Advertisement

Innovative Nutraceutical Approaches to Counteract the Signs of Aging

  • L. Genovese
  • S. SibillaEmail author
Living reference work entry

Later version available View entry history

Abstract

The following chapter regards the benefits related to the daily consumption of a nutraceutical liquid beauty supplements in the fight against skin aging. Aging is a complex biological phenomenon, caused by several factors which are genetically and environmentally determined. In the skin, aging induces a gradual decrease in the levels of collagen and elastin, which are the main proteins responsible for maintaining skin firmness and elasticity. As a consequence of aging, skin becomes more rigid and loses its ability to keep shape, and wrinkles and fine lines form. Following a healthy nutritional lifestyle can restore the homeostasis of macro- and micronutrients and support the physiology of cells and tissues in the skin. To this end, nutraceuticals offer formulations that increasingly represent a valid tool in the fight against skin aging. In this context, the consumption of hydrolyzed collagen-based beauty supplements can benefit the skin by restoring the natural production of collagen, hyaluronic acid and elastin. Blends of collagen peptides and multiple active ingredients can make them easily digestible, absorbed, and widely distributed in the human body. Importantly, they have been shown to restore skin hydration and elasticity and to reduce fine lines and wrinkles.

Keywords

Skin aging Hydrolyzed collagen Hyaluronic acid GOLD COLLAGEN® Antioxidants Nutraceutical Nutritional supplement Functional food Fine lines Wrinkles Skin hydration Skin elasticity 

Introduction

Skin aging is characterized by a gradual structural deterioration due to intrinsic genetic factors, which may be accelerated by extrinsic aging factors such as chronic sun exposure (photoaging) [1, 2] or by lifestyle factors such as smoking, alcohol, stress, and lack of sleep [3, 4].

Skin constitutes an effective environmental interface providing protection for human body homeostasis, and as such it is also exposed to several environmental toxic insults (UV rays and chemical factors), which can lead to the production of reactive oxygen species (ROS). These molecules are known to be involved in the pathogenesis of a number of skin disorders and some types of cutaneous malignancy [5] and are also believed to lead to aging. In fact, in 1956, Denham Harman first proposed that the oxygen-free radicals, endogenously formed from normal metabolic processes, could cause aging [6, 7] (although this theory does not exclude other aging mechanisms such as cell senescence, telomere shortening, and genomic instability).

Skin is capable of counteracting the action of these molecules through efficient antioxidant defense mechanisms. Unfortunately, these processes weaken with time and can be overwhelmed by increased ROS production. One approach to prevent or treat these ROS-mediated disorders is based on the administration of different antioxidants [5].

There has been some controversy on the link between aging and ROS production. Several in vivo studies have in fact shown that inhibition of antioxidants expression leads on one side to increased oxidative damage, but on the other side does not lead to the expected signs of accelerated aging nor to a reduced lifespan. This suggests how the aging process may be triggered by many factors other than ROS production [8, 9].

Many functional foods (food containing additives which provide extra nutritional value), also known as nutraceuticals, which are able to counteract oxidative stress and ROS-mediated disorders, [5] have recently come into the market in many countries. For example, a study has shown that collagen peptides, as a dietary supplement, are beneficial in suppressing UVB-induced skin damage and photoaging [10]. Another study, conducted in hairless Sod1−/− double mutant mice, showed that co-treatment with collagen peptides and vitamin C corrected age-related skin thinning by attenuating oxidative damage [11]. Also, dietary intake of astaxanthin (a powerful antioxidant) combined with collagen hydrolysate can improve elasticity and barrier integrity in photo-aged human facial skin [12]. In addition, GOLD COLLAGEN® nutraceutical products have been shown to have beneficial effects on skin properties such as hydration, elasticity, and reduction of fine lines and wrinkles [13, 14, 15], making them a valid tool in the fight against skin aging .

Skin Structure and Function

Skin covers the whole human body and represents the principal barrier to the external environment [16]. Skin has many more roles other than guarding the underlying muscles, bones, ligaments, and internal organs. For example, skin plays a key role in immunity by protecting the body against pathogens (Langerhans cells in the skin are part of the adaptive immune system). Moreover, skin prevents excessive water loss, it has a role in insulation, temperature regulation, sensation, synthesis of vitamin D, excretion, and absorption.

The skin is composed of multiple layers: the epidermis, the dermis, and the subcutaneous tissues (Fig. 1). The epidermis itself is composed of several layers: the stratum corneum as the top layer, then proceeding deeper down, there are the stratum lucidum and stratum granulosum, followed by the stratum spinosum, and finally the stratum basale just above the dermis [17]. The stratum corneum is extremely difficult to penetrate, and it represents the first barrier to the external environment. Thus, the probability of external particles reaching the dermis through the epidermis is very limited. Below the epidermal layers lies the dermis, which is rich in proteins such as collagen, elastin, and glycosaminoglycans (such as hyaluronic acid ). These proteins are the main components of the extracellular matrix (ECM) and are secreted by fibroblasts, cells of the connective tissue. The subcutaneous tissue is the deepest layer of the skin, composed primarily of fat.
Fig. 1

Human skin structure

In the epidermis, melanocytes produce melanin and are responsible for skin pigmentation (skin color) and absorb some of the potentially dangerous UV rays present in sunlight. DNA repair enzymes help reverse UV damage in the skin, such that people lacking the genes coding for these enzymes suffer higher rates of skin cancer.

Skin is directly exposed to periodical changes in light and temperature, as it forms an interface between the external environment and the body. Many physiological processes are characterized by periodic daily fluctuations such as changes in skin temperature, sebum production, pH, and transepidermal water loss [18]. Also cell division is associated with specific times of the day and exhibits a circadian periodicity [19]. Epidermal cell proliferation is in fact regulated by a circadian clock, and this could serve as a mechanism for protecting against UV-induced DNA damage by minimizing DNA replication during exposure to the sun UV rays [20].

Collagen

The extracellular matrix of connective tissues is formed by different protein families involved in providing structural integrity and several other physiological functions. In the dermis, one of the principal proteins of the ECM is collagen, an insoluble fibrous protein which, together with elastin and hyaluronic acid, is the main component of skin and has a key role in providing integrity and elasticity to this organ.

Collagen is mostly found in fibrous tissues, such as tendons and ligaments, and it is also abundant in the cornea, cartilage, bones, blood vessels, the gut, and intervertebral disks.

Collagen protein is composed of three polypeptide chains named α-chains, which form a triple helix [21]. Based on their structure and three-dimensional organization, they can be grouped into fibril-forming collagens, fibril-associated collagens (FACIT), network-forming collagens, anchoring fibrils, transmembrane collagens (MACIT), basement membrane collagens, and others with unique functions. 28 triple helical proteins have been named as collagens [22, 23].

The five most common types of collagen are:
  • Type I: dermis, tendon, ligaments, and bone

  • Type II: cartilage, vitreous body, and nucleus pulposus

  • Type III: skin, vessel wall, and reticular fibers of most tissues (lungs, liver, spleen)

  • Type IV: forms the basal lamina and the epithelium-secreted layer of the basement membranes

  • Type V: lung, cornea, hair, and fetal membranes

A collagen fibril is composed of multiple triple helices and multiple fibrils form a collagen fiber. Collagen fibrils are made of different collagen types: collagen I and III in the skin and collagen II and III in cartilage [21]. Type I collagen is the most abundant in the human body: it forms more than 90 % of bone organic mass, and it is the major collagen present in tendons, ligaments, cornea, and many interstitial connective tissues. It is also the main component of human skin (80 %) with collagen type III making up the remainder of skin collagen (15 %) [23, 24].

Together collagen fibers form a dense network throughout the dermis that confers structural integrity to the skin and also provides structural support to the epidermis.

In the connective tissues, collagen is mainly produced by fibroblasts [22]. In the dermis, fibroblasts are the main cells responsible for producing and organizing the collagen matrix. The activation of fibroblasts results in an increase in the production of collagen. Also myofibroblasts [25] and numerous epithelial cells make certain types of collagens in other tissues [26].

Studies have shown that collagen synthesis varies at different stages of life. The relative proportion of the types of collagen in skin also changes with age. Young skin is composed of 80 % type I collagen and about 15 % collagen type III. With age, the ability to replenish collagen naturally decreases by about 1 % per year [27].

Elastin

The elasticity of many tissues depends on the presence of elastic fibers which are composed by elastin and microfibrils. Elastin is a very important protein for arteries and helps in the pressure wave propagation for blood flow. Elastin is also very important for the lungs, elastic ligaments, and skin. The principal characteristic of elastic fibers is that they stretch rapidly under a load and return quickly to their original form once the load is removed.

Elastin contains many cross-linking sites [28]. Thus, elastic fibers are freely mobile with respect to one another, except at points of cross-linking. The major cross-links in elastin are two polyfunctional amino acids, desmosine and isodesmosine, which account for both the elasticity and insolubility of elastic fibers. These fibers are mainly composed of an amorphous component, which is extensively cross-linked elastin, and a fibrillar component, which are primarily the microfibrils, such as fibrillin. Fibroblasts produce multiple tropoelastin molecules, which covalently bind together with cross-links to form the final elastin protein.

Hyaluronic Acid

Another essential ECM protein is hyaluronic acid (HA). This molecule is found mainly in soft connective tissues, in particular skin and joints. HA is formed by alternating units of glucuronic acid and N-acetylglucosamine.

