CHAPTER FIVE Human Genetic Diseases That Mimic the Aging Process The search for genes that might be involved in the human aging process - human senescence - was given a major push forward with the publication, in 1978, of a landmark study by George Martin entitled Genetic Syndromes in Man with Potential Relevance to the Pathobiology of Aging. His analysis of the existing medical and scientific literature had suggested that as many as seven thousand human genes might be involved in the degenerative processes associated with aging, but he concluded that probably no more than seventy, and perhaps as few as seven, of these genes controlled processes in the body that have a major impact on senescence. He excluded from consideration genes encoding specific diseases that might cause death either early or late in life; although death is clearly the endpoint of senescence, Martin was more interested in the process of senescence, as defined by studies in both animals and humans . One of the major conclusions Martin was able to reach as a result of his analysis was that although aging-like symptoms can be found in a number of different genetic diseases, no single disease can be said to mimic completely all of the known parameters of the human aging process. There is no single “aging gene” that determines human lifespan and regulates human senescence. Nevertheless, Martin identified ten well-known genetic diseases in which there was an accelerated progression of a large number of distinct aging traits (Table 5-1). Because each of these diseases involves only certain aspects of the aging process, he called them segmental progerias; progeria is a Greek term meaning “early aging.” Seven of these disorders are known or presumed single-gene defects; three are chromosomal aneuploidies, meaning there are extra, missing or malformed chromosomes. In addition to helping focus the search for genes that might underlie the human aging process, Martin’s analysis also raised some interesting questions about the nature of the aging process itself. For instance, if many of the various symptoms accompanying each of the disorders listed in Table 5-1 reflect a normal part of the aging process, why are they referred to as diseases? Should aging be regarded as a disease? Martin himself, like many others who study senescence, referred repeatedly to the “pathobiology” of aging - it is even in the title of his paper. Another question raised by the focus on genes associated with senescence is how relevant such genetic diseases could be to normal human aging. The diseases in Table 5-1 presumably involve genes that are mutated; does normal human aging involve mutated genes? Are these (and perhaps other) genes organized into some sort of “program” that, in the totality of its execution, leads to human senescence and death? Before attempting to answer these questions, it will be useful to have a closer look at some of the diseases identified by Martin as mimicking the human aging process. In order to place the description of these diseases in some sort of perspective, we will begin with a very brief discussion of the nature of disease itself. Although enormous in both number and complexity, all human diseases derive from two fundamentally different sources. Either they are caused by external agents, or they arise through some inherent defect in the human organism itself. External agents include such things as deprivation of food or water; extremes of temperature or radiation; chemicals in the environment, whether natural or man-made, that disturb the body’s own internal chemistry; and infectious microorganisms. The latter group encompasses a wide range of bacteria, viruses, funguses and parasites that find the warm, well-regulated, food- rich mammalian body a perfect place to live and reproduce. Some of these “microbes” have learned to live in harmony with their hosts, causing no harm; a few even play a positive role, such as helping to digest food. But a great many others can cause considerable harm, in the form of what we call infectious disease. Prior to the early part of the twentieth century and the advent of effective public health and vaccination programs, infectious disease was a major source of morbidity and mortality in humans. But when all of the diseases caused by external agents are added up, a very large number of human maladies remain unaccounted for. The vast majority of these idiopathic diseases are now thought to be due to alterations in the genes that encode all of the proteins needed to construct and operate a living organism. Virtually unknown a hundred years ago, today we understand that genes are specific chemical sequences written in the language of DNA, and carried in every cell of the body. Human beings have on the order of a hundred thousand genes contained in 23 pairs of structures called chromosomes. The DNA sequences defining these genes are passed from generation to generation during reproduction, and account for the similarities between parent and offspring. However, over time these sequences can change. Changes may arise in DNA accidentally, through mutation, or purposely, as part of the reproductive process. The generation of genetic changes that can be acted on by natural selection is a vital part of the process of evolution, allowing organisms to adapt over time to changes in their environment. With evolutionary time, a given species will have tried and discarded many different forms (alleles) of its component genes in an attempt to secure its place within a given environmental