The Hidden Dangers of Shifting Fat Distribution in Middle Age

Understanding How White Fat Cells Change with Age

A new study published in Aging Cell has provided detailed insights into what happens to individual fat cells in white adipose tissue (WAT) as they age.

White Fat as a Metabolic Organ

WAT is more than an energy storage depot. Previous research has established that it functions as a metabolic regulator. When its functionality declines, WAT tends to shift toward the central abdomen, contributes to fat accumulation in other tissues, triggers insulin resistance, and promotes chronic low-level inflammation.

These declines are strongly associated with aging. Cellular senescence, a reduction in stem cell progenitors, and increased immune cell infiltration into tissue have all been cited as contributing factors.

While earlier studies relied on basic methods such as fluorescence imaging and broad cellular analysis, this research incorporated single-cell transcriptomics. The team had previously applied single-cell RNA sequencing to human fat cells and continued using this advanced methodology to determine how aging affects them.

Age-Related Differences Despite Similar BMI

The researchers examined samples from twenty individuals, ten under the age of 30 and ten over the age of 65. Although both groups had similar body mass index and insulin sensitivity, the older group showed higher systolic blood pressure, greater waist circumference, and poorer cholesterol profiles.

Using RNA analysis to evaluate gene expression, the team identified two primary fat cell groups. The Adip_1 group upregulated genes involved in oxidative stress response, while the Adip_2 group upregulated genes linked to insulin responsiveness.

Significant age-related changes were found in cell type and composition. Older individuals had more connective tissue mast cells and more M1-type pro-inflammatory macrophages. Their Adip_2 cells showed increased gene activity tied to inflammation and fibrosis. Collagen production related to reduced insulin sensitivity was elevated in these older fat cells, although overall fibrosis in WAT was not found to increase with age. However, a greater number of very large fat cells was observed in the older population.

In contrast, younger individuals showed more extracellular matrix protein expression from stem cells, greater angiogenic activity in vascular cells, and more lipid-metabolism gene activity in Adip_2 cells.

Gut Macrophages and Chronic Inflammation

Microscopic examination revealed macrophage infiltration in older males, with immune cells forming crown-like structures around damaged or dying adipocytes. This was strongly associated with fat accumulation in the abdominal region. The CXC14 gene was identified as a significant driver of inflammation and macrophage recruitment, and it was notably upregulated in older participants.

Furthermore, aging was linked to a marked increase in cellular senescence within WAT, particularly among pre-adipocytes, Adip_1 cells, and vascular tissues.

This study reveals new associations between inflammation, aging, and gene expression in white fat. Fat buildup in the gut does not occur randomly, but appears to result from an inflammatory deterioration of the fat tissue itself, a process sometimes referred to as inflammaging.

Your call to action for aging fat cells in white adipose tissue

To reduce the impact of inflammaging and preserve the function of white adipose tissue, individuals should adopt strategies that support metabolic health and reduce inflammation. These include maintaining a healthy waist circumference, engaging in regular physical activity, avoiding excessive caloric intake, and considering dietary choices that promote insulin sensitivity. By protecting fat tissue from age-related dysfunction, it may be possible to reduce chronic inflammation and support healthier aging at the cellular level.

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Study Links:

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Divoux, A., Whytock, K. L., Halasz, L., Hopf, M. E., Sparks, L. M., Osborne, T. F., & Smith, S. R. (2024). Distinct subpopulations of human subcutaneous adipose tissue precursor cells revealed by single-cell RNA sequencing. American Journal of Physiology-Cell Physiology, 326(4), C1248-C1261.

Whytock, K. L., Divoux, A., Sun, Y., Hopf, M., Yeo, R. X., Pino, M. F., … & Sparks, L. M. (2023). Isolation of nuclei from frozen human subcutaneous adipose tissue for full-length single-nuclei transcriptional profiling. STAR protocols, 4(1), 102054.

Divoux, A., Tordjman, J., Lacasa, D., Veyrie, N., Hugol, D., Aissat, A., … & Clément, K. (2010). Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes, 59(11), 2817-2825.

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