The first time I accepted that my grandpa was really aging was when I held his hand. His grip was strong as ever. But the skin on his hand was wafer thin and carried tell-tale signs of bruising across its back.
Plenty of “anti-aging” skin care products promise a younger look. But skin health isn’t just about vanity. The skin is the largest organ in the body and our first line of defense against pathogens and dangerous chemicals. It also keeps our bodies within normal operating temperatures—whether we’re in a Canadian snowstorm or the blistering heat of Death Valley.
The skin also has a remarkable ability to regenerate. After a sunburn, scraped knee, or knife cut while cooking, skin cells divide to repair damage and recruit immune cells to ward off infection. They also make hormones to coordinate fat storage, metabolism, and other bodily functions.
With age the skin deteriorates. It bruises more easily. Wound healing takes longer. And the risk of skin cancer rises. Many problems are connected to a dense web of blood vessels that becomes increasingly fragile as we age. Without a steady supply of nutrients, the skin weakens.
Now a team from New York University School of Medicine and collaborators have discovered a way to turn back the clock. In elderly mice and human skin cells, they detected a steep decline in the numbers of a particular immune cell type. The cells they studied, a type of macrophage, hug blood vessels, help maintain their integrity, and control which molecules flow in or out.
A protein-based drug designed to revive the cells’ numbers gave elderly mice a skin glow up, improving blood flow and the skin’s ability to repair damage. Because loss of these cells happens before the skin declines notably, renewing their numbers may offer “an early strategy” for keeping our largest organ humming along as the years pass.
Trusty Residents
All organs in mammals have residential macrophages. Literally meaning “big eaters,” these immune cells monitor tissues for infections, cancers, and other dangers. Once activated, they recruit more immune cells to tackle diseases and repair damaged tissues.
There’s more than one type of macrophage. The cells belong to a large family where each member has a slightly different task. How they populate different organs is still mysterious, and scientists are just beginning to decode all the jobs they do. But there’s a general consensus: With age, many macrophage types decline in numbers and health and are linked to a variety of age-related diseases, such as atherosclerosis, cancer, and neurodegeneration.
This trend could also affect aging skin.
The skin’s layers are populated by different types of macrophages. Those in the outermost layer detect pathogens, while cells in the lower, fatty layer help maintain metabolism and regulate body temperature and inflammation. But it was capillary-associated macrophages (CAMs), in the middle layer, that caught the team’s interest. These cells wrap around intricate webs of blood vessels woven through our skin, helping maintain their ability to function and heal.
Tracking Cells
To better understand how the skin’s macrophages change with age, the team developed a technology to monitor their numbers and health in mice. The researchers genetically engineered the critters such that they produced glow-in-the-dark macrophages and observed these throughout their life.
With age, the skin’s middle layer lost macrophages—which the scientists identified as CAMs—far faster than other skin layers. In mice between 1 and 18 months of age—the human equivalent of pre-teens through people in their 70s—blood vessels that had lost these macrophages behaved as if they were “older” and struggled to support oxygen-rich blood flow to the skin.
The macrophages also dwindled in their coverage of capillaries during aging. Roughly a tenth of the width of a human hair, these dainty blood vessels shuttle nutrients to tissues and dump toxic chemicals into the bloodstream. Macrophage losses eventually led to the death of capillaries in elderly mice. Similar results were found in human skin samples from people over 75.
All this reduced the skin’s ability to maintain capillary health and healing. For example, in one test, the scientists used targeted lasers to form small blood clots. In young mice, the macrophages traveled to the site and ate up damaged red blood cells in the clumps. In elderly mice, blood vessels with more macrophages better repaired injuries, but healing slowed overall.
Skin Rewind
The team next developed a protein-based therapy that directly boosts CAM levels, and injected it into one hind paw of mice the human equivalent of over 80 years of age. The other paw received a non-active control.
In a few days, the treated paw saw a jump in macrophage numbers and improved capillary flow nourishing the skin. The blood vessels also healed more rapidly after laser damage, resulting in less bruising. The injection seemingly rejuvenated old macrophages, rather than recruiting new ones from the bone marrow, suggesting even vintage cells can grow and regain their strength.
These early results are in mice, and they don’t measure the full spectrum of skin function after repairing blood vessels, which would require observing other cells. Fibroblasts, for example, generate collagen for skin elasticity and promote wound healing. Their numbers also shrink with age. The new treatment is based on a protein from these cells, and the team is planning to test how fibroblasts and CAMs interact with age, and if the shot can be further optimized.
Beyond skin health, blood vessel disease wreaks havoc in multiple organs, contributing to heart attacks, stroke, and other medical scourges of aging. A similar strategy could pave the way for new treatments. In future studies, the team hopes to optimize dosing, follow long-term effects and safety, and potentially mix-and-match the treatment with other regenerative therapies.
