REST Regulates Neural Activity and Influences Life Span

Researchers here report their findings on the activity of the REST gene, which both regulates neural activity and appears to influence life span, likely through indirect effects on the well-studied processes of insulin signaling. As such, this is interesting for the connection to neural activity, but otherwise irrelevant to the future of developing means to lengthen human life span. Effect sizes related to insulin signaling are much larger in short-lived lower species than they are in long-lived higher species, and they are in any case only a way to modestly slow aging, not a road to rejuvenation.

Researchers began their investigation by analyzing gene expression patterns in donated brain tissue from hundreds of people who died at ages ranging from 60 to over 100. The information had been collected through three separate research studies of older adults. Those analyzed in the current study were cognitively intact, meaning they had no dementia. Immediately, a striking difference appeared between the older and younger study participants: The longest-lived people - those over 85 - had lower expression of genes related to neural excitation than those who died between the ages of 60 and 80.

Next came the question that all scientists confront: correlation or causation? The team conducted a barrage of experiments, including genetic, cell and molecular biology tests in the model organism Caenorhabditis elegans; analyses of genetically altered mice; and additional brain tissue analyses of people who lived for more than a century.

These experiments revealed that altering neural excitation does indeed affect life span-and illuminated what might be happening on a molecular level. All signs pointed to the protein REST. REST, which is known to regulate genes, also suppresses neural excitation, the researchers found. Blocking REST or its equivalent in the animal models led to higher neural activity and earlier deaths, while boosting REST did the opposite. And human centenarians had significantly more REST in the nuclei of their brain cells than people who died in their 70s or 80s.

The researchers found that from worms to mammals, REST suppresses the expression of genes that are centrally involved in neural excitation, such as ion channels, neurotransmitter receptors and structural components of synapses. Lower excitation in turn activates a family of proteins known as forkhead transcription factors. These proteins have been shown to mediate a "longevity pathway" via insulin/IGF signaling in many animals. It's the same pathway that scientists believe can be activated by caloric restriction.


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