SKIN-AGING AND INFLAMMAGING TREATMENT 325 signals bind to mast cells, causing TNF-α and histamine release. (iii) TNF-α and hista- mine stimulate intercellular adhesion molecule-1 (ICAM-1) synthesis in endothelial cells of the blood vessels. (iv) ICAM-1 binds to circulating immune cells that release hydrogen peroxide to perform diapedesis and enter the dermis. (v) Immune cells in the dermis re- lease singlet oxygen and MMPs, causing connective tissue damage. (vi) Immune cells reach the damaged cell, release hydrogen peroxide, and digest the damaged cell. (vii) During the three oxidative bursts, other cells are damaged, proinfl ammatory mediators are release, and the infl ammatory cycle is maintained (11). The mic roinfl ammatory theory could explain a number of skin aging features such as loss of elasticity, and dermal fl exibility. Moreover, this theory accounts for wrinkle appearance and epidermal thinning with age (12). Bhattacharyya et al. (13) assessed the histological changes in intrinsic aged mice. Results showed that there was a notable epidermal thin- ning and reduction in the pilosebaceous unit associated with aging (13). DNA DAM AGE UV radi ation creates pyrimidine dimers, resulting in DNA mutations. Moreover, UV radiation generates ROS, which accelerate telomere shortening and interfere with en- zymes required for DNA repair (41). Continu ous DNA damage responses cause replicative cell senescence and aging processes, as illustrated by Xia et al. (10). DNA damage in aging cells contributes to a surge in the proinfl ammatory secretory phenotype, which in turn induces further DNA damage and proinfl ammatory secretion in adjacent cells. Ultimately, local infl ammation becomes sys- temic, resulting in an infl ammaging exacerbation (10). Telomer es refer to nucleotide sequences at the ends of chromosomes that protect them from degrading (42). With each cell division, telomeres shorten because of replication problems. Accordingly, the proliferation capacity of the cell deteriorates, and eventually, cellular aging occurs (2,43). However, telomerase is an enzyme that retains telomere length by adding telomere repetitions to the end (44). Therefore, regulation of telomerase activity is a key factor in DNA repair and antiaging therapy. Goyarts et al. (45) conducted a study to investigate the molecular mechanism associated with morphological changes in age spots. mRNA in skin biopsies was analyzed, and re- sults revealed that 23 genes were upregulated, whereas 17 genes were downregulated. For instance, peptidase gene and genes responsible for keratinization and basement mem- brane synthesis were downregulated. Moreover, genes related to infl ammation were up- regulated, including MMP3, which is responsible for elastic fi ber degradation in the dermis. Both upregulated and downregulated genes were highly linked to infl ammation, confi rming the role of microinfl ammation in age spots (45). OBESITY Obesity , especially central obesity, is closely correlated with a proinfl ammatory state (39). This state is attributable to declines in subcutaneous adipose tissue and increases in visceral adipose tissue (VAT), which produces more infl ammatory cytokines with age (46,47). Elevated quantities of visceral fats are accompanied by higher levels of infl ammatory

JOURNAL OF COSMETIC SCIENCE 326 markers circulating in the blood, in addition to high amounts of proinfl ammatory cells in their tissues (47). Also, a number of T-cell lymphocytes grow, and macrophages differen- tiate into M1 macrophages, with increased proinfl ammatory cytokine production (46). Because of its anatomical position, VAT provides venous blood directly to the liver through the portal vein, consequently controlling the metabolism of the whole body (47). As a result, VAT may be a source of circulating low-grade infl ammation (infl ammaging). GUT AND SKIN MICROBIOTA A new t heory links infl ammaging to permeability and changes occurring in the gut mi- crobiota (39). Those microorganisms are known for their role in counteracting pathogenic organisms and retaining the intestinal barrier integrity (48). Different studies have con- fi rmed that benefi cial normal gut fl ora is markedly reduced with aging (49). Reduced microbiota permits other bacteria to inhabit, including symbiotic bacteria that could be pathogenic under certain conditions. Moreover, gut microbiota imbalance has been hy- pothesized to increase the permeability of the mucosal barrier, allowing bacteria and their products to reach systemic circulation, resulting in a chronic proinfl ammatory state (39). This imbalance is clearly noticeable in people suffering from chronic diseases that aggra- vate with aging (39). Nonetheless, there is no defi nite evidence of heightened intestinal permeability and release of proinfl ammatory agents in older people who are not suffering from chronic infl ammatory diseases (50). Shibaga ki et al. (51) correlated skin aging to skin microbiome. The study involved char- acterization and comparison of skin bacterial communities in 2 age-groups. Results showed that in older adults, there was a reduction in genus Propionibacterium in the cheek, forearm, and forehead microbiomes (51). TREATME NT APPROACHES OF INFLAMMAGING An inte rvention to solve infl ammaging should be safe, effi cient, nontoxic, and suitable for long-term use (10). Several treatment strategies for infl ammaging are being assessed, such as antioxidants, ways of increasing adaptive immunity, lifestyle changes, and pro-/ prebiotics use (10). ANTIOXI DANTS Antioxi dants, which are either endogenous or exogenous, neutralize the harmful effects of pro-oxidants and minimize physiological disorders (52). Endogenous antioxidants are further categorized as enzymatic or nonenzymatic (52). Exogenous antioxidants are di- etary supplemented, such as vitamins, fl avonoids, and others. Defensive effects of anti- oxidants are based on different mechanisms, including prevention or elimination of free radicals and repair of damaged biomolecules (53). Antioxidants have clinical potential for antiaging (52). Several studies have addressed how antioxidants help in chronic infl ammatory states. Masaki (54) discussed how antioxidants, such as tocopherols, ascorbic acid, and polyphe- nols, can reduce skin diseases and photoaging (54). Lee et al. (55) performed an in vivo