What Causes Our Skin To Age? Inflammation A Likely Suspect

When we are young, a cut or scrape heals within a matter of days — the skin is thick and regenerates easily. But as we age, our skin loses elasticity and becomes thinner, weakening its regenerative capacity. Now, researchers at the Barcelona Institute of Science and Technology have uncovered what looks to be a key mechanism driving the aging process: a signaling protein called interleukin-17 (IL-17). Published in Nature Aging, the findings by the laboratory of Salvador Aznar Benitah provide an exciting new clue in the quest to slow, and possibly prevent, skin aging.

Skin: The First Line of Defense 

Our skin is made up of three layers: the epidermis, the dermis, and the hypodermis. The epidermis is the outermost layer, which provides the first line of protection against damage and infection. This is the skin you see when you look at your arm or leg. It’s a physical barrier that helps keep out anything unwanted. Next, you have the dermis, which is the second layer. It contains connective tissue, hair follicles, blood vessels, lymphatic vessels, and sweat glands. Finally, the hypodermis is the deepest layer, made up primarily of fat and more connective tissue.

Aside from providing physical protection, the skin also acts as a frontier for our immune system. Since anything that breaches the skin poses a risk of infection, it is stuffed full with a variety of different immune cells, including macrophages, monocytes, B cells, and T cells. These spring into action at the faintest hint of damage or infection, coming together to form a complex network of defenses.

Salvador Aznar Benitah and his colleagues were particularly interested in changes to the immune cells of the skin: Do they decrease in number as we age? Do they become less active? What’s going on?

How Does Skin Change as We Age?

To answer these questions, the team of researchers turned to a laboratory technique called single-cell RNA sequencing. This technique enables analysis of thousands of individual cells at once. Think of it as offering a snapshot of a particular cell at a particular point in time. Included in this snapshot are vital insights into cell composition and cell activity. Comparing snapshots of cells at different stages in the aging process can offer valuable clues about how cells change over time.

The researchers extracted skin cells from old mice —between 80 and 90 weeks old— and compared them to those of younger adult mice — between 17 and 25 weeks old.

First, they took a look at the nonimmune cells of the skin. To their surprise, there wasn’t much of a difference between the two groups: other than a very subtle increase in global inflammation, the skin cells between young and old mice looked quite similar.

Next, the researchers analyzed the immune cells within the skin. Here, they noticed a clear deviation between the two age groups. The myeloid lineage of immune cells —part of our innate immune response— was significantly more active in aged skin. These cells play a key role in regulating inflammation as part of the early immune response. In aged skin, however, they were activated even in the absence of an external threat, leading to a state of chronic inflammation.

The lymphoid lineage of immune cells —associated with the learned, or adaptive immune system— was equally overactive. This was particularly pronounced in CD4+ T helper cells, gamma delta T cells, and innate lymphoid cells (ILCs). Usually, these cells sit inside the dermis and act as sentries, scanning for tissue damage or foreign threats; during times of infection, they help coordinate immune defenses and regulate inflammation by secreting pro-inflammatory proteins. As with the myeloid lineage, these cells were increased in the skin of the old mice and were a lot more active despite the absence of any clear damage or microbial threat.

IL-17: A Well-Known Culprit 

The increased inflammation seen in old skin was driven by a family of signaling proteins called interleukin-17 (IL-17). The interleukin 17 family is made up of six different members (IL-17A-F). When all goes well, these proteins help regulate inflammation by rallying the immune system and directing immune cells to where they need to be. But too much inflammation can be detrimental. It’s a double-edged sword: inflammation works because it creates a destructive environment that makes it difficult for invading pathogens to survive in, but if left unchecked, this destruction will begin to hit healthy tissues and organs. Friendly fire ensues.

CD4+ T helper cells, gamma delta T cells, and innate lymphoid cells in the skin of old mice were secreting IL-17A and IL-17F, leading to runaway inflammation. IL-17A is by far the most well-researched of the interleukin family, and is often referred to as simply IL-17. Indeed, interleukin 17A is a known culprit associated with a number of inflammatory autoimmune diseases, including those of the skin, such as psoriasis. The connection, then, between skin aging and overactive IL-17 is not completely unexpected.

Rejuvenating Old Skin

To confirm the role of IL-17 in skin aging, the scientists treated 75-week-old mice with antibodies that target and block IL-17A and IL-17F. These antibodies were administered for a span of 12 weeks. Following treatment, the researchers sampled skin cells and compared them to a control group of the same age that had not received the antibodies.

Blocking IL-17 significantly reduced markers associated with old skin; genes involved in inflammation were downregulated and, in their place, there was an increase in the expression of genes related to healthy wound healing. These changes at the genetic level were accompanied by slowed skin aging. Compared to the control group, the skin of mice that received treatment was noticeably more youthful, with heightened regenerative abilities, strengthened hair follicle growth, and improved barrier function.


As skin ages, it becomes weaker —a loss of barrier function— making it more susceptible to injury, infection, and water loss. On top of this, aged skin is also less capable of regenerating itself in case of damage. With their research, Salvador Aznar Benitah and colleagues have shown that runaway inflammation, spurred on by an abundance of IL-17, is responsible for many of these issues. Their work provides exciting new avenues for slowing, and perhaps at some point even reversing, skin aging. Currently available treatments for psoriasis, which work by blocking IL-17, may potentially be repurposed to this end, possibly helping those suffering from skin dryness and impaired wound healing.

One caveat to note is that these experiments were all performed on mice. Although this is standard practice, it does not guarantee an accurate understanding of skin aging in humans: animal models often fail to predict human outcome in clinical trials. Another important caveat is that, although these findings clearly implicate IL-17, it is likely only one piece of a much larger puzzle. The other pieces remain to be uncovered.

This article was originally published on Forbes and can be read online here.

© William A. Haseltine, PhD. All Rights Reserved.