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Regimen Lab Skincare Encyclopedia
Resveratrol
V 1.0
Regimen's Take
Resveratrol is a polyphenol derived from red grapes and mulberries, and is one of the most potent antioxidants in skincare. What makes Resveratrol unique is its ability to activate Sirtuin and Splicing Factor Expression in skin cells, which is rather rare among antioxidants. What these mean for you: applying it on your skin can prevent your skin from “working too hard” and aging prematurely. It is an excellent choice of active for those looking for preventative skincare. A huge challenge when formulating with resveratrol is its solubility; high amounts of ethanol are usually required to solubilize it. Thankfully, we found a way to solubilize it without using ethanol. Look for it in combination with other antioxidants, especially those that can quench excited states of radical species.
TLDR
- Resveratrol has studied in concentrations of .25% - 1%, which is the range we recommend looking for in skincare products.
- Note: there are different forms of resveratrol - look for trans-resveratrol - some skincare uses a mixture of cis-resveratrol, which is not as effective.
- No single antioxidant can tackle the whole UV damage/ inflammation / etc. process - so it's best to look for Resveratrol (like any antioxidant) in combination with other antioxidants
What is Resveratrol?
Resveratrol is one of the most potent antioxidants in skincare. It is a plant-derived polyphenol that is found in red grapes and mulberries. It is also present in large amounts in other berries, pomegranates, and nuts. What makes Resveratrol unique is its ability to activate sirtuin, a signaling protein that regulates cellular functions, and splicing factor expression in skin cells, which is rather rare among antioxidants. This means that applying it to your skin can prevent it from “working too hard” and aging prematurely. It is an excellent choice of active ingredient if you are looking for preventative skincare. It has been shown that formulations with Resveratrol can stimulate the proliferation of fibroblasts, contributing to the increase in the concentration of collagen III.
What are the benefits of Resveratrol in the skin?
- Antioxidant
- Anti-inflammatory
- Anti-aging
- Antimicrobial
- Brightening
It has diverse bioactivities and is highly effective in controlling oxidative stress associated with extrinsic skin aging from UV damage, pollution, lifestyle, and pigmentation disorders. It inhibits and downregulates melanin production and reduces radical-induced reactive oxygen species (ROS) accumulation and apoptosis in our skin cells.3,4 These effects can prevent signs of premature aging, such as the formation of age spots, skin inflammation, and thinning epidermis. The antimicrobial properties of Resveratrol also make it a useful active in cosmetics for treating acne and excess sebum.
Facial and body creams, along with facial toners and hand creams, are some common cosmetics that contain antioxidants as active ingredients. They are effective against premature aging and inflammation in the skin. What is excellent about Resveratrol is that it exhibits potent antioxidant and anti-inflammatory activity while having low toxicity and minimal adverse effects in clinical studies and safety assessments.1,2 As an antioxidant, the hydroxyl groups of the resveratrol structure act as radical scavengers and metal ion chelators, and therefore, react readily with excess free radicals that are present in our body. The development of resveratrol analogs is in progress to enhance its stability and efficacy in cosmetic formulations.3
Resveratrol has excellent synergistic properties with a lot of ingredients. One great example would be its combination with Glycolic acid in combating hyperpigmentation. While Resveratrol is responsible for inhibiting the enzymes behind melanin production, glycolic acid increases the skin cell turnover rate by bringing pigmented skin to the surface and allowing it to “shed”.5 Moreover, glycolic acid has good dermal absorption and is shown to exhibit anti-melanogenic activity as well.6 A clinical study in South Korea showed an improvement on UV-induced skin pigmentation (with no adverse effects) when a formulation containing 0.4% resveratryl triglycolate, a hybrid compound of Resveratrol and glycolic acid, was applied twice daily for 8 weeks.7 We cannot stress more about the importance of sunscreen in the daily skincare routine. When it is used in combination with antioxidants, their ability to reduce the production of free radicals from UV exposure is significantly enhanced, which increases their photoprotective effects and anti-aging properties.8
What is Resveratrol's effective concentration?
Resveratrol has been studied in concentrations of 0.25 - 1%, which is the range we recommend looking for in skincare.
Formulation Considerations
A huge challenge when formulating with Resveratrol is its solubility, as high amounts of ethanol are usually required to solubilize it. Fortunately, we found a way to do this without using ethanol.