niche. These genetic changes, whether occurring by accident or through purposeful reproductive means, are an ongoing process. If harmful genetic mutations occur in a gene housed in any of the cells of the body other than a sperm or an ovum i.e., in a somatic cell), the results could well be lethal, but only for the cell in which it occurs or any of its immediate descendants. Since most somatic cells in an adult organism divide rarely or not at all, the number of cells affected by somatic mutations is usually quite limited . Such mutations are rarely even detectable. But when mutations occur in germ cells, they are passed on to all of the offspring of the individual in whom the mutation occurred. And because those offspring derive entirely from the DNA inherited through the germ cells, every single cell in their bodies will have the mutated form of the gene in question. Including, it should be pointed out, their own germ cells: this is the origin of what we call inherited genetic diseases, human disorders that are passed forward from generation to generation to generation. There is one additional point in the life cycle of an individual when mutations may arise, and it is an important one. If a harmful mutational event occurs during fetal development, even if it occurs in only a single somatic cell, a significant proportion of the cells of the resulting individual may be affected. At the fetal stage, most of the cells of the growing body are dividing and, particularly early in development, each dividing cell may have a great many descendents. If the mutation is not developmentally lethal, as in the case of a gene that is not expressed until later in life, the embryo will not abort. But the earlier in embryological life such a mutation occurs, the more cells will be involved. This type of mutation can give rise to what are sometimes referred to as sporadic genetic diseases; diseases caused by defective genes that affect major portions of the body - including entire organs - but which are not inherited. There are an estimated four thousand inherited genetic diseases in the human species. Some of these, like cystic fibrosis, sickle-cell anemia or Tay-Sach’s disease, are caused by defects in a single gene. Other diseases, like diabetes, involve multiple defective genes. These genetic defects may be either dominant or recessive; this distinction is important, so let us take just a moment to define it clearly. Like virtually all other eukaryotes, humans are diploid; we have two copies of each gene stored in the DNA in each cell. If one of them becomes defective (is mutated in such a way that the protein it produces doesn’t function properly,) in most cases this is simply not noticed: the other copy of the same gene can make enough normal copies of the protein to keep the cell running just fine. It is only when both copies of the gene are mutated that a problem arises, because then there are no normal copies of the protein available to the cell. Such mutations are called recessive. On the other hand, occasionally an altered protein produced by a mutant gene will, either directly or indirectly, interfere with the function of the normal protein made by the other gene; only one gene copy is dysfunctional, but the cellular function encoded by that gene is shut down even though the other gene copy is perfectly normal. These kinds of mutations are called dominant (or sometimes “dominant- negative”.) To inherit a recessive genetic disease (cystic fibrosis, for example), it is necessary to inherit a “bad” gene copy from each parent. In a dominant genetic disease (like Huntington’s disease), the inheritance of a single bad gene copy from either parent is sufficient to cause the disease. There is one other parameter of inherited genetic diseases that should be defined: they may be either autosomal or sex-linked. Human genes are arrayed along twenty-three pairs of chromosomes. In twenty-two of these pairs, the chromosomes are identical. The twenty-third “pair” is not really a pair; these are the so-called “X” and “Y” chromosomes that determine an individual’s gender. Someone who inherits two X chromosomes is “X- X”, and female; someone who is “X-Y” is male. If a gene residing on the X chromosome undergoes a recessive mutation, a female “carrier” of this mutation does not have a problem, because she has two X chromosomes. However, a male carrying the same chromosome will experience the underlying disease, since he will not have a compensating additional X chromosome. Mutations of genes lying on the X or Y chromosomes may thus lead to sex-linked genetic diseases like hemophilia A or Duchenne muscular dystrophy; alterations in genes on any of the other twenty-two pairs of autosomal chromosomes may give rise to autosomal genetic diseases. Recessive genetic diseases are almost always autosomal. Whatever the origin of a defective gene, disease arises when the protein encoded by that gene, needed to carry out a critical function in the body, is not available. If the protein is crucial during fetal development, its loss may give rise to what is called a developmental lethal, in which case it does not cause a disease per se; the fetus simply aborts and the underlying cause is rarely perceived. If the fetus survives in the womb, it may be born and manifest symptoms of the disease essentially from birth, or disease symptoms may appear only later in life. As we saw in the previous chapter, everything we know about human senescence, and about the determination of lifespan in general, suggests that it is