As we move into middle age, we commonly notice a gradual thickening around the waistline. While this change might seem merely cosmetic, it carries significant health implications. Excess abdominal fat not only accelerates the ageing process but also increases the risk of chronic conditions such as heart disease, diabetes, and metabolic disorders. Despite this, the precise biological mechanisms behind midlife weight gain have remained mysterious. However, new research from City of Hope, one of the most significant cancer research and treatment organisations in the United States and a leading centre for diabetes research, has uncovered a critical cellular trigger that might explain why our midsections tend to expand as we age. Published in Science, this breakthrough provides fresh insights into the underlying biology of age-related fat accumulation. It opens the door to potential new therapies to reduce belly fat and extend healthy lifespans.
The study, led by Dr. Qiong (Annabel) Wang, an associate professor at City of Hope’s Arthur Riggs Diabetes & Metabolism Research Institute, reveals that ageing activates a unique class of adult stem cells, leading to a surge in the creation of new fat cells, particularly around the abdomen. “People often lose muscle and gain fat as they age, even if their overall body weight remains stable,” Wang explained. “We discovered that ageing 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.” This discovery is significant because it shifts the focus from simply managing calorie intake and physical activity to understanding the cellular processes that drive midlife weight gain.
To explore this phenomenon, Wang and her colleagues at City of Hope, in collaboration with researchers at the University of California, Los Angeles (UCLA), focused their attention on white adipose tissue (WAT), the primary form of body fat responsible for age-related weight gain. While it is well-known that fat cells can grow larger as we age, researchers suspect that WAT also expands by producing entirely new fat cells, effectively providing them unlimited potential to grow. To test this hypothesis, they studied a group of stem cells within WAT known as adipocyte progenitor cells (APCs). These APCs are the precursors to fat cells and can transform into fully mature fat cells under the right conditions.
The team conducted a series of experiments involving both young and older mice. They transplanted APCs from young and older mice into a separate group of young mice. The results were striking: APCs from older animals rapidly generated a colossal amount of new fat cells, while APCs from young animals did not show the same behaviour. This confirmed that older APCs are inherently programmed to produce new fat cells at a much higher rate, regardless of the age of their host. This discovery points to a fundamental difference in the biology of these stem cells as animals age, offering a new perspective on why belly fat tends to accumulate in middle age.
Delving deeper into the genetic programming of these cells, the researchers used single-cell RNA sequencing to compare APC activity in young and middle-aged mice. They found that APCs, which remain largely dormant in youth, become highly active in middle age, transforming into a new type of stem cell known as committed preadipocytes, age-specific (CP-As). These CP-As are particularly efficient at generating new fat cells, providing a cellular explanation for the notorious “middle-age spread.” Crucially, the scientists identified a key signalling pathway – the leukaemia inhibitory factor receptor (LIFR) – that drives this process. Unlike young mice, which can produce fat cells without this signal, older mice rely heavily on LIFR to sustain CP-A growth. This finding suggests that targeting the LIFR pathway could be a promising approach for preventing age-related belly fat accumulation.
Finally, the researchers extended their findings to humans by examining APCs from people of various ages. They found that CP-A cells were also present in human tissue, where they increased in number with age, confirming that this phenomenon is not just a peculiarity of mice but a fundamental aspect of human biology. “Our findings highlight the importance of controlling new fat-cell formation to combat age-related obesity,” Wang emphasised. “By understanding the role of CP-As in metabolic disorders, we could develop new therapies that prevent the buildup of belly fat and extend healthy lifespans.” Future research will focus on tracking CP-A cells in animal models, exploring their behaviour in human tissue, and developing potential drugs to block their growth, potentially offering a new path to healthier ageing.
More information: Qiong Wang et al, Distinct adipose progenitor cells emerging with age drive active adipogenesis, Science. DOI: 10.1126/science.adj0430
Journal information: Science Provided by City of Hope