In the skin HA is synthesized by fibroblasts, keratinocytes, and other cells [29]. HA is found not only in the dermis but also in the epidermal intercellular spaces. HA has a high molecular weight (10–104 KDa), and this represents a key factor in influencing its physical-chemical properties, such as viscosity, elasticity, and the ability to retain water. In fact, HA is essential for tissue hydration, lubrication, and the production of collagen in the dermis.

Though HA is known to play a structural role in connective tissue, its overall turnover rate appears to be surprisingly quick. Studies have shown that HA has a turnover rate of 0.5 to a few (2–3) days [29, 30].

It has been shown that HA is absorbed and distributed to organs and joints after a single oral administration [31]. In vitro studies have shown that collagen peptides can stimulate not only dermal fibroblasts proliferation but also synthesis of hyaluronic acid [32].

HA has been widely used as an antiaging cosmetic ingredient. Its beneficial effects on skin are controlled by varying its molecular size. For example, lower-molecular-weight HA was shown not only to lead to a significant reduction of wrinkle depth [33] but also to penetrate the skin better and to influence the expression of many genes involved in keratinocyte differentiation and in the formation of intercellular tight junction complexes, which are reduced in aged skin [34].

Skin Aging

Aging is the process of becoming older and in humans it refers to a psychological and physical processes. In particular, aging of the skin is a complex biological phenomenon which affects several of its constituents and hence its appearance, and for this reason it can have a big social impact.

There are two primary skin-aging mechanisms, intrinsic and extrinsic [3, 4]. Both intrinsic and extrinsic aging (discussed later on) act simultaneously and are associated with phenotypic changes such as wrinkle formation.

In aged skin, collagen fibers become thicker and much shorter, resulting in a loss of collagen type I, which alters the ratio of collagen types [35]. The density of collagen and elastin in the dermis declines, and as a consequence, skin support and elasticity degrade and skin becomes thinner and more rigid. Reduced collagen can reflect two different underlying mechanisms: cellular fibroblast aging and a lower level of fibroblast cell stimulation. Hence, there is a destruction of existing collagen and a failure to replace damaged collagen with newly synthesized material [36]. Moreover, it has been shown that in the presence of damaged collagen fibers, fibroblasts have a reduced proliferative capacity and synthesize less collagen [37, 38, 39].

The aging process results also in the loss of hyaluronic acid. This reduces the moisture, suppleness, and elasticity of the skin. The diminished elasticity of the skin reduces its ability to retain its shape, and therefore, it will not conform as closely to the contours of the face. The skin appears looser and sags, lines and furrows emerge to enable movement. Gravity then pulls on the skin, all leading to sagging eyelids and bags under the eyes and jowls.

Intrinsic Aging

Intrinsic aging depends on time, it is genetically determined and the changes that occur are a result of different factors:
  • Cumulative endogenous damage due to the formation of ROS which affects cellular constituents such as membranes, enzymes, and DNA.

  • Decreased sex hormone levels (estrogen, testosterone, dehydroepiandrosterone) and other hormones (i.e., melatonin, insulin).

  • Shortening of telomere length. It has been reported, for example, that in fibroblasts of quiescent skin, more than 30 % of telomere length is lost during adulthood [40].

  • Decreased levels of cytokines and their receptors with consequent loss of several skin functions.

Several changes occur in skin layers: there is a decreased number of melanocytes and Langerhans cells in the epidermis, alteration in the epidermal-dermal junction (with a consequent reduction of exchange of nutrients between the two), loss of dermal volume, decrease in blood supply, and reduced tyrosinase activity (which is linked to melanin production) [41].

Deep inside in the dermis, fibrillar collagens, elastin fibers, and hyaluronic acid undergo different structural and functional changes. Collagen and elastin are long-life proteins and are predisposed to intrinsic molecular aging and have a half-life measured in years [3]. For this characteristic, these fibers accumulate damage over time, and this reduces their ability to function correctly. As a consequence, intrinsically aged skin is generally characterized by dermal atrophy with reduced density of collagen fibers, elastin, and hyaluronic acid (Fig. 2).
Fig. 2

Extracellular matrix remodeling in intrinsically and extrinsically aged skin. Dermal collagens, elastic fibers, and glycosaminoglycans undergo significant changes in both photo-protected and photo-exposed aged skin. When comparing with young skin, intrinsically aged skin (photo-protected) is characterized by atrophy of dermal collagens and of the elastic fiber system. Extrinsically aged skin (photo-exposed) is characterized both by a marked reduction in fibrillar collagen and by an accumulation of disorganized elastic fiber proteins throughout the dermis, a process termed solar elastosis [3].

All these changes lead to the formation of wrinkles and fine lines, which are exacerbated by gravitational forces and the loss of subcutaneous fat.

Extrinsic Aging

Extrinsic aging is caused by several factors:
  • Chronic sun exposure (UV radiation is the most important factor for skin aging). It damages DNA in keratinocytes and melanocytes and induces the production of proteolytic enzymes, such as collagen-degrading enzymes. It is also responsible for the formation of thymidine dimers (“UV fingerprints”), which lead to an accumulation of DNA mutations. Clinically UV radiation leads to the formation of actinic keratosis, solar elastosis, lentigines, and carcinomas [41].

  • High alcohol intake

  • Smoking

  • Poor nutrition

  • Overeating

  • Environmental pollution

  • Stress

Extrinsically aged skin is characterized by the degradation and the alteration of collagen fibers and the accumulation of disorganized elastin proteins throughout the dermis, a process known as elastosis (Fig. 2). Metalloproteinases can be induced by UVA and UVB [42], and their proteolytic activity results in the degradation of collagen and elastin fibers. For example, metalloproteinases were found to be induced in cells obtained from old versus young subjects [43], and many other studies show their upregulation in photodamaged skin [44, 45, 46, 47]. As a consequence, the collagen density decreases each year with a faster rate in photo-exposed skin [4]. In fact, aged fibroblasts synthesize lower levels of collagen, both in vitro and in vivo, compared to young adult fibroblasts [36], and photo-aged dermis contains disorganized collagen fibers and accumulated abnormal elastin [46, 48].

Another important aging phenomenon that takes place, especially in tissues very rich in proteins, is the production of advanced glycation end products (AGEs). These molecules form because of a chemical reaction between glucose and the free amino groups in proteins, and they remain in the tissue as they cannot be degraded normally by enzymes [49].

Clinical manifestations of extrinsic aging include leathery appearance, increased wrinkle formation, reduced recoil capacity, increased fragility of the skin, and altered color pigmentation (age spots).

The skin has two photo-protective mechanisms: the melanin in the lower layer of the epidermis and the urocanic barrier of the stratum corneum which absorbs a good amount of UV rays.

In addition, a very important role is played by antioxidants, which help counteract ROS damage. Antioxidants are naturally occurring in the skin and include superoxide dismutase, catalase, alpha-tocopherol, ascorbic acid, ubiquinone, and glutathione. A proper diet, rich in vitamins and antioxidants (e.g., coenzyme Q10 and alpha-lipoic acid), can help protect from oxidative damage [50].

Interestingly, alteration in diet can change the way skin functions as evidenced by the effects of dietary deprivation on skin health. For example, essential fatty acid deficiency [51] or the accumulation of abnormal fatty acids [52] results in the so-called skin scaling and poor barrier function.

Thus, it is important to have a correct nutritional approach, maintaining a balanced diet and a good supply of food supplements to restore the homeostasis of cells and tissues in the human body.

The Use of Hydrolyzed Collagen as a Nutraceutical

Hydrolyzed collagen is becoming an increasingly popular nutraceutical. It is produced from native collagen, and it consists of small collagen peptides with low molecular weight (0.3–8 KDa). It is formed through a process of hydrolysis which involves breaking down the molecular bonds between individual collagen strands using a combination of heat, acids, alkalis, or enzymes. Hydrolyzed collagen is widely used in cosmetics as a moisturizer, for example, in creams. The main advantage of using small collagen peptides, compared to native collagen, is that they are highly digestible, easily absorbed, and distributed in the human body. In literature there are numerous clinical trials that have been performed showing the efficacy and benefits of collagen peptides on skin properties (such as hydration, elasticity, and reduction of wrinkles). A reduction in skin collagen levels, which comes with age, can lead to a reduced mechanical tension on fibroblasts with a consequent loss in matrix production and stimulation instead of matrix-degrading enzymes [53]. In this context, hydrolyzed collagen supplementation has a dual mechanism: (1) collagen peptides and free amino acids are used as building blocks for the formation of new collagen and elastin fibers; (2) the collagen peptides bind to fibroblasts receptors and stimulate the production of new collagen, elastin, and hyaluronic acid.

When administered orally, hydrolyzed collagen reaches the small intestine and then it is absorbed into the bloodstream. The collagen peptides are distributed in the human body and to the dermis through the circulatory system.

The bioavailability of hydrolyzed collagen was demonstrated first in mice by a study published in 1999. In this study the authors showed that when orally administered 14C-labeled hydrolyzed collagen was digested, more than 90 % was absorbed within the first 12 h from the intake. In fact, radioactivity in skin peaked 12 h after the administration of 14C-labeled hydrolyzed collagen, and in contrast to plasma, the radioactivity levels remained high up to 96 h [54]. In a more recent study (published in 2005), the authors found that hydrolyzed collagen from porcine skin, chicken feet, and cartilage, ingested by healthy human volunteers after 12 h of fasting, was absorbed in the blood as small peptides. In fact, hydroxyproline-containing peptides were found to be increased in the plasma, reaching a peak level after 2 h and then decreasing to half of the maximum level after 4 h from the oral ingestion. The authors also identified a small peptide proline-hydroxyproline (Pro-Hyp) in the blood, which was present only after intake of hydrolyzed collagen [55].

