Biohacking for Better Skin: Factors That Influence Skin Health and Aging

The Significance of Healthy Skin Aging

Healthy skin is an important part of our wellbeing. It’s important for biological reasons—it helps to protect our internal organs by shielding them from environmental aggressions—and for social and aesthetic reasons—it plays a huge part in how other people perceive us.

Skin health is influenced by a diverse array of environmental and biological factors. Its greatest vulnerability is that it is exposed to all the environmental aggressions from which it so remarkably protects us. And in addition to external strains, the skin is also susceptible to physiological dysfunctions and to all the biological changes that come about as we age. But inevitable as these changes may be, the fact is that healthy skin is better equipped to deal with all the challenges of aging. And that manifests in the appearance of the skin.

The best way to understand how to keep the skin healthy and youthful is by understanding what are the factors that impact skin health and aging, which is what we’ll explore in this article. If you want to learn more about the skin before diving in, check out our companion pieces Biohacking for Better Skin: Understanding the Structure and Function of the Skin.

How Does Skin Change With Aging?

Skin aging is associated with a number of structural and functional changes that manifest as visual changes. Visible signs of skin aging include exaggerated expression lines, dryness, loss of elasticity, wrinkling, and pigment accumulation spots (age spots), for example [1,2]. But aged skin also goes through a number of less visible structural and functional alterations, including changes in sensory function, permeability, response to injury, and repair capacity [2,3].  

Figure 1 - Major changes of aged skin. Source (adapted): Harn HI, et al (2021). Front. Cell Dev. Biol. 9:635340. License: CC BY 4.0.

Our skin has two major layers: an outer layer called the epidermis and an inner layer called the dermis (beneath the dermis there’s the hypodermis or subcutis, which is not part of the skin though it supports skin structure and function). One of the major structural age-related changes in the skin is the progressive thinning of the epidermis, a process that accelerates with age. Figure 1 shows the much thinner epidermis in aged skin. The number of cell layers remains unaltered, but cell numbers decrease and layers become thinner. This loss of cells is due to a decreased proliferation and turnover of keratinocytes, the major cells of the epidermis responsible for the production of keratin—the protein that gives the skin its toughness and physical barrier properties. Skin thickness decreases, on average, by about 6.4% per decade [2–4].

Skin cells also change as we age. Keratinocytes change shape, becoming shorter and rounder, whereas corneocytes (the fully keratinized version of keratinocytes) become larger as a result of decreased epidermal turnover. The number of enzymatically active melanocytes (the cells that produce the melanin pigment responsible for skin color) also decreases between 8% to 20% per decade, but some become overactive, creating the uneven pigmentation often observable in older skin. The production of sebum (i.e., an oily, waxy secretion) by sebaceous glands also decreases up to 60% [2,3]. 

Skin hydration changes with aging. Water content in the stratum corneum (the outermost, fully keratinized layer of the skin epidermis) of aged skin is reduced, as is the epidermal lipid content (as much as 65%); consequently, the natural water and fat emulsion of the skin is also reduced. Cutaneous hydration capacity also reduces due to a decrease in natural moisturizing factors. Transepidermal water loss (TEWL)—the amount of water that evaporates from the surface of the skin, which, in healthy skin, is directly proportional to skin hydration—decreases, most likely due to the decrease in water content [2,3].

The most consistent structural change in aged skin is the flattening of the dermo-epidermal junction (i.e., the border area between the dermis and epidermis), often by more than a third. In healthy, younger skin, the dermo-epidermal junction has a wave-like configuration (see Figure 1) due to the intercalation of dermal projections with epidermal invaginations that increase the area of contact and the adhesion of the two layers. The flattening that occurs with aging results in a decreased resistance to shearing forces and an increased vulnerability to injury. Because the contact area between the two layers and the number of capillary-rich dermal papillae also decrease, the nutritional support (nutrient and oxygen supply) of the avascular epidermis by the dermis is reduced. There is also an increased risk of dermo-epidermal separation, which may be one of the mechanisms by which wrinkles form [2,3].

Dermal thickness also decreases with age. Thinning of the dermis is accompanied by a decrease in the number of fibroblasts (the main cells of the dermis) and a reduction in dermal vascularity, which diminishes nutrient and oxygen supply. The extracellular matrix (ECM) of the dermis also goes through structural changes that increase the skin’s fragility and lead to a loss of suppleness, increased rigidity, diminished elasticity, increased wrinkle development, and an increase in vulnerability to tear-type injuries [2,3,5]. 

Although the proportion of body fat tends to increase with age (until around age 70), the volume of subcutaneous fat diminishes and fat distribution changes, decreasing in the face, hands, and feet and increasing in the thighs, waist, and abdomen [3].

Factors That Influence Skin Health and Aging

Skin health is influenced by many diverse factors. Obviously, genes play a huge part in determining skin health, but our lifestyle can also have a very significant impact on skin health, perhaps even more than genetics. For example, diet can influence skin health by affecting nutrient availability and, consequently, cellular metabolism and signaling pathways [6,7]; psychological factors such as chronic stress can have an impact on skin physiology by affecting neuroendocrine signaling [8,9]; and also, skin health can be affected by all sorts of environmental aggressions to which it is naturally exposed.

Poor skin health leads to the progressive loss of its functional and structural integrity, and its manifestations are somewhat similar to those of skin aging. In fact, skin aging is the result of passing years and natural aging processes, but it can be substantially exacerbated by all the lifestyle and environmental factors that have a negative impact on skin health. In other words, skin ages as a consequence of the synergistic effects of two major categories of factors: intrinsic factors, which are chronological and determined by our biology and genetics, and extrinsic factors, which are environmental or lifestyle-related [2,3]. The latter have such a significant impact on skin health that they can actually make our skin age prematurely.

Just like every other tissue and organ in the human body, skin health is the outcome of our physiology, our environment, and our lifestyle.