Like most antioxidants with phenol, diphenol or polyphenol groups, Resveratrol is sensitive to heat and light. They tend to discolor solutions in storage. In the case of Resveratrol, it imparts a pinkish red to reddish-brown color. With these phenolic antioxidants, the higher the antioxidant or anti-pigmentation ability, the faster they are to discolor. They are also sensitive to the presence of oxidizing metals such as Fe, Cu, and Ni and, even in trace amounts, lead to brown or bluish-green discoloration. This is why antioxidant formulations should always have multiple metal chelators in the solution. Using physical quenchers in a formulation is also imperative as they can absorb the energy from excited Resveratryl radical, essentially recycling Resveratrol.
How does Resveratrol work?
Many biological properties of Resveratrol are known to be useful in cosmetics for preventing and treating aging skin. The most notable mechanisms linked to its anti-aging activity are its potent anti-inflammatory, antioxidant, and anti-melanogenic action.
Antioxidant
Resveratrol is a naturally occurring polyphenol possessing two phenol rings linked by an ethylene bridge. Its antioxidant activity depends upon the arrangement of functional groups in nuclear structure. Therefore, configuration, substitution, and total hydroxyl (-OH) group number substantially influence several mechanisms of antioxidant activity, such as radical scavenging and metal ion chelation abilities. Previous studies showed that the hydroxyl group in the 4’ position is not the sole determinant for antioxidant activity, the 3- and 5-OH groups also contribute significantly to its ability to scavenge radicals. The study of antioxidant effect against hydroxyl (•OH) and hydroperoxyl (•OOH) radicals in aqueous simulated media using density functional quantum chemistry and computational kinetics methods revealed that trans-resveratrol may act as an efficient •OOH, and also presumably •OOR, radical scavenger.15,16
Reactive oxygen species (ROS) are naturally produced by our cells in response to immune function and during metabolism. However, excess ROS levels can lead to oxidative damages, including inflammation and age-related disorders. As an antioxidant, Resveratrol modulates cellular functions, signal transduction, and gene expression that attenuate oxidative stress and control free radical formation. It is a potent scavenger of peroxynitrite (ONOO-) and the hydroxyl (•OH), nitric oxide (NO•), and superoxide anion (O2•-) radicals.15 Other potential mechanisms for the antioxidant action of Resveratrol include enhancing cellular antioxidant capacity via the nuclear factor erythroid 2-related factor (Nrf2)-mediated pathway, which is responsible for inhibiting nuclear factor (NF)-κB activation, and increasing the gene expression of proteins that neutralize ROS and many cellular antioxidant enzymes by activating antioxidant response elements (AREs).3 Resveratrol also induces nuclear accumulation of Nrf2. It modulates several cellular pathways to protect our cells from hydrogen peroxide-induced oxidative stress, promote their survival following UV- and radical-induced cell death, and balance cellular redox status.16
Anti-melanogenic
Another sign of aging is the appearance of pigmented age spots, which are largely caused by extrinsic factors such as chronic exposure to UV radiation. Melanogenic activity is also irregularly increased in our cells as we age, resulting in an uneven mixture of hypo- and hyperpigmented areas on our skin.3 Hence, melanogenesis inhibitors are commons actives in anti-aging and whitening skincare. In the biosynthesis of melanin, the amino acid L-tyrosine is oxidized to DOPA quinone by enzyme tyrosinase followed by a series of polymerization reactions that ultimately lead to the final pigment. Therefore, inhibitors of tyrosinase, such as Resveratrol, are potential actives used in cosmetics to treat dark spots.17
Anti-inflammatory
Similar to other antioxidants, Resveratrol is known to inhibit tumor necrosis factor (TNF)-α-induced expression of cytokines and other inflammatory factors.3 Other biochemical targets include the cyclooxygenase (COX) enzymes and protein kinase B, in which their expression along with transcription factors is also inhibited by Resveratrol.18 It also inhibits NF-κB, TNF-α, and interleukin (IL)-6 serum levels, and macrophage inflammatory protein-2 and COX-2 activity levels.16 The IL-1a, IL-1β, IL-2, IL-8, IL-12, IL-17, prostaglandin E2, chemoattractant protein-1, and interferon (IFN)-γ expression levels, along with mRNA synthesis, are also suppressed by Resveratrol in a dose-dependent manner.19,20 These effects play a key role in reducing inflammation and oxidative stress.
