Aging And Genetics

C.E. Yu, J. Oshima, Y.H. Fu, E.M. Wijsman, F. Hisama, R. Alisch, S. Matthews, J. Nakura, T. Miki, S. Ouais, G.M. Martin, J. Mulligan, G.D. Schellenberg, "Positional cloning of the Werner's syndrome gene," Science, 272:258-62, 1996. (Cited in more than 175 papers since publication) Comments by Gerard D. Schellenberg, associate director for research, Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Seattle Aging is a real stumper. Is it the result of natural wear and tear? Does it have a genetic cause? Some regard it as a disease to be cured. Researchers hope to get a handle on the process by studying the genetic causes behind Werner's syndrome, a recessive disorder that causes its victims to die--of old age, it appears--by their mid-20s. "...if we can understand the function of this helicase, we can understand at least one segment of the aging process..." --Gerard D. Schellenberg This paper pinpointed the gene that causes the syndrome. The protein it encodes is 1,432 amino acids in length and appears to be in the family of proteins known as DNA helicases, which unwind double-stranded DNA, according to Gerard D. Schellenberg, associate director for research, Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center in Seattle. Other research teams have since confirmed that the protein has DNA helicase activity. "Any time a cell uses genetic information, or repairs or replicates DNA, helicase has to be involved in that process," says Schellenberg. The identity of the gene made sense, as it turned out, because, "We had an idea that DNA metabolism was involved ... in the cells of Werner's syndrome patients; chromosomes seem to be chopped up pretty badly. But we didn't know if it was something that [was directly affecting] DNA or if it was a secondary effect. [The gene's similarity to the] helicases certainly answers that question." The next question is, what role does it play? There are six or seven known helicases, according to Schellenberg, and they seem to have their own responsibilities. One may be involved in replication, another in transcription, and still another in the repair process. If their functions don't overlap, inheritance of two damaged copies of the gene could be dire, indeed. "I'm not sure that one helicase can pick up the slack for another," says Schellenberg. The interest in the gene--and the number of citations the paper has garnered--isn't too difficult to explain given that aging is a condition that most scientists dread, and all of them face. "Werner's syndrome has a lot of parallels to human aging ... so if we can understand the function of this helicase, we can understand at least one segment of the aging process--the part that has to do with DNA damage," Schellenberg says. What about the rest of the aging mechanism? Werner's syndrome may not be much help, but another disease, called pregaria, could. Also a genetic disease, it causes death much earlier than Werner's syndrome. The responsible gene hasn't been found yet, but it will likely add another piece to the puzzle. "The thinking is that more is involved. ... Aging is obviously a very complex process, when you consider that in all of the major diseases--cancer, heart disease, dementia, and others--the risk increases with age. But not all of those [diseases] are elevated in Werner's syndrome. The incidences of some cancers are elevated, but it is not clear [that dementia increases]. There is bound to be a tremendous number of genes involved in aging."

Aging And Genetics

The Scientist Staff

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