AAR  Vol.3 No.4 , September 2014
Review of Major Theories of Skin Aging
Here we aim to describe each factor that leads to skin aging and describe their mechanisms. A PubMed database searches (from January 2004 to March 2014) using aging and skin as searched terms. There are substantial evidences showing that aging is associated with damage from free radicals represented by various reactive oxygen species (ROS). Mitochondria are producers and also targets of oxidative stress. The cycle of mitochondrial dysfunction can trigger the aging process. In the cellular senescence and telomeres theory, the diploid cells exhibit a limited proliferation potential. After a finite number of divisions, they enter a state of senescence with a stop replication in cell proliferation. It is suggested that aging is associated mainly with hyper-regulation of apoptosis. Obesity presumably accelerates the process of aging, which is aggravated by smoking. And the influence of the environment, called solar UV irradiation is of considerable importance to skin aging. There are several mechanisms that trigger the natural aging process and contribute to age-related changes, including oxidative stress theory of free radicals, the mitochondrial dysfunction, telomere shortening, UV radiation and other mechanisms that taken together or alone may or not accelerate the change in skin.

Cite this paper
Gragnani, A. , Cornick, S. , Chominski, V. , Ribeiro de Noronha, S. , Alves Corrêa de Noronha, S. and Ferreira, L. (2014) Review of Major Theories of Skin Aging. Advances in Aging Research, 3, 265-284. doi: 10.4236/aar.2014.34036.
[1]   Prost-Squarcioni, C., Fraitag, S., Heller, M. and Boehm, N. (2008) Functional Histology of Dermis. Annales de Dermatologie et de Venereologie, 135, 15-20.

[2]   Gragnani, A., Müller, B.R., Silva, I.D., Noronha, S.M. and Ferreira, L.M. (2013) Keratinocyte Growth Factor, Tumor Necrosis Factor-Alpha and Interleukin-1 Beta Gene Expression in Cultured Fibroblasts and Keratinocytes from Burned Patients. Acta Cirúrgica Brasileira, 28, 551-558.

[3]   Gragnani, A., Sobral, C.S. and Ferreira, L.M. (2007) Thermolysin in Human Cultured Keratinocyte Isolation. Brazilian Journal of Biology, 67, 105-109.

[4]   Sobral, C.S., Gragnani, A., Cao, X., Morgan, J.R. and Ferreira, L.M. (2007) Human Keratinocytes Cultured on Collagen Matrix Used as an Experimental Burn Model. Journal of Burns and Wounds, 7, e6.

[5]   Porcheron, A., Mauger, E. and Russell, R. (2013) Aspects of Facial Contrast Decrease with Age and Are Cues for Age Perception. PLoS ONE, 8, Article ID: e57985.

[6]   Puizina-Ivic, N. (2008) Skin Aging. Acta Dermatovenerologica Alpina, Panonica, et Adriatica, 17, 47-54.

[7]   Du, C., Anderson, A., Lortie, M., Parsons, R. and Bodnar, A. (2013) Oxidative Damage and Cellular Defense Mechanisms in Sea Urchin Models of Aging. Free Radical Biology Medicine, 63, 254-263.

[8]   Viña, J., Borras, C., Abdelaziz, K.M., Garcia-Valles, R. and Gomez-Cabrera, M.C. (2013) The Free Radical Theory of Aging Revisited: The Cell Signaling Disruption Theory of Aging. Antioxidants Redox Signaling, 19, 779-787.

[9]   Wei, Y., Zhang, Y.J., Cai, Y. and Xu, M.H. (2014) The Role of Mitochondria in mTOR-Regulated Longevity. Biological Reviews of the Cambridge Philosophical Society.

[10]   Barja, G. (2013) Updating the Mitochondrial Free Radical Theory of Aging: An Integrated View, Key Aspects and Confounding Concepts. Antioxidants Redox Signaling, 19, 1420-1445.