Intrinsic Factors of Skin Aging

Intrinsic or chronological skin aging is the outcome of the same process that affects all other organs: the time-dependent functional decline of the body. Aging is a complex and multifactorial process driven by many physiological mechanisms working in concert [10]. Particularly relevant for skin aging are changes in gene expression and oxidative metabolism [2]. 

In general, as we age, there is a decline in antioxidant defenses in cells due to changes in gene expression. This allows for a buildup of reactive oxygen species (ROS). These highly reactive molecules are able to induce oxidative stress—a process of accumulation of oxidative changes in cell membranes, enzymes, DNA, and other cellular molecules that is highly detrimental to cellular function. 

In parallel, the skin’s cellular repair processes that would normally counterbalance ROS production also decline over time, further accelerating the accumulation of oxidative changes. This ultimately results in mitochondrial and cellular dysfunction [2,3].

Another major intrinsic factor of skin aging is the breakdown of the dermal extracellular matrix (ECM). It's the ECM and its components—collagen, elastic fibers, and glycosaminoglycans (e.g., hyaluronic acid)—that maintain skin structure and underlie skin properties such as elasticity and firmness; and it’s the breakdown of the ECM that most contribute to the most visible age-related skin changes: fine lines and wrinkles.

ECM breakdown is the result of age-related changes in gene expression that, on the one hand, decrease the synthesis of ECM molecules and, on the other hand, increase the synthesis of ECM breakdown enzymes. And add to this the age-related oxidative changes that also affect ECM molecules and the result is a change in the mechanical properties of the skin that lead to a progressive loss of firmness and elasticity and to the formation of wrinkles [2,3]. 

In the article Understanding Skin Health and Aging—Mechanisms of Skin Aging, we explore these mechanisms in more detail.

The ingredients in Qualia Skin target these processes through multiple mechanisms—countering ROS production and oxidative stress, supporting endogenous antioxidant defenses, and supporting ECM integrity, for example—and may thus help to offset these changes. 

Healthy ROS levels and endogenous antioxidant defenses are supported by Zinc, Copper, Manganese, and Selenium (from inactive Koji Aspergillus oryzae culture) [11,12], Aloe Vera Inner Leaf Juice Powder [13], Amla (Emblica officinalis) Fruit Extract [14–16], Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [17], Pomanox® Pomegranate Fruit Extract [18–23], Red Orange Complex® (Citrus sinensis Fruit Extract) [24–27], SoyLife® Soy Germ Extract [28–31], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [32–34], BioVin® French Red Grapes Extract [35–38], and Rosemary (Rosmarinus officinalis) Leaf Extract [39].

The synthesis of ECM molecules is supported by Copper (from inactive Koji Aspergillus oryzae culture) [40,41], Manganese (from inactive Koji Aspergillus oryzae culture) [42–44], Silicon (from Bamboo Stem & Leaf Extract) [45,46], L-Ornithine (as L-ornithine hydrochloride) [47,48], Aloe Vera Inner Leaf Juice Powder [49–59]; Amla (Emblica officinalis) Fruit Extract [14,16,60–62], Pomanox® Pomegranate Fruit Extract [20,22,63,64], SoyLife™ Soy Germ Extract [29–31,65–68], and AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [69–71]. 

The activity of ECM breakdown enzymes is influenced by Pomanox® Pomegranate Fruit Extract [20–23,63,64,72,73], Red Orange Complex® (Citrus sinensis Fruit Extract) [74], SoyLife® Soy Germ Extract [31,65,68]; AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [69,75–77], and Rosemary (Rosmarinus officinalis) Leaf Extract [78]. Healthy dermal ECM structure in general is also supported by BioVin® French Red Grapes Extract [36,37,79,80] and Lycopene (from Tomato Fruit Extract) [81,82]. 

Extrinsic Factors of Skin Aging

As mentioned above, extrinsic factors—environmental or lifestyle-related—are accountable for the most significant age-related changes of the skin. In fact, skin that is only intrinsically aged is highly unlikely to exist. The type of changes they induce in the skin are similar to those that develop slowly with intrinsic aging, but they tend to be exacerbated. Let’s take a look at the effects of some of the most impactful environmental factors of skin aging.

UV radiation 

UVR makes up only about 3% of sunlight at the surface of the Earth (vs about 52‒55% infrared [IR] light and 44% visible light), but due to its higher energy, UVR is the main cause of skin aging—a process known as photoaging [83–86]. 

From lowest to highest energy, UV light is divided into UVA, UVB, and UVC. UVC is absorbed by the ozone layer; of the remaining UV radiation reaching the Earth, 95% is UVA. UVA radiation penetrates deep into the dermis, whereas UVB penetrates only as far as the epidermis. Because of its higher energy, UVB causes the most acute stress, being responsible for sunburn, for example; but because of its greater amount in sunlight and its deeper penetration into the skin, UVA has a more significant role in skin aging [87,88]. 

Infrared and visible light 

Although the energy of visible and IR light is much lower than that of UVR, these light wavelengths may also place some stress on skin health. In human skin, IR can generate heat, free radicals, and mitochondrial ROS, triggering a cascade of events that cause an imbalance in ECM homeostasis and that disrupts skin immunity [89–92]. Visible light also contributes to ROS production in the skin and induces DNA changes. IR plus visible light have been shown to decrease collagen synthesis, increase the expression of MMPs, and influence skin immunity [92]. Within visible light, blue-violet light, which has higher energy and can penetrate deeper into the skin, has greater potential for inducing skin stress. Depending on the intensity of exposure, blue light may potentially stress antioxidant defenses [92–95]. 

Pollution

The skin protects our body from air pollutants, but continuous and prolonged exposure to pollution—particulate matter, carbon monoxide, polycyclic aromatic hydrocarbons, volatile organic compounds, heavy metals, and ground-level ozone, for example—ends up having a negative impact on the skin [93,96–98]. 

