It is one of the most universal frustrations of growing older: no matter how carefully you eat or how consistently you exercise, the belly fat seems to appear anyway. Even people whose weight remains stable in middle age often watch their waistlines expand as muscle mass declines. New research published in Science now explains why, and points toward a way to intervene.
A team led by Qiong Annabel Wang at City of Hope’s Beckman Research Institute, together with Xia Yang at UCLA, has discovered a previously unknown population of stem cells that emerge specifically during middle age and supercharge the production of new fat cells in the abdomen. The cells, which the researchers named “committed preadipocytes, age-enriched” (CP-As), appear to be the missing biological link between aging and the notorious phenomenon of middle-age spread.
“This is the first evidence that our bellies expand with age due to the adipose progenitor cells’ high output of new fat cells,” said Adolfo Garcia-Ocana, chair of the Department of Molecular & Cellular Endocrinology at City of Hope, who was not a lead author but is quoted in the associated press release.
A new stem cell for a new problem
The discovery began with a puzzle. For decades, conventional wisdom held that the body’s ability to make new fat cells declines with age. Most adult stem cells, from muscle to bone to neural tissue, lose their proliferative and differentiative capacity as the years pass. Wang’s team, however, found the opposite in fat tissue.
Using a technique called AdipoChaser lineage tracing in mice, they labeled mature fat cells and tracked how many were newly formed at different ages. The results were striking: in young mice (2.5 months old, roughly equivalent to a human teenager), almost no new fat cells were being created. But by 9 months of age (mid-30s in human terms), 68% of visceral fat cells were newly generated. By 12 months (early 40s in human terms), that figure had climbed to 82%.
“This told us something fundamental was changing in the stem cell compartment itself,” Wang said in a statement.
The team performed single-cell RNA sequencing on more than 15,000 adipose progenitor cells (APCs) from the visceral fat of young and middle-aged mice to find out what had changed. The analysis revealed five distinct subpopulations. One of them, the CP-A, was virtually absent in young mice but made up nearly 34% of all APCs at 12 months of age before declining sharply to less than 2% in old age (18 months).
The functional difference was dramatic: CP-As showed more than fourfold higher proliferation and generated six times more fat cells than the closest equivalent cells found in young animals. When CP-As from middle-aged mice were transplanted into young hosts, they continued producing fat at high rates, the fat-making capacity was intrinsic to the cells themselves, not driven by an aging body environment.
The LIFR switch
The search for what makes CP-As so active led to a receptor called LIFR (leukemia inhibitory factor receptor), which was the most highly expressed marker on the surface of these cells. LIFR activates the JAK-STAT3 signaling pathway, a well-known driver of cell proliferation and differentiation.
Wang’s team showed that LIFR signaling was functionally required for CP-A activity. When they treated mice with EC359, an experimental LIFR inhibitor already developed for other indications, CP-A-driven fat formation was blocked in visceral fat without affecting subcutaneous fat. Importantly, the drug had no effect in young mice, whose fat cells rely on different signals.
“While young mice don’t require this signal to make fat, older mice do,” Wang said.
From mice to humans
The researchers confirmed that CP-A-like cells exist in human tissue as well. Single-cell RNA sequencing and flow cytometry on visceral white adipose tissue from human donors of different ages showed that LIFR-high cells correlate positively with age (r = 0.82, p = 0.045). Immunofluorescence confirmed that LIFR-positive cells increase with age in human visceral fat.
The study was primarily conducted in male mice, female mice showed only moderate weight gain, and the human data is correlative, not functional. No direct LIFR perturbation experiments have yet been performed in human cells, meaning the therapeutic potential in humans remains unproven. LIFR is involved in other physiological processes, and systemic blockade may have side effects that have not been explored in this context.
The bigger picture
The work challenges the long-standing assumption that adipogenesis slows with age. Previous studies using 2D culture systems had suggested APCs lose capacity, but Wang’s in vivo lineage tracing and 3D methods tell a different story. The CP-A phenomenon was specific to visceral fat, the fat that wraps around internal organs and is most strongly linked to metabolic disease, which explains why abdominal fat increases disproportionately with age.
The study also draws attention to a unique feature of fat stem cells: unlike almost every other adult stem cell type, APCs gain capacity with age rather than losing it. This makes them a target not only for understanding age-related metabolic disease but also, potentially, for intervention.
“We discovered that the body’s fat-making process is driven by LIFR,” Wang said. “While young mice don’t require this signal to make fat, older mice do.”
The paper is published in Science, Vol. 388, Issue 6745, Article eadj0430 (DOI: 10.1126/science.adj0430). A companion Perspective by Jeon and Kim appears in the same issue. First authors Guan Wang (City of Hope) and Gaoyan Li (UCLA) contributed equally to the work, which involved 22 co-authors across City of Hope, UCLA, and the Buck Institute for Research on Aging.