SKIN-AGING AND INFLAMMAGING TREATMENT 327 antiwrinkle study using an animal model to evaluate an extract of Veronica offi cinalis, showing an 18% reduction in wrinkles after cream usage for 56 d. Curcumin, a natural extract from turmeric, has demonstrated anti-infl ammatory and antineoplastic activity (56). A study among 28 women was performed to evaluate the-antiphotoaging effect of curcumin using Tricutan, a herbal extract of rosemary, turmeric, and gotu kola (57). The product improved photoaging based on skin fi rmness and general self-assessment after 1 mo of usage (57). Another clinical randomized double-blind study with 47 subjects fo- cused on the effect of curcumin on infl ammatory mediators was conducted (56). The study confi rmed anti-infl ammatory effects of water extract of Curcuma longa as evidenced by a decline in infl ammatory mediators. Quantities of TNF-α and IL-1β were markedly decreased in mRNA and proteins. The enhanced hyaluronan production with increased skin water content had a moisturizing effect (56). In sum, studies support curcumin as a potential intervention for infl ammaging. Although curcumin suffers low oral bioavailability and fi rst-pass metabolism, these drawbacks can be overcome through IV administration and current formulations (56). Naringenin (NGN) is a fl avanone that is abundant in many fruits and is characterized by antioxidant and anti-infl ammatory properties. A study by Martinez et al. (58) investigated the effi cacy of NGN for antiphotoaging in hairless mice (58). In vitro antioxidant activity was fi rst assessed through ability of ferric reduction, scavenging hydroxyl radicle, 2,20 azinobis (3 -ethylbenzothiazoline- 6 sulfonic acid (ABTS) assay, and inhibition of lipid per- oxidation (58). The effi cacy of NGN topical formulation in vivo was evaluated through skin edema measurement and several antioxidant assessments (58). The authors concluded that NGN reduces skin edema, inhibits cytokine production, maintains cellular antioxidant production, and promotes heme oxygenase-1 mRNA expression in the skin, thereby pro- viding skin protection from ultraviolet-B irradiation (Supplementary Table 1) (58). Yap evaluated the effi cacy of a topical nano-emulsion tocotrienol-rich fraction (TRF) on skin erythema (infl ammation due to UV) in an in vitro study, using immortalized human keratinocyte cell line (HaCaT) (59). ROS measurement showed a signifi cant decrease in oxidative damage caused by UV (59). Furthermore, Yap tested TRF effects on outer lobes of pig ears, measuring skin antioxidative potentials and sun protection factors (59). TRF was found to reduce free radicals in ex vivo models and decrease UV-induced erythema and tanning in human subjects in a clinical trial (Supplementary Table 1) (59). ROLE OF HORMONE IMBALANCE ON AGING Hormonal status and imbalance play a role as an internal-only inducer of aging. As de- tailed by Giacomoni and D’Alessio (7), hormonal imbalance has a direct effect on vascular aging progression and, subsequently, skin aging. Moreover, it is well-documented that immunity declines with age (60). Infl ammaging in elderly subjects is characterized by elevated proinfl ammatory mediators, such as IL-6 and TNF-α (61). Furthermore, post- menopausal women recognize a decline in estrogen hormones (60). Several studies sup- port that hormone replacement therapy improves immunological parameters (60). Estrogen therapy in postmenopausal women has decreased proinfl ammatory cytokine lev- els, such as IL-6 (60). Hormones, such as estrogens, have a weighty impact on the skin structure, function, and physiological state. This could be attributed to the abundance of estrogen receptors in the

JOURNAL OF COSMETIC SCIENCE 328 skin. Estrogen has a substantial infl uence on the skin-aging process as it enhances the collagen content, production, and quality increases skin thickness enhances skin vascu- larization and further enhances the extracellular skin matrix, which is responsible for the tone and appearance of the skin (62). Subsequently, estrogen replacement therapy reverses the harmful effect of estrogen deprivation on the skin. In a study by Brincat et al. (63), 41 postmenopausal women treated with estradiol (100-mg) subcutaneous implants ex- hibited signifi cantly increased skin thickness and metacarpal index over 1-y period of estrogen therapy. Stout et al. (64) explored the effect of 17α-estradiol in old mice (64). 17α-Estradiol im- proved metabolic disorders and infl ammaging through better nutrient sensing and al- teration of lipid redistribution related to age. These effects improved liver function and glucose homeostasis (64). 17α-Estradiol may be a promising intervention for infl ammag- ing because of its improvement of leptin signaling (64). Des pite the advantages of using HRT in postmenopausal women, further studies are needed to examine HRT side effects. Serious problems could be associated with HRT. Some studies reported that such treatment could induce breast cancer (60,61,65). More- over, users of HRT are at risk of venous thromboembolism (66). As supported in the previ- ous studies, HRT can be used in low doses for anti-infl ammaging in advanced age (60). STE M CELLS Emb ryonic stem cells have the ability to form differentiated cells and may help in treat- ment of several disorders (67). Aging is associated with reduced tissue regeneration, which is highly related to impaired functions of stem cells. Epidermal stem cell capacity to proliferate is suppressed with age. Therefore, transplantation of stem cells could be a promising approach to the treatment of skin aging (2). Dol es et al. (68) investigated the involvement of stem cells in skin infl ammaging using a mouse model. Stem cells increased during aging, with impaired function and ineptitude to endure stress. Moreover, an in vivo study by Mojallal et al. (69) using an animal model showed that fat grafting stimulated collagen synthesis and improved skin volume and quality (69). In addition, adipose-derived stem cells can be a successful treatment against skin aging along with its potentials for wound healing. Zhang et al. (70) tested the effect of adipose- derived stem cells on skin aging because of D-galactose using an animal model (Supplemen- tary Table 1). These stem cells inhibited D-galactose–induced skin aging, as confi rmed by reduced levels of glycation products and increased levels of superoxide dismutases with an- tioxidant properties. Moreover, adipose stem cells released a vascular endothelial growth factor, thereby promoting skin regeneration (70). However, concerns about stem cells limit its application in cell-based therapy. Stem cell senescence affects their subpopulation dy- namics, ruins their proliferation, and diminishes their functions (71). RET INOIDS Ret inoids are types of compounds with chemical similarity to vitamin A (2). They are used as topical application to decrease MMP expression and collagen degradation through