**7. Discussions**

In this paper, we discussed the possibility that ROS production through photosensitization reaction in the living body may be important factor for photoaging of the skin, especially damage to dermal fibroblasts caused by UVA.

In addition, the concentration of amino acids and vitamins in the human skin, especially in the dermis, must be clarified to discuss the role of sunlight on skin photoaging. There are some reports of the concentration of vitamins in the blood. It has been reported that riboflavin may exist at approximately 1–300 ng/mL [82, 83], folic acid may exist at approximately 13–57 ng/mL [84], and tryptophan may exist at approximately 12 μg/mL [85]. However, as far as we have investigated, there have been no reports of detailed verification of the concentrations of amino acids and vitamins in the dermis. In the future, we hope that the concentrations of amino acids and vitamins in the skin must be clarified by detailed studies on the mechanism of production of ROS by the UVA-photosensitization reaction in the skin.

Photosensitivity, unlike photoaging, is an acute response to light. Among photosensitivity research, there are also reports on the reduction of phototoxicity by studying combinations of ketoprofen with several antioxidants. The report investigates the effects of eight known radical scavengers on UV-induced photodegradation of ketoprofen and the production of ROS. Interestingly, quercetin was the only one that simultaneously suppressed the photolysis of ketoprofen and the production of ROS. Tocopherols eliminated ROS but did not suppress the photolysis of ketoprofen [86]. It can be inferred that quercetin directly quenched the photosensitizing reaction of ketoprofen.

It should be noted that it is important to look for antioxidants that suppress the reaction of the photosensitizer, which is effective not only for photoaging caused by ROS production through photosensitization but also for the prevention of photosensitivity. We concluded that understanding of the photosensitizing mechanism of environmental components, such as amino acids and vitamins in the skin, will be effective in reducing or preventing harmful skin symptoms induced by phototoxicity, which is caused by UVA.

In addition, in recent years, much attention has been paid to treatments targeting senescent cells, such as senolytics [87]. In 2018, Yoon reported that the elimination of nearby aging fibroblasts was effective in improving senile pigmented spots [88]. This strongly suggests that the phenomenon of skin aging may be caused by cell aging of fibroblasts. Therefore, the prevention of cellular senescence, especially the prevention of photoaging and photodamage caused by ultraviolet rays, is considered to be an even more important issue than before. For anti-photoaging to be effectively implemented, we need studies to elucidate the photosensitizing-reaction mechanism considering various components in the skin.
