The brain's neural activity -- long
implicated in disorders ranging from dementia to epilepsy -- also plays a
role in human aging and life span, according to research led by
scientists in the Blavatnik Institute at Harvard Medical School.
Roundworm Caenorhabditis elegans (stock image).
Credit: © heitipaves / Adobe Stock
The study, published Oct. 16 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.
The 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 life span," said study senior author
Bruce Yankner, professor of genetics at HMS and co-director of the Paul
F. Glenn Center for the Biology of Aging.
Neural excitation appears to act along a chain of molecular events
famously known to influence longevity: the insulin and insulin-like
growth factor (IGF) signaling pathway.
The key in this signaling 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 said.
It's not yet clear from the study whether or how a person's thoughts, personality or behavior 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
that involve neural overactivity, such as Alzheimer's disease and
bipolar disorder, the researchers said.
The findings raise the possibility that certain medicines, such as
drugs that target REST, or certain behaviors, such as meditation, could
extend life span by modulating neural activity.
Human variation in neural activity might have both genetic and
environmental causes, which would open future avenues for therapeutic
intervention, Yankner said.
All roads lead to REST
Yankner and colleagues began their investigation by analyzing gene
expression patterns -- the extent to which various genes are turned on
and off -- 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, said Yankner: 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? 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 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.
"It was extremely exciting to see how all these different lines of
evidence converged," said study co-author Monica Colaiácovo, professor
of genetics at HMS, whose lab collaborated on the C. elegans work.
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.
In addition to its emerging role in staving off neurodegeneration,
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
life span, 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.
The authors emphasize that the work would not have been possible without large research cohorts of aging people.
"We now have enough people enrolled in these studies to partition the
aging population into genetic subgroups," said Yankner. "This
information is invaluable and shows why it's so important to support the
future of human genetics."
Funding and authorship
Postdoctoral fellows Joseph Zullo and Derek Drake of the Yankner Lab
are co-first authors. Additional HMS co-authors are Liviu Aron, Patrick
O'Hern, Noah Davidsohn, Sameer Dhamne, Alexander Rotenberg and George
Church, the Robert Winthrop Professor of Genetics. Davidsohn and Church
are also affiliated with the Wyss Institute for Biologically Inspired
Engineering at Harvard University.
Other co-authors are affiliated with the University of Texas McGovern
Medical School, the University of Texas MD Anderson Cancer Center and
Rush University Medical Center.
This work was supported by an NIH Director's Pioneer Award
(DP1OD006849) and National Institutes of Health grants R01AG046174,
R01AG26651, R01GM072551, P30AG10161, R01AG15819, R01AG17917, R01AG36836,
U01AG46152, EY024376, EY011930 and K99AG050830, as well as the Glenn
Foundation for Medical Research and the Ludwig Family Foundation.
Journal Reference:
- Joseph M. Zullo, Derek Drake, Liviu Aron, Patrick O’Hern, Sameer C. Dhamne, Noah Davidsohn, Chai-An Mao, William H. Klein, Alexander Rotenberg, David A. Bennett, George M. Church, Monica P. Colaiácovo & Bruce A. Yankner. Regulation of lifespan by neural excitation and REST. Nature, 2019 DOI: 10.1038/s41586-019-1647-8
Courtesy: ScienceDaily
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