Air pollutants can stress the skin through a number of mechanisms. For example, ground-level ozone, which is highly reactive, induces a decrease in antioxidant defenses and oxidative stress in the epidermis [99]. Particulate matter (PM)—a mixture of very small particles of inorganic and organic pollutants and contaminants that remain suspended in the atmosphere—can penetrate the skin and cause oxidative changes in cellular structures [100,101]. PM can disrupt skin homeostasis and its barrier function, consequently enhancing further absorption of pollutants [102,103]. These actions, which act synergistically with UVR exposure, have a substantial negative impact on skin health and promote premature skin aging [104–106].  

Pollutants can also induce skin aging via activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that, in physiological conditions, has a role in many important skin cell functions [107,108]. AhR signaling can crosstalk with other signaling pathways, including Nrf2, NF-κB, and estrogen receptor signaling. Upon activation by xenobiotics (i.e., compounds that are not produced in the human body such as environmental contaminants), AhR promotes the expression of enzymes involved in the metabolism and elimination of those foreign substances, including cytochrome P450 (CYP)-dependent redox enzymes. However, these generate ROS as byproducts, meaning that exposure to high levels of pollutants can trigger oxidative stress, ECM breakdown, and other aging-like changes in the skin, such as age spots, for example [108,109]. 

Figure 2 - Mechanisms of extrinsic aging. Source (adapted): Kim and Park (2016). Naofumi Shiomi, IntechOpen. License CC BY 3.0.

There are several ingredients in Qualia Skin that support the skin’s capacity to adapt to environmental stressors, such as pollution. These include Aloe Vera Inner Leaf Juice Powder [57,59,110], Amla (Emblica officinalis) Fruit Extract [16,61], Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [17], Pomanox® Pomegranate Fruit Extract [18–20,22,23,111,112], Red Orange Complex® (Citrus sinensis Fruit Extract) [24,113,114], SoyLife® Soy Germ Extract [65,115–124], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [33,71,75,77,125–129], BioVin® French Red Grapes Extract [79,130–138], Rosemary (Rosmarinus officinalis) Leaf Extract [139], Lycopene (from Tomato Fruit Extract) [81,82,140–142]. For example, Rosemary (Rosmarinus officinalis) Leaf Extract [143], Pomanox® Pomegranate Fruit Extract [73], and Resveratrol (in BioVin® French Red Grapes Extract) [133–135] influence AhR signaling. Resveratrol may also support skin cells’ protection against cigarette smoke [136,137].

Supporting Skin Health for Healthy Skin Aging

Qualia Skin was formulated to promote beauty from within by supporting skin physiology through complementary and synergistic mechanisms that contribute to healthy skin function and structure. By doing so, Qualia Skin may support the skin’s natural defenses against the many factors that influence skin aging, both intrinsic and extrinsic. As a consequence, Qualia Skin may support skin youthfulness and radiance.

Many of the ingredients in Qualia Skin have been shown to support different aspects of skin health and appearance. Aloe Vera Inner Leaf Juice Powder supports skin elasticity and skin hydration [49–51,54,57,59]. Sea Buckthorn Fruit Extract supports skin hydration, elasticity, and texture [144]. Pomanox® Pomegranate Fruit Extract supports skin hydration, smoothness, and uniform skin pigmentation [20,22,64,145]. Red Orange Complex® (Citrus sinensis Fruit Extract) supports a uniform skin pigmentation [113], as does BioVin® French Red Grapes Extract [146–151]. SoyLife® Soy Germ Extract supports skin elasticity [152]. AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract supports healthy transepidermal water loss (TEWL) levels, skin hydration, smoothness, and elasticity [76,77,153–155]. HydroPeach™ Ceramides (Peach Fruit Extract) support healthy TEWL, skin hydration, smoothness, elasticity, and uniform skin pigmentation [156–168].

Ingredients that may help reduce the appearance of fine lines and wrinkles include Aloe Vera Inner Leaf Juice Powder [49–51,54,57,59], Pomanox® Pomegranate Fruit Extract [20,22], SoyLife® Soy Germ Extract [65,152,169], and AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [76,154,155]. 

