# Anti-Aging Effects of Polyoxometalates on Skin
## 1 Introduction  
Glycation, oxidation, and chronic inflammation are 3 major aging-related reactions, and reactive oxygen species (ROS), which are generated and accumulate at the sites of these reactions, have been shown to induce various aging phenomena [1, 2, 3, 4, 5]. Because these aging-related reactions occur in skin, the suppressed generation of ROS is considered to be effective for preventing wrinkles, maculae, dullness, and slackness [6]. Glycation is a non-enzymatic chemical reaction by which sugar molecules or glucose metabolism intermediates (e.g., glyceraldehyde) adhere to amino acid residues in various proteins and eventually generate advanced glycation end products (AGEs) [7]. AGEs play significant roles not only in aging phenomena in the entire body, but also in a wide variety of diseases. For example, collagen in skin is naturally glycated and, thus, the amount of glycation products increases with age. Increases in AGEs have been suggested to play a causative role in diabetes based on the finding showing that their content in cutaneous collagen was higher in diabetic patients than in healthy age-matched individuals [8]. Moreover, the formation and accumulation of AGEs in cells have been implicated in skin aging [8], Alzheimer's disease [9], hypertension [10], arteriosclerosis [11], and osteoporosis [12]. AGEs are produced under specific pathological conditions, such as oxidative stress, and function as proinflammatory mediators. They affect nearly every type of cell in the body. Many of the cellular effects of AGEs involve two different types of AGE receptors; one type has been implicated in inflammation and ROS generation through its activationof intracellular signal pathways, while the other type is involved in the degradation and elimination of AGEs through receptor-mediated endocytosis and lysosome-dependent proteolysis (Figure 1). The effects of the former AGE receptors need to be suppressed, while those of the latter need to be promoted to prevent or delay cellular senescence. AGE receptors in the former group include the receptor for advanced glycation end products (RAGE) and AGE receptor 2 (AGE-R2), and those in the latter group include fascicin EGF-like, laminin-type EGF-like, link domain-containing scavenger receptor-1 (FEEL-1), FEEL-2, AGE-R1, AGE-R3, and CD36. Among AGE receptors AGE-R1, FEEL-1, FEEL-2, and CD-36 contribute to the endocytosis of extracellular AGEs into cells and their degradation through phagosome-lysosome fusion. Other AGE receptors, such as AGE-R2, AGE-R3, and RAGE, increase intracellular ROS generation directly or indirectly through the activation of NADPH oxidase. Damage to DNA, proteins, and lipids, which is caused by ROS generated under oxidative stress conditions, is a major cellular event that has been strongly implicated in accelerated aging and the development and exacerbation of geriatric diseases [7; 13]. Therefore, it is important to suppress the accumulation of ROS and augment the levels of antioxidants, such as superoxide dismutase (SOD), to control the aging process [14]. Furthermore, aquaporin (AQP)-1 and AQP-3, which control the permeability of water molecules in the cell membrane, as well as hyaluron and elastin participate in the moisturization and anti-aging of skin. The expression levels of AQP-1 and AQP-3 have been shown to decrease under oxidative stress conditions [15]. The degradation of elastin, a core protein of elastic fibers, is regarded as a cause of wrinkle formation, while its sustainable and adequate production is closely involved in skin regeneration [16; 17]. Therefore, it  
Figure 1: AGE receptors expressed in NHDF and their roles in intracellular events under stress conditions. is important to maintain these molecules under stress conditions to suppress the aging phenomena in skin. Several hundred polyoxometalates (PMs), which are metal oxides that form several structures, have been synthesized to date, and some exhibit anti-neoplastic, anti-viral, and anti-bacterial activities [18].