Accelerated Aging: Progeria

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Accelerated Aging: Progeria

Human progeria comes in two major forms, Werner's syndrome (adult-onset progeria) and Hutchinson-Gilford syndrome (juvenile-onset progeria). Werner's patients are usually diagnosed in early maturity and have an average life span of forty-seven years. Hutchinson-Gilford patients are usually diagnosed within the first two years of life and have an average life span of thirteen years. The latter syndrome is often simply termed "progeria" and both are sometimes lumped together as progeroid syndromes.

Progeria's Effects

There is considerable controversy as to whether or not progeria is a form of aging at all. Most clinicians believe that progeria is truly a form of early aging, although only a segmental form in which only certain specific tissues and cell types of the body age early. Hutchinson-Gilford children show what appears to be early aging of their skin, bones, joints, and cardiovascular system, but not of their immune or central nervous systems.

Clinical problems parallel this observation: They suffer from thin skin and poor skin healing, osteoporosis , arthritis, and heart disease, but do not have more infections than normal children and they do not have early dementia . Death is usually due to cardiovascular disease, especially heart attacks and strokes, yet Hutchinson-Gilford children lack normal risk factors associated with these diseases, such as smoking, high cholesterol, hypertension, or diabetes.

Clinically, the children appear old, with thin skin, baldness, swollen joints, and short stature. They do not go through puberty. The face is strikingly old in appearance. The typical Hutchinson-Gilford child looks more like a centenarian than like other children, and may look more like other progeric children than like members of their own families. There is no effective clinical intervention.

Inheritance of Progeria

The segmental nature of progeria is perhaps its most fascinating feature. If progeria is actually a form of aging gone awry, then this implies that aging is more than merely wear and tear on the organism. If progeria is a genetically mediated, segmental form of aging, this may imply that aging itself is genetically mediated and, like other genetic disease, is not only the outcome of genetic error but might be open to clinical intervention.

Supporting this observation, there are a number of other less well-known forms of progeria, including acrogeria, metageria, and acrometageria, as well as several dozen human clinical syndromes and diseases with features that have been considered to have progeroid aspects. The latter category includes Wiedemann-Rautenstrauch, Donohue's, Cockayne's, Klinefelter's, Seip's, Rothmund's, Bloom's, and Turner's syndromes, ataxia telangiectasia, cervical lipodysplasia, myotonic dystrophy, dyskeratosis congenita, and trisomy 21 (Down syndrome). In each of these cases, there are features that are genetic and that have been considered segmental forms of aging.

In the most well-known of these, trisomy 21, the immune and central nervous systems both appear to senesce early, in contrast with Hutchinson-Gilford progeria, in which the opposite occurs. Bolstering the suggestion that this is a form of segmental progeria, trisomy 21 patients are prone to both infections and early onset of a form of Alzheimer's dementia.

The gene that is mutated in Werner's syndrome is known to code for a DNA helicase. This enzyme unwinds DNA for replication, transcription, recombination, and repair. The inability to repair DNA may explain the features of premature aging, as well as the increased rate of cancer in Werner's syndrome patients. Another mutated helicase is responsible for Bloom's syndrome. Both conditions are inherited as autosomal recessive disorders.

Data suggesting that Hutchinson-Gilford progeria is genetic is circumstantial. The disease is presumptively caused by a sporadic (one in eight million live births), autosomal dominant mutation, although a rare autosomal recessive mutation is not impossible. The helicase abnormality that causes Werner's syndrome is not present in Hutchinson-Gilford cells. There is a slight correlation with the paternal age at conception. Whatever the mechanism, it appears to operate prior to birth; several neonatal cases have been reported.

Germinal Mosaicism

Cellular data, particularly regarding structures called telomeres, suggests that some of the cells from Hutchinson-Gilford patients are prone to early cell senescence. Telomeres are special DNA structures at the tips of the chromosomes. These telomeres gradually shorten over time, and this shortening is associated with some aspects of cellular aging. Skin fibroblasts from Hutchinson-Gilford patients have shorter than normal telomeres and consequently undergo early cell senescence. At birth, the mean telomere length of these children is equivalent to that of a normal eighty-five-year-old.

Introduction of human telomerase into such cells leads to reextension of the telomeres and results in normal immortalization of these progeric cell cultures. Clinical interventional studies using this strategy in humans are pending. Predictably, circulating lymphocytes of Hutchinson-Gilford children have normal telomere lengths, in keeping with their normal immune function. Research thus far suggests that progeria may not be so much a genetic disease as it is an "epigenetic mosaic disease." In progeria, this means that the genes are normal, but the abnormally short telomere length in only certain cells lines causes an abnormal pattern of gene expression. The senescent pattern of gene expression in specific tissues results in the observed clinical disease of progeria.

Although consistent with all known laboratory and clinical data, the actual genetic mechanisms that underlie Hutchinson-Gilford progeria are still uncertain and arguable (the gene for Werner's syndrome, however, has been cloned). The question of what causes progeria holds a fascination largely for what it may tell us about the course of aging itself.

SEE ALSO Aging and Life Span; Alzheimer's Disease; Disease, Genetics of; DNA Repair; Down Syndrome; Inheritance Patterns; Mosaicism; Telomere.

Michael Fossel