An overactive brain may not be a healthy brain

A study published in Nature on Oct. 16, 2019 has provided some experimental evidence linking decreased neural activity as a possible mechanism for extending the lifespan of humans. So far scientific research has not given people a very clear look at what causes something to drastically increase a person’s lifespan, as these mechanisms are generally are not very well understood.

This potential breakthrough still has lots of research ahead of it that must be put in it before concrete evidence is produced suggesting a certain lifestyle change. But the study so far is promising and could potentially lead to the creation of drugs or implementation of cultural changes in the future with the purpose of down-regulating brain activity.

A group of researchers from Harvard’s genetics, neurology, and medical school, as well as a few from the medical school at the University of Texas, teamed up to look into the gene expression of a few key genes thought to regulate aging. One very important group of proteins that regulate gene expression is called transcription factors.

These transcription factors are essential for cell differentiation, as all cells have the same DNA but do not express the same genes. Essentially, they are responsible for why your bone cells perform such drastically different functions than the neurons that make up your brain and nervous system.

In this study, the transcription factor of interest is called REST. Researchers found this transcription factor is up-regulated in humans with extended lifespan and represses excitation-related genes. Research using invertebrates and mammals as model organisms has given scientists a general idea that the nervous system plays a certain role in the regulation of aging. One common invertebrate that has been extensively studied is a nematode named C. elegans.

To answer difficult questions in science, model organisms – a certain species that has been widely studied – are used for understanding conserved biological processes. These new understandings can then be applied to humans or other species to enhance our overall understanding of how key processes such as aging work.

A certain nematode (roundworm invertebrate and model organism) called C. elegans was chosen among other species to study how neural excitation affects lifespan. The researchers knew of a treatment that would decrease neural excitation in the roundworms through the addition of a drug called nemadipine. This drug inhibits calcium channels in the brain, leading to an overall decrease in neural activity.

With a continuous treatment of this drug, or others that have the same overall effect of down-regulating neural excitation, the roundworms showed an extension of lifespan. The researchers also looked at how elevating neural excitation affects the lifespan of the roundworm.

To do this, C. elegans was once again used, but the neural pathway being studied involved an overall excitation of neural activity. The nematodes were treated with a technique called RNA-mediated inhibition (RNAi) which will have the overall effect of increased excitation in a certain type of neuron in C. elegans called “ASH.” When this neuron was highly excited, the nematodes that received the RNAi treatment showed a significant decrease in lifespan.

Researchers also looked at how the REST transcription factor is expressed in the aging human brain. To test this, specific genomic analyses were run to see how highly expressed REST was. It became evident that in the extended longevity group (over 100 years of age compared to 70 – 80 years) had increased expression for REST and therefore decreased genes that mediate excitation and synaptic function.

A co-author on the paper published in Nature, Dr. Bruce Yankner, who is a genetics and neurology professor at Harvard Medical School, explained the possibility that as people age, REST could upregulate naturally. This would explain their findings that people who tend to live longer express REST in higher quantities.

More researchers looking into aging hope to better understand the mechanism in humans which opens the potential for lifestyle changes that decrease neural excitation or drug production with the purpose of extending life through this mechanism.