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Milestone or Genomania? The Relevance of the Human Genome Project to Biological Aging and the Age-Related Diseases

^a Division of Geriatric Medicine, Department of Medicine, St. Louis University School of Medicine, and the Aging and Development Program, Department of Psychology, Washington University, St. Louis, Missouri

Herman T. Blumenthal, 6203 Washington Ave., St. Louis, MO 63130.

Decision Editor: John E. Morley, MB, BCh

ON June 26, 2000, with great public fanfare, came the announcement of the near completion of a "working draft" of the human genome project. The commentaries that followed reflect a diversity of views as to its future impact on the human lifespan and on the conquest of conditions such as heart disease, stroke, cancer, diabetes, and dementia—diseases categorized as age related ⁽¹⁾. The comments were from sources such as The New England Journal of Medicine, Science, Nature, The Lancet, Scientific American, and New York Times science writers. The following is a selected spectrum of opinions:

From Dr. Francis Collins of the National Institutes of Health, Director of the Human Genome Project:

(Completion of the Human Genome Project) would include a new understanding of genetic contributions to human disease and the development of rational strategies to minimizing or preventing disease phenotypes altogether.

From Dr. Eric S. Lander, Director of the Whitehead Center for Genome Research at the Massachusetts Institute of Technology:

Some of my close colleagues are already proposing ways to "re-engineer" what they view as an imperfect human genome—to prevent cancer, slow aging, or enhance memory—by modifying the human germline.

From science writer Nicholas Wade of the New York Times:

It will take about a decade to complete the identification of the location of the definitive genes on the genome tape.

From John Bell of Oxford University, UK:

... within the next decade genetic testing will be used widely for predictive testing in healthy people and for diagnosis and management of patients.

From James Schrieve, author of a forthcoming book on the race for the human genome:

... it is not wildly optimistic to say that this translates into hundreds of thousands of lives saved or prolonged 10-15 years from now ... to slowly piece together, by 2005, a highly accurate rendition of the 3 billion letter genome that would stand the test of time.

From Dr. David Baltimore, Nobel laureate—molecular biologist:

We've got another century of work ahead of us to figure out how all these things fit together.

From Gail Collins, op-ed columnist of the New York Times, in response to some of the hyperbole:

(Some of the statements) seem to suggest our biotech guys are six months away from curing death ... to slow down the aging process so the next generation has the opportunity to live to 150.

The definitive publication of the human genome ⁽²⁾⁽³⁾ appeared 18 months later on February 16, 2001 (fittingly on Darwin's birthday). However, this time news media commentary was somewhat more subdued. Even so, in a New York Times article of the same date dealing primarily with the earlier era of eugenics aimed at perfecting the human race, Francis S. Collins is quoted as follows:

... that some people will begin to argue, as Stephen Hawkins already is, that we ought to change our own evolution and should not be satisfied with our current biological status and should as a species try to improve ourselves.

The information deriving from the two definitive reports, one from the National Human Research Institute ⁽²⁾ and the other from the Celera Corporation ⁽³⁾, provides the following breakdowns:

1. Protein coding genes—1% Noncoding DNA 24% Structural DNA 20% Repeated sequences 10% Transposable elements 45%
   
2. The number of definitive genes have been reduced from the previous estimate of 80,000 to 100,000 to 30,000 to 40,000. 41.7% of the genes have unknown functions. Of the genes with identified functions only 13.5% control activities within the nucleus of cells. 12.3% of the genes control functions inside or between cells. 10.2% of the genes produce enzymes that catalyze biochemical reactions. 5.1% are characterized as miscellaneous. 5.0% provide structures within cells. 4.8% enable molecules to move in and out of cells. 3.3% produce adhesive molecules that provide interactions between cells. 2.9% are tumor suppressor genes. 0.9% control immune functions.
   

Accompanying the reports in Nature and Science are numerous commentary articles dealing with such topics as DNA repair genes, proteomics, and behavioral genomics, as well as ethical, philosophical, and religious issues. Unlike the earlier comments, retarding aging and extending the human lifespan are hardly mentioned. The February 17, 2001 issue of The Lancet also contained a number of commentaries, of which the following contrarian unsigned editorial is particularly noteworthy:

The major risk factors for human illness are not likely to be affected by the range of applications that knowledge of the human genome will bring forward. Malnutrition, poor water and sanitation systems, unsafe sex, tobacco and alcohol make up the top five risk factors for human disability. Beyond these priorities, physical inactivity, occupation, drug misuse, and air pollution are additional important contributors to disease. Only hypertension, a substantial cause of stroke and heart disease in developed and now developing countries, might succumb to the power of genetic understanding. But even for hypertension there is no single gene-disease correlate.

