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In a nutshell
- Scientists discovered a new type of fat cell precursor (CP-A) that appears specifically during middle age, causing rapid increase in belly fat regardless of diet and exercise habits.
- Over 80% of fat cells in middle-aged mice were newly created, challenging the idea that middle-age weight gain comes primarily from existing fat cells enlarging.
- Researchers identified a specific receptor (LIFR) that drives these age-related fat cells, offering a potential target for future treatments to prevent age-related weight gain.
LOS ANGELES — That stubborn belly fat that appears in your 40s isn’t just from diet or lack of exercise. Scientists have uncovered a biological process that explains why waistlines expand in middle age, even when lifestyle habits remain consistent.
Research published in Science reveals a previously unknown type of fat cell that emerges specifically during middle age, driving rapid fat accumulation in the belly area. This discovery challenges conventional wisdom about middle-aged weight gain.
“A key finding from our work is that despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age,” the research team from City of Hope Medical Center and UCLA writes in their paper. In plain terms, our bodies begin making new fat cells at surprising rates once we reach our 40s, especially in the deep belly fat surrounding our organs.
The Surprising Biology of Middle-Age Weight Gain
Scientists tracked fat cell formation in mice at different ages. Young adult mice rarely created new fat cells, but middle-aged mice showed an explosion of fat cell creation. Over 80% of fat cells in the belly region of 12-month-old mice (roughly equivalent to a 40-something human) were newly formed, compared to almost none in younger mice.
Middle-aged mice developed patterns familiar in humans: expanded waistlines, reduced energy expenditure, and insulin resistance – all hallmarks of age-related metabolic changes that increase risk for diabetes and heart disease.
The research team identified an entirely new fat cell precursor they named “CP-A” (committed preadipocyte, age-enriched). These CP-A cells emerge specifically during middle age and have remarkable abilities to multiply and transform into mature fat cells.
Human Evidence Confirms Mouse Findings
To verify these findings weren’t just mouse-specific, the team analyzed human fat tissue samples and discovered the same CP-A cells in middle-aged humans. The number of these specialized fat precursor cells increased dramatically with age, peaking in middle age before declining in later years.
When researchers transplanted these middle-aged fat precursor cells into young mice, the cells maintained their aggressive fat-producing behavior. This reveals the cells themselves fundamentally change with age – they’re not simply responding to age-related hormonal shifts or metabolic changes.
Unlike most stem cells that lose function with age, these fat precursor cells gain enhanced abilities to multiply and transform as we get older.
A Potential Path for Prevention
The team identified a specific cell receptor called LIFR (leukemia inhibitory factor receptor) that marks and drives these age-specialized fat precursor cells. When they blocked this receptor with drugs, they prevented visceral fat expansion in mice.
The findings point to potential new targets for preventing age-related obesity. By identifying the LIFR signaling pathway as critical for CP-A cell activation, researchers have a possible drug target that might prevent middle-age spread without disrupting normal fat tissue function.
As obesity continues driving health problems globally, understanding the basic processes behind age-related weight gain offers hope for preventing the cascade of metabolic disorders that often follow. This study demonstrates that middle-age weight gain isn’t simply a willpower issue, but a programmed biological process that might eventually be modified.
Paper Summary
Methodology
The researchers used multiple complementary approaches to investigate age-related changes in fat tissue. They employed lineage tracing mouse models that allowed them to track the formation of new fat cells over time, with fluorescent labeling that distinguished between existing and newly formed fat cells. They also used 3D transplantation studies where they took fat progenitor cells from different aged mice, mixed them together, and transplanted them into young mice to observe their behavior. Additionally, they performed single-cell RNA sequencing to identify distinct cell populations and their gene expression profiles. The team validated their findings using both in vitro cell culture experiments and in vivo transplantation studies, and also tested pharmacological inhibitors of the LIFR signaling pathway to confirm its role in CP-A cell function.
Results
The study found that male mice gained significant weight during middle age primarily due to increased visceral fat mass. Tracking adipocyte (fat cell) formation revealed that over 80% of fat cells in visceral fat of 12-month-old mice were newly generated, compared to very few in young mice. Single-cell analysis identified a distinct age-specific progenitor cell population called CP-A (committed preadipocyte, age-enriched) that appeared at 9 months, peaked at 12 months, and declined by 18 months of age. These CP-A cells displayed much higher proliferation and differentiation capacities than other progenitor cells, both in laboratory tests and when transplanted. The researchers identified LIFR (leukemia inhibitory factor receptor) as a marker and functional regulator of these cells, and showed that inhibiting LIFR could prevent visceral fat expansion during middle age.
Limitations
The study primarily focused on male mice, with only limited data on females, who showed more moderate weight gain patterns. The researchers acknowledge that while they demonstrated cell-autonomous changes in fat progenitors, age-related systemic factors and tissue environment likely also play important roles in remodeling fat progenitor cells over time. Additionally, while they identified similar CP-A cells in human samples, the human data was predominantly from male donors, with only one female donor, limiting conclusions about potential sex differences in humans.
Funding/Disclosures
This work was funded by multiple grants from the National Institutes of Health, the California Institute for Regenerative Medicine, American Diabetes Association, and institutional awards from City of Hope and UCLA. The authors declared no competing interests.
Publication Information
The paper, “Distinct adipose progenitor cells emerging with age drive active adipogenesis,” by Wang G, Li G, Song A, et al. was published in Science, on April 25, 2025. DOI: 10.1126/science.adj0430.
