Keywords

1 Intrinsic Aging

Intrinsic aging is the process of senescence that affects all body organs, and the skin clearly shows the action of time and is transformed by it [1]. In 1990, there were more than 300 theories of aging . Today, the situation is even more complicated [2].

Intrinsic skin aging or chronologic aging is characterized by physiological changes genetically determined and includes structural, biochemical, and functional alterations [3, 4]. These changes are complex, and there are many theories of skin pathophysiology , like shortening of telomeres, reduction of cellular DNA repair capacity [5], cellular senescence, and decreased proliferative ability [6] mutations of extranuclear mitochondrial DNA [7]. Some of them are highlighted.

1.1 Shortening of Telomeres

Telomeres are sequences of repeating nucleopeptides present at the end of chromosomes (Fig. 2.1) [8]. Because DNA polymerase cannot transcribe the final sequence of bases present in the DNA ribbon during replication, the telomeric size is reduced at each mitotic cycle [9]. This telomere reduction is associated with cellular aging [24,25,26,13]. This mechanism contributes to the regulation of growth arrest in senescent human cell cultures the same way as stress or aberrant signaling-induced senescence (STASIS) [14]. Telomeres themselves are regarded as possible biomarkers of biological aging and cellular senescence. Other possible biomarkers are the free radicals [15].

Fig. 2.1
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Representation of a telomere , highlighted

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1.2 Free Radicals and Antioxidizing Ability

In 1956, Denham Harman proposed a theory that free radicals are also involved in this aging process: they would cause cellular damage, which would accumulate over the course of life and result in acceleration of dysfunctions [16]. Later, Yu and Yang described that not only the overexpressed production of reactive oxygen species (ROS) but also other oxidants, such as the reactive nitrogen species and reactive lipid species, cause oxidative damage [17].

In other studies, the degradation of oxidized products was unraveled. The body can neutralize ROS through the production of antioxidant enzymes , such as superoxide dismutase, catalase, and glutathione peroxidase, by an innate antioxidant defense system [18, 19]. This function is exerted by proteasome (multicatalyctic protease), whose activity seems to diminish over the course of life. With this, an incomplete degradation of oxidized proteins, increased protein aggregates, and the acceleration of cell dysfunction are observed, which, ultimately, lead to cellular aging [16, 20].

1.3 Cellular Senescence

The theory of cellular senescence has been demonstrated in keratinocytes, fibroblasts, and melanocytes [21]. There is a reduction in the proliferative potential of cells after a certain amount of division [36,37,24]. Senescent cells can also produce several cytokines, chemokines, growth factors, proteases, and matrix metalloproteases, a phenomenon described as senescence-associated secretory phenotype (SASP) [25]. A hallmark of skin aging is the degradation of collagen and other extracellular matrix components in the dermal connective tissue and can be induced through chronic MMPs secretion by senescent cells [26].

2 Intrinsic Factors

2.1 Genetic Characteristics

Many studies correlated genomes with the aging process [27, 28]. According to one of them, of all genes studied, 39 were regulated overlappingly in both sexes. They could serve as gender-independent biomarkers of endogenous skin aging . On the other hand, Wnt signaling pathway showed to be significantly downregulated in aged skin with decreased gene and protein expression for males and females [29].

Genic expression studies from aged sun-protected skins showed differential expression, possibly responsible for dysregulation of the insulin and STAT3 signaling pathway, the extracellular matrix (PI3, S100A2, A7, A9, SPRR2B), and the cell cycle (CDKs, GOS2). There was also evidence of a high regulation of proapoptotic genes, in part by a dysregulation of FOXO1. An under-expression of the JUN and FOS family members and cytoskeleton genes (KRT2A, KRT6A, and KRT16A) is also affected by intrinsic aging [30].

Another alteration observed in skin aging is the reduced expression of type I collagen due to downregulation of the transcription growth factor (TGF) β-1 and the connective tissue growth factor (CTGF) . This reduced collagen expression is even associated with increased nuclear factor-κB (NF-κB) activity and increased expression of matrix metalloproteinase (MMP)-1 [31, 32].

An interesting discovery is that DNA methylation measures the cumulative effect of an epigenetic maintenance system, like a “clock of aging,” and can determine the individual age with an error of less than 3.6 years. This additional information can be used to address a host of questions in developmental biology, cancer, and aging research [33].

