ricci h. rodriguez, md mechanisms of aging skin. aging mechanisms telomeres and aging dna damage and...

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MECHANISMS OF AGING SKIN

Ricci H. Rodriguez, MDMECHANISMS OF AGING SKIN1AGING MECHANISMS

Telomeres and AgingDNA damage and AgingAging and the Immune System

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 dyskeratosis congenita

Critically short telomeres signal for proliferative senescence or apoptosisThus, telomeres appear to serve as a biologic clock that determines proliferative life span of the cell

- Thus, telomeres appear to serve as a biologic clock that determines proliferative life span of the cell

3DNA damage and aging

The only genes implicated in the rate of aging are those in which mutations are responsible for premature aging syndromes:Cockayne syndrome patients Ataxia telangiectasiaWerner 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

- Cockayne syndrome patients display mutations in DNA helicases- Ataxia telangiectasia is caused by a mutation in the ATM gene- Werner syndrome is caused by mutation in a protein with DNA helicase and exonuclease domains- Progeria, a disease that leads to death from atherosclerotic heart disease often in the first decade of life, is caused by mutations in lamin A

4Aging 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

Pro-inflammatory cytokines: IL 1 and IL6, VEGF and TNF alpha5CUTANEOUS AGING

Two distinct phenomena:1. Intrinsic Aging/ Chronologic Aging

2. Photoaging

INTRINSIC AGINGphysiologic 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. 108-1Ais a universal, presumably inevitable change attributable to the passage of time alone

Histologic Features of Aging Human Skin

Loss of elastin contributes to vascular rigidity8Functions of Human Skin That Decline with AgeBarrier function Cell replacementChemical clearanceEpidermal hydrationImmune responsivenessMechanical protectionSebum productionSensory perceptionSweat productionThermoregulationVitamin D productionWound healing9EFFECTS 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 estrogenshot flashes, atrophy of reproductive tissue, and changes in non-reproductive tissues reduced dermal collagen contentincreased cutaneous extensibility and decreased elasticityincreased drynessincreased fine wrinklingdecreased sebum levelsPHOTOAGINGELASTOSIS A prominent feature of photoaged skin, 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 inevitablehas major morphologic as well as physiologic manifestations and corresponds more closely to the popular notion of old skin

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

MECHANISMS OF PHOTOAGING:

MEMBRANE AND NUCLEAR SIGNALINGMITOCHONDRIAL DAMAGE

PROTEIN OXIDATIONMEMBRANE and NUCLEAR SIGNALINGUV-induced collagen degradation is generally incomplete leading to accumulation of partially degraded collagen fragments in the dermis thus reducing the structural integrity of the skinMITOCHONDRIAL DAMAGEgeneration 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

MITOCHONDRIA -cellular organelles that produce energy (adenosine triphosphate) by consuming oxygen.15PROTEIN OXIDATIONProteins are affected by oxidative damage, and photodamaged skin shows accumulation of oxidized, damaged proteins in the upper portions of the dermisFEATURES OF PHOTOAGED SKINCLINICAL/ HISTOLOGICDryness (roughness) - Increased compaction of stratum corneum, increased thickness of granular cell layer, reduced epidermal thickness, reduced epidermal mucin content

Actinic keratoses - Nuclear atypia, loss of orderly, progressive keratinocyte maturation; irregular epidermal hyperplasia and/or hypoplasia; occasional dermal inflammation

Irregular pigmentationFreckling - Reduced or increased number of hypertrophic, strongly DOPA-positive melanocytesLentigines - Elongation of epidermal rete ridges; increases in number and melanization of melanocytesDiffuse irreversible hyperpigmentation (bronzing) - Increased number of DOPA-positive melanocytes and increased melanin content per unit area and increased number of dermal melanophagesGuttate hypomelanosis - Reduced number of atypical melanocytesWrinklingFine surface lines - None detectedDeep furrows - Contraction of septae in the subcutaneous fatStellate pseudoscars - Absence of epidermal pigmentation, altered fragmented dermal collagen

Elastosis (fine nodularity and/or coarseness) - Nodular aggregations of fibrous to amorphous material in the papillary dermisInelasticity - Elastotic dermisTelangiectasia - Ectatic vessels often with atrophic wallsVenous lakes - Ectatic vessels often with atrophic wallsPurpura (easy bruising) - Extravasated erythrocytes and increased perivascular inflammationComedones (maladie de Favre et Racouchot) - Ectasia of the pilosebaceous follicular orificeSebaceous hyperplasia - Concentric hyperplasia of sebaceous glands

SMOKING AND SKIN AGINGCigarette smoking exacerbates photoaging with direct correlation between the number of pack-years smoked and the severity of wrinkling and grayish discoloration

Histologic analysis of smoker's skin reveals elastic fiber thickening and fragmentation, similar to that found in sundamaged skin

However, whereas Solar elastosis is restricted in the papillary dermis, elastic fiber changes in Smoker's skin also occur in the reticular dermis. This dermal elastosis has been suggested to result from increased elastase activity in neutrophils, chronic dermal ischemia, and the pro-oxidant effects of cigarette smoke compounded by decreased levels of vitamin A, which reduce the capacity to quench free oxygen radicals and increase DNA damage.20decreased stratum corneum water dryness and atrophypoor wound healing capacity increased incidence of skin cancers increased severity of photoaging-like changes compared with nonsmokers

Presumptive Pathophysiology of Common Cutaneous Disorders in the Elderly:

Benign neoplasiaSeborrheic keratosis - focal epidermal homeostatic loss leading to increased endothelin-1Malignant neoplasiaSquamous cell carcinoma and actinic keratosis - Ultraviolet-induced DNA damageBasal cell carcinoma - Decreased DNA damage repair capacityMalignant melanoma - Cumulative age-associated DNA damageMerkel cell carcinoma - Decreased DNA damage repair capacityAngiosarcoma

SEBORRHEIC KERATOSISManagement: AHAsElectrocauteryCryosurgery

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

24Papulosquamous disordersPsoriasis - Changes in patient's environment leading to Koebnerization Systemic medicationsXerosis/asteatotic dermatitis Disturbance of epidermal maturation (decreased filaggrin production and/or altered lipid profile)Decreased water content in outer layers of stratum corneumSlower corneocyte transitPruritusPenetration of irritants through damaged stratum corneum (?)Altered sensory threshold (neuropathy) (?)Metabolic disorderEndocrine disorderMalignant neoplasmAdverse drug reactionParasitic infestation

PSORIASIS and XEROSISManagement:Medium-potency topical steroids

Emollients (liberal application)

InfectionsCompromised local cutaneous health predisposing to growth of infective organismAge-associated decreased immune functionUnderlying systemic disorder associated with decreased immune functionUlcersImpaired wound healing capacity (decreased levels of growth factors, decreased cellular proliferative capacity, increased perivascular fibrin deposition)Decreased mobilityUnderlying systemic disorderCompromised local cutaneous health (venous stasis, arteriosclerosis, hypertension)

ULCERS and BULLOUS PEMPHIGOIDManagement: Frequent turning in bed/ repositioning

Antibiotics

Debridement

Bullous pemphigoidFlattening of the dermal-epidermal junctionIncreased circulating autoantibodiesPho

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