The primary objective of this essay is to evaluate the extent to which the above spectrum of comments agrees with what is known about the biology of aging and the diseases of senescence. A paradigm is offered that covers the influence of genetic and nongenetic factors in disease causation over the human lifespan.

	A Time-Line on the Road to the Genome

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Watson ⁽⁴⁾ has provided a roadmap of the journey to the genome. As he has noted, the key conceptual breakthrough to an understanding of heredity came in the mid-1860s from the remarkable experiments on peas by the Austrian monk Gregor Mendel. Mendel crossed inbred strains of peas and demonstrated that the origin of variability lay in what he called "factors." Then, in 1909, Wilhelm Johannsen coined the word "gene" to replace "factors," and gene is now universally accepted as the unit of inheritance.

In 1910 Morgan showed that the genes were carried on the chromosomes, but it was not until 1944 that Avery and coworkers demonstrated that the genes were made up of DNA. The double-helical structure of DNA was elucidated by Watson and Crick in 1953, and the number of chromosomes in the human genome became known in 1956. The 1960s saw the demonstration of the roles of mRNA and tRNA in the assembly of the amino acids, in proper sequence, into proteins. This was followed by the discovery, in 1970, of restrictive enzymes that cut the DNA tape at specific locations. In 1973 Boyer and Cohen introduced recombinant DNA technology in which genes are inserted into cells to produce desired products. Then in 1977 came the explication of a technique to read the chemical bases A, G, C, and T of the DNA by Sanger in Cambridge, UK and by Gilbert and Maxim at Harvard, followed by the demonstration of the polymerase chain reaction (PCR) by which numerous copies of DNA strands can be generated. In 1999 came the identification of most of the genes on chromosomes 21 and 22, the two smallest ⁽⁵⁾.

Certain of these discoveries made possible the extraction of a piece of the genomic tape and the identification of single nucleotide polymorphisms (SNPs), some of which represent mutations associated with diseases such as breast cancer and colon cancer, and the recombinant DNA technology has already made possible the production of some therapeutic products. In sum, it took about a century and a half of these remarkable achievements leading up to the near completion of the human genome. By way of comparison, it took almost a century to complete the genomes of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster ⁽⁶⁾.

	The Road Ahead

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The above noted breakdown of the content of the genomic tape is indicative of the long road ahead before even a significantly partial understanding of the genome is attained. It turns out that humans have only about twice the number of genes of the nematode and only about three times that of the fruit fly (Table 1 ). The similarities with lower mammalian species will become even more manifest when the genomes of the mouse and the chimpanzee become available. Moreover, the 38,000 to 40,000 human genes have to be reconciled with at least 85,000 mRNA species.

At first sight the task appears straightforward; locate the genes and translate the coding regions to establish their protein products; perform similarity searches to establish relationships with previously characterized sequences and assign functions by evolutionary inference ... (p. 472)

The number of DNA sequence variants is estimated to occur in one of every 300 to 500 base pairs of the human genome ⁽⁹⁾, and they are linked with a large diversity of phenotypes ranging from physical and mental traits, susceptibility to disease, responses to treatments, bleeding and clotting disorders, to conditions as diverse as cancer, heart disease, dementia, and diabetes. However, not all bits of DNA specify proteins; some regulate gene expression, and the products of some genes perform several different functions.

Powledge ⁽¹⁰⁾ proposes the term "annotation" to describe the next step in the discovery process:

... annotation comprises everything that can be known about a gene; where it works, what it does and how it interacts with fellow genes. Right now, scientists often use the term simply to signify the first step; gene finding. That means discovering which parts of a stretch of DNA belong to a gene and distinguishing them from the other 96 percent or so that have no known function, often called junk DNA. (p. 17)

Beyond annotation lies the identification of the protein products of each gene and what those products do—a course called proteomics. The latter poses an even more difficult problem than genomics. Although there may be only about 40,000 human genes, they give rise to about 10 to 20 million different proteins. The sequence of DNA units that specifies a protein is broken into fragments and distributed about much longer segments of junk DNA. When a cell uses a human gene to make a protein, it first assembles mRNA copies of all the protein-specifying bits of the gene, and then tRNA acts to assemble the amino acids in proper sequence. Stix ⁽¹¹⁾ comments on what follows to complete the structure of the protein:

