Research uncovers the cellular culprit behind age-related abdominal fat

It's no secret that our waistlines often expand in middle-age, but the problem isn't strictly cosmetic. Belly fat accelerates aging and slows down metabolism, increasing our risk for developing diabetes, heart problems and other chronic diseases. Exactly how age transforms a six pack into a softer stomach, however, is murky.

Now preclinical research by 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 illnesses, has uncovered the cellular culprit behind age-related abdominal fat, providing new insights into why our midsections widen with middle age. Published today in Science, the findings suggest a novel target for future therapies to prevent belly flab and extend our healthy lifespans.

"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, one of the world's foremost scientific organizations dedicated to investigating the biology and treatment of diabetes. "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."

In collaboration with the UCLA laboratory co-corresponding author Xia Yang, Ph.D., the scientists conducted a series of mouse experiments later validated on human cells. Wang and her colleagues focused on white adipose tissue (WAT), the fatty tissue responsible for age-related weight gain.

While it's well-known that fat cells grow larger with age, the scientists suspected that WAT also expanded by producing new fat cells, meaning it may have an unlimited potential to grow.

To test their hypothesis, the researchers focused on adipocyte progenitor cells (APCs), a group of stem cells in WAT that evolve into fat cells.

The City of Hope team first transplanted APCs from young and older mice into a second group of young mice. The APCs from the older animals rapidly generated a colossal amount of fat cells.

When the team transplanted APCs from young mice into the older mice, however, the stem cells did not manufacture many new fat cells. The results confirmed that older APCs are equipped to independently make new fat cells, regardless of their host's age.

Using single-cell RNA sequencing, the scientists next compared APC gene activity in young and older mice. While barely active in young mice, APCs woke up with a vengeance in middle-aged mice and began pumping out 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. This is the first evidence that our bellies expand with age due to the APCs' high output of new fat cells."

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

Aging also transformed the APCs into a new type of stem cell called committed preadipocytes, age-specific (CP-As). Arising in middle age, CP-A cells actively churn out new fat cells, explaining why older mice gain more weight.

A signaling pathway called leukemia inhibitory factor receptor (LIFR) proved critical for promoting these CP-A cells to multiply and evolve 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."

Using single-cell RNA sequencing on samples from people of various ages, Wang and her colleagues next studied APCs from human tissue in the lab. Again, the team also identified similar CP-A cells that had an increased number in middle-aged people's tissue. Their discovery also illustrates that CP-As in humans have high capacity in creating new fat cells.

"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."

Future research will focus on tracking CP-A cells in animal models, observing CP-A cells in humans and developing new strategies that eliminate or block the cells to prevent age-related fat gain.

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