Researchers revive organ function in old age
Aug 15, 2008 - 12:20:05 PM
Washington, Aug 11 - Age retards the ability of cells to get rid of damaged protein, which only accumulates in the body as toxin and becomes more pronounced in Alzheimer's and Parkinson's disease.
However, Yeshiva University scientists have been able to prevent this age-related decline in an entire organ, the liver, for instance, showing organs of older animals functioned as efficiently as of younger ones.
These findings suggest that therapies for boosting protein clearance might help stave off some of the decline that accompany old age, said Ana Maria Cuervo, co-author of the study, associate professor in the departments of developmental & molecular biology, medicine and anatomy & structural biology of Yeshiva's Albert Einstein College.
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 researchers continue debating whether this protein build-up actually contributes to the functional losses of ageing or instead is merely associated with those losses. The Einstein College 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, Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a build-up 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, 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 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, Cuervo waited until mice were six months old - before turning on the added receptor gene.
When the mice were examined at 22 to 26 months of age -, 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.
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.
The study has been published in the online edition of Nature Medicine.
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