The readouts from the gene-sequencing machine do not tell you much about the ultimate structure and function of the cellular protein made by the gene. After a protein comes off the gene-to-amino-acid assembly line, it is altered as it assumes its place as a cog in the cellular machinery. Carbohydrates, phosphates, sulfates and other residues are pulled into it. (p. 35)

It has been proposed ⁽¹²⁾ that because these many factors intervene between the activation of a gene and the ultimate protein expression, it may be more effective and efficient to proceed directly to proteomics. Particularly relevant here is the elucidation of the post-translational modification of proteins and their folded properties involved in biological aging and age-related diseases as discussed below.

In sum, the long road ahead includes not only the gene sequences and their functions, but also epigenetic mechanisms of gene regulation, gene–gene interaction, gene environmental interactions, the processes subsumed under the designation proteomics including post-translational modification and protein folding, as well as protein–protein interactions.

In the meantime it should be noted that through the technique of identifying single nucleotide polymorphisms and other procedures, the identification of mutant genes associated with age-related diseases is progressing. More than 1.4 million SNPs in the human genome have already been identified according to the International Human Genome Sequencing Consortium. More than 30 such gene loci have been identified that are applicable to cardiovascular disease. The products of these genes involve lipid metabolism, fibrinolysis, coagulation, blood pressure, methionine/homocystine metabolism, extracellular matrix, and inflammation ⁽¹³⁾. A number of mutant genes have also been linked with breast and colon cancers.

	Some Ancient History

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The above quotation from the February 17, 2001 issue of The Lancet makes a strong case for the importance of risk factors in the causation of the age-related diseases. Other statements that also emphasize the importance of risk factors leave the impression that when disease causation cannot be attributed to risk factors it can be attributed to heredity. The diseases deriving from risk factors are often called diseases of modern civilization. The role of aging in disease causation, particularly intrinsically generated sporadic mutations or randomly acquired genetic events, is almost always ignored.

However, paleopathological studies ^(14)(15) provide a different perspective on the concept of diseases of modern civilization. They reflect a time, from approximately 2300 BC to approximately 1500 AD when lifestyle practices and environmental exposures were different from the present. Among the materials examined were the bones and soft tissues of mummies and excavated human remains that have been subjected to imaging techniques to locate lesions; such tissues have been rehydrated and examined by light and electron microscopy. Tissues were also subjected to DNA analysis after extraction and were amplified by PCR.

ABO blood groups, HLA types, immunoglobulins, lipoproteins, pathogenic bacteria, and parasites have been identified. The DNA from rehydrated skin of a 4000-year-old mummy has been cloned, and collagen has been isolated from bones of individuals who lived 2000 years ago.

The following lesions have been identified and are particularly relevant to this essay:

Lung—emphysema and pneumonia.

Bones and joints—osteoporosis, osteoarthritis, Paget's disease, skeletal hyperostosis of type associated with diabetes, osteogenic sarcoma, and multiple myeloma.

Brain—cortical atrophy and lipofuscinosis suggestive of dementia.

Heart—coronary occlusion in Egyptian mummies and in a 5300-year-old ‘ice man’ discovered in the Tyrolean Alps in 1991 with his dental wear indicative of a largely vegetarian diet.

The conclusion reached in these studies is that whatever the causes of these diseases, they are ancient ones and are "not associated with modern life and modern diet." However, because life expectancy was much shorter in ancient times, most diseases may be attributed to late-acting inherited mutations, although some may be attributable to the senescence period of the lifespan deriving from intrinsically generated somatic mutations as discussed below.

Greaves ⁽¹⁶⁾ has provided additional examples of cancer in ancients, and while not denying that social (lifestyle) and environmental factors have a role in the causation of malignancies, he posits that cancer, diabetes, heart disease, and even biological aging are examples of phenomena embodied in the concept of evolutionary or Darwinian medicine. As he states (and in compliance with stochastic concepts of aging discussed below): "Chance operates at every level in the multidimensional causal pathway of cancer, as indeed it does in biological evolution in general—not least for us in the genetic lottery that operates in the moment of conception."

