Mechanisms of skin aging

The aging process affects all organs and weakens the functioning of the central nervous, immune, endocrine and cardiovascular systems, as well as the skin.

The impairment of adaptive and homoeostatic or homoeodynamic mechanisms leads to a susceptibility of environmental or internal stresses with increasing probability of disease and death.¹

Aging is a complex biological process in which :

• Intrinsic determinants or genetically programmed aging that occurs with time,
• Extrinsic determinants caused by environmental factors,

lead progressively to a loss of structural integrity and physiological function.^2,3,4

Intrinsic aging occurs as a natural consequence of physiological changes over time at variable yet inalterable genetically determined rates.

Extrinsic factors are, to varying degrees, controllable and include exposure to sunlight, pollution or nicotine, repetitive muscle movements (i.e., squinting, frowning), and miscellaneous lifestyle components (i.e., diet, sleeping position, overall health).⁴

Together these factors lead to cumulative alterations of skin structure, function and appearance.¹ As well as changes in cutaneous structure and function, its appearance is the key observable marker of the overall aging process. Thus, our physical appearance in advanced age is important for emotional, mental, and psychosocial well-being.²

Although clearly distinct in their biological, biochemical, and molecular mechanisms, both processes result in major changes of the elastic fibers.⁷

Intrinsic, extrinsic skin aging: what differences?

Each skin aging process leads to characteristic skin aging signs.⁶

Intrinsic aging

Intrinsic aging is a time-dependent biological process leading to gradual changes in the structure and functions of all tissues. These modifications tend to decrease the capacity for adaptive responsiveness and wound healing, and therefore enhance its susceptibility to disorders and death.⁸

In addition to intrinsic genetic factors, this chronological aging is controlled through epigenetic mechanisms and is affected by environmental parameters, which clearly leads to consider this biological process as a complex multifactorial phenomenon.⁸

Intrinsic changes occur in all skin, including decreased:

• Turnover
• Chemical clearance
• Thickness and cellularity
• Thermoregulation
• Mechanical protection
• Immune responsiveness
• Sensory perception
• Sweat and sebum production
• And vascular reactivity

These changes represent a generalized atrophy with few structural alterations up to the age of 50, followed by slow deterioration.⁴

With intrinsic aging process, the skin appears dry and pale with fine wrinkles displaying a certain degree of laxity and a variety of benign neoplasms.

Extrinsic aging

In contrast, the extrinsic skin aging process is characterized by striking morphologic and physiologic changes and in general leads to a premature aging. Prominent manifestations of the extrinsic skin aging process are coarse wrinkles, solar elastosis and pigment irregularities. These signs superimpose the intrinsic skin aging signs at chronically exposed areas of the body.^6,9

With increasing age, atrophy of the dermal matrix occurs including a reduction of the deposition of type I and type III collagens.²

But, the common age-associated feature in both processes is the loss of normal elastic fiber functions, which may well explain some of the manifestations of cutaneous ageing, including wrinkling and sagging of the skin, with a loss of resilience and elasticity.⁷

As both intrinsic and extrinsic aging result in a common endpoint—the decline of skin’s physiological function—it is tempting to think of extrinsic aging as an acceleration of those processes that occur in intrinsic aging.²

Skin aging from a cellular perspective

Several mechanisms are considered to trigger the primary aging process and therefore contribute to age-related changes in adaptive and pharmacological responses.¹

• Oxidative stress
  Aging is associated with the consequence of free radical damage by various endogenous reactive oxygen species (ROS) generated in excessive quantities and altering gene and protein structure.^1,3
  In addition, the levels of antioxidants usually produced in the skin are reduced by age.³
• Mitochondrial dysfunction
  Within mitochondria, accumulation of somatic mutations of its DNA, induced by exposure to ROS, leads to errors in DNA-encoded polypeptides.¹
• Cellular senescence and telomeres
  After a finite number of divisions, skin cells enter a state of replication senescence with an arrest in cellular propagation. One explanation arises from telomeres, which shorten slightly each time the cell divides. Depletion, or rather shortening of telomere DNA prohibits further cell division.¹
• Apoptosis
  It is suggested that aging is mainly associated with up-regulation of apoptosis.¹

Extrinsic factors: what we know today

The mechanisms by which the different environmental factors can contribute to premature/extrinsic skin aging mainly lead to two processes which disrupt the skin collagen matrix:

• decreased collagen synthesis,
• increased collagen degradation,

leading to the characteristic appearance of extrinsically aged skin.

