After almost two years mired in extensive peer review, a landmark new study just published in the prestigious journal Nature is strongly associating excessive neural activity with shorter lifespans. The study suggests a protein known to suppress neural excitation affects a number of longevity pathways, effectively slowing the aging process.
The impressive research started several years ago with a gene expression study of post-mortem human brain tissue from hundreds of subjects. All the subjects were cognitively normal at the time of death. Bruce Yankner, senior author on the new study, says one thing quickly stood out to his team – the longer a person lived, the lower their expression of genes connected to neural excitement.
More specifically, the researchers identified upregulation of a protein called REST in the brains of those longest-lived subjects. REST first came to the attention of the research team back in 2014. The protein’s role in the brain was generally thought to only play a part in prenatal neurodevelopment, regulating the expression of genes in a developing brain.
The 2014 research revealed that REST seems to increase in activity in aging brains, and at the time it was suspected that downregulation of the protein in later life may play a role in the onset of Alzheimer’s and dementia.
“When in a person’s life are brain cells most vulnerable?” Yankner said back in 2014. “The first time is during fetal development, when loss of young neurons would be devastating. The second is during aging, when you’re bombarded by oxidative stress and misfolded or aggregated proteins, such as the amyloid beta and tau proteins seen in Alzheimer’s disease. It makes sense that a system would come on at those two times to protect neurons, which are largely irreplaceable.”
So, while it seemed like REST offered some kind of protection against age-related neurodegeneration, subsequent study suggested the protein’s activity correlated with lifespan in cognitively healthy adults as well. This implied general lifespan was influenced by neural activity, and excessive neural activity could be linked to early death.
To ascertain whether there was a causal connection between neural excitation and lifespan, the researchers set out to explore the effect of manipulating the REST gene in both worms and mice. And REST activity did indeed directly correlate with lifespan across several experiments. Boosting REST in worms, for example, both suppressed neural activity and extended the organism’s lifespan by around 30 percent.
Yankner notes that this reduction in neural excitability induced by enhancing REST expression did not result in dysfunctional brain activity. So it wasn’t as if the animals were so neurally slowed down they couldn’t function.
“The animals could still function – we didn’t put their brains into hibernation,” says Yankner in an interview with STATNews. “But by suppressing neural activity you can affect the aging process.”
Digging further into the mechanisms at play the researchers discovered a number of downstream processes could potentially explain how neural excitation may be interlinked with lifespan. For example, the study describes how REST seems to suppress a number of genes that influence neural excitability. One of these genetic mechanisms is related to insulin/IGF1 signaling, and low insulin/IGF1 signaling has been associated with longer lifespans in many animals.
On first glance the study’s conclusions seem somewhat counter-intuitive. After all, common scientific consensus suggests we should exercise our brains more in our senior years. And it was this discordancy that led to the study’s unusually long, two-year peer review process.
We know that as we age our brains become less neurally efficient than younger brains when tasked with cognitive challenges. We also know that hyper excitable neuronal activity is linked to the structural degeneration seen in Alzheimer’s disease.
Yankner does point out that the kind of excessive neural activity cited in his research is not the same as the neural activity that would occur in focused brain training exercises. In fact, it is unclear exactly how the excessive neural activity noted in the new research actually manifests in human behavior.
"An exciting future area of research will be to determine how these findings relate to such higher-order human brain functions,” says Yankner.
What this research does seem to interestingly validate is a small body of study linking behaviors such as mindfulness and meditation with the slowing of age-related cognitive decline. This implies behaviors that result in slowing down over-excited neurons could be beneficial to healthy aging.
But perhaps most interesting are the new research pathways introduced by the study, suggesting drugs that moderate neural excitability could extend lifespan in older adults. It is still incredibly early days, and there is absolutely no evidence that artificially stimulating REST activity in humans is safe, or effective, but Nektarios Tavernarakis, one of the peer reviewers of the new study, notes that the mechanistic links uncovered in the research are certainly very promising.
“… by buffering changes in overall neural excitation and maintaining a proper balance in neuronal-network activity, REST might also prevent age-related neurological disorders to boost longevity in humans,” Tavernarakis writes in an editorial accompanying the new study. “Indeed, accumulating evidence couples neural overexcitation to Alzheimer’s disease. So REST and other molecules that control neural excitability are possible targets for interventions aimed at battling the decline and maladies of old age.”
The new study was published in the journal Nature.
Source: Harvard Medical School
