August 12, 2008
Extra Gene Keeps Livers Younger Longer

Adding an extra copy of a gene to transgenic mice causes their liver cells to better break down accumulated intracellular trash as they age.

(BRONX, NY) 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.

A declining ability to take out intracellular trash is one of the causes of aging. Though apparently some scientists are not convinced yet.

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.

The chaperone system of intracellular removal of damaged proteins declines with age and Dr. Cuervo targeted it for genetic enhancement to keep it going stronger as mice age.

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.

But will this bit of genetic engineering extend the lives of mice? Consider that if all it took to make livers last longer was to add a copy of a gene that evolution probably would have caused that change to happen already. Mutations that just create an extra copy of a gene have happened many times and we have lots of genes in us with multiple extra copies. So if this really helps why don't mice already have this mutation?

Share |      Randall Parker, 2008 August 12 09:52 PM  Aging Treatment Studies


Comments
jp straley said at August 13, 2008 5:38 AM:

To answer the question in the last sentence of this article, how would a naturally-occurring double gene & associated controller help such mice have more offspring & thus increase the gene frequency of the modification in the population? I don't know mice so well, but if it improves quality of life in aged mice, isn't that past the time of most (perhaps all) reproduction?

JP Straley

Kane said at August 13, 2008 7:14 PM:

A liver study authored by a Dr. Cuervo?

What next, a lung study authored by Dr. Camel?

Randall Parker said at August 13, 2008 7:18 PM:

Kane,

Wasn't there a Saturday Night Live skit with surgeons named Dr. Benson and Dr. Hedges? Or maybe Dr. Winston and Dr. Salem? I seem to recall Tom Arnold was one of the doctors or the surgical patient. The medical advice involved telling the patient that they were not balancing their beef, pork, and chicken. Too much beef and not enough pork maybe?

Tj Green said at August 14, 2008 8:18 AM:

Evolution would have favored our species living longer, because the older members of a tribe would have stored information beneficial for the tribes survival.

Nick G said at August 21, 2008 4:18 PM:

Sure - humans are very similar genetically to chimps, but we live almost twice as long.

Probably doesn't help the mice.

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