Cosmetic companies promise to make you look younger, so long as you buy a multitude of their products and continually use them for the rest of your life. Humankind’s quest for the fountain of youth has often come at great expense both financially and morally, yet there has been some modicum of scientific information gleaned from our vanity driven endeavors over the years. Now, investigators at Johns Hopkins University may have just uncovered the mechanisms driving the rejuvenation process that dermatologists have exploited for many years.
Interestingly, the researchers discovered that laser treatments and the drug retinoic acid share a common molecular pathway. Moreover, that pathway—which lets skin cells sense loose RNA molecules—is also turned up in mice when they regenerate hair follicles. Findings from the new study were published recently in Nature Communications through an article titled “Noncoding dsRNA induces retinoic acid synthesis to stimulate hair follicle regeneration via TLR3.”
“Understanding the biology behind how cellular damage can lead to this type of regeneration can harness a new generation of therapeutics,” explained senior study investigator Luis Garza, MD, PhD, associate professor of dermatology at the Johns Hopkins University School of Medicine.
Researchers have known for decades that mice—unlike humans—can regenerate hair follicles after a deep wound. Recent studies by Garza and others found that loose pieces of RNA, called self-noncoding double-stranded RNA (dsRNA) can spur this regeneration. They hypothesize that this may be because dsRNA is released by damaged cells at the site of a wound. Garza and his colleagues were curious whether dsRNA also played a role in skin rejuvenation treatments such as laser therapy, microneedling, and facial abrasion, which all involve temporary damage to skin cells. Although these treatments are well-established among dermatologists, researchers haven’t been clear why they work.
Garza and his colleagues analyzed the expression levels of genes in each sample and discovered that genes involved in sensing dsRNA as well as genes involved in producing the skin’s natural retinoic acid were all expressed at higher levels after the laser treatment. Next, the researchers treated isolated human skin cells with loose dsRNA—mimicking the effect of laser treatment. The amount of retinoic acid inside the cells increased by more than tenfold. Commercially produced retinoic acid is already used to treat acne, wrinkles, and sunspots.
“It’s not an accident that laser rejuvenation and retinoic acid have both been successful treatments for premature aging of the skin from sun damage and other forms of exposure,” Garza noted. “They’re actually working in the same molecular pathways and nobody knew that until now.”
To further strengthen and understand the connection, the researchers turned back to mice. They knew that in both mice and humans, a protein called toll-like receptor 3 (TLR3) senses dsRNA. When Garza’s group engineered mice to lack TLR3, the animals could no longer regenerate hair follicles after a wound. But when the researchers gave these mice retinoic acid, they regained the ability to regenerate the follicles. The results point toward a pathway involving TLR3 that senses double-stranded RNA and turns up the synthesis of retinoic acid.
“We show that self-noncoding dsRNA activates the anti-viral receptor TLR3 to induce intrinsic retinoic acid (RA) synthesis in a pattern that predicts new hair follicle formation after wounding in mice,” the authors wrote. “Additionally, in humans, rejuvenation lasers induce gene expression signatures for dsRNA and RA, with measurable increases in intrinsic RA synthesis.”
“In retrospect, it makes a lot of sense because retinoic acid is already a mainstay of wrinkle reduction and nobody knew what turned it on,” Garza remarked. “Now we know that damage leads to dsRNA, which leads to TLR3 activation and retinoic acid synthesis.”
The findings could lead to novel strategies to reduce wrinkles and sunspots by combining retinoic acid and laser treatments in new ways, Garza says. And they could also lead to ways to regenerate hair follicles, as mice do when there’s an increase in dsRNA after a wound.
“After a burn, humans don’t regenerate structures like hair follicles and sweat glands that used to be there,” said Garza. “It’s possible in light of these new findings that double-stranded RNA may be able to improve the appearance of burn scars.”
“These results demonstrate a potent stimulus for RA synthesis by non-coding dsRNA, relevant to their broad functions in development and immunity,” the authors concluded.