Biohacking for Better Skin: Understanding Skin Aging Mechanisms

The Importance of Healthy Skin

Skin health is an important aspect of our general health. Healthy skin is better able to carry out functions that protect the rest of the body—to shield it from the external environment, to regulate its hydration and temperature, to keep pathogens out. Healthy skin also deals better with aging. And skin that is healthy tends to look healthy. So, there’s an aesthetic bonus to taking care of our skin’s health. 

One of the keys to good skincare is knowledge. Understanding the main aspects of skin health, the major processes and pathways of healthy skin physiology, and the mechanisms of skin aging is essential to learning how to keep the skin healthy and youthful. 

In our companion pieces Biohacking for Better Skin: Understanding the Structure and Function of the Skin and Understanding Skin Health and Aging—Factors of Skin Aging, you can find complementary information about skin biology and health.

Mechanisms of Skin Aging

Skin aging is associated with a number of structural and functional changes that manifest as visual changes. A summary of the major changes associated with skin aging can be found in Table 1. 

In our article Understanding Skin Health and Aging—Factors of Skin Aging we saw that there are two major types of skin aging: intrinsic aging, which is chronological and determined by our genes and physiological factors, and extrinsic aging, which is driven by environmental or lifestyle-related factors [1,2]. 

Intrinsic or chronological aging is driven by genetics, hormones, and oxidative metabolism [1]; it is the result of the buildup of oxidative stress-inducing reactive oxygen species (ROS), the decline of antioxidant defenses, the accumulation of ROS-induced detrimental changes in cell membranes, enzymes, and DNA, and the decline of repair processes over time, ultimately resulting in cellular dysfunction [2–4]. 

Extrinsic or environmental aging is responsible for an acceleration and accentuation of intrinsic processes and is driven by such factors as diet, exercise, stress, pollution, cigarette smoking, and above all, unprotected and accumulated sun exposure [5–7]. In fact, extrinsic factors are the main agents of skin aging, accounting for an estimated 80–90% of age-related changes in the skin [8]. 

The most noticeable skin aging effects are caused by environmental factors, particularly sun exposure and unhealthy dietary patterns.

But although the causes and rate of progression of intrinsic and extrinsic aging are quite different, the biochemical changes they induce in the skin follow similar patterns and are most significantly associated with oxidative changes and extracellular matrix breakdown.

Dermal Breakdown Is a Major Feature of Aged Skin

The dermal extracellular matrix (ECM) is a network of molecules that offer structural support to the cells of the skin. The most important structural components of the dermal ECM are collagen, elastin, and glycosaminoglycans (GAGs, of which hyaluronic acid is the most well-known example). While collagen fibers create the structural framework of the skin, elastin provides the “bounce back” or the elasticity of the skin. GAGs have key roles in maintaining the water content of the skin [9]. Hyaluronic acid is particularly efficient, being able to retain water molecules up to 1000-fold its molecular weight [10]. 

As the skin ages, there is a progressive decrease in collagen synthesis by fibroblasts, loss of hyaluronic acid and other GAGs, and loss of elastic fibers such as elastin. There is also an accumulation of oxidative changes in ECM proteins, particularly a thickening and cross-linking of collagen fibers and a calcification and degradation of elastin. This affects their physical properties, leading to a progressive loss of tensile strength and recoil capacity, loss of elasticity and hydration, wrinkle formation, and impaired wound healing [1,2,11]. 

Another major cause of ECM breakdown is an increased enzymatic degradation of its major proteins by proteolytic enzymes called matrix metalloproteinases (MMPs) produced by epidermal keratinocytes and dermal fibroblasts. Two of the more important MMPs in aging skin are: (1) collagenase, an enzyme that breaks down collagen, and (2) elastase, an enzyme that breaks down elastin. The basal levels of these enzymes increase naturally with aging and are further increased by extrinsic factors [12–14]. 

It is estimated that collagen levels in the skin decrease about 1% per year after 21 years of age [15]. Collagen synthesis is low after the third or fourth decade of life, insufficient to maintain collagen levels and to make up for the collagen lost in natural age-related degradation processes [16]. In women, after menopause, changes are more dramatic: about 30% of skin collagen may be lost in the first 5 years, along with an annual loss of 0.55% of elastin [17,18].  

The ingredients in Qualia Skin support ECM structural integrity through multiple mechanisms. By doing so, they may help to support the skin’s ability to healthily respond to age-related changes. 