The safety of collagen peptides and gelatin (from which hydrolyzed collagen is prepared) is widely recognized. The Food and Drug Administration (FDA) has classified gelatin as a safe substance. In addition, based on international research results, both the World Health Organization (WHO) and the European Commission for Health and Consumer Protection have confirmed that hydrolyzed collagen is safe. There may be only rarely minor side effects, such as nausea, flatulence, or dyspepsia.

The distribution of collagen peptides to the skin was demonstrated in a study in which 14C-labeled proline or 14C-labeled collagen peptides were administered to Wistar rats. After ingestion of the collagen peptides, radioactivity was measured in the different tissues until 14 days. The results showed that the radioactivity remained at high levels in the skin up to 14 days. This indicates the ability of collagen peptides to reach the dermis in the skin and stay there for prolonged periods [56].

Several in vitro and in vivo studies have demonstrated the efficacy of collagen peptides on skin health.

An in vitro study example is given by the work of Chen and coworkers [57]. These authors studied the effect of different concentrations of hydrolyzed collagen from fish on fibroblasts and keratinocytes. In particular, they investigated cell proliferation, collagen production, and mRNA type I collagen expression. The authors found that an optimal concentration of collagen ranging between 48 and 97 μg/mL resulted in 191% increase in the percentage of fibroblast cell proliferation. Also the highest keratinocytes proliferation was achieved with a collagen concentration between 0.76 and 1.53 μg/mL, and this induced an increase of 242% in proliferation percentage. They also reported an increase in the expression of collagen I mRNA in fibroblasts.

In addition to these studies, Ohara et al. [32] further demonstrated that collagen peptides can stimulate not only the proliferation of dermal fibroblasts but also the synthesis of hyaluronic acid. In this study eight different collagen-derived peptides containing Hyp were analyzed, and a positive effect on proliferation was observed for Ala-Hyp, Ala-Hyp-Gly, and Pro-Hyp. The same eight peptides were also used to evaluate their effect on hyaluronic acid synthesis, and the results were consistent with the proliferation study. In both studies, Pro-Hyp showed highest efficacy in proliferation and hyaluronic acid synthesis.

Examples of in vivo studies are those by Matsumoto et al. [58]. This research group carried out a preclinical trial in which they showed that daily ingestion of collagen peptides improved skin hydration in female volunteers after supplementation with fish collagen peptides for 6 weeks. This study was followed by a double-blind placebo-controlled study by the same research group [59]. Healthy female volunteers aged 25–45 ingested 2.5, 5, and 10 g of fish collagen peptide, and the results were compared to a placebo group. Stratum corneum hydration was measured at baseline and after 4 weeks. When all subjects were included in the analysis no significant difference between the treated groups (2.5/5/10 g) and the placebo was observed. However, when only subjects older than 30 years were considered, there was a significant difference between the treated group (5 and 10 g) and the placebo.

Koyama et al. [60] demonstrated that women ingesting 5 or 10 g of pig skin collagen had an improvement of their skin condition already after 3 weeks and at the end of the treatment after 7 weeks. Furthermore, in a double-blind, placebo-controlled study, Proksch and colleagues investigated the effects of collagen hydrolysate on skin biophysical parameters such as skin elasticity , skin moisture, transepidermal water loss, and skin roughness. Sixty-nine women (35–55 years old) were randomized to receive collagen hydrolysate (2.5 g or 5.0 g) or placebo once daily for 8 weeks. At the end of the study, skin elasticity in both collagen hydrolysate dosage groups showed a statistically significant improvement in comparison to placebo [61]. Results from several clinical trials, showing the efficacy of liquid hydrolyzed collagen -based dietary supplements, such as PURE GOLD COLLAGEN®, in reducing wrinkles and nasolabial fold depth and increasing skin hydration and elasticity, have been published recently [13, 14, 15].

A study involving 265 volunteers was carried out independently by 40 dermatologists across 5 different countries: USA, UAE, Greece, Czech Republic, and Spain. The subjects were given a standardized daily dose of PURE GOLD COLLAGEN® for 20 days before and 40 days after a cosmetic procedure. The outcome of the study showed that there was a significant increase in collagen density and skin firmness along with a significant reduction in skin dryness, wrinkles, and depth of nasolabial folds [13].

A double-blind, randomized, placebo-controlled study including 108 healthy volunteer subjects was performed by an independent Clinical Research Organization to assess the efficacy of PURE GOLD COLLAGEN® on skin condition. Volunteers consumed the products daily for 12 weeks. The effect on the skin was investigated and a significant improvement in wrinkles (19 % reduction compared to placebo) was achieved, primarily a decrease in the surface area and the mean length of wrinkles [14].

Another recent 12 weeks double-blind, randomized, placebo-controlled clinical trial was conducted on 18 female healthy subjects (between the ages of 45 and 64) to assess whether the oral consumption of PURE GOLD COLLAGEN® could improve certain specific skin properties of postmenopausal women such as depth of facial wrinkles, skin elasticity, and hydration. The results showed that the combination of specific ingredients such as hydrolyzed collagen, hyaluronic acid, and essential vitamins and minerals present in the nutritional drink acts to significantly reduce the depth of facial wrinkles within 9 weeks and increase skin elasticity (between week 9 and week 12) as well as skin hydration (after 6 weeks) [15].

Thus, on the basis of the significant amount of data now present in the literature, hydrolyzed collagen can be considered an important nutraceutical weapon in the everyday fight against skin aging.

GOLD COLLAGEN® Products: An Overview

Nutraceuticals containing collagen peptides together with vitamins and minerals are innovative liquid, nutritional food supplements. These dietary supplements help promote healthy skin, fight the early signs of aging, such as fine lines and wrinkles and promote healthy looking hair and nails. Examples of these innovative nutricosmeceuticals are the GOLD COLLAGEN® products, conceived and created by MINERVA Research Labs (http://www.gold-collagen.com).

Collaborative studies which are analyzing the mechanisms of action, safety, and efficacy of hydrolyzed collagen-based supplements, such as GOLD COLLAGEN® products, involving research and academic institutes in the UK, Europe, and USA, are currently ongoing.

Non-collagen Anti-aging Ingredients (Table 1)

Summary of Results Obtained with PURE GOLD COLLAGEN®

Table 1

Ingredients present in nutraceutical supplements: properties, benefits, and approved claims

PROPERTIES

BENEFITS/APPROVED CLAIMS

Borage oil

Borage oil is the richest known source (24 %) of gamma-linolenic acid (GLA), an essential fatty acid. GLA is converted, via a sequence of biochemical steps, into prostaglandin 1 (PG1), a key molecule for maintaining healthy skin. PG1 exhibits a potent anti-inflammatory effect on the skin and is very effective in regulating water loss and protecting the skin from injury and damage [62]

Borage oil, both taken orally and used topically, has been used for soothing disorders such as atypical dermatitis, psoriasis, eczema, and other inflammatory skin conditions [63, 64]

Borage oil/evening primrose oil

Evening primrose oil is often used in combination with borage oil for skin benefit. It contains very high levels of GLA

The combination of borage oil and evening primrose oil is often used for the treatment of eczema [65, 66]

N-acetylglucosamine

Both glucosamine and its derivative N-acetylglucosamine are substrate precursors for the biosynthesis of polymers such as glycosaminoglycans (e.g., hyaluronic acid) and for the production of proteoglycans

Because of its ability to stimulate hyaluronic acid synthesis, N-acetylglucosamine has been shown to accelerate wound healing, improve skin hydration, and decrease wrinkles [67]

Vitamin A

Approved claim:

Vitamin A consists of a group of unsaturated nutritional organic compounds that includes retinol, retinal, retinoic acid, and several provitamin A carotenoids, among which beta-carotene is the most important. Vitamin A has multiple functions such as vision, gene transcription, immune function, embryonic development and reproduction, bone metabolism, hematopoiesis, skin and cellular health, and antioxidant activity. This vitamin can be obtained from foods of animal origin such as organ meats, fish oil, and dairy products and from plant-origin foods.

Aging may reduce the efficiency of the conversion of provitamin A carotenoids to their active form [68].

Retinoids are well known as antiaging agents. For many years this vitamin has been used for the prevention and treatment of photoaging. Retinyl palmitate (vitamin A ester) has been used in skin creams, where it is broken down to retinol and metabolized to retinoic acid, which has potent biological activity. Retinoic acid, in fact, appears to maintain normal skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells [69]. This suggests that retinoids also play a role in the prevention of aging, because of their inhibitory effects on metalloproteinases expression (which degrade collagen) [70].

Vitamin A contributes to the maintenance of normal skin and vision and to normal iron metabolism

Vitamin B3

Approved claim:

Vitamin B3, also known as niacin, is a hydrophilic endogenous substance which can have antipruritic, antimicrobial, vasoactive, photo-protective, sebostatic, and lightening effect depending on its concentration. Niacin deficiency was described some centuries ago as it was responsible for pellagra (one of the most devastating nutritional diseases) characterized by extreme weakness and crusty skin. Vitamin B3 can be found in meats, cereals and grain products, and vegetables.

