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Photoprotection: An EnLIGHTening Topic

Photoprotection: An EnLIGHTening Topic. George Martin MD Dermatology and Laser Center of Maui. Conflict of Interest. Consultant: DUSA, Valeant Speaker: Scientific Ad Boards: DUSA, Valeant , Medicis Sanofi Aventis DUSA

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Photoprotection: An EnLIGHTening Topic

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  1. Photoprotection: An EnLIGHTening Topic George Martin MD Dermatology and Laser Center of Maui

  2. Conflict of Interest Consultant: DUSA, Valeant Speaker: Scientific Ad Boards: DUSA, Valeant , Medicis Sanofi Aventis DUSA Abbott Stock: Astellas Doc Martins of Maui Galderma Photocure LEO Medicis PharmaDerm/Nycomed Valeant

  3. Biological Perspectives of Aging Skin • Aging skin is a cumulative process • Consequence of genetically programmed decreases in functional capacity • Loss of ability to repair damage

  4. Intrinsic vs. Extrinsic Aging Skin at Age 100 Intrinsic Aging Extrinsic Aging

  5. Intrinsic Aging • Clinical, histologic, and physiologic changes in sun-protectedskin of older adults

  6. Causes of Intrinsic Aging • Genetic Programming and Replicative Senescence • Hormonal Effects • Mitochondrial Leakage

  7. Genetic Programming and Replicative Senescence

  8. Telomeres: Our Biologic Cellular Clock

  9. Telomere Caps on Chromosomes

  10. Telomeres • The terminal sequence of chromosomal DNA • Approx. 10,000 base pairs that shorten to around 6,000 -7,000 base pairs with age • Composed of a repeating base pair sequence of TTAGGG which form a loop structure which caps the end of DNA strands • Without telomeres you get cross DNA fusion, mutations and cell death

  11. Telomere Shortening • Critically short telomere lengths cause cells to go into a senescent state • When a critical length is reached the cell stops dividing after 50 – 60 cell replication cycles - nothing is capable of stimulating the cell to divide at that point (Greider & Blackburn. Cell, 1985)

  12. Telomeres shorten with age (50-150 bp/mitosis) in vitro and in vivo1,2,3 Telomere length correlates with longevity in persons > 60 years old4,5 Werner syndrome, progeria, progeria-like syndromes are characterized by short telomeres Evidence for Telomeres and Aging • 1. Lindsay et al. Mut Res, 1991; 2. Vaziri et al. PNAS, 1994; 3. Dimri et al. PNAS, 1995; 4. Cawthon et al. Lancet, 2003; 5. Valdes et al. Lancet, 2005

  13. The Role of Telomerase • Telomerase is the enzyme complex responsible for lengthening telomeres by adding TTAGGG sequences to the DNA • Telomerase is expressed in germline cells, stem cells and >90% of malignant cells1 • Telomerase is also expressed transiently in S phase in normal cells2 • Telomerase is intermittently active in normal somatic cells. • Telomerase slows but doesnotprevent telomere shortening 1.Karlseder et al, Science 1998; 2.Masutomi et al. Cell, 2003)

  14. Extrinsic Aging (Photoaging) • Clinical, histologic, and physiologic changes in habitually sun-exposed skin of older adults

  15. Causes of Extrinsic Aging • Sunlight exposure • Environmental pollution (smog, ozone, NO2) • Smoking: 10,000,000,000,000,000 free radicals/cigarette

  16. Continuum from Photodamage to Carcinoma SCC AK Early AK Photodamage

  17. Histology of Aging and Photoaging UP TO 80% OF THE DAMAGE ON AN AGING FACE CAN BE ATTRIBUTED TO PHOTODAMAGE • Young Skin • Healthy organized • epidermis • Normal dermal matrix • Intrinsic Aging • Thin disorganized epiderm. • Collagen: Irregular, • disorganized ,  synthesis • Loss of elasticity, •  firmness • Fragile skin Photodamage Elastin tissue:  but amorphous, coarse bundles (solar elastosis) Dermal matrix: GAG but disorganized/dec.fcn Loss of elasticity Hyperpigmentation Immune fcn. Fisher et al. N Engl J Med. 1997; 337:1419-28; Bosset et al. Br J Dermatol. 2003; 149:826-835; Contet-Audonneau et al. Br J Dermatol. 1999:140:1038-1047

  18. Young vs. OldCollagen & Fibroblasts

  19. Intrinsic vs. Extrinsic Aging: Skin Appearance vs. Function Intrinsic Aging • Less effect on appearance • More effect on cellular function i.e. dysfunction Extrinsic “Photoaging” • Greater effect on appearance • Accelerates loss of cellular and immune function of immune function • Carcinogenesis

  20. Understanding the UV Spectrum

  21. UV Penetration

  22. UV Spectrum and DNA Damage UVC 200 – 290 nm (Filtered out by our ozone) DNA Strand Breaks Prymidine Dimers Prymidine Photoadducts UVB 290 – 320 nm Prymidine Dimers Photodynamic Actions (ROS – Reactive Oxygen Species Production) UVA 320 -400 nm Photodynamic Actions (ROS) Photosensitization reactions ( Protein and DNA cross- linking, DNA -photosensitizer photo-adducts)

