Investigating the factors involved in skin rejuvenation processes, researchers have identified the role of hyaluronan and proteoglycan link protein 1 (HAPLN1) in restoring collagen and hyaluronic acid in aged skin [1].
The most noticeable sign of aging
Skin aging, one of the most visible forms of aging, is influenced by both intrinsic and extrinsic factors. The extrinsic ones, such as sunlight exposure, air pollution, and cigarette smoke, are well known. However, the intrinsic ones, such as age-induced hormonal changes, are less well-researched and understood.
On a molecular level, some of the most prominent changes are to the skin’s extracellular matrix (ECM). The ECM is a structure built from such components as collagen, hyaluronic acid (HA), and proteoglycans. During aging, collagen and hyaluronic acid levels decrease. This decrease impacts the integrity of the ECM.
The claim of slowing down skin aging by promoting collagen synthesis is a common feature of cosmetics advertising. However, so far, “no effective agents for preventing or restoring aged skin have been identified.”
While reversing the signs of skin aging has aesthetic value, this study’s authors argue that their research on this topic can be a stepping stone to a better understanding of whole-body aging and therapies to address it.
Sharing circulation
To investigate skin aging, the researchers used a parabiosis experiment in which two animals are connected following surgery to share the bloodstream. In this experiment, the researchers connected the circulation of young and old animals, along with control groups of connected young animals and connected old animals.
The researchers examined the animals’ hyaluronic acid and collagen levels after three weeks after surgery. They observed that the levels of hyaluronic acid of old animals connected to young ones “were almost completely restored.” This treatment also increased newly synthesized collagen and the gene activity of some of the procollagen types in the deep skin (dermis) of old mice connected to the bloodstream of the young mice were also increased compared to the old mice.
They also tested the thickness of the dermis 10 weeks after surgery, observing improvement in dermal thickness. The dermis thickness of the old animals that shared the circulation system with the young ones was similar to that of the young control animals.
The authors suggested that blood-borne factors contribute to the restoration of the dermis in old animals. Therefore, they tested the differences in the composition of proteins in these animals’ plasma. After identifying several differences, they focused on one protein: HAPLN1.
HAPLN1 plasma and skin levels were decreased in aged animals, but parabiosis led to its increase. HAPLN1 plays a structural role in ECM architecture, as it connects two proteins, aggrecan and hyaluronic acid. It also plays a signaling role.
The authors note that this protein was not previously linked to aging. However, their investigation suggests a rejuvenating effect of HALPN1 and a possible role in depositing collagen and hyaluronic acid in aged skin.
Multiple molecular processes involved
As their next step, the researchers specifically tested HALPN1’s role in skin rejuvenation. Injection of recombinant HAPLN1 significantly increased newly synthesized collagen and total hyaluronic acid levels in skin tissues. They also observed an increase in versican, another molecule important in ECM remodeling. These results suggest that HAPLN1 has a positive role in reversing aging-induced changes, although the authors suggest future testing using different doses.
The authors also aimed to understand the molecular mechanisms behind these changes, so they treated human dermal fibroblasts with recombinant HAPLN1. The results of this experiment suggest the involvement of TGF-β in HAPLN1-induced collagen and hyaluronic acid restoration. The results also suggest the involvement of HAPLN1 in protecting “against oxidative stress-induced degradation of TGF-β R2.”
This participation in antioxidant pathways also prompted an investigation into intertwined pathways related to inflammation and senescence, and the results here suggest that HAPLN1 has possible effects against both. The authors summarize that HAPLN1 “could negatively regulate cellular senescence, suggesting its contribution to reversing skin aging that occurs during oxidative stress and the inflammatory process.”
The authors stress that this study is the first to discuss the role of HAPLN1 in skin rejuvenation processes. They also suggest that their findings can help improve anti-aging skin treatments. However, since this research has been done on mice and cell cultures, further testing on humans is still required.
Literature
[1] Fu, Z., Yang, G., Yun, S. Y., Jang, J. M., Ha, H. C., Shin, I. C., Back, M. J., Piao, Y., & Kim, D. K. (2024). Hyaluronan and proteoglycan link protein 1 – a novel signaling molecule for rejuvenating aged skin. Matrix biology : journal of the International Society for Matrix Biology, S0945-053X(24)00111-2. Advance online publication.
