Researchers here show that increased levels of a mitochondrial sirtuin, sirt4, can modestly extend life in flies. Unfortunately, this sort of manipulation of metabolism - connected to nutrient sensing, mitochondrial activity, and calorie restriction - scales poorly as the life span of species increases. Short-lived species are comparatively sensitive to periodic lack of resources, and exhibit a sizable extension of life span in response to a lack of nutrients. This improves their prospects for current survival and then later reproduction when nutrients are once more available. Longer-lived species - such as our own - have for much of their evolutionary history enjoyed life spans far longer than any common period of famine, however. Thus we have a much smaller response to periods of reduced dietary nutrients, at least when considered in terms of additional healthy life, even though short-term measures of improved health are somewhat similar to those found in short-lived species.
"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. We also demonstrate that overexpressing the gene for Sirt4 can extend lifespan of the fly." The results suggest that boosting Sirt4 activity may be an important avenue for treating age-related metabolic decline and disorders, such as diabetes and obesity, and promoting a healthy lifespan.
In the study, flies modified to produce extra Sirt4 saw their healthy lifespans extended by 20 percent. Removing the ability of flies to produce Sirt4 cut their healthy lives by 20 percent. Also, without Sirt4 in their cells, flies when removed from food died rapidly, even when nutrients and fats were still present in their bodies. Sirt4 belongs to a class of proteins, called sirtuins, known to regulate aspects of longevity, metabolism, genome stability, diabetes and neurodegeneration. Sirt4 is found in mitochondria, which are cellular structures where respiration and energy production take place.
Human cells contain seven different sirtuins, including three mitochondrial sirtuins, Sirt3, Sirt4 and Sirt5. Fruit fly cells contain just one mitochondrial sirtuin, Sirt 4. Increasing or decreasing expression of Sirt4 in living flies allowed the researchers to discover what function Sirt4 played in the insects - and possibly in humans. "We show for the first time that increasing the activity of a mitochondrial sirtuin can extend lifespan. No previous research has found that increasing the activity of a mitochondrial sirtuin such as Sirt4 extends the healthy lifespan of a living organism."
The study also shows Sirt4 may be a gene responsible for the metabolic action of fasting, particularly the gene vital to regulating when an organism switches from carbs to fat. A creature that lacks the gene starves to death much more rapidly than normal under poor nutritional conditions. Without Sirt4, the fly cannot access many of the nutrients and stored fats when fasting. Researchers know that temporary fasting in a living organism is valuable in resetting its metabolism. Such findings gave rise to what are called "near-starvation" diets to improve health and extend lifespan. But scientists don't know how that fasting-to-reverse-aging mechanism works. Sirtuins likely play a role. "We want to understand more about the role of sirtuins and their involvement in pathways of calorie restriction."