Sci. Aging Knowl. Environ., 8 October 2003
WRN-defective cells and old cells switch same genes on and off
Key Words: RecQ helicase exonuclease progeria transcription factor
The premature aging disease Werner syndrome appears to be a flip-flop of how Monet might have portrayed aging. From far away, the two conditions--unlike the artist's indecipherable hodgepodge of dots--don't coalesce into a coherent scene, because the disease doesn't quite represent regular aging. But when viewed from up close, the details capture the essence of the process, according to new research: Afflicted cells show the same gene activity profiles as do cells from healthy old people. The results strongly support the contention that researchers can use Werner syndrome cells to study molecular changes that aging induces.
People with Werner syndrome appear to age inordinately fast. Starting at puberty, they go gray, lose their hair, and develop cardiovascular problems and osteoporosis--and they die in their 50s (see "Of Hyperaging and Methuselah Genes"). But the disease doesn't proceed the same way normal aging does; for example, Werner syndrome patients suffer from unusual cancers, their osteoporosis hits different bones, and they rarely develop Alzheimer's dementia. The ailment strikes people who carry a mutation in the WRN gene. When it's functioning properly, this gene encodes a protein that performs multiple jobs. It unwinds and trims DNA, which are important parts of copying and repairing DNA. The protein might also turn genes on and off, but that idea remains unconfirmed (see Fry Review).
To determine how closely Werner syndrome resembles aging at the molecular level, molecular gerontologist Vilhelm Bohr of the National Institute on Aging branch in Baltimore, Maryland, and colleagues compared cells from four "middle-aged" Werner patients (average age 29), six healthy young people (average age 23), and five non-Werner elderly people (average age 90). The team measured the amount of messenger RNA produced by 6912 genes in cultured skin cells from all three groups and found that 435 of the genes produced different quantities of messenger RNA in Werner or old cells compared with the young ones. Scientists know the function of 239 of those genes. Of those, 218, or 91%, shifted their activity in the same direction in Werner and old samples, suggesting that Werner syndrome affects cells almost the same as aging does. Seven alterations were found only in Werner cells, and 14 only in old cells; the identity of the corresponding genes did not reveal any secrets about the differences between Werner patients and healthy seniors, says Bohr.
"It's quite exciting," says cell biologist David Chen of Lawrence Berkeley National Laboratory in California. The study shows "solid evidence" that Werner syndrome and normal aging toy with genes similarly, suggesting that Werner cells provide a good model with which to study normal aging even though Werner syndrome patients aren't perfect copies of old people. Different skin cells from a healthy person would yield different gene activity profiles, so the observation that 91% of the known, affected genes behave the same way is "quite remarkable," he says. Furthermore, the observation that genes involved in DNA and RNA metabolism represented more than a fifth of the identified genes and were turned down in Werner syndrome cells supports the notion that WRN helps switch genes on and off, Chen says. Perhaps an even closer examination of Werner syndrome might clarify the big picture of aging.
--Mary Beckman; suggested by Nick Bishop and Amir Sadighi Akha
October 8, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150