Gene therapy, in which nucleic acid polymers are
delivered as a drug and are either expressed as proteins, interfere with the
expression of proteins, or correct genetic mutations, has been proposed as a future
strategy to prevent aging.
Overall, for the last 20 years, there has been a growing
effort among researchers to understand the genetic basis of aging, or, to be
more precise, senescence, which is the deleterious side of increasing age.
Scientists have made substantial progress using experimental animals. This has
led to an unexpected finding—that life span and the aging process can be
genetically manipulated. Research has also yielded evidence for genetic
influence on aging in humans, raising the question of whether genetic
interventions in our species will alter future life spans.
A large array of genetic modifications have been found to
increase lifespan in model organisms such as yeast, nematode worms, fruit
flies, and mice. As of 2013, the longest extension of life caused by a single
gene manipulation was roughly 150% in mice and 10-fold in nematode worms.
Evidence from
Experimental Animals
Four model systems, all of which have been employed for
decades in genetics research, are widely used for basic research on the
genetics of aging: the nematode (Caenorhabditis elegans), the fruit fly
(Drosophila melanogaster), the baker’s yeast (Saccharomyces cerevisia), and the
house mouse (Mus musculus). The genomes of these species are completely
sequenced, and a versatile array of tools is available for manipulating their
genes. In addition, because the invertebrate species can be studied in large
numbers, accurate estimation of survival and mortality rates in laboratory
populations is possible.
The body of aging research on these animals is growing,
and the list of single-gene mutations and other genetic modifications that are
known to increase life span in experimental animals is long.
The following are highlights from this work:
* The first longevity-enhancing gene to be identified is
the C. elegans gene age-1. It encodes phosphatidylinositol 3-kinase (PI3K),
which plays a role in regulating insulin-like growth factor (IGF), stress
resistance, and metabolism. Also in C. elegans, a large number of
life-extending mutations affect mitochondrial function. Mitochondria are the
primary source of intracellular free radicals, which are thought to be a major
contributor to cellular senescence.
* In D. melanogaster, the average adult life span can be
significantly increased by artificial selection. Following 20 generations of
selective breeding for advanced age at reproduction, selected populations live
about twice as long as unselected controls in the same laboratory environment.
These long-lived flies have normal resting metabolic rates and normal levels of
lifetime fecundity.
* Drosophila that have been genetically engineered to
carry extra copies of superoxide dismutase (SOD), an enzyme that detoxifies
superoxide radicals that have the potential to damage cells, often exhibit
enhanced antioxidant levels and longer life spans than non-modified animals.
* Drosophila that have been genetically engineered to
carry extra copies of heat shock protein 70 produce excess gene product and
experience reduced mortality for several weeks following a mild 10-minute heat
stress. Heat shock genes encode molecular chaperones that protect cells from environmental
damage and are rapidly expressed in response to environmental insults.
* Methuseluh (mth), I’m not dead yet (Indy), and Target
of rapamycin (Tor) are single-gene mutations that extend adult life spans in
Drosophila by 20% to 50%. The mechanisms of action of mth and Indy are not
known. Tor encodes a protein that plays a role in sensing amino acid
availability.
* The S. cerevisiae gene Sir2 encodes an NAD-dependent
deactylase that plays a role in gene silencing. The presence of extra copies of
Sir2 in the genome extends life span in both yeasts and nematodes.
* In mice, the Klotho gene encodes the enzyme
beta-glucuronidase that declines in concentration with age. Mice deficient in
this protein exhibit accelerated arteriosclerosis, impaired angiogenesis, and
other cardiovascular problems. Overexpression of Klotho increases life span by
about 20% on average.
* Snell dwarf (dw) and little (lit) mutations in mice
extend life span and reduce body size. Both mutations cause diminished
signaling through growth hormone and insulin-like signaling (IGF-1) pathways.
What the Evidence
Shows
The study of life-extending genes and genetic
manipulation is far enough along to allow us to make several generalizations.