internally regulated, which means that ultimately it must reflect events at the level of genes and DNA. How are instructions for the aging process written into our genes? What might such a program look like? How would it operate, and how is it regulated through time? The segmental progerias presented in Table 5-1 are thought by many to represent various portions of an aging program in humans. Before we discuss the merits of this hypothesis, let’s continue with a closer examination of just what is involved in a few of these diseases. The Hutchinson-Gilford Progeria Syndrome The first formal description of what would come to be known as a progeric syndrome was presented at a meeting of the Royal Medical and Chirurgical Society in 1886 by the renowned English physician-surgeon Jonathon Hutchinson. Born in 1828 into a Quaker family in Yorkshire, Hutchinson received his formal medical training at the prestigious St. Bartholomew’s Hospital in London. He was subsequently appointed a Professor of Surgery at London Hospital, but his interests ranged over the entire field of medical inquiry. Although elected a Fellow (and later President) of the Royal College of Surgeons, his most important contributions were in the study of venereal disease, especially congenital syphilis. But he published over a thousand papers before his death in 1913 in areas as disparate as ophthalmology and dermatology, surgery and neurology. It is perhaps no wonder, then, that his far-roving eye would be the first to detect a case of Congenital Absence of Hair, with Atrophied Condition of the Skin and its Appendages. In his presentation to his medical colleagues in 1886, Hutchinson described “...the case of a boy three and a half years old, who presented a very withered ‘old-mannish’ appearance. His skin was remarkably thin, in some places not being thicker than brown paper. The genitals presented a marked contrast to the rest of the body, being in a state of a normally plump child. He had no nipples, their sites being occupied by little patches of scar.” This report lay largely unremarked upon in the medical literature until, in 1904, another English physician, Hastings Gilford, described a second case. This patient was also a male, although not seen by Gilford until he was fourteen years old. Gilford also examined Hutchinson’s patient, who was by then fifteen years of age. Hutchinson’s patient died at age seventeen; Gilford’s at age eighteen. Like Hutchinson, Gilford noted the wizened appearance, the aged condition of the skin, growth retardation, and general lack of hair and of body fat. But he also reported that at autopsy his patient had a normal (e.g. young-appearing) brain, liver and genitalia. It was Gilford who first suggested the term progeria for this condition. Gilford wrote a lengthy and scholarly paper on these two patients, and tried to put their cases into the context of disorders of accelerated senescence. He commented that no cases had been reported prior to Hutchinson’s 1886 paper, even in the popular literature on “medical curiosities;” nevertheless, Gilford felt the two patients were so similar that they could not represent random events, but must be suffering from the same disease. The descriptions provided by Hutchinson and Gilford in their initial reports could be used to diagnose this form of progeria today, and the disorder they described is formally referred to as the Hutchinson-Gilford progeria syndrome (HGPS.) The addition of some seventy or so well-described cases since their initial reports does allow a slightly more detailed picture to be drawn, however. First of all, it is clear that this is an exceedingly rare disease; the frequency is estimated at perhaps one in one million live births in the United States. It is now apparent that males and females are affected equally, and there is no discernible racial correlation. Most HG progerics appear relatively normal at birth. The only signs of a possible problem during the first few months of life are a faint cyanosis (slight blue coloring) of the mid-facial region, and a failure of the skull bones to fuse together properly after birth. In fact, the two patients seen by Gilford at ages fourteen and fifteen still had small but detectable openings at the front of the skulltop. Although the time of onset of more definitive symptoms varies from case to case (ranging from the day of birth to ten months or so of age), generally by the end of the first year of life there is noticeable growth retardation, and the appearance of physical features commonly associated with HGPS (Figure 5-1). HG progerics only rarely exceed four feet in height during their brief lives. All body hair, including the eyebrows and eyelashes, either fails to develop or is lost; any hair that remains on the head is white and usually described as “downy” or “fuzz-like.” There are also skeletal and structural abnormalities. These may be relatively minor, such as the receding chin, large cranium, beak-like nose and protruding eyes seen in almost all HG progerics. These features are caused by the slow growth of facial bones, including the teeth, and wasting of facial flesh; the comparatively normal size of the skull results in what have been described as small, bird- like faces. Voices are usually thin and high-pitched. Other physical problems are more serious and debilitating: the long bones are lacking in proper calcification, and as a result are thinner and shorter than normal. The clavicles (collar bones) often fail to develop properly, causing the shoulder and chest