As many people age, they notice the familiar change in their waistline that gradually expands, even if their overall weight doesn’t change dramatically. This increase in abdominal fat is more than just a cosmetic issue. Excess belly fat is associated with slower metabolism, accelerated aging, type 2 diabetes, heart disease, and other chronic health problems.
Scientists have long known that body composition changes with age, but exactly why fat is more likely to accumulate around the midsection remained unclear.
Now, City of Hope researchers have identified what may be the main biological cause of age-related belly fat. Their findings were published in the journal sciencerefers to a newly identified type of stem cell that emerges during aging and may promote the generation of new fat cells. This discovery could ultimately lead to new strategies to reduce belly fat and promote healthier aging.
“People often lose muscle and gain body fat as they age, even if their weight remains the same,” said study co-corresponding author Qiong (Annabel) Wang, Ph.D., associate professor of molecular and cellular endocrinology at City of Hope’s Arthur Riggs Institute for Diabetes and Metabolism, a leading center for diabetes research. “We found that aging triggers the emergence of new types of adult stem cells, which promote mass production of new fat cells, especially around the abdomen.”
Look beyond enlarged fat cells
The research team collaborated with scientists at UCLA and conducted a series of experiments in mice that were later supported by studies in human cells.
Their research focused on white adipose tissue (WAT), the body’s main fat storage tissue. White adipose tissue is responsible for storing excess energy and is the main cause of weight gain and belly fat accumulation.
Scientists have long known that existing fat cells can grow larger as we age. But the researchers suspected that another process, the generation of entirely new fat cells, might also be contributing to the widening of the waistline.
If this is true, it means that aging adipose tissue can continue to grow by constantly adding new cells, not just expanding existing cells.
To test this idea, the research team studied adipocyte progenitor cells (APCs), a type of stem cell found within adipose tissue. These cells act as precursors that can mature into fully developed adipocytes.
Older stem cells produce much more fat
The researchers transplanted APCs from both young and old mice into another group of young mice.
The results were amazing. APCs taken from older animals generated large numbers of new adipocytes.
The reverse experiment yielded completely different results. When APCs from young mice were transplanted into older mice, relatively few new adipocytes were generated.
This suggested that the ability to actively generate fat is built into the old APC itself and is independent of the age of the animal administered it.
To understand what was happening at the molecular level, the researchers used single-cell RNA sequencing, a technique that allows scientists to examine gene activity in individual cells.
Our analysis revealed that APCs are relatively quiet in young mice. However, in middle-aged mice, these cells became highly active and began producing large numbers of new fat cells.
“While the proliferative capacity of most adult stem cells declines with age, the opposite is true for APCs. Aging unleashes the evolutionary and spreading power of these cells,” said Adolfo Garcia-Ocana, Ph.D., chair of the Ruth B. Lanman and Robert K. Lanman Endowed Chair in Gene Regulation and Drug Discovery Research and chair of the Department of Molecular and Cellular Endocrinology at City of Hope. “This is the first evidence that APCs produce large amounts of new fat cells, which causes our bellies to expand as we age.”
Discovery of new age-related stem cells
Scientists have discovered that aging does more than simply activate APCs.
As mice reached middle age, some APCs transformed into a newly identified stem cell population called age-specific committed preadipocytes (CP-A).
These cells specifically appear during aging and have proven to be particularly effective at generating new fat cells. Their appearance may help explain why older mice gained more fat as they aged.
The researchers then explored the biological signals that control this process.
They identified an important signaling pathway known as leukemia inhibitory factor receptor (LIFR). Signal transduction pathways are communication systems that allow cells to receive instructions and coordinate their actions. In this case, LIFR appears to play a major role in helping CP-A cells proliferate and develop into adipocytes.
“We discovered that the body’s adipogenic process is driven by LIFR. Young mice do not need this signal to produce fat, but older mice do,” Wang explained. “Our study shows that LIFR plays an important role in helping CP-A generate new adipocytes and increase abdominal fat in older mice.”
Similar adipogenic cells found in humans
To determine whether this finding applies beyond mice, the research team used the same single-cell RNA sequencing approach to analyze human tissue samples taken from people of different ages.
Researchers have identified cells that closely resemble the newly discovered CP-A. These cells were found in greater numbers in the tissues of middle-aged people.
Human CP-A also shows a strong ability to generate new fat cells, suggesting that a similar biological process may be occurring in humans.
“Our findings highlight the importance of controlling new adipocyte formation to combat age-related obesity,” Wang said. “Understanding the role of CP-A in metabolic disorders and how these cells emerge during aging may lead to new medical solutions to reduce abdominal fat and improve health and longevity.”
Potential new target for age-related obesity
Although further research is needed, this discovery provides scientists with a promising new target for future treatments.
The researchers now plan to track CP-A cells in animal experiments, investigate how these cells behave in humans, and look for ways to block or eliminate them. If successful, such an approach could help prevent the accumulation of abdominal fat that typically accompanies aging.
The study’s first authors were City of Hope researcher Dr. Guan Wang and UCLA researcher Dr. Gaoyan Li.
