**1. Introduction**

Damage caused by excessive, long-term sun exposure contributes to signs of ageing and is most readily recognizable on our external surface, the skin. The damaging effects of the sun are mainly caused by ultraviolet radiation (UVR) which, on earth, consists of UVA (320 to 400 nm) and UVB (280 to 320 nm). The third type of UV radiation, UVC, also called short‐ wave or ionizing radiation, is absorbed by gasses in our atmosphere, does not reach the earth's surface and does not normally contribute to photodamage of skin. Ozone is one of the gases that absorbs UVC – fortunately, since UVC's ionizing effects can significantly alter cellular structures and molecules. Although UVB and UVA radiation does not have enough energy to ionize atoms, it can alter chemical bonds in molecules, thus altering their structure and functions. Skin cells are particularly susceptible to alterations mediated principally by the creation of free radicals and oxidative stress and changes in DNA structure can result in constitutive expression of protocongenes and ultimately the development of cancerous skin lesions.

Through its changes of molecular structures, UV radiation causes a series of biochemical and structural changes in skin tissues. Some of these effects, such as the induction of vitamin D production, are actually very beneficial to skin health. Niels Ryberg Finsen, a Danish physician and scientist, was one of the first to show that light can be both beneficial and det‐ rimental to human skin and his works *Om Lysets Indvirkninger paa Huden* ("On the effects of light on the skin"), published in 1893 and *Om Anvendelse i Medicinen af koncentrerede kemiske Lysstraaler* ("The use of concentrated chemical light rays in medicine"), published in 1896 cre‐ ated the paradigm on which photoaging and photodamage research was based for the next fifty years. Finsen won the Nobel Prize in Physiology in 1903 for his work on phototherapy in which he showed that certain wavelengths of light (UV in particular) could treat *lupus*

© 2013 Kulka; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*vulgaris*, cutaneous tuberculosis. However, UV radiation can also initiate some deleterious effects that fundamentally change the structure and function of the skin and its constituent components. In fact, it has been shown that repeated, excessive sun exposure can initiate and perpetuate an inflammatory response that, given time, causes breakdown of the skin's immunological functions.

This review will focus on the effects of sun exposure on the skin microenvironment – partic‐ ularly the structural proteins and immune cells that are key players in the skin's protective functions. There is sufficient evidence to suggest that photodamage is associated with a low level of chronic inflammation that ultimately breaks down the skin's structure and results in some of the manifestations of skin aging. Consequently, skin treatments that target these processes are primarily focused on rebuilding the skin's architecture and promoting its bio‐ chemical regeneration. While some treatments have been found to have some beneficial ef‐ fects to the underlying cellular immune systems regulating skin inflammation and regeneration, others may, in fact, be deleterious to these processes. In this review, I will dis‐ cuss some naturally-derived bioactive compounds and formulations that have been shown or are suggested to be effective at modulating the pathophysiological changes associated with photodamage and photoaging. Bioactive compounds that can address these immuno‐ logical changes are uniquely poised to not only reduce the damage associated with photo‐ damage but may ultimately improve the resiliency and protective nature of the skin surface.

### **2. Skin is a protective organ**

#### **2.1. The three layers of defense**

Healthy human skin is an important physical barrier to the environment and protects the body from a variety of insults. It is the largest human organ and comprises approximately 15 percent of a person's body weight and covers about 1.5 to 2.0 m2 of our surface area. Skin is mainly composed of water (70%), protein (25%) and lipids (2%) forming an effective barri‐ er to dehydration, pathogens and mechanical insults such as abrasion. In a mechanical sense, the main function of the skin is to serve as a protective barrier to keep good things in (water, nutrients and heat) and keep bad things out (pathogens, UV radiation, toxins).