areas to appear narrow. The fingers and toes are usually very short, due to degeneration and resorption of the distal bones. In most cases there is marked degeneration of the hip structure, resulting in a “bow-legged” condition. Elbow and knee joints are of normal size, but tend to fill with fibrotic scar tissue, giving them a swollen appearance and making limb movement difficult. Overall, the apparent physical similarity of HG progerics is rather startling; it is often said of them that they look more like one another than like other members of their own families. Some of the most striking changes take place in the skin. The subcutaneous layers, with their fat and nutritive cells, degenerate; the remaining superficial layers of the skin become thin, rather dry, and somewhat transparent. (As noted by both Hutchinson and Gilford, these changes often do not extend to the pubic region.) Thus one of the characteristic features of progeric children, in addition to their baldness, is the visual prominence of numerous veins, particularly in the scalp. The skin itself becomes wrinkled, lacking in tone, exhibits “liver spot” discolorations, and heals poorly. These changes involve all regions of the body, and mimic quite closely changes in the skin normally seen in very old adults. The very striking observation has been made that fibroblasts grown from the skin of progerics have a doubling potential in vitro of a very old person, rather than the child or teenager from whom they were taken. Children with HGPS have an average lifespan of twelve to thirteen years; survival beyond twenty years is rare. They never develop sexually. Voices do not deepen in males; females do not develop breasts; neither sex develops hair associated with sexual maturation. (The absence of nipples remarked by Hutchinson is seen in about half of affected individuals.) In cases examined at autopsy, the germ cells (sperm and ova) are also clearly incapable of reproductive function, and no individual with HGPS has ever produced children. They are of normal intelligence throughout life, and their personalities are also remarkably normal in light of their condition, of which they are entirely aware. HG progerics appear to proceed directly from childhood to old age, without ever passing through adolescence or young adulthood. It is for this reason that HGPS has been proposed to represent both a precocious (early onset) and accelerated manifestation of the normal human aging process. And indeed, nearly all progerics die at the end of their brief lives of the same causes as the extremely aged: most from heart attacks or strokes, a few from congestive heart failure, and occasionally one or two from respiratory collapse. Virtually all show extensive atherosclerosis (“hardening of the arteries”) at autopsy. On the other hand, as Martin and many others have pointed out, there are many features seen in normal aging that are absent in HGPS. The metabolism of HG progerics, and in particular the function of the numerous proteins required to operate the body’s various metabolic systems, seem quite normal for their true calendar age, and do not reflect the changes seen in the metabolism of the elderly. Their vision and hearing are excellent. Moreover, they experience none of the senile dementia common in older adults, and they have normal neurological function throughout life. Cancer, so common in the true elderly, is absent in HGPS. Clearly there is something terribly wrong in these children. But what? What could possibly explain this bizarre and tragic compression of a human life into a handful of years? The marked uniformity of symptoms expressed in progerics suggests a common underlying disease mechanism. But what kind of a disease could account for what we see unfolding in these children? And what, if anything, can it tell us about the normal aging process? One powerful piece of evidence that the aging process as manifested these patients is connected to senescence as studied in other systems comes from analysis of their fibroblasts growing in vitro. In a study published in 1971, it was shown that skin-derived fibroblasts from HGPS children, when cultured in vitro, grew much more slowly than such fibroblasts taken from other children in the same family, and even more slowly than fibroblasts taken from their parents. In fact, doublings were scarcely detectable. Not only does the skin look old, its component cells behave as if they were old. By the criterion of replicative senescence, the HGPS children appeared to be even older than their parents! By virtually any definition, HGPS is a disease, and it is a disease unlikely to be caused by external agents. By exclusion, we can confidently expect that it is ultimately explicable in terms of a genetic derangement - a mutation in one or more genes affecting one or more critical proteins. The question then becomes, how does this genetic defect arise? Is it a spontaneous mutational event occurring in the lifetime of the afflicted individual, or is it inherited? Is it a dominant mutation, or is it recessive? Is it autosomal, or is it sex-linked? Questions like these are normally answered by following the disease in succeeding generations of families. Because there are so few HGPS individuals alive at any given time, and because they do not produce children who could inherit the disease, these questions are more difficult to resolve, but there are a number of things we can say about its genetic pattern. Since it affects both males and females equally, it is clearly autosomal and