Anti-apoptotic
Polyphenols have been reported to modulate the properties of apoptosis markers caspases 3 and 9. Resveratrol exhibits protective action against radical-initiated cellular damage by reducing the number of apoptotic cells and reversing the loss of mitochondrial membrane potential.4
Anti-aging
Signs of skin aging are dryness, loss of elasticity, sagging, and the appearance of wrinkles. Matrix metalloproteinases (MMPs) are a family of enzymes called zinc endopeptidases that play a key role in the turnover of extracellular matrix macromolecules, such as collagen I.3 When MMPs are activated in our skin cells, they can impair the structural integrity of our skin and trigger skin tissue remodeling. This results in the formation of wrinkles and other visual signs of skin aging.21 Resveratrol exhibits anti-aging activity by decreasing MMP1 and MMP9 levels and inhibiting their catalytic activity and increasing Nrf2 and heme oxygenase 1 levels to reduce oxidative stress and inflammation.22 It also activates sirtuin 1, which is an enzyme that regulates cellular functions, including aging, inflammation, and detoxification, but is decreased in expression as a result of aging.23
Does Resveratrol Penetrate the skin?
The topical route of delivery through dermal absorption is a potent way for Resveratrol to mediate anti-aging activities in our skin cells. It is well-absorbed in ointment and gel-based formulations. Compared to oral administration of Resveratrol, topical application inhibits ear edema to a greater extent. This study suggests topical Resveratrol can be absorbed and metabolized and may be more effective in preventing acute inflammation in the skin than the oral route.24 While it exhibits powerful antioxidant and anti-inflammatory effects through dermal absorption, it does not reach the systemic circulation making it a suitable and safe active used in cosmetics.1
Clinical Trials
| Concentration | Conclusion | Source |
| 1-30 µM resveratrol |
Objective: Investigate the possible existence of specific plasma membrane polyphenol binding sites in the human epidermis that mediate protective action (e.g. anti-apoptotic or anti-aging activity) of resveratrol Subjects: Human skin tissue, HaCaT cells Methods: (1) Used autoradiography to determine the distribution of resveratrol binding sites in human skin sections and HaCaT cells, and (2) exposed cells to nitric oxide (NO) free radical donor sodium nitroprusside (SNP) and determined cell viability and reactive oxygen species (ROS) accumulation in cells treated with resveratrol, piceatannol, and epigallocatechin gallate Results: A significant number of specific resveratrol binding sites was observed in the epidermis (and to a lesser extent in the dermis) and HaCaT cells, both with high binding affinity. SNP at concentrations of 0.3-3 mM exerted an apoptotic effect, loss of mitochondrial membrane potential, significant ROS accumulation, and inhibited growth of HaCaT cells. However, treatment with 1-30 µM resveratrol strongly attenuated SNP-induced toxicity, and a significant protective effect was observed at 10 µM resveratrol, with a maximal effect at 30 µM. Resveratrol was the most effective, compared to piceatannol and epigallocatechin gallate, to protect HaCaT cells against SNP-induced toxicity. However, antioxidant activity (i.e. ability to block ROS accumulation) of resveratrol and other polyphenols did not correlate with protective activity against SNP-induced toxicity. Conclusions: The protective action of resveratrol against NO-induced cell death may be related to its anti-apoptotic properties, reducing the number of apoptotic cells and mitochondrial apoptotic events. Specific polyphenol binding sites in the epidermis exist in which resveratrol act on to mediate anti-aging activity. The protective effects of resveratrol in this study are not related to its antioxidant activity. |
Bastianetto S, Dumont Y, Duranton A, Vercauteren F, Breton L, Quirion R. (2010). Protective Action of Resveratrol in Human Skin: Possible Involvement of Specific Receptor Binding Sites. PLoS One. 5(9): e12935. doi: 10.1371/journal.pone.0012935 |
| 1 mg resveratrol (in 10 µL/cm2 resveratrol solution) |
Objective: To determine skin permeation ability of resveratrol |
Alonso C, Marti M, Barba C, Carrer V, Rubio L, Coderch L. (2017). Skin permeation and antioxidant efficacy of topically applied resveratrol. Archives of Dermatological Research. 309: 423-431 |
