Clinical aspects and molecular mechanisms of skin aging

M.YOUSRY ABDEL_MAWLA,MD Prof of Dermatology&VenereologyZagazig Faculty of Medicine,Zagazig,EGYPT

Skin has long been recognized to protect the organism from deleterious environmental effects (physical, chemical, microbiologic) .

It is crucial for the maintenance of temperature and of electrolyte and fluid balance.

skin is a sensory organ, a biofactory for the synthesis, processing, and metabolism of a wide range of structural proteins, glycans, and lipids.

It fulfils the requirements of a classic endocrine organ

SKIN FUNCTIONS

Human skin cells produce a variety of hormones, including growth factors, sex steroids, and essential vitamins such as vitamin D.

With accelerating age skin looses its structural and morphologic characteristics, and all of these functions deteriorate as a consequence.

SKIN FUNCTIONS

Intrinsic aging Extrinsic aging There are shared molecular mechanisms between

these 2 types of skin .aging

Types of Skin Aging

Changes in Intrinsically Aged Skin

Morphologic Changes in Extrinsically Aged Skin

With time, the epidermis develops an abnormality in permeability barrier homeostasis that is accentuated further in photoaged skin.

This resultsare due to a global reduction of the lipids in the stratum corneum and a profound abnormality in cholesterol synthesis.

Skin becomes more susceptible to mechanical trauma and infectious diseases.

Cytokine dysregulation, particularly of the interleukin (IL)-1 family, contributes to this effect

Permeability barrier function

Imbalances of the serum levels of sex steroids, which naturally occur at menopause, result in changed skin sensitivity or barrier function.

Testosterone or androsterone delays barrier recovery. The delay can be overcome by the coapplication of β-

estradiol. Progesterone, however, may delay the barrier

recovery as well, but the delay in this case is enhanced by β-estradiol.

Permeability barrier function

The dysregulated expression of matrix metalloproteinases (MMPs) and elevated proteinase activity are involved in the disturbance of wound healing.

Raised wound-fluid levels of MMP-2 and MMP-9, decreased tissue inhibitor of MMP-1 levels, and breakdown products of fibronectin have been described in chronic wounds.

Hormones play a profound role in the process of wound healing.

Reduced levels of estrogens observed in post- menopausal women have been associated with disturbed effects on tissue regeneration through impaired cytokine transduction, altered protein balance and uncontrolled inflammation.

Wound healing

Topical application of estrogens on skin can significantly accelerate the wound-healing process and is accompanied by an activation of the transforming growth factor (TGF)-β signalling pathway:

Estrogens inhibit the expression of the macrophage migration inhibitory factor influencing the initiated local inflammation.

Estrogens induce dermal cellular expression of estrogen receptor-β within the wound indicating the importance of estrogen receptor-β in wound healing

Wound healing

Estrogen receptor modulators inhibit wound expression of the proinflammatory cytokines macrophage migration inhibitory factor, IL-6, and tumor necrosis factor (TNF)-α.

Topical estrogens on cutaneous ulcerations induce the expression of fibronectin and decrease elastase levels secondary to reduced neutrophil numbers, resulting in a rapid progress of wound healing.

Endogenous testosterone, inhibit the skin wound healing response in men.

Smad3 is crucial in mediating androgen signaling and is associated with an enhanced inflammatory response

Wound healing

Angiogenesis during wound healing or hair growth is critically affected with age.

An age-associated reduction of cutaneous vessel size and a marked loss in dermal vessel density and surface area for exchange have been described in both types of skin aging.

This explains why aged skin is characterized by:1. Reduced cutaneous vascular responsiveness, 2. Reduced UV-induced erythema, 3. Decreased skin temperature and 4. Disturbed nutrient supply.

Angiogenesis

The horizontal pattern of the vascular plexuses remains unchanged in sun-protected skin.

The normal architecture is significantly disturbed in photoaged skin. The connective tissue damage accompanying photoaged skin contributes

to the disorientation of the vessels. Acute UV exposure may induce angiogenesis and the formation of new

blood vessels. This is through 1. Upregulation of the angiogenic inducer vascular endothelial growth factor.

