05 July 2022

New life of old skin

Human skin begins to age relatively early, and this process has spawned a huge skin care industry. Unfortunately, most of the advertised anti-aging products do not live up to their promises.

A few years ago, experiments on combining the cardiovascular systems of two mice of different ages (heterochronous parabiosis) demonstrated that young blood can rejuvenate various tissues of an old mouse. Despite promising results, the model itself is far from ideal, since it requires the physical connection of two separate organisms. In a new study, a group of researchers from Israel tried to implement the principle of heterochronous parabiosis in a different way by transplanting old human skin into young mice.

Reliable rejuvenation

The researchers used immune-compromised mice to prevent rejection. They were divided into one control group and four experimental ones: old mice implanted with young human skin (“young in old”, or YiO), old mice implanted with old human skin ("old in old", or OiO), young mice transplanted with young human skin ("young in young", or YiY), and young mice that received old human skin ("old in young", or OiY).

Researchers have found that transplanting old skin to a young body eliminates many signs of skin aging. In the OiY group, the grafts showed an increase in the thickness of the epidermis by 2.4 times compared to OiO. The proliferation of keratinocytes – the main type of epidermal cells – increased more than three times. Comparison of the OiY graft with the skin of old people gave similar results. Interestingly, the effect weakened as the young mice aged, and a year after transplantation, the xenografts restored their original old phenotype.

Skin rejuvenation has also been confirmed at the molecular level. A sevenfold decrease in the levels of β-galactosidase, the main marker of cellular aging, was found in OiY transplants. Several other well-known markers of aging, including low levels of SIRT-1, have also been reversed. The researchers registered an almost threefold increase in the expression of filagrin, a protein that protects the outer layer of the skin from environmental influences. The level of type XVII collagen, which is known to protect epithelial cells from aging, has also increased dramatically.

Xenografts have shown the ability to resist oxidative stress: for example, there was a noticeable increase in the level of glutathione reductase, which is involved in the production of the powerful antioxidant glutathione. Conversely, markers of inflammation, an important cause of aging, have decreased significantly.

The researchers checked whether rejuvenation extends to the dermis. They found that the balance between thin and thick collagen fibers was restored in OiY xenografts (thick collagen bundles decrease in number and thin with age). The level of elastin protein, which decreases with age, has also recovered.

New blood vessels

In the OiY model, angiogenesis significantly increased four weeks after transplantation. At first, the researchers assumed that these were the blood vessels of the host mouse. However, it turned out that the vast majority of them were human blood vessels: they originated in transplanted human skin. Something in the mouse environment contributed to the creation of new capillaries inside the transplanted human skin.

Gene expression analysis revealed significant changes in OiY xenografts compared to old skin, with the most active genes involved in angiogenesis, especially vascular endothelial growth factor A (VEGF-A), which is known to decrease with age.

When VEGF-A attaches to its VEGFR receptor, it increases the production of VEGF-A through a complex positive feedback loop. Since VEGF-A levels are high in young mice, the researchers suggest that mouse VEGF-A, interacting with human receptors, caused an increase in the production of human VEGF-A in xenografts. This increase led to morphological rejuvenation.

Thus, VEGF-A mediated angiogenesis is a key factor contributing to the rejuvenation of OiY xenografts. According to this hypothesis, blocking VEGF-A by antibodies led to the almost complete disappearance of the rejuvenating effect.

In another experiment, injection of VEGF-A-loaded lipid nanoparticles into OiO xenografts resulted in reproduction of most of the changes observed in YiO xenografts. Finally, the researchers tested VEGF-A on an in vitro human skin sample that was separated from a human or mouse environment. Even under these conditions, VEGF-A treatment significantly improved various parameters associated with aging.


Thus, VEGF-A is a factor necessary and sufficient for the rejuvenation of old skin. This means that enhancing VEGF-A expression may be a potentially effective anti-aging therapy.

Article by A.Keren et al. Human organ rejuvenation by VEGF-A: Lessons from the skin is published in the journal Science Advances.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru .

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