References

[1]M. Yaar, M.S. Eller, B.A. Gilchrest, J. Investig. Dermatol. Symp. Proc. 7 (2002) 51–58.
[2]D.J. Tobin, J. Tissue Viability 26 (2017) 37–46.
[3]M.A. Farage, K.W. Miller, P. Elsner, H.I. Maibach, Adv. Wound Care 2 (2013) 5–10.
[4]J.M. Waller, H.I. Maibach, Skin Res. Technol. 11 (2005) 221–235.
[5]L. Junqueira, J. Carneiro, in: A.L. Mescher (Ed.), Junqueira’s Basic Histology Text and Atlas, McGraw-Hill Education, 2018.
[6]A. Pappas, A. Liakou, C.C. Zouboulis, Rev. Endocr. Metab. Disord. 17 (2016) 443–448.
[7]C.A. O’Neill, G. Monteleone, J.T. McLaughlin, R. Paus, Bioessays 38 (2016) 1167–1176.
[8]C.M. Lee, R.E.B. Watson, C.E. Kleyn, J. Eur. Acad. Dermatol. Venereol. 34 (2020) 54–58.
[9]H.J.A. Hunter, S.E. Momen, C.E. Kleyn, Clin. Exp. Dermatol. 40 (2015) 540–546.
[10]C. López-Otín, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, Cell 153 (2013) 1194–1217.
[11]Y. Sheng, I.A. Abreu, D.E. Cabelli, M.J. Maroney, A.-F. Miller, M. Teixeira, J.S. Valentine, Chem. Rev. 114 (2014) 3854–3918.
[12]M. Richelle, M. Sabatier, H. Steiling, G. Williamson, Br. J. Nutr. 96 (2006) 227–238.
[13]L. Yuan, X. Duan, R. Zhang, Y. Zhang, M. Qu, J. Dermatolog. Treat. 31 (2020) 300–308.
[14]S. Pientaweeratch, V. Panapisal, A. Tansirikongkol, Pharm. Biol. 54 (2016) 1865–1872.
[15]R.K. Chaudhuri, Skin Pharmacol. Appl. Skin Physiol. 15 (2002) 374–380.
[16]M. Majeed, B. Bhat, S. Anand, A. Sivakumar, P. Paliwal, K.G. Geetha, J. Cosmet. Sci. 62 (2011) 49–56.
[17]A. Gęgotek, A. Jastrząb, I. Jarocka-Karpowicz, M. Muszyńska, E. Skrzydlewska, Antioxidants (Basel) 7 (2018).
[18]F. Afaq, N. Khan, D.N. Syed, H. Mukhtar, Photochem. Photobiol. 86 (2010) 1318–1326.
[19]Y.-C. Hseu, C.-W. Chou, K.J. Senthil Kumar, K.-T. Fu, H.-M. Wang, L.-S. Hsu, Y.-H. Kuo, C.-R. Wu, S.-C. Chen, H.-L. Yang, Food Chem. Toxicol. 50 (2012) 1245–1255.
[20]S.-J. Kang, B.-R. Choi, S.-H. Kim, H.-Y. Yi, H.-R. Park, C.-H. Song, S.-K. Ku, Y.-J. Lee, Exp. Ther. Med. 14 (2017) 1023–1036.
[21]M.A. Zaid, F. Afaq, D.N. Syed, M. Dreher, H. Mukhtar, Photochem. Photobiol. 83 (2007) 882–888.
[22]J.-Y. Bae, J.-S. Choi, S.-W. Kang, Y.-J. Lee, J. Park, Y.-H. Kang, Exp. Dermatol. 19 (2010) e182–90.
[23]B. Baek, S.H. Lee, K. Kim, H.-W. Lim, C.-J. Lim, Korean J. Physiol. Pharmacol. 20 (2016) 269–277.
[24]A. Saija, A. Tomaino, R. Lo Cascio, P. Rapisarda, J.C. Dederen, Int. J. Cosmet. Sci. 20 (1998) 331–342.
[25]P. Pratheeshkumar, Y.-O. Son, X. Wang, S.P. Divya, B. Joseph, J.A. Hitron, L. Wang, D. Kim, Y. Yin, R.V. Roy, J. Lu, Z. Zhang, Y. Wang, X. Shi, Toxicol. Appl. Pharmacol. 280 (2014) 127–137.
[26]Y. He, Y. Hu, X. Jiang, T. Chen, Y. Ma, S. Wu, J. Sun, R. Jiao, X. Li, L. Deng, W. Bai, J. Photochem. Photobiol. B 177 (2017) 24–31.
[27]G. Chandra Jagetia, Transcriptomics 03 (2015).
[28]M.A. Rahman Mazumder, P. Hongsprabhas, Biomed. Pharmacother. 82 (2016) 379–392.
[29]E. Duchnik, J. Kruk, I. Baranowska-Bosiacka, A. Pilutin, R. Maleszka, M. Marchlewicz, Postepy Dermatol Alergol 36 (2019) 760–766.
[30]P. Sienkiewicz, A. Surazyński, J. Pałka, W. Miltyk, Acta Pol. Pharm. 65 (2008) 203–211.
[31]R. Gopaul, H.E. Knaggs, E.D. Lephart, Biofactors 38 (2012) 44–52.
[32]N.E. Chalyk, V.A. Klochkov, T.Y. Bandaletova, N.H. Kyle, I.M. Petyaev, Nutr. Res. 48 (2017) 40–48.
[33]E. Camera, A. Mastrofrancesco, C. Fabbri, F. Daubrawa, M. Picardo, H. Sies, W. Stahl, Exp. Dermatol. 18 (2009) 222–231.
[34]X.-L. Xue, X.-D. Han, Y. Li, X.-F. Chu, W.-M. Miao, J.-L. Zhang, S.-J. Fan, Stem Cell Res. Ther. 8 (2017) 7.
[35]J. Soeur, J. Eilstein, G. Léreaux, C. Jones, L. Marrot, Free Radic. Biol. Med. 78 (2015) 213–223.
[36]E.D. Lephart, M.B. Andrus, Exp. Biol. Med. 242 (2017) 1482–1489.

