ReviewOxidation events and skin aging
Introduction
In the twenty-first century, the average age of the population all over the world is still rising, especially in the industrialized countries (World Population Ageing: 1950–2050, United Nations Population Division). The consequences of human aging are predominantly visible in the skin, as increased wrinkling, sagging, and increased laxity of the skin (Jenkins, 2002). Often considered as undesirable for cosmetic reasons, skin aging is also associated with physical disorders of the skin as discussed in this review. There has always been a fascination for conserving youth. People invest much time and money in rejuvenation procedures, of which many lack proven efficacy (Zouboulis and Makrantonaki, 2011).
It has been suggested that aged skin has a disturbed barrier function, resulting in a dry appearance of the skin and an enhanced risk on skin disorders (Hashizume, 2004). Another health drawback is the enhanced risk on malignancies (Goukassian and Gilchrest, 2004). Knowledge about the mechanisms of skin aging is important to develop better skin care products that slow down skin aging and reduce the hazardous effects of aging (Farage et al., 2008, Elsner et al., 2011).
Aging of the skin is induced by both intrinsic, and extrinsic factors (Farage et al., 2008, Landau, 2007), all leading to reduced structural integrity and loss of physiological function (Landau, 2007). Typical extrinsic factors for skin aging are UV-exposure and smoking (Farage et al., 2008, Bernhard et al., 2007). This review describes the central role of oxidative processes in the initiating – and often prolonged – events of aging. Most other aging-contributing events, such as mitochondrial dysfunction, altered intracellular communication, genomic instability, cellular senescence and breakdown of the extracellular matrix (ECM) are a consequence of these oxidative processes.
Intrinsic aging affects all skin areas. Intrinsically aged skin is thin, transparent and dry, shows fine wrinkles and irregular hair growth, is unable to sweat sufficiently, and suffers from loss of subcutaneous fat tissue, leading to hollowed cheeks and eye sockets, insufficient perspiration, and thinning of nail plates (Sjerobabski-Masnec and Situm, 2010). These symptoms may vary per body site. It has been observed that the intrinsic aging process differs per ethnic group (Davis and Callender, 2011), probably caused by the degree of pigmentation, and possibly more not yet identified contributing factors. Skin that is aged only by intrinsic factors does actually not exist. Individuals that live strictly indoor all their life, may have a close approximation to that skin status. In general, individuals carry skin that reflects various stages of extrinsic aging, superimposed on the level of intrinsic aging.
Reactive oxygen species (ROS) play an important role in skin aging. In the skin, about 1.5–5% of the consumed oxygen is converted into ROS by intrinsic processes (Poljsak et al., 2012). ROS are continuously produced as side products in the electron transport chain of the aerobic metabolism in the mitochondria, and are regarded as the main cause of intrinsic aging (Farage et al., 2008). Keratinocytes and fibroblasts are the main producers of ‘mitochondrial’ ROS in the skin. A ROS that is predominantly formed in mitochondria from ground state oxygen, is the reactive superoxide anion radical (
O2−) by the addition of an electron to each oxygen (O2) molecule (Fig. 1). Abundant generation of superoxide anions, as ROS-particles, may harm cellular function. Recent experimental evidence however shows that moderate levels of ROS have a useful signaling function, especially when superoxide anions are converted into hydrogen peroxide (Section 5).
Manganese superoxide dismutase (MnSOD) is the primary mitochondrial neutralizer of continuously produced superoxide anions. Other forms of SOD exist outside the mitochondria, but only MnSOD has been shown to be essential for the survival of aerobic life (St Clair and Kasarskis, 2003). Genetic polymorphisms of the human (Mn)SOD gene and the corresponding alterations in the mature enzyme have been identified. The alterations lead to aberrant efficiencies of the Mn-SOD enzyme (St Clair and Kasarskis, 2003). Consequently, these polymorphisms may largely determine the natural ability of the cells to neutralize superoxide anions, and the ability to withstand degeneration of (skin) tissue. The variation in genotypes may partially explain the differences in aging conditions among individuals of the same age. The effect of excess of superoxide anions on aging has been shown in Tet-mev-1 mice, which have mutations in mitochondrial complex II subunits and overproduction of superoxide anions. These mice show excessive apoptosis, which led to low birth weight, growth retardation, precocious aging and other pathologies (Ishii et al., 2011).
Two other main events associated with intrinsic skin aging are a decrease in replicative ability of cells and increased degradation of the extracellular matrix. The replicative ability of all dividing cells decreases with time. In the skin, this particularly affects keratinocytes, fibroblasts and melanocytes. This process is called cellular senescence. Senescent, non-dividing cells are found in higher levels in aged skin (Dimri et al., 1995). The process of cellular senescence is related to the maximum number of cell divisions that somatic cells can undergo. With each division, a small fragment of the telomere, is lost at the chromosome ends. After 25 to 30 divisions, telomeres become critically short, and the DNA loss during subsequent cell divisions can affect areas of essential genes and lead to loss of somatic cell function. In germ cells, the telomerase enzyme prevents this fate by adding six-nucleotide repeats TTAGGG to the 3′ end of DNA strands to the telomere region of chromosomes upon each cell division.
The other factor involved in skin aging is the increased expression of enzymes that degrade the extracellular matrix (ECM) of the dermis upon aging. An increase in matrix metalloproteinase (MMP) expression has been shown in senescent fibroblasts while the expression of the MMP inhibitors (TIMP) is reduced (Millis et al., 1992). These events may be triggered by ROS and can be reduced by antioxidants, such as quercetin (Lee et al., 2013). Moreover, gradual oxidative damage during life to DNA bases in genes coding for the dermal matrix components collagen and elastin leads to their reduced expression in aged skin (Uitto, 1979).
