Therapies which boost the clearance of faulty proteins in cells may slow down ageing

Scientists say as people age, their cells become less efficient at getting rid of damaged protein and the result is a buildup of toxic material; this is particularly apparent in Alzheimer's, Parkinson's disease and other neurodegenerative disorders associated with ageing.

Now scientists at the Albert Einstein College of Medicine of Yeshiva University have for the first time prevented this age-related decline in an entire organ.

In research with specially bred mice the scientists have found that when this decline was halted, the livers of older animals functioned as well as they did when the animals were much younger.

They suggest that therapies which boost the clearance of protein might help stave off some of the declines in function that accompany old age.

Dr. Ana Maria Cuervo, the study's senior author says the study shows that functions can be maintained in older animals as long as damaged proteins continue to be efficiently removed and strongly supports the idea that protein buildup in cells plays an important role in aging itself.

Dr. Cuervo says more importantly, the results show that it's possible to correct this protein 'logjam' that occurs in cells as people get older, thereby helping them to enjoy healthier lives well into old age.

Other research has shown that the cells of all organisms have several surveillance systems designed to find, digest and recycle damaged proteins and many studies have documented that these processes become less efficient with age, allowing protein to gradually accumulate inside cells.

Some researchers question whether this protein buildup actually contributes to the functional losses of aging or instead is merely associated with those losses and Dr. Cuervo's team aimed to resolve the controversy.

One of these surveillance systems is responsible for handling 30 percent or more of damaged cellular protein and uses molecules known as chaperones to seek out damaged proteins.

After it finds such a protein, the chaperone ferries it towards one of the cell's many lysosomes, membrane-bound sacs filled with enzymes and 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.

Dr. Cuervo had previously found that the chaperone surveillance system 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 was a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins.

The team set out to explore whether replenishing the lost receptors in older animals would maintain the efficiency of this system throughout an animal's lifespan and, possibly also maintain the function of the animal's cells and organs.

Using mice bred for the purpose, transgenic mice with an extra gene that codes for the receptor that normally declines in number with increasing age, Dr. Cuervo was able to turn on this extra gene only in the liver and at a time of her choosing, by changing the animals' diet.

When the mice reached middle age (six months old - when the chaperone system begins to decline) the added receptor gene was activated.

When the mice were examined at 22 to 26 months of age (equivalent to approximately 80 years old in humans), the liver cells of the transgenic mice digested and recycled protein far more efficiently than their normal counterparts of the same age and just as efficiently as in normal six-month old mice.

In order to establish whether maintaining efficient protein clearance in liver cells of an older animal translates into better functioning for the liver as a whole, Dr. Cuervo tested the ability of the livers of the very old transgenic mice and very old normal mice, by injecting them with a muscle relaxant.

It was found that 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.

The researchers say the next step is 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.

Dr. Cuervo says because protein-clearance systems can handle abnormal proteins when the person is younger but get overwhelmed as their efficiency falls with age, it maybe be possible to prevent this decline and keep people free of symptoms for a longer period.

The research was supported by grants from the National Institute on Aging, an Ellison Medical Foundation Award and a Glenn Foundation Award and is published in the online edition of Nature Medicine.

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