Skin Care

Skin care

KEYWORDS

Skin energy,

Cordycepin,

Longevity,

Sirtuins

Adaptogen.


peer-reviewed

Exploring the adaptogenic potential of cordyceps sinensis to promote skin longevity

DANILA FALANGA 1, RITAMARIA DI LORENZO 2, ANNALISA TITO* 1, MAURA ANGELILLO3, SONIA LANERI* 2

*Corresponding authors

1. Arterra Bioscience SpA, Naples, Italy

2.Department of Pharmacy, University of Naples Federico II, Naples, Italy

3. Vitalab Srl, Naples, Italy

ABSTRACT:In recent years, there has been a growing interest in harnessing Traditional Chinese Medicine principles and natural bioactive compounds to address age-related conditions and promote longevity. This study focused on a Cordyceps sinensis mycelium hydroethanolic extract (CsEx), standardized in cordycepin and adenosine, to explore its adaptogenic properties. Through in vitro assays and a double-blind, placebo-controlled clinical trial involving 40 subjects, CsEx exhibited notable effects. At a concentration of 0.0006%, it significantly increased sirtuin expression and NAD+ synthesis, while boosting ATP production in skin cells. CsEx also reduced cytosolic reactive oxygen species and enhanced collagen production, both in vitro and in vivo, leading to improved skin energy and reduced wrinkles. These findings highlight CsEx's potential in regulating skin cell energy metabolism and influencing mechanisms associated with skin longevity control.

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“A study in healthy women providing probiotic yogurt for four weeks showed an improvement in emotional responses as measured by brain scans”

Figure 1. Skin Section with Microbiome. Most microorganisms live in the superficial layers of the stratum corneum and in the upper parts of the hair follicles. Some reside in the deeper areas of the hair follicles and are beyond the reach of ordinary disinfection procedures. There bacteria are a reservoir for recolonization after the surface bacteria are removed.

Materials and methods

Studies of major depressive disorder have been correlated with reduced Lactobacillus and Bifidobacteria and symptom severity has been correlated to changes in Firmicutes, Actinobacteria, and Bacteriodes. Gut microbiota that contain more butyrate producers have been correlated with improved quality of life (1).


A study in healthy women providing probiotic yogurt for four weeks showed an improvement in emotional responses as measured by brain scans (2). A subsequent study by Mohammadi et al. (3) investigated the impacts of probiotic yogurt and probiotic capsules over 6 weeks and found a significant improvement in depression-anxiety-stress scores in subjects taking the specific strains of probiotics contained in the yogurt or capsules. Other studies with probiotics have indicated improvements in depression scores, anxiety, postpartum depression and mood rating in an elderly population (4-7).


Other studies have indicated a benefit of probiotic supplementation in alleviating symptoms of stress. In particular, researchers have looked at stress in students as they prepared for exams, while also evaluating other health indicators such as flu and cold symptoms (1). In healthy people, there is an indication that probiotic supplementation may help to maintain memory function under conditions of acute stress.

INTRODUCTION

The process of aging is a multifaceted phenomenon that encompasses a myriad of physiological, psychological, and biochemical changes, which occur in living organisms over time [1]. Despite significant advancements in medical science, the complexities of aging remain a formidable challenge, necessitating a comprehensive approach to mitigate its effects. Traditional Chinese Medicine (TCM) offers a holistic framework that views aging as a natural process influenced by the balance and harmony of bodily systems [2]. In recent years, there has been growing interest in leveraging the principles of TCM and the therapeutic potential of natural bioactive molecules to address age-related disorders and promote healthy aging. Fungi have gained significance in TCM due to their potent therapeutic properties, notably as adaptogens [3]. Adaptogens aid the body in resisting stressors like pollution and disease, maintaining homeostasis without harming normal functions, and improving performance by promoting balance and resilience without notable side effects. Plant-originated adaptogens reduce harm from stress, provide positive excitatory effects without causing insomnia, and do not damage the human body [4-6].


Cordyceps sinensis,[1] a type of ascomycete parasitic fungus belonging to the family Clavicipitaceae [7], is highly esteemed in traditional Chinese medicine (TCM) for its adaptogenic qualities. Previous studies have shown that it can enhance mitochondrial function [8], energy metabolism, and oxygen utilization in cells [9], potentially contributing to its anti-aging effects [10]. It contains bioactive compounds like polysaccharides, cordycepin, and adenosine, which are responsible for its pharmacological activity [11,8,10,12]. While traditionally used in TCM for various health purposes, research on its effects on human skin aging is limited, primarily linked to its photoprotection against UV rays [13,14].


