Scientists slow ageing, extend lifespan of fruit flies
Biologists have developed an intervention that serves as a cellular time machine — turning back the clock on a key component of ageing.
The researchers at the University of California – Los Angeles (UCLA), United States (US), in a study on middle-aged fruit flies, substantially improved the animals’ health while significantly slowing their ageing. They believe the technique could eventually lead to a way to delay the onset of Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease and other age-related diseases in humans.
The approach focuses on mitochondria, the tiny power generators within cells that control the cells’ growth and determine when they live and die.
Mitochondria often become damaged with age, and as people grow older, those damaged mitochondria tend to accumulate in the brain, muscles and other organs. When cells can’t eliminate the damaged mitochondria, those mitochondria can become toxic and contribute to a wide range of age-related diseases, said David Walker, a UCLA professor of integrative biology and physiology, and the study’s senior author.
In the new research, Walker and his colleagues found that as fruit flies reach middle age — about one month into their two-month lifespan — their mitochondria change from their original small, round shape.
“We think the fact that the mitochondria become larger and elongated impairs the cell’s ability to clear the damaged mitochondria,” Walker said. “And our research suggests dysfunctional mitochondria accumulate with age, rather than being discarded.”
The study, published September 6 in the journal Nature Communications, reports that the UCLA scientists removed the damaged mitochondria by breaking up enlarged mitochondria into smaller pieces — and that when they did, the flies became more active and more energetic and had more endurance. Following the treatment, female flies lived 20 percent longer than their typical lifespan, while males lived 12 percent longer, on average.
The research highlights the importance of a protein called Drp1 in ageing. At least in flies and mice, levels of Drp1 decline with age.
To break apart the flies’ mitochondria, Anil Rana, a UCLA project scientist and the study’s lead author, increased their levels of Drp1. This enabled the flies to discard the smaller, damaged mitochondria, leaving only healthy mitochondria. Drp1 levels were increased for one week starting when the flies were 30 days old.
At essentially the same time, Rana demonstrated that the flies’ Atg1 gene also plays an essential role in turning back the clock on cellular aging. He did this by “turning off” the gene, rendering the flies’ cells unable to eliminate the damaged mitochondria. This proved that Atg1 is required to reap the procedure’s anti-aging effects: While Drp1 breaks up enlarged mitochondria, the Atg1 gene is needed to dispose of the damaged ones.
“It’s like we took middle-aged muscle tissue and rejuvenated it to youthful muscle,” said Walker, a member of UCLA’s Molecular Biology Institute. “We actually delayed age-related health decline. And seven days of intervention was sufficient to prolong their lives and enhance their health.”
One specific health problem the treatment addressed was the onset of leaky intestines, which previous research by Walker’s team found commonly occurs about a week before fruit flies die. Subsequent research in other laboratories has determined that an increase in intestines’ permeability is a hallmark of aging in worms, mice and monkeys. In the UCLA study, the condition was delayed after flies were given more Drp1.
Fruit flies are often used for studies on aging because their short lifespan enables scientists to track the effects of specific treatments within a manageable period of time, and many of the features of aging at the cellular level are similar to those of humans. In addition, scientists have identified all of the fruit fly’s genes and know how to switch individual ones on and off.
Walker hopes that a technique similar to the one his team developed for fruit files could eventually help humans by slowing aging and delaying aging-related diseases. He said the fact that the new approach was effective even after a short time is especially significant because long-term use of nearly any drug can have harmful side effects in humans.
Walker said one of the long-term goals of his research is to develop pharmaceuticals that would mimic the effects of Drp1, in order to extend people’s lives and lengthen what he calls people’s “health spans,” meaning the number of healthy years in their lives.
In another part of the experiment, also involving middle-aged fruit flies, the scientists turned off a protein called Mfn that enables mitochondria to fuse together into larger pieces. Doing so also extended the flies’ lives and improved their health.
Meanwhile, as more people live into their 80s and 90s, researchers have delved into the issues of health and quality of life during aging. A recent mouse study at the UC Davis School of Veterinary Medicine sheds light on those questions by demonstrating that a high fat, or ketogenic, diet not only increases longevity but also improves physical strength.
“The results surprised me a little,” said nutritionist Jon Ramsey, senior author of the paper that appears in the September issue of Cell Metabolism. “We expected some differences, but I was impressed by the magnitude we observed — a 13 percent increase in median life span for the mice on a high fat vs high carb diet. In humans, that would be seven to 10 years. But equally important, those mice retained quality of health in later life.”
Ramsey has spent the past 20 years looking at the mechanics that lead to aging, a contributing factor to most major diseases that impact rodents and humans alike. While calorie restriction has been shown in several studies to slow aging in many animals, Ramsey was interested in how a high fat diet may impact the aging process.
Ketogenic diets have gained popularity for a variety of health benefit claims, but scientists are still teasing out what happens during ketosis, when carbohydrate intake is so low that the body shifts from using glucose as the main fuel source to fat burning and producing ketones for energy.
The study mice were split into three groups: a regular rodent high-carb diet, a low carb/high fat diet, and a ketogenic diet (89-90 percent of total calorie intake). Originally concerned that the high fat diet would increase weight and decrease life span, the researchers kept the calorie count of each diet the same.
“We designed the diet not to focus on weight loss, but to look at metabolism,” Ramsey said. “What does that do to aging?”
In addition to significantly increasing the median life span of mice in the study, the ketogenic diet increased memory and motor function (strength and coordination), and prevented an increase in age-related markers of inflammation. It had an impact on the incidence of tumors as well.
“In this case, many of the things we’re looking at aren’t much different from humans,” Ramsey said. “At a fundamental level, humans follow similar changes and experience a decrease in overall function of organs during aging. This study indicates that a ketogenic diet can have a major impact on life and health span without major weight loss or restriction of intake. It also opens a new avenue for possible dietary interventions that have an impact on ageing.”
A companion study published by the Buck Institute for Research on Aging in the same issue of Cell Metabolism shows that a ketogenic diet extends longevity and improves memory in aging mice.