Copper (from inactive Koji Aspergillus oryzae culture) supports the synthesis of collagen and elastin fiber components by fibroblasts and supports signaling by TGF-β, an inducer of collagen synthesis [19]; it also supports the levels of HSP47, a protein that plays an important role in collagen structure stabilization (and one that is downregulated in aged skin) [20]. Manganese (from inactive Koji Aspergillus oryzae culture) is required for the activation of prolidase, an enzyme that can provide the amino acid proline for collagen synthesis in human skin cells [21,22]; GAG synthesis also requires manganese-activated enzymes [23]. Silicon (from Bamboo Stem & Leaf Extract) is important for collagen synthesis, GAG synthesis, and the activation of enzymes that support skin strength and elasticity [24]; accordingly, silicon supports skin collagen levels [25] and skin firmness [26]. L-Ornithine (as L-ornithine hydrochloride) is a precursor for the synthesis of L-proline, which is one of the primary amino acids in collagen; it supports skin levels of collagen-constituting amino acids [27] and collagen deposition [28].

Fibroblast function and ECM structural molecule levels are supported by several other ingredients: Aloe Vera Inner Leaf Juice Powder supports collagen and hyaluronic acid levels [29–39]; Amla (Emblica officinalis) Fruit Extract supports fibroblast proliferation [40] and collagen and hyaluronic acid synthesis [40–44]; Pomanox® Pomegranate Fruit Extract supports dermal collagen and hyaluronan levels [45–48]; SoyLife™ Soy Germ Extract supports fibroblast renewal and collagen, elastic fiber, and hyaluronic acid levels [49–55]; AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract supports collagen levels [56–58]. 

The activity of ECM breakdown enzymes (e.g., collagenase, elastase) is influenced by Pomanox® Pomegranate Fruit Extract [45–48,59–62], Red Orange Complex® (Citrus sinensis Fruit Extract) [63], SoyLife® Soy Germ Extract [49,53,54]; AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [56,64–66], and Rosemary (Rosmarinus officinalis) Leaf Extract [67]. Healthy dermal ECM structure in general is also supported by BioVin® French Red Grapes Extract [68–71] and Lycopene (from Tomato Fruit Extract) [72,73]. 

How Oxidative Stress Promotes ECM Breakdown

Reactive oxygen species (ROS) have a central role in the mechanisms of skin aging. Both intrinsic and extrinsic skin aging involve the generation of ROS, either as byproducts of oxidative metabolism, in the case of chronological aging, or as products of environmental stress.

ROS are continually generated in skin cells as part of natural physiological processes. Healthy young skin has the ability to maintain ROS levels under control and to respond and protect itself from ROS accumulation and oxidative stress through its own endogenous antioxidant defenses. These include antioxidant enzymes such as superoxide dismutase (SOD), redox systems such as glutathione (GSH), and antioxidant molecules such as vitamin E (α-tocopherol) and vitamin C (ascorbic acid). However, these defenses decline naturally with age, which contributes to a rise in ROS levels and an increased susceptibility to the oxidation of lipids, proteins, and DNA [74,75]. 

ROS production and oxidative stress can be countered by many of the ingredients in Qualia Skin, either by supporting the skin’s natural antioxidant defenses or through the action of bioactive antioxidant molecules. Zinc, Copper, and Manganese (from inactive Koji Aspergillus oryzae culture) support the activity of the antioxidant enzyme SOD, which exists in cells in two forms: a copper and zinc-dependent SOD (CuZnSOD), the main cytosolic form of SOD, and a manganese-dependent SOD (MnSOD), the mitochondrial form [76]. Selenium (from inactive Koji Aspergillus oryzae culture) can be converted by the liver into selenocysteine and be used in the biosynthesis of selenoproteins, which includes the antioxidant defense enzymes glutathione peroxidase and thioredoxin reductase [77]. 

The botanical extracts found in Qualia Skin are rich in bioactive molecules with antioxidant activity and most have been shown to support the skin’s antioxidant defenses and counter ROS production and oxidative stress in the skin. That’s the case with Aloe Vera Inner Leaf Juice Powder [78], Amla (Emblica officinalis) Fruit Extract [41,44,79], Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [80], Pomanox® Pomegranate Fruit Extract [46,47,61,62,81,82], Red Orange Complex® (Citrus sinensis Fruit Extract) [83–86], SoyLife® Soy Germ Extract [50,53,55,87], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [88–90], BioVin® French Red Grapes Extract [69,70,91,92], and Rosemary (Rosmarinus officinalis) Leaf Extract [93].