In order to understand the essential functions of the skin, it is important to review the com‐ plexity of this large organ. The skin is composed of three main layers, the uppermost epider‐ mis, the lower dermis and the hypodermis (Fig. 1). Each of these layers is composed of a specific set of cells that perform an essential function in that layer. The epidermis contains keratinocytes, melanocytes and Langerhans cells which are critical for the structural and functional integrity of the epidermis. Keratinocytes are the major population of cells and originate in the bottom-most stem-cell pool in the stratum spinosum (Fig. 1). The epidermis itself is composed of five layers: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. The uppermost layer of the skin, the keratinous stra‐ tum corneum, renews itself every 3-5 weeks and is principally composed of dead keratino‐ cytes (see section below on keratinocytes for more detail). Keratinocytes have the capacity to renew themselves every 4 weeks but this process can be increased during injury or inflam‐ mation. The underlying dermis is a vascularized, connective tissue containing nerve end‐ ings, glands and lymphatic vessels and provides structural and nutritional support to the upper epidermal cells. The dermis is, in fact, the a mucopolysaccharide matrix composed of collagen and elastin fibers. In this layer, there is a great variety of cells including mast cells, fibroblasts, macrophages and Langerhans cells all of which contribute to the immune re‐ sponse observed in some skin pathologies such as atopic dermatitis. These cells also main‐ tain and regulate the essential healthy functions of skin such as repairing injury, preventing infection, regulating circulation, preventing dehydration and providing nutrition. Beneath the dermis is the superficial fascia, or hypodermis, which is comprised primarily of fat tis‐ sue.

*vulgaris*, cutaneous tuberculosis. However, UV radiation can also initiate some deleterious effects that fundamentally change the structure and function of the skin and its constituent components. In fact, it has been shown that repeated, excessive sun exposure can initiate and perpetuate an inflammatory response that, given time, causes breakdown of the skin's

256 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

This review will focus on the effects of sun exposure on the skin microenvironment – partic‐ ularly the structural proteins and immune cells that are key players in the skin's protective functions. There is sufficient evidence to suggest that photodamage is associated with a low level of chronic inflammation that ultimately breaks down the skin's structure and results in some of the manifestations of skin aging. Consequently, skin treatments that target these processes are primarily focused on rebuilding the skin's architecture and promoting its bio‐ chemical regeneration. While some treatments have been found to have some beneficial ef‐ fects to the underlying cellular immune systems regulating skin inflammation and regeneration, others may, in fact, be deleterious to these processes. In this review, I will dis‐ cuss some naturally-derived bioactive compounds and formulations that have been shown or are suggested to be effective at modulating the pathophysiological changes associated with photodamage and photoaging. Bioactive compounds that can address these immuno‐ logical changes are uniquely poised to not only reduce the damage associated with photo‐ damage but may ultimately improve the resiliency and protective nature of the skin surface.

Healthy human skin is an important physical barrier to the environment and protects the body from a variety of insults. It is the largest human organ and comprises approximately 15 percent of a person's body weight and covers about 1.5 to 2.0 m2 of our surface area. Skin is mainly composed of water (70%), protein (25%) and lipids (2%) forming an effective barri‐ er to dehydration, pathogens and mechanical insults such as abrasion. In a mechanical sense, the main function of the skin is to serve as a protective barrier to keep good things in (water, nutrients and heat) and keep bad things out (pathogens, UV radiation, toxins).

In order to understand the essential functions of the skin, it is important to review the com‐ plexity of this large organ. The skin is composed of three main layers, the uppermost epider‐ mis, the lower dermis and the hypodermis (Fig. 1). Each of these layers is composed of a specific set of cells that perform an essential function in that layer. The epidermis contains keratinocytes, melanocytes and Langerhans cells which are critical for the structural and functional integrity of the epidermis. Keratinocytes are the major population of cells and originate in the bottom-most stem-cell pool in the stratum spinosum (Fig. 1). The epidermis itself is composed of five layers: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. The uppermost layer of the skin, the keratinous stra‐ tum corneum, renews itself every 3-5 weeks and is principally composed of dead keratino‐ cytes (see section below on keratinocytes for more detail). Keratinocytes have the capacity to

immunological functions.