not sex-linked. Its extreme rarity could be consistent with a spontaneous autosomal dominant mutation arising in a mature germ cell of one parent. This is rendered unlikely by the fact that there are several well-documented cases of more than one child in a single family with HGPS. We would then have to imagine that this rare mutation occurred spontaneously more than once in the parents of such families. From the limited information at hand, it seems most likely that HGPS represents an autosomal recessive genetic disease, in which both parents must be carriers of the defective gene. We do not yet know the identity of the gene (or genes) which, when mutated, can cause such a complex and devastating disease. But that a single genetic error can cause diseases of this type is suggested by another disorder on Martin’s list: Werner’s syndrome. Werner’s syndrome Werner’s syndrome is named for Otto Werner, who first described this condition in his thesis for the MD degree in Germany in 1904 - the same year that Gilford described his first patient. Like the Hutchinson-Gilford syndrome, this is clearly a progerial disorder, in which affected individuals experience some form of an accelerated aging process. It is nearly as rare: only about 200 cases have been described to date. But Werner’s syndrome is without doubt distinct from HGPS. In his original report, Werner described four siblings with essentially identical symptoms: growth retardation; general atrophy of muscle and connective tissues; an aged appearance due to graying hair and atrophy of the skin; and crippling joint deformities. But unlike HGPS, the onset of definitive symptoms in Werner’s syndrome (WS) rarely begins before age twenty. Affected individuals seem perfectly normal as children, but they generally stop growing altogether early in the adolescent years. Men are rarely more than five feet tall, with women several inches under this.The average age of death in Werner’s patients is forty-seven years. The accumulation of additional patients since Werner’s time has allowed a clearer picture of the symptoms defining this disease. Hair graying and loss is one of the earlier symptoms, beginning, like growth retardation, during the adolescent years. It is usually not as complete as in HGPS. Secondary sexual hair develops reasonably normally in many cases, but may be lost as the syndrome progresses. During this period as well, patients start to display prematurely aged skin, although not as extensively as individuals with HGPS. The skin of the feet and hands is particularly affected, exhibiting the thin, dry, pigmented condition seen in HGPS, but also including the development of very thick calluses that sometimes ulcerate and even bleed. Facial skin also seems very “old” in appearance, due to loss of subcutaneous fat and nutritive cell layers. On the other hand skin in the trunk region is only minimally affected. Fibroblasts taken from skin in the extremities of WS patients show a greatly curtailed replicative lifespan in vitro, and quickly acquire a senescent morphology, similar to the fibroblasts of HGPS patients. There is also a general wasting of muscle tissue in the extremities, accompanied by loss of bone mass, again with reasonable maintenance of both of these parameters in the trunk. The overall appearance is thus of small, old-looking limbs appended to a robust, young-looking trunk. The joints are often thickened and calcified, making movements difficult and painful. One of the most distinctive features of WS is the development of cataracts. Normally seen only in persons over fifty, cataracts develop in nearly all WS patients over thirty years of age, setting in as early as ten years in a few individuals. The cataracts usually affect both eyes simultaneously. Other eye problems associated with old age are also common in these individuals. As in HGPS, WS patients develop cardiovascular problems that are a common cause of death, although in those afflicted with WS there is a more generalized problem with occluded blood vessels that can lead to gangrene and limb amputation. This could be due to the fact that WS patients live longer: the average age at death is about 44 years. This longer survival may also account for other differences between Werner’s and HGPS patients, such as the occurrence of maturity-onset (Type II) diabetes and certain cancers in WS patients in the third and fourth decades of life; cancer is also a common cause of death in WS. Although somewhat sexually underdeveloped, individuals with this disease are in fact often fertile, and a number have reproduced. As with HGPS patients, fibroblasts taken from persons afflicted with WS show greatly reduced growth in vitro, comparable to fibroblasts taken from very old persons. Studies with fibroblasts from WS patients have provided insight into the types of changes that occur in these cells as they age, and these changes appear to parallel those seen during normal aging. Fibroblasts (which are scattered throughout the entire body, especially in skin) are one of a number of cell types that produce a protein called collagen. Collagen is well known as the soft precursor substance of bones, laid down in embryos and newborns and later fortified by calcium into classical hard bone. But collagen plays a much wider role in the body, in the form of something called extracellular matrix, a semi- rigid, lattice-like structure to which cells adhere, and which gives tissues and organs their shape. Without collagen and extracellular matrix, the body would likely collapse