A biotech solution to a digitally-induced desynchronisation of the skin’s circadian cycle

A crisis can make people analyse and change their values. ​

Over the complex and convoluted past years, consumers have taken stock of their lives and are now trying to chart a new path forward. In 2015, only 12% of consumers prioritised time for themselves; this doubled to 24% in 2021.¹ ​This “Great Life Reset” can be defined as the drastic personal changes and a collective reboot of values, lifestyles, and goals triggered by a crisis. This mental and physical reset will turn activities and products that positively impact mental and physical health into factors that influence purchasing decisions.

Humans have always reset and synchronised their body via the circadian cycle, which is regulated by diverse stimuli such as light, cortisol, temperature, food, and melatonin. Although the suprachiasmatic nucleus (SCN) is the main pacemaker responsible for controlling circadian rhythms, recent studies show the presence of peripheral circadian clocks in the epidermis, too.²​

The rhythm-generating molecular circuitry in both hypothalamic neurons and peripheral cells is mainly controlled by a network of feedback loops composed of activators and repressors regulated by two key “clock genes”:

1. CLOCK (circadian locomotor output cycles kaput)
2. BMAL1 (brain and muscle ARNT-like)

The CLOCK/BMAL1 complex regulates hundreds of genes related to various physiological functions including cell growth, DNA damage-repair, immune function, and many other metabolic processes. Furthermore, some of the products of such expressions will simulate and/or repress the circadian circuitry. For example, the proteins CRY (Cryptochrome) and PER (Period) have a direct inhibitory effect on the BMAL1/CLOCK complex, further stabilising the circadian circuitry.^3,4,5​ 

Ageing, the seasons, variable sun exposure, fatigue, stress, insomnia, jet lag and blue light from electronic devices during sleeping hours are responsible for variations in biorhythms.³​

Photo-ageing is a well-known concept, but it is usually only associated with UV light. However, the blue light of the High Energy Visible (HEV) can also be phototoxic in human skin, decreasing cell vitality, ATP synthesis and increasing free radicals and ROS production as well as DNA damage – all processes regulated in the sleep-wake cycle.⁶​  In response to the negative effects on the circadian rhythm from artificial blue light, Provital decided to develop a natural active ingredient that ‘reset’ the paradigm of the effects of digital stress on the skin.^4,7​ Circanblue™ (Lactococcus ferment lysate​) was the result, aligning with the idea of skin detox as an integrated skin revitalisation in sync with the body’s natural circadian rhythm.

The ‘greenest blue’

Fermentation-enabled food and drink wellness products are on the rise, and this trend has extended into the skincare space with prebiotic, probiotic, postbiotic and fermented ingredients.^8,9​ Prebiotics are fibres that feed beneficial bacteria, while postbiotics are beneficial by-products of bacteria. Probiotics (live microorganisms) are well established in the food industry thanks to their benefits for the human body. Over the last five years, the cosmetics industry has also seen a global escalation in of products containing biotics.⁹​ There is still much potential here, especially for postbiotic lab-grown ingredients whose sustainable properties (via fermentation) will attract the consumers.

Circanblue™ is obtained from a lysate of the probiotic Lactococcus lactis​, which essentially contains the cell debris, such as fragments of cell wall, metabolites, and cytoplasmic components of the bacterium.⁵​ Because it derives from a bacterial fermentation, it is considered as a postbiotic ingredient with a probiotic and vegan origin.

Vegan post-biotic? Yes, this is a biotechnological cosmetic active ingredient obtained via a ‘green’ fermentation of the probiotic Lactococcus lactis​. The different strains of this non-pathogenic bacterium have been studied for their various biochemical properties, such as sugar and exopolysaccharide production, antioxidant activity and antimicrobial activity.⁹​

Although various strains have been widely used in the dairy industry, mainly as technology for the rapid production of lactic acid in milk, Provital used a vegan-based fermentation of L. lactis​, where the culture medium was plant-based.¹⁰​

Bio-induced resynchronisation for skin well-ageing

The postbiotic ingredient has been proven to induce a comprehensive epidermal resynchronisation of the biological clock and cellular processes as indicated in the following in vitro studies, all performed on human primary keratinocytes (HPK).