[37]E.D. Lephart, J.M. Sommerfeldt, M.B. Andrus, J. Funct. Foods 10 (2014) 377–384.
[38]Y. Ido, A. Duranton, F. Lan, K.A. Weikel, L. Breton, N.B. Ruderman, PLoS One 10 (2015) e0115341.
[39]A.C. Carvalho, A.C. Gomes, C. Pereira-Wilson, C.F. Lima, Free Radic. Biol. Med. 83 (2015) 262–272.
[40]N. Philips, P. Samuel, H. Parakandi, S. Gopal, H. Siomyk, A. Ministro, T. Thompson, G. Borkow, Connect. Tissue Res. 53 (2012) 373–378.
[41]M. Pyo, J.S. Park, Y.H. Lee, D.H. Lee, J.H. Chung, S.-T. Lee, J. Dermatol. Sci. 86 (2017) e92.
[42]R. Besio, M.C. Baratto, R. Gioia, E. Monzani, S. Nicolis, L. Cucca, A. Profumo, L. Casella, R. Basosi, R. Tenni, A. Rossi, A. Forlino, Biochim. Biophys. Acta 1834 (2013) 197–204.
[43]A. Lupi, R. Tenni, A. Rossi, G. Cetta, A. Forlino, Amino Acids 35 (2008) 739–752.
[44](2014).
[45]L.A. de Araújo, F. Addor, P.M.B.G.M. Campos, An. Bras. Dermatol. 91 (2016) 331–335.
[46]M.R. Calomme, D.A. Vanden Berghe, Biol. Trace Elem. Res. 56 (1997) 153–165.
[47]D. Harada, S. Nagamachi, K. Aso, K. Ikeda, Y. Takahashi, M. Furuse, Biochem. Biophys. Res. Commun. 512 (2019) 712–715.
[48]H.P. Shi, R.S. Fishel, D.T. Efron, J.Z. Williams, M.H. Fishel, A. Barbul, J. Surg. Res. 106 (2002) 299–302.
[49]M. Tanaka, Y. Yamamoto, E. Misawa, K. Nabeshima, M. Saito, K. Yamauchi, F. Abe, F. Furukawa, Skin Pharmacol. Physiol. 29 (2016) 309–317.
[50]C. Kaminaka, Y. Yamamoto, M. Sakata, C. Hamamoto, E. Misawa, K. Nabeshima, M. Saito, M. Tanaka, F. Abe, M. Jinnin, J. Dermatol. 47 (2020) 998–1006.
[51]S. Cho, S. Lee, M.-J. Lee, D.H. Lee, C.-H. Won, S.M. Kim, J.H. Chung, Ann. Dermatol. 21 (2009) 6–11.
[52]A. Atiba, M. Nishimura, S. Kakinuma, T. Hiraoka, M. Goryo, Y. Shimada, H. Ueno, Y. Uzuka, Am. J. Surg. 201 (2011) 809–818.
[53]P. Chithra, G.B. Sajithlal, G. Chandrakasan, J. Ethnopharmacol. 59 (1998) 179–186.
[54]M. Tanaka, E. Misawa, K. Yamauchi, F. Abe, C. Ishizaki, Clin. Cosmet. Investig. Dermatol. 8 (2015) 95–104.
[55]P. Chithra, G.B. Sajithlal, G. Chandrakasan, Mol. Cell. Biochem. 181 (1998) 71–76.
[56]F. Ali, N. Wajid, M.G. Sarwar, A.M. Qazi, Curr. Pharm. Biotechnol. (2020).
[57]E. Misawa, M. Tanaka, M. Saito, K. Nabeshima, R. Yao, K. Yamauchi, F. Abe, Y. Yamamoto, F. Furukawa, Photodermatol. Photoimmunol. Photomed. 33 (2017) 101–111.
[58]R. Yao, M. Tanaka, E. Misawa, M. Saito, K. Nabeshima, K. Yamauchi, F. Abe, Y. Yamamoto, F. Furukawa, J. Food Sci. 81 (2016) H2849–H2857.
[59]M. Saito, M. Tanaka, E. Misawa, R. Yao, K. Nabeshima, K. Yamauchi, F. Abe, Y. Yamamoto, F. Furukawa, Biosci. Biotechnol. Biochem. 80 (2016) 1416–1424.
[60]T. Fujii, M. Wakaizumi, T. Ikami, M. Saito, J. Ethnopharmacol. 119 (2008) 53–57.
[61]M.D. Adil, P. Kaiser, N.K. Satti, A.M. Zargar, R.A. Vishwakarma, S.A. Tasduq, J. Ethnopharmacol. 132 (2010) 109–114.
[62]P. Chanvorachote, V. Pongrakhananon, S. Luanpitpong, B. Chanvorachote, S. Wannachaiyasit, U. Nimmannit, J. Cosmet. Sci. 60 (2009) 395–403.
[63]H.M. Park, E. Moon, A.-J. Kim, M.H. Kim, S. Lee, J.B. Lee, Y.K. Park, H.-S. Jung, Y.-B. Kim, S.Y. Kim, Int. J. Dermatol. 49 (2010) 276–282.
[64]S.J. Kang, B.R. Choi, S.H. Kim, H.Y. Yi, H.R. Park, S.J. Park, C.H. Song, J.H. Park, Y.J. Lee, S. Kwang, J. Cosmet. Sci. 66 (2015) 145–159.
[65]S.-Y. Kim, S.-J. Kim, J.-Y. Lee, W.-G. Kim, W.-S. Park, Y.-C. Sim, S.-J. Lee, J. Am. Coll. Nutr. 23 (2004) 157–162.
[66]K. Miyazaki, T. Hanamizu, R. Iizuka, K. Chiba, Skin Pharmacol. Appl. Skin Physiol. 16 (2003) 108–116.
[67]A. Accorsi-Neto, M. Haidar, R. Simões, M. Simões, J. Soares Jr, E. Baracat, Clinics 64 (2009) 505–510.
[68]E.D. Lephart, Pharm. Biol. 51 (2013) 1393–1400.
[69]H.-Y. Chou, C. Lee, J.-L. Pan, Z.-H. Wen, S.-H. Huang, C.-W.J. Lan, W.-T. Liu, T.-C. Hour, Y.-C. Hseu, B.H. Hwang, K.-C. Cheng, H.-M.D. Wang, Int. J. Mol. Sci. 17 (2016).
