This project intends to develop and validate new antioxidant molecules, obtained through a rational delivery process by specifically targeting mitochondria, with the purpose to improve mitochondrial function. These molecules can be used in a near future as potent and selective active ingredients for cosmetic purposes. Today's society, as global population keeps aging, pressures us to look ever more beautiful and young increasing the demand for cosmetic solutions that can provide the answers. Currently, most topical products aiming to fight skin aging by minimizing the effects of oxidative stress do so by trying to deliver antioxidants to the skin cells in an untargeted way. Although the relative efficacy of these molecules has been shown in vitro, positive results are obtained only for high concentrations. Oxidative stress plays a major role in both intrinsic and extrinsic skin aging, the latter being of an even greater importance. Chronic free radical assault subverts the structural framework of the skin, giving rise to wrinkles and sagging skin. Mitochondria are sub-cellular organelle intimately involved in the development of skin aging. When mitochondria oxidize, they swell up and become dysfunctional, losing their ability to provide energy. If this process keeps going, mitochondria can stop generating ATP and the cell dies, a point of no return. This whole sequence of events is one of the main causes of skin aging. Thus, efficient ROS detoxification is particularly important in the skin, which is frequently challenged by UV light and mechanical insults or exposed to various irritants. Phytochemicals exert beneficial effects on animal's health by activating adaptive stress response signaling pathways. Knowledge of hormesis mechanisms is leading to novel approaches for preventing and treating a range of human diseases. In this scenario, mitochondria have been considered a key target for pharmacological intervention strategies. Mitochondria can adapt to external factors andcan respond to energetic demand by producing effectors that activate multiple pathways, related to oxidative stress, in a process called mitochondrial hormesis. Moreover, recent results indicate multi-mechanistic general antioxidants or mitochondrial-targeted antioxidants to be effective in preventing oxidative stress-based damage to skin cells. We developed a library of innovative mitochondrial-targeted natural antioxidants (MitoCINs and MitoBENs), in a process that was driven by a biology-oriented approach, effective in preventing mitochondrial oxidative disruption in isolated organelles and cells. The current project is established to mechanistically dissect the hormetic mode-of-action of MitoCINs and MitoBENs and acquire data to validate the performance (proof of concept) in the improvement the phenotype associated with skin aging in different cell models. This is a high-impact and high-profit project, with promising outcomes resulting from its progression and conclusion.
The main goal is to demonstrate that mitochondrial-directed antioxidants (MitoCINs and MitoBENs) prevents/delay skin aging by regulating antioxidant responses, mainly through Nrf2-induced stress response.