down into a mass of tissue hanging from a skeletal frame. The collagen secreted by fibroblasts is used to make up this extracellular matrix. But fibroblasts are also capable of producing the enzyme collagenase, which degrades collagen. As fibroblasts senesce, either in vitro or in vivo, they switch from a collagen-producing to a collagenase-secreting (collagen- degrading) cell phenotype. Destruction of the extracellular matrix by fibroblasts could certainly cause many of the features associated with aging, such as wrinkled and sagging skin, and possibly some of the apparent wasting in muscle tissue. A significant number of WS patients are born to consanguinous parents, particularly in Japan where first- and second-cousin marriages are more common than in the West; about three-quarters of all WS cases have been reported from Japan.The fact that WS occurs more frequently in consanguinous marriages, and affects offspring of both sexes, indicates that it is an autosomal recessive defect. About one in five thousand persons is estimated to carry the WS gene, leading to the appearance of WS in about one in 25 million births. Determining exactly which autosomal gene is defective in WS has been somewhat easier to approach than was the case for HGPS. Patients live longer, and occasionally even have offspring to whom the gene is passed. There is also a reasonable number of cases where more than one child is afflicted in the same family, which further supports the case for autosomal recessiveness and greatly helps in tracing the chromosomal location of genes. A close study of the inheritance pattern of WS in Japan and in the US traced the underlying gene to the short arm of chromosome 8. Using advanced techniques for gene mapping at the DNA level , the chromosomal location of the WS gene was determined with sufficient accuracy to allow the very first isolation and sequencing of an apparent aging-associated gene, described in a joint Japanese-US report published in April, 1996. When the DNA sequence for the WS gene was converted into an amino acid sequence and compared with other known sequences, the resulting 1,432 amino acid protein looked very much like an enzyme called DNA helicase. This enzyme is so named because it plays a role in unwinding the two strands of DNA that form the DNA double helix (Figure 5-2.) Once the gene was cloned, and the corresponding protein produced artificially, its identity as a DNA helicase was confirmed by direct testing for helicase activity. This is an exciting finding, because one of the major theories of aging is that it results from the inability either to read, repair or replicate DNA. While helicases themselves are not involved directly in any of these functions, they prepare the DNA for all three. And WS patients show extensive DNA abnormalities in their final decade of life. But how could a defect in a single gene cause such a complex and specific set of symptoms, many of which mimic closely some of the phenotypes of aging, such as replicative senescence of fibroblasts in vitro? This is the question now occupying the new breed of doctors and scientists who look at human health at the level of molecular genetics. The answer may lie in a fact about genes discussed in the last chapter. The majority of our hundred thousand or so genes - the so-called housekeeping genes - are expressed in every cell in the body. But there are many different kinds of cells in the body, and these different cells are organized into different tissues and organs, each with its own local environment. These individual environments are created largely by the “special function genes” typical of each tissue, for example the gene for insulin in pancreatic ?- cells, or some of the cytokine genes in cells of the immune system. A mutation in a single housekeeping gene, which may play basically the same role in cells throughout the body, may have a sharply different impact in different tissues, depending largely on the special function genes and gene products with which it interacts in those cells and tissues. DNA helicases could certainly be considered housekeeping genes. The impact of an impairment of the ability to unwind DNA may play out differently in different cells and tissues. But before we try to refine this answer in greater detail, let us look at yet another aging syndrome in which a quite similar type of gene may very well be involved. Cockayne Syndrome Another rare type of progeria, first detected in a brother-sister pair, was described in England by E. A. Cockayne in 1936. He did not classify these cases as progerias at first; the title of both his initial paper, and a follow-up report on the same patients ten years later, was Dwarfism with Retinal Atrophy and Deafness. Over the decade following his second report, other cases were identified with the same symptoms, and a closer following of affected individuals showed that they, too, were experiencing at least some facets of an accelerated aging process. “Cockayne syndrome” (CS) soon took its place along with HGPS and Werner syndrome as one of the principal progerias. The dwarfism, deafness and blindness noted by Cockayne are still hallmarks of this condition. The children seem perfectly normal during the first year or two of life. Growth retardation and slowness to speak and comprehend normal language become of increasing concern in the third year, although some cases are not fully recognized until the fifth or sixth year. Both males and females are very small in stature, rarely reaching more than four feet in