	Concepts of Biological Aging and The Age–Disease Conundrum

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From a historical perspective, there are two competing concepts of biological aging. The first is that aging is genetically programmed, segmented into a juvenile period, a period of sexual maturity, followed by adult and senescence periods. At the end of each period its genetic program is turned off, and the program for the succeeding period is turned on. However, the presence of a genetic program that specifies senescence has not been resolved, although it is now being addressed by those touting the genome project as promising the slowing of biological aging and extending the human lifespan. Whereas the Moorehead-Hayflick finite replicative limit of fibroblasts in culture is regarded by many as a model of genetically programmed cellular senescence, Hayflick ⁽¹⁷⁾ takes a different view. He regards this model as supporting a genetic determination of maximum lifespan rather than a representation of biological aging. The fact that the number of doubling generations between mammalian species is proportionate to their lifespan supports this view.

In Hayflick's view, "Ageing is a stochastic (random) process that occurs after reproductive maturation and results from the diminishing energy available to maintain molecular fidelity." This view is detailed below in the context of causes and defenses.

Those who regard the finite replicative model of cells in culture (commonly termed replicative senescence) as a representation of biological aging have focused on the telomeres at chromosomal ends that shorten with each replicative generation—a counting mechanism with senescence occurring only when the telomeres reach a critical short length. If the enzyme telomerase is introduced into the culture, the telomeres lengthen rather than shorten. Some have interpreted the latter phenomenon as a rejuvenating process, returning cells to a youthful state, whereas others regard the cells as becoming "immortal," comparable to cancer cells.

There are noteworthy exceptions to telomere shortening as a biological aging phenomenon that need to be taken into account. Telomerase is normally active in human germline, embryonic, and stem cells, in cells of the immune and hemopoietic systems, in skin, the intestinal lining, hair follicles, and in cancer cells. Moreover, there are studies ⁽¹⁸⁾ showing that in parenchymal cells, telomere shortening in vivo is completed by about age 40 even in centenarians and may be related to the gradual reduction in cell turnover with advancing age.

Blackburn ⁽¹⁹⁾ has reviewed studies showing that the telomere is a dynamic nucleoprotein complex that can switch stochastically between capped and uncapped states. When cultured fibroblasts of old people are uncapped, even though they lack active telomerase, cellular senescence takes place no faster than the cells of younger donors (i.e., in vitro senescence is not simply related to the age of the donor). Capping serves to protect the telomere from being seen as a broken end, thereby allowing time for the repair of a DNA break.

Moreover, the telomere-shortening phenomenon does not hold for all mammalian species ⁽²⁰⁾. Rodent cells do not use telomere shortening as a counting mechanism. Nevertheless, they stop dividing after 10 to 15 doublings, with the latter attributed to inappropriate culture conditions. Furthermore, the presence of telomerase activity does not explain why rodent cells in culture grow indefinitely.

In sum, if the Hayflick-Moorehead phenomenon is viewed from the perspective of comparing the number of doubling generations between mammalian species to the end-point of cessation of cell division, the result supports the conclusion that maximum lifespan is species specific, thereby implying a genetic determination of a species' maximum lifespan.

However, Hayflick ⁽¹⁷⁾ also separates biological aging from "age-associated diseases" on the basis of the following criteria:

Resolution of the age-associated diseases would add only 15 years to human life expectancy, after which aging would become the leading cause of death.

Aging occurs in every animal that reaches adulthood. Aging takes place in virtually all species and in all members of a species after reaching adulthood.

Aging occurs in all animals removed from the wild and protected by humans "even though the species has not experienced aging for thousands or even millions of years."

In sum, Hayflick holds that biological aging is a universal phenomenon, whereas no single disease can account for death at the end of the human lifespan. However, he attributes biological aging to the same stochastic phenomena that have been shown to generate disease as detailed below.

Biogerontologists are also actively pursuing the identification of gerontogenes, species-specific germline genes that influence a basic aging rate and maximum lifespan in species such as C. elegans and D. melanogaster, the ultimate objective being to identify homologous human genes that might be manipulated to extend the human lifespan. The strategy in these lower species is to increase the lifespan by delaying reproduction in keeping with the evolutionary concept of aging ⁽²¹⁾. But these species (with the exception of melanomas in Drosophila) are not encumbered by the disease processes that limit lifespan in rodents, primates, and humans. Moreover, C. elegans and adult D. melanogaster lack an epigenetic mechanism such as adding methyl groups to DNA in the regulation of the activity of genes present in mammals and plants ^(22)(23). The lack of this epigenetic mechanism is associated with age-related diseases including cancer. The lifespan in mammals is likely to be modulated by a large number of disease-associated somatic–genetic loci. Contrary to Hayflick's view, evolution has introduced differences between species as to how lifespan is terminated, in accord with the concept of Darwinian medicine ⁽¹⁶⁾.

