Progeria

An 1886 issue of the Lancet carried a brief article by Dr. Jonathan Hutchinson describing a patient of his, a six yearold boy. The child's birth had been unremarkable but, by age one, the infant's growth slowed perceptibly; he became bald and wizened. By age six he weighed but 20 pounds and had all of the outer appearances of an aged man. His skin, for example, was thickened, excessively wrinkled and had lost the elasticity associated with youth. It seemed as though the child had skipped adolescence and proceeded, without interruption, into an accelerated senescence.

Yet another case of premature aging in a child surfaced about 20 years later; and gradually, physicians came to recognize a specific disorder of childhood, fortunately rare, characterized by rapid aging. Based upon a Greek word for aging, they called it progeria.

It was a bizarre disorder, with virtually all of the customary stigmata of aging, including cataracts of the eyes, premature deafness, baldness, and even accelerated sclerosis of the coronary and cerebral arteries. But the morbid fascination which this rare hereditary disease provided for medicine went deeper. Physicians wondered whether the secret mechanisms of normal aging might somehow be encapsulated, and then exaggerated, in these afflicted children. Perhaps, in their plight [progeric children rarely live beyond age 16], these youngsters might harbor the mysterious mechanisms, though amplified, underlying the aging process affecting the remainder of human society. And further, if the disease process in progeric children, whatever it is, can be slowed or even neutralized, such knowledge might be applicable to the bulk of humanity as it undergoes what is called "normal" aging. Some geneticists have even dared to wonder whether the "normal" aging is not, in reality, a reversible disease afflicting all.

Certainly aging is not uniformly applied to all who survive childhood. Some humans age more rapidly than others [males, for example, more than females]. And in the absence of major trauma, both genetic inheritance as well as life-style seem to determine jointly the span of life allotted to each human. Life-style, of course, embraces a multitude of factors, including prudent diet, physical exercise, avoidance of ambient pollution, avoidance of major emotional stress and social strife and a conscious intent to live a purposeful life.

As medical science delved more deeply into the countless metabolic pathways and interactions which serve the functioning vertebrate body, inevitably a search has been initiated to explain the phcnomc-non of aging. Why, for example, do large mammals, such as elephants, live beyond 70, while little mammals, such as mice, live at most three years? Physiologists, pondering the varied life expectancies of a wide assortment of creatures, have sought some rational explanation for this wide diversity. They noted that the ratio between the creature's volume and its skin area is proportional to its average life-span. Still other observers observed that the number of heart beats during a mouse's life is about equal to the number of heart beats during an elephant's span of year. Small creatures, it seems, live fast and the young while the hulking animals creep slowly through a much longer life. In the words of the ecologist Brian Enquist, "You can spend it all at once or slowly dribble it over a long time."

Scientists first distinguished between life-span, the inexorable biological limits of life, under the best of circumstances; and life-expectancy which represents the actual duration of life. The latter is reality and the former, the ideal limits of life.

The critical biological factors modulating the process of aging, however, have remained elusive. Environmental circumstances clearly determine why Norwegian women live, on average, to age 83 while Ethiopian woman survive, on average, to age 35 years. The thought that aging is merely the residue of a cumulative wear and tear process, in some settings more stressful and life-shortening than in others, seemed unsatisfactory.

How then, it was asked, do stress, poor diet and exposure to certain chemicals accelerate aging? Recent findings indicate a variety of separate avenues of inquiry, each quite promising, including the role of chemicals involved in the metabolism of connective tissue, the role of free radicals, cumulative errors in the production of body proteins, mutational changes in the body's DNA, mistakes in the body's immune response such that it may attack its own tissues as though they were foreign invaders; and, of course, the inheritance of certain genes which may create additional time limits on the life span.

Progeria is a rare event, arising about once in every eight million births. And other than the victims and their parents, the disease has not prompted much public health concern. Yet science has extensively investigated this disorder seeking for a specific gene variant which can be held responsible for the "fast-forward" velocity of aging in these children.

In 2003 a team of scientists at the National Institutes of Health, aided by investigators from a number of universities including Brown, identified the genetic mutation responsible for childhood progeria, the most dramatic form of premature aging. [This abnormal gene, called LMNA, plays an important role in coding for critical cell membrane proteins.] Francis Collins, the Director of the national Human Genome Research Institute, declared: "This genetic discovery represents the first piece in solving the tragic puzzle of progeria. The implications of our work may extend far beyond progeria - to each and every human being. What we learn about the molecular basis of this model of premature aging may provide us with a better understanding of what occurs in the body as we all grow older."

In recent years, often employing the procedure called "positional cloning," geneticists have identified the genes responsible for cystic fibrosis, Huntington's disease and a number of other hereditary maladies. Inevitably, ethicists will also explore the societal implications of extending active adult life for a decade or two. Seneca, who knew no genetics, said, however, that old age is an incurable disease.

STANLEY M. ARONSON, MD

Copyright Rhode Island Medical Society May 2005
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