Population ageing will present enormous health, social and economic challenges in the coming decades. As people live longer, preventing the physical decline and frailty that come with age has become a primary goal. Effective interventions in this area are expected to yield significant social and economic benefits. Indeed, by some estimates, a slowdown in ageing that increases life expectancy by one year could be worth US$38 trillion.
In a landmark discovery published in the journal Nature, a team of scientists at Duke-NUS Medical School in Singapore may have found a key to slowing aging. The team has shown in preclinical models that the protein interleukin-11 (IL11) actively promotes aging. Administering an anti-IL11 therapy not only counteracts the harmful effects of aging, but also increases life expectancy. This finding has the potential to play a crucial role in countries’ efforts to help their populations live longer and healthier lives.
IL11 causes fat accumulation and loss of muscle mass
In preclinical studies, the team found that with age, organs expressed increasing levels of the protein IL11, which promoted fat accumulation in the liver and abdomen, and reduced muscle mass and strength, two conditions that are hallmarks of human aging. These results are the first in the world to show that IL11 is a major factor in aging, according to the research team.
Researchers observed improved muscle function, better overall health, and an increase in life expectancy of up to 25% in both sexes.
Associate Professor Anissa Widjaja from the Cardiovascular and Metabolic Disorders Programme at Duke-NUS, who is the first and co-corresponding author, said: “This project started in 2017 when a collaborator of ours sent us some tissue samples for another project. Out of curiosity, I performed some experiments to check IL11 levels. From the readings, we could clearly see that IL11 levels increased with age and that’s when we really got excited.”
How anti-IL11 therapy counteracts the effects of aging
After establishing IL11’s role in aging, the team showed that by applying an anti-IL11 therapy in the same preclinical model, metabolism was significantly improved, shifting from generating white fat to beneficial brown fat. Brown fat breaks down sugar and fat molecules in the blood to help maintain body temperature and burn calories.
Researchers also observed improved muscle function, better overall health and an increase in life expectancy of up to 25% in both sexes.
Unlike other drugs known to inhibit specific pathways involved in aging, such as metformin and rapamycin, anti-IL11 therapy blocks multiple important signaling mechanisms that become dysfunctional with age. This offers protection against multimorbidity from cardiometabolic diseases, age-related loss of muscle mass and strength, as well as frailty.
In addition to these externally observable changes, anti-IL11 therapy also reduced the rate of telomere shortening and preserved the health of mitochondria and their ability to generate energy.
Senior author Stuart Cook, Tanoto Foundation Professor of Cardiovascular Medicine at SingHealth Duke-NUS Academic Medical Centre and member of the Duke-NUS Cardiovascular and Metabolic Disorders Programme, said: “Our aim is to one day see anti-IL11 therapy used as widely as possible, so that people around the world can live healthier lives for longer. However, this is not easy as the approval pathways for drugs to treat ageing are not well defined and raising funds for clinical trials in this area is very difficult.”
Commenting on the potential of this research, Professor Thomas Coffman, Dean of Duke-NUS, said: “Although average life expectancy has increased markedly in recent decades, there is a notable disparity between years lived and years of healthy, disease-free life. For rapidly ageing societies such as Singapore, this discovery could be transformative, enabling older adults to prolong healthy ageing, reducing frailty and the risk of falls, while improving cardiometabolic health.”
They will test the effectiveness of the drug in reducing fragility
The team’s previous research into the role of IL11 in the heart and kidneys (published in Nature in 2017), the liver (published in Gastroenterology in 2019), and the lungs (published in Science Translational Medicine in 2019) led to the development of an anti-IL11 therapy. Enleofen Bio, a spin-out of Singapore institutions including Duke-NUS, took on the development of these therapeutic candidates in 2020 under a deal that could be worth up to $1 billion per product. The company has since advanced the therapy to first-in-human studies, the first of which was completed earlier this year.
According to Ilaria Bellantuono, Professor of Musculoskeletal Ageing at the University of Sheffield, who was not involved in the study, “This is another potential therapy targeting an ageing mechanism, which may benefit frailty. I don’t see it being better than other interventions previously published (e.g. senolytics). Potentially this intervention is less cost effective. Antibody-based therapies are typically more expensive than small molecules. Furthermore, there is no evidence that it works in older age, when deficits are more significant. The intervention in this study started at 18 months of age. In mice, this is equivalent to a 50-year-old person with no serious signs of ageing,” she told SMC.