2.2 Sexual Hormones

With aging, the functional reserves of the endocrine system are reduced. As a result, the levels of sexual hormones decline. In females, hormonal changes are well documented. Women have a rapid decline of estrogen during menopause [34]. Estrogen is related to the stimulus of keratinocyte proliferation, which leads to the thickening of the epidermis, avoiding its atrophy [35]. In the dermis, the stimulus is of blood vessels and fibroblast production, thereby preserving collagen, elastic fibers, and glycosaminoglycans [36, 37]. With the reduction of this hormone, the maintenance of these processes would be compromised.

The characterization of hormonal changes in males is a challenge, as there is not a remarkable hormonal decrease when compared with females. During the aging process, most men show a gradual reduction of circulating testosterone—something around 1% a year after 30 years of age. However, this number substantially varies among men [38]. Testosterone reduction is related to intrinsic aging because it broadly interacts with the skin, the whole body, and the male behavior itself [39].

3 Extrinsic Aging

Extrinsic aging results from the exposure to environmental factors—critical for the final result of the process [35]. Sun exposure intensifies skin aging due to ultraviolet radiation, a process referred to as photoaging [40]. Factors such as smoking and pollution may also lead to aging [41]. All these factors can lead to ROS generation, reducing collagen synthesis and increasing its degradation, contributing to premature skin aging (Fig. 2.2).

Fig. 2.2
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Air pollution, smoking, and sun exposure leading to ROS generation, reducing collagen synthesis and increasing its degradation, contributing to premature aging

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4 Extrinsic Factors

4.1 Air Pollution

The World Health Organization defines air pollution as contamination of the indoor or outdoor environment by any chemical, physical, or biological agent that modifies the natural characteristics of the atmosphere [42]. The skin acts as a physical, chemical, and immunological barrier against the environmental factors. This barrier can fail when the exposure to stressors is prolonged and repetitive, leading to the development of various skin diseases [43]. Major air pollutants which affect the skin are solar ultraviolet radiation, polycyclic aromatic hydrocarbons, volatile organic compounds, nitrogen oxides, particulate matter, cigarette smoke, heavy metals, and arsenic [44]. Air pollutants damage the skin by inducing oxidative stress and can lead to aging of the skin [41, 44].

Some pollutants stand out, such as ozone, particulate matter (PM), and polycyclic aromatic hydrocarbons. Ozone can affect the integrity of the skin on murine cutaneous tissue, can act as a strong oxidative agent, and can induce the expression of MMP-9, indicating a role in matrix remodeling [45, 46]. Oxidation of epidermal lipids and disturbed activity of matrix metalloproteinases contribute to wrinkling and extrinsic skin aging [47].

Particulate matter in the air consists of complex and varying mixtures of different sizes and composition. After penetrating the skin either through hair follicles or transdermally, PM exerts its detrimental effects through the generation of oxidative stress, contributing to extrinsic skin aging, characterized particularly by pigment spots on the face and nasolabial folds and less so by coarse wrinkles, solar elastosis, and telangiectasia [61,62,50]. Furthermore, particles can serve as carriers for organic chemicals and metals that are capable of localizing in mitochondria and generating ROS directly in mitochondria [51], leading to skin aging by mitochondrial damage [41].

Polycyclic aromatic hydrocarbons (PAHs) are adsorbed on the surface of suspended PM in the air of urban areas [52] and are converted into quinines, redox-cycling chemicals that produce reactive oxygen species [53]. They are associated with extrinsic skin aging, pigmentation, cancers, and acneiform eruption [52].

4.2 Smoking

In 1969 it was recognized that smokers look older than non-smokers [54]. Later, smoking was found to be an independent risk factor for premature facial wrinkling even after controlling for sun exposure, age, sex, and skin pigmentation [55]. A dose–response relationship between wrinkling and smoking has been identified, with smoking being a greater contributor to facial wrinkling than sun exposure [56].

Reactive oxidants and free radicals from cigarette smoke cause oxidative stress or secondary oxidative events and inhibition of antioxidant mechanisms [70,71,59]. Components of cigarette smoke increase transepidermal water loss, degeneration of connective tissue in the skin, and upregulation of matrix metalloproteinases-1 and -3 which degrade collagen and elastic fibers, which causes skin to become less elastic [43, 60, 61].