The second concept, while recognizing that genetic programs may specify the juvenile period and that of sexual maturity, holds that the period of senescence is dominated by intrinsically generated stochastic (random) events accumulated over the lifespan, or as Martin ⁽²⁴⁾ opines, there is no aging program, nor are there aging genes.

In this concept, aging rates are viewed as determined by an interplay between the accumulation of damaged macromolecules in somatic tissues and the maintenance–repair functions that have evolved to restrict such damage. Late-onset diseases are considered to be due to a combination of basic processes of tissue aging and the sum of genetic and environmental risk factors.

Among the causes of biological aging listed by Holliday ⁽²⁵⁾ are spontaneous DNA and RNA coding errors, errors in transcription and translation, microsatellite instabilities, frame-shift mutations, failure of epigenetic switches in gene expression, and faulty post-translational modification of proteins as described above by Stix ⁽¹¹⁾, including inappropriate protein folding as happens in amyloidosis, a common phenomenon in biological aging and in Alzheimer's disease ⁽²⁶⁾, as well as the effects of oxygen free radicals and advanced glycosylation end (AGE) products that damage DNA, lipids, and proteins. It is of note that a frame-sift mutation has been linked with the amyloid plaques of Alzheimer's disease ⁽²⁷⁾ and that oxygen free radicals, particularly those emanating from the mitochondria, and AGE products are causally linked with several age-related diseases ^(28)(29)(30).

Among the defenses are apoptosis, suppressor genes, redundancy of genetic information, DNA and RNA editing mechanisms, DNA repair enzymes, free radical scavengers, mechanisms for the removal of defective proteins, and the removal of aberrant cells by the immune system.

It is particularly noteworthy that Holliday maintains that these causal phenomena, and the failure of defenses against them, apply to both biological aging and the intrinsic genesis of the diseases of the senescence period of the lifespan.

	The Search for Extended Longevity

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Whereas germline genes affect lifespan, several human phenomena suggest a role for a germline contribution to biological aging. Individual germ cells accumulate faults similar to those of somatic cells, as evidenced by the age-related decline in ovarian follicles and the aneuploid pregnancies of older mothers (such as those occurring in the Down syndrome) as well as the germline mutations of other examples of precocious aging (such as the Bloom, Cockayne, and Werner syndromes). The Werner germline mutation, the WS helicase ⁽³¹⁾, is particularly apropos because it is linked with the genetic instability associated with biological aging as well as several of the age-related diseases prevalent in mid- and late life in normal aging.

The potential of the human genome project to identify germline genes that regulate biological aging therefore seems to be limited. However, there may be opportunities for identifying germline genes that control defense mechanisms, particularly those that provide a defense against the effects of oxygen free radicals and AGE proteins.

Although the mitochondrion is recognized as a major source of free radicals, also termed reactive oxygen species (ROS), it is also an important causal source of biological aging manifestations and of age-related degenerative diseases ⁽²⁹⁾. The genome of the mitochondrion has been known for some time, but the manipulation of its genome appears to have been overlooked in the fascination with the nuclear genome.

Determinants of Extended Longevity
Two strategies have been proposed that are aimed at discovering determinants of extended human longevity. The first involves detection of the particular phenotypic and genotypic characteristics that are associated with the lifespan of centenarians. As regards phenotypic characteristics, studies ^(32)(33)(34) have revealed that when centenarians are compared with subjects of lesser longevity they show a lower level of oxidative stress, a lower resting metabolic rate, and, relatedly, a lower operational level of the hypothalamic-pituitary-thyroid axis. Centenarians also exhibit a delayed immunosenescence ⁽³⁵⁾. A review of studies ⁽³⁶⁾ supporting the counterbalancing roles of oxidative stress and its defenses in the determination of lifespan provides the following relevant information:

Human diploid fibroblasts in cultures grown in low oxygen tension exhibit a prolonged lifespan; conversely, when grown in high oxygen tension they have a reduced lifespan.