[11]   Fisard, M. and Ravussin, E. (2006) Energy Metabolism and Oxidative Stress: Impact on the Metabolic Syndrome and the Aging Process. Endocrine, 29, 27-32.

[12]   Rattan, S.I. (2006) Theories of Biological Aging: Genes, Proteins and Free Radicals. Free Radical Research, 40, 1230-1238.

[13]   Ma, Y.S., Wu, S.B., Lee, W.Y., Cheng, J.S. and Wei, Y.H. (2009) Response to the Increase of Oxidative Stress and Mutation of Mitochondrial DNA in Aging. Biochimca et Biophysica Acta, 1790, 1021-1029.

[14]   Gladyshev, V.N. (2014) The Free Radical Theory of Aging Is Dead. Long Live the Damage Theory! Antioxidants & Redox Signaling, 20, 727-731.

[15]   Kohl, E., Steinbauer, J., Landthaler, M. and Szeimies, R.M. (2011) Skin Ageing. Journal of the European Academy of Dermatology and Venereology, 25, 873-884.

[16]   Ott, M., Gogvadze, V., Orrenius, S. and Zhivotovsky, B. (2007) Mitochondria, Oxidative Stress and Cell Death. Apoptosis, 12, 913-922.

[17]   Godic, A., Poljsak, B., Adamic, M. and Dahmane, R. (2014) The Role of Antioxidants in Skin Cancer Prevention and Treatment. Oxidative Medicine and Cellular Longevity, 2014, Article ID: 860479.

[18]   Fraga, C.G., Motchnik, P.A., Shigenaga, M.K., Helbock, H.J., Jacob, R.A. and Ames, B.N. (1991) Ascorbic Acid Protects against Endogenous Oxidative DNA Damage in Human Sperm. Proceedings of the National Academy of Sciences of the United States of America, 88, 11003-11006.

[19]   Tanigawa, T., Kanazawa, S., Ichibori, R., Fujiwara, T., Magome, T., Shingaki, K., Miyata, S., Hata, Y., Tomita, K., Matsuda, K., Kubo, T., Tohyama, M., Yano, K. and Hosokawa, K. (2014) (+)-Catechin Protects Dermal Fibroblasts against Oxidative Stress-Induced Apoptosis. BMC Complementary & Alternative Medicine, 14, 133.

[20]   Randhawa, M., Sangar, V., Tucker-Samaras, S. and Southall, M. (2014) Metabolic Signature of Sun Exposed Skin Suggests Catabolic Pathway Overweighs Anabolic Pathway. PLoS ONE, 9, Article ID: e90367.

[21]   Bennett, M.F., Robinson, M.K., Baron, E.D. and Cooper, K.D. (2008) Skin Immune Systems and Inflammation: Protector of the Skin or Promoter of Aging? Journal of Investigative Dermatology Symposium Proceedings, 13, 15-19.

[22]   Slominski, A., Tobin, D.J., Shibahara, S. and Wortsman, J. (2014) Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation. Physiological Reviews, 84, 1155-1228.
Menck, C.F.M. and Munford, V. (2014) DNA Repair Diseases: What Do They Tell Us about Cancer and Aging? Genetics and Molecular Biology, 37, 220-233.

[23]   McKay, B.C., Becerril, C. and Ljungman, M. (2001) P53 Plays a Protective Role against UV- and Cisplatin-Induced Apoptosis in Transcription-Coupled Repair Proficient Fibroblasts. Oncogene, 20, 6805-6808.

[24]   Andrade, L.N., Nathanson, J.L., Yeo, G.W., Menck, C.F. and Muotri, A.R. (2012) Evidence for Premature Aging Due to Oxidative Stress in iPSCs from Cockayne Syndrome. Human Molecular Genetics, 21, 3825-3834.