This study explores the potential of natural bioactive molecules, integrating TCM wisdom with modern science, focusing on age-related disorders. Specifically, an extract from Cordyceps sinensis mycelium (CsEx), prepared under the guidance of Traditional Chinese Medicine experts at the University of Florence, was investigated for its activity on age-related markers using in vitro assays. As reported in Di Lorenzo 2024 [15], [2] recent research has explored how various substances can influence key markers of longevity, such as SirT1, SirT3, and SirT6, known as sirtuins, which are crucial for regulating cellular processes that directly impact lifespan across various organisms [16]. Studies have analyzed the effects of these substances on ATP production, vital for cellular energy, and on Pro-Collagen I, essential for maintaining skin integrity and hydration [15].


Sirtuins are central to cellular health and protect against age-related damage through their anti-inflammatory and antioxidant properties, contributing to overall health and the cells' ability to withstand environmental stress [16]. Additionally, adenosine triphosphate (ATP) is a crucial cellular energy currency, supporting all fundamental biological functions, reflecting an efficient energy metabolism crucial for healthy longevity. Pro-collagen I, essential for preserving skin youthfulness and elasticity, plays a vital role in structural support of the skin and protection against visible signs of aging. These markers not only highlight crucial aspects of cellular health and aging processes but also underscore the importance of further studies to better understand effective interventions in promoting healthy longevity and mitigating signs of aging [15,16].


In this study, we underline the effect of a Cordyceps sinensis mycelium hydroethanolic extract (CsEx) on skin energy by in vitro and clinical studies. A double-blind, placebo-controlled clinical trial involving 40 subjects with various skin aging-related disorders, such as a lack of firmness and laxity, wrinkles, and tired-looking and dull skin. These subjects were treated for 28 days with a topical formulation containing the CsEx, following the verification of its skin tolerability through an occlusive patch test. This comprehensive approach aims to elucidate the molecular mechanisms underlying the adaptogenic properties of the CsEx and assess its efficacy in alleviating common signs of skin aging by acting through energy boosting.

MATERIALS AND METHODS​​​​​​​

Cordyceps sinensis extract

A hydroethanolic extract from mycelium of C. sinensis was prepared as reported in Di Lorenzo 2024 [15].


Cell line

HaCaT (Human keratinocytes) and HDFs (Human dermal fibroblasts) cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% foetal[1] bovine serum (FBS), at 37°C in a 5% CO2 atmosphere.


In-vitro assays

Sirtuin Expression Assay

For basal gene expression analysis, HaCaT cells were treated with the extract (0.0006% w/v) or resveratrol (0.002% w/v) for 6 hours. Total RNA was extracted using the PureLink RNA Mini Kit (Invitrogen-Thermo Scientific). Semi-quantitative RT-PCR analyses were performed using 18S primer/competimer (Invitrogen-Thermo Scientific) as internal standards.


NAD/NADH Ratio Assay

The NAD/NADH ratio was quantified in HaCaT incubated with the extract using the NAD/NADH quantitation kit (Merck KGaA), following the manufacturer's instructions. Absorbance values were recorded using the Victor Nivo instrument (Perkin Elmer).


ATP Production Assay

The quantity of ATP in HaCaT incubated with the extract was determined using the CellTiter-Glo Reagent (Promega Corporation). The luminescent signal of the samples was then measured using the Victor Nivo instrument (Perkin Elmer) after 15 minutes.


Cytosolic ROS Assay

The quantity of reactive oxygen species (ROS) was measured in HaCaT incubated with the extract or ascorbate, used as positive control, for 2 h. At the end, the cells were washed in PBS and incubated with the dye CM-DCFDA (5-(e-6)-clorometil-2,7-dichloro dihydrofluorescein diacetate, Invitrogen). The fluorescence of the samples was then measured at 535 nm (excitation 490 nm), using the instrument Victor Nivo (PerkinElmer).


Collagen Production Assay

Pro-Collagen I measured in HDF by ELISA using specific primary antibody, followed by secondary HRP-labelled antibodies. The proteins were measured by a colorimetric reaction according to the manufacturer’s protocol (p-Phenylendiamine). The absorbance at 490nm was measured by a multiplate reader Nivo (Perkin Elmer). The absorbance values were normalized to cell density determined by crystal violet staining.

All data were assessed using the Student’s t-test, which provides a probability denoted as "p" for determining the significance of differences between the average of three independent experiments in triplicate. The significance level for this study was established as follows: if p < 0.1 (#), this indicated a 90% probability of the two batches being significantly different; if p is 0.05 (*), this indicated a 95% probability of significant difference; and if p < 0.001 (**), this indicated a 99% probability of significant difference.