Vitamin B3 is a well-tolerated and safe substance often used in cosmetics. It has been shown to protect from inflammatory dermatoses and photoaging [71]

Vitamin B3 contributes to the maintenance of normal skin and to the reduction of tiredness and fatigue

Vitamin B6

Approved claim:

Vitamin B6 is a water-soluble vitamin that is naturally present in many foods, and it is a cofactor in many cell reactions (primarily in the metabolism of amino acids but also carbohydrates and lipids). Vitamin B6 plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood. Vitamin B6 affects all aspects of metabolic function and cellular homeostasis, and it is a vitamin widely distributed in foods of plant and animal origin

Vitamin B6 contributes to normal energy-yielding metabolism and to the reduction of tiredness and fatigue

Vitamin B12

Approved claim:

Vitamin B12 is involved in:

 Nervous system maintenance

 Formation of blood

 Cell metabolism (DNA synthesis and regulation, fatty acid metabolism and amino acid metabolism).

Humans obtain vitamin B12 from products of animal origin including meats, fish, shellfish, dairy products, and eggs. Altered vitamin B12 levels are associated with dermatological manifestations such as hyperpigmentation, hair and nail changes, vitiligo, atopic dermatitis, and acne [72].

Vitamin B12 contributes to a normal function of the immune system

Vitamin C

Approved claim:

Vitamin C (L-ascorbic acid) is a powerful antioxidant and a common enzymatic cofactor in mammals used in the synthesis of collagen. It is a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). It is therefore involved into the development and maintenance of several biological systems: immune system, blood vessels, bones, gums and teeth, cell metabolism, nervous system, and skin condition. Low intakes of fresh fruits and vegetables increase the risk of scurvy (characterized by fatigue, skin spots, and bloody gums). Dietary vitamin C can aid with iron absorption. Vitamin C is widely used in cosmetic products to improve several skin parameters such as wrinkles [73, 74, 75]

Vitamin C contributes to normal collagen formation and the normal function of bones, cartilage, and skin

Vitamin D

Approved claim:

Vitamin D is responsible for enhancing intestinal absorption of calcium, iron, magnesium, phosphate, and zinc. The intake of Vitamin D can be through the diet, but mainly the body can synthesize it in the skin, from cholesterol, and with sun exposure. Sunlight exposure is the primary source of vitamin D for the majority of people. In the skin, vitamin D is produced in the two innermost layers, the stratum basale and stratum spinosum of the epidermis. One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestine, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Also other physiological systems respond to vitamin D such as the cardiovascular system, the immune system, muscle, pancreas, metabolic homeostasis, and the brain. Vitamin D reduces DNA damage, inflammation, and photo-carcinogenesis caused by UV rays, and it is very often recommended as a supplement, especially during childhood and pregnancy [76, 77]

Vitamin D contributes to normal absorption of calcium and phosphorous and maintenance of normal bones, normal muscle function, teeth, and the immune system

Vitamin E

Approved claim:

Vitamin E (or tocopherol) is a fat-soluble compound and has many biological functions: enzymatic activity, gene expression, neurological function and antioxidant function (which is the most important). It neutralizes reactive oxygen species, and as such, it protects cells and tissues from free radical damage; this is the reason why it is often used in antiaging skin creams. Vitamin E often works together with vitamin C, as the latter can help to activate vitamin E. Vitamin E works in lipid environment and halts lipid peroxidation in lipoproteins and membranes. The richest sources of vitamin E are plant oils, such as soya, corn, and olive oil. This vitamin works as a soothing and anti-inflammatory agent. In fact, vitamin E has been shown to protect the skin from chemical-induced irritation [78] and has been shown to have photo-protective effects against skin UV photodamage [79]

Vitamin E contributes to the protection of cell constituents from oxidative damage

Zinc

Approved claim:

Zinc is a trace element which has a role in catalytic, structural, and regulatory reactions. It serves as structural ions in transcription factors, and it stabilizes the tertiary structure of many proteins. Zinc is stored and transferred in metallothioneins. It is important in helping the body to make new cells, process food, and heal wounds. It also has antioxidant effects and is pivotal for the body’s resistance to infection and for tissue repair. Classic signs of zinc deficiency include reduced growth, diarrhea, skin and eye lesions, neuropsychiatric changes, and alopecia [80].

The food plants that contain the most zinc are wheat (germ and bran) and various seeds (sesame, poppy, alfalfa, celery, mustard). Zinc is also found in beans, nuts, almonds, whole grains, pumpkin seeds, sunflower seeds, and blackcurrant

Zinc contributes to the maintenance of normal skin, hair, and nails

Copper

Approved claim:

Copper is a transition metal that is vital for all eukaryotic organisms. It is involved in important biochemical reactions including cellular respiration, antioxidant defense, detoxification, blood clotting, melanin production, and connective tissue formation. Copper is part of several enzymes and proteins that are essential for an adequate use of iron by the body. Copper is required for the formation of hemoglobin, red blood cells, and bones. It also helps with the formation of collagen and elastin, making them available for wound healing. Copper is useful to maintain joint and nerve health. Copper deficiency may lead to anemia, neutropenia, hypopigmentation, and abnormalities in the skeletal, cardiovascular, and immune system. Copper is present in many common foods, including legumes (beans), grains, and nuts

Copper contributes to normal skin and hair pigmentation and protects cell constituents from oxidative damage

Biotin

Approved claim:

Biotin, also known as vitamin H, is a water-soluble B vitamin. It is an essential coenzyme for several important enzymes, and it is necessary for cell growth, energy production, and maintenance of adequate blood sugar levels. Biotin helps in the production of fatty acids and the metabolism of amino acids. It is sometimes used as part of weight reduction efforts. Proper fat production is critical for the health of the skin because fatty acids protect skin cells against damage and water loss. Biotin is often recommended as a dietary supplement for strengthening hair and nails, and it is found in many cosmetic and health products for hair and skin. Biotin deficiency may lead to developmental delay in children and to skin and hair disorders. Food rich in biotin include egg yolk, liver, and some vegetables

Biotin contributes to the maintenance of normal skin and hair

Bioperine®

Bioperine® is an extract derived from black pepper, Piper nigrum. Piperine is what gives peppers their spicy taste. This extract is marketed as a nutritional supplement, and it is believed to enhance cell bioavailability and so to increase the absorption of a variety of nutrients [81, 82]

Black pepper extract is clinically proven to increase bioavailability by 60 %

Glucosamine hydrochloride

Glucosamine is a derivative of cellular glucose metabolism. It is also a component of glycosaminoglycans and proteoglycans of the cartilage matrix, covering the ends of bones, and hyaluronic acid which is a part of the synovial fluid within the joints. The primary source of exogenous glucosamine is the exoskeleton of shellfish. It exists in primarily two formulations, glucosamine hydrochloride and glucosamine sulfate. Glucosamine hydrochloride lacks the sulfate group and has 99 % purity. Glucosamine is readily absorbed from the gastrointestinal tract with oral administration, rapidly undergoes metabolism via the liver, and is eliminated through feces and urine. Because glucosamine is a part of the cartilage matrix in joint tissues, it has been theorized for many years that its administration could affect symptomatic relief for osteoarthritis

Glucosamine and chondroitin sulfate are often used together in the treatment of osteoarthritis [83, 84, 85]

L-Carnitine

L-Carnitine is a naturally occurring compound, synthesized in the body from the essential amino acids lysine and methionine. L-carnitine is mainly found in the skeletal muscle, where it is required for the transport of fatty acids from the cytosol into the mitochondria for the beta-oxidation process. For its properties in increasing oxidative metabolism of fatty acids and muscle glycogen, supplementation of carnitine could have a potential role in muscular performance enhancement, in mental function increase and may be considered as a fat burner in weight loss diets (although all these properties need further scientific investigation)

Although the results present in literature related to the role of L-carnitine to improve energy performance are controversial, some studies have shown that this compound can positively impact the muscle recovery process after exercise, therefore allowing a more active lifestyle [86, 87]

Chondroitin sulfate

Chondroitin sulfate is a sulfated glycosaminoglycan. It is usually found attached to proteins as part of a proteoglycan. Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for the treatment of osteoarthritis

Chondroitin sulfate and glucosamine sulfate have been shown to exert beneficial effects on the metabolism of in vitro models of cells derived from synovial joints: chondrocytes, synoviocytes, and cells from subchondral bone, all of which are involved in osteoarthritis. They increase type II collagen and proteoglycan synthesis in human articular chondrocytes and are also able to reduce the production of some pro-inflammatory mediators and proteases, to reduce cellular death process, and to improve the anabolic/catabolic balance of the extracellular cartilage matrix [88].

See glucosamine hydrochloride above for other references

Resveratrol

Resveratrol is an antioxidant polyphenol found in the skin of red grapes and in other fruits. It has several benefits: cardiovascular system (via increased nitric oxide production, downregulation of vasoactive peptides, lowered levels of oxidized low-density lipoprotein, and cyclooxygenase inhibition), Alzheimer’s disease (by breakdown of beta-amyloid and direct effects on neural tissues), phytohormonal actions, anticancer properties (via modulation of signal transduction, which translates into anti-initiation, anti-promotion, and anti-progression effects), and antimicrobial effects [89]

A study showed that resveratrol helped to increase the rate of skin fibroblast proliferation and inhibited collagenase activity [90]. In fact, resveratrol is used also for skin care formulations against a wide range of cutaneous disorders including skin aging and skin cancers [91].

