AGING FACE: PATHOPHYSIOLOGYByDr. D R Dhaked

Aging Begins day we are born and highly individualizedNo single measure of how old a person isProceeds at different rates in different peopleGradual decline in organ functional reserves with reduction in ability to maintain homeostasis under stress

Facial Aging

Begins with surface and subsurface structural changes in multiple facial tissue layers, including skin, fat, muscle and bone.Facial tissue layers age interdependently, contributing to overall facial appearance. Changes in one tissue layer have an effect on the other layers.

Skin

With age, skin undergoes several changes. More likely to wrinkle or sag Reduction in collagen Thinner Drier Less elastic

Fat

-A youthful look depends on having the right amount of facial fat in right places. Redistribution, accumulation, and atrophy of fat lead to facial volume loss. Some areas lose fat (forehead and cheeks). Other areas gain fat (mouth and jaw). Modification of the fat pads leads to contour deficiencies.

Bone

There is a significant loss of facial bone with age.Aging of the craniofacial skeleton may be due to changes in relative dynamics of bone expansion and bone resorption. Bone resorption leads to biometric volume loss. Without the structural support of bone, there are noticeable changes in the other layers of overlying soft tissue and skin

Signs of Facial Aging

Greater visibility of bony landmarks, lines and wrinkles Prominence of transverse forehead lines Nasolabial folds become more prominent Hollowing of the mid-face (loose skin) Changes in area around the mouth (vertical wrinkles, lipthinning and flattening) Development of prejowl depression

AgingINTRINSIC SKIN AGING (chronologic aging) or normal agingEXTRINSIC AGING

INTRINSIC SKIN AGING (chronologic aging)

Inevitable natural aging process that occurs in all people Occurs as part of a pre-programmed degeneration within cells and extracellular matrix in all skin layers. Although begin in 20s, visible signs are not apparent for many decades. Intrinsic aging proceeds at highly variable rates between different people Primarily determined by unique genetic make-up and underlying type of skin

Intrinsic Aging: Role of Telomeres

TelomeresTandem repeats of short base sequences, ...TTAGGG... in mammals, at end of each chromosome, that are required for chromosome stability. With continued cell division, telomeres are shortened, resulting in loss of ability of cells to divide.

TelomeresTelomerase activity is detected in vitro and in vivo in normal human epidermis, primarily in the proliferative basal layer Not found in the dermal compartment of skin or in cultured fibroblastsHarle-Bachor, C, Boukamp, P: Telomerase activity in the regenerative basal layer of the epidermis in human skin and in immortal and carcinoma-derived skin keratinocytes. Proc Natl Acad Sci USA 1996 93: 64766481,

Cytoskeleton and Skin agingAged skin has increased rigidityDue to an increase in F actin filamentsImportant in age related loss of elasticity of the skin.

Endocrine System and AgingWith aging, the levels of epidermal precursor of vitamin D3 decrease.Older individuals are more susceptible to vitamin D3 deficiency in absence of regular sun exposure.May lead to osteoporosis, psoriasis and skin cancer

Endocrine System and AgingEstrogen stimulates fibroblasts to make collagenDecreased levels of estrogen are associated with loss of collagen and increased wrinklingHRT protects skin from agingBaumann, L. A dermatologist's opinion on hormone therapy and skin aging, Fertility and Sterility 2005 Aug;84(2):289-290.

Age related changes in metabolic functions Reduced oxidative phosphorylation by mitochondria Diminished synthesis of structural, enzymatic and regulatory proteins Decreased capacity for uptake of nutrientsIncreased DNA damage and diminished repair of chromosomal damage Accumulation of oxidative damage in proteins and lipids (eg lipofuscin pigment) Accumulation of advanced glycosylation end products

Morphological alterations Irregular and abnormally lobed nuclei Swollen, pleomorphic and vacuolated mitochondria Decreased endoplasmic reticulum Distorted Golgi apparatus

INTRINSIC SKIN CHANGESEpidermisKeratinocytes demonstrate slower turnover.Keratin sloughs more slowly with thickening of keratin layer.Melanoctyes decrease in number and produce less melanin.Uneven melanin pigment distribution.Flattening of the epidermis-dermis junction. Prone to blistering.

