[tt] Aging slowned down in mouse liver

Mon Aug 11 19:20:47 UTC 2008

In Scientific First, Researchers Correct Decline In Organ Function
Associated With Old Age

http://www.sciencedaily.com/releases/2008/08/080810213958.htm

ScienceDaily (Aug. 11, 2008) - As people age, their cells become less
efficient at getting rid of damaged protein - resulting in a buildup
of toxic material that is especially pronounced in Alzheimer's,
Parkinson's disease, and other neurodegenerative disorders.

Now, for the first time, scientists at the Albert Einstein College of
Medicine of Yeshiva University have prevented this age-related decline
in an entire organ - the liver - and shown that, as a result, the
livers of older animals functioned as well as they did when the
animals were much younger. Published in the online edition of Nature
Medicine, these findings suggest that therapies for boosting protein
clearance might help stave off some of the declines in function that
accompany old age. The study's senior author was Dr. Ana Maria Cuervo,
associate professor in the departments of developmental & molecular
biology, medicine and anatomy & structural biology at Einstein.

The cells of all organisms have several surveillance systems designed
to find, digest and recycle damaged proteins. Many studies have
documented that these processes become less efficient with age,
allowing protein to gradually accumulate inside cells. But aging
researchers continue debating whether this protein buildup actually
contributes to the functional losses of aging or instead is merely
associated with those losses. The Einstein study was aimed at
resolving the controversy.

One of these surveillance systems - responsible for handling 30
percent or more of damaged cellular protein - uses molecules known as
chaperones to seek out damaged proteins. After finding such a protein,
the chaperone ferries it towards one of the cell's many lysosomes -
membrane-bound sacs filled with enzymes. When the chaperone and its
cargo "dock" on a receptor molecule on the lysosome's surface, the
damaged protein is drawn into the lysosome and rapidly digested by its
enzymes.

In previous work, Dr. Cuervo found that the chaperone surveillance
system, in particular, becomes less efficient as cells become older,
resulting in a buildup of undigested proteins within the cells. She
also detected the primary cause for this age-related decline: a
fall-off in the number of lysosomal receptors capable of binding
chaperones and their damaged proteins. Could replenishing lost
receptors in older animals maintain the efficiency of this
protein-removal system throughout an animal's lifespan and, perhaps,
maintain the function of the animal's cells and organs as well?

To find out, Dr. Cuervo created a transgenic mouse model equipped with
an extra gene - one that codes for the receptor that normally declines
in number with increasing age. Another genetic manipulation allowed
Dr. Cuervo to turn on this extra gene only in the liver and at a time
of her choosing, merely by changing the animals' diet.

To keep the level of the receptor constant throughout life, Dr. Cuervo
waited until mice were six months old (the age that the chaperone
system's efficiency begins to decline) before turning on the added
receptor gene. When the mice were examined at 22 to 26 months of age
(equivalent to approximately 80 years old in humans), the liver cells
of transgenic mice digested and recycled protein far more efficiently
than in their normal counterparts of the same age - and, in fact, just
as efficiently as in normal six-month old mice.

Does maintaining efficient protein clearance in liver cells of an
older animal translate into better functioning for the liver as a
whole? Since a key function of the liver is metabolizing chemicals,
Dr. Cuervo answered this question by injecting a muscle relaxant into
very old transgenic mice and very old normal mice. The very old
transgenic mice metabolized the muscle relaxant much more quickly than
very old normal mice and at a rate comparable to young normal mice.

"Our study showed that functions can be maintained in older animals so
long as damaged proteins continue to be efficiently removed - strongly
supporting the idea that protein buildup in cells plays an important
role in aging itself," says Dr. Cuervo. "Even more important, these
results show that it's possible to correct this protein 'logjam' that
occurs in our cells as we get older, thereby perhaps helping us to
enjoy healthier lives well into old age."

Dr. Cuervo next plans to study animal models of Alzheimer's,
Parkinson's and other neurodegenerative brain diseases to see whether
maintaining efficient protein clearance in the brain might help in
treating them. "Most people with these conditions are born with a
mutation that gives rise to defective proteins, but they don't
experience symptoms until later in life," says Dr. Cuervo. "We think
that's because their protein-clearance systems can handle abnormal
proteins when the person is younger but get overwhelmed as their
efficiency falls with age. By preventing this decline in protein
clearance, we may be able to keep these people free of symptoms for a
longer time."

Dr. Cuervo will also investigate whether maintaining efficient protein
clearance in all the body's tissues will influence longevity and
prevent the functional losses associated with growing old. "There's
reason to hope that drugs exerting a similar effect throughout the
body may help us enjoy healthier lives well into old age," says Dr.
Cuervo. Meanwhile, she notes, evidence is mounting that two dietary
interventions -low-fat and calorie-restricted diets - help cells to
maintain efficient protein clearance.

Cong Zhang, a graduate student working in Dr. Cuervo's laboratory, was
the lead author of the Nature Medicine study. The research was
supported by grants from the National Institute on Aging, an Ellison
Medical Foundation Award and a Glenn Foundation Award.

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