it had not been for such technological
and medical advances, the surgery Ms. Hart underwent could not have been
possible.
Why is
cryogenics viewed with such mistrust by the scientific world, leading to
minimal funding? Hal Sternberg, Vice President of research at BioTime, Inc.,
believed it is because scientists are not aware of the importance of this
field. "Uninformed, they believe that this field is of secondary
importance. It?s a vicious cycle because we have no money to educate
either." It doesn?t help that many cults such as, transhumanism, have
adopted cryopreservation as part of their agendas, thus compromising the
respectability of it as a valid science.
Along with
the problem of funding, cryogenics itself is a newly developing field with its
own scientific hurdles. For example, Sternberg said, "The question is how
to freeze tissues and organs without accumulating damages in the process. It?s
easy to freeze a single cell. People are born from frozen, fertilized
eggs. With more complex tissues,
however, when the fluids in the body are lowered to the low temperatures needed
for low temperature surgery, the water freezes. Ice likes to take its own shape
and destroys the nature of tissue and its interactions. Skin can be frozen pretty well because it is
a noncomplex tissue, which we have successfully done, grafting frozen samples
onto the backs of host animals. We know
it can be done though. Frogs have been found in the far North which, during the
wintertime, freeze and then thaw out later. Nature is much more successful than
we are."
Cryotechnology
has further applications that have excited a growing number of people. Many
people look to the future of cryogenics as the pause button in the ongoing continuum
of life. They hope to stop the aging process through self-freezing until a
point in the future when technology has advanced far enough for them to be
unfrozen without complications or damages, and when aging has been successfully
reversed.
While this
may sound like science fiction, hamsters and larger animals exhibiting all
signs of "medical death," have been successfully revived. Nell
Gramlich, a research assistant at BioTime, Inc. who has conducted such
experiments, said, "We?ve gotten the heart to start beating and breathing
to begin, although long-term survival has been difficult to sustain. The
animals are thawed too quickly for their metabolic processes, resulting in
leaking vessels, ruptured cells. It does, however, make you question the clinical
definition of death."
Another
vision of technology looked on with both skepticism, because of its huge
technological demands, and hope, because of its societal implications, is
nanotechnology. The term "nanotechnology" or "molecular
nanotechnology" has been used to refer to any technology that works at a
submicron scale that controls the structure of matter. More specifically, it is
the construction of giga-ops computers smaller than a cubic micron that perform
a number of functions such as repairing cells or building complex molecules
from scratch. The central tenet is that almost any chemically stable structure
can be built. The placement of these miniscule intelligent computers in the
body would serve to repair damaged and senescent cells, tissues and organs.
The human
impulse to extend life has spurred a flurry of research activity, ranging from
conservative to creative. When asked whether he would advocate for an
indefinite lifespan, Stephen Kehrer, director of the surgical research lab at
BioTime, Inc. said, "In a flash. People might be more responsible for
their actions if they knew they had to live with the consequences of their
decisions later." Although Campisi did not believe life could be extended
indifinitely, she commented, "There?s no reason to believe evolution has
selected a magic cutoff. I?m optimistic that we can push back lifespan and more
importantly, health span." If this aging research succeeds in nothing but
the improvement of health, then society will still benefit a great deal.
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