Also, resveratrol is responsible for epidermal homeostasis and has therefore potential cosmetic and/or dermatological applications [74]

Acai berry

The fruit of Euterpe oleracea, commonly known as acai berry, has been shown to exhibit significantly high antioxidant activity in vitro, especially as a scavenger for superoxide and peroxyl radicals, and it has therefore health benefits

Together with licorice, green tea, arbutin, soy, turmeric, and pomegranate, acai berry exhibits strong antioxidant properties, and it is among those plants and compounds found to be most beneficial to treat skin hyperpigmentation [92]

It is a natural compound often used in cosmetic dermatology [93]

Coenzyme Q10

Coenzyme Q10 (CoQ10) is an antioxidant, and it is a vitamin-like substance found throughout the body, especially in the heart, liver, kidney, and pancreas. It is present in most eukaryotic cells, primarily in the mitochondria. This molecule can exist in a completely oxidized form and a completely reduced form, and this enables it to perform its functions as an antioxidant [94]. Besides endogenous synthesis, CoQ10 is also supplied to the organism by various foods (present in small amounts in meat and seafood)

CoQ10 positively influences the age-affected cellular metabolism and helps to counteract signs of aging at the cellular level. As a consequence to topical application, CoQ10 is beneficial for human skin as it rapidly improves mitochondrial function in skin in vivo [95].

Moreover, CoQ10 has been shown to promote proliferation of fibroblasts, increase collagen expression, and reduce UVR-induced matrix metalloproteinases. It also increased elastin production, and it was shown to have depigmentation properties [96]

Pomegranate

Pomegranate is rich of polyphenols and has therefore antioxidant properties which have been shown to have health-promoting effects [97]. In fact, the oil of pomegranate contains ellagic acid, which is a natural phenol antioxidant and it is found in many fruits and is believed to have anticancer properties

Pomegranate is considered part of the botanic ingredients used in the prevention of skin aging [98]. Moreover, it was shown that ellagic acid, of which pomegranate is rich, prevented collagen destruction and inflammatory responses caused by UVB. Therefore, its dietary supplementation may be a promising treatment strategy to reduce skin wrinkling and inflammation (which come with photoaging) [99]

Lycopene

Lycopene is known to be one of the most effective antioxidants in the carotenoids family, with excellent stability and bioavailability. Its powerful antioxidant activity is effective in maintaining the strength, thickness, and fluidity of cellular membranes which form the cell external layer. Strong and healthy cellular membranes are of pivotal importance in the prevention from many diseases. Moreover, lycopene acts as an antioxidant preventing free radicals from disrupting the balance of new bone formation and bone loss that naturally occurs with age [100]

Carotenoids are widely used in the cosmetic industry as skin care products [101].

Moreover, it has been shown that β-carotene and lycopene are able to modulate skin properties when ingested as supplements or as dietary products. While they cannot be compared with sunscreen, there is evidence that they protect the skin against sunburn (solar erythema) by increasing the basal defense against UV light-mediated damage [102]

L-Carnosine

Carnosine is an endogenous free radical scavenger. It is concentrated in muscles when they are working, and it is also found in the heart, brain, and many other parts of the body. Carnosine is used to prevent aging and to prevent or treat complications of diabetes such as nerve damage, eye disorders (cataracts), and kidney problems

The latest research has indicated that apart from the function of protecting cells from oxidation-induced stress damage, carnosine is able to extend the lifespan of cultured cells, rejuvenate senescent cells, and maintain cellular homeostasis [103]. Thus, carnosine-containing products can be used in preparations to reduce skin wrinkles [104, 105]

Numerous clinical trials on PURE GOLD COLLAGEN® (patented formula) have been carried out since 2012, and as mentioned above, three clinical studies have been successfully completed and published to date [13, 14, 15].

One of these studies [13] was an open-label multicenter study conducted by 40 dermatologists who worked independently in different countries (namely, the UK, USA, UAE, Greece, and the Czech Republic). The study involved 265 healthy volunteer subjects, ingesting one bottle (50 ml) of the dietary supplement daily for 60 days. Subjects had a skin assessment before, during, and at the end of the treatment.

In summary this study showed:
  1. 1.

    Significant reduction in wrinkles and depth of nasolabial folds (Fig. 3)

     
  2. 2.

    Twelve and nineteen percent increase in collagen density after 12 weeks of treatment both in the forearm and Crows feet area (Fig. 4)

     
  3. 3.
    Significant increase in skin firmness after 80 and 130 days of treatment (Fig. 5)
    Fig. 3

    Percentage of subjects showing an improvement in wrinkles (a) and an improvement in the average score of nasolabial folds (b) after 60 days of treatment with PURE GOLD COLLAGEN®. (c) Significant and comparable decrease of nasolabial folds, after 60 days, both in subjects who underwent a specific treatment for nasolabial folds or not.

    Fig. 4

    Collagen density measurements in the left ventral forearm and in the crow’s feet area around the left eye. An increase in collagen density (12 % increase in forearm and 19 % in the crow’s feet area) is clearly visible after 12 weeks in the both areas measured.

    Fig. 5

    Increase in skin firmness after 80 and 130 days.

     

Preliminary Results Obtained with GOLD COLLAGEN® FORTE

An independent double-blind, randomized, placebo-controlled clinical trial was performed to investigate the effects of GOLD COLLAGEN® FORTE on skin elasticity in subjects who underwent a cosmetic treatment (fillers and Botox in the face) and subjects who did not while using this nutraceutical supplement.

Subjects participating in the trial were divided into two groups: 30 volunteer subjects (28 females and 2 males, between 40 and 60 years old) who consumed GOLD COLLAGEN® FORTE daily and other 30 volunteer subjects (27 females and 3 males, between 40 and 60 years old) who consumed placebo. Subjects drank one bottle (50 ml) of product daily over a period of 90 days.

DermaLab SkinLab USB elasticity module was used to measure skin elasticity on each subject forearm at baseline (day 0) and at the end of the treatment at day 90.

A self-assessment questionnaire including questions related to skin, hair, nails, joints, mood, and photoaging conditions and questions regarding the subjects’ opinion about the product was filled by each subject. The questionnaire comprised of two parts: the first section was completed by the subjects at baseline (day 0), while the second section was completed at the end of the trial (day 90).

To evaluate the efficacy of the product on skin, histological examination was performed in two subjects who took the product for 90 consecutive days. Histological exam was performed staining the sections with hematoxylin and eosin (E-E) for the assessment of skin structures and, in particular, of collagen and elastin fibers.

In summary this study showed:
  1. 1.

    Increase in skin elasticity after 90 days of treatment, Fig. 6.

    Interestingly, the overall increase in skin elasticity in the subjects taking GOLD COLLAGEN® FORTE (from 8.42 to 9.17 mm) was statistically significant (p < 0.05, T-test), and an increase in skin elasticity was observed singularly both in subjects who underwent a cosmetic treatment and subjects who did not. Moreover, no significant change in skin elasticity was observed in the placebo group, both in subjects who underwent or did not undergo a cosmetic treatment. The increase in skin elasticity suggests that this functional food supplement, containing collagen peptides among other active ingredients, has an effect in restoring the correct levels of extracellular matrix proteins such as elastin. In fact, hydrolyzed collagen has a dual action mechanism in the dermis: (1) collagen peptides and free amino acids provide building blocks for the formation of collagen and elastin fibers; (2) hydrolyzed collagen binds to receptors present on the membrane of fibroblasts and stimulates the production of new collagen, elastin, and hyaluronic acid.
    Fig. 6

    Overall increase in skin elasticity in subjects consuming GOLD COLLAGEN® FORTE versus placebo for 90 days.

     
  1. 2.

    Reduction in solar elastosis and in hyperkeratosis, Fig. 7.

    Histological sections of healthy skin (by hematoxylin-eosin staining) relative to two female subjects before and after 90 days of treatment with GOLD COLLAGEN® FORTE revealed a reduction in epidermal hyperkeratosis and of solar elastosis in the dermis.

     
  2. 3.

    Self-assessment questionnaire outcome.

    The subjects’ perception of GOLD COLLAGEN® FORTE versus placebo on skin, hair, nails, joints, and mood and their feedback about the product were further investigated. Results from the self-assessment questionnaires showed that the perception of the overall skin, hair, nails, and joints condition was dramatically improved after 90 days of treatment. Importantly, these improvements were not observed in the subjects taking placebo.

    Together with other cosmetic treatments or taken alone, daily consumption of a liquid hydrolyzed collagen-based nutritional supplement , such as GOLD COLLAGEN® FORTE, led to significant benefits in terms of efficacy and patient compliance, suggesting that hydrolyzed collagen can help counteract signs of aging and boost the effect of cosmetic treatments (Fig.6 and Fig.7).
    Fig. 7

    Skin histological sections from two patients before and after treatment with GOLD COLLAGEN® FORTE.

     

Preliminary Results Obtained with ACTIVE GOLD COLLAGEN®

An in-house clinical trial has been carried out to evaluate the effect of the systemic treatment with a hydrolyzed collagen-based nutraceutical supplement, such as ACTIVE GOLD COLLAGEN®, on collagen density, skin elasticity, and body composition in healthy and active volunteer subjects.

The study was conducted in 20 male volunteer subjects aged 20–60 years. Each subject was administered 1 × 50 ml daily dosage for a maximum of 14 weeks.

In summary this study showed:
  1. 1.

    Increase in skin elasticity, Fig. 8.

    An increase in skin elasticity was observed at 7 and 14 weeks in the subjects who were taking ACTIVE GOLD COLLAGEN® with a statistically significant improvement detected at week 14 (65% increase).