| 1 mg resveratrol (in 10 µL/cm2 resveratrol solution) | Objective: To investigate percutaneous absorption of resveratrol Subjects: Porcine skin (back area), in vitro. Note: porcine skin was used as a representative membrane since it has similar permeation characteristics and hair follicle density as human skin Methods: Using a vertical glass Franz diffusion cell, applied a 10 µL/cm2 resveratrol solution, total 1 mg resveratrol, to the entire surface. After 24 hours of exposure, excess solution on the pigskin was removed by the tape-stripping method (5 times). Raman spectroscopy was used to generate a resveratrol concentration profile in the treated pigskin at depth increments of 7 µm (up to 49 µm). Results: Resveratrol was detected in all regions from the surface of the stratum corneum to a depth of 49 µm. Over time, resveratrol was able to penetrate deeper into the stratum corneum and up to the viable epidermis (~ 20 µm). However, the highest concentration was in the layers closer to the skin surface (0-10 µm). The concentration was constant between 20-40 µm. Conclusions: Resveratrol was detected in the stratum corneum layer and in the viable epidermal layer. Permeation of resveratrol was able to reach at least a depth of 49 µm in the skin. |
Alonso C, Marti M, Barba C, Carrer V, Rubio L, Coderch L. (2017). Skin permeation and antioxidant efficacy of topically applied resveratrol. Archives of Dermatological Research. 309: 423-431 |
| 7 to 100 µM resveratrol in culture medium | Objective: To investigate the influence of the resveratrol isomers and chemical structure on antioxidant activity Subjects: Human embryonic fibroblasts and HT1080 fibrosarcoma cells, in vitro Methods: The cells were treated with culture medium media containing resveratrol at final concentrations of 7 to 100 µM, which are typical doses found in red wine and grapes. Lipid peroxidation was induced and antioxidant activity was assessed in untreated and treated cell cultures. Results: Significant antioxidant activity was documented by the 4’ hydroxyl group in trans-resveratrol, but it acts synergistically with the 3- and 5-hydroxyl groups. A cytostatic effect by inhibiting DNA polymerase, a major enzyme in DNA synthesis, was observed in cancer cell lines treated with resveratrol. Cis-resveratrol was significantly less effective. Conclusions: The antioxidant properties of resveratrol are attributed to its hydroxyl groups in the polyphenol structure. The trans isomer demonstrated much greater potential for therapeutic applications than the cis isomer. |
Stivala L, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi, Vannini V. (2001). Specific Structural Determinants Are Responsible for the Antioxidant Activity and the Cell Cycle Effects of Resveratrol. Metabolism and Bioenergetics. 276(25): 22586-22594. doi: 10.1074/jbc.M101846200 |
| 0.4% Resveratryl Triglycolate (hybrid compound of resveratrol and glycolic acid) | Objective: To investigate the combination of resveratrol and glycolic acid to inhibit cellular melanin synthesis Subjects: Human (n = 22), all women aged between 25 and 49 Route of Administration: Topical, in vivo Tested Area: Forearm Methods: A topical formulation containing resveratryl triglycolate (RTG), a hybrid compound derived from the esterification of resveratrol with glycolic acid, was applied to artificially pigmented skin by UV induction. The topical was applied twice daily for up to 8 weeks after artificial pigmentation, and the tested skin area was assessed every 2 weeks. Results: By Weeks 6 and 8, data on skin lightness, colour, and melanin index from visual assessment and analytical instrumentation indicated enhanced depigmentation in participants treated with RTG, compared with the untreated group. No adverse skin reactions were observed in any of the participants during the study. Conclusions: The combination of resveratrol and glycolic acid, specifically RTG in this case, is a potential skin-depigmenting active used in cosmetics. |
Jo DJ, Seok JK, Kim SY, Park W, Baek JH, Kim YM, Boo YC. (2018). Human skin-pigmenting effects of resveratryl triglycolate, a hybrid compound of resveratrol and glycolic acid. Int J Cosmet Sci. doi: 10.1111/ics.124458 |