[25]   Pascucci, B., Lemma, T., Iorio, E., Giovannini, S., Vaz, B., Iavarone, I., Calcagnile, A., Narciso, L., Degan, P., Podo, F., et al. (2012) An Altered Redox Balance Mediates the Hypersensitivity of Cockayne Syndrome Primary Fibroblasts to Oxidative Stress. Aging Cell, 11, 520-529.

[26]   Brooks, P.J. (2012) Blinded by the UV Light: How the Focus on Transcription-Coupled NER Has Distracted from Understanding the Mechanisms of Cockayne Syndrome Neurologic Disease. DNA Repair, 12, 656-671.

[27]   Batista, L.F., Roos, W.P., Kaina, B. and Menck, C.F. (2009) p53 Mutant Human Glioma Cells Are Sensitive to UVC-Induced Apoptosis Due to Impaired Cyclobutane Pyrimidine Dimer Removal. Molecular Cancer Research, 7, 237-246.

[28]   Rastogi, R.P., Richa, K.A., Tyagi, M.B., et al. (2010) Molecular Mechanisms of Ultraviolet Radiation-Induced DNA Damage and Repair. Journal of Nucleic Acids, 2010, Article ID: 592980.

[29]   Amano, S. (2009) Possible Involvement of Basement Membrane Damage in Skin Photo Aging. Journal of Investigative Dermatology Symposium Proceedings, 14, 2-7.

[30]   Tian, L.M., Xie, H.F., Xiao, X., Yang, T., Hu, Y.H., Wang, W.Z., Liu, L.S., Chen, X. and Li, J. (2011) Study on the Roles of β-Catenin in Hydrogen Peroxide-Induced Senescence in Human Skin Fibroblasts. Experimental Dermatology, 20, 836-838.

[31]   Liu, J. and Lin, A. (2005) Role of JNK Activation in Apoptosis: A Double-Edged Sword. Cell Research, 15, 36-42.

[32]   Volonte, D., Liu, Z., Musille, P.M., Stoppani, E., Wakabayashi, N., Di, Y.P., Lisanti, M.P., Kensler, T.W. and Galbiati, F. (2013) Inhibition of Nuclear Factor-Erythroid 2-Related Factor (Nrf2) by Caveolin-1 Promotes Stress-Induced Premature Senescence. Molecular Biology of the Cell, 24, 1852-1862.

[33]   Sanz, A., Pamplona, R. and Barja, G. (2006) Is the Mitochondrial Free Radical Theory of Aging Intact? Antioxidants & Redox Signaling, 8, 582-599.

[34]   Lesenefsky, E. and Hoppel, C. (2006) Oxidative Phosphorylation and Aging. Ageing Research Reviews, 5, 402-433.

[35]   Wang, C.H., Wu, S.B., Wu, Y.T. and Wei, Y.H. (2013) Oxidative Stress Response Elicited by Mitochondrial Dysfunction: Implication in the Pathophysiology of Aging. Experimental Biology and Medicine, 238, 450-460.

[36]   Gregersen, N., Hansen, J. and Palmfeldt, J. (2012) Mitochondrial Proteomics—A Tool for the Study of Metabolic Disorders. Journal of Inherited Metabolic Disease, 35, 715-726.

[37]   Menon, G.K., Dal Farra, C., Botto, J.M. and Domloge, N. (2010) Mitochondria: A New Focus as an Anti-Aging Target in Skin Care. Journal of Cosmetic Dermatology, 9, 122-131.

[38]   Avci, P., Sadasivam, M., Gupta, A., De Melo, W.C., Huang, Y.Y., Yin, R., Chandran, R., Kumar, R., Otufowora, A., Nyame, T. and Hamblin, M.R. (2013) Animal Models of Skin Disease for Drug Discovery. Expert Opinion on Drug Discovery, 8, 331-355.

