Scientists Find Genetic Switch That Keeps Organs Young In Old Age

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Main Category: Seniors / Aging
Also Included In: Genetics;  Biology / Biochemistry
Article Date: 11 Aug 2008 - 12:00 PDT

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Using genetically altered mice, US scientists have found a genetic switch that keeps organs young in old age by making sure that spent cellular protein is recycled efficiently and is not allowed to pile up and cause "toxic waste" in tissue, which is a characteristic feature of degenerative diseases like Alzheimer's and Parkinson's.

The study is the work of researchers at the Albert Einstein College of Medicine in New York and is published in the 10 August online issue of the journal Nature Medicine.

Proteins do the millions of essential jobs that keep cells and tissue alive and working, and a range of "cellular quality control systems" ensure that spent proteins, which could potentially cause damage because they are chemically altered once they have performed their vital functions, are "recycled" or turned into safe waste products. One such quality control system responsible for disposing of about 30 per cent of spent cellular protein is called chaperone-mediated autophagy (CMA), where special molecules seek out and "chaperone" spent proteins into lysosome sacs where they can be digested by enzymes. Entry to the sac is controlled by receptors.

The senior author of the study was Dr Ana Maria Cuervo, associate professor in the departments of developmental and molecular biology, medicine and anatomy and structural biology at Einstein.

Cuervo and colleagues had already found that CMA activity slows down in older organisms, and this was primarily because of a decline in the receptors on the lysosomes. They wondered if this led to the backlog of chemically altered proteins that is often found in tissue of people who have various types of diseases of old age, and if the decline were slowed down or prevented, would it stop the backlog, prevent tissue degeneration, and maintain healthy functioning? Researchers are not sure if these protein accumulations cause or are merely present at the same time as the loss of vital functions.

So they decided to shed some light in this area by seeing if they could stop the slow down of CMA in genetically altered mice. They managed to do this successfully in one organ, the liver. They used two linked mechanisms to achieve it.

The first mechanism that Cuervo and colleagues used was to give the mice an extra gene that codes for the lysosome receptor, and the other mechanism was to make it switch on only when they wanted it to, which they did by changes to the animals' diet.

So they waited until the mice were six months old, which is when the CMA would normally start to decline, and turned on the gene that coded for extra receptors by changing their diet. They then examined the mice at 22 to 26 months (equivalent to a human of 80 years of age), and found that the liver cells were digesting and recycling protein more effectively than other mice of the same age that had not been altered, and in fact the livers on the altered mice were functioning as effectively as the livers of normal 6 month old mice.

But this did not prove that the liver as a whole was performing better, only that the CMA cycle was working more effectively. So Cuervo and colleagues injected the older genetically altered mice and some same age non-altered mice with a muscle relaxant to see how well their livers dealt with it. They found that the genetically altered old mice metabolized the muscle relaxant much more quickly than the non-altered old mice, at a similar speed as younger mice in fact.

Cuervo said that:

"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."

"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," she added.

Cuervo and her team plan to study this effect in the brains of animal models of Alzheimer's, Parkinson's and other neurodegenerative diseases. They hope to show that by slowing the decline in spent protein clearance, people can be kept clear of symptoms for much longer. They also hope to study the effects of these processes on longevity, and living more healthily for longer. Cuervo suggested that studies of two dietary systems, the low fat and the calorie restricted diet, are suggesting evidence of a similar nature, that it's to do with helping cells get rid of spent protein effectively.

"Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function."
Cong Zhang & Ana Maria Cuervo.
Nature Medicine, Published online: 10 August 2008.
doi:10.1038/nm.1851

Click here for Abstract.

Sources: CDC.

Written by: Catharine Paddock, PhD
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