Why Our Waistlines Expand in Midlife: The Role of Stem Cells

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 down the 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.

Certain Stem Cells that Develop Into Fat Cells

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 diseases, has discovered the cellular cause of age-related belly fat, providing new insights into why our waists expand as we age. The results, published in Science, point to a new target for future therapies to prevent belly fat and extend our healthy life expectancy.

“As people age, they often lose muscle mass and gain body fat—even if their body weight remains the same,” said Qiong (Annabel) Wang, Ph.D., co-author of the study 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 for diabetes biology and treatment. “We discovered that aging triggers the emergence 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 co-author Xia Yang, Ph.D., from the UCLA lab, the scientists conducted a series of mouse experiments that were later confirmed in human cells. Wang and her colleagues focused on white adipose tissue (WAT), the type of fat responsible for age-related weight gain. While it is known that fat cells grow larger with age, the scientists suspected that WAT also increases in size through the production of new fat cells, which would mean that it has 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 older mice into a second group of young mice. The APCs from the older animals quickly produced an enormous amount of fat cells. However, when the team transplanted APCs from young mice into older mice, the stem cells did not form many new fat cells. The results confirmed that older APCs are capable of forming new fat cells regardless of the age of their host.

Controlling the Formation of New Fat Cells to Combat Age-Related Obesity

Using single-cell RNA sequencing, the scientists then compared APC gene activity in young and older mice. While APCs were barely active in young mice, they suddenly became very active in middle-aged mice and began to produce new fat cells. “While the growth capacity of most adult stem cells declines with age, the opposite is true for APCs—aging unleashes the potential of these cells to develop and proliferate,” said Dr. Adolfo Garcia-Ocana, Ruth B. & Robert K. Lanman Endowed Professor of Gene Regulation and Drug Discovery and chair of the Department of Molecular and 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 APCs into a new type of stem cell called age-specific preadipose cells (CP-As). CP-A cells arise in middle age and actively produce new fat cells, explaining why older mice gain more weight. A signaling pathway called leukemia inhibitory factor receptor (LIFR) was found to be critical for the proliferation and development of these CP-A cells into fat cells. The scientists discovered that the body’s fat formation process is controlled by LIFR. While young mice do not need this signal to form fat, it is necessary for older mice. Their research shows that LIFR plays a crucial role in stimulating CP-As to form new fat cells and increase belly fat in older mice.

Using single-cell RNA sequencing on samples from people of different ages, Wang and her colleagues then examined APCs from human tissue in the laboratory. Here, too, the team identified similar CP-A cells, whose numbers were elevated in the tissue of middle-aged people. Their discovery also shows that CP-As have a high capacity to form new fat cells in humans. “Our findings underscore the importance of controlling the formation of new fat cells to combat age-related obesity,” said Wang. According to the researchers, understanding the role of CP-As in metabolic disorders and the development of these cells in old age 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 to eliminate or block these cells to prevent age-related fat gain.