2. Downregulation of the angiogenic inhibitor thrombospondin-1 by mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2).

Angiogenesis

Topical pretreatment with all trans-retinoic acid under occlusion inhibits

1. UV-induced vascular endothelial growth factor upregulation and angiogenesis with a significant reduction of vessel density .

2. UV-induced ERK1/2 activation in human skin.

Angiogenesis

With advanced age the number of the antigen-presenting Langerhans cells (LCs) significantly decreases .

The cells also undergo morphologic alterations comprising less dendrite formation, less Birbeck granules, and reduced antigen-trapping capacity.

In elderly photoprotected skin, TNF-α–induced LC migration is significantly affected.

These LCs do not respond to TNF-α stimulation to such an extent as do LCs in young skin making skin

susceptible to infections..

Immune function

The sebaceous gland cells, responsible for the sebum production and the lubrication of the skin, lose their morphologic and functional characteristics with age.

After an initial hypertrophy to compensate for the loss of function, their size finally decreases and their secretory output declines resulting in a decrease in the surface lipid levels and xerosis and chronic eczema.

Hormone-dependent function of the sebaceous gland cells support the hypothesis that skin xerosis observed in old age may be attributed to the lack of hormones.

Hormone substitution, such as topical and systemic administration of estrogens, may significantly reverse skin xerosis.

Lipogenesis

Skin is the major site for UVB-mediated vitamin D3 and 1,25-dihydroxyvitamin D3 [1, 25(OH)2D3] synthesis.

1,25 (OH)2D3 is also essential for numerous physiologic functions, including immune response, release of inflammatory cytokines, and regulation of growth and differentiation in normal and malignant tissues.

1,25(OH)2D3 protects human skin cells from UV-induced cell death and apoptosis,

Vitamin D synthesis

It can inhibit the activation of stress-activated protein kinases (SAPKs), such as the c- Jun NH2-terminal kinase and p38, and

It can suppress IL-6 production. 1,25(OH)2D3 shows a protective effect of against

UVB-induced skin damage & carcinogenesis. 1,25(OH)2D3 induces the expression of antimicrobial peptide genes in human skin and is significantly

involved in preventing opportunistic infections.

Vitamin D synthesis

With increasing age, the capacity of the skin to produce vitamin D3 declines, and consequently, the protective effects of the vitamin are reduced.

Several factors contribute to this deficiency state, among them:

1. Behavioral factors, including limited sun exposure and malnutrition, that can be partially altered by behavior modification

2. Various intrinsic factors such as reduced synthesis capacity. Vitamin D and calcium supplementation is of great

importance in the elderly population.

Vitamin D synthesis

A disturbance of the thermoregulatory function of skin occurs with age.

Elderly individuals are characterized by a significant reduced sweat output, higher core and skin temperatures, and by a decrease in sensory thermal sensitivity.

This appears to reflect : 1. A diminished response of the sweat glands to central or

peripheral stimuli, 2. An age-related structural alteration in the eccrine glands

or surrounding skin cells, 3. Both mechanisms.

Sweat production

Age-associated skin diseases

The noxious cumulative effects of environmental factors such as UV and ionizing radiation on our skin can be seen

in later years. These include 1. The premalignant lesions of actinic keratoses and lentigo

maligna, 2. Malignant lesions of basal cell carcinoma (BCC),

squamous cell carcinoma (SCC) and melanoma.3. Benign skin changes, such as seborrheic keratoses, dry,

atrophic inelastic and deep wrinkled skin, telangiectasia, lentigines, and various pigmentary changes

Age-associated skin diseases

Most clinical changes in aging skin result from a com-bination of molecular and cellular factors including

1. Endogenous (eg, gene mutations, cellular metabolism, hormone) factors.

2. Exogenous (eg, chemicals, toxins, pollutants, UV, and ionizing radiation) factors.

Molecular aspects of skin aging

Several theories have been proposed, including1. The theory of cellular senescence,2. Decrease in cellular DNA repair capacity loss of

telomeres,3. Point mutations of extranuclear mitochondrial DNA,4. Oxidative stress,5. Increased frequency of chromosomal abnormalities

Pathogenesis of aged skin

Single gene mutations can contribute to the initiation of aging and induce premature aging syndromes.

