While we can all recognize a radiant and healthy (facial) skin when we see it, we have a poor characterization of it on a molecular level. Mostly, we would say healthy skin is defined by the absence of disease. Even as we look across age, the state of our skin is mostly defined by its deficiencies.
In many areas of human physiology we have a good understanding of what healthy means. We know what a “good” cholesterol is, we know what blood glucose levels should be etc. While these reference measurements are getting challenged by new technologies enabling measurements on population scale, we still have some grounding. But as stated above, this is not the case for our largest and most visible organ, the skin.
Skin changes as we age
If we look at the skin of a newborn or young child, their skin is not yet fully matured. Their skin barrier is more permeable, their lipid production is decreased compared to adults, and have less water retention. Together this makes young children (< 10 years of age) more susceptible to irritation and inflammation [1]. As children reach their teens, hormones start to induce a series of structural changes in the skin: increased sweat and sebum production, changes in pro- and anti-inflammatory signal, enhanced skin barrier and most prominently shifts in the skin microbiome with associated risks for acne vulgaris which affects roughly 85% of adolescents and young adults (12–25 years old). Reaching adulthood in the early to mid 20’s the immune system stabilizes, the microbiome starts to become stable [2] and the skin reaches a short window of “optimality”. While collagen starts to decline from around age 25, the skin benefits of estrogen (for females) lasts until the beginning of the 30’s. As estrogen levels starts to decline until menopause, there is also a steady decline in the biological functions of the skin. We start to see the early signs of skin senescence (commonly known as skin aging). In aged skin, post menopause, there are multiple changes in the skin structure, from thinning of the skin, to loss of structural support, decline in wound healing capabilities, decrease in sebum production etc. Ultimately leading of a fragile, wrinkled and dry skin.
Following the chronological changes in skin it appears that there is no singular “optimal” health state. Rather our skin undergoes a continuous transformation in sync with our body, constantly adjusting to internal and external events. By mapping out the deleterious responses to these events, we start to form an understanding of skin health defined via the “absence of” specific deregulation of biological pathways. In other words, we start to define skin health as a “problem free” skin, which is very different from having reference measurements of health. This is a problematic situation as it can create unrealistic expectations of what is obtainable. As an analog I know my VO2 max is in the very good to excellent range, according to age, however, this would be average if I was 20 years younger. Such references do not exist for skin partly due to the multifactorial nature of what constitutes a “problem free” skin.
Internal mediators of skin aging
Focusing on the internal events in the skin, there are a few major contributors to skin’s deterioration. Please note that this is not an exhaustive summary, and many excellent review articles dive much further into this subject, see for instance He at al. [3] and Alfred et al. [4].
There are multiple “grand” theories about (internal) skin aging: the theory of free radicals and oxidative stress, the theory of inflammatory aging, the theory of skin photoaging, and the theory of nonenzymatic glycosyl chemistry. The difference between these theories is mostly what is the prime mover. They all encompass more or less the same biological pathways, and differ on the emphasis placed on each.
In the following I will lean more towards the inflammatory aging or inflammaging theory. This theory states that our immune system becomes less and less perfect at protecting us as we age, leading to a low-level chronic inflammation. This leads an increase to pro-inflammatory molecules which disrupt the normal function of our cells and accelerates the aging process.
Decrease in antioxidants: As we age the effectiveness of our endogenous antioxidant system is diminished and reactive oxygen species (ROS) starts to wreak havoc. This buildup not only induces DNA damage, but also, intracellular lipid peroxidation, abnormal protein oxidation reactions, all of which result in cell damage, inflammation, immune suppression, oxidative stress, and hyperplastic responses in the skin. Both oral intake of and topical application of antioxidants benefits skin, and alleviate some of the age dependent effects. While most oral studies have been performed on antioxidant supplements, normal healthy diets (carrots, broccoli, berries, seeds etc.) are rich sources of antioxidants.
Accumulation of senescent cells: Senescent cells are “exhausted” cells that stop growing / divide and communicate this to their environment by sending our pro-inflammatory signals. Such senescent keratinocytes and fibroblasts appear to accumulate with age in human skin. This leads to the formation of the so called senescence-associated secretory phenotype (SASP). SASP is characterized by, among other, increase in pro-inflammatory cytokines and chemokines, matrix metalloproteinases and ROS which leads to the elimination of the senescent cells, but may also induce the generation of senescence in functional normal neighboring cells [5]. Based on in vitro assays quercetin, hydroxytyrosol and a series of flower extracts has been shown to display senolytic effects.
