Clinical and Health Affairs
Genes, Aging, and Prospects for Extended Life Span
By James W. Curtsinger, Ph.D.
Abstract
Our current understanding of the genetics of aging stems largely from 2 decades of research involving animal models. The research is yielding evidence that aging is a complicated process involving multiple genes and their interactions. It is also showing that aging and life span can be manipulated. This article highlights findings from these studies and discusses their implications. It also highlights other research on humans and aging. The author makes the point that genetic research will likely lead to longer human life spans but that change will be incremental.
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. This article reviews some of the basic findings of this work and suggests that extensions in the human life span will continue to be incremental rather than revolutionary.
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.1 The following are highlights from this work:
- The first longevity-enhancing gene to be identified is the C. elegans gene age-1.2 It encodes phosphatidylinositol 3-kinase (PI3K), which plays a role in regulating insulin-like growth factor (IGF), stress resistance, and metabolism.3
- Also in C. elegans, a large number of life-extending mutations affect mitochondrial function.4 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.5 These long-lived flies have normal resting metabolic rates and normal levels of lifetime fecundity.6
- 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 nonmodified animals.7 Although it was originally thought that this would be the case in other organisms, it is now known that only those with genotypes for a relatively short life span and low antioxidant levels benefit from the transgene.8
- 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.9 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%.1,10 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.11 There is evidence that, because of its NAD dependence, the function of Sir2 is linked to metabolism and may play a role in mediating life extension through dietary restriction.12
- 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.13,14
- 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.15
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.5,10 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 nongenetic 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 nongenetic 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.10
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%.16 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.17
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.18 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.19 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.20 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.21 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.22
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.23
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.24 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.24 Maximum life span in industrialized countries has been steadily increasing for a century.25 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.1,10
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.25 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.26,27 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. But 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. 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, on the order of 5- to 10-fold, is far greater than the effect of any known mutant or combination of mutants in any experimental system. Further, the 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.28 Also, the 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.8
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. MM
James Curtsinger is a professor in the department of ecology, evolution, and behavior at the University of Minnesota.
The author thanks Huber Warner, Ph.D., associate dean for research in the College of Biological Sciences at the University of Minnesota, for his helpful comments.
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