When molecular biologist Cynthia Kenyon began to research the genetics of aging, she had the field much to herself. “When we first started studying aging, we had trouble getting anyone interested in it,” she recalled, “because they thought it was incredibly boring.”

But then Kenyon’s lab uncovered a single gene mutation in roundworms that doubled their lifespan, and aging became one of the hottest topics in biology. As she told her audience at the AAAS Annual Meeting, scientists began to see the process of getting older as a newly dynamic force. Now, she and others are searching for ways to manipulate the process to allow humans to live healthier and longer lives.

“It wasn’t so long ago that aging was something that just happened,” like a car slowly breaking down, said Kenyon, who serves as director of the Hillblom Center for the Biology of Aging at the University of California, San Francisco.

Cynthia Kenyon speaking at the AAAS Annual Meeting on aging and biology. Credit: Atlantic Photography Boston

But, most major biological events do not just unfold on their own. Instead, she noted in her Plenary Lecture, they are subject to an “incredibly complex system of regulation by genes and proteins.” It seemed to Kenyon that aging might have its own complicated backstory.

That story sprang to life with the 1993 discovery of the roundworm daf-2 gene in her laboratory. Worms with a mutation in the gene lived twice as long as their peers, Kenyon said, and were much more spry than those companions in the worm “nursing home.”

The daf-2 gene extends lifespan through a molecular pathway leading to another key gene called daf-16; daf-2 sends signals to daf-16, prodding it to begin switching a variety of other genes on and off. Over the years, Kenyon’s lab and others have explored the details of this key relationship, discovering that mutations in these genes affect a number of important jobs in the cell, including protection against stress, protein folding, metabolism and immune response.

At the same time, laboratories around the world have uncovered equivalent genes in mice, fruit flies and humans, including a human counterpart of daf-16, called FOXO3A, that has been associated with exceptional longevity in populations around the world, Kenyon said.

Under normal conditions, the daf genes—and their counterparts in humans—help cells grow and thrive. When daf-2 is mutated, however, the cells read this as a danger signal and mount an impressive protective response. The worms become “resistant to just about anything you can do to them,” Kenyon said, including staving off the effects of heat, cold, drying and toxins.

It’s this response that slows the rate of aging and leads to longer lifespan, Kenyon noted. She compared it to a proactive building maintenance supervisor who wisely watches the weather report and boards up the windows in advance of a storm.

Kenyon’s lab and others are searching for ways to bring on these storms, albeit in a controlled way, to trigger the protective response. Restricting calories, lowering rates of respiration and removing the cells that give rise to eggs and sperm are a few of the methods that researchers have used to extend animal lifespan in the lab.

The search is now on to find small molecules that could be used to manipulate aging’s molecular pathways. “These pathways that slow aging also have the wonderful property of counteracting age-related disease,” Kenyon said. 

Researchers have documented lower rates of cancer, cardiovascular diseases and Alzheimer’s-like disorders in mice with these aging mutations, she said.