Anatomical and Histological Changes
Intrinsic factors are the combination of various physiological, biochemical, and genetic changes that an individual undergoes during its lifespan. An overall reduction in the thickness of aging skin is attributed to the progressive decline in the dermal and epidermal cellular ability to divide and proliferate over time. Thus, a decline in the number of keratinocytes and fibroblasts will reduce skin's elastin and collagen level causing it to become thin and saggy [19].
4.2.3.2 Telomere Shortening
The fact that skin cells lose their regenerative ability after several divisions are associated with a phenomenon known as “Hayflick's Limit,” and was proposed by Leonard Hayflick and colleagues [11]. According to him, somatic cells have a finite proliferative ability, which can be extrapolated to predict the lifespan of any species. Mechanistic insights into Hayflick's limit theory was described independently by Watson and Olovnikov in the 1970s. According to them, “telomere” being the terminal portion of linear eukaryotic genome gets shortened progressively upon successive cellular division, and cell ceases to divide further upon reaching a threshold [20, 21].
Figure 4.2 Various intrinsic and extrinsic skin aging factors.
4.2.3.3 Metabolic ROS Production
Reactive oxygen species (ROS) are oxygen‐containing reactive molecules that are normally produced in cells as a metabolic by‐product. The major source of metabolic ROS is mitochondria [22]. Young cells have sufficient levels of antioxidant enzymes like superoxide dismutase and peroxidase to counter the damaging effects of oxidative stress generated by ROS [23]. It is, however, known that aged cells lose the ability to express the sufficient levels of antioxidant enzymes, and hence remedial ROS can progressively damage essential cellular components leading to senescence [24]. Such damaging implications are also true for aging skin cells resulting in cell reduction. ROS can also degrade the components (collagen, elastin, etc.) of the epidermal extracellular matrix, causing an overall decrease in strength and elasticity of skin [25].
4.2.3.4 Upregulation of Matrix Metalloproteinases
Matrix metalloproteinases (MMPs) belong to the family of endopeptidases whose function is to maintain the proteinaceous content of the extracellular matrix in the connective tissues. In the skin, MMPs degrade the excessive matrix collagen, thereby maintaining the flexibility of the skin [26]. Aged cells are found to produce suboptimal levels of MMPs, which enhances the collagen degradation in aging skin. Elevated ROS levels are also known to increase MMPs expression, thereby enhancing skin damage [19, 25].
4.2.3.5 Mitochondrial Dysfunction
Aging, in many ways, affects organellar efficiency. Mitochondria, which is regarded as the powerhouse of the cell, also maintains a fine balance of ROS and antioxidants in the cell. A dysfunctional mitochondria arising due to mutations or ROS damage increases the propensity of oxidative stress in the cell, thereby increasing the damage [27]. Mitochondrial dysfunction associated senescence (MiDAS) is one of the major intrinsic factors involved in skin aging [28, 29].
4.2.3.6 Mutations and Oncogenesis
Nuclear and mitochondrial DNA mutate either spontaneously or due to exposure to mutagens. Eukaryotic cells have efficient repair systems to neutralize these mutations. Aging cells (and also young cells in specific genetic variants) lack efficient DNA repair systems, which may lead to activation of oncogenes (like ras), causing oncogene‐induced senescence [30]. Activation of oncogenes in the skin can increase the levels of proteases known as senescence‐associated secretory phenotypes, which can induce early senescence in fibroblasts and keratinocytes [31]. Double‐stranded breaks, mutations, and telomere shortening can affect the overall structure of chromatin in aging cells [32]. Abrogation in the chromatin remodeling mechanism can arrest the cells at G1 checkpoint and can lead to early senescence. A nonfunctional or inhibited histone deacetylase severely affects the chromatin remodeling process and causes early senescence in fibroblasts [33].
4.3 Extrinsic Skin Aging Factors
Skin is an anatomical protective barrier of the human body towards the harmful biotic and abiotic agents of the environment. Younger skin can efficiently repair and recover against the damaging effects of these harmful factors. However, overexposure to any of these extrinsic factors has a detrimental effect on skin and triggers aging.
4.3.1 Photoaging
Photoaging refers to an accelerated skin aging process due to overexposure with the UV component of sunlight [34]. For an individual with light skin, prolonged exposure to the sun will have histological, biochemical, and genetic consequences. UV‐exposed skin display thickened epidermis with an increased quantity of melanocytes and abnormal elastic fibers [35]. Conversely, the dermis layer reduces in density with a decrease in the number of fibroblasts, keratinocytes, and reduced levels of extracellular matrix collagen [10]. Sustained UV exposure to skin is also known to induce higher expression of MMPs, leading to the degradation of elastin and collagen, causing fibroblast senescence [36]. In the normal state, tissue inhibitor of metalloproteinase (TIMP) keeps a check on the levels of MMPs, thereby maintaining the homeostasis. However, during photoaging, expression of TIMP reduces reinforcing the MMPs‐mediated collagen and elastin degradation [15]. Solar UV component is thoroughly studied for causing direct DNA damage and indirect cellular damage by producing ROS. Trans‐urocanic acid is a subcutaneous chromophore known to absorb the UV‐A radiation. Upon excitation, it generates many ROSs causing oxidative stress and senescence in fibroblasts and associated cells. Dermal collagen also contains significant composition UV‐B absorbing amino acids such as cysteine, histidine, tyrosine, tryptophan, and phenylalanine. They collectively contribute to the generation of ROS beyond a certain threshold [37]. UV‐induced ROS can also damage nuclear and mitochondrial DNA causing an alteration in gene expression, dysfunctional mitochondria, oncogenesis, and senescence.
4.3.2 Tobacco Smoking
Tobacco smoking is highly addictive due to nicotine dependence and is considered to be one of the leading cause of several types of cancers and premature deaths. The nicotine content of tobacco triggers the neural reward pathway reinforcing its dependence and addiction [38]. Tobacco smoke elicits skin aging in two ways. First, the tobacco smoke gets absorbed on the exposed skin depositing numerous toxic compounds. These compounds act as ROS stressors elevating the oxidative stress in skin cells. Such conditions will enhance skin wrinkles via mechanisms already mentioned in previous sections. Recurrent skin exposure to tobacco smoke causes irreversible damage to the skin’s texture and its regenerative ability [39]. Second, the inhaled smoke can enhance the expression of MMPs, disturbing the extracellular matrix components. The toxic compounds present in tobacco smoke also increase the plasma neutrophil elastase activity, causing the degradation of elastin fibers from the extracellular matrix. Additionally, tobacco smoke can significantly downregulate TGF‐β1 receptor causing the subsequent reduction in procollagen gene expression [40].
4.3.3 Air Pollution
With the advancement in technology and industries, our environment is flooded with pollutants having a broad range of pathophysiological implications. Any substance released in the environment with harmful consequences can be regarded as a pollutant. Skin is exposed to a variety of chemical and biological pollutants present in the indoor and outdoor air [41]. The major categories of air pollutants consist of particulate matter (PM2.5 and PM10),