Synopsis

Intrinsic and extrinsic aging are two separate and independent mechanisms that contribute to the multifactorial process of skin aging. Because youthful skin has a high water content, it maintains qualities like turgor, resilience, and pliability. Moisture loss results from everyday external damage in addition to aging naturally. Hyaluronic acid (HA) is the primary molecule responsible for skin hydration because of its exceptional ability to hold onto water. The intricacy of HA metabolism is reflected in the various locations for control over HA production, deposition, cell and protein interaction, and destruction. The multigene families of enzymes that synthesis or catabolize HA and HA receptors, which are involved in numerous HA functions, have unique tissue expression patterns. The ability to rationally regulate skin moisture will be aided by knowledge of the metabolism of HA in the various skin layers and its interactions with other skin components.

Aging skin

Ageing of human skin is a complicated biological process that is still poorly understood. It is the outcome of two separate biological processes. The first is inherent aging, also known as intrinsic aging, which is an unavoidable process that affects all internal organs in the same pattern as the skin. Extrinsic aging, commonly known as photoaging, is the second type of aging that results from exposure to outside causes, primarily ultraviolet (UV) irradiation. Age-related hormonal changes, such as the steady decline in sex hormone production starting in the mid-20s and the reduction in estrogen and progesterone associated with menopause, can have an impact on intrinsic skin aging. It is commonly known that low levels of estrogens and androgens cause the skin to become dry, brittle, lose its suppleness, develop epidermal atrophy, and wrinkle.

Despite being different processes, intrinsic and extrinsic skin aging have similar molecular mechanisms. For instance, both activities heavily rely on reactive oxygen species (ROS), which are produced by oxidative cell metabolism. In both intrinsic and extrinsic skin aging, ROS trigger the transcription factor c-Jun through mitogen-activated protein kinases (MAPK), which in turn causes the expression of procollagen-1 to be inhibited and matrix metalloproteinase (MMP)-1, MMP-3, and MMP-9 to be overexpressed. Thus, diseases arising in intrinsically aged as well as photoaged skin include elevated amounts of damaged collagen and impaired collagen synthesis.

Loss of skin hydration is also linked to skin aging. Hyaluronan, also known as hyaluronic acid (HA), is a glycosaminoglycan (GAG) that plays a crucial role in skin hydration because of its exceptional ability to bind and hold onto water molecules. HA is a chemical found in the extracellular matrix (ECM). The components of the skin have been thoroughly defined in recent decades. The cells that make up the layers of skin, including the dermis, epidermis, and subcutis underneath, were the subject of the majority of early research. It has recently become clear that the extracellular matrix (ECM) molecules that exist between cells not only provide a useful framework but also have a significant impact on cellular activity. These extracellular matrix (ECM) components, which mostly consist of glycogen-binding proteins (GAG), proteoglycans, growth factors, and structural proteins like collagens, form a highly ordered structure despite seeming amorphous under light microscopy. But HA makes up the majority of the skin's extracellular matrix.

The involvement of HA in angiogenesis, reactive oxygen species, chondrocytes, cancer, lung damage, immunological modulation, and skin has been discussed in recent reviews. This review focuses on the role of HA in skin aging and provides a brief overview of recent findings in HA biology and function.

Properties of chemistry and physicochemistry

As a non-sulphated GAG, HA comprises repeated polymeric disaccharides connected by a glucuronidic β (1→3) connection between D-glucuronic acid and N-acetyl-D-glucosamine. HA creates particular stable tertiary structures in aqueous solutions. HA possesses a wide range of physicochemical characteristics and a simple composition devoid of branching points or changes in its sugar content. HA polymers can take various forms and topologies based on pH, size, salt concentration, and related cations. Proteoglycans can form aggregates with HA, although HA is not covalently bound to a protein core like other GAGs. Even at low concentrations, HA gives solutions a high viscosity because it contains a lot of water.