Mitochondria are important players in the oxidative process underlying skin aging. Oxidative stress can cause mutations in mitochondrial DNA (mtDNA) and affect mitochondrial efficiency [94]. Because the mitochondrial electron transport chain, where cell energy as ATP is produced, is a major site of ROS production, mitochondrial dysfunction can increase ROS levels and oxidative stress [95]. 

Mitochondrial inefficiency also decreases the output of cell energy required for tissue maintenance processes. The skin has a few processes that have high energetic requirements, namely cell division associated with epidermal renewal, and protection, repair, and regeneration processes associated with the effects of environmental stressors. Mitochondrial function and energy production decline can significantly hamper the activities of epidermal keratinocytes and dermal fibroblasts and be a key factor in premature skin aging [96,97]. 

There are a few ingredients in Qualia Skin that are able to support mitochondrial function. Iron (from inactive Koji Aspergillus oryzae culture) is important for mitochondrial respiration by participating in the electron transfer reactions of the electron transport chain. Iron also regulates mtDNA synthesis [98]. Manganese (from inactive Koji Aspergillus oryzae culture) supports the activity of MnSOD, the principal antioxidant enzyme in mitochondria [76]. Red Orange Complex® (Citrus sinensis Fruit Extract), a blood orange extract, is rich in two compounds that support skin mitochondrial function: cyanidin-3-glucoside [99] and hesperidin [100]. Mitochondrial function is also supported by Pomanox® Pomegranate Fruit Extract [82,101–112], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [113–115], and BioVin® French Red Grapes Extract [116–128].

Because ROS are signaling molecules, excessive ROS production can also dysregulate cell signaling. ROS generation leads to the activation of signaling pathways and transcription factors that cause changes in gene expression and that drive age-associated alterations in the skin, particularly dermal ECM degeneration [129]. Two major transcription factors activated by ROS and involved in ECM changes are activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) [130].

AP-1 reduces collagen levels by inhibiting TGFβ signaling—an inducer of collagen synthesis. NF-κB, which is a  redox-sensitive transcription factor involved in immune signaling, can stimulate the production of damaging cytokines which, in a positive feedback loop, stimulate additional production of ROS. Both NF-κB and AP-1 stimulate the expression of MMP genes and contribute to an increased secretion of matrix-degrading enzymes by dermal fibroblasts and the consequent degradation of the dermal ECM [129,131–134]. Together, oxidative stress and immune signaling trigger a cascade of signaling molecules and enzymes that contribute to the senescence of skin cells and to the functional decline and aging of the skin [135,136]. 

Qualia Skin includes a set of ingredients that influence skin degenerative signaling pathways via AP-1 and NF-κB and that, by doing so, may help minimize the impact of ROS signaling on skin physiology. AP-1 and/or NF-κB are modulated by Sea Buckthorn (Hippophae rhamnoides) Fruit Extract [137,138], Pomanox® Pomegranate Fruit Extract [81,139], Red Orange Complex® (Citrus sinensis Fruit Extract) [63,84,85,140–142], SoyLife® Soy Germ Extract [143–145], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [146], BioVin® French Red Grapes Extract [147–151], and Rosemary (Rosmarinus officinalis) Leaf Extract [67,152,153]. 

The Role of Nrf2 in Maintaining the Skin’s Redox Balance

The transcription factor nuclear factor erythroid 2-like 2 (Nrf2) is a master regulator of the antioxidant response that has been associated with skin aging. Nrf2 regulates skin homeostasis and redox balance by activating cytoprotective genes in response to oxidative stress [154]. 

Under homeostatic conditions, Nrf2 resides in the cytosol (the fluid matrix of cells) in an inactive form. Upon exposure to ROS, Nrf2 is activated and translocates to the nucleus, where it binds to regulatory regions of its downstream genes [154]. Nrf2 activates a protection system that regenerates endogenous antioxidant molecules and upregulates antioxidant and detoxifying enzymes (phase II detoxification enzymes) that promote cell adaptation to oxidative stress [155–157]. Nrf2 also controls the bioavailability of mitochondrial electron transport chain substrates [158], thereby having a role in the regulation of oxidative metabolism, and consequently, ROS production as metabolic byproducts. 

The activity of Nrf2 declines during the aging process [159]. Older adults have lower nuclear content and diminished Nrf2 activation than younger individuals and this is associated with a decrease in the levels of Nrf2 target genes, along with an increase in several NF-κB target genes [160]. Therefore, age-related Nrf-2 downregulation can decrease the skin’s natural defenses against oxidative stress [161]. 