height. There are some of the same skin and muscle tissue atrophy problems seen in HGPS and WS, difficulties with occluded joints, and the same progressive thinning of the bones. Sexual development is also retarded. As in HGPS, afflicted individuals rarely live beyond their early twenties. However, CS patients do not show many of the features of the other two progerias, and have several quite distinctive features of their own (Table 5-2). For example, there is no noticeable atherosclerosis, and no cardiovascular disease in CS patients; on the other hand, there is progressive degeneration of central nervous system tissues, which may be related to the loss of sight and hearing functions. CS patients die of neurological degeneration rather than heart failure. Of great interest to gerontologists, many of the changes seen in the brain at autopsy closely parallel those seen in normal humans beyond the seventh decade or so of life. Whether or not CS patients undergo true senile dementia or not is unclear; they are often quite retarded in mental development because of blindness and loss of hearing, which makes assessment of mental function difficult. One of the most characteristic features of Cockayne syndrome is an extreme sensitivity of the skin to UV light. This symptom, missing in the other progerias we have discussed, is also one of the hallmarks of the normal aging process in humans, and is thought to be due to a progressive loss of the ability to repair light-induced damage to DNA. There is some evidence that a helicase defect may be involved in CS as well. Since only cells at the very surface of the body are exposed to UV light, this obviously is not a cause of aging in tissues other than skin. However, the inability to repair DNA generally may reflect a deeper problem that could have major implications for senescence. We now know that cells constantly monitor their DNA for irregularities, and have several mechanisms for restoring any changes that might creep into inherited DNA sequences throughout the life of the organism. “Normal” mutational events - those that do not alter the basic chemical nature of the DNA itself, and which might give rise to useful new forms of genes, are not corrected by these repair mechanisms. However, mutations such as those caused by radiation, certain mutagenic chemicals, or even some of the highly oxidative molecules that are byproducts of normal cellular metabolism, can cause distortions in the structure of the DNA itself, and are readily detected and corrected by excising the distorted region and filling it in with unaltered building blocks. Defects in the ability to repair DNA damage are known to be the cause of yet another genetic disease called xeroderma pigmentosum (XP.) Persons afflicted with XP do not normally experience problems with accelerated aging, but like WS patients they are extremely sensitive to ultraviolet light. It turns out that mutations in any one of about seven different genes - all presumably involved in DNA repair - can cause XP. One of these genes was very recently shown to encode a helicase-like molecule. Whether it is the same as the helicase molecule in WS is unclear at present, but very interestingly this is the one XP gene which, when mutant, causes CS-like symptoms. And yet another genetic disorder with UV sensitivity and some features of a progeria - Bloom syndrome - was shown in mid-1996 to be caused by a faulty helicase-like gene. We will explore the possible involvement of defective DNA repair mechanisms in senescence and cancer in more detail in later chapters. The progerias in themselves have by no means solved the riddle of aging and senescence. Some have argued that they do not reflect the true aging process at all. In none of them do we see all of the phenotypes of human aging, and in some a particular phenotype may differ slightly from “normal” aging. We even see some changes that are not thought to be part of the aging process at all. But so-called normal aging is itself highly variable; what we define as the norm is itself only an average of all the individual phenotypes we have seen. The aging events taking place in the progerias may represent only one highly restricted variant of a given “normal” aging process. The diseases discussed here are all single-gene defects; no one ever claimed that aging is caused by a single gene, so it is not surprising that these “segmental progerias,” as George Martin called them, do not display the full range of aging defects. Nevertheless, they reveal several very important things that we should bear in mind as we proceed through the following chapters. First of all, we see in the progerias that variations in a single gene can have very far reaching effects in terms of the phenotypes of aging. This would not be predicted by theories of senescence that postulate the random accumulation over evolutionary time of senescence-related genes in different species. Proponents of these theories would expect large numbers of different aging genes, each affecting a different tissue in a different way. Thus mutations in no single one of these genes would be expected to have more than a local effect, causing accelerated aging in a restricted number of cells or tissues. Perhaps that may account for some of the resistance to accepting the progerias as reflective of the true aging process. Looking at the progerias, however, it is not at all difficult to imagine that a relatively small number of genes, probably housekeeping genes, could account for most if not all of the aging