Skin, the largest organ of the body, is the organ in which changes associated with aging are most visible. The development of topical cosmetic antiaging products is becoming increasingly sophisticated. Many mechanisms and pathways that contribute to the skin aging have been recently detected. Among them, there are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, extracellular matrix, lipid synthesis, ubiquitin-induced proteolysis and cellular metabolism, and physiologic decline of hormones occurring with age 1. In the fight against skin aging, the most important is prophylaxis; the genetically determined aging can only be minimally controllable, whereas prevention of extrinsic aging is still in our hands. Avoiding ultraviolet (UV) radiation, stress, pollution, smoking, together with diet restriction, physical activity, and sunscreens all help minimizing the extrinsic aging effects 2.
Cosmetic antiaging ingredients were identified to be able to improve skin barrier function, promote normal/natural exfoliation and skin turnover, help control reactive oxygen species and oxidative stress, and help maintain consistent synthesis and replacement of extracellular matrix components 3,4. In this review, we are reporting on the mechanisms behind effectiveness of the topical noninvasive antiaging compounds in use and also on the mechanism of action of potential topical antiaging substances under research.
Aging-related decline in hormonal and vitamin levels raised the hormone substitution as a therapeutic concept in treatment of skin aging. Postmenopausal hormone substitution leads to improvement of the skin barrier and skin quality through preservation of the dermal collagen content and improving cutaneous circulation and hair quality. Postmenopausal women respond well to hormone substitution when substitution is administered from the beginning of menopause. In the last decades, not only the systemic hormonal and vitamin substitution, but also the topical use of these substances played a role as antiaging therapy 5.
The role of estradiol as a systemic hormone replacement therapy on skin aging has been well documented. Since the mid 90s, the topical use of estradiol was discussed 6. Topical estradiol increases skin thickness and keratinocyte proliferation. It improves skin moisture through induction of mucopolysaccharide and hyaluronic acid production; it also improves the skin surface texture, skin microcirculation, and hair quality 7.
17β-Estradiol was used in a 0.01% concentration and could increase the epidermal thickness, number of dermal papillae, fibroblasts, and vessels after 24 weeks of application 8. Although topical estradiol could induce collagen production in the sun-protected skin and counteract the chronological skin aging, it failed in counteracting the effect of photoaging, as it neither induced collagen production nor reduced the production of metalloproteinase (MMP)-1 in photoaged skin 9,10. Topical estradiol also improved functional skin aging, as it accelerated wound healing in humans of both sexes through estrogen-induced increase in latent transforming growth factor (TGF)-β1 secretion by dermal fibroblasts 11,12.
Progesterone 2% cream improved the elastic skin properties measured by skin elasticity parameters, counteracting different signs of aging in the skin of perimenopausal and postmenopausal women. It also reduced wrinkle counts and wrinkle depth and increased skin firmness. This is achieved by increasing the collagen-1 levels and reduction of MMP-1 activity 13,14.
As a drawback, progesterone is highly absorbed in tissues and is difficult to monitor, as it could be demonstrated both in saliva and capillary blood about 10–100 folds more than that demonstrated in serum samples 15.
Age-related changes in the circulating androgen levels influence the morphology as well as the key functions of the skin, such as epidermal barrier homeostasis, wound healing, sebaceous gland growth and differentiation, and hair growth. Androgen treatment has been proposed to be an effective way to reverse the age-associated deterioration of skin 16.
Using dehydroepiandrosterone (DHEA) as local treatment for the skin markedly increased the expression of androgen receptor, procollagen 1 and 3 mRNA, and heat shock protein 47 – a molecule believed to affect procollagen biosynthesis – both on the protein and mRNA levels 17. On the gene level, DHEA modulated the genes involved in the proliferation and differentiation of keratinocytes, increased the expression of COL 1, COL 3, and COL 5 as well as the genes required for normal maturation and deposition of collagen fibers (SPARC). It also reduced the expression of genes associated with terminal differentiation and cornification of keratinocytes 18. The collagen-promoting ability of DHEA is magnified by inhibition of UV-induced MMP synthesis and stimulation of tissue MMP inhibitor 19.
