MECHANISMS OF AGING SKIN

1. MECHANISMS OF AGING SKIN Ricci H. Rodriguez, MD

2. AGING MECHANISMS • Telomeres and Aging • DNA damage and Aging • Aging and the Immune System

3. Telomeres and Aging • Telomeres is the terminal portions of eukaryotic chromosomes, consist of up to many hundreds of tandem short sequence repeats (TTAGGG in all mammals). • Human telomeres shorten more than 30% during adulthood even in relatively quiescent skin fibroblasts, and telomeres of patients with premature aging syndromes, such as: • Werner syndrome,progeria, and dyskeratosiscongenita • Critically short telomeres signal for proliferative senescence or apoptosis

4. DNA damage and aging • The only genes implicated in the rate of aging are those in which mutations are responsible for premature aging syndromes: • Cockaynesyndrome patients • Ataxia telangiectasia • Werner syndrome • Progeria • These human premature aging diseases suggest that decreased DNA repair capacity is associated with accelerated aging and that cumulative DNA damage plays a major role in the aging process

5. Aging and the Immune System • The function of APCs, antigen-specific B and T cells, and lymphocyte cytokine secretion declines with age. • Conversely, the level of pro-inflammatory cytokines increases with age. • These changes have been attributed to oxidative stress and contribute to the increased incidence of infections and malignancies in the elderly. The immune system has two major roles: defense against external insults and internal immunologic surveillance

6. CUTANEOUS AGING Two distinct phenomena:1. Intrinsic Aging/ Chronologic Aging2. Photoaging

7. INTRINSIC AGING • physiologic alterations with subtle but undoubtedly important consequences for both healthy and diseased skin • cumulative damage to biomolecules, such as DNA as a result of continuous generation of free radicals, results in increased cellular vulnerability and eventually terminates in senescence or apoptosiS • is continuously exposed to ROS generated during aerobic metabolism (Fig. 108-1A is a universal, presumably inevitable change attributable to the passage of time alone

8. Histologic Features of Aging Human Skin

9. Functions of Human Skin That Decline with Age • Barrier function • Cell replacement • Chemical clearance • Epidermal hydration • Immune responsiveness • Mechanical protection • Sebum production • Sensory perception • Sweat production • Thermoregulation • Vitamin D production • Wound healing

10. EFFECTS OF MENOPAUSE • Age-associated decrements in keratinocyte barrier function, immune-regulation, and wound healing appear to be compounded by decreased estrogen levels and/or decreased responsiveness of cells to existing estrogens • hot flashes, atrophy of reproductive tissue, and changes in non-reproductive tissues • reduced dermal collagen content • increased cutaneous extensibility and • decreased elasticity • increased dryness • increased fine wrinkling • decreased sebum levels

11. PHOTOAGING • ELASTOSIS – A prominent feature of photoagedskin, a process characterized clinically by yellow discoloration and pebbly surface and histologically by tangled masses of degraded elastic fibers that further deteriorate to form an amorphous mass composed of disorganized tropoelastin and fibrillin superposition on intrinsic aging of changes attributable to chronic sun exposure, which are neither universal nor inevitable has major morphologic as well as physiologic manifestations and corresponds more closely to the popular notion of old skin

12. PHOTOAGING Photoaging: heliodermatitis. Pronounced furrowing, yellow discoloration, and pebbly surface (solar elastosis) with plugged follicles on the neck. Arrows denote small actinic keratoses.

13. MECHANISMS OF PHOTOAGING: • MEMBRANE AND NUCLEAR SIGNALING • MITOCHONDRIAL DAMAGE • PROTEIN OXIDATION

14. MEMBRANE and NUCLEAR SIGNALING • UV-induced collagen degradation is generally incomplete leading to accumulation of partially degraded collagen fragments in the dermis thus reducing the structural integrity of the skin

15. MITOCHONDRIAL DAMAGE • generation of ROS damages mitochondrial DNA (mtDNA)  resulting in decreased mitochondrial function, leading to further accumulation of ROS and compromising the cell's ability to generate energy

16. PROTEIN OXIDATION • Proteins are affected by oxidative damage, and photodamaged skin shows accumulation of oxidized, damaged proteins in the upper portions of the dermis

