"Only one person still loves your devout soul, and loves the wrinkles on your face grown old." Recently revisiting the song When You Are Old – the poet Yeats, with profound tenderness, sketches the weight of time and enduring warmth in life's journey. It invites deep reflection: youth, however glorious its prime, must eventually embrace the reality of aging. This is nature's irreversible passage for every living being. Though youth fades, our passion for life and pursuit of dreams should not fade with the passing years.

Factors affecting skin aging

Skin aging is a multifaceted process driven by both intrinsic and extrinsic factors, commonly categorized as endogenous (internal) aging and exogenous (external) aging.

Intrinsic factors refer to unavoidable biological changes within our bodies that progress naturally over time.

Extrinsic factors stem from elements in our environment that directly influence the skin—many of which can be modified or controlled. For example, external environmental exposure (ultraviolet, infrared, visible light exposure), environmental pollution (pollutants, dust, smoke), bad habits and mental stress can all accelerate skin aging.

The field of skin anti-aging has made remarkable development in recent years. With the progress of society and the improvement of people's living standards, people have paid higher attention to the anti-aging. Skin care products market continues to segment, for different skin types, different ages and different parts of the anti-aging needs of skin care products are endless, and these signs of skin aging fundamentally from the skin's internal tissue structure and physiological changes. The following is a discussion about the changes in aging skin, effective entry points for anti-aging products and in vitro efficacy assessment.

Mechanisms and clinical manifestations of skin aging

There is a difference in skin appearance and clinical manifestations resulting from the skin aging of intrinsic factors or extrinsic factors.

Skin changes of intrinsic factors: change of facial contour, sunken cheeks, deepening of eye sockets; appearance of fine lines and wrinkles, especially radiating wrinkles at the corners of the eyes and mouth; loose and sagging skin, blurring of facial contours; uneven skin color, pigmentation and discoloration, and dull and lifeless complexion.

Skin changes of extrinsic factors: roughness of the skin with fine lines, wrinkles and sagging; uneven skin tone with discoloration and pigmentation, especially in exposed areas such as the face and the back of the hands; and dilated capillaries with redness and reticulated blood vessels.

Organizational and physiological changes in skin aging

Both intrinsic and extrinsic aging lead to significant changes in skin tissue structure and physiological function.

Histologic and physiologic changes in intrinsic aging skin:

Tissue structure changes: 1. Epidermis: thinning of the epidermis, reduction of the viable cell layer, reduction of the cell division ability of the basal layer, change in pH of the stratum corneum, reduction of lipids, protein and metabolic enzyme disorders, and impairment of the barrier function. 2. Dermis: reduction of the extracellular matrix (ECM) of the dermis such as collagen and elastic fibers, structural disorganization, and the emergence of cross-border areas in the papillary region of the dermis.

Changes in physiological function: 1. Moisturizing ability: the skin's moisturizing ability is weakened, and it is easy to be dry and flaky. 2. Barrier function: the skin's barrier function is damaged, and it is easy to be exposed to external stimuli and infections. 3. Metabolism and repair: the skin's metabolism and repair ability decreases, and the speed of wound healing slows down. 4.

Histologic and physiologic changes in extrinsic aging skin:

Changes in tissue structure: 1. Epidermis: Thickening of the stratum corneum, rough texture, poor light reflection and dullness of the skin. The epidermal barrier function is impaired, water evaporation increases, and the skin becomes drier.2. Dermis: UV light induces enzymes related to elastin and collagen degradation, accelerating the loss of ECM structural proteins and the degeneration of hyaluronic acid (dermal atrophy). A large number of coarse, disorganized and abnormally proliferated elastic fibers appear in the dermis. Damage to the vasculature of the dermis, with capillary dilatation and erythema.

Changes in physiological function: 1. Moisturizing ability: the skin's moisturizing ability is weakened and dryness is aggravated. 2. Barrier function: the skin's barrier function is impaired, making it susceptible to external stimuli and infections. 3. Hyperpigmentation: melanocytes are over-activated and the dermal melanin content is elevated, resulting in chloasma and other hyperpigmented phenomena.