[39]   Chiba, Y., Yamashita, Y., Ueno, M., Fujisawa, H., Hirayoshi, K., Hohmura, K., Tomimoto, H., Akiguchi, I., Satoh, M., Shimada, A. and Hosokawa, M. (2005) Cultured Murine Dermal Fibroblast-Like Cells from Senescence-Accelerated Mice as in Vitro Models for Higher Oxidative Stress Due to Mitochondrial Alterations. The Journals of Gerontology Series A, 60, 1087-1098.

[40]   Orren, D.K. (2006) Werner Syndrome: Molecular Insights into the Relationships between Defective DNA Metabolism, Genomic Instability, Cancer and Aging. Frontiers in Bioscience, 11, 2657-2671.

[41]   Crabbe, L., Jauch, A., Naeger, C.M., Holtgreve-Grez, H. and Karlseder, J. (2007) Telomere Dysfunction as a Cause of Genomic Instability in Werner Syndrome. Proceedings of the National Academy of Sciences of the United States of America, 104, 2205-2210.

[42]   Kelland, L. (2007) Targeting the Limitless Replicative Potential of Cancer: The Telomerase/Telomere Pathway. Clinical Cancer Research, 13, 4960-4963.

[43]   Finkel, T., Serrano, M. and Blasco, M.A. (2007) The Common Biology of Cancer and Ageing. Nature, 448, 767-774.

[44]   Nakagawa, H. and Opitz, O.G. (2007) Inducing Cellular Senescence Using Defined Genetic Elements. Methods in Molecular Biology, 371, 167-178.

[45]   Olovnikov, A.M. (2007) Hypothesis: Lifespan Is Regulated by Chronomere DNA of the Hypothalamus. Journal of Alzheimer’s Disease, 11, 241-252.

[46]   Buckingham, E.M. and Klingelhutz, A.J. (2011) The Role of Telomeres in the Ageing of Human Skin. Experimental Dermatology, 20, 297-302.

[47]   Burton, D.G. (2009) Cellular Senescence, Ageing and Disease. Age, 31, 1-9.

[48]   Burton, D.G.A., Allen, M.C., Bird, J.L.E. and Faragher, R.G.A. (2005) Bridging the Gap: Ageing, Pharmacokinetics and Pharmacodynamics. Journal of Pharmacy and Pharmacology, 57, 671-679.

[49]   Burton, D.G.A., Sheerin, A., Ostler, E.L., Smith, K., Giles, P.J., Lowe, J., et al. (2007) Cyclin D1 Over-Expression Permits the Reproducible Detection of Senescent Human Vascular Smooth Muscle Cells. Annals of the New York Academy of Sciences, 1119, 20-31.

[50]   Campisi, J. (1997) Aging and Cancer: The Double-Edged Sword of Replicative Senescence. Journal of the American Geriatrics Society, 45, 482-488

[51]   Campisi, J. (1997) The Biology of Replicative Senescence. European Journal of Cancer, 33, 703-709.

[52]   Campisi J. (1998) The Role of Cellular Senescence in Skin Aging. Journal of Investigative Dermatology Symposium Proceedings, 3, 1-5.

[53]   Mancini, M., Lena, A.M., Saintigny, G., Mahé, C., Di Daniele, N., Melino, G. and Candi, E. (2014) MicroRNAs in Human Skin Ageing. Ageing Research Reviews.

[54]   Lotfi, R.A., El Zawahry, K.M., Kamar, Z.A. and Hashem, Z. (2014) Effects of Smoking on Human Telomerase Reverse Transcriptase Expression in the Skin. International Journal of Dermatology.

[55]   Yin, B. and Jiang, X. (2013) Telomere Shortening in Cultured Human Dermal Fibroblasts Is Associated with Acute Photodamage Induced by UVA Irradiation. Postepy Dermatologii i Alergologii, 30, 13-18.

[56]   Herbig, U., Ferreira, M., Condel, L., Carey, D. and Sedivy, J.M. (2006) Cellular Senescence in Aging Primates. Science, 311, 1257.