Clinical Study

A double-blind clinical study enrolled forty subjects aged 40 to 65 years (included), with Fitzpatrick skin types I–III and a dull face marked by aging with wrinkles and fine expression lines, were included in this study. Only generally healthy subjects were enrolled and randomly assigned to the two treatment groups. One group received treatment with an O/W emulsion containing 0.0006% w/v of CsEx, while the other received a placebo formulation. The emulsions were applied to the face twice daily for four consecutive weeks. Data were collected regarding four parameters: skin energy, collagen production, reduction in roughness, and CsEx tolerability. Instrumental assessments were conducted before product use (baseline) and after specified intervals (Day 7, Day 14, and Day 28). Tewameter® TM Hex (C+K electronic GmbH) was utilized to analyze skin energy. Ultrasonography (DermaScan® C, Cortex Tech.) and VISIA 7th (Canfield Scientific Inc.) were employed to evaluate collagen production and roughness reduction. For CsEx tolerability assessment, its potential irritant properties were evaluated using a 48-hour occlusive patch test on intact human skin, specifically on the volar forearm due to its suitability for such testing. This test aimed to identify and classify CsEx’s irritant potential following EEC Directive 76/768 guidelines [17]. Finn Chambers® AQUA patch delivery system was used, adhering to established procedures [18]. Results were assessed based on morphological criteria recommended by the International Contact Dermatitis Research Group [19], with an irritancy limit set at 1.5 on a 0–3 scale for visual scoring. The tests adhered to the principles of the Helsinki Declaration [20] and the Colipa Guidelines [21]. Good clinical practice was maintained throughout the study period.


Statistical Analysis in Clinical Trial

A sample size of 40 panelists, randomly assigned (approximately 20 subjects per group), was considered sufficient to achieve adequate statistical power for detecting differences between the CsEx cream and placebo. Inter-group differences for both primary and secondary endpoints were assessed using the ANOVA test, while intra-group differences, expressed as average percentage variations compared to baseline, were analyzed using the student t-test. The significance level for all analyses was set at a two-sided p-value of 0.05.

RESULTS AND DISCUSSION

Effect of CsEx on NAD/NADH ratio and ATP Production In Vitro and Boosting Skin Energy In Vivo

Mitochondria are essential powerhouses of the cell, playing a crucial role in cellular metabolism by generating adenosine triphosphate (ATP), the primary energy currency for various cellular processes [22]. To evaluate the impact of CsEx on ATP production, we treated keratinocytes with CsEx and observed remarkable results. Figure 1a illustrates that CsEx stimulated ATP production by approximately 68% at a concentration of 0.0006% w/v and by 25% at 0.002% w/v. These results were comparable to the efficiency seen with resveratrol. We further investigated the impact of CsEx on the induction of NAD by measuring the NAD/NADH ratio in HaCaT cells treated with CsEx and using resveratrol as a positive control. As shown in Figure 1a, CsEx increased the NAD/NADH ratio by 20%, whereas resveratrol achieved an increase of more than 50%.


The study also focused on cellular respiration in skin cells, which involves the release of heat, a crucial parameter reflecting the local energy balance directly linked to cellular respiration and ATP production [23]. Using the Tewameter TM Hex, we quantified the heat loss in volunteers treated with CsEx. Skin energy was recorded during the clinical trial after 7, 14, and 28 days of treatment with a topical cosmetic formulation containing 0.0006% w/v CsEx. Figure 1b demonstrates a significant increase in skin energy over the treatment period with CsEx, showing a 17% increase at Day 7, 25.5% at Day 14, and an impressive 52.0% by Day 28. The placebo, on the other hand, showed no significant effect on skin energy.


Figure 1. (a1) Effect of the C. sinensis extract (CsEx) on ATP production in keratinocytes. (a2) Effect of the C. sinensis extract (CsEx) on NAD/NADH ratio in keratinocytes. The keratinocytes were stimulated with 0.0006% w/v and 0.002% w/v of CsEx for 24 h and then induced to lysis. The reported values represent the averages of three independent experiments; the control was set to 100%. The bars represent the standard deviations, and the asterisks indicate the p-value according to Student’s t test (* p < 0.05, ** p < 0.01). (b) Effect of the C. sinensis extract (CsEx) on skin energy boosting in treated volunteers vs. placebo. (b1) Skin energy average value ± SD; (b2) Skin energy average percentage variation vs. D0. The asterisks indicate statistically significant values vs. D0 (*** p-value was between 0.0001 and 0.001). The $ indicates statistically significant values vs. placebo ($ p < 0.05, $$$ p < 0.001).