All these mechanisms are also involved in the intrinsic skin aging process but they are increased by environmental exposure.⁶

Solar radiation

It is the most important environmental factor leading to extrinsically aged skin. Its detrimental effect on the facial appearance was already recognized in the late 19th century, comparing the skin of sailors and farmers to that of indoor workers.⁶

The effects of sunlight are estimated to account for up to 90% of visible skin aging, particularly in those without the natural protection associated with higher levels of melanocytes in the skin.⁴

Solar radiation is responsible for the majority of age-related changes, including fine wrinkles, roughness, mottled hyperpigmentation, dilated blood vessels, and loss of skin tone.⁹

The so-called photoaging is the superposition of this solar damage on the normal aging process.⁴

UV radiation: UV radiation affects both epidermal keratinocytes and dermal fibroblasts.⁸
The UV photo-aging histological hallmark is dermal elastosis, which largely consists of thickened, tangled and ultimately granular amorphous elastin structures. The magnitude of the progressive accumulation of elastic fibers depends on the degree of sun exposure.⁷
It increases hydrogen peroxides and other ROS
It decreases anti-oxidant enzymes
In addition, it accelerates many key aspects of the chronological aging process in human skin.¹
Although the primary effect of UV damage is skin thickening, severe damage results more in dramatic thinning. UV exposure creates a state of chronic inflammation, with ongoing release of proteolytic enzymes by inflammatory cells, disrupting the dermal matrix. Irradiated skin was observed to have a decreased capacity for inflammatory response. UV light also reduced the quantity of epidermal Langerhans cells, while it induced proliferation of suppressor T cells, facilitating tumor induction. In addition, vitamin A is destroyed by sun exposure, although plasma concentration of retinol increases with age, within the epidermis.⁴

Visible light and IR radiation: One thought to minimally impact the skin, apart from the heat sensation provided by IR radiation, visible light (400-740 nm) and IR are now known to induce dermal matrix degradation, to modify stratum corneum lipid composition and to modulate skin pigmentation.

Smoking

Striking associations between cigarette smoking and wrinkling were fund in 1971.⁶

Smoking accelerates signs of skin aging enhancing the unwanted appearance of “looking old” and decreases the cutaneous strength, impairs wound healing and connective tissue turnover, and slows epidermal regeneration.²

The association between smoking and skin aging seems to be mediated through higher expression of MMP-1 and MMP-3 mRNA, but not of their specific inhibitors as well as a decrease of collagen I and III. Smoking seems also to be associated with increased elastosis, in both sexes, and telangiectasias, in men indicating further molecular pathways in addition to the induction of MMP-1 expression.⁶

Smoking causes skin damage, primarily by decreasing capillary blood flow to the skin which, in turn creates oxygen and nutrient deprivation in cutaneous tissues.

It has been shown that smokers have fewer collagen and elastin fibers in the dermis, which causes skin to become slack, hardened and less elastic. Smoke causes damage to collagen and elastin in lung tissue and may do so in skin as well. In addition, constriction of the vasculature by nicotine may contribute to wrinkling. Smoking increases keratinocyte dysplasia and skin roughness. A clear dose–response relationship between wrinkling and smoking has been identified, with smoking being a greater contributor to facial wrinkling than even sun exposure.⁴

Smoking also increases free radical formation and is an important risk factor in cutaneous squamous cell carcinoma.⁴

Note: Smoking is an independent risk factor for premature wrinkling even when age, sun exposure and pigmentation were controlled. It has been shown that wrinkle scores are three times greater in smokers than in non-smokers, with a significant increase in the risk of wrinkles after 10 pack-years (Pack-years are calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked).^4,6

Pollution

Air pollution represents another environmental threat to which millions of humans worldwide are exposed.⁶

Pollutants, exhaust, smog-derived ozone exposure have been associated with precipitated skin aging and increased cancer risks.⁵

These factors share a common mechanism involving the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor found in keratinocytes, fibroblasts, melanocytes and Langerhans cells.^5,6

Activation of AhR by UVB and xenobiotic factors in skin. Activation of the aryl hydrocarbon receptor (AhR) by light and xenobiotics results in its translocation to the cell nucleus, where it regulates the expression of a number of genes involved in melanogenesis, skin inflammation, immunosuppression, skin ageing, and carcinogenesis.

A direct link has been established between airborne particulate matter (PM) exposure and the occurrence of prominent skin aging signs especially pigment spots, but also wrinkles.⁶

Lifestyle factors

Epidemiological studies have evidenced the influence of lifestyle factors on skin aging.⁵