[57]   Coppe, J.P., Kauser, K., Campisi, J. and Beausejour, C.M. (2006) Secretion of Vascular Endothelial Growth Factor by Primary Human Fibroblasts at Senescence. The Journal of Biological Chemistry, 281, 29568-29574.

[58]   Kletsas, D., Pratsinis, H., Mariatos, G., Zacharatos, P. and Gorgoulis, V.G. (2004) The Proinflammatory Phenotype of Senescent Cells: The p53-Mediated ICAM-1 Expression. Annals of the New York Academy of Sciences, 1019, 330-332.

[59]   Warner, H.R. (2007) Is Cell Death and Replacement a Factor in Aging? Mechanisms of Ageing and Development, 128, 13-16.

[60]   Orrenius, S., Gogvadze, V. and Zhivotovsky, B. (2007) Mitochondrial Oxidative Stress: Implications for Cell Death. Annual Review of Pharmacology and Toxicology, 47, 143-183.

[61]   Hasty, P. and Christy, B.A. (2013) p53 as an Intervention Target for Cancer and Aging. Pathobiology of Aging & Age-Related Disease, 3.

[62]   Cho, J.H., Lee, J.H., Lee, E.J., Nam, D., Shim, B.S., Song, M.Y., Kim, S.S., Kim, S.H., Jung, S.H., Chung, W.S. and Ahn, K.S. (2013) 8β-Hydroxy-3-Oxopimar-15-Ene Exerts Anti-Inflammatory Effects by Inhibiting ROS-Mediated Activation of the TRAF6-ASK1-p38 Signaling Pathway. Immunopharmacology and Immunotoxicology, 35, 549-557.

[63]   Wada, T. and Penninger, J.M. (2004) Mitogen-Activated Protein Kinases in Apoptosis Regulation. Oncogene, 23, 2838-2849.

[64]   Strozyk, E. and Kulms, D. (2013) The Role of AKT/mTOR Pathway in Stress Response to UV-Irradiation: Implication in Skin Carcinogenesis by Regulation of Apoptosis, Autophagy and Senescence. International Journal of Molecular Sciences, 14, 15260-15285.

[65]   Schagen, S.K., Zampeli, V.A., Makrantonaki, E. and Zouboulis, C.C. (2012) Discovering the Link between Nutrition and Skin Aging. Dermato-Endocrinology, 4, 298-307.

[66]   Draelos, Z.D. (2013) Aging Skin: The Role of Diet: Facts and Controversies. Clinics in Dermatology, 31, 701-706.

[67]   Pluijm, S.M., Visser, M., Puts, M.T., Dik, M.G., Schalk, B.W., et al. (2007) Unhealthy Lifestyles during the Life Course: Association with Physical Decline in Late Life. JAMA, 297, 986-994.

[68]   Testa, G., Biasi, F., Poli, G. and Chiarpotto, E. (2014) Calorie Restriction and Dietary Restriction Mimetics: A Strategy for Improving Healthy Aging and Longevity. Current Pharmaceutical Design, 20, 2950-2977.

[69]   Jeyapalan, J.C., Ferreira, M., Sedivy, J.M. and Herbig, U. (2007) Accumulation of Senescent Cells in Mitotic Tissue of Aging Primates. Mechanisms of Ageing and Development, 128, 36-44.

[70]   Freund, A., et al. (2010) Inflammatory Networks during Cellular Senescence: Causes and Consequences. Trends in Molecular Medicine, 16, 238-246.

[71]   Passos, J.F., et al. (2010) Feedback between p21 and Reactive Oxygen Production Is Necessary for Cell Senescence. Molecular Systems Biology, 6, 347.

[72]   Xue, W., et al. (2007) Senescence and Tumour Clearance Is Triggered by p53 Restoration in Murine Liver Carcinomas. Nature, 445, 656-660.

