Introduction
The process of aging becomes perceptible in the second decade of life, introducing a plethora of significant transformations. Though initially subtle, by the third decade these structural and functional changes become substantially more pronounced. The skin, a crucial protective shield against unwanted external stimuli , fulfills a number of critical roles in maintaining sensitivity and defense against physical, chemical, and biological attacks on the human body . Given its constant exposure to environmental elements, the skin often experiences changes that can impact not just its condition, but overall human health . It is this reason that spurs the food, cosmetic, and pharmaceutical industries to consistently strive for innovative and enhanced products designed to hinder, delay, or reduce the signs of aging, and to safeguard and rejuvenate the skin.
The term “nutraceuticals” represents a combination of ‘nutrition’ and ‘pharmaceutical.’ They refer to foods, food components, or pharmaceutical/cosmetic items that demonstrate distinct physiological effects without any negative side effects, and are consumed with the objective of augmenting health status . In response to a growing population and evolving dietary needs, nutraceutical consumption has seen an uptick. Nutraceutical products sourced from plants contain antioxidants, polyunsaturated fatty acids, prebiotics and probiotics. Recent approaches to treating collagen deficiencies have involved the use of bioactive peptides, which are acquired via the enzymatic hydrolysis of food proteins. Bioactive peptides, such as hydrolyzed collagen, are among the most popular ingredients in the creation of nutraceuticals. Collagen, constituting about 30% of the body’s protein mass, is crucial to the structure of various tissue types, imparting firmness and integrity to bones and skin. The triple helical structure of collagen fibers is composed of α chains. Type I collagen, found in mammals, is composed of two α1(I) and one α2(I) chains. Skin contains type I and III collagen, while cartilage includes type II and III collagen. These collagen fibers impart tensile strength to these tissues. Hydrolyzed collagen, rich in amino acids such as glycine and proline, accumulates in the skin or cartilage after digestion and contributes to their stability or regeneration.
The extracellular matrix primarily consists of collagen proteoglycans, which determine resistance, molecular filtration, and skin hydration. These proteoglycans also have an impact on cellular behavior and cell-matrix interactions. Changes in the expression or structure of collagen proteoglycans, which are a significant source of cytokines and growth factors, can notably affect tissue homeostasis.
Considering the decrease in collagen and elastin deposits with age, particularly due to sun exposure, the cosmetic industry is seeking solutions to enhance the appearance of skin on the face and neck. Collagen plays a vital role in pharmaceutical or food products and influences the connective tissues of skin, tendons, ligaments, and teeth. Collagen peptides are incorporated as dietary supplements in malnutrition or other degenerative diseases to restore bone density. Several clinical studies (Table I) have validated the beneficial effect of collagen peptides on skin elasticity, such as minimizing wrinkles or increasing collagen deposition in the dermis. For these benefits to take effect in the skin’s deep layers, hydrolyzed collagen must penetrate the bloodstream by crossing the intestinal barrier.
Skin Aging – Natural Phenomenon and External Influences
The skin’s primary constituents are the epidermis, made up of proliferative basal cells, and the dermis, composed of keratinocytes. Dermal fibroblasts generate elastin and type I and III collagen, alongside other extracellular matrix proteins. Given that the dermis supplies critical nutrients to the skin through blood vessels and offers structural support to the epidermis, it’s crucial to maintain the integrity of the dermal layer for the proper functionality of skin cells. Skin aging can be attributed to intrinsic, chronological or natural aging which are processes accumulated or intensified over time, or it can be due to extrinsic factors like exposure to solar radiation (photo-aging). Changes to the skin’s dermal layer, modifications of the extracellular matrix, an increase in inflammatory markers, and diminished blood flow collectively contribute to skin aging.
The aging process exacerbates cumulative exposure to detrimental stimuli such as hemodynamic stress and oxidized lipids, and is associated with hindered angiogenesis and endothelial dysfunction (21). The dermal structure can be compromised by natural aging, with aged fibroblasts synthesizing less collagen. Ultraviolet radiation produces reactive oxygen species which activate matrix metalloproteinases, affecting collagen production through neocolagenesis, resulting in an altered ratio of type I to type III collagen. This causes a breakdown of the extracellular matrix and triggers photo-aging of the skin. The depletion of collagen in the skin, coupled with the onset of elastosis—a phenomenon causing disorganized accumulation of elastin proteins in the dermis—results in dermal atrophy, giving the skin an aged appearance. The process of elastosis particularly impacts areas of the body exposed to solar radiation. As a result, fibroblast activity and mechanical tension decline, leading to degradation of existing collagen fibers. Due to the escalation of collagen breakdown in the dermis and a decrease in its synthesis, fine lines become visible.
Skin alterations are noticeable in smokers, and chronic stress influencing the circadian cortisol/corticosterone rhythm can alter collagen synthesis and degradation. Sun-exposed, aging skin tends to become drier, looser, and more wrinkled. As the aging process progresses, wrinkles become more pronounced and skin laxity augments.
