This is very promising and somehow it seems plausible to manipulate
the expression of this particular gene or even introduce it to
assist. It is at least a significant tool to improve health and
implied longevity.
As posted before, longevity research is hitting its stride and
appears to be responding very well.
We are so used to long research cycles that rapid progress in
biological discovery seems impossible. However even researchers here
are seriously motivated to take real chances and that can really
speed the process.
Boosting 'cellular
garbage disposal' can delay the aging process
UCLA biologists report
By Stuart Wolpert May
06, 2013
UCLA life scientists
have identified a gene previously implicated in Parkinson's disease
that can delay the onset of aging and extend the healthy life span of
fruit flies. The research, they say, could have important
implications for aging and disease in humans.
The gene, called
parkin, serves at least two vital functions: It marks damaged
proteins so that cells can discard them before they become toxic, and
it is believed to play a key role in the removal of damaged
mitochondria from cells.
"Aging is a major
risk factor for the development and progression of many
neurodegenerative diseases," said David Walker, an associate
professor of integrative biology and physiology at UCLA and senior
author of the research. "We think that our findings shed light
on the molecular mechanisms that connect these processes."
In the research,
published today in the early online edition of the journal
Proceedings of the National Academy of Sciences, Walker and his
colleagues show that parkin can modulate the aging process in fruit
flies, which typically live less than two months. The researchers
increased parkin levels in the cells of the flies and found that this
extended their life span by more than 25 percent, compared with a
control group that did not receive additional parkin.
"In the control
group, the flies are all dead by Day 50," Walker said. "In
the group with parkin overexpressed, almost half of the population is
still alive after 50 days. We have manipulated only one of their
roughly 15,000 genes, and yet the consequences for the organism are
profound."
"Just by
increasing the levels of parkin, they live substantially longer while
remaining healthy, active and fertile," said Anil Rana, a
postdoctoral scholar in Walker's laboratory and lead author of the
research. "That is what we want to achieve in aging research —
not only to increase their life span but to increase their health
span as well."
Treatments to increase
parkin expression may delay the onset and progression of Parkinson's
disease and other age-related diseases, the biologists believe. (If
parkin sounds related to Parkinson's, it is. While the vast majority
of people with the disease get it in older age, some who are born
with a mutation in the parkin gene develop early-onset,
Parkinson's-like symptoms.)
"Our research may
be telling us that parkin could be an important therapeutic target
for neurodegenerative diseases and perhaps other diseases of aging,"
Walker said. "Instead of studying the diseases of aging one by
one — Parkinson's disease, Alzheimer's disease, cancer, stroke,
cardiovascular disease, diabetes — we believe it may be possible to
intervene in the aging process and delay the onset of many of these
diseases. We are not there yet, and it can, of course, take many
years, but that is our goal."
'The garbage men in
our cells go on strike'
To function properly,
proteins must fold correctly, and they fold in complex ways. As we
age, our cells accumulate damaged or misfolded proteins. When
proteins fold incorrectly, the cellular machinery can sometimes
repair them. When it cannot, parkin enables cells to discard the
damaged proteins, said Walker, a member of UCLA's Molecular Biology
Institute.
"If a protein is
damaged beyond repair, the cell can recognize that and eliminate the
protein before it becomes toxic," he said. "Think of it
like a cellular garbage disposal. Parkin helps to mark damaged
proteins for disposal. It's like parkin places a sticker on the
damaged protein that says 'Degrade Me,' and then the cell gets rid of
this protein. That process seems to decline with age. As we get
older, the garbage men in our cells go on strike. Overexpressed
parkin seems to tell them to get back to work."
Rana focused on the
effects of increased parkin activity at the cellular and tissue
levels. Do flies with increased parkin show fewer damaged proteins at
an advanced age? "The remarkable finding is yes, indeed,"
Walker said.
Parkin has recently
been shown to perform a similarly important function with regard to
mitochondria, the tiny power generators in cells that control cell
growth and tell cells when to live and die. Mitochandria become less
efficient and less active as we age, and the loss of mitochondrial
activity has been implicated in Alzheimer's, Parkinson's and other
neurodegenerative diseases, as well as in the aging process, Walker
said.
Parkin appears to
degrade the damaged mitochondria, perhaps by marking or changing
their outer membrane structure, in effect telling the cell, "This
is damaged and potentially toxic. Get rid of it."
If parkin is good, is
more parkin even better?
While the researchers
found that increased parkin can extend the life of fruit flies, Rana
also discovered that too much parkin can have the opposite effect —
it becomes toxic to the flies. When he quadrupled the normal amount
of parkin, the fruit flies lived substantially longer, but when he
increased the amount by a factor of 30, the flies died sooner.
"If you bombard
the cell with too much parkin, it could start eliminating healthy
proteins," Rana said.
In the lower doses,
however, the scientists found no adverse effects. Walker believes the
fruit fly is a good model for studying aging in humans — who also
have the parkin gene — because scientists know all of the fruit
fly's genes and can switch individual genes on and off.
Previous research has
shown that fruit flies die sooner when you remove parkin, Walker
noted.
Walker and Rana do not
know what the optimal amount of parkin would be in humans.
While the biologists
increased parkin activity in every cell in the fruit fly, Rana also
conducted an experiment in which he increased parkin expression only
in the nervous system. That, too, was sufficient to make the flies
live longer.
"This tells us
that parkin is neuroprotective during aging," Walker said.
"However, the beneficial effects of parkin are greater — twice
as large — when we increased its expression everywhere."
"We were excited
about this research from the beginning but did not know then that the
life span increase would be this impressive," Rana said.
The image that
accompanies this news release shows clumps or aggregates of damaged
proteins in an aged brain from a normal fly (left panel) and an
age-matched brain with increased neuronal parkin levels (right
panel). As can be seen, increasing parkin levels in the aging brain
reduces the accumulation of aggregated proteins.
Scientists have found
that this kind of protein aggregation occurs in mammals as well,
including humans, Rana said.
"Imagine the
damage the accumulation of protein trash is doing to the cell,"
Walker said. "With increased Parkin, the trash has been
collected. Without it, the garbage that should be discarded is
accumulating in the cells."
Walker's research was
funded by the National Institutes of Health's National Institute on
Aging (grants R01 AG037514 and R01 AG040288) and the Ellison Medical
Foundation. Rana was supported by a Rubicon fellowship from the
Organization for Scientific Research in the Netherlands, where he
earned his doctorate (University of Groningen). Michael Rera, a UCLA
postdoctoral scholar in Walker's laboratory, is a co-author of the
PNAS research.
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