SickKids team identifies precision approach to selectively eliminate old, damaged fat cells

In collaboration with researchers in South Korea, a team from The Hospital for Sick Children (SickKids) has discovered a promising therapeutic target in fat tissue that improves cellular function, reduces inflammation, and may protect against obesity-related diseases. The study was published today in Nature Communications. 

“For many years, metabolic conditions such as type 2 diabetes were viewed primarily as problems of excess weight,” says Dr. Hoon-Ki Sung, Senior Scientist in the Translational Medicine program at SickKids. “More recently, however, evidence shows that chronic inflammation and tissue dysfunction play a central role.”    

As fat tissue ages or expands in obesity, older damaged cells — known as senescent cells — can build up. Research shows that these cells slowly impair the tissue’s ability to adapt and regenerate, contributing to insulin resistance and other metabolic problems. While the body normally replaces aging fat cells with new ones, childhood obesity and aging can disrupt this process, allowing dysfunctional cells to accumulate. 

Investigators at Yeungnam University in South Korea sought a way to target senescent cells and turned to the Sung lab for its expertise in fat tissue biology and super-resolution cellular imaging.  

Unearthing a new therapeutic strategy  

Together, they screened more than 2,000 clinically approved compounds, aiming to find any that could selectively target senescent cells while sparing healthy ones.  

They discovered, first in-vivo and then in preclinical models, that a low dose of an approved leukemia medication called homoharringtonine (HHT) had a strong therapeutic action. In obese, aging mice, HHT eliminated senescent cells, which then improved fat tissue function, reduced inflammation, and prevented metabolic problems. Meanwhile, it left healthy fat cells alone.  

Importantly, HHT treatment preserved lean mass and muscle function, an unexpected finding given the drug’s original use in cancer therapy. “It’s striking that a leukemia drug can have this effect but what’s even more surprising was that it maintained muscle mass in the preclinical models while also making them leaner,” Sung says. 

Over the years, several research groups have established that senescent fat cells are linked to metabolic disease. These include the Sung lab, which had previously discovered that intermittent fasting could reduce senescent cell burden and inflammation in fat tissue.  

Medication also shown to improve cellular health  

In conducting this research, the SickKids team explored the molecular mechanisms that drive HHT’s ability to eliminate senescent cells. They found the drug interacts directly with the stress-response protein HSPA5, which they believe is the primary target of HHT and ultimately what inspires the therapeutic benefit.  

What’s more is that the team observed signs that HHT delayed aging-related decline and extended lifespan in the preclinical models. This rejuvenation, as with the muscle mass finding, was unexpected. 

“Here we have an approved medication that, when used at low doses, can selectively eliminate aged fat cells while at the same time making other cells healthier and in fact younger,” Sung says. “This is very surprising, and we are now studying this in greater depth.”  

Aging itself is linked to the buildup of older cells across many tissues. While Sung’s work focuses on fat tissue, the findings may provide new insights for researchers investigating other organs that are affected by aging and chronic disease, including the heart and brain. 

The study is funded by the National Research Foundation of Korea, Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council, Diabetes Canada, Canada Foundation for Innovation, and Sun Life Financial New Investigator Award from the Banting & Best Diabetes Centre (BBDC) of University of Toronto.