Sources of Collagen Peptides
Gelatin formation emerges from the irreversible denaturation of collagen molecules. This denaturation process can be halted via chemical or thermal treatment. Heat treatment of collagen denaturation finds application in beauty techniques, medical procedures such as orthopedics, plastic surgery, and dental or ophthalmological treatments, as well as in the pharmaceutical or food industry. Owing to the unique bioactivities of collagen peptides—particularly their high biocompatibility and bioavailability—gelatin is widely utilized in the food industry.
Currently, there is active research to identify new collagen sources. The commonly used hydrolyzed collagen and gelatin are derived from porcine or bovine type I collagen. Compared to gelatin, hydrolyzed collagen is more digestion-friendly as it dissolves in water or brine and is readily absorbed. Research has indicated that the age of the animal can affect collagen’s solubility, with collagenous tissue from older animals being harder to solubilize than that obtained from a younger animal. Numerous techniques have been developed to obtain collagen-based macromolecules, taking into account the collagen source and its degree of solubilization. High-quality gelatin is extracted from bovine bone, with its peptides acting on bone metabolism, proving useful in treating osteoarthritis, influencing bone metabolism, and inhibiting bone loss. Due to the emergence of bovine spongiform encephalopathy, the use of this type of gelatin is limited, necessitating other collagen sources. Collagen can be extracted from both animal and plant sources, algae, and marine organisms, including fish.
In the pharmaceutical, cosmetic, and food industries, collagen derived from marine sources is preferred. Collagen and other bioactive substances can be extracted from marine organisms. Among the marine organisms from which collagen is derived are invertebrates such as jellyfish, sponges, and sea urchins, octopuses, as well as vertebrates like cod, salmon, and marine mammals. Compared to animal-derived collagen, marine-sourced collagen is more easily absorbed, exhibits a low molecular weight, and is favored in the industry due to its lower potential for inflammatory reactions and contaminants. In terms of biocompatibility and amino acid content, marine collagen is akin to porcine or bovine-derived collagen. Abundant in marine organisms is type I collagen. Regenerative medicine, which primarily focuses on tissue engineering for the replacement or restoration of damaged tissues, uses biomaterials, cells, and biochemical factors. Collagen, which supports cell migration and interaction between the extracellular matrix and cell, thus leading to tissue regeneration, is the most suitable biomaterial for tissue engineering.
In the cosmetic industry, marine collagen has found success in treating wounds, burns, and ulcers, providing antimicrobial protection, and preventing moisture and heat loss from the injured tissue.
Marine collagen is an important source, and the peptides derived from this collagen can pass into the bloodstream intact after gastrointestinal digestion. Also, these biopeptides have demonstrated wound-healing properties, making this type of collagen desirable in the industry. The only potential drawback is the risk of heavy metal contamination.
Clinical Evidence for the Beneficial Roles of Collagen-Based Products for Skin Care
Hydrolyzed collagen, used extensively in food supplements and the pharmaceutical industry, has demonstrated benefits such as bioavailability, rapid absorption in the digestive tract, and migration into the bloodstream as small peptides, which accumulate in the skin after 96 hours of ingestion. Studies have found proline and hydroxyproline, components of collagen, in the bloodstream following ingestion of hydrolyzed collagen. With their low molecular weight and rapid absorption, collagen peptides distribute to various tissues, including the skin, where their efficacy and benefit are evident (Fig. 1).
Numerous in vitro studies have investigated the antioxidant activity of collagen peptides. They have shown that blood peptides, derived from ingested hydrolyzed collagen, exhibit chemotactic properties for skin fibroblasts, thereby promoting migration and proliferation of murine fibroblasts. These fibroblasts, activated by hydrolyzed collagen, induce the production of collagen, hyaluronic acid, and elastin. Following ingestion, collagen peptides can remain in the dermis for up to 14 days, providing protection against sunlight, enhancing moisture retention, and aiding in repairing endogenous elastin and collagen fibers.
Several commercial products leveraging collagen’s benefits have been based on these clinical studies. For example, Pure Gold Collagen® Food Supplement, a product consisting of type I hydrolyzed collagen derived from fish, low molecular weight hyaluronic acid, and several vitamins and minerals, was shown to reduce skin dryness, wrinkle depth, and nasolabial folds, as well as firm the skin and increase collagen density when consumed daily for 60 days.
Another product, BioCell Collagen®, is composed of type II hydrolyzed collagen, low molecular weight hyaluronic acid, and chondroitin sulfate. A study demonstrated its beneficial effect after 12 weeks of daily administration, leading to a significant reduction in skin dryness and wrinkles. Also, lab investigations showed an increase in hemoglobin and collagen content in the dermis after BioCell Collagen® administration for six weeks.
Another product, VERISOL® (type I porcine hydrolyzed collagen), was tested on 69 healthy women who received 2.5-5g of hydrolyzed collagen daily. After four weeks, significant improvements in skin elasticity were observed in the group of older women, which persisted even after treatment cessation.
