Groundbreaking research from City of Hope has identified a key cellular mechanism behind the accumulation of belly fat in middle age, providing new insight into age-related weight gain and unveiling a potential therapeutic target to combat aging and chronic disease.

Published today in Science, the study reveals that aging activates a previously unknown subtype of adult stem cells that drives the production of abdominal fat. This process not only alters body composition but also increases the risk of conditions like diabetes, cardiovascular disease, and metabolic disorders.

“People often lose muscle and gain fat as they age, even when their weight remains stable,” said Dr. Qiong (Annabel) Wang, co-corresponding author and associate professor at City of Hope’s Arthur Riggs Diabetes & Metabolism Research Institute. “We discovered that aging triggers the emergence of a new adult stem cell that significantly boosts fat production, especially around the belly.”

In collaboration with UCLA’s Dr. Xia Yang, the research team focused on white adipose tissue (WAT), the primary fat type responsible for midlife weight gain. By studying adipocyte progenitor cells (APCs) stem cells that mature into fat cells the team found that APCs from older mice generated much more fat when transplanted into young mice. In contrast, young APCs implanted in older mice produced little to no new fat.

“This is the first direct evidence that belly expansion with age is driven by the heightened activity of aged APCs,” said Dr. Adolfo Garcia-Ocana, co-author and chair of the Department of Molecular & Cellular Endocrinology at City of Hope. “While most adult stem cells slow down with age, APCs actually become more active aging enhances their fat-producing capacity.”

The team identified a new, age-specific subtype of APCs called committed preadipocytes, age-specific (CP-As), which emerge in midlife and drive the surge in fat cell formation. A signaling molecule known as leukemia inhibitory factor receptor (LIFR) was found to play a central role in this process, promoting CP-A development and belly fat expansion.

“Our study found that while young organisms don’t rely on LIFR to generate fat, older ones do,” Wang explained. “LIFR appears to be the switch that activates these potent CP-A cells in aging tissues.”

Using single-cell RNA sequencing on human fat tissue samples from donors of varying ages, researchers also identified CP-A cells in humans, confirming their heightened fat-forming potential in middle-aged individuals.

“Our findings underscore the importance of managing new fat cell formation to address age-related obesity,” Wang said. “Targeting CP-A cells could lead to new treatments that reduce belly fat and improve overall metabolic health and longevity.”

The study was led by first authors Dr. Guan Wang of City of Hope and Dr. Gaoyan Li of UCLA. Future research will explore ways to track CP-A cells in living organisms and develop therapies to suppress or eliminate them, potentially helping to slow age-related weight gain and its associated health risks.