[70]J. Meephansan, A. Rungjang, W. Yingmema, R. Deenonpoe, S. Ponnikorn, Clin. Cosmet. Investig. Dermatol. 10 (2017) 259–265.
[71]X. Li, T. Matsumoto, M. Takuwa, M. Saeed Ebrahim Shaiku Ali, T. Hirabashi, H. Kondo, H. Fujino, Biomedicines 8 (2020).
[72]F. Afaq, M.A. Zaid, N. Khan, M. Dreher, H. Mukhtar, Exp. Dermatol. 18 (2009) 553–561.
[73]J.K. Seok, J.-W. Lee, Y.M. Kim, Y.C. Boo, Skin Pharmacol. Physiol. 31 (2018) 134–143.
[74]H.J. Lee, A.-R. Im, S.-M. Kim, H.-S. Kang, J.D. Lee, S. Chae, BMC Complement. Altern. Med. 18 (2018) 39.
[75]K. Suganuma, H. Nakajima, M. Ohtsuki, G. Imokawa, J. Dermatol. Sci. 58 (2010) 136–142.
[76]K. Tominaga, N. Hongo, M. Fujishita, Y. Takahashi, Y. Adachi, J. Clin. Biochem. Nutr. 61 (2017) 33–39.
[77]T. Komatsu, S. Sasaki, Y. Manabe, T. Hirata, T. Sugawara, PLoS One 12 (2017) e0171178.
[78]M. Park, J. Han, C.S. Lee, B.H. Soo, K.-M. Lim, H. Ha, Exp. Dermatol. 22 (2013) 336–341.
[79]J. Kim, J. Oh, J.N. Averilla, H.J. Kim, J.-S. Kim, J.-S. Kim, J. Food Sci. 84 (2019) 1600–1608.
[80]J. Wittenauer, S. Mäckle, D. Sußmann, U. Schweiggert-Weisz, R. Carle, Fitoterapia 101 (2015) 179–187.
[81]M. Rizwan, I. Rodriguez-Blanco, A. Harbottle, M.A. Birch-Machin, R.E.B. Watson, L.E. Rhodes, Br. J. Dermatol. 164 (2011) 154–162.
[82]S. Grether-Beck, A. Marini, T. Jaenicke, W. Stahl, J. Krutmann, Br. J. Dermatol. 176 (2017) 1231–1240.
[83]L.H. Kligman, A.M. Kligman, Photodermatol. 3 (1986) 215–227.
[84]M.A. Farage, K.W. Miller, P. Elsner, H.I. Maibach, Int. J. Cosmet. Sci. 30 (2008) 87–95.
[85]E.C. Naylor, R.E.B. Watson, M.J. Sherratt, Maturitas 69 (2011) 249–256.
[86]H.W. Lim, M.-I. Arellano-Mendoza, F. Stengel, J. Am. Acad. Dermatol. 76 (2017) S91–S99.
[87]A.R. Young, Prog. Biophys. Mol. Biol. 92 (2006) 80–85.
[88]A. Han, A.L. Chien, S. Kang, Dermatol. Clin. 32 (2014) 291–9, vii.
[89]P. Schroeder, C. Calles, J. Krutmann, Skin Therapy Lett. 14 (2009) 4–5.
[90]L. Zastrow, N. Groth, F. Klein, D. Kockott, J. Lademann, R. Renneberg, L. Ferrero, Skin Pharmacol. Physiol. 22 (2009) 31–44.
[91]J. Krutmann, P. Schroeder, J. Investig. Dermatol. Symp. Proc. 14 (2009) 44–49.
[92]S. Cho, M.J. Lee, M.S. Kim, S. Lee, Y.K. Kim, D.H. Lee, C.W. Lee, K.H. Cho, J.H. Chung, J. Dermatol. Sci. 50 (2008) 123–133.
[93]C. Parrado, S. Mercado-Saenz, A. Perez-Davo, Y. Gilaberte, S. Gonzalez, A. Juarranz, Front. Pharmacol. 10 (2019) 759.
[94]B.H. Mahmoud, C.L. Hexsel, I.H. Hamzavi, H.W. Lim, Photochem. Photobiol. 84 (2008) 450–462.
[95]J.G. Coats, B. Maktabi, M.S. Abou-Dahech, G. Baki, J. Cosmet. Dermatol. 20 (2021) 714–717.
[96]D. McDaniel, P. Farris, G. Valacchi, J. Cosmet. Dermatol. 17 (2018) 124–137.
[97]E. Araviiskaia, E. Berardesca, T. Bieber, G. Gontijo, M. Sanchez Viera, L. Marrot, B. Chuberre, B. Dreno, J. Eur. Acad. Dermatol. Venereol. 33 (2019) 1496–1505.
[98]K.B. Fuks, B. Woodby, G. Valacchi, Hautarzt (2019).
[99]Q.C. He, A. Tavakkol, K. Wietecha, R. Begum-Gafur, S.A. Ansari, T. Polefka, Int. J. Cosmet. Sci. 28 (2006) 349–357.
[100]M.P. Sierra-Vargas, L.M. Teran, Respirology 17 (2012) 1031–1038.
[101]M.J. Piao, M.J. Ahn, K.A. Kang, Y.S. Ryu, Y.J. Hyun, K. Shilnikova, A.X. Zhen, J.W. Jeong, Y.H. Choi, H.K. Kang, Y.S. Koh, J.W. Hyun, Arch. Toxicol. 92 (2018) 2077–2091.
[102]T.-L. Pan, P.-W. Wang, I.A. Aljuffali, C.-T. Huang, C.-W. Lee, J.-Y. Fang, J. Dermatol. Sci. 78 (2015) 51–60.
[103]C.-W. Lee, Z.-C. Lin, S.C.-S. Hu, Y.-C. Chiang, L.-F. Hsu, Y.-C. Lin, I.-T. Lee, M.-H. Tsai, J.-Y. Fang, Sci. Rep. 6 (2016) 27995.
[104]A. Vierkötter, T. Schikowski, U. Ranft, D. Sugiri, M. Matsui, U. Krämer, J. Krutmann, J. Invest. Dermatol. 130 (2010) 2719–2726.
[105]S.-Y. Park, E.J. Byun, J.D. Lee, S. Kim, H.S. Kim, Int. J. Mol. Sci. 19 (2018).