     
  2. 2.

    Increase in collagen density, Fig. 9.

    The same subjects were also measured for collagen density in the ventral forearm. In 55% of the subjects, a constant statistically significant increase was observed in the collagen density over 14 weeks.

    This study supports published literature demonstrating increased collagen production in the skin as a result of an oral treatment with collagen peptides [106].

     
  3. 3.

    Improvement in body composition and fitness level, Fig. 10.

    Body fat, muscle mass, bone density, and hydration were measured in the 20 subjects who took part in this study using Ozeri Touch II Digital Scale, a multifunction scale that provides profile-driven measurements for these parameters. A decrease in weight and body fat was detected over the 14-week treatment with ACTIVE GOLD COLLAGEN®, together with an improvement in hydration, muscle mass, and bone density (Fig. 10).

    As shown in Table 2, the resting heart rate can vary according to the fitness level and with age: the fitter a person is, generally the lower the resting heart rate. This is due to the heart getting bigger and stronger with exercise and getting more efficient at pumping blood around the body – so at rest more blood can be pumped around with each beat, and therefore, less beats per minute are required. In 55 % of the subjects, a 9 % reduction in the resting heart rate (from 71 to 64 on average) was noticed after 5 weeks (Fig. 10). According to Table 2, this means that those subjects moved from an average level (highlighted in yellow) to a good level (highlighted in cyan) of fitness, improving their performances.

    These results suggest that daily oral consumption of a dietary supplement containing collagen peptides, vitamins, and minerals, in this case ACTIVE GOLD COLLAGEN®, does lead to a detectable improvement in skin properties, such as elasticity and collagen density. Moreover, the active ingredients present in this liquid supplement have a positive effect on the level of fitness, muscle mass, bone density and decrease body fat and resting heart rate ( Fig. 8, Fig. 9, Fig. 10 and Table 2).
    Fig. 8

    Increase in skin elasticity (blue line) at 7 and 14 weeks of treatment (* = p ≤ 0.05).

    Fig. 9

    Increase in collagen density in 55 % of the subjects after 4, 8, 12, and 14 weeks of treatment.

    Fig. 10

    Effects of ACTIVE GOLD COLLAGEN® on body fat, muscle mass, bone density, hydration, and heart beat at rest.

    Table 2

    Chart relating resting heart rate and fitness level.

    Resting heart rate for men

    Age

    1825

    2635

    3645

    4655

    5665

    65+

    Athlete

    49–55

    49–54

    50–56

    50–57

    51–56

    50–55

    Excellent

    56–61

    55–61

    57–62

    58–63

    57–61

    56–61

    Good

    6265

    6265

    6366

    6467

    6267

    6265

    Above average

    66–69

    66–70

    67–70

    68–71

    68–71

    66–69

    Average

    7073

    7174

    7175

    7276

    7275

    7073

    Below average

    74–81

    75–81

    76–82

    77–83

    76–81

    74–79

    Poor

    82+

    82+

    83+

    84+

    82+

    80+

     

Conclusions

Innovation in Liquid Hydrolyzed Collagen-Based Supplementation

The novelty of nutraceutical supplements (sometimes referred to as nutricosmeceuticals) for skin care, such as GOLD COLLAGEN® products, is based on their orally ingestible formulation and the use of the highest-quality hydrolyzed collagen together with a specific blend of active ingredients that can be easily absorbed and distributed, by the bloodstream, throughout the whole body.

Many topical collagen-containing products such as creams, lotions, and serums are unable to reach the dermis to boost the production of skin collagen. This is because collagen has a large molecular size and cannot penetrate the skin surface (epidermis). A daily oral intake of a product containing hydrolyzed collagen is therefore more effective, as collagen peptides are able to reach the dermis from the inside, with no need to penetrate the epidermis. Liquid nutritional supplements are easier to swallow than a pill and work from within, in the dermis, to nourish and rejuvenate your skin.

Proven Benefits of GOLD COLLAGEN® Products

Several independent clinical trials have shown visible and significant benefits on skin, hair, and nails after daily intake of GOLD COLLAGEN® nutricosmeceutical supplements. The subjects taking these hydrolyzed collagen-based drinks also perceived an improvement in their mood and energy levels. Additional clinical trials and explorative research projects are currently in progress to further investigate the benefits and mechanisms of action of these supplements.

Nutricosmeceutical products represent an innovative and powerful tool in the fight against skin aging. It is important to underline how the interaction between the ensemble of all the ingredients present in these liquid supplements, such as GOLD COLLAGEN® products, gives these nutricosmeceuticals the ability to have a multipurpose action so to benefit not only the skin but also other structures of the connective tissue such as hair and nails, to boost the body’s energy and to contribute to the person’s general well-being. Although aging is in fact an irreversible biological process, which is mostly visible on skin, it involves the whole body leading to a slow and progressive deterioration of all human tissues, particularly cartilage in the joints. In this context, nutricosmeceutical supplements containing collagen peptides and other active ingredients, such as vitamins, minerals, and antioxidants, might appear to represent a powerful tool to slow down the aging process.

Notes

Acknowledgments

We would like to thank Dr. Martin Godfrey for his time and expertise in critically reviewing the manuscript. We would also like to thank all the dermatologists who collected the data, in particular Professor Andrea Corbo.

