Scientists have long known that body composition changes with age, but exactly why fat tends to accumulate around the midsection has remained unclear.

Now, researchers at City of Hope have identified what may be a key biological driver of age-related belly fat. Their findings, published in the journal Science, point to a newly identified type of stem cell that appears during aging and may help fuel the production of new fat cells. The discovery could eventually lead to new strategies for reducing abdominal fat and promoting healthier aging.

"People often lose muscle and gain body fat as they age -- even when their body weight remains the same," said Qiong (Annabel) Wang, Ph.D., the study's co-corresponding author and an associate professor of molecular and cellular endocrinology at City of Hope's Arthur Riggs Diabetes & Metabolism Research Institute, a leading center for diabetes research. "We discovered aging triggers the arrival of a new type of adult stem cell and enhances the body's massive production of new fat cells, especially around the belly."

Looking Beyond Enlarged Fat Cells

The research team worked with scientists at UCLA and conducted a series of experiments in mice that were later supported by studies of human cells.

Their investigation focused on white adipose tissue (WAT), the body's primary fat-storage tissue. White adipose tissue is responsible for storing excess energy and is a major contributor to weight gain and belly fat accumulation.

Scientists have long known that existing fat cells can become larger as people age. However, the researchers suspected that another process might also be contributing to expanding waistlines: the creation of entirely new fat cells.

If true, that would mean aging fat tissue could continue growing not just by enlarging existing cells, but by constantly adding new ones.

To test this idea, the team studied adipocyte progenitor cells (APCs), a type of stem cell found within fat tissue. These cells serve as precursors that can mature into fully developed fat cells.

Older Stem Cells Produced Far More Fat

The researchers transplanted APCs from both young and older mice into a separate group of young mice.

The results were striking. APCs taken from older animals generated large numbers of new fat cells.

The opposite experiment produced a very different outcome. When APCs from young mice were transplanted into older mice, they generated relatively few new fat cells.

This suggested that the ability to aggressively produce fat was built into the older APCs themselves and did not depend on the age of the animal receiving them.

To understand what was happening at a molecular level, the researchers used single-cell RNA sequencing, a technique that allows scientists to examine gene activity in individual cells.

The analysis revealed that APCs were relatively quiet in young mice. In middle-aged mice, however, these cells became highly active and began producing large numbers of new fat cells.

"While most adult stem cells' capacity to grow wanes with age, the opposite holds true with APCs -- aging unlocks these cells' power to evolve and spread," said Adolfo Garcia-Ocana, Ph.D., the Ruth B. & Robert K. Lanman Endowed Chair in Gene Regulation & Drug Discovery Research and chair of the Department of Molecular & Cellular Endocrinology at City of Hope. "This is the first evidence that our bellies expand with age due to the APCs' high output of new fat cells."

Discovery of a New Age-Related Stem Cell

The scientists found that aging did more than simply activate APCs.

As mice reached middle age, some APCs transformed into a newly identified stem cell population called committed preadipocytes, age-specific (CP-As).

These cells appeared specifically during aging and proved especially effective at producing new fat cells. Their emergence may help explain why older mice gained more fat as they aged.

The researchers then searched for the biological signals controlling this process.

They identified an important signaling pathway known as leukemia inhibitory factor receptor (LIFR). Signaling pathways are communication systems that allow cells to receive instructions and coordinate their behavior. In this case, LIFR appeared to play a major role in helping CP-A cells multiply and develop into fat cells.

"We discovered that the body's fat-making process is driven by LIFR. While young mice don't require this signal to make fat, older mice do," explained Wang. "Our research indicates that LIFR plays a crucial role in triggering CP-As to create new fat cells and expand belly fat in older mice."

Similar Fat-Producing Cells Found in Humans

To determine whether the findings might apply beyond mice, the team analyzed human tissue samples from people of different ages using the same single-cell RNA sequencing approach.

The researchers identified cells that closely resembled the newly discovered CP-As. These cells were found in greater numbers in tissue from middle-aged individuals.

The human CP-As also showed a strong ability to generate new fat cells, suggesting that a similar biological process may occur in people.

"Our findings highlight the importance of controlling new fat-cell formation to address age-related obesity," said Wang. "Understanding the role of CP-As in metabolic disorders and how these cells emerge during aging could lead to new medical solutions for reducing belly fat and improving health and longevity."

A Potential New Target for Age-Related Obesity

Although more research is needed, the discovery provides scientists with a promising new target for future therapies.

Researchers now plan to track CP-A cells in animal studies, investigate how these cells behave in humans, and explore ways to block or eliminate them. If successful, such approaches could potentially help prevent the accumulation of belly fat that commonly accompanies aging.

The study's first authors were City of Hope researcher Guan Wang, Ph.D., and UCLA researcher Gaoyan Li, Ph.D.