Ageing in mice livers blocked
2008-08-11 10:42
Paris - Researchers have blocked the ageing process in mice livers by halting the accumulation of harmful proteins inside the organ's cells, according to a groundbreaking study released on Sunday.
This is the first time that age-related decline due to protein build-up has been arrested in an entire organ or in a live animal, it said.
The findings could pave the way to therapies for life-threatening liver conditions common in the late stages of life, the study said.
They could even lead to a recipe for boosting longevity.
In experiments, livers in genetically modified mice 22-to-26 months old - the equivalent of octogenarians in human years - cleaned blood as efficiently as those in animals a quarter their age.
By contrast, the livers of normal mice in a control group began to fail.
The benefits of restoring the cleaning mechanisms found inside all cells could extend far beyond a single organ, said the study's main architect Ana Maria Cuervo, a researcher at the Albert Einstein College of Medicine at Yeshiva University in New York City.
'Misbehaving' proteins
"Our findings are particularly relevant for neurodegenerative disorders such as Parkinson's and Alzheimer's," she said.
"Many of these diseases are due to 'misbehaving' or damaged proteins that accumulate in neurons. By preventing this decline in protein clearance, we may be able to keep these people free of symptoms for a longer time," she explained in an e-mail.
If the body's ability to dispose of cell debris within the cell were enhanced across a wider range of tissues, she added, it could extend life as well.
The study goes a long way toward settling a sharp debate in the booming field of ageing research.
Published online in the British journal Nature Medicine, it shows that the failure to remove damaged proteins are a cause, and not the consequence, of the reduced functions that characterises the biological endgame.
Cuervo's experiments also point to at least one way those functions can be fixed.
In healthy organisms, a surveillance system inside cells called chaperone-mediated autophagy (CMA) locates, digests and destroys damaged proteins.
Specialised molecules - the "chaperones" - ferry the harmful material to membrane-bound sacs of enzymes within the cells known as lysosomes.
Once the cargo has been "docked", a receptor molecule transfers the protein into the sac, where it is rapidly digested.
With age, these receptors stop working as well, resulting in a dangerous build up of faulty proteins that has been linked - in the liver - to insulin resistance as well as the inability to metabolise sugar, fats or alcohol.
The same breakdown of the cell's cleaning machinery can also impair the liver's ability to remove the toxic build-up of drugs at a stage in life when medication is often part of daily diet.
In genetically modified mice, Cuervo compensated for the loss of the receptors in the animals by adding extra copies. "That was enough to maintain a clean liver and to prove that if you keep your cells clean they work better," she explained.
Genetic manipulation is not an option for humans. But Cuervo said her results are likely to spur research to develop drugs that can mimic the results of the experiment, and to extend them to other kinds of tissue.
"Now that we know that repairing that defect is enough to restore a system to its 'youth', we will start screening compounds," she said.
"In light of the enormous improvement that we observed, my opinion is that repairing other systems will have a similar effect."
Enhancing longevity
It is also possible that the same kind of "cellular clearance" can be achieved through diet, she said.
Research over the last decade has shown that restricted calorie intake in animals, including mammals, significantly enhances longevity.
In research yet to be published, Cuervo has found that calorie restriction prevents the age-related decrease in CMA.
"My ideal intervention in the future would be a better diet rather than a pill," she commented.