[106]J. Soeur, J.-P. Belaïdi, C. Chollet, L. Denat, A. Dimitrov, C. Jones, P. Perez, M. Zanini, O. Zobiri, S. Mezzache, D. Erdmann, G. Lereaux, J. Eilstein, L. Marrot, J. Dermatol. Sci. 86 (2017) 162–169.
[107]K.E. Burke, Mech. Ageing Dev. 172 (2018) 123–130.
[108]S.E. Mancebo, S.Q. Wang, J. Eur. Acad. Dermatol. Venereol. 29 (2015) 2326–2332.
[109]C. Dietrich, Stem Cells Int. 2016 (2016) 7943495.
[110]D. Rodrigues, A.C. Viotto, R. Checchia, A. Gomide, D. Severino, R. Itri, M.S. Baptista, W.K. Martins, Photochem. Photobiol. Sci. 15 (2016) 334–350.
[111]K. Kasai, M. Yoshimura, T. Koga, M. Arii, S. Kawasaki, J. Nutr. Sci. Vitaminol. 52 (2006) 383–388.
[112]S.M. Henning, J. Yang, R.-P. Lee, J. Huang, M. Hsu, G. Thames, I. Gilbuena, J. Long, Y. Xu, E.H. Park, C.-H. Tseng, J. Kim, D. Heber, Z. Li, Sci. Rep. 9 (2019) 14528.
[113]C. Puglia, A. Offerta, A. Saija, D. Trombetta, C. Venera, Journal of Cosmetic Dermatology 13 (2014) 151–157.
[114]F. Cimino, M. Cristani, A. Saija, F.P. Bonina, F. Virgili, Biofactors 30 (2007) 129–138.
[115]B. Iovine, M.L. Iannella, F. Gasparri, V. Giannini, G. Monfrecola, M.A. Bevilacqua, Int. J. Mol. Sci. 13 (2012) 16444–16456.
[116]B. Iovine, M. Garofalo, M. Orefice, V. Giannini, F. Gasparri, G. Monfrecola, M.A. Bevilacqua, Clin. Exp. Dermatol. 39 (2014) 391–394.
[117]T.-M. Chiu, C.-C. Huang, T.-J. Lin, J.-Y. Fang, N.-L. Wu, C.-F. Hung, J. Ethnopharmacol. 126 (2009) 108–113.
[118]S. Widyarini, D. Domanski, N. Painter, V.E. Reeve, Photochem. Photobiol. Sci. 11 (2012) 1186–1192.
[119]H. Wei, R. Saladi, Y. Lu, Y. Wang, S.R. Palep, J. Moore, R. Phelps, E. Shyong, M.G. Lebwohl, J. Nutr. 133 (2003) 3811S–3819S.
[120]J.O. Moore, Y. Wang, W.G. Stebbins, D. Gao, X. Zhou, R. Phelps, M. Lebwohl, H. Wei, Carcinogenesis 27 (2006) 1627–1635.
[121]V.A. Terra, F.P. Souza-Neto, M.A.C. Frade, L.N.Z. Ramalho, T.A.M. Andrade, A.A.C. Pasta, A.C. Conchon, F.A. Guedes, R.C. Luiz, R. Cecchini, A.L. Cecchini, J. Photochem. Photobiol. B 144 (2015) 20–27.
[122]Y.N. Wang, W. Wu, H.C. Chen, H. Fang, J. Dermatol. Sci. 58 (2010) 19–27.
[123]K. Isoherranen, K. Punnonen, C. Jansen, P. Uotila, Br. J. Dermatol. 140 (1999) 1017–1022.
[124]B. Iovine, M.L. Iannella, F. Gasparri, G. Monfrecola, M.A. Bevilacqua, J. Biomed. Biotechnol. 2011 (2011) 692846.
[125]Y. Yoshihisa, M.U. Rehman, T. Shimizu, Exp. Dermatol. 23 (2014) 178–183.
[126]N.M. Lyons, N.M. O’Brien, J. Dermatol. Sci. 30 (2002) 73–84.
[127]M. Santocono, M. Zurria, M. Berrettini, D. Fedeli, G. Falcioni, J. Photochem. Photobiol. B 85 (2006) 205–215.
[128]T. Niwano, S. Terazawa, H. Nakajima, Y. Wakabayashi, G. Imokawa, Cytokine 73 (2015) 184–197.
[129]H. Nakajima, K. Fukazawa, Y. Wakabayashi, K. Wakamatsu, K. Senda, G. Imokawa, Arch. Dermatol. Res. 304 (2012) 803–816.
[130]K. Park, J.-H. Lee, Oncol. Rep. 19 (2008) 413–417.
[131]F. Zhou, X. Huang, Y. Pan, D. Cao, C. Liu, Y. Liu, A. Chen, Biochem. Biophys. Res. Commun. 499 (2018) 662–668.
[132]S. Reagan-Shaw, F. Afaq, M.H. Aziz, N. Ahmad, Oncogene 23 (2004) 5151–5160.
[133]M.A. Choi, J.K. Seok, J.W. Lee, S.Y. Lee, Y.M. Kim, Y.C. Boo, J. Soc. Cosmet. Sci. Korea 44 (2018) 249–258.
[134]M.-H. Tsai, L.-F. Hsu, C.-W. Lee, Y.-C. Chiang, M.-H. Lee, J.-M. How, C.-M. Wu, C.-L. Huang, I.-T. Lee, Int. J. Biochem. Cell Biol. 88 (2017) 113–123.
[135]J.-W. Shin, H.-S. Lee, J.-I. Na, C.-H. Huh, K.-C. Park, H.-R. Choi, Int. J. Mol. Sci. 21 (2020).
[136]C. Sticozzi, G. Belmonte, F. Cervellati, X.M. Muresan, F. Pessina, Y. Lim, H.J. Forman, G. Valacchi, Free Radic. Biol. Med. 69 (2014) 50–57.
[137]C. Sticozzi, F. Cervellati, X.M. Muresan, C. Cervellati, G. Valacchi, Food Funct. 5 (2014) 2348–2356.