**2. Skin is a protective organ**

**2.1. The three layers of defense**

**Figure 1.** Structure of skin. Skin is comprised of three main layers as shown. The epidermis contains keratinocytes, mel‐ anocytes and Langerhans cells which are critical for the structural and functional integrity of the epidermis. The epi‐ dermis itself is composed of five layers: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. The strata granulosum, spinosum and basale all contain keratinocytes whereas the strata cor‐ neum and lucidum have only dead keratinized cells. The underlying dermis is a vascularized, connective tissue contain‐ ing nerve endings, glands and lymphatic vessels. Beneath the dermis is the superficial fascia, or hypodermis, which is comprised primarily of fat tissue.

#### **2.2. Melanin and melanogenesis — A protective response**

As a result of its optical properties, the stratum corneum scatters photons and reflects UV radiation, providing some degree of protection. However, a portion of UV radiation pene‐ trates this uppermost layer and can potentially damage the delicate structures beneath. Mel‐ anin plays an important role in the skin's function as a protective barrier by absorbing UV radiation and thus protecting the underlying cells from DNA damage. The word melanin comes from the Greek word *melan*, meaning black. Melanin is a polymeric pigment derived from tyrosine and, in humans, it is synthesized in two main forms: the brown/black eumela‐ nin and the cysteine-rich red/brown pheomelanin. The chemical structures of these two types of melanin are different resulting in different properties and functions (Fig. 2). Where‐ as eumelanin is composed of dihydroxyindole carboxylic acids, pheomelanin is a polymer of benxothiazine units. The carboxylic structure may account for pheomelanin's weak shield‐ ing capacity against ultraviolet radiation relative to eumelanin. In fact, pheomelanin has been shown to amplify UVA-induced reactive oxygen species (ROS)[1]. For this reason, pheomelanin is sometimes referred to as a UV-sensitizer and in some instances has been considered to have a weak carcinogenic effect in terms of melanoma formation.

**Figure 2.** Chemical structure of eumelanin and pheomelanin.

Melanogenesis refers to the biochemical process by which melanin is formed. Melanocytes are the principal cell type responsible for the production and distribution of melanin in the skin. Since melanocyte differentiation and proliferation is linked very closely with their abil‐ ity to produce melanin, melanogenesis is sometimes used to describe the process of melano‐ cyte viability and reproduction. Indeed, many cosmetic products on the market that profess to alter or manipulate melanogenesis are actually cytotoxic to melanocyte and by killing healthy melanocytes they indirectly decrease the amount of melanin in the human epider‐ mis. For example, hydroquinone (HQ), which is an U.S. Food and Drug Administration (FDA) -approved product, is used in 2 – 4 percent concentration as a skin-lightening agent but is considered to be cytotoxic to melanocytes[2]. Interestingly, some antibiotics used to treat ear infections, such as amikacin, are cytotoxic to melanocytes as well and one of its principal side-effects is ototoxicity[3].

anin plays an important role in the skin's function as a protective barrier by absorbing UV radiation and thus protecting the underlying cells from DNA damage. The word melanin comes from the Greek word *melan*, meaning black. Melanin is a polymeric pigment derived from tyrosine and, in humans, it is synthesized in two main forms: the brown/black eumela‐ nin and the cysteine-rich red/brown pheomelanin. The chemical structures of these two types of melanin are different resulting in different properties and functions (Fig. 2). Where‐ as eumelanin is composed of dihydroxyindole carboxylic acids, pheomelanin is a polymer of benxothiazine units. The carboxylic structure may account for pheomelanin's weak shield‐ ing capacity against ultraviolet radiation relative to eumelanin. In fact, pheomelanin has been shown to amplify UVA-induced reactive oxygen species (ROS)[1]. For this reason, pheomelanin is sometimes referred to as a UV-sensitizer and in some instances has been

258 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

considered to have a weak carcinogenic effect in terms of melanoma formation.

