Some people live longer than others. Why is that? Setting aside life-shortening causes, such as accidents, violent acts, and infectious diseases, some people seem to age more slowly than others. Their physical and mental powers decline at a slower rate. Some of this is due to lifestyle and diet choices, but there is more to it than that.

A recent paper by Joseph M. Zullo and colleagues in the 17 October 2019 issue of the high-impact scientific journal, Nature, analyzed the brains of 573 people who had died. The data fell largely into two clusters, one of people aged less than 80 and the other consisting of people aged 85 and over. The people who had died at a younger age had lower levels of a transcription factor named REST (repressor element 1-silencing transcription factor), and the people who had died at older ages had more of it. Centenarians had about 70% more REST in their prefrontal cortical neurons than did people who died in their seventies.

The question that naturally arises is, “What does REST do in the brain?” Bruce Yankner’s group, including Zullo, at the Harvard Medical School, has studied REST and found that it represses neural excitation. A certain amount of neural excitation is good. It would be hard to get any thinking done without it. However, excessive excitation is harmful, leading to diseases such as epilepsy. The correlation of high levels of REST with extended lifespan in humans also led to the hypothesis that less neural excitation might extend lifespan.

To test the hypothesis, Zullo turned to the well-studied nematode worm Caenorhabditis elegans. C. elegans has proteins that correspond to REST in mammals. These proteins repressed neural excitation in the worms and extended their lifespans. To confirm this finding, Zullo next turned to mice, finding that REST represses neural excitation in them also and leads to life extension.

The experiments with worms and mice seem to confirm the conclusion from mining human datasets that recorded REST levels in the brains of deceased individuals. People who survived longer had more REST in their brains.

Can we apply these findings to our own quests to lead long and healthy lives?

Yes. Any time we learn something new about factors that affect the aging process, we come closer to controlling that process. There are drugs that are known to act to downregulate genes that mediate excitatory neurotransmission. Some of these drugs were used in the C. elegans experiments and lifespans were extended compared to untreated control organisms. Much additional work must be done before we will know whether an intervention similar to those performed on the worms and mice in these experiments, can extend the lives of humans. However, we are now one step closer to the day when such an experiment can be performed.