Collagen peptide-based nutritional products supplemented with antioxidants have also been studied, demonstrating increased skin elasticity after 90 days of consumption. Bioactive peptides in the dermis perform dual functions: they aid in forming collagen fibers, and they bind to receptors on the fibroblast membrane, stimulating their proliferation and consequently the production of hyaluronic acid, collagen, and elastin (23).
Studies have also demonstrated that supplementing with vitamins from groups C or E can improve skin appearance, as these nutrients possess properties that attract water molecules, improving skin hydration, scavenging free radicals, or reducing inflammation. Vitamin C is also an essential co-factor in the biosynthesis of collagen.
A study conducted by Campos et al. on a product composed of a combination of amino acids (hydrolyzed collagen peptides: glycine, proline, and hydroxyproline), supplemented with hydrosoluble vitamins (A and C), liposoluble vitamins (E), and zinc, found a visible reduction of wrinkles and large pores, good skin elasticity, and improved structure of the dermis after daily consumption for three months.
While the beneficial effects of hydrolyzed collagen have been demonstrated for several skin conditions, more research is needed to investigate their potential application for other dermatological ailments. For instance, further exploration is required to understand the efficacy of collagen-based topical treatments for conditions such as Aacanthosis nigricans, which presents as hyperpigmented, velvety, hyperkeratotic plaques on the skin.
AminoCollagen C with Hyaluronic Acid is another product that combines collagen with vitamin C and hyaluronic acid. A study observed significant improvement in skin appearance and a substantial reduction in the depth of wrinkles in subjects after oral consumption of this product for 9 weeks. Additionally, it was demonstrated that daily oral supplementation with 1g of this type of hydrolyzed collagen for up to 12 weeks led to a significant reduction of wrinkles and improvement of skin elasticity and skin dryness.
Collagen supplements that also contain antioxidants have also been examined for their effect on skin health. Antioxidants help to neutralize harmful free radicals that can damage skin cells and contribute to signs of aging. Collagen peptides provide amino acids that are necessary for the body to produce its own collagen, and studies have shown that these peptides can stimulate fibroblast activity and promote healthy tissue growth of hair, skin, and nails.
Collagen-based products also appear to be useful in wound healing and the treatment of burns and ulcers, thanks to the ability of collagen to promote cell proliferation and migration, and hence, tissue regeneration. Furthermore, collagen supplements may also aid in maintaining skin hydration and barrier function, crucial factors in skin health and appearance.
However, it is important to note that while many studies have shown promising results, more rigorous and comprehensive clinical trials are needed to firmly establish the benefits of collagen supplements for skin health. Several variables, such as the type of collagen, the source of collagen, the dosage, and the form of administration (topical or oral), also need to be considered in such trials to provide more definitive conclusions.
Conclusion
Skin aging is an unavoidable natural process that stems from the intricate interplay between intrinsic factors such as genetics, and extrinsic factors such as UV radiation, pollution, and lifestyle habits. In particular, the intrinsic aging process is linked with gradual alterations in the composition, structure, and function of the skin’s extracellular matrix, which is composed of collagen, elastin, and hyaluronic acid. These modifications ultimately lead to the clinical manifestations of skin aging, including increased skin laxity, dryness, fragility, and the formation of wrinkles.
Given the central role of collagen in maintaining skin structure and function, interventions that aim to boost collagen levels in the skin are an appealing strategy to delay and mitigate signs of skin aging. Hydrolyzed collagen, also known as collagen peptides, has gained attention for its potential in this regard. Derived from various sources such as bovine and porcine skin, marine organisms, chicken skin, and fish cartilage, hydrolyzed collagen is easily absorbed and utilized by the body. Importantly, it can stimulate the body’s own collagen production, thereby reinforcing the skin’s collagen framework and improving skin health.
Importantly, due to the bovine spongiform encephalopathy (BSE) crisis, there has been a growing interest in non-mammalian sources of collagen, particularly marine sources. Marine collagen, in particular, is considered safer and more sustainable compared to its mammalian counterparts, and shows promising bioactive properties, including high bioavailability, biocompatibility, and lower risks of triggering allergic reactions.
The daily consumption of hydrolyzed collagen, sometimes combined with other nutrients like vitamins, has been shown to yield several beneficial effects for the human body, from alleviating joint pain to enhancing skin health. Various studies have revealed its potential in slowing skin aging by increasing skin hydration, elasticity, and density, reducing wrinkles, and boosting the production of collagen, elastin, and hyaluronic acid.
Nevertheless, while the current body of research supports the benefits of hydrolyzed collagen supplementation for skin health, it is crucial to acknowledge that more comprehensive and rigorous clinical trials are required to solidify these claims. Future research should also aim to identify the most effective sources, forms, and doses of collagen supplements for skin health, in order to optimize their potential benefits and ensure their safety and efficacy for the wider population.
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