Ultraviolet radiation, aging and the skin: prevention of damage by topical cAMP manipulation

Abstract

Being the largest and most visible organ of the body and heavily influenced by environmental factors, skin is ideal to study the long-term effects of aging. Throughout our lifetime, we accumulate damage generated by UV radiation. UV causes inflammation, immune changes, physical changes, impaired wound healing and DNA damage that promotes cellular senescence and carcinogenesis. Melanoma is the deadliest form of skin cancer and among the malignancies of highest increasing incidence over the last several decades. Melanoma incidence is directly related to age, with highest rates in individuals over the age of 55 years, making it a clear age-related disease. In this review, we will focus on UV-induced carcinogenesis and photo aging along with natural protective mechanisms that reduce amount of "realized" solar radiation dose and UV-induced injury. We will focus on the theoretical use of forskolin, a plant-derived pharmacologically active compound to protect the skin against UV injury and prevent aging symptoms by up-regulating melanin production. We will discuss its use as a topically-applied root-derived formulation of the Plectranthus barbatus (Coleus forskolii) plant that grows naturally in Asia and that has long been used in various Aryuvedic teas and therapeutic preparations.

Figure 1

UV radiation in ambient sunlight is composed primarily of UVA and UVB energy. Most UVC is absorbed by the ozone, therefore although it is highly bioactive, terrestrial organisms are not exposed to significant levels of UVC. UVB can cause direct damage to DNA and reach the epidermis. UVA can penetrate the dermis and increases levels of ROS that indirectly induce DNA mutagenesis.

Figure 2

MC1R signaling cascade in melanocytes. Activated by its agonist alpha-MSH, MC1R promotes cAMP second messenger generation which induces melanocyte differentiation and survival pathways involving PKA, CREB and Mitf. In this way, cAMP induces both melanin production and antioxidants that reduce cellular ROS. cAMP, cyclic adenosine monophosphate. PKA, protein kinase A. pCREB, phosphorylated cAMP response binding element. ROS, reactive oxygen species. MITF, microphthalmia (Mitf) transcription factor.

Figure 3

Cellular antioxidant defenses. UV induces a variety of free radical and oxidative molecules, which because of their chemical reactivity alter the molecular structure and damage lipids, proteins and nucleic acids [79]. Antioxidant enzymes mediate the removal of ROS, with different enzymes functioning in specific compartments (e.g., MnSOD localized to mitochondria). If not removed, ROS may react with DNA and other cell signal proteins, impairing their function. ECSOD, Extracellular Superoxide dismutase. Cu/Zn SOD, copper/zinc superoxide dismutase. MnSOD, Manganese Superoxide dismutase.