Everybody wants to live longer, but really, what's the point of reaching your 120th birthday if your last 50 years will be spent in pain and too infirm to do much? Rather than focusing purely on a longer lifespan, it's a better use of scientists' time to improve our "healthspan" – the amount of time we can enjoy good health. A new study from Brown University has linked the protein Sirt4 with an extended healthy lifespan in fruit flies, and the find may carry across to humans.

Sirtuin proteins are involved in metabolic processes, and have been associated with aging and age-related diseases. To study their effect, and how they could be manipulated to grant longer and healthier lives, the Brown researchers turned to fruit flies, a common animal model for metabolism studies.

Of the seven sirtuins in human cells, three are found in the mitochondria – the energy-producing parts of cells. Fruit flies, on the other hand, only have one mitochondrial sirtuin, Sirt4, and since humans share that protein it was a clear target for experiments.

To pinpoint Sirt4's role, the Brown scientists engineered two groups of flies – some that overexpressed Sirt4 and some that were unable to produce it at all. Those with extra Sirt4 were found to live healthier for 20 percent longer than average flies, while those that went without had their healthy lifespans cut short by 20 percent.

"We show that Sirt4 is responsible for regulating both lifespan and metabolism in an organism, and specifically that it coordinates the metabolic response to fasting," says Jason Wood, lead author on the study. "We also demonstrate that overexpressing the gene for Sirt4 can extend lifespan of the fly."

The researchers found that without food, the Sirt4-less flies tended to starve to death much faster than normal. The insects still had nutrients and fats stored in their bodies, but were apparently unable to access those reserves. That suggests that Sirt4 plays a role as a fasting "fuel switch," controlling when the body switches from burning carbs to burning fats. This could help scientists understand why caloric restriction, a dieting technique centered on intense fasting, appears to be so beneficial to health and lifespan.

"We think Sirt4 is an attractive target to help improve diseases of metabolism and possibly extend healthy life," says Stephen Helfand, senior author of the study. "In living flies, we saw that it worked, but we're not sure how."

The Brown scientists want to continue studying Sirt4, including figuring out what activates it and how it might function in mammals and particularly humans.

The research was published in the journal Proceedings of the National Academy of Sciences.

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