[73]   Krtolica, A. and Campisi, J. (2002) Cancer and Aging: A Model for the Cancer Promoting Effects of the Aging Stroma. The International Journal of Biochemistry & Cell Biology, 34, 1401-1414.

[74]   Parrinello, S., et al. (2005) Stromal-Epithelial Interactions in Aging and Cancer: Senescent Fibroblasts Alter Epithelial Cell Differentiation. Journal of Cell Science, 118, 485-496.

[75]   Baker, D.J., et al. (2008) Opposing Roles for p16Ink4a and p19Arf in Senescence and Ageing Caused by BubR1 Insufficiency. Nature Cell Biology, 10, 825-836.

[76]   Berryman, D.E., et al. (2008) Role of the GH/IGF-1 Axis in Lifespan and Healthspan: Lessons from Animal Models. Growth Hormone & IGF Research, 18, 455-471.

[77]   Masoro, E.J. (2006) Dietary Restriction-Induced Life Extension: A Broadly Based Biological Phenomenon. Biogerontology, 7, 153-155.

[78]   Higami, Y., et al. (2006) Energy Restriction Lowers the Expression of Genes Linked to Inflammation, the Cytoskeleton, the Extracellular Matrix and Angiogenesis in Mouse Adipose Tissue. Journal of Nutrition, 136, 343-352.

[79]   Wang, C., et al. (2010) Adult-Onset, Short-Term Dietary Restriction Reduces Cell Senescence in Mice. Aging, 2, 555-566.

[80]   Ezure, T. and Amano, S. (2010) Increased Subcutaneous Adipose Tissue Impairs Dermal Function in Diet-Induced Obese Mice. Experimental Dermatology, 19, 878-882.

[81]   Hiebert, P.R., Boivin, W.A., Abraham, T., Pazooki, S., Zhao, H., Granville, D.J. and Granzyme, B. (2011) Contributes to Extracellular Matrix Remodeling and Skin Aging in Apolipoprotein E Knockout Mice. Experimental Gerontology, 46, 489-499.

[82]   Ohnishi, M. and Razzaque, M.S. (2010) Dietary and Genetic Evidence for Phosphate Toxicity Accelerating Mammalian Aging. The FASEB Journal, 24, 3562-3571.

[83]   Nagase, T., Akase, T., Sanada, H., Minematsu, T., Ibuki, A., Huang, L., Asada, M., Yoshimura, K., Nagase, M., Shimada, T., Aburada, M., Nakagami, G. and Sugama, J. (2013) Aging-Like Skin Changes in Metabolic Syndrome Model Mice Are Mediated by Mineralocorticoid Receptor Signaling. Aging Cell, 12, 50-57.

[84]   Browner, W.S., Kahn, A.J., Ziv, E., Reiner, A.P., Oshima, J., et al. (2004) The Genetics of Human Longevity. American Journal of Medicine, 117, 851-860.

[85]   Kirkwood, T. (2006) Ageing: Too Fast by Mistake. Nature, 444, 1015-1107.

[86]   Waaijer, M.E., Gunn, D.A., Catt, S.D., van Ginkel, M., de Craen, A.J., Hudson, N.M., van Heemst, D., Slagboom, P.E., Westendorp, R.G. and Maier, A.B. (2012) Morphometric Skin Characteristics Dependent on Chronological and Biological Age: The Leiden Longevity Study. Age, 34, 1543-1552.

[87]   Fisher, G.J. (2005) The Pathophysiology of Photoaging of The Skin. Cutis, 75, 5-9.

[88]   Rattan, S.I. and Ali, R.E. (2007) Hormetic Prevention of Molecular Damage during Cellular Aging of Humanskin Fibroblasts and Keratinocytes. Annals of the New York Academy of Sciences, 1100, 424-430.

[89]   Yaar, M. and Gilchrest, B.A. (2007) Photoageing: Mechanism, Prevention and Therapy. British Journal of Dermatology, 157, 874-887.