Melanogenesis refers to the biochemical process by which melanin is formed. Melanocytes are the principal cell type responsible for the production and distribution of melanin in the skin. Since melanocyte differentiation and proliferation is linked very closely with their abil‐ ity to produce melanin, melanogenesis is sometimes used to describe the process of melano‐ cyte viability and reproduction. Indeed, many cosmetic products on the market that profess to alter or manipulate melanogenesis are actually cytotoxic to melanocyte and by killing healthy melanocytes they indirectly decrease the amount of melanin in the human epider‐ mis. For example, hydroquinone (HQ), which is an U.S. Food and Drug Administration (FDA) -approved product, is used in 2 – 4 percent concentration as a skin-lightening agent but is considered to be cytotoxic to melanocytes[2]. Interestingly, some antibiotics used to

**Figure 2.** Chemical structure of eumelanin and pheomelanin.

One of the most obvious and controversial side-effects of exposing our skin to UV radiation is an increase in skin pigmentation. Certainly the issue of tanning and tanning beds has re‐ cently gained a great deal of attention because it has been shown that exposure to prolonged UV radiation (either from tanning beds or outside exposure) can cause melanoma and an effort is underway to limit the amount of time that people, especially children, spend tan‐ ning in any setting. The process of tanning is a protective mechanism and the skin's way of protecting its internal biochemical reactions from UV damage. Increased pigmentation is caused by increased production of melanin which is able to absorb some UV radiation and thus protect more sensitive biological pathways in the cell[4]. Epidemiological studies have shown that people who have high levels of constitutive pigment in their skin and are able to "tan well" are less likely to develop skin cancer[5], [6].

We still do not fully understand the precise mechanisms that initiate the malignancies asso‐ ciated with skin cancer and we certainly have an incomplete understanding of how photo‐ damage and repair functions in people of different skin colors. However, mouse models and human studies have shown that albinos have a lower incidence of melanoma than their fair skinned counterparts[7] suggesting that melanin cannot just function as a protective UV-en‐ ergy absorber. Recently, several groups have shown that melanin, especially pheomelanin (a yellow/red form of melanin), acts as a potent UVB photosensitizer to induce DNA damage and cause apoptosis in mouse skin. These groups believe that pheomelanin contributes to UV-induced DNA damage that is incompletely repaired. They further believe that this DNA damage maps to specific sequences of BRAF and N-RAS genes, both of which are frequently mutated in human melanoma[8], [9].

Some organic and inorganic compounds mimic the effects of melanin by absorbing or scat‐ tering UVR due to their particulate nature – often in the nanoscale. These chemicals are processed and made available as lotions, sprays, gels or other topical applications common‐ ly known as sunscreens. There are 17 different chemicals that have been approved by the U.S. FDA as active ingredients in sunscreens. Oxybenzone (benzopehone-3) is the most widely used sunscreen chemical worldwide but other chemicals include octinoxate, avoben‐ zone, and octyl salicylate. Some of the physical sunscreens are micro or nano-ionized to cre‐ ate particulate formulations capable of forming a protective UV barrier on the skin's surface. Titanium dioxide (TiO2) are often used as a inorganic protective sunscreens in cosmetic products and to adjust their protective factor (SPF), they are often coupled with organic chemicals such as p-amino benzoic acid (PABA) which absorbs UVB but not UVA radiation. Recently, some have suggested that these nanoparticles (NP; around 200 nm) may penetrate the skin and modify the skin's immune-environment. However, several groups have shown that although nanoparticles are unable to penetrate healthy, intact human epidermis[10] they can significantly disturb cell functions through direct contact when the skin barrier is compromised[11], [12]. In fact, NP can reach the epidermal layer via hair follicles in certain circumstances such as laser-treatment[13] or inflammation[14], [15] but most compounds, al‐ though targeting the follicular region, do not permeate past the pilosebaceous region[16].