4.3 Ultraviolet Radiation and Photoaging

Photoaging is a cumulative process that is dependent on sun exposure degree and skin pigmentation level. Clinical presentation of sun-aged skin includes dryness of the skin; yellowish, wrinkled, atrophic, irregular pigmentation; telangiectasias; and pre-malignant lesions [62, 63]. Histologically there is thinning of the stratum spinosum, increased thickness of granular cell layer, flattening of the dermoepidermal junction, and an increased number of hypertrophic dopa-positive melanocytes [62, 64].

In aging process it is observed that keratinocytes become resistant to apoptosis and susceptible to DNA mutations. The number of melanocytes is also reduced, and the melanocytic density is altered. Langerhans cells also decrease in number with aging, resulting in loss of antigenic ability [62].

The immediate effect of sun exposure on the skin is cutaneous hyperpigmentation with delay in the formation of new melanin, which is reversible. The prolonged, recurrent sun exposure implies definitive changes in the quantity and distribution of melanin in the skin. The deposition of amorphous material in the papillary dermis, in place of conjunctive tissue, is the main element in differentiating chronologic aging and photoaging [62].

The morphological changes resulting from photoaging are, essentially, different from those observed in intrinsic aging. A parallel between such changes is shown in Table 2.1 [62, 40, 64, 65].

Table 2.1 Skin changes caused by intrinsic and extrinsic aging
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The ultraviolet (UV) B (290–320 nm) and A (320–400 nm) fractions [66] as well as the infrared (IR) A (770–1400 nm) fraction [79,80,69] can induce the extrinsic skin aging process [41].

Ultraviolet radiation penetrates the skin, and in accordance with the wavelength, it interacts with the different cells located in the different strata. Shortwave radiation (UVB) is more absorbed in the epidermis and predominantly affects keratinocytes but is also able to cross this layer and reach the papillary dermis [70]. Longer waves (UVA) penetrate more deeply and hit epidermal keratinocytes and dermal fibroblasts [71, 72]. IRA is able to penetrate through all three layers of the skin: the epidermis, dermis, and subcutis [41].

The UV-induced skin aging process is complex and can occur by various pathways including receptor-initiated signaling, mitochondrial damage, protein oxidation, DNA damage, and arylhydrocarbon receptor (AhR) signaling [41]. Table 2.2 compares the main mechanisms of intrinsic and extrinsic aging.

Table 2.2 Main mechanisms involved in aging
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4.4 Receptor-Initiated Signaling Pathway

The reactive oxygen species produced by ultraviolet radiation activate cell surface receptors of cytokines and growth factors in keratinocytes and fibroblasts, which activate kinases, that induce expression and transcription factors such as nuclear κB transcription factor (NF-κB) and protein 1 (AP-1) [41, 63].

The activated NFkB stimulates the transcription of inflammatory cytokines (IL1, IL6, TNFa), attracting neutrophils and collagenases, associated in collagen degrading [73].

Increased AP-1, in turn, decreases the gene expression of dermal collagens I and III in fibroblasts, reducing collagen synthesis. Besides that, AP-1 stimulates the transcription of genes of matrix-disintegrating enzymes, such as metalloproteins (MMP-1, MMP-3, MMP-9), degrading mature dermal collagen [74, 75]. The radiation is not only related to collagen degradation but also contributes to reducing its synthesis. UVA ray exposure triggers two factors related to photoaging: induction of matrix metalloproteinases (MMPs) and mitochondrial mutation [72, 76, 77].

4.5 Mitochondrial Damage

Actually, mitochondrial DNA damages are likely to be mediated through ROS. Mitochondria contain multiple DNA copies and generate ROS during energy production (adenosine triphosphate—ATP), by consuming oxygen via the respiratory chain. ROS can easily damage lipids, proteins, and even the mtDNA itself [78, 79]. The mitochondrial DNA shows a high mutation rate due to its histone deficiency, limited capacity of base excision repair, and proximity to ROS [79, 80].