[138]H.P. Decean, I.C. Brie, C.B. Tatomir, M. Perde-Schrepler, E. Fischer-Fodor, P. Virag, J. Environ. Pathol. Toxicol. Oncol. 37 (2018) 261–272.
[139]N. Sánchez-Marzo, A. Pérez-Sánchez, E. Barrajón-Catalán, J. Castillo, M. Herranz-López, V. Micol, Antioxidants (Basel) 9 (2020).
[140]W. Stahl, U. Heinrich, S. Wiseman, O. Eichler, H. Sies, H. Tronnier, J. Nutr. 131 (2001) 1449–1451.
[141]O. Aust, W. Stahl, H. Sies, H. Tronnier, U. Heinrich, Int. J. Vitam. Nutr. Res. 75 (2005) 54–60.
[142]A. Ascenso, T. Pedrosa, S. Pinho, F. Pinho, J.M.P.F. de Oliveira, H. Cabral Marques, H. Oliveira, S. Simões, C. Santos, Oxid. Med. Cell. Longev. 2016 (2016) 8214631.
[143]A. Mohebati, J.B. Guttenplan, A. Kochhar, Z.-L. Zhao, W. Kosinska, K. Subbaramaiah, A.J. Dannenberg, Cancer Prev. Res. 5 (2012) 593–602.
[144]B. Yang, A. Bonfìgli, V. Pagani, L.T. von-Knorring Asa, A.V.-P.J. Jutila, Journal of Applied Cosmetology 27 (2009) 13–35.
[145]M. Kanlayavattanakul, W. Chongnativisit, P. Chaikul, N. Lourith, Planta Med. 86 (2020) 749–759.
[146]J. Yamakoshi, A. Sano, S. Tokutake, M. Saito, M. Kikuchi, Y. Kubota, Y. Kawachi, F. Otsuka, Phytother. Res. 18 (2004) 895–899.
[147]J. Yamakoshi, F. Otsuka, A. Sano, S. Tokutake, M. Saito, M. Kikuchi, Y. Kubota, Pigment Cell Res. 16 (2003) 629–638.
[148]Y.-S. Lin, H.-J. Chen, J.-P. Huang, P.-C. Lee, C.-R. Tsai, T.-F. Hsu, W.-Y. Huang, Biomed Res. Int. 2017 (2017) 5232680.
[149]T.H. Lee, J.O. Seo, S.-H. Baek, S.Y. Kim, Biomol. Ther. 22 (2014) 35–40.
[150]Q. Liu, C. Kim, Y.H. Jo, S.B. Kim, B.Y. Hwang, M.K. Lee, Molecules 20 (2015) 16933–16945.
[151]R.A. Newton, A.L. Cook, D.W. Roberts, J.H. Leonard, R.A. Sturm, J. Invest. Dermatol. 127 (2007) 2216–2227.
[152]T. Izumi, M. Saito, A. Obata, M. Arii, H. Yamaguchi, A. Matsuyama, J. Nutr. Sci. Vitaminol. 53 (2007) 57–62.
[153]N. Ito, S. Seki, F. Ueda, Nutrients 10 (2018) 817.
[154]L. Phetcharat, K. Wongsuphasawat, K. Winther, Clin. Interv. Aging 10 (2015) 1849–1856.
[155]K. Tominaga, N. Hongo, M. Karato, E. Yamashita, Acta Biochim. Pol. 59 (2012) 43–47.
[156]S. Guillou, S. Ghabri, C. Jannot, E. Gaillard, I. Lamour, S. Boisnic, Int. J. Cosmet. Sci. 33 (2011) 138–143.
[157]J. Kawamura, S. Kotoura, T. Okuyama, M. Furumoto, H. Fuchuu, K. Miake, M. Sugiyama, M. Ohnishi, Journal of The Japanese Society for Food Science and Technology 60 (2013) 218–224.
[158]M. Yeom, S.-H. Kim, B. Lee, J.-J. Han, G.H. Chung, H.-D. Choi, H. Lee, D.-H. Hahm, J. Dermatol. Sci. 67 (2012) 101–110.
[159]T. Koikeda, Y. Tokudome, M. Okayasu, Y. Kobayashi, K. Kuroda, J. Yamakawa, K. Niu, K. Masuda, M. Saito, Immunol. Endocr. Metab. Agents Med. Chem. 17 (2017).
[160]M. Hori, S. Kishimoto, Y. Tezuka, H. Nishigori, K. Nomoto, U. Hamada, Y. Yonei, Anti-Aging Med 7 (2010) 129–142.
[161]H. Shimoda, S. Terazawa, S. Hitoe, J. Tanaka, S. Nakamura, H. Matsuda, M. Yoshikawa, J. Med. Food 15 (2012) 1064–1072.
[162]T. Uchiyama, Y. Nakano, O. Ueda, H. Mori, M. Nakashima, A. Noda, C. Ishizaki, M. Mizoguchi, J. Health Sci. 54 (2008) 559–566.
[163]K. Tsuji, S. Mitsutake, J. Ishikawa, Y. Takagi, M. Akiyama, H. Shimizu, T. Tomiyama, Y. Igarashi, J. Dermatol. Sci. 44 (2006) 101–107.
[164]K.-I. Kawano, K. Umemura, Phytother. Res. 27 (2013) 775–783.
[165]R. Ideta, T. Sakuta, Y. Nakano, T. Uchiyama, Biosci. Biotechnol. Biochem. 75 (2011) 1516–1523.
[166]T. Hasegawa, H. Shimada, T. Uchiyama, O. Ueda, M. Nakashima, Y. Matsuoka, Lipids 46 (2011) 529–535.
[167]K. Miyanishi, N. Shiono, H. Shirai, M. Dombo, H. Kimata, Allergy 60 (2005) 1454–1455.
[168]S. Fukunaga, S. Wada, T. Sato, M. Hamaguchi, W. Aoi, A. Higashi, J. Nutr. Sci. Vitaminol. 64 (2018) 265–270.
[169]A. Oyama, T. Ueno, S. Uchiyama, T. Aihara, A. Miyake, S. Kondo, K. Matsunaga, Menopause 19 (2012) 202–210.