Effect of CsEx on Collagen Production

The ability of CsEx to induce collagen production was analyzed by measuring newly synthesized collagen type I in human dermal fibroblasts (HDFs) treated with CsEx or TGFβ as the positive control. As shown in Figure 2a, CsEx at both concentrations significantly stimulated Pro-Collagen I production, like TGFβ, indicating a positive role of the extract in maintaining dermal tone.


To confirm these promising in vitro results, we examined the ability of formulated CsEx to increase collagen production in subjects. Collagen levels were assessed using ultrasound detection at various follow-ups. Figure 2b shows that CsEx significantly induced collagen production after 14 and 28 days by 10.5% and 10.0% respectively, compared to the placebo which showed no effect on collagen production. Echographic images in Figure 2 demonstrate that CsEx densified the skin by increasing collagen amount and improving dermal bundles


Figure 2. (a) Effect of the C. sinensis extract (CsEx) on Pro-Collagen I production in skin fibroblasts. The cells were stimulated with 0.0006% and 0.002% CsEx for 24 h. The reported values represent the averages of three independent experiments. The asterisks indicate statistically significant values (** p-value was between 0.001 and 0.01). (b) Effect of the C. sinensis extract (CsEx) on collagen production during 28-day topical application. Collagen index average percentage variation vs. D0 recorded for 20 volunteers throughout the study period (after 7, 14, and 28 days of treatment) for CsEx and placebo, intra-group difference t-test ** p < 0.01, *** p < 0.001), and inter-group difference ANOVA test $ p < 0.05, $$$ p < 0.001). The echo-graphic images were obtained with a 20 MHz HFUS ultrasound probe (DermaScan® C, Cortex Technology Aps), after placing it on test subjects’ faces.

Effect of CsEx on Wrinkle Appearance Reduction

Aging alters both the structure and mechanical properties of the skin, leading to the development of wrinkles [24]. Microscopically, the fine mesh of the skin surface deteriorates, and each wrinkle becomes more prominent as its width and height increase with age [24]. The stimulating action of CsEx on fibroblasts, combined with its antioxidant and energizing properties, plays a pivotal role in mitigating the phenotypic manifestations of skin aging, such as wrinkles and fine lines. Our study demonstrated that CsEx treatment significantly reduced the appearance of facial wrinkles. Specifically, T-zone wrinkles (forehead and frown lines) were measured using a VISIA 7th (Canfield Scientific Inc), showing a statistically significant decrease over time by −12.5%, −19.0%, and −28.0% at Day 7, Day 14, and Day 28 respectively, compared to baseline (Figure 3). In contrast, the placebo-treated group showed no significant improvement. These results validate the effectiveness of CsEx in treating common signs of skin aging.


Figure 3. Effect of the C. sinensis extract (CsEx) on collagen production during 28 day topical application. Collagen index average percentage variation vs. D0 recorded for 20 volunteers throughout the study period (after 7, 14, and 28 days of treatment) for CsEx and placebo, intra-group difference t-test * p < 0.05, ** p < 0.01, *** p < 0.001), and inter-group difference ANOVA test $ p < 0.05, $$ p < 0.01). The images of forehead wrinkles over a 28-day treatment with 6 mg/L CsEx vs. placebo were obtained with a Visia 7th (Canfield Scientific Inc).

The study on CsEx treatment has shown promising results but presents several significant limitations that need to be addressed to improve future research quality and relevance. These limitations include a small and non-diverse sample size and a brief 28-day study duration, which may not adequately capture long-term effects or side effects.


Future research could focus on further elucidating the mechanism of action of CsEx, identifying additional molecular targets, optimizing efficacy, and extending the duration of clinical studies. Prioritizing larger, more diverse participant samples across different demographics and extending study durations are crucial for more comprehensive assessments. Comparative studies with established treatments would provide clearer insights into the effectiveness of CsEx.


CONCLUSION

In conclusion, this study highlights the promising anti-aging properties of a Cordyceps sinensis mycelium extract (CsEx). Significant increases in sirtuin expression, NAD+ synthesis, ATP production, ROS scavenging, and collagen synthesis were observed following CsEx treatment, indicating its exciting potential to enhance skin longevity through natural adaptogen sources. This suggests that CsEx could be a valuable addition to skincare regimens, leveraging the body's natural defenses and repair mechanisms to promote healthier, more resilient skin over time. The study has several limitations, such as a small and non-diverse sample size, a short duration. Future research could focus on further elucidating CsEx's mechanism of action, identifying additional molecular targets, optimizing efficacy, and extending the duration of clinical trials involving larger and more diverse populations to address the limitations encountered in the present study.