However, no special genes that can cause aging-associated damages.

The manifestation of aging is mostly due to the failure of maintenance and repair mechanisms.

Studies on human keratinocytes have demonstrated altered expression of growth-regulating molecules with age.

Molecular mechanisms of skin aging

There is an increase of the baseline expression of the differentiation-associated genes like SPR2 and IL-1 receptor

antagonist,and epidermal growth factor binding. In fibroblasts, genes like the c-fos proto-oncogene,the helix-

loop-helix Id-1, and Id-2 genes and components of the E2F transcription factor are downregulated.

Fibroblasts show an increased expression of IL-1 and of the epidermal growth factor-like cytokine heregulin that modulates growth and differentiation.

Negative growth regulators are overexpressed, including the p21 and p16 inhibitors of cyclin-dependent protein kinases.

Molecular mechanisms of skin aging

Elastin gene expression is markedly reduced after the age of 40 to 50.

Endogenous and exogenous aging may share some fundamental pathways and may have some common mediators.

Photoaging is thought to be the superposition of UV-irradiation from the sun on intrinsic aging.

Some of the similarities are changes in the MAPK signalling pathways, such as :

1. Decreases in ERK- dependent MAPK activity .2. Increases in stress-activated JNK and p38 kinase that result in

reduced cell proliferation, differentiation, and cell survival 3. Enhanced growth arrest, apoptosis, and stress-related responses.

Molecular mechanisms of skin aging

As a consequence of the stress-activated MAPK pathways, the expression of c-jun and c-jun N terminal kinase, an upstream activator of c-jun, is elevated in

aged compared with young skin. Because c-jun is a constituent of the transcription factor

AP-1: 1. AP-1 is also elevated.2. the AP-1–regulated connective tissue-degrading

enzymes MMP-1 (interstitial collagenase), MMP-3 (stromelysin 1), and MMP-9 (gelatinase B) are elevated.

3. There is an observed reduction in the expression of4. tissue inhibitors of MMPs.

Molecular mechanisms of skin aging

Another common feature is the increased insoluble degraded collagen and the reduction of type I and III procollagen synthesis, which may result from the impaired TGF-β/Smad signalling pathway.

Connective tissue growth factor (CTGF)/CCN2, a down- stream target of the TGF-β/Smad pathway, is a physiologic regulator of collagen expression.

The TGF-β/Smad/CTGF axis is significantly reduced in dermal fibroblasts, the major collagen-producing cells, in aged human skin.

Molecular mechanisms of skin aging

Shared molecular mechanisms in intrinsic &extrinsic skin aging

Gene mutations accompanying progeroid syndromes, such as Hutchinson-Gilford progeria, Werner syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, ataxia telangiectasia, and Down syndrome warrant searching

The most common skin manifestations of these syndromes, are :

1. An acceleration of the aging phenotype. 2. Alopecia. 3. Skin atrophy and sclerosis. 4. Telangiectasia. 5. Poikiloderma. 6. Thinning and graying of hair.7. Several malignancies.

Lessons to learn

Most of these syndromes are inherited in an autosomal recessive way .

They mostly display defects in DNA replication, recombination,repair, and transcription.

An assessment of mRNA levels in fibroblasts isolated from patients with progerian shows that chromosomal pathologies may lead to misregulation of key structural, signalling, and metabolic genes associated with the aging phenotype.

Lessons to learn

Isolated GH deficiency, multiple pituitary hormone deficiency, including GH as well as primary insulin-like growth factor-I deficiency (GH resistance, Laron syndrome), present signs of early skin aging, such as:

1. Dry, thin and wrinkled skin, obesity.2. Hyperglycemia, reduced body lean mass, osteopenia.3. Lowered venous access, rise in serum cholesterol. 4. Tendency for cardiovascular diseases and

subsequent premature death.

Lessons to learn

THANK YOU