Neurocosmetics and the Brain-Skin Axis Part 2: What Stress, What Test?

The consequences of psychological stress depend on the type of stress, as well as on the attitude of the stressed individual subjected to stress. The story goes that people who think they can resist stress inhibit blood proteases and end up with thrombosis, whereas people who think they cannot resist stress activate blood proteases and end up with leaky blood vessels. 

When it comes to skin, the skin-brain axis works in both ways: stressed skin sends messages to the brain which decides what to do, and stressed brain releases hormones and neuropeptides that arrive in the skin which does not know what to do and trigger inflammation. Measurements of biological and biophysical parameters in skin of stressed individuals could teach something, but could also be misleading. For instance, the electrical conductivity of the skin of gamblers increases during gambling, as if gambling hydrates skin  because of the arousal that occurs when placing the bet, but one could also suggest that excited gamblers tend to sweat, and sweaty skin has higher conductivity than dry skin. Transepidermal water loss (TEWL) does also increase in gambler’s skin, as if the stress of gambling decreases the barrier function. And yet, since TEWL measures the gradient of the concentration of water vapor above the skin; the increase in TEWL is also compatible with an increase in sweating. 

Since it might be ethically questionable to subject volunteers to selected psychological stresses, we have to enter the epidemiology of existing stresses, often associated to a specific profession or detected by appropriate questionnaires.  With defined stress, we can study the accessible biochemical and biophysical parameters in the stressed cohort and in an appropriately selected control group, that is not always easy to define. And of course, the endpoint of the study needs to be relevant for skin care. Unfortunately, all this is not always the case.

Stressed Populations & Biological Parameters

Last month we discussed the cutaneous consequences of sleep deprivation in three controlled clinical studies. Let’s discuss today the skin properties of a few populations subjected to psychological stress, as described in several publications. 

One study concerned two cohorts of professional caregivers, premenopausal women who perceived their stress as low or moderate. A control group of women perceiving themselves as non-stressed was not envisioned. The study analyzed telomere lengths in Peripheral Blood Mononuclear Cells (PBMC) and found that telomeres were shorter in the moderate than in the low stress cohort, and that the longer the duration of the activity as caregiver, the shorter were the telomeres.¹ In spite of a very poor correlation, this study is often quoted by those who hold telomerase and its activation as the holy grail of the anti-aging skincare. I would like to point out, though, that PBMC are neither keratinocytes, who replicate daily as long as the individual is alive, nor poorly cycling epidermal or dermal cells whose telomere length is practically constant. And therefore, telomere shortening cannot be invoked to explain skin aging.

In another study, cultured human keratinocytes and fibroblasts were exposed to 0, 0.1, 0.5, 1 and 5 micromolar cortisol. It was observed that at or above 0.5 micromolar, cortisol induced a linearly concentration-dependent DNA damage (as tested with the semiquantitative Comet assay) and that cortisol inhibited by about 50% the synthesis  of mRNA of Collagen I, by 30% the production of mRNA for Collagen III, and by about 40% the mRNA of one Heat Shock Protein, as well as of Lysil Oxidase-Like 1 (necessary for the maturation of collagen and elastin) and of Tissue Inhibitor of Matrix Metallo-Proteinase.² One might quickly conclude from these data that cortisol provokes DNA damage, inhibits collagen synthesis, favors its breakdown and therefore provokes skin aging. 

That would be a bit too quick. 

The maximum level of cortisol in the blood, in the morning spike, is of the order of 0.3 micromolar, and one can reasonably assume that the level of cortisol in the epidermis or in the dermis, during the morning spike, cannot be larger than 0.03 micromolar, that is about one hundred times smaller than the concentration used in these experiments, whose interpretation needs to be revisited.

One should also be attentive when reading review papers, since too often the authors of such papers quote results without having undertaken a critical reading of what they quote. Let’s take for example a study quoted in³ as:” Stress due to marital disruption significantly delayed skin barrier recovery after tape stripping (159)” In reality, this reference 159 is a paper by Muizzuddin and coworkers,⁴ that studied 28 females undergoing divorce, divided in two groups (high perceived stress and low perceived stress). The paper analyzed their capability to repair disrupted barrier by measuring TEWL at different times after tape stripping and compared the results to those from a cohort of self-perceived non-stressed and “happily” married, age-matched, females. In the words of the authors: “There was no correlation between the degree of stress and barrier strength. However, individuals with high stress recovered slower than the individuals with low stress after 3 h (R = 0.64) and 24 h (R = 0.74)”. Nothing is said about the kinetics of barrier repair of happily married women.

Conclusion

The literature is rich with papers describing interesting results in the field of psychological stress and skin. The reader should avoid taking the results and drawing conclusions before performing a minimum of critical thinking and of quantitative consideration. This is true in general, and more so when the results deal with physiological phenomena that are difficult to model in reductionistic experimentations. 

As far as we know, neuropeptides and hormones released in the skin by the neural system have the capability to induce the synthesis of Inter-Cellular Adhesion Molecule 1 and to trigger a self-maintained micro-inflammatory response that is responsible for three oxidative bursts and the release of proteases. This microinflammatory process is therefore able to damage the extra cellular matrix and to increase the rate of skin aging. In my opinion, there is no need to administrate psychotropic ingredients meant to limit the secretion of hormones and neuropeptides: the inflammatory pathway is well known and anti-inflammatory agents palatable to the FDA are at hand and can successfully be used as long as they are properly formulated for topical application.

Paolo Giacomoni, PhD

Insight Analysis Consulting
[email protected]

Paolo Giacomoni acts as an independent consultant to the skin care industry. He served as Executive Director of Research at Estée Lauder and was Head of the Department of Biology with L’Oréal. He has built a record of achievements through research on DNA damage and metabolic impairment induced by UV radiation as well as on the positive effects of vitamins and antioxidants. He has authored more than 100 peer-reviewed publications and has more than 20 patents. He is presently Head of R&D with L.RAPHAEL—The science of beauty—Geneva, Switzerland.

References

1. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17312-5. doi: 10.1073/pnas.0407162101. Epub 2004 Dec 1. PMID: 15574496; PMCID: PMC534658.
2. Pujos M, Chamayou-Robert C, Parat M, Bonnet M, Couret S, Robiolo A, Doucet O. Impact of Chronic Moderate Psychological Stress on Skin Aging: Exploratory Clinical Study and Cellular Functioning. J Cosmet Dermatol. 2025 Jan;24(1):e16634. doi: 10.1111/jocd.16634. Epub 2024 Nov 6. PMID: 39506493; PMCID: PMC11743297.
3. Chen Y, Lyga J. Brain-skin connection: stress, inflammation and skin aging. Inflamm Allergy Drug Targets. 2014;13(3):177-90. doi: 10.2174/1871528113666140522104422. PMID: 24853682; PMCID: PMC4082169.
4. Muizzuddin N, Matsui MS, Marenus KD, Maes DH. Impact of stress of marital dissolution on skin barrier recovery: tape stripping and measurement of trans-epidermal water loss (TEWL). Skin Res Technol. 2003 Feb;9(1):34-8. doi: 10.1034/j.1600-0846.2003.00354.x. PMID: 12535282.