References

  1. 1.
    Kligman LH. Photoaging. Manifestations, prevention, and treatment. Clin Geriatr Med. 1989;5:235–51.PubMedGoogle Scholar
  2. 2.
    Guercio-Hauer C, Macfarlane DF, Deleo VA. Photodamage, photoaging and photoprotection of the skin. Am Fam Physician. 1994;50:327–32. 34.PubMedGoogle Scholar
  3. 3.
    Naylor EC, Watson RE, Sherratt MJ. Molecular aspects of skin ageing. Maturitas. 2011;69:249–56.PubMedCrossRefGoogle Scholar
  4. 4.
    Baumann L. Skin ageing and its treatment. J Pathol. 2007;211:241–51.PubMedCrossRefGoogle Scholar
  5. 5.
    Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol. 2006;126:2565–75.PubMedCrossRefGoogle Scholar
  6. 6.
    Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci. 2006;1067:10–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Benz CC, Yau C. Ageing, oxidative stress and cancer: paradigms in parallax. Nat Rev Cancer. 2008;8:875–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Van Raamsdonk JM, Hekimi S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 2009;5:e1000361.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Speakman JR, Selman C. The free-radical damage theory: accumulating evidence against a simple link of oxidative stress to ageing and lifespan. Bioessays. 2011;33:255–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Tanaka M, Koyama Y, Nomura Y. Effects of collagen peptide ingestion on UV-B-induced skin damage. Biosci Biotechnol Biochem. 2009;73:930–2.PubMedCrossRefGoogle Scholar
  11. 11.
    Shibuya S, Ozawa Y, Toda T, Watanabe K, Tometsuka C, Ogura T, Koyama Y, Shimizu T. Collagen peptide and vitamin C additively attenuate age-related skin atrophy in Sod1-deficient mice. Biosci Biotechnol Biochem. 2014;78:1212–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Yoon HS, Cho HH, Cho S, Lee SR, Shin MH, Chung JH. Supplementating with dietary astaxanthin combined with collagen hydrolysate improves facial elasticity and decreases matrix metalloproteinase-1 and -12 expression: a comparative study with placebo. J Med Food. 2014;17:810–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Borumand M, Sibilla S. Daily consumption of the collagen supplement Pure Gold Collagen(R) reduces visible signs of aging. Clin Interv Aging. 2014;9:1747–58.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Borumand M, Sibilla S. A study to assess the effect on wrinkles of a nutritional supplement containing high dosage of hydrolysed collagen. Cosmeceuticals 2014;2014:93–96.Google Scholar
  15. 15.
    Borumand M, Sibilla S. Effects of a nutritional supplement containing collagen peptides on skin elasticity, hydration and wrinkles. J Med Nutr Nutraceuticals 2015;4:47–53.Google Scholar
  16. 16.
    Freinkel RK, Woodley DT. The biology of the skin. Pantheon Publishing, USA (New York) and UK (London), 2001.Google Scholar
  17. 17.
    Wickett RR, Visscher MO. Structure and function of the epidermal barrier. Am J Infect Control. 2006;34:98–110.CrossRefGoogle Scholar
  18. 18.
    Le Fur I, Reinberg A, Lopez S, Morizot F, Mechkouri M, Tschachler E. Analysis of circadian and ultradian rhythms of skin surface properties of face and forearm of healthy women. J Invest Dermatol. 2001;117:718–24.PubMedCrossRefGoogle Scholar
  19. 19.
    Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H. Control mechanism of the circadian clock for timing of cell division in vivo. Science. 2003;302:255–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Geyfman M, Kumar V, Liu Q, Ruiz R, Gordon W, Espitia F, Cam E, Millar SE, Smyth P, Ihler A, Takahashi JS, Andersen B. Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. Proc Natl Acad Sci U S A. 2012;109:11758–63.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3:a004978.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Matsuda N, Koyama Y, Hosaka Y, Ueda H, Watanabe T, Araya T, Irie S, Takehana K. Effects of ingestion of collagen peptide on collagen fibrils and glycosaminoglycans in the dermis. J Nutr Sci Vitaminol (Tokyo). 2006;52:211–5.CrossRefGoogle Scholar
  23. 23.
    Gelse K, Poschl E, Aigner T. Collagens – structure, function, and biosynthesis. Adv Drug Deliv Rev. 2003;55:1531–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Fleischmajer R, MacDonald ED, Perlish JS, Burgeson RE, Fisher LW. Dermal collagen fibrils are hybrids of type I and type III collagen molecules. J Struct Biol. 1990;105:162–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol. 2007;127:526–37.PubMedCrossRefGoogle Scholar
  26. 26.
    Langness U, Udenfriend S. Collagen biosynthesis in nonfibroblastic cell lines. Proc Natl Acad Sci U S A. 1974;71:50–1.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Shuster S, Black MM, McVitie E. The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol. 1975;93:639–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007;81:229–40.PubMedCrossRefGoogle Scholar
  29. 29.
    Laurent TC, Fraser JR. Hyaluronan. FASEB J. 1992;6:2397–404.PubMedGoogle Scholar
  30. 30.
    Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med. 1997;242:27–33.PubMedCrossRefGoogle Scholar
  31. 31.
    Balogh L, Polyak A, Mathe D, Kiraly R, Thuroczy J, Terez M, Janoki G, Ting Y, Bucci LR, Schauss AG. Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs. J Agric Food Chem. 2008;56:10582–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Ohara H, Ichikawa S, Matsumoto H, Akiyama M, Fujimoto N, Kobayashi T, Tajima S. Collagen-derived dipeptide, proline-hydroxyproline, stimulates cell proliferation and hyaluronic acid synthesis in cultured human dermal fibroblasts. J Dermatol. 2010;37:330–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Pavicic T, Gauglitz GG, Lersch P, Schwach-Abdellaoui K, Malle B, Korting HC, Farwick M. Efficacy of cream-based novel formulations of hyaluronic acid of different molecular weights in anti-wrinkle treatment. J Drugs Dermatol. 2011;10:990–1000.PubMedGoogle Scholar
  34. 34.
    Farwick M, Gauglitz G, Pavicic T, Kohler T, Wegmann M, Schwach-Abdellaoui K, Malle B, Tarabin V, Schmitz G, Korting HC. Fifty-kDa hyaluronic acid upregulates some epidermal genes without changing TNF-alpha expression in reconstituted epidermis. Skin Pharmacol Physiol. 2011;24:210–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Oikarinen A. The aging of skin: chronoaging versus photoaging. Photodermatol Photoimmunol Photomed. 1990;7:3–4.PubMedGoogle Scholar
  36. 36.
    Varani J, Dame MK, Rittie L, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006;168:1861–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Varani J, Spearman D, Perone P, Fligiel SE, Datta SC, Wang ZQ, Shao Y, Kang S, Fisher GJ, Voorhees JJ. Inhibition of type I procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro. Am J Pathol. 2001;158:931–42.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Varani J, Perone P, Fligiel SE, Fisher GJ, Voorhees JJ. Inhibition of type I procollagen production in photodamage: correlation between presence of high molecular weight collagen fragments and reduced procollagen synthesis. J Invest Dermatol. 2002;119:122–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Varani J, Schuger L, Dame MK, Leonard C, Fligiel SE, Kang S, Fisher GJ, Voorhees JJ. Reduced fibroblast interaction with intact collagen as a mechanism for depressed collagen synthesis in photodamaged skin. J Invest Dermatol. 2004;122:1471–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992;89:10114–8.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Puizina-Ivic N. Skin aging. Acta Dermatovenerol Alp Pannonica Adriat. 2008;17:47–54.PubMedGoogle Scholar
  42. 42.
    Berneburg M, Plettenberg H, Krutmann J. Photoaging of human skin. Photodermatol Photoimmunol Photomed. 2000;16:239–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Millis AJ, Sottile J, Hoyle M, Mann DM, Diemer V. Collagenase production by early and late passage cultures of human fibroblasts. Exp Gerontol. 1989;24:559–75.PubMedCrossRefGoogle Scholar
  44. 44.
    Quan T, Little E, Quan H, Qin Z, Voorhees JJ, Fisher GJ. Elevated matrix metalloproteinases and collagen fragmentation in photodamaged human skin: impact of altered extracellular matrix microenvironment on dermal fibroblast function. J Invest Dermatol. 2013;133:1362–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Quan T, Qin Z, Xia W, Shao Y, Voorhees JJ, Fisher GJ. Matrix-degrading metalloproteinases in photoaging. J Investig Dermatol Symp Proc. 2009;14:20–4.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med. 1997;337:1419–28.PubMedCrossRefGoogle Scholar
  47. 47.
    Vayalil PK, Mittal A, Hara Y, Elmets CA, Katiyar SK. Green tea polyphenols prevent ultraviolet light-induced oxidative damage and matrix metalloproteinases expression in mouse skin. J Invest Dermatol. 2004;122:1480–7.PubMedCrossRefGoogle Scholar
  48. 48.
    El-Domyati M, Attia S, Saleh F, Brown D, Birk DE, Gasparro F, Ahmad H, Uitto J. Intrinsic aging vs. photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin. Exp Dermatol. 2002;11:398–405.PubMedCrossRefGoogle Scholar
  49. 49.
    Tanaka H, Ono Y, Nakata S, Shintani Y, Sakakibara N, Morita A. Tobacco smoke extract induces premature skin aging in mouse. J Dermatol Sci. 2007;46:69–71.PubMedCrossRefGoogle Scholar
  50. 50.
    Perricone N. The wrinkle cure: unlock the power of cosmeceuticals for supple, youthful skin. New York: Warner books; 2001.Google Scholar
  51. 51.
    Prottey C. Essential fatty acids and the skin. Br J Dermatol. 1976;94:579–85.PubMedCrossRefGoogle Scholar
  52. 52.
    Dykes PJ, Marks R, Davies MG, Reynolds DJ. Epidermal metabolism in heredopathia atactica polyneuritiformis (Refsum’s disease). J Invest Dermatol. 1978;70:126–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Lambert CA, Soudant EP, Nusgens BV, Lapiere CM. Pretranslational regulation of extracellular matrix macromolecules and collagenase expression in fibroblasts by mechanical forces. Lab Invest. 1992;66:444–51.PubMedGoogle Scholar
  54. 54.
    Oesser S, Adam M, Babel W, Seifert J. Oral administration of (14)C labeled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). J Nutr. 1999;129:1891–5.PubMedGoogle Scholar
  55. 55.
    Iwai K, Hasegawa T, Taguchi Y, Morimatsu F, Sato K, Nakamura Y, Higashi A, Kido Y, Nakabo Y, Ohtsuki K. Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates. J Agric Food Chem. 2005;53:6531–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Watanabe-Kamiyama M, Shimizu M, Kamiyama S, Taguchi Y, Sone H, Morimatsu F, Shirakawa H, Furukawa Y, Komai M. Absorption and effectiveness of orally administered low molecular weight collagen hydrolysate in rats. J Agric Food Chem. 2010;58:835–41.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen RH, Hsu C, Chung MY, Tsai WL, Liu CH. Effect of different concentrations of collagen, ceramides, n-acetyl glucosamine, or their mixture on enhancing the proliferation of keratinocytes, fibroblasts and the secretion of collagen and/or the expression of mRNA of type i collagen. J Food Drug Anal. 2008;16:66–74.Google Scholar
