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'Runaway' development implicated in loss of
function of the aging brain
July 20, 2010 – The brain undergoes rapid growth and
development in the early years of life and
then degenerates as we progress into old
age, yet little is known about the
biological processes that distinguish brain
development and aging.
In a report published online today in Genome Research
(http://www.genome.org),
researchers have identified a gene
regulatory link between changes in the young
and aging brain, describing "runaway"
development as a potentially significant
factor in age-related loss of function.
The brain grows and changes dramatically during the early
years of life, with some developmental
processes extending well into adulthood. In
later years, the brain undergoes destructive
changes, such as a drop in brain volume,
synapse loss, and cognitive decline.
While brain development and aging are areas of intense
research, they are traditionally studied
separately, and little is known about the
boundaries between the two processes.
Underlying brain development is the complex and coordinated
process of gene regulation. "In development,
many genes are turned on and off by
regulators, such as transcription factors
and microRNAs." said Mehmet Somel,
postdoctoral researcher at the Shanghai
Institutes for Biological Sciences. "The
question is, do all of these regulatory
processes cease once adulthood is reached,
or are they still active in aging?"
Somel and an international team of researchers addressed
this question by investigating messenger RNA
(mRNA), microRNA, and protein expression
changes in the prefrontal cortex of humans
and rhesus macaque monkeys over the life
span of each species. The prefrontal cortex
is believed to be involved in functions such
as complex behavior, personality, and
decision-making.
The group found that distinct patterns of gene regulation
in the prefrontal cortex do not stop at
maturity, instead persisting into old age, a
phenomenon that was observed for many
different functional processes. One
particularly striking example was the
down-regulation of genes related to neuronal
function.
Previous work has shown that neuronal genes gradually lose
activity with age, attributed to an
accumulation of damage in neuronal cells
over a lifetime. Somel and colleagues have
now shown that this process begins as early
as three to four years of age, suggesting
that these changes may be normal
developmental regulation that continues long
into old age. While this regulation is
likely to be beneficial during development,
at old age continuation of the gene
regulation, or "runaway" development, might
be detrimental.
Interestingly, they found the runaway neuronal development
to be conserved in macaques, but it occurs
an accelerated rate. Because the regulatory
processes progress much faster, the authors
suggest that this could be a significant
contributor toward limiting the life span of
macaques to only about one-third that of
humans.
The authors caution that aging is a very complex process
stemming from many contributing factors, but
explain that their work suggests runaway
development may be a significant contributor
to age-related decline.
Why has evolution not eliminated such a potentially harmful
process? Philipp Khaitovich of the Shanghai
Institutes for Biological Sciences and
senior author of the study explained that
detrimental effects experienced during old
age could spread throughout and fix within
populations, especially when those effects
are beneficial early in life.
"Evolutionarily, species are optimized to reproduce and
ensure survival of the next generation, not
to live as long as possible as individuals,"
said Khaitovich. "In fact, long lifespan
precludes rapid genetic adaptations to
changing environment."
Khaitovich added that as they now begin to understand the
biological consequences of this evolutionary
feature, researchers may find ways to shift
the balance from early reproduction to
individual longevity and enhanced health at
old age.
