Fountain of youth| MEDICUS 2024 Issue 3

Duke-NUS team unlocks secret to potential fountain of youth
By Tan Ruilin, Writer

Asst Prof Anissa Widjaja pipettes material out of a test tube in the Widjaja-Cook laboratory, housed in the Duke-NUS’ Khoo Teck Puat building, where the study was conducted. // Credit: Norfaezah Abdullah, Duke-NUS

The quest for staving off ageing and prolonging youth is a tale almost as old as mortality itself.

Thanks to a team of researchers from Duke-NUS Medical School’s Cardiovascular and Metabolic Disorders Programme, we might have just stepped closer to the mystery of getting older. Through this long-elusive discovery, which has been published in the journal Nature, these researchers may have found the key to what makes mice, and maybe humans, grow old and frail—a protein called interleukin-11 (IL11), which they demonstrated to actively drive ageing through increasing inflammation, fat accumulation, muscle loss and other hallmarks of ageing.

Upon administering anti-IL11 therapy over 25 weeks, the team found that the deleterious effects of ageing were not only counteracted, but that lifespan and healthspan—the number of years lived in good health—were increased. Lifespan was increased by an average of 25 per cent.

A greying world? Perhaps not

As people live longer across the world, staving off the physical decline and frailty that come with age has become a holy grail. Put differently, to address the colossal health, social and economic challenges of an ageing population in the coming decades, effective interventions against ageing come with high expectations and large rewards. Their impact projected to unlock significant societal and economic benefits, with estimates suggesting that an ageing slowdown that increases life expectancy by just one year alone is worth US$38 trillion.

According to the team from Duke-NUS, their results are the first in the world to demonstrate that IL11 is a principal factor in ageing.

First and co-corresponding author of the paper, Assistant Professor Anissa Widjaja from Duke-NUS, describes how the study was germinated, almost on a whim.

“This project started back in 2017 when a collaborator of ours sent us some tissue samples for another project. Out of curiosity, I ran some experiments to check for IL11 levels. From the readings, we could clearly see that the levels of IL11 increased with age and that’s when we got really excited!”

“Despite average life expectancy increasing markedly over recent decades, there’s a notable disparity between years lived and years of healthy living, free of disease. For rapidly ageing societies like Singapore’s, this discovery could be transformative, enabling older adults to prolong healthy ageing, reducing frailty and risk of falls while improving cardiometabolic health.”
Prof Thomas Coffman

Hallmarks of ageing: Fat accumulation and muscle loss

In their studies in mice, the team found that, with age, organs expressed increasing levels of IL11, which, in turn, promoted fat accumulation in the liver and abdomen, and reduced muscle mass and strength—two conditions that are hallmarks of human ageing. IL11 behaves much like a warning system that perceives damaged cells as a kind of infection, galvanising an immune response in the body and resulting in inflammation, which increases and drives physical ageing.

Conventional wisdom would argue that anti-IL11 therapy should counteract these ageing effects—and the study’s results show as much. The team demonstrated that applying anti-IL11 therapy in the same preclinical models improved metabolism by creating a shift from generating white fat to beneficial brown fat. Brown fat breaks down blood sugar and fat molecules to help maintain body temperature and burn calories.

They also observed improved muscle function and overall better health in the mice, as well as an increased lifespan by up to 25 per cent in both sexes.

Unlike other drugs known to inhibit specific pathways involved in ageing, such as metformin and rapamycin, anti-IL11 therapy blocks multiple major mechanisms that become dysfunctional with age. This affords protection against multimorbidity from cardiometabolic diseases, the age-related loss of strength and muscle mass, as well as frailty.

Besides these externally observable changes, anti-IL11 therapy also reduced the rate of telomere shortening, which is a process that precedes cell ageing and death, and preserved cell mitochondria’s health—specifically, their ability to generate energy.

Asst Prof Anissa Widjaja viewing a western blot, a type of experimental data that first clued the researchers in to IL11's role in ageing. // Credit: Norfaezah Abdullah, Duke-NUS

Revolutionising the push against ageing

Though in the early stages of research, these astonishing defensive effects against ageing engender hope that the struggle against ageing has gained a robust stronghold—especially as anti-IL11 therapy has been assessed in preclinical trials¹² to suggest an excellent safety profile and no observed toxicity.

Senior author of the study and Tanoto Foundation Professor of Cardiovascular Medicine at the SingHealth Duke-NUS Academic Medical Centre Stuart Cook, who is also with Duke-NUS’ Cardiovascular and Metabolic Disorders Programme, and at the National Heart Centre Singapore, said:

“Our aim is that one day, anti-IL11 therapy will be used as widely as possible, so that people the world over can lead healthier lives for longer. However, this is not easy, as approval pathways for drugs to treat ageing are not well-defined, and raising funds to do clinical trials in this area is very challenging.”

Undaunted by the challenges ahead, the team is forging ahead, committed to finding partners who will help to translate their discovery into clinical care.

¹https://www.gastrojournal.org/article/S0016-5085(19)40858-5/fulltext

²https://www.nature.com/articles/s41586-024-07701-9