phenotypes. The progerias also make it clear that the aging process per se in humans is not rigidly time-dependent. Changes that would normally take sixty or seventy years to manifest in the normal aging process - hearts or kidneys wearing out; skin becoming thin and discolored - are brought to completion in a decade or so in HGPS. These hearts did not cave in from a lifetime of physical exertion; the skin did not age from years of exposure to the sun. These changes are thus unlikely to be caused directly by a “wearing- out” process per se. In terms of a three-gene scenario for senescence, what we could be sseing in the progerias is either a defect in senescence repressor genes, or a malfunction in senescence regulator genes. Defective senescence repressor genes might result in gene products unable to prevent or repair damage caused by senescence effector genes, allowing senescent damage to accumulate at an accelerated rate. Defects in senescence regulator genes might result in an earlier than normal turn-off of senescence repressor genes, allowing senescence to begin ahead of schedule. As far as we know, all of the progerias are, like WS, caused by a defect - a harmful allelic variation - in a single gene. Each of these allelic variants is able to induce a broad range of the symptoms associated with normal aging phenotype. We must remember that these may not be the variants associated with the normal aging process. But what the progerias suggest is that the genes that these alleles represent are excellent candidates for genes involved in a fundamental way in the aging process. Increasingly, these appear to be genes involved in causing damage to DNA, or in repairing that damage. Aging is almost certainly, as George Martin guessed twenty years ago, a multigenic process. As we will see in coming chapters, a number of “normal” genes have already been proposed as candidates for genes that contribute to aging late in life. It is sometimes assumed that the total number of these “gerontogenes” must be quite large, based on the complexity of the aging phenotype, and on the many genes already under investigation. On the other hand, the incredible spectrum of aging-like phenotypic changes wrought in the single-gene progerias suggests that the actual number of such genes may not have to be terribly large. Table 5-1. Human genetic disorders reflecting various aspects of the human aging process. Known single-gene defects Principle senescence-related features Ataxia telangectasia Senile dementia; diabetes Myotonic dystrophy Diabetes; hair graying; cataracts Werner syndrome Skin; hair graying and loss; atherosclerosis; cataracts; cancer; diabetes; osteoporosis Presumed single-gene defects Hutchinson-Gilford syndrome Skin; hair loss; atherosclerosis; osteoporosis; hypertension Cockayne syndrome Senile dementia; U.V. sensitivity; cataracts; osteoporosis; hypertension Seip syndrome Hypertension; diabetes; dementia; Familial cervical lipodysplasia Diabetes; arthritis; hair loss; dementia Chromosomal aneuploidies Down syndrome Senile dementia; cataracts; diabetes; hair graying; cancer Klinefelter syndrome Diabetes; hair graying; cancer Turner syndrome Hypertension; diabetes; cancer (Table 5-1 legend). Disorders are listed as known single-gene defects where the causative gene has been isolated and identified. The presumption of a single-gene defect is based on genetic mapping studies. Of the aneuploidies with progeric features, Down syndrome individuals have an extra chromosome 21 (“trisomy 21”). Individuals with Klinefelter syndrome are males with 1-3 additional X chromosomes. In Turner syndrome, females have only the X chromosome (“X0”.) Diabetes, where indicated, is Type II, or maturity onset. Senile dementia may include any of a number of changes in brain tissue associated with dementia. Table 5-2. A comparison of normal aging and accelerated aging in various progerias. Feature Normal Aging Hutchinson-Gilford Progeria Werner Syndrome Cockayne syndrome Hair loss Sixth decade First year Second decade Some body hair loss Skin changes Global; fourth decade Global; first year Extremities only; second decade Moderate Atherosclerosis Fourth decade First decade Second decade Absent Cataracts Sixth decade Absent Third decade Absent Sexual development Second decade Absent; no reproduction Moderate; second decade; reproduction possible Slight; no reproduction Maturity-onset (type II) diabetes Fifth decade Absent Fourth decade Absent Senile dementia Eighth decade Absent Mild or absent Second decade (some aspects.) Cancer Common after fifth decade Absent Common after third decade Absent U.V sensitivity Sixth decade Absent Absent Common from birth This may be too narrow a view of senescence. As discussed earlier, internally programmed events in an organism that lead to lethal idiopathic disease, or increase susceptibility to death through external disease or accident, should probably be considered part of the overall senescence program of that organism. A major exception is cells of the blood system and the immune system, many of which divide throughout life. Here somatic mutations occur continuously, and in fact are an important mechanism of diversification in the immune system. For further information, see W. R. Clark, At War Within: The Double-edged Sword of Immunity, Oxford University Press, 1995. For a discussion of the methods used to map, isolate and clone human disease-associated genes, see W. R. Clark, The Gene Doctors: Molecular Medicine in the Twenty-first Century, Oxford University Press, 1997. 93