Studies by scientists at the Blavatnik Institute, Harvard Medical School (HMS), have provided the first evidence that the level of activity in the human nervous system may impact on lifespan. Neural activity in the brain has previously been implicated in disorders including dementia and epilepsy, but while previous studies have suggested that parts of the nervous system can influence aging in animals, the role of neural activity in aging, especially in humans, hasn’t been well understood.

The newly reported research combines data from studies in humans, mice and the nematode model organism Caenorhabditis elegans. The combined results suggest that increased neural activity in the brain is linked with shorter lifespan, while suppressing neuronal excitability extends lifespan. The degree of neuronal activity appears to be under the control of a known transcriptional repressor, REST, which the researchers suggest could represent a target for holding back the ageing process in humans. “We suggest that activation of REST and reduction of excitatory neural activity could be an approach to slowing ageing in humans,” they report in Nature.

“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,” said study senior author Bruce Yankner, PhD, professor of genetics at HMS and co-director of the Paul F. Glenn Center for the Biology of Aging. Yankner and colleagues report their findings in a paper titled, “Regulation of lifespan by neural excitation and REST.”

Studies in invertebrate and mammalian models suggest that specific types of sensory or neurosecretory neurons and signalling circuits my play a role in the regulation of ageing, but “whether the activity state of the nervous system affects the ageing process is unclear,” the authors wrote. To investigate this in greater detail, Yankner and colleagues looked at gene expression patterns in the brains of older people, by analyzing RNA sequencing and microarray data from the donated frontal cortex brain tissue of hundreds of people who died at ages ranging from 60 years to over 100 years. The data were collected from three studies, ROSMAP, CommonMind Consortium (CMC), and Gibbs, and included only individuals without dementia.

The results showed that the most significant difference in gene expression patterns between the extended longevity groups, who lived until 85 years or more, and those who lived for 60-80 years, was the downregulation of genes related to neural excitation and synaptic function, and the upregulation of genes involved in immune function. “These results suggest that extended human longevity may be associated with reduced excitatory neurotransmission,” the authors stated.

To further study the neural regulation of longevity the scientists monitored neural excitation in C. elegans, which is a well-established model system for ageing studies. They found that using either genetic or chemical manipulation to reduce neural excitation in young or adult worms extended the animals’ lifespan. “Together, these results suggest that continuous or late-life repression of neural excitation in multiple neuronal cell populations extends lifespan in C. elegans,” they stated. Conversely, increasing neural excitation in the worms resulted in shorter lifespan. “Thus, the effects of neurotransmission on lifespan are bidirectional; lifespan is extended by reducing excitation and shortened by increasing excitation.”

New research links excess neural activity — the flickering light seen in this image — to reduced longevity. [Yankner lab, Harvard Medical School]

The researchers next set out to address whether the results were simply correlation, or were actually causal, in other words, was this disparity in neural excitation and lifespan simply a symptom of other factors that were causal in determining lifespan, or were excitation levels directly affecting longevity, and if so, how? To investigate this the team carried out a suite of genetic, cell and molecular biology tests in C. elegans, as well as in genetically altered mice, and undertook additional brain tissue analyses of people who live to 100 years or more.

They found that levels of the transcriptional repressor, REST, were increased in the prefrontal cortical neurons of centenarians, when compared with individuals who lived to 70-80 years of age. REST has previously been shown by the Yankner Lab to protect aging brains from dementia and other stresses. “These results suggest that REST repressor function is upregulated in the brain in individuals with extended longevity, resulting in downregulation of genes that mediate excitation and synaptic function,” the team noted. The results of further experiments in mice also indicated that REST globally acts to repress neural activity and prevent hyperexcitation in the ageing brain.

Interestingly, blocking REST or its equivalent – including SPR-3 and SPR-4 in C. elegans – led to higher neural activity and earlier death. Conversely, increasing REST resulted in extended lifespan. The researchers found that from worms to mammals, REST or its equivalent suppressed the expression of genes that are centrally involved in neural excitation, such as ion channels, neurotransmitter receptors and the 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. “It was extremely exciting to see how all these different lines of evidence converged,” said study co-author Monica Colaiácovo, PhD, professor of genetics at HMS, whose lab collaborated on the C. elegans work.

“We have shown that extended longevity and cognitive preservation in humans is associated with coordinate downregulation of genes that mediate excitatory neurotransmission,” the authors concluded. “Our findings suggest that REST and the C. elegans orthologues SPR-3 and SPR-4 regulate ageing by acting as transcriptional repressors of synaptic genes and thereby reducing neural activity. Ageing conditional REST-deficient mice exhibit increased cortical neural activity and hyperexcitability. This is consistent with previous studies in neuronal cell culture, which suggested that REST maintains neural network homeostasis by buffering changes in neural excitation.”

What’s not yet clear from the study is whether or how a person’s thoughts, personality or behavior might 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 findings could also help to inform the design of new treatment strategies for disorders that involve neural overactivity, such as Alzheimer’s disease or bipolar disorder, the researchers said. Human variation in neural activity might have both genetic and environmental causes, which would open future avenues for therapeutic intervention. In addition to its emerging role in staving off neurodegeneration, the discovery of REST’s role in longevity could provide even greater motivation to develop drugs that target the protein. “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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