Distribution of HA in tissues and cells

Widespread in both prokaryotic and eukaryotic cells is HA. Human HA is found in all bodily tissues and fluids, including skeletal tissues, heart valves, lung, aorta, prostate, tunica albuginea, corpora cavernosa, and corpus spongiosum of the penis. It is most prevalent in the skin, where it makes up 50% of the body's total HA, as well as the vitreous of the eye, the umbilical cord, and synovial fluid. Mesenchymal cells are the main source of HA, while other cell types can also make it.

HA's biological role

Significant research over the previous 20 years has shown the functional significance of HA in molecular pathways and suggested that HA may play a role in the creation of novel therapeutic approaches for a variety of disorders.

Hydration, joint lubrication, gap filling, and providing a framework for cell migration are among the functions of HA. Increased production of HA occurs during tissue damage and wound healing. HA controls multiple elements of tissue repair, such as the immunological response boosted by inflammatory cell activation and the fibroblast and epithelial cell response to injury. Moreover, HA offers the structural basis for fibroblast migration and blood vessel creation, both of which may aid in the development of tumors. It has also been documented that the aggressiveness of tumors is correlated with the amount of HA present on the cell surface of cancer cells.With regard to the several roles that HA plays that were previously mentioned, its magnitude seems to be crucial. Smaller polymers of HA are distress signals and strong inducers of inflammation and angiogenesis, while high molecular size HA, often over 1,000 kDa, is found in intact tissues and is antiangiogenic and immunosuppressive.

HA biosynthesis

HA synthases (HAS) are specialized enzymes that produce HA. These enzymes are membrane-bound, producing HA on the plasma membrane's inner surface, which is subsequently extruded into the extracellular space through pore-like structures. Three mammalian enzymes, HAS -1, -2, and -3, are known to generate HA chains of different lengths and display unique enzymatic characteristics.

HA degradation

HA's rate of turnover is dynamic. The half-lives of HA in the blood are 3 to 5 minutes, in the skin they are less than a day, and in cartilage they are 1 to 3 weeks. Hyaluronidases (HYAL) hydrolyze the hexosaminidic β (1–4) links between N-acetyl-D-glucosamine and D-glucuronic acid residues in HA, breaking it down into fragments of different sizes. Six HYAL have been found in humans thus far: PH-20, HYAL-1, -2, -3, -4, and HYALP1. Because the HYAL enzyme family is found at very low quantities and is challenging to purify, define, and quantify due to its high yet unstable activity, it has gotten little attention until recently. HYAL has now been able to be isolated and characterized thanks to new protocols. The predominant HYAL in serum is HYAL-1. Mucopolysaccharidosis type IX and HYAL deficiency are linked to mutations in the HYAL-1 gene. Compared to plasma HYAL-1, HYAL-2 exhibits much lower activity. It hydrolyzes mostly high molecular weight HA, producing HA fragments that are about 20 kDa in size. PH-20 then further breaks these fragments down into tiny oligosaccharides. In addition to other organs including the human lung, the bone marrow and testis are the primary sites of HYAL-3 expression. It has been proposed that HYAL-3 may aid in the breakdown of HA by increasing HYAL-1's activity, albeit its precise function in the catabolism of HA is unknown.

In the presence of reducing agents such ascorbic acid, thiols, ferrous, or cuprous ions, HA can also be broken down non-enzymatically through a free-radical mechanism; this process necessitates the presence of molecular oxygen. Therefore, it can be helpful to apply agents that can postpone the HA's destruction caused by free radicals in order to preserve the integrity of dermal HA and its moisturizing qualities.

Hormone-like acid receptors

Hyaladherins are a class of proteins that bind to HA and are found in the cytoplasm, nucleus, cell surface, and extracellular matrix (ECM). HA receptors are those that bind HA to the surface of cells. The transmembrane glycoprotein "cluster of differentiation 44" (CD44), which is produced by a single gene with variable exon expression, is the most well-known of these receptors. It exists in several isoforms. With the exception of red blood cells, almost all cells have CD44 on them. It controls metastasis from cancer as well as cell adhesion, motility, lymphocyte activation, and homing.