HPK were first synchronised with the aim of replicating the response of the epidermal cells to electronic devices, with dexamethasone, which simulates the body's natural cortisol peak in its circadian cycle.¹¹​ Once synchronised, the cells were then exposed to blue light using an LED device, delivering a dose equivalent to five hours of screen exposure per day for a month.¹²​ Results were compared to non-blue light exposure as well as to blue light exposure in the presence of the same ingredient as follows:

1. Chronobiological synchronisation​

To determine the positive impact of Lactococcus​ ferment lystate​ on resynchronising the disruption of the biological rhythm caused by excessive blue light exposure, the expression of two main circadian genes (CLOCK and CRY1) was evaluated. Furthermore, the phase and amplitude of treated and non-treated cells were compared through a sinusoidal curve fitting to better observe the effect on the cyclic gene expression characteristic of these circadian-related genes.

This study unveiled a new way to quantify the chrono-protective effect of a cosmetic ingredient thanks to its ability to resynchronise the circadian expression rhythm of CLOCK and CRY1 that was previously altered by blue light exposure. The resulting amplitude of both CLOCK and CRY1 gene expression curve changed compared to the control (which was not irradiated with blue light) but when treated with Provital’s Lactococcus​ ferment lystate​, the rhythms of CLOCK and CRY1 gene expression were restored.

2. ​Melatonin-like well-ageing​

The levels of melatonin decrease with age, thus decreasing the antioxidant capacity of the skin. This reduction is also associated with the intrinsic dysregulation of circadian rhythm with age. However, an additional age-dependent decline in one of its receptors (MTR1) was reported recently, resulting in a higher propensity for cellular damage and a loss of repair in the skin from melatonin.¹³​

In this study, Provital showed how there is a significant upregulation of the expression of MTR1 induced by this new biotech ingredient. Combined with its previously described effects on the resynchronisation of the circadian rhythm (higher melatonin receptor levels will increase the responsiveness of these cells to melatonin signalling), this creates a holistic effect on skin homeostasis after this same homeostasis is threatened by exposure to blue light.

3. “Good-night” circadian repair for the skin​

Sirtuins are enzymes known to regulate a wide variety of proteins in the nucleus, cytosol, and mitochondria, which are crucial regulators of tissue homeostasis and adaptation under metabolic, oxidative, or genotoxic stress. They also are called “youth proteins” because of their essential role in the control of physiological processes including DNA repair, telomere integrity, inflammation, and cellular survival.¹⁴​ Sirtuin 1 (SIRT1) is considered an ageing biomarker that downregulates as human fibroblasts age ) and is a potent detoxifying enzyme.^15,16​ Moreover, it has been described that CLOCK/BMAL1 and SIRT1 form a feedback loop, preparing cells for a new circadian cycle, thus providing a direct relation between the skin repair activities commonly attributed to a well-synchronised circadian cycle and this enzyme.^17,18​

It is therefore unsurprising that Lactococcus​ ferment lystate ​reverts the downregulation of the expression of this gene caused by irradiating HPK to blue light, restoring its level of expression, and giving back the level of night repair needed by the skin to maintain total the circadian homeostasis that is especially useful in today’s digitally overexposed lifestyles.

4. Protective circadian detox​

To finish the in vitro​ evaluation and its impact on healthy skin ageing, the expression levels of two additional genes were measured and given to the ingredient’s manufacturer to discover how this Lactococcus​ ferment lystate ​is mimicking the skin’s circadian detox due to a significant increase in the expression of both NQO-1 and HMOX1. The detoxification marker NQO-1 is an enzyme that reduces the well-known multi-toxic quinones, while also scavenging superoxides.^19,20 ​On the other hand, HMOX1 is also an important enzyme against stress factors as it catalyses the rate-limiting reaction in heme catabolism.²¹​ Its deficiency leads to reduced cell proliferation and increased cellular senescence.²²​

Both HMOX1 and NQO-1 play protective roles since they have antioxidant, anti-inflammatory, anti-apoptotic properties that will help counteract the blue light-induced production of low levels of radicals.²³​ Therefore, the significant upregulation of both detoxifying enzymes caused by this Lactococcus​ ferment lystate ​can be interpreted as an additional protective effect from the digital stress created by electronic devices and the subsequent contribution of this active to skin well-ageing.

Circanblue™ appears to be the first postbiotic active that demonstrates an integrated skin revitalisation in sync with the body’s natural circadian rhythm post-digital overexposure. It triggers a well-known mechanism, the circadian cycle, with a different and new approach. Due to its innovative tested efficacy as a blue-light reverser on the skin, and its vegan and postbiotic origin, this active brings the right tools to the table for an understandable – and yet, never heard of – ingredient story.

Want to know more? Listen to the podcast episode​ featuring the latest brands and end cosmetic products related to the circadian cycle.

References​

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