In animals the rate of production of ROS species together with the ability to respond to oxidative stress is intrinsically connected with aging and lifespan. For example, in the caloric restriction model, not only is there a reduction in ROS generation, but there is also a delay in the age-at-onset of reproductive capacity and postponement of the diseases of senescence.

As regards genotypic characteristics of centenarians, there appears to be a strong relation between genetics and longevity with genetic influences being greatest in the oldest-old ^(37)(38). However, in centenarians, a complex trait appears more likely than a monogenic one. There is an increased frequency of certain HLA-DR alleles and of a variant of PAI-1 in centenarians. A polymorphism in or near the BRCA1 gene associated with breast cancer is enriched in centenarians compared with control subjects. Rose ⁽²¹⁾ suggests that in humans the genes that code for APOE (proteins involved in cholesterol transport) and the angiotensin-converting enzyme involved in regulating blood pressure, variants of which have been found to be more common in centenarians than in somewhat younger adults, might participate in postponing aging.

The second strategy proposed by Martin ⁽³⁹⁾ for extending the human lifespan emphasizes studies of molecular misreading in cells of "elite" middle-aged subjects for specific phenotypes because he believes that the latter are far less likely to be polygenic. He defines the elite aging as those who exhibit rates of decline in specific physiological parameters that are slower than observed in 99% of the population at interest. He also writes that "lifespan is likely to be modulated by a large number of disease associated genetic loci." In part Martin bases his conclusion that the senescence phenotype includes disease processes on the fact that aged tissues exhibit a mix of atrophy, hyperplasia, benign neoplasia, and frequently the malignant phenotype.

Relatedly here as regards lifespan extension, it should be noted that the above-mentioned strategy employed to extend the lifespans of C. elegans and D. melanogaster is not applicable to mammals. The successful strategy in these lower species consists of altering a few alleles that results in a delay in the onset of reproductive capacity. But these species, as also noted above, lack epigenetic mechanisms that regulate the activity of genes in mammals, failure of which account for age-related diseases in mammals ⁽²⁵⁾.

	The Bi-Modal Paradigm

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This model, proposed by Childs and Scriver ⁽⁴⁰⁾, is graphically illustrated in Fig. 1. It incorporates disorders of congenital-hereditary origin and those attributed to risk factors, but it also regards biological aging as a direct cause of the degenerative diseases of the senescent period of the lifespan.

View larger version (15K): [in this window] [in a new window]   Figure 1. The Bi-Modal Paradigm.

The trough (Segment II) represents the period of maximal reproductive capacity during which biological defense mechanisms against aging and disease are at their maximum capacity and disease is at its lowest prevalence, in accord with the evolutionary principle of assuring the survival of the species by maximizing reproductive capacity.

Segment III is represented on approximately the lower half of the ascending curve. Here the causation of diseases such as cardio- and cerebrovascular disease, hypertension, non-insulin–dependent diabetes, early-onset Alzheimer's disease, Werner's syndrome, and malignancies are linked with late-acting mutant genes, with pleiotropic genes such as the "thrifty gene" ⁽⁴¹⁾, and with risk-factors such as obesity, dietary indiscretions, tobacco use, and environmental mutagens.

Segment IV is represented on approximately the upper half of the ascending curve. The same phenotypic diseases represented on Segment III are represented on this segment, but in higher prevalence. The degenerative diseases of Segment IV are posited to be derived from sporadic, randomly acquired somatic-cell mutations in conformity with biological aging phenomena. A second plot is included to illustrate that Segments III and IV are in compliance with the Gompertz principle. However, the mortality rate declines after about age 90, most likely because frail individuals drop out of the population at younger ages leaving behind the most robust cohort.

As Perls ⁽⁴²⁾ posits, with advancing age hereditary and environmental risk factors play a progressively diminishing role because those of advanced age represent an elite population that has escaped such influences. Also noteworthy is the fact that this model can account for the common comorbidities of aged persons and that the latter may have commonalities with respect to causality (e.g., the effects of free radicals and AGE products and the effects of biological aging that are applicable to the pathogenesis of vascular disease, cancer, diabetes, and dementia).

Furthermore, the prevention or cure of a phenotypic disease in the age groups represented on Segments I and III does not assure that the same phenotypic disease will not reappear in the senescence period of the lifespan.

