The quest to keep skin from aging may lead here

The epidermis, the dermis, the hypodermis — they are the body’s frontline defense against wound infliction and infection. Changes to the skin, as the three layers are collectively known, are among the most obvious signs of aging. Some of those changes come from sun exposure and having to constantly fend off an often-hostile outside world. But there are also inflammatory processes that bear some responsibility for aging skin. The term “inflammaging” — a portmanteau of “inflammation” and “aging” — has been coined to describe the chronic, low-grade inflammation that alters the skin as people travel through the lifespan

Inflammation is complex with an unruly menagerie of cytokines, chemokines, growth factors and other molecules involved. But Japanese investigators reported research findings in the Journal of Investigative Dermatology this month that identify what they believe is the chief culprit in the skin-damaging inflammation: immunoglobulin G (IgG).

IgG is one of the five varieties of immunoglobulins — commonly known as antibodies — in the human immune body. It is produced mainly in the secondary immune response to pathogens and can activate the classical pathway of the complement system. IgG is the only immunoglobulin that crosses the placenta. As a result, it is the immunoglobulin that is most abundant in newborns.

Corresponding author Yuichi Oike, M.D., Ph.D., a professor at Kumamoto University, and his colleagues referenced prior research that has found that IgG stirs up inflammation as it piles up in fat, muscle, heart and liver tissue as people age and that does so by activating macrophages. They also point to animal studies suggesting that IgG is associated with age-related white adipose tissue and insulin resistance.

Oike and his colleagues used skin tissue from mice and humans in their research. In the mouse research, they compared skin taken from the back of 2-month-old mice (young mice) to skin taken from 25-month-old mice (old mice). Using common staining techniques, they found that IgG levels were notably higher in the old mice than the younger ones. They also looked at IgG levels in the skin of what be considered middle-aged mice (older than two months but younger than 25) and found that IgG started to accumulate when mice were 6 months old.

They used tissue from skin biopsies of seven people with skin cancer or epidermal cysts in their human research. Again, using common staining techniques, they found IgG accumulation in the five patients who were 44 or older, whereas in the 13- and 17-year-old individuals, IgG was “nearly absent.”

Beyond measuring IgG levels, Okie and his colleagues also set out to understand how IgG accumulates in the skin. In the mice, they found that IgG levels in the blood increase with age. They also tested whether IgG in the blood reaches the skin by injecting mice intraperitoneally with the immunoglobulin on a weekly basis for a month. They found that after they did so, IgG levels in the skin of the mice had climbed and also that the dermis contained macrophages and T cells that are involved in inflammation. The researchers also conducted a variety of experiments that together make a case for IgG playing a role in recruiting and stimulating macrophages and T cells to the skin, where they have inflammaging effects.

“In summary," wrote Okie and his colleagues, “our findings strongly suggest that IgG is an aging factor in skin.”

Much evidence points to the anti-aging effects of caloric restriction, and Okie and his colleagues reference research that suggests that caloric restriction stymies pro-inflammatory pathways that cause skin to age. It will take more research, they wrote, to see if the anti-aging effects of caloric restriction are achieved by reducing IgG levels.

The path from this kind of basic science to clinical application is often a long and winding one that involves numerous recalibrations. On the other hand, the demand for products and services that can mitigate aging’s effect on the skin is seemingly boundless, so the identification of reduced IgG levels as a possible dermal fountain of youth seems likely to catch the eye of drug developers and other researchers. In the discussion section of their paper, Okie and his colleagues mention efgartigiomod alfa, sold under the brand name Vyvgart, as an intravenous treatment for myasthenia gravis, as a possible IgG-reducing candidate. Efgartigimod alfa is a human IgG1 antibody fragment that binds to the neonatal Fc receptor, resulting in the reduction of circulating IgG.