[90]   Kosmadaki, M.G. and Gilchrest, B.A. (2004) The Role of Telomeres in Skin Aging/Photoaging. Micron, 35, 155-159.

[91]   Baumann, L. (2007) Skin Ageing and Its Treatment. The Journal of Pathology, 211, 241-251.

[92]   Sugimoto, M., Yamashita, R. and Ueda, M. (2006) Telomere Length of the Skin in Association with Chronological Aging and Photoaging. Journal of Dermatological Science, 43, 43-47.

[93]   Spiewak, R. (2012) The Substantial Differences between Photoallergic and Phototoxic Reactions. Annals of Agricultural and Environmental Medicine, 19, 888-889.

[94]   Landau, M. (2007) Exogenous Factors in Skin Aging. Current Problems in Dermatology, 35, 1-13.

[95]   Federman, D.G. and Kravetz, J.D. (2007) Peripheral Arterial Disease: Diagnosis, Treatment and Systemic Implications. Clinics in Dermatology, 25, 93-100.

[96]   Morita, A., Torii, K., Maeda, A. and Yamaguchi, Y. (2009) Molecular Basis of Tobacco Smoke-Induced Premature Skin Aging. Journal of Investigative Dermatology Symposium Proceedings, 14, 53-55.

[97]   Ono, Y., Torii, K., Fritsche, E., Shintani, Y., Nishida, E., Nakamura, M., Shirakata, Y., Haarmann-Stemmann, T., Abel, J., Krutmann, J. and Morita, A. (2013) Role of the Aryl Hydrocarbon Receptor in Tobacco Smoke Extract-Induced Matrix Metalloproteinase-1 Expression. Experimental Dermatology, 22, 349-353.

[98]   Garbe, C. and Eigentler, T.K. (2007) Diagnosis and Treatment of Cutaneous Melanoma: State of the Art 2006. Melanoma Research, 17, 117-127.

[99]   Norval, M., Cullen, A.P., de Gruijl, F.R., Longstreth, J., Takizawa, Y., et al. (2007) The Effects on Human Health from Stratospheric Ozone Depletion and Its Interactions with Climate Change. Photochemical Photobiological Sciences, 6, 232-251.

[100]   Arnold, S.F. and Price, P.S. (2007) Modeling Mixtures Resulting from Concurrent Exposures to Multiple Sources. Toxicology and Applied Pharmacology, 223, 121-124.

[101]   Valacchi, G., Sticozzi, C., Pecorelli, A., Cervellati, F., Cervellati, C. and Maioli, E. (2012) Cutaneous Responses to Environmental Stressors. Annals of the New York Academy of Sciences, 1271, 75-81.

[102]   Vierkötter, A. (2011) Environmental Pollution and Skin Aging. Der Hautarzt, 62, 577-581.

[103]   Sarchio, S.N., Kok, L.F., O’Sullivan, C., Halliday, G.M., Byrne, S.N. (2012) Dermal Mast Cells Affect the Development of Sunlight-Induced Skin Tumours. Experimental Dermatology, 21, 241-248.

[104]   Nagai, H., Noguchi, T., Takeda, K. and Ichijo, H. (2007) Pathophysiological Roles of ASK1-MAP Kinase Signaling Pathways. Journal of Biochemistry and Molecular Biology, 40, 1-6.

[105]   Cornwell, D.G. and Ma, J. (2007) Studies in Vitamin E: Biochemistry and Molecular Biology of Tocopherol Quinones. Vitamins Hormones, 76, 99-134.

[106]   Azzi, A., Gysin, R., Kempna, P., Munteanu, A., Negis, Y., et al. (2004) Vitamin E Mediates Cell Signaling and Regulation of Gene Expression. Annals of the New York Academy of Sciences, 1031, 86-95.