| 40 mg resveratrol/kg body weight (oral) 1 mg resveratrol in ethanol directly on dorsal skin (topical) 0.4% resveratrol mixed with 230 mg base (e.g. hydrophilic ointment, macrogel, or CMC gel) on dorsal skin, on a surface area of 2 cm2 (topical) |
Objective: Compared the absorption efficiency between oral uptake and topical application of resveratrol Subjects: Mice Methods: (Oral route) Resveratrol was dissolved in ethanol and dosed at about 40 mg/kg body weight. (Topical Route) 1 mg of resveratrol was either directly applied on the dorsal skin, or mixed with 230 mg base (e.g. ointment or gel containing 0.4% resveratrol) and applied on the dorsal skin with a surface area of 2 cm2. Levels of resveratrol and its metabolites were measured in the blood, liver, and dorsal skin after 4 hours of treatment. Results: Resveratrol was well-absorbed through the skin using ethanol as a solvent (control), though, this would not be practical for clinical applications. Resveratrol in the gel formulations had similar absorption and penetration efficiencies as ethanol alone. Overall, resveratrol metabolites were detected more abundantly in ethanol and gel bases, compared to the ointment. Topical applications were able to inhibit induced edema in mice ears, but not the oral route. (Human) In human blood samples, resveratrol metabolites were detected after the oral route, but not skin administration. Conclusions: Skin absorption of resveratrol could be a complementary, potent way to achieve therapeutic effects. |
Murakami I, Chaleckis R, Pluskai T, Ito K, Hori K, Ebe M, Yanagida M, Kondoh H. (2014). Metabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin. PLoS One. 9(12): e115359. doi: 10.1371/journal.pone.0115359 |
Abbreviations and Definitions:
|
Term |
Definition |
|
apoptosis |
Programmed cell death, a process that is involved in the elimination of damaged cells or cancer cells, and aging |
|
caspases |
Protease enzymes that are involved in the reactions leading to cell death |
|
COX-2 |
Cyclooxygenase-2; an enzyme that is expressed during an inflammatory response |
|
cytokine |
A small protein that is secreted during an inflammatory response to facilitate cell signaling and immune function |
|
HaCaT |
A human keratinocyte cell line used in clinical studies |
|
IL |
Interleukin; a cytokine that is secreted during an inflammatory response to signal the migration of immune cells to the site of inflammation |
|
IFN-γ |
interferon gamma; a cytokine that is secreted during an immune response to activate mechanisms that further enhance the innate and adaptive immune system, including antigen presentation, macrophage activation, and leukocyte interaction |
|
MAPK pathway |
Mitogen-activated protein kinase pathway; a series of cellular processes involved in cellular signaling that regulate cell proliferation, differentiation, migration, survival, and apoptosis |
|
MMPs |
matrix metalloproteinases; protease enzymes that break down collagen and are responsible for tissue repair and remodeling |
|
NF-κB |
Nuclear factor kappa B; a transcription factor that regulates the expression of genes important for cell survival and cytokine production |
|
Nrf2 |
Nuclear factor-erythroid factor 2-related factor 2; a transcription factor that regulates the expression of proteins responsible for antioxidant activity |
|
prostaglandin |
Lipids that sustain homeostatic functions, including inflammatory response |
|
sirtuins |
Enzymes that regular cellular functions including aging, inflammation, detoxification, metabolism, and circadian rhythm |
|
TNF-α |
Tumor necrosis factor alpha; a cytokine produced during inflammation to promote necrosis or apoptosis |
|
transcription factor |
a protein that regulates the expression of genes that are needed to perform a biological function in the body |
References
1. Alonso C, Marti M, Barba C, Carrer V, Rubio L, Coderch L. (2017). Skin permeation and antioxidant efficacy of topically applied resveratrol. Archives of Dermatological Research. 309: 423-431
2. Cosmetic Ingredient Review Expert Panel. (2012). Safety Assessment of Vitis vinifera (Grape)-Derived Ingredients as Used in Cosmetics. Cosmetic Ingredient Review. https://www.cir-safety.org/sites/default/files/vitis092012rep.pdf
3. Boo YC. (2019). Human Skin Lightening Efficacy of Resveratrol and its Analogs: From In Vitro Studies to Cosmetic Applications. Antioxidants (Basel). 8(9): 332. doi: 10.3390/antiox8090332