17. FEATURES OF PHOTOAGED SKIN CLINICAL/ HISTOLOGIC • Dryness (roughness) - Increased compaction of stratum corneum, increased thickness of granular cell layer, reduced epidermal thickness, reduced epidermal mucincontent • Actinic keratoses - Nuclear atypia, loss of orderly, progressive keratinocyte maturation; irregular epidermal hyperplasia and/or hypoplasia; occasional dermal inflammation • Irregular pigmentation • Freckling - Reduced or increased number of hypertrophic, strongly DOPA-positive melanocytes • Lentigines - Elongation of epidermal rete ridges; increases in number and melanization of melanocytes

18. Diffuse irreversible hyperpigmentation (bronzing) - Increased number of DOPA-positive melanocytes and increased melanin content per unit area and increased number of dermal melanophages • Guttatehypomelanosis - Reduced number of atypical melanocytes • Wrinkling • Fine surface lines - None detected • Deep furrows - Contraction of septae in the subcutaneous fat • Stellatepseudoscars- Absence of epidermal pigmentation, altered fragmented dermal collagen

19. Elastosis (fine nodularity and/or coarseness) - Nodular aggregations of fibrous to amorphous material in the papillary dermis • Inelasticity - Elastoticdermis • Telangiectasia - Ectaticvessels often with atrophic walls • Venous lakes - Ectaticvessels often with atrophic walls • Purpura (easy bruising) - Extravasatederythrocytes and increased perivascular inflammation • Comedones (maladie de Favre et Racouchot) - Ectasiaof the pilosebaceous follicular orifice • Sebaceous hyperplasia - Concentric hyperplasia of sebaceous glands

20. SMOKING AND SKIN AGING • Cigarette smoking exacerbates photoaging with direct correlation between the number of pack-years smoked and the severity of wrinkling and grayishdiscoloration • Histologicanalysis of “smoker's skin” reveals elastic fiber thickening and fragmentation, similar to that found in sundamagedskin • However, whereas Solar elastosis is restricted in the papillary dermis, elastic fiber changes in Smoker's skin also occur in the reticular dermis.

21. decreased stratum corneum water • dryness and atrophy • poor wound healing capacity • increased incidence of skin cancers • increased severity of photoaging-like changes compared with nonsmokers

22. Presumptive Pathophysiology of Common Cutaneous Disorders in the Elderly: • Benign neoplasia • Seborrheickeratosis - focalepidermal homeostatic loss leading to increased endothelin-1 • Malignant neoplasia • Squamous cell carcinoma and actinic keratosis - Ultraviolet-induced DNA damage • Basal cell carcinoma - Decreased DNA damage repair capacity • Malignant melanoma - Cumulative age-associated DNA damage • Merkel cell carcinoma - Decreased DNA damage repair capacity • Angiosarcoma

23. SEBORRHEIC KERATOSIS Management: AHAs Electrocautery Cryosurgery

24. SCC and BCC, MALIGNANT MELANOMA and MERKEL CELL CARCINOMA Prevention: Avoidance of chronic sun exposure

25. Papulosquamous disorders • Psoriasis - Changes in patient's environment leading to Koebnerization Systemic medications • Xerosis/asteatoticdermatitis • Disturbance of epidermal maturation (decreased filaggrin production and/or altered lipid profile) • Decreased water content in outer layers of stratum corneum • Slower corneocyte transit • Pruritus • Penetration of irritants through damaged stratum corneum (?) • Altered sensory threshold (neuropathy) (?) • Metabolic disorder • Endocrine disorder • Malignant neoplasm • Adverse drug reaction • Parasitic infestation

26. PSORIASIS and XEROSIS Management: Medium-potency topical steroids Emollients (liberal application)

27. Infections • Compromised local cutaneous health predisposing to growth of infective organism • Age-associated decreased immune function • Underlying systemic disorder associated with decreased immune function • Ulcers • Impaired wound healing capacity (decreased levels of growth factors, decreased cellular proliferative capacity, increased perivascular fibrin deposition) • Decreased mobility • Underlying systemic disorder • Compromised local cutaneous health (venous stasis, arteriosclerosis, hypertension)

28. ULCERS and BULLOUS PEMPHIGOID Management: Frequent turning in bed/ repositioning Antibiotics Debridement

29. Bullouspemphigoid • Flattening of the dermal-epidermal junction • Increased circulating autoantibodies • Photosensitivity reactions • Medications with unsaturated ring structures

30. THANK YOU!!! =)