For reasons that science has not yet fathomed, life span differs radically among creatures, even among those roughly similar in size and physiology.

Mice, canaries and bats are small, warm-blooded animals of the same approximate size, but the mouse lives 2 years, the canary 13 and the bat more than 30. For humans, development and senescence can take 70 to 100 years, while their best friends -- dogs -- have a life ten times shorter.

It might seem that people age simply because their bodies become damaged and wear out. But evidence emerging from studies of a tiny worm is beginning to suggest that our length of stay on Earth instead may be governed largely by the normal patterns whereby genes are either activated or are made dormant.

A new study reported by UCSF scientists in today’s (Nov. 14) issue of Science demonstrates that gene activity can be manipulated to alter life span.

According to a research team led by Cynthia Kenyon, PhD, the Herbert Boyer Professor of Biochemistry and Biophysics at UCSF, changes in the activity of a single gene--at least in the lint-sized, free-living roundworm, Caenorhabditis elegans--is sufficient to more than double the animal’s life span.

The relevance of C. elegans’ anatomy, genetics and physiology to humans may not be obvious, but it is well accepted by biomedical researchers. In fact, in conjunction with the much celebrated Human Genome Project, aimed at mapping all human genes, researchers are similarly mapping the ten-fold smaller complement of genes possessed by C. elegans. The simplicity of C. elegans may permit scientists to more quickly advance their understanding of basic biological phenomena.

"Worms look different and are simpler than vertebrates such as ourselves, but the basic processes of life are carried out by similar genes, including those governing patterns of growth and development," Kenyon says.

"We know next to nothing about aging," she adds. "But because so many of these basic biological processes are conserved throughout evolution, it is likely that what we learn about aging in the worm will apply to more complex organisms, including humans."

Investigations by Kenyon's research team of the gene called daf-16 show that it is related to a large class of genes that is also present in vertebrates, including humans. These genes are called "forkhead" genes, because of the shape of the proteins they encode.

Forkhead proteins perform a supervisory role in the cell's nucleus. They attach to DNA and thereby control the activity of genes. These genes, through the production of additional proteins, in turn, guide development and growth. However, specific functions are known for only a few forkhead proteins.

Kenyon's group has discovered that the uninhibited activity of the forkhead gene daf-16 in C. elegans can more than double the worm's two to three week life span, apparently without altering growth or development. The finding suggests that similar, as yet unidentified forkhead genes may govern life span in vertebrates, including humans, according to Kenyon.

Now that daf-16 has been cloned by members of Kenyon's group, and independently by another research team led by Gary Ruvkun of Massachusetts General Hospital and Harvard Medical School, researchers can now manipulate its activity to investigate how it affects other genes.

Kenyon hopes to identify these "downstream" genes, one or more of which may be more directly involved in controlling life span, she says. Once these genes are identified in C. elegans, it will be easier to look for life span controlling counterparts in vertebrates, including humans, she adds.

By Jeffrey Norris

1st appeared 11/14/97

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