  23. Pyrimidine Dimer Formation Due to UVB Irradiation UVB

  24. UVB’s “Fingerprint Mutation” UVB causes a very specific type of “fingerprint mutation “* carried thru subsequent cell divisions *UVB causes a mutation in which cytosine (C) is changed to thymidine (T) (C -> T transversion) or when two cytosines are adjacent to two thymidines (CC -> T T transversion) There is no other carcinogenic agent that can cause this pattern of mutations UV radiation is unique in that it functions as both initiator and promoter in carcinogenesis

  25. “UVA Signature” via ROS • UVA generated ROS cause oxidation of DNA guanosine nucleotides to form the “UVA signature” adduct, 8-oxo-7,8-dihydro-2 –deoxyguanosine. • UVA is also capable of generating “UVB signature” CPDs in cultured cells and human skin in vivo. “UVA Signature”

  26. Sunburn: Ultraviolet A and B Factoids • UVB @295nm is 1250 times more erythemogenic (sun burning) than UVA @365nm • More UVA photons reach the earth’s atmosphere (10 – 100x) than UVB

  27. The Action Spectra for Sun Damage are Primarily (80:20) UVB Erythema1 Squamous cell carcinoma2 Elastosis3 10 The “ideal” sunscreen proportion is SPF: UVAPF of 3:1 1 Sensitivity 0.1 0.01 0.001 UVB 0.0001 UVA 0.00001 280 320 360 400 Wavelength (nm) 1. ISO 17166/CIE S007/E. 2. de Gruijl FR, Van der Leun JC. Health Phys. 1994;67(4):319-325. 3. Kligman LH, Sayre RM. Photochem Photobiol. 1991;53(2):237-242.

  28. What Happens After a Sunburn?

  29. How UV Causes Photodamage Fisher GJ et al. Arch Dermatol. 2002; 138:1462-1470.

  30. As Little as .01% MED Can Induce This Cytokine Cascade Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138:1462–1470

  31. Chronic UVA Exposure

  32. Prevention of Photodamage

  33. Direct, Indirect & Reflected UV INDIRECT DIRECT REFLECTED

  34. SUMMARY • Diffuse “Indirect” radiation: • Approx. 80% of the annual UV exposure • Significant levels measured on cloudy days • Direct radiation: • 15 – 24% annual UV dose • Occurred mostly during peak summer hours • Reflected radiation: • Negligible • Increased on cloudless days with surface reflector (eg. snow)

  35. Nationwide Public Awareness Programs • Promote the importance of using sunscreens, UV protective clothing, broad brimmed hats, sunglasses, umbrellas as well as sun avoidance during hours of peak UV exposure • Demonstrated effectiveness in stabilizing NMSC1and reducing the incidence of melanoma 2in Australia. 1. Staples M, Elwood M, Burton R, Williams J, Marks R, Gilles G. Non-melanoma skin cancer in Australia: the 2002 national survey trends since 1985. Med J Aust 2006; 184: 6 – 10. 2 Giles GG, Armstrong BK, Burton RC, Staples MP, Thrusfield VJ. Has mortality from melanoma stopped rising in Australia? Analysis of trends between 1931 and 1994. BMJ 1996; 312: 1121-5.

  36. Discourage Sunbathing

  37. Have Your Pets Discourage Sunbathing

  38. Momma Don’t Let Your Babies Get Sunburned! • Use sunblock on your children 6 months and older.

  39. Sunscreen Absorption Spectrum

  40. Physical Blockers (TiO2 and ZnO) Work Predominantly via Absorption

  41. UVB Protection vs. SPF

  42. SPF Protection is Proportional to the Amount of Sunscreen Applied Ou-Yang H., Stanfield J., Cole C., Appa Y., Rigel D. J. Amer. Acad. Dermatol. 67:6, pp 1220 – 1227. 2012.

  43. FDA Monograph on Sunscreens • “Broad Spectrum” defined by CW test • Broad spectrum claims not allowed for products with SPF<15 • “Waterproof” and “Sweatproof” no longer usable • Reapply every 2 hrs. stated • Statement recognizing use of sunscreens for skin cancer prevention and skin aging is permitted

  44. Not Addressed by the FDA Monograph • Whether to limit package labeling of sunscreens with > SPF 50 to SPF 50+ • Protocols for dealing with spray sunscreens ie the SPF in the bottle does not translate after spraying into the SPF on the skin

  45. “Broad Spectrum” Determination CW = 382 2.0 1.8 1.6 1.4 1.2 1.0 0.8 Absorbance 90% of total Absorbance area under the curve 0.6 0.4 0.2 0.0 290 310 330 350 370 390 Wavelength • “Critical Wavelength” in vitro absorbance calculation • Wavelength below which 90 % of the absorbance is present • 370nm is the “pass/fail” critical wavelength for “Broad Spectrum Protection” Amplitude Breadth Diffey et al JAAD 43: 1024,2000

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