Our brain-skin connection controls the interaction between the brain, stress, inflammation and the skin's ageing. The relationship between stress and a variety of skin conditions is well documented. Recent studies have linked psychological stress to the onset and worsening of multiple skin diseases. Not only that but stress, in turn, causes chronic inflammation which is linked to skin ageing whilst also negatively impacting the quality, and synthesis, of collagen in the skin - leading to a loss of firmness and elasticity.11
Psychological stress arises when people are under mental, physical, or emotional pressure. The brain senses this and releases stress hormones, such as corticotropin-releasing hormone (CRH), glucocorticoids and epinephrine. This triggers a wide range of behaviour changes and responses that try to adapt the body to the stress being experienced.
Skin and its appendages are not only targets of key stress mediators; they are also a local source for these factors, which induce various immune and inflammation responses.
Stress conditions exert their effects on the skin mainly through the hypothalamic-pituitary-adrenal (HPA) axis. “The HPA axis is a term used to represent the interaction between the hypothalamus, pituitary gland, and adrenal glands; it plays an important role in the stress response. “8
When sensing stress, neurons in the hypothalamus secrete corticotropin-releasing hormone (CRH), which is transported to the pituitary gland, where it stimulates the secretion of neuropeptides, like adrenocorticotropin (ACTH). In turn, ACTH travels to the outer layer of the adrenal cortex and stimulates the production of glucocorticoids (GC), including cortisol and corticosterone.
The video below explains this interaction.
Cortisol is the primary stress hormone in humans that controls a wide range of stress responses. Cortisol levels fluctuate throughout the day, this is regulated by our 24-hour internal clock, or circadian system, with peak levels normally occurring in the early morning and the lowest point happening around midnight. Stress can significantly disrupt cortisol levels and this oscillation curve. A high level of stress leads to elevated cortisol levels, this can have a major impact on the immune system (by suppressing it) and influences our overall health over time.
Skin peripheral HPA axis
In the skin there is a peripheral HPA axis, like the one already explained. Glucocorticoids from the adrenals are the key feedback molecules of this peripheral HPA axis and essential for equilibrium in the skin’s interdependent elements. In fact, keratinocytes produce hormones like CRH, ACTH, and cortisol. They also produce neurotransmitters (e.g., adrenaline, noradrenaline, dopamine, histamine, acetylcholine, etc.), neurotrophins (e.g., nerve growth factor, brain-derived neurotrophic factor), and neuropeptides that also respond to stress. The epidermis continuously senses the environment and responds to stressors to maintain epidermal homeostasis (balance) and adjust skin barrier functions. Dysfunction in the skin’s HPA can lead to conditions like atopic dermatitis.2
In mast cells, the stress hormone causes changes that result in inflammation. There is also a link between elevated psychological stress and an increase in inflammation. In keratinocytes, it stimulates the production of Interleukin 6 (IL-6), which triggers chronic inflammation and autoimmune responses3. These reactions can aggravate allergies, worsening conditions like psoriasis and eczema.
Sympathomedullary Pathway (SAM) axis
When stress triggers the hypothalamus, responses are either via the HPA axis (in long term stress) or the SAM axis (for short term stress). This short-term response is what we also know as the “fight or flight” response. This is our survival mode – and it happens without any conscious control. The adrenal medulla releases epinephrine (adrenaline) and norepinephrine (noradrenaline) in the case of short-term stress5. Adrenaline causes your heart to race - sweating and blood pressure are also elevated.
The skin also holds a peripheral catecholamine system where epinephrine is produced by the keratinocytes. It is possible that epinephrine can affect epidermal health. In melanocytes, the epinephrine created by their surrounding keratinocytes can promote melanogenesis (a darkening of the skin).
The skin contains many peripheral nerves, which can also impact skin health through secreted factors like neuropeptides and neurotrophins. These serve as local stress responders that regulate erythema, swelling, temperature increase, tenderness, and pain due to neurogenic inflammation.
Substance P (SP) is a stress-related pro-inflammatory neuropeptide, which is released from cutaneous peripheral nerve terminals. It stimulates inflammation of the nervous tissue, which can accelerate the brain’s ageing processes and eventually lead to neurodegenerative diseases like Alzheimer’s or Parkinson’s.
Skin health during stress responses
Stress is known to aggravate various conditions, for example, asthma, arthritis, migraines, and multiple sclerosis. Specifically, in the skin, multiple neuro-inflammatory conditions can be triggered or aggravated by stress, such as psoriasis, atopic dermatitis, acne, contact dermatitis, alopecia areata, itch or Pruritus, and erythema.
Psoriasis is a chronic skin inflammatory disease, affecting about 2% of populations worldwide. It is characterised by an over-proliferation of keratinocytes and inflammation, which leads to epidermal hyperplasia, an alteration in epidermal growth leading to an increase in the number of cells within the epidermis. This is the hallmark of psoriatic skin.
Acne vulgaris (or simply acne) is a common skin disease affecting most of the population at some point in their lives. It affects skin with the densest population of sebaceous follicles – which are found on the face, the upper part of the chest, and the back.
Stress has long been suspected to induce acne flares, but it was only recently confirmed. In a student stress study performed at exam time it was shown that increased acne severity is significantly associated with increased stress levels.
Atopic dermatitis (AD), is a chronic and recurrent inflammatory skin disease often associated with eczema and itch.
The impact of stress on the skin barrier function and wound healing
The stratum corneum (SC) plays an important role in barrier functions – regulating epidermal permeability and homeostasis. This protein/lipid barrier creates a surface seal essential for the maintenance of hydration, and for protection against microbial infection. Disruption of the skin barrier function can lead to flaky or dry skin. Changes in the lipid composition have also been linked to skin diseases like atopic dermatitis and psoriasis.
