Longevity: Gene-Mapping Gives Glimpse into Life Span

Susan Van Dusen

What do humans have in common with a millimeter-long, translucent roundworm? Based on the findings of Robert J. S. Reis, D.Phil., more than you would imagine.

For more than 30 years, Reis has mapped the genes of these roundworms, known as C. elegans, in an effort to understand the genetics of why we age. They are, he said, “a wonderful model for studying longevity.”

After earning his doctorate degree in Britain under the mentorship of the late John Maynard Smith, one of the world’s leading evolutionary biologists, Reis worked in the U.K. and Canada before coming to UAMS in 1980. Ten years later, Tom Johnson, Ph.D., a scientist and friend at the University of Colorado, invited him for a sabbatical to study aging in nematodes, also known as roundworms.

“That gave me a jump-start for a project I had been considering for years,” said Reis, a professor in the UAMS Departments of Geriatrics, Biochemistry/Molecular Biology and Pharmacology/Toxicology. “I had devised a way to find the genes that allow longevity to evolve, by mapping those genes on chromosomes and studying their interactions.  The nematode provided an ideal model system for that study.” 

At the time, there were no gene mapping procedures in animal biology, but Reis used his own protocols to map 13 genes in the nematode that strongly determined lifespan.  Recently, one of those genes was identified; it encodes a protein that stabilizes the genome of germline cells, important for tuning lifespan in worms, yeast and whales. 

Most genes that make up key pathways in development and aging are so critical that they have maintained similar structures and functions from worms to humans. The nematode insulin-­like pathway, for example, corresponds gene-for-gene to human insulin and insulin-like growth factor response pathways.  

“We have made huge strides in understanding the processes that contribute to aging.”
“We pursued a gene that encodes the class-I PI3K enzyme, which lies at the crossroads between insulin-like signaling and other pathways for stress, innate immunity and nutrient signaling,” he said.  Reis and his colleague, Srinivas Ayyadevara, Ph.D., found that inactivating mutations in that gene extend worm life span 10-fold, a record for any organism.  

Reis also serves as senior research career scientist at the Central Arkansas Veterans Healthcare System.

C.elegansReis is now collaborating with Peter Crooks, Ph.D., chairman of the Department of Pharmaceutical Sciences in the UAMS College of Pharmacy, to develop a novel drug to inhibit PI3K. Other drugs developed by Crooks also are being tested in Reis’ lab for ability to alleviate or delay the onset of neurodegenerative conditions such as Alzheimer’s, Huntington’s and Parkinson’s diseases.

“Some of these drugs work remarkably well in nematode models of these diseases, to delay symptoms and reduce nerve damage,” he said.

But while many of these studies look promising, it’s a long road before that translates into a drug for humans. That’s one reason Reis also has begun looking at biomarkers of longevity and age to help determine a person’s molecular youthfulness.  These discoveries could allow us to see much more rapidly whether lifestyle changes or specific drugs are able to set back the biological clock, he said.

“We have made huge strides in understanding the processes that contribute to aging,” he said.  “Now we are beginning to use that knowledge to find new ways to reduce the burden of age-related diseases. I can’t tell you yet what will work – only that biology is full of surprises.”