Increase in glycation end products: Glycation end products is a result of the interaction between reducing sugars and protein, lipids or DNA. Similar to what happens when forming the crust on a brioche bun. This leads to non-functional biological molecules which the body needs to breakdown to avoid deleterious effects and accumulation.
During aging there is a buildup of Advanced Glycation End Products (AGEs). AGEs are spontaneously formed and accumulate in the body under physiological metabolic conditions [6], and cause shortened, thinned, and disorganized collagen fibrils, consequently reducing elasticity and skin/scar thickness with increased contraction and delayed wound closure. AGE formation is highly related to diet and diabetics have increased levels of AGEs. Collagen types I and IV, exhibiting a slow turnover rate of about 10 years, and other dermal long-lived proteins like fibronectin mainly suffer from glycation during intrinsic chronological aging [7]. While diet has a major impact on AGE formation, multiple natural compounds offers protection [8], among others, olive leaf and milk thistle extracts.
Declining estrogen production: After its peak at around age 30, estrogen starts to decline. Estrogens modulate skin physiology on a profound level, impacting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing, and immune responses [9]. Estrogen-deficiency results in atrophic skin changes and accelerated skin aging. Estrogen replacement therapy has been shown to impact keratinocyte proliferation, epidermal thickness, epidermal hydration, and skin elasticity, reduce skin wrinkles, augment the content and quality of collagen, and increase the level of vascularization. In cosmetic skincare there is a wide variaty of phytoestrogens which show reverse of the clinical manifestations. Genistein, daidzein, reservatrol, and equol are among the more wellknown ones. In terms of side effects, a large study from 2009 including 9000+ subjects conclude that there is no increase risk compared to the placebo group [10].
Reduced skin barrier integrity: The skin barrier is the outermost skin layer, forming the protective layer between the living cells in the skin and the external environment. It keep pathogens, toxins etc out, and is essential for moisture retention and thermoregulation of the skin. With age the sebaceous glands enlarge but reduce sebum production, leading to a drier skin. This is combined with a slower lipid processing and impaired skin barrier formation (due to acidification of the outermost skin layer, the stratum corneum). Finally, the epidermal cell turn-over is slowed and halves between the 3rd and 7th decade of life, resulting in reduced wound healing capacity. Maintaining a strong skin barrier is paramount to overall skin health as it is the most prominent defense against external threats. Aiding the skin barrier can be done in multiple ways, from film forming occlusions, to stimulation of sebum production, proliferation of keratinocytes, supplying ceramides etc.
Changes in pigmentation: Pigmentation, melanin, is produced by specialized cells in the skin, melanocytes. These are located in the basal layer of the epidermis, and have melanosomes, which based on various triggering mechanisms produce melanin. The number of functional melanocytes decrease by up to 20% per decade after the age of 30 and results in less photo-protection. At the same time, the remaining melanocytes show reduced proliferation capability and a change in interaction with keratinocytes resulting in a mottled, uneven pigmentation. The first and foremost treatment for pigmentation issues is protection from sun-damage. As both external trauma (sun-damage) and internal triggers (inflammation) can lead to pigmentation issues, anti-inflammatory is a strong secondary choice of preventative treatment. Lastly, to rid the skin of already existing pigmentation lesions, increasing the cell turn over rate of the epidermis will help with superficial lesions, and tyrosinase inhibtors blocking formation of melanin production will help with dermal lesions.
Loss of nutritional support: The nutritional support for the skin, a steady supply of both nutrients and oxygen is reliant on something called the dermo-epidermal junctions. This is the 80nm thick interface between the epidermis and the dermis. With age there is a flattening of this dermo-epidermal junction. That leads to less resistance to shearing forces, as well as reduced supply of nutrients and oxygen. With an associated loss of the vertical capillary loops, the skin gets more pale, have less nutrients for repair processes and starts to have issues with thermoregulation. Ingredients that promote angiogenesis (formation of new blood vessels) may lessen this effect, as will ingredients that support the structural integrity of the skin.
Loss of structural support: Our skin’s firmness and smoothness is reliant on the collagen elastin matrix of the dermis. Within the dermis there is general atrophy of the extracellular matrix, accompanied by fewer fibroblasts, and with reduced synthetic ability. Collagen-degrading enzymes (e.g., matrix metalloproteinases (MMPs)) are upregulated during both photoaging and intrinsic aging, mainly via the production of reactive oxygen species (ROS). This leads to fine lines and wrinkles formation, and decreased hydration and turgor capacity.
