1. Clinical aspects and molecular mechanisms of skin aging M.YOUSRY ABDEL_MAWLA,MD Prof of Dermatology&Venereology Zagazig Faculty of Medicine,Zagazig,EGYPT

2. 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

3. 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

4. Intrinsic aging Extrinsic aging There are shared molecular mechanisms between these 2 types of skin .aging Types of Skin Aging

5. Changes in Intrinsically Aged Skin

6. Morphologic Changes in Extrinsically Aged Skin

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

8. 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

9. 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

10. 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

11. 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

12. 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: Reduced cutaneous vascular responsiveness, Reduced UV-induced erythema, Decreased skin temperature and Disturbed nutrient supply. Angiogenesis

13. 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 Upregulationof the angiogenic inducer vascular endothelial growth factor. Downregulationof the angiogenic inhibitor thrombospondin-1 by mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2). Angiogenesis

14. Topical pretreatment with all trans-retinoic acid under occlusion inhibits UV-induced vascular endothelial growth factor upregulation and angiogenesis with a significant reduction of vessel density . UV-induced ERK1/2 activation in human skin. Angiogenesis

15. 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

16. 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

17. 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

18. 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

19. 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: Behavioral factors, including limited sun exposure and malnutrition, that can be partially altered by behavior modification Various intrinsic factors such as reduced synthesis capacity. Vitamin D and calcium supplementation is of great importance in the elderly population. Vitamin D synthesis

20. 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 : A diminished response of the sweat glands to central or peripheral stimuli, An age-related structural alteration in the eccrine glands or surrounding skin cells, Both mechanisms. Sweat production

21. Age-associated skin diseases

22. The noxious cumulative effects of environmental factors such as UV and ionizing radiation on our skin can be seen in later years. These include The premalignant lesions of actinic keratoses and lentigomaligna, Malignant lesions of basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. Benign skin changes, such as seborrheickeratoses, dry, atrophic inelastic and deep wrinkled skin, telangiectasia, lentigines, and various pigmentary changes Age-associated skin diseases

23. Most clinical changes in aging skin result from a com-binationof molecular and cellular factors including Endogenous (eg, gene mutations, cellular metabolism, hormone) factors. Exogenous (eg, chemicals, toxins, pollutants, UV, and ionizing radiation) factors. Molecular aspects of skin aging

24. Several theories have been proposed, including The theory of cellular senescence, Decrease in cellular DNA repair capacity loss of telomeres, Point mutations of extranuclear mitochondrial DNA, Oxidative stress, Increased frequency of chromosomal abnormalities Pathogenesis of aged skin

25. 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

26. There is an increase of the baseline expression of the differentiation-associated genes like SPR2 and IL-1 receptor antagonist,andepidermal growth factor binding. In fibroblasts, genes like the c-fosproto-oncogene,thehelix-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

27. Elastingene 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 : Decreases in ERK- dependent MAPK activity . Increases in stress-activated JNK and p38 kinase that result in reduced cell proliferation, differentiation, and cell survival Enhanced growth arrest, apoptosis, and stress-related responses. Molecular mechanisms of skin aging

28. Molecular mechanisms of skin aging As a consequence of the stress-activated MAPK pathways, the expression of c-jun and c-junN 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: AP-1 is also elevated. the AP-1–regulated connective tissue-degrading enzymes MMP-1 (interstitial collagenase), MMP-3 (stromelysin 1), and MMP-9 (gelatinaseB) are elevated. There is an observed reduction in the expression of tissue inhibitors of MMPs.

29. 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/Smadsignallingpathway. 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.

30. Shared molecular mechanisms in intrinsic &extrinsic skin aging

31. Lessons to learn Gene mutations accompanying progeroidsyndromes, 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 : An acceleration of the aging phenotype. Alopecia. Skin atrophy and sclerosis. Telangiectasia. Poikiloderma. Thinning and graying of hair. Several malignancies.

32. 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 misregulationof key structural, signalling, and metabolic genes associated with the aging phenotype. Lessons to learn

33. 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: Dry, thin and wrinkled skin, obesity. Hyperglycemia, reduced body lean mass, osteopenia. Lowered venous access, rise in serum cholesterol. Tendency for cardiovascular diseases and subsequent premature death. Lessons to learn

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