Atherosclerosis and Diabetic Foot Share a Common Molecular Signature of Cellular Senescence: A Multi-Omics and Machine Learning Study

Diabetes is a condition that affects the body's ability to manage sugar, but its most dangerous consequences often appear far from the bloodstream. Two of the most serious complications are atherosclerosis, a hardening and narrowing of the arteries that can lead to heart attacks and strokes, and diabetic foot ulcers, which are open sores on the feet that struggle to heal. For decades, doctors have treated these as separate problems: one a disease of the blood vessels deep inside the body, the other a wound on the skin. Yet, they frequently occur in the same patients, suggesting a hidden link. At the heart of this mystery is a biological process called cellular senescence. As cells age, they sometimes stop dividing but do not die. Instead, they become like stubborn, clogged drains in a house; they linger in the tissue and release a toxic mix of inflammatory chemicals that damage their neighbors and prevent healing. The question researchers have long asked is whether this same aging process is the common thread tying together the clogged arteries of atherosclerosis and the non-healing wounds of the diabetic foot.

A team of researchers from hospitals and universities in China set out to find the answer by treating these two conditions as parts of the same puzzle. They began by gathering vast amounts of genetic data from previous studies, looking at the molecular blueprints of tissue from patients with diabetic foot ulcers and patients with atherosclerosis. Using powerful computer algorithms, they sifted through thousands of genes to find the specific ones that were behaving strangely in both diseases. They then cross-referenced these findings with a known list of genes associated with cellular aging. This process narrowed the field down to a shared set of seventy-two genes that seemed to drive the aging process in both the blood vessels and the skin. From this group, the researchers used three different machine learning methods to identify the three most critical genes that acted as the core of this shared problem. These three genes were named CALCOCO1, CCND2, and FUCA1.

To see if these findings held up in the real world, the team examined tissue samples from twenty-two patients, half of whom had diabetic foot ulcers and half of whom had non-diabetic foot wounds. They looked directly at the cells under microscopes and measured the levels of specific proteins. The results were clear: the tissues from the diabetic foot patients were filled with a much higher number of these aging, non-dividing cells. These cells showed high levels of damage markers and were releasing the inflammatory chemicals that block healing. Crucially, the three key genes the computer had identified behaved exactly as predicted in these human samples. In the diabetic wounds, the levels of one gene, CCND2, were unusually high, while the other two, CALCOCO1 and FUCA1, were significantly lower than in healthy tissue. This confirmed that the molecular signature found in the computer data was physically present in the patients.

The researchers then turned their attention to understanding how these genes functioned within the complex environment of a wound. By analyzing single cells, they discovered that the aging process was not uniform; different types of cells were affected in different ways. The gene CALCOCO1 was mostly active in fibroblasts, the cells responsible for building the framework of skin and healing wounds. The gene FUCA1 was prominent in immune cells called macrophages, which clean up debris. The gene CCND2 was found in skin cells and fibroblasts. This suggested that the failure to heal was not just one broken part, but a coordinated breakdown across multiple cell types. The aging fibroblasts were failing to build new tissue, while the aging immune cells were stuck in a state of inflammation, creating a hostile environment that prevented the wound from closing.

Finally, the team tested whether a common medication could reverse this process. They took human skin cells from a donor and exposed them to high levels of sugar and fat, mimicking the harsh conditions of a diabetic body. This treatment caused the cells to age rapidly, showing the same genetic changes seen in the patients. However, when the researchers added metformin, a widely used drug for diabetes, the cells responded. The drug reduced the number of aging cells and brought the levels of the three key genes back toward normal. Specifically, it helped restore the function of the genes that had been suppressed by the diabetic environment. This suggests that metformin might work not just by lowering blood sugar, but by directly repairing the cellular machinery that fails in diabetic wounds.

The study concludes that atherosclerosis and diabetic foot ulcers are not just coincidental companions but are driven by the same fundamental mechanism of cellular aging. By identifying the three specific genes that act as the signature of this shared problem, the researchers have provided a new way to look at these diseases. They propose that a single molecular network involving autophagy, which is the cell's way of cleaning up its own waste, and the regulation of the cell cycle, is breaking down in both conditions. While the team notes that further studies are needed to confirm these findings in larger groups and to test the drug directly in patients, their work offers a clear path forward. It suggests that treating the underlying aging of the cells, rather than just the symptoms, could be the key to preventing both the clogging of arteries and the failure of wounds to heal in people with diabetes.