The visible impacts of depression and stress that
can be seen in a person's face - and contribute to
shorter lives - can also be found in alterations in
genetic activity, according to newly published
research. In a series of studies involving both C.
elegans worms and human cohorts, researchers from
the Indiana University School of Medicine and the
Scripps Research Institute have identified a series
of genes that may modulate the effects of good or
bad mood and response to stress on lifespan.
In particular, the research pointed to a gene known
as ANK3 as playing a key role in affecting
longevity. The research was published May 24, 2016
in the Nature Publishing Group journal Molecular
Psychiatry.
"We were looking for genes that might be at the
interface between mood, stress and longevity", said
Alexander B. Niculescu III, M.D., Ph.D., professor
of psychiatry and medical neuroscience at the IU
School of Medicine. "We have found a series of genes
involved in mood disorders and stress disorders
which also seem to be involved in longevity.
"Our subsequent analyses of these genes found that
they change in expression with age, and that people
subject to significant stress and/or mood disorders,
such as people who completed suicide, had a shift in
expression levels of these genes that would be
associated with premature aging and reduced
longevity" said Dr. Niculescu, who is also attending
psychiatrist and research and development
investigator at the Indianapolis Veterans Affairs
Medical Center.
The research began with studies in C. elegans, a
worm widely used in life sciences research. An
earlier study by one of the study co-authors,
Michael Petrascheck, Ph.D., of the Scripps Research
Institute, found that exposing C. elegans to the
antidepressant mianserin, which is used to treat
mood and stress disorders, extended the animal's
lifespan.
In the Molecular Psychiatry study, the researchers
methodically conducted a series of analyses to
discover, prioritize, validate, and understand the
genes involved, comprising ten steps:
In C. elegans, 231 genes were identified whose
activities were altered after administration of
mianserin and for which there were 347 similar genes
in humans.
The 347 human genes were cross-referenced with a
genome analysis of data from 3,577 older adults to
identify those genes that might be associated with
depressive symptoms in humans, resulting in 134
genes that overlapped.
The 134 genes were prioritized for involvement in
mood disorders and stress disorders, using the
Niculescu lab's Convergent Functional Genomics
approach and comprehensive databases of human and
animal model genetic and gene expression studies in
psychiatric disorders. The top scoring gene from the
list was ANK3, which in recent years has become well
known as playing a role in psychiatric disorders.
Returning to the C. elegans model, the researchers
tested the effects of mianserin and of oxidative
stress on worms with mutated -- and therefore
inactive -- versions of the ANK3 gene, compared to
non-mutated wild-type worms. ANK3 expression
increases with age in worms. Mianserin maintains
lower, youthful levels of ANK3 expression, but does
require some ANK3 to be present for its effects on
longevity. Thus, there seems to be a "Goldilocks"
effect.
Next, using more than 700 blood samples from
patients diagnosed with psychiatric disorders, as
well as studying samples from the Marion County
(Indianapolis, Ind.) Coroner's office of people who
had committed suicide, the investigators found
significantly higher levels of expression of ANK3 in
older (middle aged) patients than in younger
patients, and a shift towards higher ANK3 levels in
those who had committed suicide. Higher levels of
ANK3 have also been reported independently by others
in individuals with Hutchinson-Gilford progeria
syndrome, a form of accelerated aging.
Adding genes that had scored nearly as high as ANK3
in the Convergent Functional Genomics analysis to
create a panel of biomarkers showed similar but
somewhat stronger results, particularly among those
who had committed suicide.
Mitochondrial dysfunction was the top biological
pathway where the top candidate genes for mood and
stress-modulated longevity mapped. Over the last
decade, accumulating evidence has suggested a
causative link between mitochondrial dysfunction and
aging.
A few of the genes identified in this study are
changed in opposite direction in longevity compared
to previous reports in Alzheimer's disease, raising
the possibility that the treatment of mood and
stress disorders earlier in life might have an
impact on later life Alzheimer's disease.
A large number of top genes identified in this study
were changed in opposite direction in longevity
compared to patterns of expression in suicide
revealed by previous studies from the Niculescu
group, suggesting the possibility of an evolutionary
organismal "life switch", actively controlled by
mood and stress.
For more information
Molecular Psychiatry
Mood, stress and longevity: convergence on ANK3
Link...
Indiana University
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