Accelerated Aging: Human Progeroid Syndromes
ACCELERATED AGING: HUMAN PROGEROID SYNDROMES
Human aging is a complex process resulting from the interaction between a person's genetic makeup, their environment, and time. Individuals mature to adulthood, then undergo a gradual degenerative process that eventually results in death. Most of us go through these processes at roughly equivalent rates; indicating that a carefully controlled developmental program operates until adulthood. It is not clear, however, whether aging is also programmed or whether maturation is simply followed by random deterioration in the decades after our reproductive years. Such questions remain unresolved, although decreased performance of many body systems is directly related to increasing age—our bodies wrinkle and lose muscle, our hair turns gray and thins, our bones become brittle, and increasingly we succumb to age-related diseases, including cancer, diabetes, hypertension, atherosclerosis, and several neurological disorders.
Although most of us feel that we age too quickly, we should count ourselves lucky. Several human genetic diseases are noteworthy for their accelerated development of certain aging characteristics. Specifically, accelerated aging is defined as the earlier than normal onset or increased frequency of an age-related attribute or disease. Importantly, no genetic disorder exhibits acceleration of all signs of human aging. For this reason, these diseases are known as segmental progeroid syndromes, meaning each partially mimics an accelerated aging phenotype. Also, each disorder has a variable age of onset and rate of development of its distinct set of accelerated aging characteristics. Despite this variability, these syndromes provide valuable insight into the mechanisms involved in accelerated aging, and, by extrapolation, in normal human aging as well.
Progeroid syndromes as models of aging
Detractors argue that segmental progeroid syndromes do not reflect normal aging, usually pointing out symptoms unrelated to aging or the lack of specific normal aging characteristics. Moreover, some accelerated aging symptoms described in progeroid syndromes may have subtle physiological differences that distinguish them from similar features of normal aging. This would suggest that the defect that underlies such an accelerated aging characteristic is distinct from defects that occur during normal aging. Clearly, normal aging is a genetically complex process that cannot be fully explained by comparison to several diseases involving a very small set of genes.
However, these weaknesses of progeroid syndromes as models of normal aging also highlight their strengths. The specific genetic defects that cause progeroid syndromes facilitate examination of biochemical deficiencies associated with certain accelerated aging characteristics. By contrast, the contributions of the many genes that impinge on normal aging are almost impossible to evaluate. It is likely that there are multiple underlying causes for all of the features of normal aging. Thus, the acceleration of specific aging characteristics that occur in progeroid syndromes may provide insight into specific pathways that fail and underlying mechanisms that operate, albeit at a slower pace, during the later development of similar characteristics during normal aging. Moreover, identification of defective genes that result in accelerated aging allows discovery of beneficial disadvantageous alleles of those genes (and other functionally related genes) that might delay or modestly hasten, respectively, the onset of normal aging characteristics. Below are brief descriptions of five genetic diseases that are regarded as the best models of accelerated aging.
Down syndrome occurs about once in seven hundred births and is characterized by delayed and incomplete development as well as degeneration of many organ systems. Down syndrome exhibits an early onset of many aging characteristics, including graying and loss of hair, hearing loss, cataracts, increased tissue lipofuscin, and degenerative vascular disease, as well as increased frequency of autoimmunity and cancer, particularly childhood leukemia. Multiple neurological abnormalities, including early onset of senile dementia similar to that associated with Alzheimer's disease, may result from both decreased proliferation and increased apoptosis of neurons. Individuals with Down syndrome usually die by the age of forty.
Down syndrome is caused by having three (instead of two) copies of part or all of human chromosome 21, making it genetically much more complex than other segmental progeroid syndromes. Hypothetically, the extra chromosome alters gene expression levels that, in turn, cause metabolic defects that result in both the developmental problems and degenerative effects of Down syndrome. Chromosome 21 harbors the gene for the amyloid precursor protein. Increased production of this protein could be a factor in amyloid plaque development, which is diagnostic for senile dementia associated with Down syndrome and Alzheimer's disease. This chromosome also contains the Cu/Zn (copper/ zinc) superoxide dismutase gene that is involved in the metabolism of reactive oxygen species. Imbalances in oxidative metabolism could lead to increased cellular damage, a scenario consistent with both the increased lipofuscin and oxidative DNA damage observed in Down syndrome and the proposed relationship between accumulation of oxidative damage and aging characteristics. However, the contribution of any particular gene on chromosome 21 to specific premature aging characteristics associated with Down syndrome remains unclear.
Adult progeria (Werner syndrome)
Werner syndrome is known as adult progeria because affected individuals appear relatively normal until adolescence and develop aging characteristics thereafter. It is an autosomal recessive disorder that afflicts fewer than ten out of a million persons, with the highest incidences in Japan and Sardinia. Werner syndrome patients have accelerated development of many aging characteristics (including graying and loss of hair, wrinkling and ulceration of skin, cataracts, atherosclerosis, and osteoporosis) and increased incidence of certain age-related diseases (such as cancer, diabetes, and hypertension). They do not have increased neurodegenerative problems such as Alzheimer's, Parkinson's, or Huntington's disease, although some dementia has been reported. Werner syndrome patients invariably die before age fifty, usually from cancer or complications due to severe atherosclerosis.