There are many ingredients in Qualia Skin that influence Nrf-2 signaling and that, by doing so, support the skin’s antioxidant and detox defenses and redox homeostasis. Nrf-2 signaling is supported by Aloe Vera Inner Leaf Juice Powder [78], Sea Buckthorn Fruit Extract [80], Pomanox® Pomegranate Fruit Extract [62,82], Red Orange Complex® (Citrus sinensis Fruit Extract) [142], SoyLife® Soy Germ Extract [162,163], AstaPure® Astaxanthin Haematococcus pluvialis Microalgae Extract [89,90,164–166], BioVin® French Red Grapes Extract [68,91,167], Rosemary (Rosmarinus officinalis) Leaf Extract [93,168], and Lycopene (from Tomato Fruit Extract) [169].

The Role of Estrogen in the Hormonal Mechanisms of Aging

Estrogens are a group of steroid hormones most known for their role in the promotion of female sex characteristics and reproduction. Women have significantly more estrogen receptors than men have; they are found in nearly every tissue in the body and influence the function of all organ systems. But estrogens also have a role in male reproductive function, as well as in a number of other physiological functions in several tissues of the human body (regardless of biological sex), including bone, fat, and skin, for example [170].  

Estrogens act mostly through the activation of nuclear estrogen receptors (ER), which bind an estrogen response element in DNA to regulate gene expression. There are two isoforms of nuclear estrogen receptors: ERα and ERβ [171]. The predominant subtype of ER in the skin is ERβ, found in keratinocytes and fibroblasts [172,173]. Estrogen signaling via ERβ supports skin health and regulates ROS production, antioxidant enzyme expression, and oxidative stress [171]; it also supports skin immunity [174,175]. In addition to activating these protective pathways, ERβ can also directly influence the skin’s structural integrity by modulating collagen deposition and dermal thickness [176]. Therefore, estrogens can have a significant influence on skin structure and function.

Threshold levels of estrogen may be critical for the maintenance of skin integrity. In women, estrogen levels strongly influence skin integrity and the age-related decline in estrogen levels, particularly during menopause, contribute to earlier signs of skin aging [2].

Healthy estrogen levels support skin quality and dermal health in both women and men [177]. But naturally, this is particularly important in postmenopausal women, for whom skin aging can be significantly delayed with the support of estrogen signaling [178]. In fact, nearly every structural and functional change accompanying menopause has been demonstrated to be at least partially reversible with estrogen support [2]. Estrogen signaling counters the thinning of aging skin by supporting collagen synthesis and preventing collagen degradation, helping to prevent wrinkles by stimulating the synthesis of collagen, elastin, and hyaluronic acid, and supporting skin hydration and barrier function [2,178]. 

The importance of estrogen signaling for skin health is the reason why phytoestrogens may be helpful in supporting skin health [2]. Phytoestrogens are compounds that occur naturally in plants and that have a chemical structure similar to that of estrogen. They are thus able to bind to and activate estrogen receptors, thereby acting as estrogen-like signaling molecules and exerting estrogen-like actions in the human body. 

Qualia Life includes a source of phytoestrogens in its formulation: SoyLife®, a soy germ extract. Soy is rich in isoflavones, a type of polyphenolic compounds that act as phytoestrogens. Soy isoflavones are phytoestrogens that preferentially bind to and activate ERβ, the predominant subtype of ER in the skin. By activating ERβ, isoflavones may mimetize some of the physiological actions of estrogen on the skin, thereby supporting healthy skin structure and function [179]. Through ERβ signaling, soy isoflavones support the redox balance of the skin via the Nrf2 signaling pathway [162,163], support antioxidant defenses [53,54], counter oxidative stress [50,55,87,180], influence skin degenerative signaling pathways (AP-1, NF-κB) [143–145], and support dermal ECM structure (collagen, elastic fibers, hyaluronic acid levels) [49–55]. Isoflavones have also been shown to counter the expression of human skin aging biomarkers [53]. In accordance with these mechanisms of action, soy isoflavones (in SoyLife® Soy Germ Extract) have been shown to support a healthy skin structure and skin elasticity, and to help reduce the appearance of fine lines and wrinkles [49,52,181,182]. 

Supporting Skin Health for Healthy Skin Aging

When we have healthy skin, we are better equipped to respond to the challenges of chronological aging and of the external environment. There’s growing awareness and appreciation that “beauty comes from within.” Skin health does as well: it’s in large part an inside-out process.  And, it’s a reflection of what we've been feeding the skin.

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. And by doing so, Qualia Skin may also support the skin’s natural defenses against the detrimental processes that underlie and even accelerate aging. As a consequence Qualia Skin may support skin appearance and a healthy glow.

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