5th November 2019

Link found between neural activity and human longevity

Researchers from Harvard Medical School have identified a link between neural activity and human longevity. Neural excitation is linked to a shorter lifespan, while suppression of overactivity appears to extend lifespan.

The brain's neural activity – long implicated in disorders ranging from dementia to epilepsy – plays a role in human aging and lifespan, according to research led by scientists in the Blavatnik Institute at Harvard Medical School (HMS). The study, published in Nature, is based on findings from human brains, mice and worms and suggests that excessive activity in the brain is linked to shorter life spans, while suppressing such overactivity extends life.

These findings offer the first evidence that the activity of the nervous system affects human longevity. Although previous studies had suggested that parts of the nervous system influence aging in animals, the role of neural activity in aging, especially in humans, remained murky.

"An intriguing aspect of our findings is that something as transient as the activity state of neural circuits could have such far-ranging consequences for physiology and lifespan," says Bruce Yankner, Professor of Genetics at HMS and senior study author.

Neural excitation appears to act along a chain of molecular events famously known to influence longevity: the insulin and insulin-like growth factor (IGF) signalling pathway. The key in this "signalling cascade" appears to be a protein called REST, previously shown by the Yankner Lab to protect aging brains from dementia and other stresses. Neural activity refers to the constant flicker of electrical currents and transmissions in the brain. Excessive activity, or excitation, could manifest in numerous ways, from a muscle twitch to a change in mood or thought, the authors say. However, it is not yet clear how exactly a person's thoughts, personality or behaviour affect their longevity.

"An exciting future area of research will be to determine how these findings relate to such higher-order human brain functions," said Yankner.

The study could inform the design of new therapies for conditions involving neural overactivity, such as stress, anxiety and bipolar disorder. The findings raise the possibility that new drugs targeting REST – or calming activities such as meditation, yoga, and floatation tanks – could extend human lifespans by modulating neural activity, according to the researchers.



Image courtesy of Floatworks

Yankner and colleagues began their study by analysing gene expression patterns (the extent to which various genes are turned on and off), in brain tissue donated from hundreds of people who died at ages ranging from 60 to over 100. Each was "cognitively intact", meaning they had no dementia. A striking difference appeared between the older and younger study participants: the longest-lived people – those over 85 – had a 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? Was this disparity in neural excitation merely occurring alongside more important factors determining life span, or were excitation levels directly affecting longevity? If so, how?

The team conducted a whole series of experiments – including genetic, cell and molecular biology tests in the worm Caenorhabditis elegans; analyses of genetically altered mice; and additional brain tissue analyses of people who lived more than a century. These experiments revealed that altering neural excitation does indeed affect lifespan, and illuminated what might be happening on a molecular level.

All signs pointed to the protein known as REST, mentioned earlier. RE1-Silencing Transcription factor (REST) is known to regulate genes, but also suppresses neural excitation, the scientists found. Blocking REST or its equivalent in the animal models led to higher neural activity and earlier deaths – while boosting REST did the opposite. Meanwhile, humans who reached the age of 100 or above had significantly more REST in the nuclei of their brain cells than people who died in their 70s or 80s.

"It was extremely exciting to see how all these different lines of evidence converged," said Monica Colaiácovo, study co-author and Professor of Genetics at HMS, whose lab collaborated on the C. elegans work. As shown in the video below, neural activity was much higher in normal worms (orange flashes, left) than in extremely long-lived worms (right).

From worms to mammals, the researchers found that 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 signalling in many animals – the same pathway that scientists believe is activated by caloric restriction.

In addition to its emerging role in staving off neurodegeneration, the discovery of REST's role in longevity provides additional motivation to develop drugs that target the protein. Although it will take time and many tests to determine whether such treatments reduce neural excitation, promote healthy aging or extend human lifespan, the concept has captivated some researchers.

"The possibility that being able to activate REST would reduce excitatory neural activity and slow aging in humans is extremely exciting," said Colaiácovo.

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