It's no secret that our waistlines often expand in middle age, but the problem isn't just cosmetic. Belly fat accelerates the aging process and slows metabolism, increasing the risk of diabetes, heart problems, and other chronic diseases. However, exactly how age transforms a six-pack into a softer belly is unclear.
Now, preclinical research from City of Hope®, one of the largest and most advanced cancer research and treatment organizations in the United States and a leading research center for diabetes and other life-threatening diseases, has uncovered the cellular culprit behind age-related belly fat and provided new insights into why our midsections widen in middle age. The findings, published in the journal Science, suggest a new target for future therapies to prevent belly fat and extend our healthy lifespan.
“People often lose muscle and gain body fat as they age — even if their body weight remains the same,” said Dr. Quiong (Annabel) Wang, Ph.D., study co-author and associate professor of molecular and cellular endocrinology at the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, one of the world’s leading scientific institutions dedicated to the study of the biology and treatment of diabetes. “We discovered that aging triggers the arrival of a new type of adult stem cell and promotes the massive production of new fat cells in the body, especially in the abdominal area.”
In collaboration with the UCLA lab and co-author Xia Yang, Ph.D., the scientists conducted a series of mouse experiments that were later validated on human cells. Wang and her colleagues focused on white adipose tissue (WAT), the fat tissue responsible for age-related weight gain.
While it is known that fat cells get larger with age, the scientists suspected that WAT also increases through the production of new fat cells, meaning it may have unlimited growth potential.
To test their hypothesis, the researchers focused on adipocyte precursor cells (APCs), a group of stem cells in WAT that develop into fat cells.
The City of Hope team first transplanted APCs from young and old mice into a second group of young mice. The APCs from the older animals quickly generated a huge amount of fat cells.
However, when the team transplanted APCs from young mice into older mice, the stem cells did not produce many new fat cells. The results confirmed that older APCs are capable of creating new fat cells regardless of their host's age.
Using single-cell RNA sequencing, the scientists then compared the gene activity of APCs in young and old mice. While barely active in young mice, the APCs in middle-aged mice sprang to life with full force, beginning to produce new fat cells.
"While the ability of most adult stem cells to grow declines with age, the opposite is true for APCs – aging unleashes the ability of these cells to develop and proliferate," 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 grow as we age due to the high production of new fat cells by APCs."
Aging also transformed the APCs into a new type of stem cell, called age-associated pro-adipocytes (CP-As). CP-A cells, which emerge in middle age, actively produce new fat cells, explaining why older mice gain more weight.
A signaling pathway called Leukemia Inhibitory Factor Receptor (LIFR) proved crucial for promoting the proliferation of these CP-A cells and their development into fat cells.
"We discovered that the body's own process of fat generation is controlled by LIFR. While young mice do not need this signal to make fat, older mice do," explained Wang. "Our findings suggest LIFR plays a critical role in prompting CP-As to make new fat cells and enlarge abdominal fat in older mice."
Using single-cell RNA sequencing of samples from people of different ages, Wang and her colleagues next examined APCs from human tissue in the lab. Here too, the team identified similar CP-A cells, with their numbers increased in the tissue of middle-aged people. Their discovery also shows that CP-As have a high capacity to create new fat cells in humans.
