By David N. Leff
Death is nature's way of telling you to slow down.
This is just as true of the common roundworm as it is of your high-powered over-achiever.
Roundworms, a.k.a. nematodes (Caenorhabditis elegans) have a normal life-span of 15 days, at a temperature of 18 degrees Celsius. Human beings (Homo sapiens) are genetically determined to live 100 years or so -- if not for life-shortening traumas and diseases.
So it comes as intriguing news that mutating a certain gene in C. elegans added days to the worm's two-week life expectancy.
With its millimeter-long transparent body, 18,000-gene genome and 3.5-day cycle from egg to adult, the nematode makes an ideal laboratory model for studying developmental genetics.
However remote from the human condition, pointed out geneticist Siegfried Hekimi, C. elegans made a seminal contribution to our understanding of oncogenes, among other useful lessons. "It did so, he told BioWorld Today, by classical studies defining the development of the worm's vulva. Many of the genes involved in this process," he explained, "are homologs of known oncogenes. They defined how oncogenes work in a signal transduction cascade." He added, "All this oncogene business owes a lot to C. elegans."
Hekimi, a professor of biology at McGill University, in Montreal, is senior author of a paper in today's Science, dated Feb., 14, 1997. Its title: "Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1."
When he and his co-authors mutated that clock gene, the creatures' cells went into an "all-systems-slow" mode, and they survived 20 days instead of 15. Then, the team constructed a double mutant, combining its altered clk-1 with Das-2, a mutated unrelated gene involved in metabolism.
"That double mutation," Hekimi told BioWorld Today, "raised the worms' life-spans five- to six-fold."
Can This Aging Slow-Down Work In Humans Too?
"In humans," Hekimi said, "there is a gene extremely similar to clk-1, a homolog by any definition. Nothing more is known in humans about it. Our paper," he continued, "shows that in vertebrates, worms and yeast the homologs are all having, probably, the same biochemical function -- whatever that is. So by studying it in worms, we're going to learn about that function."
Hekimi made the point: "That is not to say that we would then know in advance what a gene knockout in humans would entail. We might do a mouse knockout to get some idea what the consequences in vertebrates might be."
He added, "I am not going to do the mouse knockouts myself, but I have an indirect collaboration with a biotechnology company in the U.S. to pursue this line of research.
"Any gene that affects the life-span," said geneticist/molecular biologist Leonard Guarente, "gives one a possible window into the aging processes. That's the hope. A window into what it is in cells that is changing and causes aging. Those clock genes are the first real handle on that."
Thus, Guarente told BioWorld Today, "for a biotech company, one would want to go from gene to cellular process to maybe a way to influence that process, maybe to slow down aging. We're not there yet, of course; we're just now uncovering the genes. But that would be the path for the future."
Guarente, a professor of biology at Massachusetts Institute of Technology (MIT), wrote an editorial accompanying Hekimi's paper in Science.
Roundworms defecate every 50 seconds, by Hekimi's stopwatch. To quantify in real time the rate at which his mutated clk-1 timing genes slow down a worm's metabolism, he measured the defecation cycle. It slowed to about 90 seconds.
"We know some of the functions of the clk-1 gene homolog in yeast cells," Hekimi observed. "The yeast life span is like the Hayflick limit, which is the number of buddings a yeast cell can go through before stopping. We're checking into that."
Guarente makes the point that metabolism is not the sole arbiter of aging. Mice and bats, he observed, have about the same body mass, which supposedly correlates with metabolism, and hence with life expectancy. Yet mice survive about three years, and bats up to 20.
"What we're going to have to understand eventually," he said, "is both the input of metabolism, and also the other genetic strategies that organisms have to counteract the effects of metabolism, and which go together to read out the life-span."
He foresees that over the next five to 10 years "we're going to look in toto at all the genes that can be identified that affect life span, and see: Are there five? Are there 10? Hundreds? Do they all affect one or only a few processes in cells?"
Guarente suggests that, absent all traumatic and pathogenic curtailers of human life, including the accumulating infirmities of old age, the maximum human life span would be in the range of 120 years.
"If we understood aging," he concluded, and why our cells and our muscles change, and so on, maybe we could delay the infirmities. I think that's the benefit of slowing the aging processes. Not to live longer, but to delay the infirmities." *