In sum, a fundamental principle deriving from this model is that the same phenotypic disease can emerge at all periods of the lifespan, but evolving from different pathogenetic pathways—hence the designation "age-related" rather than aging-related.

Moreover, as already noted, with advancing age germline mutations and risk factors play a progressively diminishing role, whereas somatic-cell mutations become a major factor in the causality of diseases of the senescent period of the lifespan. Viewed from a segmented demographic perspective, if corrective measures were to be implemented for the genes that cause the diseases of the juvenile period, the individual with those diseases would become susceptible to the same or another age-related disease that would appear in the adult or senescence periods of the lifespan. Similarly, if prevention or cures could be found for the diseases of the adult period of the lifespan, then the same or another phenotypic disease could appear in the senescence period. If the bi-modal paradigm is a valid one, the conquest of the diseases of the juvenile and adult periods would thus serve to increase the burden of disease in the oldest-old. Like the caloric restriction model, delaying biological aging serves only to postpone the age-at-onset of these diseases.

	Genomics and the Age-Related Diseases

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As Lander noted in his commentary at the beginning of this essay, the primary objective of the human genome project is to locate the germline genes on the DNA tape and to identify the genetic variations associated with human diseases. However, Holtzman and Marteau ⁽⁴³⁾, in stressing the limitations of germline mutations in disease causation, have pointed out that the 1:1 gene–disease connection inherent in some of the commentaries may apply to mendelian disorders such as Huntington's disease and some inherited diseases of the juvenile period of the lifespan, but that "... most genotypes for common, complex diseases are incompletely penetrant, and correlations between the genotype and the phenotype are therefore weak." They note further that susceptibility-conferring genotypes for breast cancer, colon cancer, early-onset type 2 diabetes, and Alzheimer's disease account for less than 3% of all cases. Whereas they regard environmental factors as accounting for the overall prevalence of these diseases, they make no mention of the role of biological aging, nor do they account for the high prevalence of comorbidities in aged persons. Absent from the commentaries cited earlier is the role of unpredictable somatic-cell mutations that dominate disease causation in the senescent period—or an interplay of the two.

The Many Faces of the Diabetes Phenotype
The diabetes mellitus phenotype serves as a particularly unique example of the genetic complexities and associated comorbidities in the pathogenesis of an age-related disease. It occurs in all segments of the lifespan and there is an ill-defined borderline between the well-documented aging-related deterioration in glucose tolerance, insulin resistance associated with obesity and aging, and clinical diabetes. Like the latter, the former also contribute to comorbidities such as hypertension, heart and renal disease, as well as stroke, vascular dementia, and peripheral vascular disease.

As Meneilly and Tessier ⁽⁴⁴⁾ have pointed out, diabetes may be the most important epidemic of the 21st century. Its overall current prevalence probably stands at about 16 million. There is a progressive increase with age to a peak of about 20% at age 70 followed by a decline to about 7% in centenarians.

With regard to the bi-modal paradigm described above, type 1 insulin-dependent diabetes (IDDM) is an autoimmune disease with some predisposing genetic factors such as certain HLA alleles, leading to the lymphocytic destruction of the pancreatic islets. It occurs predominantly in the juvenile age group but also less commonly as an adult disease.

Although type 2 non-insulin-dependent diabetes (NIDDM) occurs in a form known as maturity-onset diabetes of the young and in a maternally transmitted mode in which it has been linked with a mitochondrial DNA mutation ⁽⁴⁵⁾, it is predominantly a disease of the adult and senescence periods of the lifespan. However, NIDDM can become an insulin-dependent disorder as amyloid destroys and replaces the islets of Langerhans.

Morley ⁽⁴⁶⁾ further subdivides NIDDM into types 1-1/2 and 2 in which the former occurs in the old thin or mildly obese subjects, and the latter in those of middle age who display greater obesity. As he also notes that whereas islet cell antibodies are a common feature of IDDM, 10% of NIDDM cases also display such antibodies. Iueda and colleagues ⁽⁴⁷⁾ sum up the present state of knowledge as to the genetics of type 2 diabetes as follows:

