Age and wound healing

Mouse study identifies rare example where being older improves tissue function, helping skin heal with less scarring

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PHILADELPHIA—Typically, we associate advancing age with increasingly less desirable results in terms of healing and recovery, whether from physical injury or infection or something else. Broken bones don’t mend as well; influenza and pneumonia pose more risk. But as with so many things in life, there is almost always an exception to the rule, and one such exception here is that older people scar less than younger ones.
“Dermatologists and plastic surgeons have consistently observed that older people’s wounds heal with thinner scars than younger patients’, but until now, no one has been able to answer the question of why that’s the case,” said Dr. Thomas H. Leung, an assistant professor of dermatology at the Perelman School of Medicine at the University of Pennsylvania.
As it happens, the primary reason for that phenomenon may be a compound secreted in the bloodstream that is known as stromal cell-derived-factor-1 (SDF1). In a paper titled “Aging Suppresses Skin-Derived Circulating SDF1 to Promote Full-Thickness Tissue Regeneration” published recently in Cell Reports, researchers from the Perelman School of Medicine showed that blocking the compound could influence scar formation and tissue regeneration in mouse models and in lab-grown human skin.
The benefit, of course, could be to have a means to either reduce or eliminate scarring in human wound healing.
In the study, Leung (senior author of the paper in Cell Reports) and his team pierced the ears of mice of two different age groups, one consisting of the equivalent of 12-year-old humans in mouse years, and the other equivalent to 70-year-olds. In the older mice, the hole closed without forming scars, while the younger mice did have visible scarring. Researchers then exchanged the blood of young mice with old mice, pierced their ears, and found that the ears of old mice now scarred, concluding that the answer must be something in the blood.
The team then took tissue samples from young and old mice and compared their gene expression signatures. Eventually focusing only on which gene products were found in the bloodstream, they narrowed the initial and daunting list of 80 differences between the two groups to 13 differences, one of which was SDF1. Given that this particular signaling molecule had been previously shown to play a role in scar formation in the skin, liver and lungs, it seemed a likely candidate for being the cause of the age-related differences in scar formation.
And, indeed, the researchers found that SDF1 was expressed in younger mice but not in the older ones. They then created a mouse model lacking SDF1 in its skin, and when SDF1 function was inactivated, even young mice began to regenerate skin in a manner similar to older mice.
“This is a rare instance where aging actually improves the body’s ability to heal rather than diminishing it,” Leung said. “When we’re younger, we secrete more SDF1 into the blood stream to form scars, but as we age, we lose this ability, which allows tissue to regenerate.”
To further cement their hypothesis and findings, the researchers exchanged the blood between young SDF1-deficient mice and older mice. This time, neither mouse scarred. The team went one step further and grew human skin in the lab, then injured it with a scalpel. Human skin also exhibited an age-dependent expression of SDF1.
As the authors wrote in their paper, “We speculate that, from an evolution perspective, a young injured animal favors fast and imperfect wound repair over slow and perfect tissue regeneration. Future studies are needed to assess the relationship between skin re-epithelialization speed and scar formation.”
Leung and his team plan to study the effect of SDF1 inhibitors in preventing scar formation in humans. If the results from the mice carry over similarly, enhancing wound healing in the clinic might not be that far down the road, as there are already SDF1 inhibitors on the market, currently used as a treatment to mobilize stem cells.

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