Fig. 1 Skin aging mechanism

Skin aging is inevitable, but it can be delayed

We have introduced the changes in the physiology and organization of aging skin, and the "foundation" and "framework" of skin structure. Therefore, starting from the mechanism of occurrence and physiological pathways, targeted screening of efficacy evaluation methods and active substance ingredients can effectively slow down skin aging.

Fig. 2 Mechanisms and pathways for skin aging

Antioxidant

Cellular oxidation is an oxidative stress reaction that occurs within the cell and these reactions produce free radicals. Free radicals are highly reactive molecules or groups of atoms that have unpaired electrons and are therefore very unstable and prone to react with other molecules. Reactive oxygen species (ROS) is a general term for reactive substances consisting of oxygen in the body or in the natural environment, including both free and non-free radicals. Accumulation of ROS causes DNA damage, induces inflammatory reactions in the skin, decreases antioxidant enzyme activity, and inhibits collagen production. In addition, ROS stimulate cells to produce large amounts of matrix metalloproteinases (MMPs), which degrade the two "springs" in the dermis, collagen and elastin, resulting in a loss of skin elasticity and firmness. Cellular oxidation also destroys the skin barrier function, making the skin more susceptible to external stimuli and infections.

Antioxidants work by scavenging free radicals, increasing antioxidant enzyme activity, reducing lipid metabolites, protecting important cellular organelles, and modulating cellular signaling pathways to inhibit apoptosis. In conjunction with the mechanism of antioxidant action, chemical methods, cellular methods, and skin models can be used for in vitro evaluation. Many substances have antioxidant activity, such as superoxide dismutase, glutathione peroxidase, vitamin E, vitamin C, carotenoids, coenzyme Q10, tea polyphenols, grape seed extract, resveratrol and proanthocyanidins and other botanicals.

Antiglycosylation

Fig. 3 Mechanisms and pathways for skin glycation

Skin glycation, a non-enzymatic reaction between proteins and natural reducing sugars, is one of the underlying causes of endogenous skin aging. The complex array of glycosylation products produced at different stages and pathways during the reaction are collectively referred to as advanced glycosylation end products (AGEs). AGEs accumulate in the skin with age and are amplified by exogenous factors such as ultraviolet radiation, leading to wrinkles, dullness, yellowing, and other skin problems. AGEs are capable of causing cross-linking and denaturation of structural proteins, such as collagen and elastin in the skin, thereby destroying skin elasticity and firmness, as well as decreasing skin barrier function and promoting inflammatory responses.

Active substances that inhibit skin glycation include vitamin C, vitamin E, resveratrol, tea polyphenols and proanthocyanidins. In addition, reducing sugar intake, consistent exercise, sun protection and the use of antioxidant products are also effective in inhibiting glycation.

Anti-inflammatory

Fig. 4 Mechanism of UV-induced inflammatory response occurrence

Inflammation accelerates skin aging by affecting the skin barrier, leading to enhanced epidermal water loss, and by affecting keratinocyte growth, making it more difficult to recover from a damaged barrier. In addition, inflammation breaks down the extracellular matrix, causing the skin to collapse while inhibiting collagen synthesis. Chronic inflammation leads to increased cellular oxidative stress and damage to cellular DNA, proteins and lipids, which accelerates cellular aging and tissue degeneration.

In order to combat inflammatory skin aging, a number of anti-inflammatory measures are needed. These include supplementing with nutrients that have antioxidant and anti-inflammatory effects, such as flavanols, carotenoids, curcumin, vitamin D, vitamin C, omega-3 fatty acids, etc.; staying away from environmental pollutants and protecting against the sun; maintaining a regular routine and creating a good sleep environment; and exercising in a way that reduces the levels of inflammatory markers and enhances immune system function.

Extracellular matrix (ECM)

The extracellular matrix (ECM) lies in a complex network of collagen, elastin, polysaccharides, and proteins between cells that provide structural support and physical strength to the skin while influencing cell behavior and tissue repair. As we age, the ECM gradually loses its original structure and function, leading to wrinkles and sagging skin.