First, it is clear that genetic modification of life span
in experimental animals is a multifactorial process. That is, diverse classes
of genes and physiological processes can be targeted to retard aging, with
insulin signaling and stress-resistance genes predominating. It is also clear,
that there are no genes that have as their primary function the regulation of
aging per se. Rather, life extension occurs as a pleiotropic effect of genes
that have other primary functions. This interpretation is entirely consistent
with the evolutionary theory of aging, which postulates that senescence arises
because of the accumulation of mutations that have deleterious effects
expressed late in life. Although detrimental to individuals, those effects are
invisible to natural selection because they occur in advanced age after
reproduction has ceased and have no influence on the makeup of the gene pool in
the next generation. These age-specific deleterious mutations can thus
accumulate in the gene pool, unimpeded by selection.
It should be noted that although these genetic effects
are real and replicable, environment still plays a significant role. When
genetically identical animals are reared under environmental conditions that
are as uniform and carefully controlled as possible, there remains substantial
non-genetic variation in life span. Evidently, there is random variation during
development and maturation that influences life span and is beyond the control
of experimentalists, much like the small differences between identical human
twins. For instance, it is not unusual to see a 2- or 3-fold variation in the
life spans of individual Drosophila even when they are genetically identical
and reared in the same bottle. The presence of substantial non-genetic
variation does not invalidate the claim that genes are important; but it does
complicate the process of gene discovery and intervention.
Finally, one of the more exciting developments is the
observation that some genetic mechanisms of life span modification show
evolutionary conservation. Species as diverse as yeast, nematodes, fruit flies,
and mice share some common pathways that modulate aging. Shortly after the
age-1 gene of C. elegans was cloned and sequenced, its function in regulating
IGF became clear. This observation led quickly to tests of mutations in
Drosophila and mice that affect IGF and its homologs, and those mutations were also
found to extend life span. A decade ago, it would have seemed outlandish to
suggest that similar pathways modulate aging in diverse species; but now the
homologies are an important part of ongoing research.
Choose Your
Parents Carefully
As one would expect from studies in experimental animals,
genes also modulate life span and aging in humans. Direct evidence comes from
research on human twins and also investigation of genes that influence
susceptibility to age-related diseases.
The life spans of human twins have been studied
extensively during the last century. Some of the early studies used only
identical twins and do not provide reliable estimates of genetic influence
because estimates of genetic and environmental effects are confounded. More reliable
information comes from research that includes both identical and fraternal
twins. The generalization that has emerged from those studies is that the
heritability of life span in human populations is moderate in magnitude, on the
order of 25%. Heritability estimates are, unfortunately, widely misunderstood.
Heritability is a number that varies from 0 to 1; it expresses the proportion
of total variance in a population that is explained by genetic differences. A
heritability of 1 indicates that all of the phenotypic differences between
individuals in a population are explained by their genetic differences; a
heritability of 0 indicates that none of the phenotypic differences are
explained by genetic differences. This moderate level of heritability in life
span probably explains the well-documented observation that exceptional life
span tends to cluster in families—relatives of centenarians generally live
longer than other individuals in the same population.
An important recent development in life span studies of
twins is the understanding that the effects of genetic differences between
individuals and, therefore, the heritability, are greater at older ages. That
is, having parents who die in middle age is not particularly informative about
life span expectations, but having parents with very long life spans is
predictive. This is consistent with the evolutionary theory of senescence,
which postulates that the accumulation of mutations alters mortality
specifically in old age.
Perhaps the most dramatic examples of genetic effects on
aging in humans are the progeroid (rapid aging) syndromes. Although syndromes
such as Werner’s and Hutchinson-Guilford are not exact models of accelerated
normal aging, they manifest some features of ordinary senescence and might
provide information that could be useful in retarding normal aging. Werner’s is
now known to be a result of genomic instability, related to mutations in RecQ
helicase, an enzyme that plays a role in DNA-unwinding prior to replication. It
is likely that Hutchinson-Guilford is also a result of the disruption of DNA
metabolism.
Also relevant to aging are genes that modulate
susceptibility to diseases of old age. The most dramatic case is the
association between apolipoprotein E4 and Alzheimer’s disease. Individuals who
carry 2 copies of the susceptibility allele have a very high probability of
developing Alzheimer’s in old age compared with carriers of alternative
alleles. Consequently, population samples of old individuals exhibit high
frequencies of the alternative, protective alleles because carriers of the
susceptible allele have largely died out.