[107]   Liu, M., Xu, Y., Han, X., Liang, C., Yin, L., Xu, L., Qi, Y., Zhao, Y., Peng, J. and Sun, C. (2014) Potent Effects of Flavonoid-Rich Extract from Rosa laevigata Michx Fruit against Hydrogen Peroxide-Induced Damage in PC12 Cells via Attenuation of Oxidative Stress, Inflammation and Apoptosis. Molecules, 19, 11816-11832.

[108]   Tulah, A.S. and Birch-Machin, M.A. (2013) Stressed out Mitochondria: The Role of Mitochondria in Ageing and Cancer Focussing on Strategies and Opportunities in Human Skin. Mitochondrion, 13, 444-453.

[109]   OyetakinWhite, P., Tribout, H. and Baron, E. (2012) Protective Mechanisms of Green Tea Polyphenols in Skin. Oxidative Medicine and Cellular Longevity, 2012, Article ID: 560682.

[110]   Korkina, L.G., Pastore, S., Dellambra, E. and De Luca, C. (2013) New Molecular and Cellular Targets for Chemoprevention and Treatment of Skin Tumors by Plant Polyphenols: A Critical Review. Current Medicinal Chemistry, 20, 852-868.

[111]   Zouboulis, C.C. and Makrantonaki, E. (2011) Clinical Aspects and Molecular Diagnostics of Skin Aging. Clinics in Dermatology, 29, 3-14.

[112]   Kuphal, S. and Bosserhoff, A. (2009) Recent Progress in Understanding the Pathology of Malignant Melanoma. The Journal of Pathology, 219, 400-409.

[113]   Kasper, M., Jaks, V., Hohl, D. and Toftgård, R. (2012) Basal Cell Carcinoma—Molecular Biology and Potential New Therapies. Journal of Clinical Investigation, 122, 455-463.

[114]   Mimeault, M. and Batra, S.K. (2010) Recent Advances on Skin-Resident Stem/Progenitor Cell Functions in Skinregeneration, Aging and Cancers and Novel Anti-Aging and Cancer Therapies. Journal of Cellular and Molecular Medicine, 14, 116-134.

[115]   Jackson, R.L., Greiwe, J.S. and Schwen, R.J. (2011) Ageing Skin: Oestrogen Receptor β Agonists Offer an Approach to Change the Outcome. Experimental Dermatology, 20, 879-882.

[116]   Emmerson, E. and Hardman, M.J. (2012) The Role of Estrogen Deficiency in Skin Ageing and Wound Healing. Biogerontology, 13, 3-20.

[117]   Thornton, M.J. (2013) Estrogens and Aging Skin. Dermato-Endocrinology, 5, 264-270.

[118]   Pageon, H. (2010) Reaction of Glycation and Human Skin: The Effects on the Skin and Its Components, Reconstructed Skin as a Model. Pathologie Biologie, 58, 226-231.

[119]   Salbach, J., Rachner, T.D., Rauner, M., Hempel, U., Anderegg, U., Franz, S., Simon, J.C. and Hofbauer, L.C. (2012) Regenerative Potential of Glycosaminoglycans for Skin and Bone. Journal of Molecular Medicine, 90, 625-635.

[120]   Farris, P.K. (2011) Innovative Cosmeceuticals: Sirtuin Activators and Anti-Glycationcompounds. Seminars in Cutaneous Medicine and Surgery, 30, 163-166.

[121]   Babizhayev, M.A. and Yegorov, Y.E. (2010) Therapeutic Uses of Drug-Carrier Systems for Imidazole-Containing Dipeptide Compounds That Act as Pharmacological Chaperones and Have Significant Impact on the Treatment of Chronic Diseases Associated with Increased Oxidative Stress and the Formation of Advanced Glycation End Products. Critical Reviews in Therapeutic Drug Carrier Systems, 27, 85-154.

[122]   Poljsak, B., Dahmane, R. and Godic, A. (2013) Skin and Antioxidants. Journal of Cosmetic and Laser Therapy, 15, 107-113.