8th May 2013

Maximum lifespan of fruit flies increased by 28%

Life scientists at the University of California - Los Angeles (UCLA) have identified a gene that can delay the onset of aging and extend the healthy lifespan of fruit flies. The research, they say, could have important implications for aging and disease in humans.

The gene, called parkin, serves at least two vital functions:

• Marking damaged proteins, so that cells can discard them before they become toxic
  
  
• Removal of damaged mitochondria from cells.

The researchers found that parkin can modulate the aging process in fruit flies, which typically live less than two months. Boosting parkin levels in the cells of fruit flies (Drosophila melanogaster) extended their mean and more importantly their maximum lifespan by more than a quarter, compared with a control group that did not receive additional parkin. Furthermore, they appeared healthy, with no loss of function.

Prof. David Walker, senior author of the research: "In the control group, the flies were all dead by Day 50. In the group with parkin overexpressed, almost half of the population was still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."

Anil Rana, a postdoctoral scholar in Walker's laboratory: "Just by increasing the levels of parkin, they live substantially longer while remaining healthy, active and fertile. That is what we want to achieve in aging research – not only to increase their lifespan, but to increase their healthspan as well."

Treatments to increase parkin expression could delay the onset and progression of age-related diseases in humans. Previous research has already shown that people born with a mutation in the parkin gene can develop early-onset, Parkinson's-like symptoms (hence the similar name).

"Parkin could be an important therapeutic target for neurodegenerative diseases and perhaps other diseases of aging," Walker said. "Instead of studying the diseases of aging one by one – Parkinson's disease, Alzheimer's disease, cancer, stroke, cardiovascular disease, diabetes – we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it can, of course, take many years, but that is our goal."

To function properly, proteins must fold correctly, and they fold in complex ways. As we age, our cells accumulate damaged or misfolded proteins. When proteins fold incorrectly, the cellular machinery can sometimes repair them. When it cannot, parkin enables cells to discard the damaged proteins.

"If a protein is damaged beyond repair, the cell can recognise that and eliminate the protein before it becomes toxic," Walker said. "Think of it like a cellular garbage disposal. Parkin helps to mark damaged proteins for disposal. It's like parkin places a sticker on the damaged protein that says 'Degrade Me,' and then the cell gets rid of this protein. That process seems to decline with age. As we get older, the garbage men in our cells go on strike. Overexpressed parkin seems to tell them to get back to work."

Rana focused on the effects of increased parkin activity at the cellular and tissue levels. Do flies with increased parkin show fewer damaged proteins at an advanced age? The remarkable finding was yes, indeed, Walker said.

Parkin has been shown to perform a similarly important function with regard to mitochondria, tiny power generators in cells that control growth and tell cells when to live and die. Mitochandria become less efficient and less active as we age, and the loss of mitochondrial activity has been heavily implicated in the aging process.

Parkin appears to degrade the damaged mitochondria, perhaps by marking or changing their outer membrane structure, effectively telling the cell, "This is damaged and potentially toxic. Get rid of it."

While the researchers found that increased parkin can extend the life of fruit flies, Rana also discovered that too much can have the opposite effect – it becomes toxic to the flies. When he quadrupled the normal amount of parkin, the fruit flies lived substantially longer, but when he increased the amount by a factor of 30, the flies died sooner.

"If you bombard the cell with too much parkin, it could start eliminating healthy proteins," Rana said.

In the lower doses, however, the scientists found no adverse effects. Walker believes the fruit fly is a good model for studying aging in humans – who also have the parkin gene – because scientists know all of the fruit fly's genes and can switch individual genes on and off. It is unknown what the optimal level of parkin would be in humans, but future studies may reveal this, using drugs which can activate, enhance or mimic the gene's effects. Walker and Rana's work is published this week in Proceedings of the National Academy of Sciences.

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