Cellular "scavenger" slows down aging

Parkin protein increases the lifespan of fruit flies,
ridding cells of biochemical "garbage"

LifeSciencesToday based on UCLA materials:
Boosting 'cellular garbage disposal' can delay the aging process, UCLA biologists reportScientists at the University of California at Los Angeles (University of California - Los Angeles, UCLA) have identified a gene associated with the development of Parkinson's disease that can delay the onset of aging and prolong the healthy life of fruit flies.

In their opinion, this study may have important implications for studying the aging process and the development of age-related diseases in humans.

The parkin protein performs at least two vital functions: it marks damaged proteins so that cells can destroy them before they become toxic, and is believed to play a key role in removing defective mitochondria from cells.

"Aging is a major risk factor for the development and progression of many neurodegenerative diseases," says study leader David Walker, associate professor of integrative biology and physiology at UCLA. "We believe that the data we have obtained sheds light on the molecular mechanisms that unite these processes."

In a study published in the online edition of the journal Proceedings of the National Academy of Sciences (Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan), Dr. Walker and his colleagues showed that parkin can modulate the aging process in fruit flies that usually live less than two months. By increasing the levels of parkin in the cells of flies, the scientists observed an increase in their life expectancy by more than 25 percent compared to the control group.

"In the control group, all the flies died by the 50th day," Dr. Walker comments on the results of the experiments. "In the group with increased parkin expression, almost half of the population was still alive after 50 days. We have manipulated only one of their approximately 15,000 genes, and yet the consequences for the body are very significant."

"Only by increasing the level of parkin do they live significantly longer, while remaining healthy, active and able to reproduce," adds lead author of the study Anil Rana, a postdoctoral researcher in Walker's laboratory. "This is what we want to achieve by studying aging – to increase not only their life expectancy, but also the duration of its healthy period."

Methods of treatment that increase parkin's expression can delay the onset and slow down the progression of Parkinson's disease and other age-related diseases, biologists believe.

"Our study suggests that parkin may become an important therapeutic target for the treatment of neurodegenerative, and possibly other age–related diseases," says Professor Walker. "We believe that instead of studying the diseases of aging separately – Parkinson's disease, Alzheimer's disease, cancer, stroke, cardiovascular diseases, diabetes - it is possible to intervene in the aging process and delay the onset of many of them. We are still far from that, and it will take many years, but that is our goal."

In order to properly perform their functions, proteins must fold properly. As we age, damaged or misfolded proteins accumulate in our cells. In some cases, the molecular machinery of a cell can fix defective protein molecules, but if it fails, Parkin allows you to get rid of them, explains Walker, a researcher at the UCLA Institute of Molecular Biology.

"If the protein is beyond repair, the cell can find out about it and eliminate the protein before it becomes toxic," the scientist continues. "Imagine this as the removal of cellular garbage. Parkin helps to label damaged proteins intended for disposal. It's as if he was attaching a "Destroy me" sticker to defective proteins. And the cell gets rid of such proteins. With age, this process seems to be disrupted. When we get older, the scavengers in our cages go on strike. The overexpressed parkin seems to be forcing them back to work."

Anil Rana focused his attention on the consequences of increased parkin activity at the cellular and tissue levels. Does aging flies with elevated parkin levels accumulate fewer damaged proteins in the body? "The positive answer we received to this question is a really important result," Walker believes.

As recently shown, parkin performs an equally important function in relation to mitochondria – tiny energy generators that control cell growth and tell them when to live and when to die. As mitochondria age, they become less efficient and less active, and the loss of their activity contributes to the development of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, as well as to the aging process.

Apparently, parkin destroys damaged mitochondria, possibly by labeling or altering the structure of their outer membrane, essentially telling the cells, "They are damaged and potentially toxic. Get rid of them."

However, while an increased level of parkin prolongs the life of fruit flies, too much of it produces the opposite effect – the protein becomes toxic. When the amount of parkin is four times higher than normal, fruit flies live much longer, but a thirty-fold excess leads to premature death of insects.

"If you bombard a cell with too much parkin, it begins to eliminate healthy proteins," explains Dr. Rana. But at lower doses of parkin, the scientists did not observe any side effects.

Previous studies have shown that when parkin is removed, flies die faster.

Professor Walker considers Drosophila melanogaster a good model for studying the aging of the human body (which also has the Parkin gene), since scientists know all the genes of the fruit fly and can turn them on and off. But they do not yet have an answer to the question of what is the optimal amount of parkin in the human body.

Biologists increased the activity of the Parkin gene both in every cell of the flies' body and only in the cells of the nervous system, which also turned out to be sufficient to increase the lifespan of insects.

"This suggests that during the aging process, parkin has a neuroprotective effect," Walker comments. "However, the positive effect of parkin is greater –twice as much –when we increase its expression everywhere."

A photo illustrating the results of increased expression of the parkin gene shows green aggregates of damaged proteins in the aging brain of a normal fly (left). In the brains of old fruit flies, with increased parkin expression (right), fewer protein aggregates accumulate. Red shows F-actin – the cytoskeleton of the cell, blue – the nuclei of the cells. Photo: Anil Rana/UCLA Life Sciences.

"We were obsessed with this study from the very beginning, but we did not expect that the increase in life expectancy would be so impressive," adds Rana.

Scientists have found that this kind of protein aggregation is characteristic of mammals, including humans.

"Imagine the damage caused to the cell by the accumulation of protein debris in it," Walker concludes. "Increasing the amount of parkin allows you to remove it. Without Parkin, the garbage that needs to be destroyed accumulates in the cells."

Portal "Eternal youth" http://vechnayamolodost.ru13.05.2013