Scientists have succeeded in extending by 20 percent the lifespan of killifish, a species used in the study of aging

Dorian Gray, the protagonist of Oscar Wilde’s renowned novel, yearned to remain young and handsome forever. Similarly, Voldemort, the relentless antagonist in J.K. Rowling’s seven-book Harry Potter series, craved immortality. It seems that nearly all of us dream of living long and healthy lives. Recently, scientists have taken another promising step towards this aspiration, by discovering a method to extend the lifespan of killifish (Nothobranchius furzeri), a species frequently used in the study of the genetics of aging. However, the fish won’t enjoy the extension for very long, as killifish were specifically selected for the experiment due to their inherently short lifespan, averaging only 4–6 months.

The aging process, characterized by a decline in cognitive function and memory, is strongly affected by the gradual decrease in the quality of metabolic processes that occur within the body. Metabolism encompasses a series of intricate chemical processes involved in the processing and breakdown of the nutrients we consume, and, specifically, their conversion into an energy-storing molecule known as adenosine triphosphate (ATP), which is essential for fueling every process taking place in living cells.

One of the key challenges in the study of old age is the time factor. Most of the model organisms commonly used in biological and physiological research, such as mice and zebrafish, have relatively long lifespans. This poses a significant obstacle for studies that focus on the later stages of life. In light of this, researchers have increasingly turned to killifish as a model organism due to their short lifespans, for studies exploring the biology of aging. Recently, a team of researchers led by Tehila Atlan and Gwendoline Astre from the Hebrew University of Jerusalem, achieved a remarkable result by introducing a genetic modification that extends the lifespan of killifish for the first time. Intriguingly, this alteration appears to exclusively affect male killifish, while females remain unaffected, for reasons yet to be determined.

Commonly used in the study of the biology of aging due to its brief lifespan. A young killifish (above) and an aged killifish (below) | Photo: Itamar Harel

Improved Energy Management

Previous studies have indicated that increasing the activity of an enzyme called AMPK, which serves as a cellular sensor for energy balance, can extend the lifespan of Caenorhabditis elegans worms and Drosophila fruit flies. This sensor is particularly critical during periods of hunger or physical activity. A living organism usually derives its energy from consistent food intake. However, in situations when the food supply fails to meet the body’s requirements, the body taps into its energy reserves, such as stored sugars and fats, that were accumulated during times of abundance. The decision to access these energy stores is triggered by the sensor detecting an imbalance in the energy equilibrium. 

However, when it comes to animals that are biologically closer to humans, such as mice, a problem emerged. Amplifying or diminishing the activity of the sensor in mice was detrimental for the health of the mice. In the new study the researchers decided to undertake a different approach. “The energy sensor in the cell is a very complex mechanism involving numerous processes in the body”, explains Itamar Harel, the head of the research group. “We searched for an indirect method to alter the activity of the sensor without compromising its structure. Instead of tampering with the sensor, we chose to alter the components that it identifies”.

The researchers introduced a mutation into the gene responsible for producing a protein involved in the synthesis of a molecule detectable by the cell’s energy sensor. As expected, the reduced activity of the modified protein altered the response pattern of the energy sensor, resulting in an average lifespan extension of approximately 20% in the killifish.

"Intermittent fasting” extends the lifespan of the killifish. The food plate remains empty for most hours of the day | Source: Oleksandra Naumenko, Shutterstock

The researchers noticed several changes that likely contributed to the extended lifespan of the fish. Firstly, fish with the engineered gene continued to exhibit similar metabolic patterns at an advanced age as those observed in young fish, such as good control of blood sugar levels and high resistance to weight gain. Secondly, an examination of all the biological mechanisms affected by the mutation revealed that the fish cells displayed metabolic processes characteristic of fasting, even when they consumed food regularly.

In order to determine whether this genetic change did, in fact, induce fasting-like metabolic patterns in the fish cells, the researchers conducted an additional experiment. This time, they reared both normal fish and fish carrying the engineered gene, on an eating regimen known as intermittent fasting, an approach that has gained widespread popularity in recent years. This method encompasses several recognized approaches, with the most popular one involving a continuous 16-hour fasting period, followed by an 8-hour window for consuming all food.

They found that all the fish that were subjected to intermittent fasting, including females, lived longer than regular non-fasting fish. Surprisingly, among those that fasted intermittently, no difference in lifespan was found between genetically modified fish and those that had not undergone the genetic change. The strong metabolic similarity between engineered males and fish subjected to intermittent fasting convinced the researchers that the metabolic pattern observed following the genetic change indeed mimics the metabolic patterns characteristic of fasting.

The research team has succeeded in extending the lifespan of male killifish. Itamar Harel at the fish rearing facility | Courtesy of Itamar Harel

What About The Females?

This pertinent question still remains unanswered: why was the lifespan of the engineered males extended, while that of the females remained unchanged? To date we don’t have a clear answer, but the researchers have begun to examine the unique biological mechanisms affected by fasting in females, searching for ways to manipulate them without the need for actual fasting.

"Studies performed on many animal species show that males and females respond differently to fasting”, relates Harel. “Now that we have a mutation that extends the lifespan of only the male fish, while intermittent fasting affects both sexes equally, I believe that we’ll also be able to uncover a specific biological mechanism that will extend the lives of the females”.

In the meantime, Itamar Harel’s lab team has also engineered mice that carry the same genetic mutation, in order to examine its effect in mammals. Looking further ahead, they hope that their findings will pave the way for the development of an effective medication for weight loss and life extension. Such a treatment would induce a state resembling intermittent fasting in human cells, promoting them to adopt “younger” metabolic patterns, break down fat reserves, thereby encouraging weight loss, and potentially even enhancing the quality of life of those consuming the medication.