Another important HA receptor that is expressed in different isoforms is the receptor for HA-mediated motility (RHAMM). Numerous cell types, including endothelial cells and smooth muscle cells from the pulmonary arteries and airways of humans, have functional receptors for RHAMM. Through a complex network of signal transduction processes and connections with the cytoskeleton, the interactions between HA and RHAMM regulate cell growth and migration. The synthesis and expression of RHAMM and HA are triggered by the powerful cell motility stimulant, transforming growth factor (TGF)-β1, which also starts the process of locomotion.

Skin's hyaluronic acid

The application of biotinylated HA-binding peptide demonstrated that HA may be synthesized by cells other than those of mesenchymal origin and allowed HA to be histolocalized in the skin's dermal compartment and epidermis. With the use of this approach, it was possible to see HA in the epidermis, primarily in the top spinous and granular layers' extracellular matrix (ECM), while HA is primarily intracellular in the basal layer.

The skin's ability to act as a barrier is partially ascribed to structures known as lamellar bodies, which are believed to be altered lysosomes that contain hydrolytic enzymes. They can partially change their polar lipids into neutral lipids and acidify through proton pumps when they unite with the mature keratinocytes' plasma membranes. These lipids are produced by keratinocytes in the stratum granulosum and prevent aqueous material from diffusing through the epidermis. The amount of HA staining correlates with this border effect. Water from the moisture-rich dermis may be absorbed by the HA-rich area under this layer, but it cannot pass through to the lipid-rich stratum granulosum. Skin hydration is primarily dependent on the stratum granulosum, but it is also crucially dependent on HA-bound water in the dermis and the important portion of the epidermis. Dehydration brought on by a significant loss of stratum granulosum in burn patients might result in major clinical issues.

As was already noted, the majority of the body's total HA is found in the skin. The dermis has a substantially higher HA content than the epidermis, and the papillary dermis has a much higher HA content than the reticular dermis. The vascular and lymphatic systems are continuous with the dermal HA. In the dermis, HA improves the extracellular domain of cell surfaces, controls ion flow, osmotic pressure, and water balance. It also acts as a sieve, filtering out certain molecules and stabilizing skin structures through electrostatic interactions. Prolonged presence of HA ensures scar-free tissue repair, as elevated amounts of HA are generated during embryonic tissue repair. The synthetic machinery for dermal HA is provided by dermal fibroblasts, which is why pharmacologic approaches to improve skin hydration should focus on them. Regrettably, exogenous HA is quickly broken down and removed from the dermis.

Skin hyaluronic acid synthases

TGF-β1 differently upregulates the expression of HAS-1 and HAS-2 genes in the skin's dermis and epidermis, suggesting that the functions of HA in the dermis and epidermis are distinct and that HAS isoforms are independently controlled. Keratinocyte growth factor has the ability to increase the mRNA expression of HAS-2 and HAS-3. This, in turn, can activate keratinocyte migration and drive wound healing, resulting in the accumulation of intermediate-sized HA within keratinocytes and in the culture medium. The enhanced synthesis of HA stimulates the migratory response of keratinocytes during wound healing. In addition, fibroblasts' IL-1β and TNFα as well as rat epidermal keratinocytes' epidermal growth factor stimulate HAS-2 mRNA.

There have been reports of dysregulated HA synthase expression during tissue damage. After a skin injury in mice, there is a large rise in HAS-2 and HAS-3 mRNA, which results in enhanced epidermal HA. The rare autosomal recessive illness juvenile hyaline fibromatosis is characterized by the deposition of hyaline material and many skin lesions. The lower synthesis of HA in skin lesions is explained by a considerable decrease in the expression of HAS-1 and HAS-3. Glucocorticoids virtually entirely suppress HAS mRNA in dermal fibroblasts, where HAS-2 is the main isoform. This finding suggests a mechanistic foundation for the decreased HA in atrophic skin that results from local glucocorticoid treatment.

skin's hyaluronidases

Which of the several HYAL in the skin regulates the HA turnover in the dermis and epidermis is still unknown. By understanding the biology of HYAL in the skin, new pharmaceutical targets to address the age-related turnover of HA in the skin may become available.