Conclusion

The future of cosmetics lies in the continued evolution of holistic approaches which represents a transformative shift in the industry, merging scientific advancements, natural ingredients, and wellness principles. By understanding and embracing the interconnectedness of these elements, the cosmetics industry can cultivate products that not only enhance external beauty but also contribute to the overall well-being of individuals and the planet.


The interplay between beauty from within and topical cosmetics is the key for future products. The integration of biotechnology and green chemistry is revolutionizing cosmetic formulations, offering sustainable and biocompatible alternatives.


Developers can implement blockchain to trace the journey of ingredients from source to product. Nevertheless, the efficacy of the natural products should be scientifically proven. Marketers can communicate transparency as a brand value, and parallelly educate consumers by highlighting how specific ingredients contribute to radiant and healthy skin.


By embracing the synergy between these approaches and leveraging scientific advancements, the cosmetics industry can provide consumers with comprehensive beauty solutions that cater to both internal and external dimensions of beauty.

References and notes

Surfactant Applications

The application area lends itself particularly well to the use of AI. Active today in this area is the US company Potion AI (6). The company provides AI-powered formulation tools for beauty and personal care R&D. Their offerings include Potion GPT, next generation ingredient and formula databases and AI document processing. Potion’s work could have a significant impact on the entire surfactant value chain, from raw material suppliers to end consumers. By using their GPT technology, they can help target work toward novel surfactant molecules that have optimal properties for specific applications. By using their ingredient and formula databases, they can access and analyze a vast amount of data on surfactant performance, safety, and sustainability. By using their AI document processing, they can extract and organize relevant information from patents, scientific papers, and regulatory documents. These capabilities could enable Potion AI's customers to design and optimize surfactant formulations that are more effective, eco-friendly, and cost-efficient. A particularly interesting application for this type of capability is deformulation.


Deformulation is the process of reverse engineering a product's formulation by identifying and quantifying its ingredients. Deformulation can be used for various purposes, such as quality control, competitive analysis, patent infringement, or product improvement. However, deformulation can be challenging, time-consuming, and costly, as it requires sophisticated analytical techniques, expert knowledge, and access to large databases of ingredients and formulas.


AI can potentially enhance and simplify the deformulation process by using data-driven methods to infer the composition and structure of a product from its properties and performance. For example, AI can use machine learning to learn the relationships between ingredients and their effects on the product's characteristics, such as color, texture, fragrance, stability, or efficacy. AI can also use natural language processing to extract and analyze information from various sources, such as labels, patents, literature, or online reviews, to identify the possible ingredients and their concentrations in a product.


Figure 2. Skin Section with Microbiome. Most microorganisms live in the superficial layers of the stratum corneum and in the upper parts of the hair follicles. Some reside in the deeper areas of the hair follicles and are beyond the reach of ordinary disinfection procedures. There bacteria are a reservoir for recolonization after the surface bacteria are removed.

About the Authors

SONIA LANIERI

has 20 years’ experience in Cosmetic Chemistry. Sonia holds a PhD in Pharmaceutical Chemistry and she is an Associate Professor at University of Naples Federico II, Department of Pharmacy in Analysis and Chemistry of Cosmetics. She is the Head of the RD Cosmetics lab. She is notably in charge of in-vivo studies enabling claim substantiation for cosmetic active products and new cosmetic ingredients from waste material or by biotechnology. Sonia is also the Coordinator of the Master’s degree in Cosmetic Science of UNINA. She is an active member in different journals of the cosmetic sector as Editorial board of Beauty Horizon and Topic Editor, Guest editor for Molecules and Cosmetics (MDPI journals). She has an HI=21, 67 publications and 1199 citations (Scopus source).

Sonia Lanieri

Department of Pharmacy, University of Naples Federico II, Naples, Italy

ANNALISA TITO

Holding a PhD in Biotechnology, she joined Arterra Bioscience SPA in 2008, where she is Director of Molecular and Cellular Biology. She is responsible of the internal biology efficacy-platform supporting the active ingredients claim substantiation through the use of innovative methodologies. She coordinated the development of more than 60 active ingredients for Vitalab (Intercos Group) and published 40 scientific articles.

Annalisa Tito

Arterra Bioscience SpA, Naples, Italy

References and notes

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