  58. 58.
    Matsumoto H, Ohara H, Ito K, Nakamura Y, Takahashi S. Clinical effect of fish type I collagen hydrolysate on skin properties. ITE Lett. 2006;7:386–390.Google Scholar
  59. 59.
    Ohara H, Ito K, Iida H, Matsumoto H. Improvement in the moisture content of the stratum corneum following 4 weeks of collagen hydrolysate ingestion. Nippon Shokuhin Kogaku Kaishi. 2009;56:137–145.CrossRefGoogle Scholar
  60. 60.
    Koyama Y. Effect of collagen peptide on the skin. Shokuhinto Kaihatsu. 2009;44:10–12.Google Scholar
  61. 61.
    Proksch E, Segger D, Degwert J, Schunck M, Zague V, Oesser S. Oral supplementation of specific collagen peptides has beneficial effects on human skin physiology: a double-blind, placebo-controlled study. Skin Pharmacol Physiol. 2014;27:47–55.PubMedCrossRefGoogle Scholar
  62. 62.
    Ziboh VA, Miller CC. Essential fatty acids and polyunsaturated fatty acids: significance in cutaneous biology. Annu Rev Nutr. 1990;10:433–50.PubMedCrossRefGoogle Scholar
  63. 63.
    De Spirt S, Stahl W, Tronnier H, Sies H, Bejot M, Maurette JM, Heinrich U. Intervention with flaxseed and borage oil supplements modulates skin condition in women. Br J Nutr. 2009;101:440–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Foster RH, Hardy G, Alany RG. Borage oil in the treatment of atopic dermatitis. Nutrition. 2010;26:708–18.PubMedCrossRefGoogle Scholar
  65. 65.
    Bamford JT, Ray S, Musekiwa A, van Gool C, Humphreys R, Ernst E. Oral evening primrose oil and borage oil for eczema. Cochrane Database Syst Rev. 2013;4:CD004416.PubMedGoogle Scholar
  66. 66.
    Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC. Dietary supplements for established atopic eczema. Cochrane Database Syst Rev. 2012;2:CD005205.PubMedGoogle Scholar
  67. 67.
    Murad H, Tabibian MP. The effect of an oral supplement containing glucosamine, amino acids, minerals, and antioxidants on cutaneous aging: a preliminary study. J Dermatolog Treat. 2001;12:47–51.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang Z, Yin S, Zhao X, Russell RM. Tang G: beta-Carotene-vitamin A equivalence in Chinese adults assessed by an isotope dilution technique. Br J Nutr. 2004;91:121–31.PubMedCrossRefGoogle Scholar
  69. 69.
    Fuchs E, Green H. Regulation of terminal differentiation of cultured human keratinocytes by vitamin A. Cell. 1981;25:617–25.PubMedCrossRefGoogle Scholar
  70. 70.
    Fisher GJ, Talwar HS, Lin J, Voorhees JJ. Molecular mechanisms of photoaging in human skin in vivo and their prevention by all-trans retinoic acid. Photochem Photobiol. 1999;69:154–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Surjana D, Damian DL. Nicotinamide in dermatology and photoprotection. Skinmed. 2011;9:360–5.PubMedGoogle Scholar
  72. 72.
    Brescoll J, Daveluy S. A review of vitamin B12 in dermatology. Am J Clin Dermatol. 2015;16:27–33.PubMedCrossRefGoogle Scholar
  73. 73.
    Tran D, Townley JP, Barnes TM, Greive KA. An antiaging skin care system containing alpha hydroxy acids and vitamins improves the biomechanical parameters of facial skin. Clin Cosmet Investig Dermatol. 2015;8:9–17.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Lorencini M, Brohem CA, Dieamant GC, Zanchin NI, Maibach HI. Active ingredients against human epidermal aging. Ageing Res Rev. 2014;15:100–15.PubMedCrossRefGoogle Scholar
  75. 75.
    Fitzpatrick RE, Rostan EF. Double-blind, half-face study comparing topical vitamin C and vehicle for rejuvenation of photodamage. Dermatol Surg. 2002;28:231–6.PubMedGoogle Scholar
  76. 76.
    Gordon-Thomson C, Tongkao-on W, Song EJ, Carter SE, Dixon KM, Mason RS. Protection from ultraviolet damage and photocarcinogenesis by vitamin D compounds. Adv Exp Med Biol. 2014;810:303–28.PubMedGoogle Scholar
  77. 77.
    Leccia MT. Skin, sun exposure and vitamin D: facts and controversies. Ann Dermatol Venereol. 2013;140:176–82.PubMedCrossRefGoogle Scholar
  78. 78.
    Schempp CM, Meinke MC, Lademann J, Ferrari Y, Brecht T, Gehring W. Topical antioxidants protect the skin from chemical-induced irritation in the repetitive washing test: a placebo-controlled, double-blind study. Contact Dermatitis. 2012;67:234–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Wu Y, Zheng X, Xu XG, Li YH, Wang B, Gao XH, Chen HD, Yatskayer M, Oresajo C. Protective effects of a topical antioxidant complex containing vitamins C and E and ferulic acid against ultraviolet irradiation-induced photodamage in Chinese women. J Drugs Dermatol. 2013;12:464–8.PubMedGoogle Scholar
  80. 80.
    Aggett PJ. Severe zinc deficiency. In: Colin F. Mills (ed.) Zinc in human biology. International Life Sciences Institute, Springer, London, 1989:259–79.Google Scholar
  81. 81.
    Umesh K Patil, Amrit Singh, Anup K Chakraborty. Role of piperine as a bioavailability enhancer. Int J Recent Adv Pharm Res. 2011;4:16–23.Google Scholar
  82. 82.
    Johnson JJ, Nihal M, Siddiqui IA, Scarlett CO, Bailey HH, Mukhtar H, Ahmad N. Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res. 2011;55:1169–76.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Henrotin Y, Lambert C. Chondroitin and glucosamine in the management of osteoarthritis: an update. Curr Rheumatol Rep. 2013;15:361.PubMedCrossRefGoogle Scholar
  84. 84.
    Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham 3rd CO, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008;58:3183–91.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, Bradley JD, Bingham 3rd CO, Weisman MH, Jackson CG, Lane NE, Cush JJ, Moreland LW, Schumacher Jr HR, Oddis CV, Wolfe F, Molitor JA, Yocum DE, Schnitzer TJ, Furst DE, Sawitzke AD, Shi H, Brandt KD, Moskowitz RW, Williams HJ. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795–808.PubMedCrossRefGoogle Scholar
  86. 86.
    Wachter S, Vogt M, Kreis R, Boesch C, Bigler P, Hoppeler H, Krahenbuhl S. Long-term administration of L-carnitine to humans: effect on skeletal muscle carnitine content and physical performance. Clin Chim Acta. 2002;318:51–61.PubMedCrossRefGoogle Scholar
  87. 87.
    Huang A, Owen K. Role of supplementary L-carnitine in exercise and exercise recovery. Med Sport Sci. 2012;59:135–42.PubMedCrossRefGoogle Scholar
  88. 88.
    Henrotin Y, Marty M, Mobasheri A. What is the current status of chondroitin sulfate and glucosamine for the treatment of knee osteoarthritis? Maturitas. 2014;78:184–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Baxter RA. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol. 2008;7:2–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Giardina S, Michelotti A, Zavattini G, Finzi S, Ghisalberti C, Marzatico F. [Efficacy study in vitro: assessment of the properties of resveratrol and resveratrol + N-acetyl-cysteine on proliferation and inhibition of collagen activity]. Minerva Ginecol. 2010;62:195–201.PubMedGoogle Scholar
  91. 91.
    Ndiaye M, Philippe C, Mukhtar H, Ahmad N. The grape antioxidant resveratrol for skin disorders: promise, prospects, and challenges. Arch Biochem Biophys. 2011;508:164–70.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Fowler Jr JF, Woolery-Lloyd H, Waldorf H, Saini R. Innovations in natural ingredients and their use in skin care. J Drugs Dermatol. 2010;9:S72–81; quiz s2-3.PubMedGoogle Scholar
  93. 93.
    Baumann L, Woolery-Lloyd H, Friedman A. “Natural” ingredients in cosmetic dermatology. J Drugs Dermatol. 2009;8:s5–9.PubMedGoogle Scholar
  94. 94.
    Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol Biotechnol. 2007;37:31–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Prahl S, Kueper T, Biernoth T, Wohrmann Y, Munster A, Furstenau M, Schmidt M, Schulze C, Wittern KP, Wenck H, Muhr GM, Blatt T. Aging skin is functionally anaerobic: importance of coenzyme Q10 for anti aging skin care. Biofactors. 2008;32:245–55.PubMedCrossRefGoogle Scholar
  96. 96.
    Zhang M, Dang L, Guo F, Wang X, Zhao W, Zhao R. Coenzyme Q(10) enhances dermal elastin expression, inhibits IL-1alpha production and melanin synthesis in vitro. Int J Cosmet Sci. 2012;34:273–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Mertens-Talcott SU, Jilma-Stohlawetz P, Rios J, Hingorani L, Derendorf H. Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum l.) polyphenols after ingestion of a standardized extract in healthy human volunteers. J Agric Food Chem. 2006;54:8956–61.PubMedCrossRefGoogle Scholar
  98. 98.
    Suggs A, Oyetakin-White P, Baron ED. Effect of botanicals on inflammation and skin aging: analyzing the evidence. Inflamm Allergy Drug Targets. 2014;13:168–76.PubMedCrossRefGoogle Scholar
  99. 99.
    Bae JY, Choi JS, Kang SW, Lee YJ, Park J, Kang YH. Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation. Exp Dermatol. 2010;19:e182–90.PubMedCrossRefGoogle Scholar
  100. 100.
    Rao LG, Krishnadev N, Banasikowska K, Rao AV. Lycopene I – effect on osteoclasts: lycopene inhibits basal and parathyroid hormone-stimulated osteoclast formation and mineral resorption mediated by reactive oxygen species in rat bone marrow cultures. J Med Food. 2003;6:69–78.PubMedCrossRefGoogle Scholar
  101. 101.
    Schagen SK, Zampeli VA, Makrantonaki E, Zouboulis CC. Discovering the link between nutrition and skin aging. Dermatoendocrinology. 2012;4:298–307.CrossRefGoogle Scholar
  102. 102.
    Stahl W, Heinrich U, Aust O, Tronnier H, Sies H. Lycopene-rich products and dietary photoprotection. Photochem Photobiol Sci. 2006;5:238–42.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang AM, Ma C, Xie ZH, Shen F. Use of carnosine as a natural anti-senescence drug for human beings. Biochemistry (Mosc). 2000;65:869–71.Google Scholar
  104. 104.
    Babizhayev MA, Deyev AI, Savel’yeva EL, Lankin VZ, Yegorov YE. Skin beautification with oral non-hydrolized versions of carnosine and carcinine: effective therapeutic management and cosmetic skincare solutions against oxidative glycation and free-radical production as a causal mechanism of diabetic complications and skin aging. J Dermatolog Treat. 2012;23:345–84.PubMedCrossRefGoogle Scholar
  105. 105.
    Kaczvinsky JR, Griffiths CE, Schnicker MS, Li J. Efficacy of anti-aging products for periorbital wrinkles as measured by 3-D imaging. J Cosmet Dermatol. 2009;8:228–33.PubMedCrossRefGoogle Scholar
  106. 106.
    Schwartz SR, Park J. Ingestion of BioCell Collagen((R)), a novel hydrolyzed chicken sternal cartilage extract; enhanced blood microcirculation and reduced facial aging signs. Clin Interv Aging. 2012;7:267–73.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Minerva Research Labs LtdLondonUK

Personalised recommendations