The skin's HA receptors

Together with CD44, HA is co-localized in the dermis and epidermis. The precise CD44 variations found in the various skin compartments, however, remain unclear. It has been observed that CD44-HA interactions promote the binding of Langerhans cells to HA in the keratinocyte matrix through their CD44-rich surfaces as the keratinocytes migrate through the epidermis. The human skin expresses RHAMM as well. RHAMM mediates the TGF-β1-induced stimulation of fibroblast motility, and fibroblasts can undergo fibroblast transformation if RHAMM is overexpressed.

Ageing skin and hyaluronic acid

While HA is still present in the dermis, the most notable histochemical alteration seen in senescent skin is the remarkable loss of epidermal HA. It is uncertain why HA homeostasis changes as people age. As was previously mentioned, the underlying dermis affects the production of epidermal HA, which is regulated differently from dermal HA synthesis. It has also been documented that aging causes the HA polymers in skin to gradually shrink in size. Skin moisture is lost as a result of the epidermis losing the primary molecule that binds and holds water molecules. The primary age-related alteration in the dermis is the growing avidity of HA with tissue structures and the corresponding decrease in HA extractability. This is similar to the gradual reduction of collagen extractability with age and the progressive cross-linking of collagen. The apparent atrophy, suppleness loss, and dehydration that accompany aging skin are caused by all of the aforementioned age-related processes.

Repeated and prolonged exposure to UV light causes premature aging of the skin. About 80% of the aging of facial skin is caused by UV radiation. Damage from UV light initially results in a modest type of wound healing and is first linked to an increase in dermal HA. In naked mice, as little as 5 minutes of UV exposure resulted in increased HA deposition, suggesting that UV radiation-induced skin damage happens very quickly. The skin's initial redness after being exposed to UV radiation could be the result of a modest edematous reaction brought on by increased histamine release and HA deposition. Ultimately, prolonged and repeated UV exposures mimic the normal wound healing response by depositing scar-like type I collagen instead of the normal combination of types I and III collagen that provides pliability and resilience to the skin.

Photoaging of the skin leads to abnormal GAG distribution and content compared to scars, or the wound healing response, with decreased HA and increased levels of chondroitin sulfate proteoglycans. Collagen fragments activated αvβ3-integrins were found to be responsible for this reduction in HA synthesis in dermal fibroblasts, which in turn inhibited Rho kinase signaling and nuclear translocation of phosphoERK, lowering HAS-2 expression. Some of the molecular alterations that may differentiate photoaging from natural aging have recently come to light. By utilizing human skin tissue specimens from the same patient that were both photoexposed and photoprotected, we have demonstrated a notable rise in the expression of HA with a smaller molecular mass in the photoexposed skin when compared to the photoprotected skin. A notable decrease in HAS-1 expression and an increase in HYAL-1, -2, and -3 expression were linked to this rise in degraded HA. In addition, HA receptor expression on CD44 and RHAMM was considerably lower in photoexposed skin than in photoprotected skin. These results suggest that a unique HA homeostasis characterizes photoexposed skin, and hence extrinsic skin aging. Additionally, we examined photoprotected skin tissue specimens from both adult and pediatric patients, and found that intrinsic skin aging was linked to a significant decrease in HA content as well as downregulation of CD44, RHAMM, HAS-1, and HAS -2. Comparable outcomes for photoprotected skin have also been documented for HA, HAS-2, and CD44 in both sexes.

In summary

According to the information that is now available, HA homeostasis shows a unique profile in intrinsic skin aging that differs greatly from that in extrinsic skin aging. Further knowledge is required to comprehend how HA interacts with other skin constituents and how it is metabolized in skin layers. This data will make it easier to control skin moisture in a sen

.sible way, which could help improve the efficacy of existing medications and lead to the creation of new skin aging treatments.