UVA exposure can further increase ROS generation and induce mutations at the mitochondrial DNA [72, 81], like deletion of 4977 bp (base pair), the most often found mutation in aged tissues [63, 93,94,95,96,97,87]. While this genic change can be detected in tissues that are non-susceptible to solar rays [83], mtDNA mutations can be tenfold more frequent in photoaged skin in comparison to sun-protected skin [64, 78, 79, 99,100,101,102,92].

4.6 DNA Damage

Sunlight-induced DNA damage is considered the main cause for the genetic changes leading to skin lesions and carcinogenesis including malignant melanoma [93]. DNA, the main intracellular chromophore for UVB [70], absorbs photons from UVB. This interaction increases ROS production and creates dimeric photoproducts, such as pyrimidines, which may be related to pre-malignant skin lesions [94, 95]. The DNA photoproducts that are induced by UVA are potentially more mutagenic than those induced by UVB, although UVB induces more cyclobutane pyrimidine dimers than UVA [96].

Ultraviolet radiation also alters RNA and implies the formation of dysfunction-causing proteins. A blockade in RNA transcription by a DNA photoproduct allows p53 activation, thereby inducing the apoptosis of irradiated keratinocytes [94].

These events activate multiple important signaling pathways related to cell growth, differentiation, senescence, DNA damage repair, connective tissue degradation, and inflammation [97]. This is followed by an irreversible blocking of cell cycle progression to prevent further DNA damage and increase the expression of senescence-associated genes [97, 98].

4.7 Arylhydrocarbon Receptor Signaling

It is known that UVB also generates ROS species [99] initiating DNA damage, in the nucleus, once DNA is chromophore of UVB [100]. But, in the recent years, arylhydrocarbon receptor (AhR) was demonstrated to integrate part of the UVB stress response associated with photoaging.

This DNA damage-independent pathway is initiated outside the nucleus by the cluster ring and the internalization of cell membrane-bound growth factor receptors, such as the epidermal growth factor receptor (EGFR) [101]. AhR is activated in human epidermal keratinocytes upon exposure to UVB radiation, producing a series of photoproducts from tryptophan, which is free in the cytoplasm. These photoproducts are ligands of the AhR and activate it. This process leads to regulation of inflammation-associated genes, such as cyclooxygenase2 (COX2), that increase the expression of matrix metalloproteinases such as MMP-1 and MMP-3, among other proteases [113,114,115,105], melanocyte proliferation, and melanin synthesis [58, 106]. In this scenario, the molecular response to solar aggression is evident. These mechanisms are briefly illustrated in Fig. 2.3.

Fig. 2.3
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Cellular effects of ultraviolet radiation . AhR signaling pathway. UVB forming photoproducts that lead to pre-malignant lesions. UVA/UVB action on p53, producing cancer cells. Deletion of mitochondrial 4977 bp and ROS production by UVA radiation, ultimately, resulting in photoaging. (Adapted with permission from Montagner and Costa [65])

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4.8 Infrared Radiation

IRA irradiation is mainly absorbed by mitochondria, where copper could serve as a chromophore [107], and increases intra-mitochondrial production of ROS [108, 109]. ROS can increase intra-cytoplasmic calcium levels, activate the MAP kinases signaling pathway, and lead to elevated MMP-1 expression. Approximately 600 genes are IRA responsive [110], and thus IRA radiation might further induce the extrinsic skin aging process through various other pathways. Important functions of the human skin which are characteristic for photoaging, such as angiogenesis [111] and production of mast cells [54], can be induced by IRA. Though IR does not induce tumorigenesis in the skin to the same extent as UVB, it is associated with a more aggressive tumor growth [112].

5 Conclusion

Ultimately, simply put, aging results from the modulation imbalance of collagen (with higher degradation and reduction of its synthesis) caused by excessive free radicals . Exposure to certain environmental factors, such as ultraviolet radiation, smoking, and air pollution, induces or enhances this process, thereby leading to premature or exogenous aging.

Even with all biomolecular advances, prevention is still the best way to fight aging and its consequences, by avoiding the exposure to well-known exogenous factors. Endogenous and exogenous aging are objects of many research studies involving diet components in order to avoid or minimize the signs of time; however, there is still a lot to be proven. The advance in the knowledge of its pathogenesis is expected to corroborate with new therapeutic findings.