Melatonin is a lipophilic hormone produced in the pineal gland, influencing biorhythm and modulating the immune mechanisms. It has an antioxidant effect capturing the hydroxide free radicals. UV-exposed fibroblasts pretreated with melatonin showed a significant decrease in lipid peroxidation and cell death. In addition, melatonin protected keratinocytes against UV-mediated apoptosis. It inhibits the mitochondria-dependent intrinsic apoptosis through inhibition of caspase 9 and 3 20. Early in the mid 90s, topically applied melatonin in a 0.5% nanocolloid gel form has been reported to reduce the UVB-induced erythema. This effect could be useful for the prevention of light-induced skin aging 21. However, clinical studies with melatonin have shown no positive effects on skin so far. Recently, the combined use of melatonin, vitamin E, and betaglucan both systemically and topically was shown to improve the biophysical and clinical parameters of aging 22.
Vitamins and vitamin derivatives
Vitamin B, vitamin C, and vitamin E
Oxidative stress, mainly produced because of UV exposure, is one of the most important causes of aging. The body deals with oxidative stress by using a series of low molecular weight antioxidants that neutralize the reactive oxygen species before they can produce oxidative changes in the tissues 23. Vitamin C – being water soluble – protects the fluids of the body, and vitamin E – being lipid soluble – protects the cell membranes and stratum corneum. Oral supplements of vitamin C and E increase the photoprotection by about 1.5-fold; topical application however increases the photoprotection up to four-fold 24.
Adding ferulic acid to a combination of vitamin C and E in a topically applied solution serves for the stability of the compound and augments the photoprotective and antioxidant effect 25. Vitamins A, C, and E are known to stimulate collagen production and act as antioxidants, which prevent free radical damage and skin aging. Topical niacinamide (vitamin B3) has been observed to be well tolerated by the skin and to provide a broad array of improvements in the appearance of aging facial skin (e.g. reduction in the appearance of hyperpigmentated spots and red blotchiness) 26.
Retinoids – vitamin A derivatives – are nuclear receptor agonists. They influence the expression of the genes involved in keratinocyte cornification and maturation, as well as in collagen synthesis. They have a well-known antiphotoaging 27, anti-inflammatory, and antitumour effects. Retinoic acid inhibits monocyte production of interleukin (IL) 1, 6, and 8 28. They inhibit cellular proliferation through intracellular isomerization to tretinoin, which acts on retinoic acid receptors. The anti-inflammatory effect is also achieved through inhibition of MMP, and hence hindering the neutrophil migration 29,30.
Retinoids have a massive healing effect through influencing collagen metabolism. They not only downregulate MMP, but also upregulate tissue inhibitor of MMP-1 and stimulate tissue fibroblasts to produce additional collagen. They also induce an increased production of water-adsorbing glycosaminoglycans. The most commonly used topical retinoids in cosmetic and antiaging purposes are retinol, retinol palmitate, and retinaldehyde 29,30.
Topically used tretinoin not only attenuates and reverses the signs of photodamage, such as coarse wrinkling, but also achieves histological changes in the form of smoothing of the epidermis, a slightly thinner keratin layer, and thin, comparatively straight elastic and collagen fibers in the mid-to-deep dermal layer 31.
Elastin fibers decrease with age. Retinol exerts its antiaging benefits not only by enhanced epidermal proliferation and increased collagen production, but also through an increase in elastin production and assembly 32.
Retinoids downregulate the UV-induced MMP-1 and enhance the collagen synthesis, and hence improve photoaged skin. Retinoids also antagonized the UVA-induced downregulation of prolidase – an important enzyme in the recycling of proline and hydroxyproline from degraded collagen molecules – through increasing the production of insulin-like growth factor-1 and 2 33.
Moreover, retinoids suppress the cysteine-rich protein 61 (CCN1), which downregulates collagen and promotes collagen degeneration and is in part responsible for the age-related abnormalities. Topical retinol reduces the CCN1 mRNA expression in both chronologically and photoaged skin 34.
Enzymes and coenzymes
Idebenone is one of the known antioxidants used as topical antiaging product. Clinically, it could reduce skin roughness and fine lines. Immunohistochemical investigations showed decrease in IL-1β, IL-6, and MMP-1 and an increase in collagen I after 6 week topical application at concentrations of 0.5 and 1% 35. Idebenone has a higher oxidative stress protection compared with α-lipoic acid and ascorbic acid 36. Allergic contact dermatitis is one of the most limiting complications for its use 37,38.
11-β Hydroxysteroid dehydrogenase inhibitor
11-β Hydroxysteroid dehydrogenase (11β-HSD1) is an enzyme that activates cortisol. Its activity and expression increase both with age and light exposure. Such effects were detected in human tissue explants and human dermal fibroblast cultures, whereas they could contribute to the morphological and functional changes associated with chronological and photoaging 39.