4. Bastianetto S, Dumont Y, Duranton A, Vercauteren F, Breton L, Quirion R. (2010). Protective Action of Resveratrol in Human Skin: Possible Involvement of Specific Receptor Binding Sites. PLoS One. 5(9): e12935. doi: 10.1371/journal.pone.0012935
5. Milstone LM. (2004). Epidermal desquamation. Journal of Dermatological Science. 36(3): 131-140. doi: 10.1016/j.jdermsci.2004.04.004
6. Usuki A, Ohashi A, Sato H, Ochiai Y, Ichihashi M, Funasaka Y. (2003). The inhibitory effect of glycolic acid and lactic acid on melanin synthesis in melanoma cells. Exp Dermatol. 12(2): 43-50. doi: 10.1034/j.1600-0625.12.s2.7x
7. Jo DJ, Seok JK, Kim SY, Park W, Baek JH, Kim YM, Boo YC. (2018). Human skin-pigmenting effects of resveratryl triglycolate, a hybrid compound of resveratrol and glycolic acid. Int J Cosmet Sci. doi: 10.1111/ics.124458
8. Liebel F, Kaur S, Ruvolo E, Kollias N, Southall MD. (2012). Irritation of Skin with Visible Light Induces Reactive Oxygen Species and Matrix-Degrading Enzymes. Journal of Investigative Dermatology. 132(7): 1901-1907. doi: 10.1038/jid.2011.476
10. Xia N, Förstermann U, Li H. (2014). Resveratrol and endothelial nitric oxide. Molecules. 19(10): 16102-16121. doi: 10.3390/molecules191016192
11. Mendes K, et. al. (2016). Distinct metabolic effects of resveratrol on lipogenesis markers in mice adipose tissue related with high-polyunsaturated fat and high-protein diets. Life Sci. doi: 10.1016/j.lfs.2016.04.014
12. Bonnefont-Rousselot D. (2016). Resveratrol and Cardiovascular Diseases. Nutrients. 8(5): 250. doi: 10.3390/nu8050250
13. Regitz C, Fitzenberger E, Mahn FL, Dubling LM, Wenzel U. (2016). Resveratrol reduced amyloid-beta (Aβ1-42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans. Eur J Nutr. 55(2): 741-747. doi: 10.1007/s00394-015-0894-1
14. Venturini CD, Merlo S, Souto AA, de Crus Fernandes M, Gomez R, Rhoden CR. (2010). Resveratrol and Red Wine Function and Antioxidants in the Nervous System without Cellular Proliferative Effects during Experimental Diabetes. Oxid Med Cell Longev. 3(6): 434-441. doi: 10.4161/oxim.3.6.14741
15. Holthoff JH, Woodling KA, Doerge DR, Burns ST, Hinson JA, Mayeus PR. (2010). Resveratrol, a dietary polypeptide phytoalexin, is a functional scavenger of peroxynitrite. Biochem Pharmacol. 80: 1260-1265. doi: 10.1016/j.bcp.2010.06.027
16. Salehi B, et. al. (2018). Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines. 6(3): 91. doi: 10.3390/biomedicines6030091
17. Olivares C, Solano F. New insights into the active site structure and catalytic mechanisms of tyrosinase and its related proteins. Pigment Cell Melanoma Res. 22: 750-760. doi: 10.1111/j/1755-148X.2009.00636.x
18. Kong F, Zhang R, Zhao X, Zheng G, Wang Z. (2017). Resveratrol raises in vitro anticancer effects of paclitaxel in NSCLC cell line A548 through COX-2 expression. Korea J Physiol Pharmacol. 21: 465-474. doi: 10.4196/kjpp.2017.21.5.465
19. Meng T, Xiao D, Muhammed A, Deng J, Chen L, He J. (2021). Anti-Inflammatory Action and Mechanisms of Resveratrol. Molecules. 26(1): 229. doi: 10.3390/molecules26010229
20. Fuggetta MP, et. al. (2016). Downregulation of proinflammatory cytokines in HTLV-1-infected T cells by Resveratrol. J Exp Clin Cancer Res. 35: 118. doi: 10.1186/s13046-016-0398-8
21. Dong KK, et. al. (2008). UV-induced DNA damage initiates release of MMP-1 in human skin. Exp. Dermatol. 17: 1037-1044. doi: 10.1111/j.1600-0625.2008.00747.x
22. Kim J, Oh J, Averilla JN, Kim HJ, Kim JS, Kim JS. Grape Peel Extract and Resveratrol Inhibit Wrinkle Formation in Mice Model Through Activation of Nrf2/HO-1 Signaling Pathway. J Food Sci. 84: 1600-1608. doi: 10.1111/1750-3841.14642
23. Man AWC, Li H, Xia N. (2019). The Role of Sirtuin1 in Regulating Endothelial Function, Arterial Remodeling and Vascular Aging. Front Physiol. doi: 10.3389/fphys.2019.01173
24. Murakami I, Chaleckis R, Pluskai T, Ito K, Hori K, Ebe M, Yanagida M, Kondoh H. (2014). Metabolism of Skin-Absorbed Resveratrol into Its Glucuronized Form in Mouse Skin. PLoS One. 9(12): e115359. doi: 10.1371/journal.pone.0115359
25. Stivala L, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi, Vannini V. (2001). Specific Structural Determinants Are Responsible for the Antioxidant Activity and the Cell Cycle Effects of Resveratrol. Metabolism and Bioenergetics. 276(25): 22586-22594. doi: 10.1074/jbc.M101846200