The primary mechanism of UV-induced skin aging is mediated by the generation and accumulation of free radicals including reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS or free radicals not only can damage proteins, DNA, cellular membrane and cellular organelles, it also function as an intracellular signals to initiate different signal transduction pathways which regulate and activate genes that are either involved in the skin aging process or to further regulate other signaling pathways for cellular aging process. Levels of MMP (MMP1, 2, 3. 9), COX-2, HO-1, iNOS, ODC, p53, bcl2, bax, c-jun, c-fos, AP-1, NF-kB, TNF-alpha, IL-1, IL-6, are increased in response to UV irradiation.
1. genes that cause the photo skin aging phenotypes
MMP, the matrix metalloproteinase, are a group of extra cellular matrix degradation enzymes that degrade skin connective tissue fiber networks, primarily the collagen and elastin fibers. MMPs is the effector molecules for phenotypes of skin aging and its activities and amount is increased in both chronologic and photo skin aging. Collagenase (MMP1) degrades the Collagens I, II, III, VII and X, collagen I and III is the major collagen type forming dermis fiber network of the skin, collagen VII is the component in skin’s base membrane at the dermal-epidermal junction (DEJ). MMP-2 degrades degrades type IV collagen. Stromelysin (MMP-3) degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin. Collagen IV and laminin is the main components in the basal lamina of the base membrane. Elastin is the other main skin structural proteins found in the dermis connective tissue. The damage of the ECM of the dermis and DEJ is causatively related to the observed skin aging signs. Gelatinase (MMP-9) degrades type IV and V collagens.
COX-2 (cyclooxygenase-2) is one of the mediators in inflammaging and ROS generation as a result of inflammaging.
iNOS (inducible Nitric oxide synthase) produces NO from L-arginine. iNOS was found to reduce the proliferative activity of dermal fibroblast and may be related to fibroblast senescence. iNOS is increased in chronological skin aging as well.
NF-kB is a transcription factor that regulate and activate genes in immune response and is involved in inflammaging mechanism in intrinsic aging and photo skin aging. UV induced ROS signaling activates NF-kB. NF-kB activity is further amplified by many of its signaling pathway effectors – the proinflammatory cytokines (e.g. IL-1, IL-6) are themselves activators of NF-kB.
see “Is NF-kB the Secret to Skin Aging?”
AP-1 is transcription factor complex composed of c-Jun and c-Fos. AP-1 is induced by ROS-triggered signaling pathways. AP-1 regulate and activate genes that result in the increased extracellular matrix fiber network degradation (collagen breakdown) and decreases the production of new collagen. see “AP-1 Signaling Activates MMP in Chronological and Photo Skin Aging” and “NF-kB and AP-1 Molecular Signaling Mechanisms of Intrinsic And Extrinsic Skin Aging” for detail.
c-Jun is a transcription factor activated by JNK (c-Jun N-terminal kinases) pathway. JNK is activated by MAP kinase pathways which also mediate ROS-induced AP-1 and NF-kB activation. UV induced c-Jun interferes with the type I and type III procollagen transcription, thus block partly the procollagen synthesis in dermal fibroblast. c-Fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors.
TNF-alpha (tumor necrosis factor-alpha) has the primary role in regulation of immune cells. TNF-alpha may be related to the age-related decrease of cutaneous immunity. TNF-alpha signaling pathway also activate transcription factor AP-1 and NF-kB.
IL-1 (Interleukin-1) is a proinflammatory cytokine that has several effects in the immune and inflammatory response and inflammaging process. UV induced ROS activate IL-1 via NF-kB pathway. ROS also activate IL-1 receptor. When IL-1 binds to its cell-surface receptor, IL-1 initiates a signaling cascade that leads to activation of the transcription factor NF-kB and AP-1 in fibroblast. Both IL-1α and IL-1β are produced by macrophage and fibroblasts of the dermis. IL-1α is constitutively produced by epithelial cells. It is found in substantial amounts in epidermis. The essential role of IL-1α in maintenance of skin barrier function is due to the constitutive production of large amounts of IL-1α precursor by healthy epidermal keratinocytes. A wide variety of other cells only upon stimulation can be induced to transcribe the IL-1α genes and produce the precursor form of IL-1α such as dermal fibroblasts. IL-1 signaling in infiltrated immune cells produce more free radicals and oxidative stress which resulting in skin aging.
IL-6 (Interleukin-6) is an interleukin that acts as both a pro-inflammatory cytokine and anti-inflammatory cytokine after the acute immune response. It is secreted by T cells and macrophages to stimulate immune response. Increasing amounts of measurable serum IL-6 is associated with aging. IL-6 is is mainly modulated by NF-KB. IL-6 signaling activates JAK pathway – the transducer and activator of STAT transcription factor and SHP2/ERK/MAP kinase pathway. There is also trans signaling pathway by IL-6 which may be related to the chronic inflammation mechanism of aging.
2. genes that are the UV-induced endogenous protective mechanism
HO-1 (Heme oxygenase) is a redox regulated enzyme that have antioxidant and anti-inflammatory activities and its level is affected by cellular redox state such as the level of glutathione (GSH, a natural antioxidant) and/or GSSH to GSH ratio. Increased HO-1 in response to UV irradiation appears to be part of the natural photoprotective mechanism.
ODC (Ornithine decarboxylase) is an enzyme in the polyamine-biosynthesis pathway and has a role in the in the regulation of DNA synthesis and cell proliferation. The polyamine produced has the function to stabilize DNA structure and as antioxidants . UV-induced ODC response decreases with age, suggesting the photoprotective role of ODC induction.
p53 is a tumor suppressor protein functions as a tumor suppressor and is a transcription factor that is involved in preventing cancer. p53 has been described as “the guardian of the genome” because of its role in conserving stability by preventing genome mutation. p53 becomes activated in response to a myriad of stress types (e.g. UV induced DNA damage, oxidative stress). In skin, p53 is activated when epidermal skin cells are damaged by UV radiation. p53 signaling activate mechanism of protection for skin cancer – the DNA repair mechanism or apoptosis mechanism when excess DNA damage/mutation is accumulated.
Bcl2 (B-cell lymphoma 2) is an apoptosis regulator proteins an apoptosis suppressor. UVB irradiation induces apoptosis of keratinocytes by sequential activation of caspase 8, 3 and 1 in keratinocytes. In vitro and in vivo transfer of bcl-2 gene into keratinocytes suppresses UV-induced apoptosis. Decreased bcl-2 level is observed in UV irradiated skin in vivo and in vitro via p53 regulation. Bax (Bcl-2–associated X protein) is pro-apoptotic member of the Bcl-2 protein family. Bax is activated by p53 signaling.