Amazingly, all of the characteristics of Werner syndrome result from mutations in one gene, known as WRN. Biochemical study of the WRN protein demonstrated its DNA unwinding (helicase) and DNA degradation (exonuclease) activities. Although the exact function of WRN remains unknown, its catalytic activities and reported interactions with proteins involved in DNA metabolism point to possible roles in DNA replication, repair, or recombination. The loss of WRN function in Werner syndrome causes DNA metabolic errors that result in elevated deletions, insertions, and translocations of chromosomal DNA. Cells lacking WRN also shorten their telomeres (the protective DNA sequences at each chromosome end) much faster than normal cells, suggesting a direct role for WRN in telomere maintenance. In somatic cells, telomere shortening occurs during each round of replication, and thus is a biomarker of cellular aging. Critically short telomeres prevent cell division, suggesting a relationship between cellular senescence and aging of organisms. Cells from individuals with Werner syndrome undergo rapid cellular senescence, probably caused by accelerated telomere loss, supporting the proposed relationship between short telomeres, cellular senescence, and certain aging characteristics. In general, the Werner syndrome phenotype points to a connection between the accumulation of genetic changes, cellular senescence, and aging.
Progeria (Hutchinson-Gilford syndrome)
In contrast to Werner syndrome, the symptoms of Hutchinson-Gilford syndrome (progeria) appear in infancy. Premature aging characteristics associated with progeria are loss of hair, reduction in subcutaneous fat, wrinkling of the skin, skeletal abnormalities (including osteoporosis), and severe atherosclerosis. Growth retardation and other features not associated with aging are also observed, but mental development appears normal. Progeria patients usually succumb by their early teens due to complications from atherosclerosis.
Progeria is extremely rare, striking about one in ten million individuals. The lack of an inheritance pattern implicates sporadic dominant mutations as the underlying cause. The most prevalent physiological abnormality associated with progeria is elevated hyaluronic acid in the urine. Notably, hyaluronic acid levels in the urine normally increase with age, although not approaching the levels observed in progeria. Hyaluronic acid is involved in maintenance of the skeletal, muscular, cutaneous, and vascular systems of the body, and is thought to block angiogenesis (vascularization). A potential defect in hyaluronic acid metabolism may thus disrupt many developmental pathways. Cells from Hutchinson-Gilford patients appear to have diminished replicative capacity, but not nearly as short a life span as cells from Werner patients. Nevertheless, the genetic and biochemical causes of progeria remain unknown.
Cockayne syndrome is an autosomal recessive disease that also appears early in childhood, although the age of onset and severity of symptoms are variable. Individuals with this disorder have growth retardation and multiple degenerative problems, including central nervous system degeneration that often results in deafness, vision deficits, and motor problems. Other agerelated features are premature arteriosclerosis, progressive joint deformities, and loss of subcutaneous fat. Sun sensitivity is associated with Cockayne syndrome, although increased malignancy (including UV-related skin cancer) is not. Death usually occurs by early adolescence as a result of progressive neurodegeneration.
Cockayne syndrome is the result of mutations in one of five genes. Most affected individuals have defective CSA or CSB genes, although specific XPB, XPD, or XPG gene mutations result in Cockayne syndrome combined with another disease, xeroderma pigmentosum. This genetic complexity indicates that these five gene products impinge on a common pathway that is faulty in Cockayne syndrome. Extensive research has demonstrated that the problem lies in the complex coordination of transcription with DNA repair. In normal cells, certain types of DNA damage are removed faster from the template strand of transcribed genes than from the remainder of the genome. Individuals with Cockayne syndrome are deficient in this highly efficient repair of the transcribed strand of active genes and, consequently, have difficulty in resuming transcription following DNA damage. Persistent damage in the transcribed strand may sequester RNA polymerase, and the concomitant transcription deficits may explain many Cockayne syndrome abnormalities. Another hypothesis is that transcription blockage induces programmed cell death (apoptosis), and sufficient cell loss elicits aging signs and other characteristics of Cockayne syndrome. Inhibition of transcription or induction of apoptosis in neurons that contain increased endogenous oxidative DNA damage could explain the profound neurodegeneration associated with this disease. Ultimately, a failure in DNA metabolism is responsible for Cockayne syndrome.
Ataxia telangiectasia is an autosomal recessive disease that occurs in about one in forty thousand to three hundred thousand individuals. Characteristics of this disease appear during infancy and develop during childhood. There is a striking increase in cancer frequency, immunodeficiency, and acute neurodegeneration (particularly of the cerebellum) leading to multiple motor difficulties. Individuals with ataxia telangiectasia die prematurely of cancer or pulmonary disease (probably due to immunodeficiency).