A selective inhibitor of 11β-HSD1 promoted proliferation of keratinocytes and fibroblasts in cell cultures and in the skin of hairless mice and promoted wound healing 40.
The glucocorticoid excess may account for the age-associated impairments in dermal integrity and wound healing, and topical application of 11β-HSD1 inhibitor may be a therapeutic option for the aging skin 41.
Sphingosine-1-phosphate and sphingosine kinase activator
These substances are still in the research phase but promise a potential antiaging topical treatment. Sphingosine-1-phosphate and sphingosine kinase activator (S1P) is a bioactive sphingolipid metabolite that regulates multiple cellular responses such as Ca2+ signaling, growth, survival, and differentiation. An activator for sphingosine kinase – an enzyme directly responsible for production of S1P – has been proven to have an antiaging effect on human fibroblast cell cultures and when topically applied in aging mice. It enhanced fibroblast proliferation, collagen production, and eventually increased dermal thickness; it also promoted specific epidermal differentiation marker proteins, including involucrin, loricrin, filaggrin, and keratin 5. It was also helpful against photoaged murine skin, where it increased fibroblasts and collagen production, stratum corneum integrity, corneodesmosome density, and barrier recovery rate 42,43. It could also improve the skin innate immunity and inhibit the Staphylococcus aureus invasion of murine skin 44.
α-Lipoic acid functions as an essential cofactor of the mitochondrial multienzyme complex, and thus plays an important role in energy metabolism. It has a very sensitive chemical structure rendering it vulnerable to UV radiation 45.
Topically applied α-lipoic acid could achieve a reduction in facial lines, almost complete resolution of fine lines in the periorbital region and upper lip area and overall improvement in skin color and texture 46. This is achieved through enhancing type I collagen synthesis in the fibroblasts by activation of TGF-β; it also facilitated the expression of a collagen-processing enzyme, prolyl-4-hydroxylase 47.
On rat skin, the topical application of α-lipoic acid enhances wound healing both clinically and histologically, influencing vascular proliferation, collagen synthesis, and reepithelialization 48.
In the diabetic wounds, the application of antioxidants such as epigallocatechin gallate, α-lipoic acid, and gold nanoparticles reduced the receptor of advanced glycation end product protein expression in fibroblasts and increased the vascular endothelial growth factor and decreased the CD68 expression, hence achieving angiogenesis, anti-inflammatory effect, and antioxidant effects; this combination could accelerate the diabetic wound healing 49. α-Lipoic acid is also an effective coantioxidant agent for the stabilization of epigallocatechin gallate 50.
Omega-3 polyunsaturated fatty acids
Although the systemic skin antiaging and photoprotective effect of polyunsaturated fatty acids is well known 51, the topically applied polyunsaturated fatty acids are less recognized as antiaging agents. Eicosapentaenoic acid was proven to have a photoprotective and anti-inflammatory effect on murine hairless skin. It attenuated UV light-induced epidermal and dermal thickness and infiltration of inflammatory cells, and impairment of skin barrier function. In addition, it suppressed the expression of IL-1β, cyclooxygenase-2, and MMP-13 induced by UV radiation. Eicosapentaenoic acid could represent a potential safe topical therapy against photoaging 52.
The cinnamon extract upregulated the mRNA protein expression of the type 1 collagen in human fibroblasts. Cinnamaldehyde significantly increased the phosphorylation levels of the insulin-like growth factor-I receptor and its downstream signaling molecules 53.
Boswellic acids are pentacyclic triterpenes extracted from the gum resins of the tropical tree Boswellia serrata, which grows in Africa and India. They have well-known anti-inflammatory and immunomodulatory activities as well as stimulatory effects on fibroblasts. A base cream containing 0.5% boswellic acid was found effective in the treatment of clinical manifestations of photoaging of facial skin and improving the extensibility firmness of the skin 54,55.
Resveratrol is one of the botanical antioxidants, a polyphenol phytoalexin, which is present in red wine and grapes. In mice, it was proved to have estrogenic, antiplatelet, and anti-inflammatory properties. It can induce the expression of several longevity genes including Sirt1, Sirt3, Sirt4, FoxO1, FoxO3a, and PBEF and prevent aging-related decline in cardiovascular functions 56. It also has photochemopreventive effects by reducing UVB-induced reactive oxygen species formation through influencing the mitochondrial function and enhancing UVB-induced apoptosis in cultured human keratinocytes, thus reducing the possibility to start malignant transformation 57.
