How Overexcited Neurons Might Affect How You Age

A thousand seemingly insignificant things change as an organism ages . Beyond the obvious signs like graying hair and memory problems are myriad shifts both subtler and more consequential: Metabolic processes run less smoothly; neurons respond less swiftly; the replication of DNA grows faultier.Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research develop­ments and trends in mathe­matics and the physical and life sciences.

But while bodies may seem to just gradually wear out, many researchers believe instead that aging is controlled at the cellular and biochemical level. They find evidence for this in the throng of biological mechanisms that are linked to aging but also conserved across species as distantly related as roundworms and humans. Whole subfields of research have grown up around biologists’ attempts to understand the relationships among the core genes involved in aging, which seem to connect highly disparate biological functions, like metabolism and perception. If scientists can pinpoint which of the changes in these processes induce aging, rather than result from it, it may be possible to intervene and extend the human life span.

So far, research has suggested that severely limiting calorie intake can have a beneficial effect, as can manipulating certain genes in laboratory animals. But recently in Nature, Bruce Yankner, a professor of genetics and neurology at Harvard Medical School, and his colleagues reported on a previously overlooked controller of life span: the activity level of neurons in the brain. In a series of experiments on roundworms, mice and human brain tissue, they found that a protein called REST, which controls the expression of many genes related to neural firing, also controls life span. They also showed that boosting the levels of the equivalent of REST in worms lengthens their lives by making their neurons fire more quietly and with more control. How exactly overexcitation of neurons might shorten life span remains to be seen, but the effect is real and its discovery suggests new avenues for understanding the aging process.Genetic Mechanisms of AgingIn the early days of the molecular study of aging, many people were skeptical that it was even worth looking into. Cynthia Kenyon, a pioneering researcher in this area at the University of California, San Francisco, has described attitudes in the late 1980s: “The ageing field at the time was considered a backwater by many molecular biologists, and the students were not interested, or were even repelled by the idea. Many of my faculty colleagues felt the same way. One told me that I would fall off the edge of the Earth if I studied ageing.”
That was because many scientists thought that aging (more specifically, growing old) must be a fairly boring, passive process at the molecular level — nothing more than the natural result of things wearing out. Evolutionary biologists argued that aging could not be regulated by any complex or evolved mechanism because it occurs after the age of reproduction, when natural selection no longer has a chance to act. However, Kenyon and a handful of colleagues thought that if the processes involved in aging were connected to processes that acted earlier in an organism’s lifetime, the real story might be more interesting than people realized. Through careful, often poorly funded work on Caenorhabditis elegans, the laboratory roundworm, they laid the groundwork for what is now a bustling field.

Cynthia Kenyon, professor emeritus at the University of California, San Francisco, pioneered the study of aging mechanisms at a time when many biologists considered that field a “backwater.”Photograph: Cindy Chew/UCSF
A key early finding was that the inactivation of a gene called daf-2 was fundamental to extending the life span of the worms. “daf-2 mutants were the most amazing things I had ever seen. They were active and healthy and they lived more than twice as long as normal,” Kenyon wrote in a reflection on these experiments. “It seemed magical but also a little creepy: they should have been dead, but there they were, moving around.”

This gene and a second one called daf-16 are both involved in producing these effects in worms. And as scientists came to understand the genes’ activities, it became increasingly clear that aging is not separate from the processes that control an organism’s development before the age of sexual maturity; it makes use of the same biochemical machinery. These genes are important in early life, helping the worms to resist stressful conditions during their youth. As the worms age, modulation of daf-2 and daf-16 then influences their health and longevity.