Stress can have detrimental physiological and functional consequences for the skin. One of the skin’s major functions is the physical protection of our bodies, and wound repair upon injury. An extensive literature search has revealed that chronic systemic corticosteroids, which occur during stress, have a negative impact on all three phases of wound healing.
The negative impact of stress on wound healing was first observed clinically in humans when caregivers of demented relatives were found to need 20% more time for complete healing of wounds on the skin. Anxiety and depression are also associated with delayed healing in chronic wounds. It was found that perceived stress, and the resulting elevated cortisol levels, contributed to this result.
Long term skin damage with chronic stress
Acute stress can cause a significant redistribution of lymphocytes from the blood to the skin, leading to enhanced skin immunity and successful stress adaptation. Acute stress also suppresses ROS production.6
In contrast to acute stress, which may augment innate and adaptive immune responses, chronic stress usually suppresses the immune system’s protection, increases our susceptibility to infections, and worsens some allergic and inflammatory diseases. This is because of altered stress responses which happen after repeated or prolonged stress, known as stress habituation. This reduces HPA axis activation but also lessens the ability of our systems to react to new stimuli.
Chronic stress causes a significant decrease in T-cell infiltration in the skin, impacting the cell’s ability to play a part in immunity. Longer-term stress also slows your body’s ability to digest food. This impacts the bacteria in your gut, causing inflammation and leaky gut syndrome – where your intestinal walls become more permeable. Particles of undigested food and even bacteria can move into the bloodstream, causing chronic inflammation in the body. Ongoing disturbances in our gut microbiome can also aggravate anxiety or depression.7
There are two major theories for skin ageing:
- the programmatic theory which focuses on reduced cellular life spans, decreased responsiveness and functionality, and dysfunctional immune responses;
- the stochastic theory which points towards environmental damages, focusing on DNA damage, inflammation and free radical formation.
UV radiation is one of the major external stressors responsible for premature skin ageing, giving us the well-known term “photo-ageing”. This radiation is one of the major stimulants of the skin’s HPA axis.
Smoking and air pollution have been confirmed as critical chronic stressors that significantly impact skin ageing. In areas of the skin that are protected from light these years of smoking & the number of packs smoked per day will cause premature skin ageing.
Airborne particles from exposure to traffic pollution are associated with significant increases in pigment spots and facial wrinkles. ROS production is the major underlying mechanism at work here.
A recent study established that sleep deprivation also has a negative impact on the skin, adding to ageing. It was found that those who regularly have poor-quality sleep showed increased signs of intrinsic skin ageing including fine lines, uneven pigmentation and reduced elasticity.
Conclusion and future perspectives
In recent years, emerging research has demonstrated that skin is not only a target of psychological stress, it also actively participates in the stress response by means of its peripheral HPA axis, peripheral nerve endings, and local skin cells including keratinocytes, mast cells, and immune cells. Feedback mechanisms and crosstalk between the brain and the skin, plus pro-inflammatory cytokines and neurogenic inflammatory pathways play a large role in controlling such responses.
Skin mast cells are activated by stress, and in turn, they produce stress hormones and inflammatory factors. This could lead to a vicious cycle of stress-induced inflammatory events. Indeed, mast cells have been implicated in numerous skin diseases including acne, atopic dermatitis, psoriasis and pruritus.
If you know you are dealing with long term stress there are things you can do to offset this, and support your system overall:
- Get at least 7 hours of sleep a night. Reduce or stop using your devices in the evenings - blue light from these screens delays the release of melatonin, upsetting your body’s internal clock and interfering with your ability to get to sleep, and your quality of sleep overall.
- Exercise a couple of times a week – not only does this help with endorphins but it will also help you sleep.
- Watch your diet to improve your gut and skin health. Dietary supplements combining active flavonoids with proteoglycans could also be helpful in atopic and inflammatory conditions.
- Consider meditation or deep breathing exercises. Even a long walk on the beach or in nature will help you relax and unwind.
Hypochlorous acid (HOCl) also holds huge promise for the long-term control of inflammation in the skin. Its anti-neoplastic effect, confirmed by a Stanford Study, further supports its function as a skin protection agent and its skin rejuvenation effects show it has a future as a major new player in the control and reversal of prematurely aged skin.
- Ying Chen and John Lyga. Brain-Skin Connection: Stress, Inflammation and Skin Aging. Inflammation & Allergy - Drug Targets, 2014, 13, 177-190 177
- Tzu-Kai Lin,Lily Zhong and Juan Luis Santiago. Association between Stress and the HPA Axis in the Atopic Dermatitis. Int J Mol Sci. 2017 Oct; 18(10): 2131
- Toshio Tanaka, Masashi Narazaki and Tadamitsu Kishimoto. IL-6 in Inflammation, Immunity, and Disease. Retrieved from https://cshperspectives.cshlp.org/content/6/10/a016295.full
- McLeod, S. A. (2010). What is the stress response? Retrieved from https://www.simplypsychology.org/stress-biology.html
- Upadhyayula SaiSrinivas, Bryce W.Q.Tan, Balamurugan A.Vellayappan, Anand D.Jeyasekharan (2018). ROS and the DNA damage response in cancer. Retrieved from https://www.sciencedirect.com/science/article/pii/S2213231718309017
- Tim Newman (2018). How fiber and gut bacteria reverse stress damage. Retrieved from https://www.medicalnewstoday.com/articles/322636.php