Chronic inflammation: Aging skin also experiences changes in immune function, with decrease in IL-2 and increase in IL-4 which causes reduced intensity of delayed hypersensitivity reactions thus increased susceptibility to carcinogenesis and chronic skin infections. The imbalance is even more pronounced in photoexposed skin, where underlying chronic inflammation can be observed already in the 20’s, with increase in senescence related components in the 30’s to 40’s to a shift into hypoxia and subsequent metabolic changes in the 50’s [11]. Part of the explanation is a steady expression of IL-8 and a shift in IL-1RA/IL-1α present already in the early 20’s, indicating that preventative treatment could lessen the effects of premature photoaging.
Summary
As skin is continuously transforming throughout our lifetime there is no single (age-related) definition of healthy skin. Instead we can point to the observed decline and deficiencies in our skin to start forming a scientific basis for targeted treatment.
With signs of chronic inflammation starting in the early 20’s preventative treatment, and subsequent more targeted and specialized treatments should be considered to counteract intrinsic age related skin changes. However, it is important to note that these are only internal changes. Just as important are extrinsic factors and acute events that impact our skin. This will be the topic of future posts. Likewise I will dive into more details on the fascinating intrinsic changes in skin.
If there is one take home message you should get from reading this post, it is that your skin is highly dynamic, and no single hero ingredient nor single regimen is going to solve for your skin needs throughout your lifetime. There must be a continuous adaptation to both acute and chronic skin changes, and that our understanding of skin health is still evolving.
References
[1] Kong, Fanqi, Carlos Galzote, and Yuanyuan Duan. “Change in skin properties over the first 10 years of life: a cross-sectional study.” Archives of Dermatological Research 309, no. 8 (2017): 653–658.
[2] Townsend, Elizabeth C., and Lindsay R. Kalan. “The dynamic balance of the skin microbiome across the lifespan.” Biochemical Society Transactions 51, no. 1 (2023): 71–86.
[3] He, Xin, Fang Wan, Wenhui Su, and Weidong Xie. “Research Progress on Skin Aging and Active Ingredients.” Molecules 28, no. 14 (2023): 5556.
[4] Alfredo, G., M. C. Sarita, C. Veronica, M. R. N. Samuel, A. A. C. N. Silvana, and M. F. Lydia. “Review of major theories of skin ageing.” Adv Aging Res 3 (2014): 265–84.
[5] Höhn, Annika, Daniela Weber, Tobias Jung, Christiane Ott, Martin Hugo, Bastian Kochlik, Richard Kehm, Jeannette König, Tilman Grune, and José Pedro Castro. “Happily (n) ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence.” Redox biology 11 (2017): 482–501.
[6] Chen, Chun-yu, Jia-Qi Zhang, Li Li, Miao-miao Guo, Yi-fan He, Yin-mao Dong, Hong Meng, and Fan Yi. “Advanced glycation end products in the skin: Molecular mechanisms, methods of measurement, and inhibitory pathways.” Frontiers in Medicine 9 (2022): 837222.
[7] Gkogkolou, Paraskevi, and Markus Böhm. “Advanced glycation end products: key players in skin aging?.” Dermato-endocrinology 4, no. 3 (2012): 259–270.
[8] Song, Qinghe, Junjun Liu, Liyuan Dong, Xiaolei Wang, and Xiandang Zhang. “Novel advances in inhibiting advanced glycation end product formation using natural compounds.” Biomedicine & Pharmacotherapy 140 (2021): 111750.
[9] Liu, Tao, Nan Li, Yi‐qi Yan, Yan Liu, Ke Xiong, Yang Liu, Qing‐mei Xia, Han Zhang, and Zhi‐dong Liu. “Recent advances in the anti‐aging effects of phytoestrogens on collagen, water content, and oxidative stress.” Phytotherapy research 34, no. 3 (2020): 435–447.
[10] Tempfer, Clemens B., Georg Froese, Georg Heinze, Eva-Katrin Bentz, Lukas A. Hefler, and Johannes C. Huber. “Side effects of phytoestrogens: a meta-analysis of randomized trials.” The American journal of medicine 122, no. 10 (2009): 939–946.
[11] Jarrold, Bradley B., Christina Yan Ru Tan, Chin Yee Ho, Ai Ling Soon, TuKiet T. Lam, Xiaojing Yang, Calvin Nguyen et al. “Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades.” bioRxiv (2022): 2022–03.