DermisFibroblasts Decreased number and less collagen production.Collagen Decreased quantity. Abnormal, weakened structure.Elastin Thickened fibers with less elasticity.Matrix Decreased quantity.Blood vessels dilated, thinned and weakened walls, prone to rupture.

Subcutaneous LayerFat loss and thinning.Weakening of the retaining ligaments.Fewer blood vessels.Sweat glands - decreased.Sebaceous glands Fewer with less sebum production.Hair shafts fewer and thinner with less pigment.

EXTRINSIC AGING

Outside factors that accelerate intrinsic aging. Photoaging Smoking MalnutritionHormonal Disorders Chronic Disease States Repetitive facial expressionsGravity

Photoaging

Caused by harmful effects of sunlight Ultraviolet light is the prinicipal cause of photoagingUVB penetrates only into epidermis and is responsible for redness and blistering associated with sunburns. UVA penetrates more deeply into dermis, related to photoaging

Photoaged skin shows deep coarse wrinkling, excessive dryness, severe brown spots dry leathery texture when compared to intrinsically aged skin

*PHOTOAGING3 types of reactions to UV exposure:Free Radicals, essentially due to UVADirect cell death, essentially due to UVBMMP Enzymes

*FREE RADICALSFree radicals or ROS (reactive oxygen species) can lead to breakage of important molecules: DNA (mutations, renewal failure, cell death) collagen, elastin, GAG (skin firmness)lipids (membrane or structural)

*UV DAMAGE AND OXIDATIVE STRESSUV damage

DNA effects

DNA fragmentation

Matrix effects

MMP : TIMP ratio

Membrane effects:

ROS

Lipids peroxidation

Hydroperoxides

Enzymatic systems

SOD

Glutathion peroxidase

Heme oxidase

*DNA DAMAGE

UVA acts through oxidative stress forming reactive oxygen species (ROS) that will damage the DNA and lead to cancerUVB impact on DNA in the cell creating damages which may lead to cancer: non-melanoma skin cancer (NMSC)

Advanced Glycosylation End ProductsPost-translational modification of collagen by sugar (AGE products)Non-enzymatic attachment of glucose to proteinsFormation of irreversible cross links

*UVB DAMAGEFollowing structural changes in DNA, there is an altered expression of oncogenes and tumor suppression genes, such as p53

NMSC show a high incidence of mutation in p53 gene

*p 53 GENEPlays an important role in:blocking the cell cycle after exposure to DNA-damaging agents e.g. UV, in order to allow for repair before duplication

or killing the cell to avoid multiplication of damaged cells (formation of sunburn cells)

*p 53 GENE

The induction of detectable levels of p53 in human epidermis after UV exposure is relevant to skin carcinogenesis

*Collagen & PhotodamageMajor structural component of ECM70% of the dry weight of skin

Collagen degradation is believed to play a role in formation of wrinkles

Collagen Cross LinksIntermolecular cross links between lysine residues in adjacent collagen helicesNon-reducible cross links increase with ageArise as a side effect of free radical damage

*MMP ENZYMESCollagenases (1 to 4) are specific to various collagen, Gelatinases (A & B) are non specificStromelysins (1-3) specific of fibronectin, laminin, collagen IV,Elastase: elastin

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SmokingActs primarily via vasoconstriction of blood vessels going to and through skin layers. Decreased blood flow results indecreased nutrients, decreased oxygen supply increased inflammatory byproducts (free radical oxidation byproducts). Net effectdecreased collagen production and turnover, poor quality collagen and elastin, decreased quantity of matrix components and less gland secretions.

Gravity.Constantly pulls on bodies. In 50s, when skins elasticity declines dramatically, effects of gravity become evident. Causes tip of nose to droop, ears to elongate, eyelids to fall, jowls to form, and upper lip to disappear while lower lip becomes more pronounced.

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**Telomeres of human chromosomes (yellow) are shown by in situ hybridization with a telomeric probe. These structural components of chromosomes are essential for genomic stability and play a key role in cancer. In normal somatic cells telomeres shorten each cell division, a process that limits cellular lifespan. However, cancer cells overcome this proliferative blockade by activating telomerase, which elongates telomeres.The epidermis is one of the few regenerative tissues to express telomerase. Slide from: Christopher Counter Associate Professor Department of Pharmacology and Cancer Biology, Duke University Program in Cell and Molecular Biology.********