By David N. Leff

In sketching the final stage of aging, Shakespeare got it right:

"Last scene of all . . . is second childishness . . . sans teeth, sans eyes, sans taste, sans everything."

So did Otto Werner, a German physician who described a century ago the premature-aging syndrome that bears his name.

"Werner's syndrome," said molecular biologist David Sinclair, in the laboratory of Leonard Guarente, at the Massachusetts Institute of Technology, in Boston, "is a heritable, recessive autosomal disease. In the U.S., it affects one in a million people, but in Japan, where consanguineous marriage is commoner, so is Werner's syndrome [WS]."

The old-age signs of WS usually appear in early adulthood. A victim's skin wizens like parchment. Hair turns gray, and baldness sets in. Cataracts cloud the eyes. Hearing fails. Teeth fall out. Typically, a WS victim looks twice his or her age. Death, usually from atherosclerosis or cancer, intervenes typically before the age of 50.

Besides these visible hallmarks, WS also brings on the many ills that superannuated flesh is heir to: arteriosclerosis, malignant tumors, Type II diabetes, osteoporosis, acute arthritic attacks, hypogonadism.

"Surprisingly, though," Sinclair told BioWorld Today, "the loss of cognition, memory and mentation associated with neurodegenerative diseases in the elderly does not occur in Werner's syndrome."

(Scientists at the Darwin Molecular Corp., in Bothell, Wash., reported last year to the annual meeting of the American Society of Human Genetics that they had identified the 5.2-kilobase gene responsible for WS, on the short arm of human chromosome 8.)

Sinclair is first author of a paper in today's Science, dated Aug. 29, 1997, which reports inflicting Werner's syndrome on yeast cells as a model for studying the aging process.

"Perhaps for the first time," he said, "we've determined that lower organisms may age the same way humans do. With this yeast model, we now have a very elegant tool with which to try and explore aging."

A dividing yeast cell, he explained, "would give off 20 to 40 daughter cells, which we can count under the microscope. We counted the number of divisions they can go through, the number of offspring they have, and when they die." He and his co-authors mutated a yeast gene, SGS1 (which denotes "slow growth suppressor"), from the genome of Saccharomyces cerevisiae.

As mother cells grew older, they developed the yeast equivalent of WS premature aging: Their size increased; their cell cycle slowed; and they lost mating potential and the ability to produce small daughter cells with full lifespan.

According to Hayflick's limit, human cells go through about 50 divisions before dying out. "Werner cells divide half as many times," Sinclair pointed out. "In yeast cells, which divide every 90 to 120 minutes, the lifespan number runs from 20 to 40 divisions. "You can extend their life span," Sinclair observed, "by putting them in colder temperatures."

Genetic Stability: Anchor Of Aging?

The team tracked the mutated SGS1 cells' premature aging signs — enlargement and sterility — to a gross destabilization of their DNA.

"Recent work that hasn't been published yet," Sinclair said, "shows that one of the main causes of aging, at least in yeast, is a lot of recombination between similar or identical highly repeated gene sequences, which then lose their stability." He added: "In the yeast genome, these repeats are 9 kilobases long. In human's, it's close to 40 kb, but in humans we don't know which ones are important."

In yeast cells made old before their time, they localized these unstable components to the cell's nucleolus. "The nucleolus," Sinclair explained, "is the site where ribosomes are assembled. Ribosomal DNA forms the dense core of the nucleolus, where it combines with many proteins to form the complete ribosome. This is then exported from the cell's nucleus to process protein synthesis in the cytoplasm."

The MIT group found that the genetic instability of their prematurely aged cells fragmented that dense core of the nucleolus. That fragmentation is now their conceptual target of therapeutic opportunity.

"Now that we think we know it's the genetic instability of the ribosomal DNA," Sinclair said, "we're trying to use drugs to determine ways that we can slow the instability process and extend the life span of the yeast. I envisage," he continued, "that if we're right, there should be some drugs that can counteract the damage that is occurring in the nucleolus."

Can S. cerevisiae Really Model H. sapiens Disorders?

Is the MIT team convinced that it can extrapolate the effect of such a drug from a yeast nucleolus to the human nucleolus?

"Without a doubt," Sinclair replied. "That's our hope. Currently in this lab there's intensive research going on to see if the same effects are happening in the human."

At Stanford University, in California, molecular geneticist David Botstein shares that conviction. In an editorial in today's Science, commenting on the MIT paper, he raises the question: "How good a model organism is yeast?"

Botstein compared all yeast protein sequences to the mammalian sequences in GenBank, and found "a robust homologue" for nearly 31 percent of yeast's potential protein-coding genes. Further analysis suggested that "The likelihood that a newly discovered human gene will have a yeast homologue with at least some functional information about one of its domains is . . . quite good." He added: "At least 71 human genes [including Werner's syndrome] complement yeast mutations; this is certain to be an underestimate."

Sinclair made the point: "The way we view our research is to benefit society, not to make people live forever." Rather than tackling aging as if it were a disease in itself, he added, "We think we can tackle a lot of the diseases of aging, as listed in WS, right at their source. So while others investigate these individual diseases at some certain level, we think we can go even deeper, to the primary source of a lot of these troubles. In doing so," he concluded, "we think we can just prevent disease and extend life span by making people healthier, longer." *