It is thus apparent that aging and life span in humans,
like that of experimental animals, is subject to genetic modification by a
variety of factors, including single-gene mutations.
Prospects for Life
Extension by Genetic Engineering
Most of the evidence regarding genetic modification of
aging and life span has been collected in the last 15 to 20 years. The results
have produced a paradigm shift in the research community. The old view that
aging and life span is too complicated to study has been replaced by a new and
more optimistic view that the underlying processes can be dissected, analyzed,
and modulated using genetic techniques. During the same timeframe, a major
shift has also occurred in the fields of demography and its hybrid offspring,
biodemography, which uses experimental systems to address questions that have
traditionally been the province of human population studies.
Recent demographic work in both humans and experimental
systems argues against the old ideas that life span is predetermined, that
historical gains in survival occur only at younger ages, and that maximum life
span is immutable. Instead, there is now recognition that mortality rates have
been declining at even the oldest ages. For instance, in industrialized
countries, mortality among 80-year-old women is now half the rate experienced by
that age group in the 1950s. Maximum life span in industrialized countries has
been steadily increasing for a century. Together, the new genetic and
biodemographic information suggests that aging and life span are not fixed,
preordained phenomena. Instead, the underlying processes of senescence can be
slowed, and life span, including maximum life span and healthy life span, can
be extended.
Given that rates of aging can be manipulated, the
question naturally arises about applying genetic techniques to slow senescence
and extend life span in humans. The conventional demographic view is that
healthy life span will continue to increase at a moderate rate in
industrialized countries, adding approximately 1 year to life expectancy per
decade. A more extreme view is that of Cambridge University researcher Aubrey
de Grey, who has argued that the cellular and biochemical causes of senescence
are sufficiently well-understood to justify research on curing the ills of old
age through genetic engineering. It is time, de Grey argues, to embark on a
major applied research effort that will eliminate senescence, first in mice and
then in humans.
In de Grey’s view, given appropriate biological
engineering, human life spans could reach 500 years to 1,000 years. To spur
this research effort, de Grey helps administer the Methuselah Prize (www.mprize.org),
which offers millions of dollars committed by private donors to researchers who
succeed in significantly prolonging the lives of laboratory mice. In the
scientific community, de Grey’s ideas are highly controversial. However, they
hold considerable public appeal. His theories have been explored in popular
magazines and on CBS’s news program 60 Minutes in addition to mainstream
scientific journals. Though his ideas are extreme, de Grey is no huckster; he
has legitimate scientific credentials and is not profiting financially from the
promotion of his views.
Conclusion
Predictions about future life extension need to be
understood in the context of current genetic and biodemographic knowledge. Here
are the significant achievements we may acknowledge in the area of scientific
research:
* Restoring youthful gene expression may help turn back
the clock on aging and potentially extend healthy life span.
* In animal models, scientists have dramatically extended
life span by modulating the expression of a few genes.
* Environmental influences such as diet and exercise may
strongly influence gene expression and longevity.
* Mimicking the effects of genes associated with extreme
longevity may provide another avenue to lengthening life span.
* Nutrigenomics is the field of nutritional interventions
developed on a genetic basis.
* The field of anti-aging medicine is poised for
tremendous growth and advancement in coming years, similar to what the field of
computer science has seen in the past 60 years.
Although aging can be genetically modified in
experimental animals and in humans, current knowledge suggests that the aging
process is sufficiently complex and that progress in life extension is likely
to be incremental rather than revolutionary.
The reasons:
* The magnitude of life extension that de Grey envisions,
about 5- to 10-fold, is far greater than the effect of any known mutant or
combination of mutants in any experimental system.
* Тhe known mutations in model systems often have
deleterious side effects in addition to their life-extending properties such as
reduced fertility early in life or reduced ability to compete for resources.
* Тhe
efficacy of a particular genetic modification may depend on each individual’s
genetic background, making it unlikely that a universal treatment regimen could
be developed.
For the present, radical modification of the human life
span seems unlikely. But there is consolation: Many of us who live in
industrialized countries have been fortunate to enjoy the fruits of at least
several centuries of steady progress that has resulted in longer and healthier
lives—progress that seems likely to continue.
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