Extracellular matrix protectors include retinoids, fucoidan, polyethylene glycol/peptide hydrogels, glycyrrhizic acid, astragalus extract (polysaccharides and flavonoids), marigold extract, nettle extract, etc., and photodynamic immunomodulators that increase the expression of hyaluronan synthase-3 (HAS3) and hyaluronan synthase-2 (HAS2).

Inhibition of matrix metalloproteinases (MMPs)

Fig. 6 Classes of Matrix Metalloproteinases (MMPs) (image from the web)

MMPs are a family of zinc-containing proteases capable of degrading almost all components of the extracellular matrix. Based on substrate specificity and post-secretory form, MMPs are classified into the categories of collagenase, gelatinase, matrix lysin, and membrane-type MMPs.MMPs are capable of degrading collagen and elastin in the dermis, regulating pro-angiogenic factors and producing endogenous types of angiogenesis inhibitory factors, and facilitating vascularization by solubilizing the surrounding matrix. Ultraviolet (UV) irradiation is the most important exogenous factor contributing to skin aging. UV irradiation induces overexpression of active MMPs, which in turn degrades collagen and other dermal extracellular matrix components, leading to skin photoaging.

Active substances capable of inhibiting matrix metalloproteinases (MMPs) include retinol, boswelline, peptides, yeast extract, curcumin, calendula extract, vitamin C and its derivatives, and ceramides.

Promotes cell proliferation and stemness expression

Fig 7 Distribution of epidermal stem cells and their senescence

As we age, the proliferative capacity of cells decreases, mainly in the form of altered gene expression, decreased protein synthesis, and diminished cellular function. Fibroblasts are responsible for producing ECM, including collagen and elastin. Decreased proliferative capacity and activity of fibroblasts leads to decreased ECM synthesis, which further aggravates skin laxity and wrinkle formation. Therefore, cellular aging can be slowed down by promoting cell division and proliferation, e.g. retinol and retinoic acid can promote the division of human epidermal cells.

Epidermal stem cells can promote the division of epidermal basal cells and accelerate the rate of cell renewal, which helps to maintain the healthy state of the skin and reduce the formation of wrinkles. In addition, they can promote the secretion of collagen by fibroblasts to increase skin elasticity. Secretion of cytokines such as epidermal growth factor (promotes the synthesis of tissue fibers and collagen), vascular endothelial growth factor (promotes angiogenesis), nerve cell growth factor (promotes the development, differentiation and expression of the functional properties of neurons) and other cytokines to promote the repair of various tissues and organs of the body and slow down the aging process. The link between stemness expression of epidermal stem cells and anti-aging is reflected in various aspects, including activation of skin cells, promotion of collagen synthesis, improvement of dullness and pigmentation, moisturization, elimination of free radicals, promotion of skin proliferation, secretion of cytokines, and the role of exosomes.

Evaluation of the anti-aging efficacy of the product

Anti-aging products on the market are publicized in a variety of ways, such as wrinkle, anti-aging, firming, brightening, smoothing fine lines and other concepts are endless. Part of the efficacy of the product publicity is through rigorous scientific experiments to reach a conclusion, but there are also some products only as a gimmick used for marketing. With the increasingly strong regulation of the efficacy of publicity, those who have a scientific basis, real and credible publicity will become the mainstream, but also become an effective bridge to build trust between brands and consumers.

There are various existing methods for assessing anti-aging efficacy, which aim to scientifically and objectively evaluate the actual effects of anti-aging products. Among them, with the help of advanced cell culture technology, such as epidermal stem cell photoaging models and fibroblast aging models have been established. In addition, with cell-constructed 3D skin models (e.g. Epikutis and Fulkutis) as well as ex vivo skin (Exvivo) testing, we can realize a more comprehensive and multi-dimensional evaluation. These techniques not only cover multiple assessment metrics, but also allow for a more intuitive, visualized and clearly presented in a data-driven form

Skin aging is a complex process, which stems from the interaction between an individual's internal metabolic mechanisms and external environmental factors. Comprehensive and in-depth research has been conducted on this topic. Next, we will launch a series of special articles to explore the aging mechanism and anti-aging strategies for readers' reference and reference.

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