Type 2 diabetes is a complex trait with both genes and environmental factors contributing to susceptibility. Genetic factors play an important role in the development of type 2 diabetes as evidenced by familial clustering of the disease and by a higher concordance rate in monozygotic twins than in dizygotic twins. Except for an early-onset subtype with monogenic inheritance, maturity-onset diabetes of the young (MODY) and rare mutations of candidate genes, such as insulin, insulin receptor and glucokinase, the genes accounting for an appreciable proportion of late-onset type 2 diabetes are unknown because of the complex and polygenic nature of the disease. (p. 1168)

	Conclusions

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The prognosticators who commented on the potential of the completion of the human genome were not the only ones of recent years with forecasts of retarding aging and extending the human lifespan. Some gerontologists have also gotten into the act. In the concluding chapter of his book The Clock of Ages, one of many published over the past decade or so with similar prophecies, Medina ⁽⁴⁸⁾ quotes several gerontologists who forecast an effective slowing of aging in 25 to 30 years, including one who predicted the following:

Possibly in 40 years we will have in hand the major genes that determine longevity, and will be in a position to double, triple, even quadruple our maximum lifespan of 120 years ... (p. 313)

And then there is the article in Anti-Aging Medical News of Fall 2000 by a Dr. Ronald M. Klatz, President of the National Academy of Anti-Aging Medicine, titled "Making the quantum leap to human immortality in the year 2029" in which his predictions are based on research exploiting the aforementioned discovery of the telomere–telomerase connection. We appear to be repeating the history of the rejuvenation efforts of the turn of the past century, but on a more sophisticated biological level.

Whether it will ever be possible to separate biological aging from age-associated diseases and attain a state of the termination of the lifespan in the absence of disease, as Hayflick posits, is a matter of conjecture. As matters now stand lifespan, as Martin ⁽³⁹⁾ holds, is limited by a large number of disease associated genetic loci deriving largely from randomly acquired sporadic mutations. Identifying these loci on a population basis is beyond the capacity of the genome project because of their stochastic origin. What is needed is a strategy to reduce the burden of the diseases of senescence even if, as Hayflick ⁽¹⁷⁾ holds, it would lead only to a 15-year increase in average life expectancy. The only such strategy to emerge thus far, as indicated by the caloric restriction animal model and the evidence in centenarians, is a reduction in the generation of ROS and AGE proteins.

Several strategies involving germline genes that are within the capacity of the genome project come to mind. One is the identification of the genes that provide defenses against biological aging and the diseases of senescence, and an enhancement of their effects. Another, already in progress, is the identification and correction of the mutated germline genes of the diseases of the juvenile and adult periods, as well as the identification and neutralization of the activity of the pleiotropic genes in the adult period. A more promising strategy falls within the scope of proteomics. Not addressed in all of the forecasts are biological processes that are not amenable to genetic manipulation. The prion diseases, an example of which is Creutzfeld-Jakob disease, fall within this category. Also included here are diseases subsumed under the designation "annotation" errors in the post-translational modification of proteins and their improper folding. The objective of proteomics would be to identify the abnormal protein products that directly account for the pathogenesis of the diseases of senescence and to devise methods of counteracting their effects. Amyloid, a product of protein misfolding, is an underappreciated phenomenon particularly prevalent in the senescence period. It almost attains a prevalence in the very old in compliance with Hayflick's requirement of universality. Not only are the amyloid plaques of the brain in dementia and the amyloid deposits in the islets in diabetes common in aged persons, but as Gray and colleagues ⁽⁴⁹⁾ report, myocardial fibrillation due to amyloid deposits in the heart may be the leading cause of death in the industrialized world.

However, none of these strategies would completely eliminate the diseases of senescence. As the bimodal paradigm reveals, the same or another disease would later emerge. It has been projected ⁽⁵⁰⁾ that by 2050 our health care system will have to accommodate a population in which about 70 million Americans will be over age 65 and about 50 million over 85. Centenarians will number about 300,000 ⁽⁵¹⁾, and they "will still be dying of disease, not of old age."

Perhaps the prognosticators should heed the advice of Peter Medawar, whose research included determinants of aging and longevity. As recorded by Simmons ⁽⁵²⁾, when asked to predict future developments he responded:

I would be obliged to weary you with endless qualifications and reservations and disclaimers, or else try to disguise the thinness of the reasoning by taking refuge in apocalyptic prose.

A necessary discussion that does not fall within the scope of this essay is the societal effects of a population dominated by an overwhelming number of those of advanced age.

Received September 22, 2000

Accepted March 27, 2001

	References

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