Ataxia telangiectasia is caused by mutations in a large gene (designated ATM ) that codes for a protein with phosphorylation (kinase) activity. Cells lacking ATM function are profoundly sensitive to ionizing radiation, have chromosomal instability (including increased telomere shortening), and premature replicative senescence. Research has demonstrated that ATM kinase is involved in regulating cell cycle progression in response to DNA damage by phosphorylating protein targets, particularly the tumor suppressor protein p53 that, in turn, either delays cell cycle progression or initiates programmed cell death. Thus, loss of ATM function results in survival of cells with damaged DNA and/or increased chromosomal breaks following replication of damaged DNA. These outcomes certainly contribute to increased tumorigenesis in ataxia telangiectasia. Notably, individuals with one mutated ATM allele (approximately 1 percent of the population) have a slightly elevated cancer risk, although without the overt phenotype of ataxia telangiectasia.
If segmental progeroid syndromes are informative with respect to normal aging, what have they revealed thus far? These diseases support the view that aging results from the accumulation of damage to cellular components caused by biochemical errors and/or deleterious agents over a lifetime—and they undermine the idea of a genetic program for aging. By this reasoning, the rare occurrence of metabolic errors and the appropriate cellular maintenance processes in normal individuals cause damage to accumulate slowly, but this damage eventually causes enough harm to result in multiple aging characteristics. Specific types of errors are amplified in progeroid syndromes, resulting in increased cellular damage and certain premature aging characteristics. Interestingly, several progeroid syndromes show genetic instability (chromosomal aberrations and/or telomere shortening), suggesting connections between DNA damage and aging characteristics. Clearly, genetic damage accumulates even during normal life span and is directly related to increased cancer frequency with age. Although the relationship between DNA damage and other signs of normal aging is unclear, accumulation of oxidative damage to DNA, proteins, and membranes has been strongly implicated in many features of normal aging. Even if the biochemical defects in segmental progeroid syndromes do not directly imitate the types of mistakes made during normal aging, the cellular outcomes are probably similar—loss of cell cycle control (cancer), decrease in cell function, cellular senescence, and cell death (apoptosis). In turn, the accumulation of these cellular effects manifests itself in the physiological degeneration that we recognize as human aging.
David K. Orren
See also Cellular Aging; DNA Damage and Repair; Genetics; Longevity: Selection; Molecular Biology of Aging; Physiological Changes.
Arking, R. "Genetic Determinants of Longevity." In Biology of Aging, 2d ed. Edited by R. Arking. Sunderland, Mass.: Sinauer Associates, 1998. Pages 251–309.
Blackburn, E. H. "Telomere States and Cell Fates." Nature 408 (2000): 53–56.
Capone, G. T. "Down Syndrome: Advances in Molecular Biology and the Neurosciences." Developmental and Behavioral Pediatrics 22, no. 1 (2001): 40–59.
Dyer, C. A. E., and Sinclair, A. J. "The Premature Aging Syndromes: Insights into the Ageing Process." Age and Ageing 27 (1998): 73–80.
Finkel, T., and Holbrook, N. J. "Oxidants, Oxidative Stress, and the Biology of Aging." Nature 408 (2000): 239–247.
Goto, M. "Hierarchical Deterioration of Body Systems in Werner's Syndrome: Implications for Normal Aging." Mechanisms of Ageing and Development 98 (1997): 239–254.
Hanawalt, P. C. "The Bases for Cockayne Syndrome." Nature 405 (2000): 415–416.
Martin, G. M. "Genetic Syndromes in Man with Potential Relevance to the Pathobiology of Aging." In Genetic Effects on Aging. Edited by . Bergsma and D. E. Harrison. New York: Alan R. Liss, 1978. Pages 5–39.
Martin, G. M., and Oshima, J. "Lessons from Human Progeroid Syndromes." Nature 408 (2000): 263–266.
Oshima, J. "The Werner Syndrome Protein: An Update." Bioessays 22, no. 10 (2000): 894–901.
Rapin, I.; Lindenbaum, Y.; Dickson, D. W.; Kraemer, K. H.; and Robins, J. H. "Cockayne Syndrome and Xeroderma Pigmentosum." Neurology 55 (2000): 1442–1449.
Reeves, R. H.; Baxter, L. L.; and Richtsmeier, J. T. "Too Much of a Good Thing: Mechanisms of Gene Action in Down Syndrome." Trends in Genetics 17, no. 2 (2001): 83–88.
Sarkar, P. K., and Shinton, R. A. "Hutchinson-Guilford Progeria Syndrome." Postgraduate Medical Journal 77 (2001): 312–317.
Shiloh, Y. "Ataxia-Telangiectasia and the Nijmegen Breakage Syndrome: Related Disorders but Genes Apart." Annual Review of Genetics 31 (1997): 635–662.
van Gool, A. J.; van der Horst, G. T. J.; Citterio, E.; and Hoeijmakers, J. H. J. "Cockayne Syndrome: Defective Repair or Transcription." The EMBO Journal 16, no. 14 (1997): 4155–4162.
Yu, C.; Oshima, J.; Fu, Y.; Wijsman, E. M.; Hisama, F.; Alisch, R.; Matthews, S.; Nakura, J.; Miki, T.; Ouais, S.; Martin, G. M.; Mulligan, J.; and Schellenberg, G. D. "Positional Cloning of the Werner's Syndrome Gene." Science 272 (1996): 258–262.
ACTIVITIES OF DAILY LIVING
See Functional ability