• Diet
  Unhealthy food is associated with all kind of skin problems, including signs of skin aging. On the opposite, a healthy diet rich in antioxidants may delay chronological aging effects.⁵
• Sleep
  Having regular sleeping habits tends to be associated with healthier and younger looking skin.⁵
• Exercise
  Exercising is beneficial for skin by stimulating blood circulation helping to evacuate metabolic wastes and bringing oxygen to skin tissues.⁵
• Medical treatments
  Medicine intake may present additional risks for the skin, as some can increase skin’s photosensitivity and therefore decrease the time it takes to burn.5 Some medications affect the skin as well, particularly hypocholesterolemic drugs, which may induce abnormal increased desquamation.⁴
• Ambient conditions
  Skin is affected by temperature and humidity. An increase in skin temperature of 7–8°C doubles the transepidermal water loss (TEWL). Low temperature stiffens skin and decreases TEWL even with plenty of humidity in air, as structural proteins and lipids in the skin are critically dependent on temperature for appropriate conformation.⁴

Skin aging from a clinical perspective

Epidemiological studies have evidenced the influence of lifestyle factors on skin aging.⁵

Signs of intrinsically aged skin rarely manifest before the age of 70 years; skin becomes pale and dry, and is characterized by fine wrinkles.
However, in areas that have been exposed to chronic solar UVR, the clinical appearance is strikingly different; it appears sallow and roughened and often presents with hypo- and hyperpigmented lesions (age spots).

Extrinsically aged skin also features coarse wrinkles with increased laxity, especially in areas of dynamic change due to facial expression such as periorbital “crow’s feet.”2

Aged skin is characterized by:^3,8

• A flattening of the dermal-epidermal junction
• A marked atrophy and a loss of elasticity of the dermal connective tissue
• A reduction and disorganization of its major extracellular matrix components, such as collagen and other elastic fibers, proteoglycans and glycosaminoglycans.
• Lipid processing declines with advancing age
• Enzymes necessary for the production of ceramides critical to healthy epidermal barrier function are all diminished in the elderly.
• Epidermal CD44, the keratinocyte transmembrane glycoprotein thought to play a regulatory role in keratinocyte proliferation and maintaining local hyaluronic acid homeostasis, decreases with increasing age and may contribute to epidermal thinning and reduction in its viscoelastic properties.

Such epidermal alterations increase the susceptibility to a wide range of skin problems: colonization by pathogenic bacteria, reduced stratum corneum cohesion and hydration, leading to dry skin and pruritus, conditions highly prevalent in aged individuals leading to a substantial negative impact on quality of life.²

Genetically programmed intrinsic aging causes structural and functional changes in all layers of the skin.

In the epidermis: a progressive decrease in the renewal rate of epidermal cells causes thinning of the epidermis giving aged skin a translucent appearance. Diminished epidermal renewal also adversely affects skin barrier function and repair and cell exfoliation.^3,9
The corneocytes tend to clump together on the surface, giving a rough, scaly appearance, and texture.⁹
The decrease of melanocytes and decreased functional activity of the remaining melanocytes result in dyschromic changes, such as mottled pigmentation, freckles, and lentigines. Because the skin is thinner and has fewer melanocytes, it is more susceptible to sunburn.⁹

Aging also affects the Langerhans cells with nearly a 50% decrease in late adulthood, compromising the skin’s level of immune surveillance and leading to a higher risk of skin cancer.⁹

Histologically, one of the most prominent changes with intrinsic aging is a flattening of the dermal–epidermal junction, which increases skin fragility and decreases transfer of nutrients between the two layers.^3,9

In the dermis: the number of fibroblasts - as well as synthesis of the fibroblast products collagen and elastin - decreases resulting in skin wrinkling and loss of elasticity.^3,9
A considerable loss of dermal microvasculature reduces blood supply to the skin and contributes to atrophy of the skin and its appendages.^3,9
Loss of sebaceous glands makes the skin dry due to reduced sebum production.^3,9
Further, intrinsic aging causes a decrease in subdermal fat tissue. This loss of support contributes to wrinkling and sagging (laxity) of the skin. With less padding, skin is more susceptible to trauma and bruising. Decreased insulation also affects the body’s ability to conserve heat.9

Skin aging: ethnicity plays a role

The intrinsic skin aging process rather occurs similarly in all different populations; on the contrary, the extrinsic skin aging process manifests differently between populations regarding the time of development and regarding prominent skin aging signs. By example, Caucasians have an earlier onset and greater skin wrinkling than other populations and in general increased pigmentary problems are seen in Asians and in African-Americans.⁶

On an individual basis, the rate of extrinsic skin aging depends on the individual exposure pattern to different environmental factors and also on the individual genetic make-up. Some individuals might be more susceptible regarding skin damages by environmental exposure than other individuals.⁶

One main influencing factor for the ethnic-specific skin aging manifestation is the genetically determined skin type as there is an ethnic variation in melanin content and composition.

It has also been documented that wrinkling occurs later and with less severity in Asians than in Caucasians, although the reason for these observations was not explored.⁴

Other underlying reasons for the ethnic-specific manifestation of skin aging might lay in further genetic variations beyond the skin type and/or in different exposure habits to environmental factors, which influence skin aging.⁶