The highly unstable epigallocatechin gallate – a catechin extract of green tea – exhibits high antioxidant activity, and it has been reported to provide protection to the skin against damage induced by solar UV light radiation. Treatment of human dermal fibroblasts with epigallocatechin gallate significantly reversed the H2O2-induced decrease in superoxide dismutase and glutathione peroxidase, and the inhibition of malondialdehyde levels. Epigallocatechin gallate possessed antioxidant activity and was effective against H2O2-induced human dermal fibroblast injury. It has the potential to be an effective antiaging substance 58.
Ginseng extract was shown to reduce the UVB-induced photodamage by reducing the MMP-1 enzyme in the dermal fibroblasts. Clinically, it could reduce skin dryness, thickness, and fragmented collagen fibers in UVB-exposed hairless mice 59.
The mainstay in the prevention of skin aging is photoprotection. Topical sunscreens reduce UV effects by scattering, reflecting, or absorbing radiation. Chemical UV filters have the capacity to absorb short wavelength UV and transform photons into infrared radiation. They could either absorb the UVB spectrum (p-aminobenzoic acid derivatives and zincacid esters), the UVA spectrum (butyl methoxydibenzoylmethane), or absorb both UVA and B photons (benzophenone). The most frequently used physical filters are the microparticles of zinc oxide and titanium dioxide with diameters in the range of 10–100 nm. They are capable of reflecting a broad spectrum of UVA and B rays. Wrinkles are induced and/or worsened by cumulative exposure to UVB at suberythemal doses, which significantly reduces the elastic properties of the skin. Cytokine expression is activated by UV light irradiation and triggers dermal fibroblasts to increase the expression of elastase. The increase in elastase results in the deterioration of the three-dimensional architecture of elastic fibers, reducing skin elasticity and finally leading to the formation of wrinkles 60.
Exposure to UV results, at least initially, in hypertrophic repair response with thickened epidermis and increased melanogenesis, in the dermis massive elastosis (deposition of abnormal elastic fibers), collagen degeneration, and twisted, dilated microvasculature.
Regular use of a sunscreen appears to partially reverse the clinical and histologic changes induced by the combination of UV exposure and chronologic aging as well as to protect from further photodamage. Regular use of sunscreens could reconstitute rete pegs, repair the keratinocyte ultrastructural damage, evenly distribute melanocytes and melanin pigment, deposit new papillary dermal collagen, and improve vasculature. Large randomized controlled studies have shown that regular use of sunscreens could not only protect against, but also retard the skin aging 61.
Soldium salicylate produced significant increases in the fibrillin and collagen-1, an effect similar to retinol cream. On the clinical level, soldium salicylate formulation significantly reduced wrinkle depth and skin roughness. The antiaging effects of soldium salicylate are derived from its intrinsic stratum corneum exfoliation effects 62.
Dihydroquercetin and natural triterpenoids
These substances have been proven to possess anti-inflammatory and antiaging properties through downregulation of UVB-induced MMP-1 63.
Facial expression wrinkles are the result of chronic contraction of mimic muscles. Nifedipine is a dihydropyridinic calcium antagonist that blocks the muscular cell calcium channels, therefore inhibiting their contraction. The application of topical 0.05% nifedepine was able to reduce the periocular wrinkles and improve the transepidermal water loss 64 as well as to improve pigmentation by an unrevealed mechanism 65.
Botulinum toxin type A
Botulinum toxin is one of the most effective antiaging agents through skin injection; it blocks the neuromuscular junction, prevents releasing of acetylcholine, and leads chemical denervation of the muscles responsible for dynamic wrinkles. Topically applied botulinum toxin cream (2 U/ml) significantly improved facial features and age appearance, as measured by the patients and clinicians 66.
The major target of topical noninvasive antiaging compounds is protection against UV light, the main inducer of extrinsic aging, and combating the reactive oxygen species through scavenging of free radicals. The already established aging-related histological and molecular skin changes could be partly reversed by rebuilding collagen and elastic fibers, and hindering their future damage by inhibition of different tissue proteinases. The extreme age-related deep wrinkles, severe skin and muscle redundancy, and extreme hyperpigmentational changes or benign tumor formation could be only corrected by more invasive or surgical procedures, which are behind the scope of this review.
Conflicts of interest
There are no conflicts of interest.
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