Targeting CD47 Improves Insulin Sensitivity Without Weight Loss

A new research paper was published in Volume 17, Issue 12 of Aging-US on December 1, 2025, titled “CD47 antisense oligonucleotide treatment improves glucose homeostasis and alleviates dyslipidemia in aged male mice.”

Led by Taesik Gwag and Shuxia Wang from the University of Kentucky and the Lexington Veterans Affairs Medical Center, the research shows that reducing CD47 levels improves blood sugar regulation and lipid balance in older mice. These findings are significant because metabolic disorders linked to aging increase the risk of diabetes, cardiovascular disease, and other chronic conditions. The results suggest that CD47 may be a promising target for improving metabolic health during aging.

As people age, metabolic problems such as insulin resistance, high cholesterol, and increased abdominal fat become more common, even without significant weight gain. CD47 is known to play roles in immune signaling and aging-related inflammation, and earlier studies have linked it to metabolic dysfunction. This study examined whether lowering CD47 activity could reverse age-related metabolic decline.

Researchers treated aged male mice with an antisense oligonucleotide (ASO) designed to reduce CD47 for ten weeks. The treatment led to lower fasting blood glucose, improved glucose tolerance, and enhanced insulin sensitivity. Circulating lipid levels, including cholesterol and free fatty acids, were also reduced. Importantly, these benefits occurred without changes in overall body weight, indicating improved metabolic efficiency rather than weight loss.

“Twenty-month-old male mice were treated with control ASO or CD47 ASO (25 μg/g) for 10 weeks.”

One of the most notable findings was a selective reduction in visceral fat, the deep abdominal fat closely associated with metabolic disease. Fat cells in this tissue were smaller, reflecting reduced fat production within the cells rather than increased fat breakdown. This change helps explain why metabolic health improved without weight loss.

Treatment also improved brown fat tissue function. Brown fat plays a key role in energy use and metabolism. Treated mice showed increased activity of genes involved in energy burning and hormone-like signaling, supporting improved whole-body glucose and lipid balance. Moreover, the liver showed improved glucose metabolism. While liver fat content was unchanged, genes involved in glucose uptake and processing were more active, further contributing to better blood sugar control.

Together, these findings identify CD47 as a key regulator of age-related metabolic dysfunction. By improving glucose control, lipid balance, and fat tissue function in aged male mice, CD47 antisense therapy offers a promising path for future strategies aimed at reducing metabolic disease risk in aging populations.

Reference: Gwag T, Newcomb A, Otuagomah J, et al. CD47 antisense oligonucleotide treatment improves glucose homeostasis and alleviates dyslipidemia in aged male mice. Aging. 2025;17(12):2884-2901. doi: 10.18632/aging.206343

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