Extrinsic aging is caused by environmental oxidative factors, such as solar radiation (Gilchrest, 1989, Kligman and Kligman, 1986, Wlaschek et al., 2001), cigarette smoke (Bernhard et al., 2007) or other pollution factors. An epidemiological study revealed that long term contact with tobacco smoke and UVA-exposure both independently caused accelerated skin aging (Yin et al., 2001). These factors add to intrinsic aging. Exposure to UV radiation is the primary factor of extrinsic skin aging, also referred as to photoaging. The degeneration of the skin by UV radiation is a cumulative process and the rate of degeneration depends on the frequency, duration and intensity of solar exposure and the natural protection by skin pigmentation (Ortonne, 2002).
Photoaging accounts for as much as 80% of facial aging (Friedman, 2005). Photo-aged skin is characterized by deep wrinkling, loss of elasticity, dryness, laxity, rough-textured appearance, teleangiectasies and pigmentation disorders (Fig. 2) and its appearance is quite distinct from predominantly intrinsically aged skin (Farage et al., 2008, Fisher et al., 2002). The severity of photoaging also depends on the skin type, being more prominent in fair skin individuals (skin types I and II) and less noticeable in people with skin type III or higher (Situm et al., 2010, Davis and Callender, 2011). Thus, the severity of photoaging primarily depends on the cumulative dose of UV exposure received and on the pigmentation status of the skin. The aged appearance of photodamaged skin is specifically caused by damage to the structural components of the connective tissue of the dermis. The connective tissue is produced by fibroblasts and is composed of three major classes of biomolecules: glucosaminoglycans (GAGs), proteoglycans, structural proteins (collagen and elastin) and special macromolecules (fibrillin, fibronectin, laminin and hyaluronan) (Naylor et al., 2011, Uitto, 2008). During the last decades, extensive progress has been made understanding the molecular changes in photoaged skin. This review describes the direct and indirect effects of UV radiation on epidermal and dermal structures in relation to aging and the role of oxidative events herein. Although triggered by different factors, intrinsic aging and extrinsic aging partly involve similar molecular pathways (Gilchrest, 1989).
Section snippets
Global situation
Solar UV radiation that reaches the earth's surface has a wavelength range from 290 to 400 nm. Solar ultraviolet radiation is divided into three categories according to their wavelength, including UVA (320–400 nm), UVB (290–320 nm) and UVC (200–290 nm). Considering that solar radiation of wavelengths <290 nm do virtually not reach the earth, 290 nm represents a relevant wavelength limit for UV exposure on earth, whereas the distinction between UVB and UVA at 320 nm, (some authors refer to 315 nm) is an
Oxidants
UV radiation can induce biological damage and accelerate aging through indirect pathways with endogenous or exogenous photosensitizers that absorb UVA and even visible (VIS) wavelengths of radiation from the sun or artificial sources. Consequences are the generation of singlet oxygen or direct photochemical changes to biomolecules. UVA and VIS radiation are less absorbed by epidermal components and hence penetrate deeper, into the dermis. UVA and VIS can create excited states of the
UV-induced damage to skin connective tissue
As a result of chronic UV exposure, most visible damage occurs in the connective tissue, also referred to as the dermal extracellular matrix (ECM). The most important and abundant structures of the dermal ECM are collagen, elastin and glycosaminoglycanes (GAGs). Their main functions are to maintain the strength, elasticity and hydration of the skin (Oxlund and Andreassen, 1980). In both intrinsic and extrinsic aging, qualitative and quantitative changes in these structures are observed. This
Relation between exposure to ROS and aging
The collected evidence for damage and degeneration by oxidative events during aging raises the question: do we live shorter when massive oxidative degeneration to tissue occurs? Results from animal experiments relating oxidative stress (the ‘free radical theory’) to aging and life span (Bakaev and Lyudmila, 2002, Chang et al., 2012, Dai et al., 2009, Ishii et al., 1998, Ishii et al., 2011, Kim et al., 2008, Melov et al., 2000, Quick et al., 2008, Schriner et al., 2005, Shibamura et al., 2009)
Discussion and conclusions
In this review evidence is collected that multiple oxidation pathways lead to degeneration and aging. Several studies from approximately 2006 have dampened the relevance of the ‘free radical damage theory of aging’, as also outlined in this review. The correlation between elevated oxidative stress conditions and lifespan is dependent on the extent of local ROS-levels induced. Tissue degeneration, inherently linked to aging, becomes more significant through the lack of tissue regeneration. An
Acknowledgement
The authors wish to thank Ms. A. van Lier for her initial literature search on this subject and prof. Dr. J.D. Bos for critical reading of the manuscript.
References (149)
- et al.
Oxidative and nitrosative modifications of tropoelastin prevent elastic fiber assembly in vitro
J. Biol. Chem.
(2010) - et al.
The metabolism and function of urocanic acid in skin
J. Invest. Dermatol.
(1967) - et al.
Increased sensitivity of histidinemic mice to UVB radiation suggests a crucial role of endogenous urocanic acid in photoprotection
J. Invest. Dermatol.
(2011) Metabolism of 8-iso-prostaglandin F2alpha
FEBS Lett.
(1998)- et al.
Protein oxidation in aging, disease, and oxidative stress
J. Biol. Chem.
(1997) - et al.
Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion
J. Biol. Chem.
(1999) - et al.
Cigarette smoke—an aging accelerator?
Exp. Gerontol.
(2007) Catabolism and turnover of collagens: collagenases
Methods Enzymol.
(1987)How DNA-repair pathways may affect cancer risk
Lancet
(1998)- et al.
Mitochondrial signaling: the retrograde response
Mol. Cell
(2004)