# Skin Depigmenting Agents in Anti-Aging Cosmetics: A Medicinal Perspective on Emerging Ingredients
## 1 Introduction  
Skin aging is a complex biologic process that results from genetic programming--or intrinsic aging--and cumulative environmental damage--or extrinsic aging [1, 2]. Together, these factors lead to structural and physiological alterations over time at variable, yet inalterable, genetically determined rates [3]. Endogenous or intrinsic aging is usually attributed to the passage of time, largely influenced by genetics, cellular metabolism, hormone, and metabolic processes, whereas exogenous or extrinsic aging is influenced by chronic exposure to sunlight, pollution, and ionizing radiation among other factors [1, 2, 4, 5]. In addition to roughness, loss of elasticity, wrinkling, and pigmentary disorders can occur insun-exposed areas, and they significantly impact patients' quality of life and psychological well-being [6]. The latter is usually characterized by altered melanocyte density, melanin concentration, or both, and they result in altered skin pigmentation (e.g., lentigos) [6]. Therefore, anti-aging products can contain depigmenting agents to tackle all the signs of skin aging. Melanogenesis, the physiological process of melanin formation, is initiated by tyrosinase, a copper-dependent enzyme [7]. This enzyme plays a central role in this process, by catalyzing the first step of melanin formation. Several options, including cosmetic products, topical drugs, oral drugs, chemical peels, and light treatments are available for hyperpigmentation treatments [8]. The depigmenting effectiveness can be achieved by different action mechanisms. Hydroquinone, azelaic acid, 4-butylresorcinol, and arbutin are known tyrosinase inhibitors, thus targeting the rate-limiting step in melanin production [9; 10]. Another approach involves the use of kojic acid and ascorbic acid (either in combination or alone) to interact with copper, an important co-factor in the melanogenesis pathway, thus inhibiting tyrosinase activity [9]. Other depigmenting agents have different mechanisms of action such as the inhibition of tyrosinase transcription (tretinoin, glucosamine, retinol, retinaldehyde, \(N\)-acetyl glucosamine), epidermal turnover accelerant (vitamin C, vitamin E, thiotic acid, retinoids, lactic acid, glycolic acid, salicylic acid, liquiritin, gluconolactone), inhibition of melanosome transfer (linoleic acid, niacinamide), anti-inflammatory activity (niacinamide, soy milk), and free radical scavenging agents (topical steroids, glycyrrheticin acid, ubiquitine, bakuchiol) [7; 11; 12]. Cosmetic researchers have been investigating new compounds to be incorporated into anti-aging products acting on melanogenesis inhibition with greater efficacy and a suitable safety profile [13]. Cosmetic products are governed by the EU Cosmetics Regulation (Regulation (EC) No. 1223/2009). This regulation and corresponding annexes establish the safety requirements for cosmetic products and ingredients and are regularly updated. Several depigmenting agents are prohibited in cosmetic products in the EU (Annex II) while others are allowed with strict concentration limits (Annex III). As an example, hydroquinone is prohibited in cosmetics products, as it is listed in Anne II of Regulation No 1223/2009. Hence, new compounds aimed to be incorporated as skin depigmenting agents in anti-aging cosmetics should comply with this regulation in order to ensure the safety of the consumers which includes a comprehensive safety assessment. Nonetheless, studies analyzing the type of depigmenting agents and their prevalence in commercial antiaging products have not yet been performed. Insights on the cosmetic market and industry trends are valuable since this scientifically-driven industry is based on constant innovation and product development. The knowledge on which depigmenting agents are currently being used allows product differentiation, providing a wider variety between drugstore brands and high-end brands.