White Paper: Cannabinoids for the prevention of aging

Aging: A tale as old as time

Skin aging is a complex process driven by a range of intrinsic and extrinsic factors which cumulatively deteriorate the composition, structure and functioning of the skin. This impairment is responsible for the classical signs of aging skin, which manifest as a loss of skin elasticity, uneven and dull skin tone, textural changes leading to an increase in skin roughness, the formation of fine lines and wrinkles, and skin that becomes dryer and more sensitive^1,2. As UV exposure is the culprit behind most visible signs of aging, a robust skincare routine aimed at maintaining skin health and addressing signs of aging should focus on mitigating the detrimental effects of UV radiation, including inflammation, lipid peroxidation, and the formation of reactive oxygen species (ROS).

Awareness and demand

With signs of aging being a universal concern for skincare consumers, there are consequentially countless products, procedures, and other strategies that promise to resolve signs of aging and restore a youthful appearance. This interest in “anti-aging”, combined with an aging global population and renewed focus on health and wellness following the COVID-19 pandemic, is expected to fuel massive growth in this market. The global market for anti-aging products is projected to reach US$47.8 Billion by 2027 following a CAGR of 4.9%³.

In keeping with this trend, consumers are increasingly seeking information on new skincare ingredients to assist with signs of aging. The most searched ingredients in 2020 were vitamin C and retinol, which are widely regarded as the most effective anti-aging ingredients^4,5. In 2021 however, L’Oréal Paris USA reported that CBD oil was the new top trending ingredient, linking this cannabinoid’s anti-inflammatory properties to potential benefits for acne, psoriasis and eczema⁶. Similarly, interest in cosmetic antioxidants has boomed, with the global cosmetic antioxidants market size expected to reach US$158 Million by 2025 from US$119 million in 2020 at a CAGR of 5.9%⁷.

This growing interest in preventing or reversing signs of aging can only be met with the development of innovative ingredients with proven efficacy and established safety profiles. Cannabinoids such as CBG and CBD can meet this need, given their potent antioxidant and anti- inflammatory properties which can counteract extrinsic aging caused by UV exposure and inflammation. Their superior tolerability compared to other anti-aging actives, namely vitamin C, retinoids, and exfoliating acids, further positions these unique compounds at the forefront of a new generation of ingredients that prevent signs of aging. In many ways, cannabinoids represent the future of aging prevention and the key to optimizing consumer health and wellness.

Intrinsic aging: a time dependent phenomenon

Intrinsic (or chronological) aging is inevitable, highly controlled by genetics and begins following birth⁸. It is linked to a gradual decline in physiological functioning and the body’s ability to repair damage that occurs on a cellular level by inflammation, free radicals, disease and other degenerative factors. This degeneration is a large focus of the fascinating and ever-growing study of senescence, which aims to understand the mechanisms by which cells irreversibly age, stop dividing, and cease normal function^9,10.

In the context of skin health and appearance, these impaired cellular functions present in several ways:

• A thinning epidermis and dermis along with a reduction in the proliferation (or exchange) of keratinocytes, fibroblasts, and melanocytes between skin compartments that impairs the skin’s ability to repair following an injury or trauma^1,11,12.
• A decrease in the production, density, and organization of our skin’s essential building blocks, namely collagen, elastin, fibrillin, and proteoglycans, which overtime weakens the extracellular matrix (ECM) leading to a loss in volume, density, and elasticity, and the formation of wrinkles and fine lines^2,13,14.
• An uneven distribution and altered activity of melanocytes, resulting in a paler complexion and uneven skin tone^15,16,17.
• A reduction in sebum production, loss of subcutaneous fat and decrease in the skin’s lipid content which further degrades the skin’s structural integrity and ability to prevent water loss^18,19.

Taken together, these intrinsic factors are responsible for classical signs of aging skin, which are characterized as skin that appears thinner, dryer, and less elastic, along with an uneven skin tone and a paler, more translucent complexion.

Extrinsic aging: the role of external aggressors on skin health

Extrinsic aging is caused by external factors that are often linked to lifestyle choices. In particular, UV exposure accounts for almost 80% of aging signs, for which reason UV-induced extrinsic aging is sometimes referred to as photoaging^8,20. Anti-aging skincare solutions commonly revolve around the use of ingredients that can counteract or proactively mitigate the damage caused by UV exposure, such as antioxidants and other compounds that are capable of blocking UV radiation.

Inflammation is another culprit behind extrinsic aging. Inflammation can be caused by a range of external factors, including UV exposure, bacterial pathogens, chemical irritants, and allergens. A growing body of evidence is revealing that the multifaceted effects of inflammation can accumulate overtime and accelerate signs of skin aging in a process known as “inflammaging”^21-24.

Finally, emerging research suggests that blue light exposure from light emitting diodes (LEDs) in screens and other electronic devices may further aggravate skin by inducing the formation of reactive oxygen species (ROS) which cause oxidative stress, a major factor in extrinsic aging^25-28.

A robust skincare routine aimed at maintaining skin health and addressing signs of aging should therefore focus on mitigating the detrimental effects of UV exposure and inflammation. However, the selection of active ingredients that are capable of providing these benefits requires a fundamental understanding of the impact these extrinsic factors induce on skin health.

The detrimental effects of UV exposure

Chronic UV exposure wreaks havoc on human skin, causing a cascade of chemical and physiological changes that deteriorate the health, functioning and appearance of skin. In particular, UV exposure can lead to oxidative stress and lipid peroxidation (both of which are two major driving forces responsible for extrinsic aging), as well as glycation, solar elastosis, and skin thickening. CBG and CBD possess potent antioxidant and anti-inflammatory properties and can counteract drivers of aging caused by UV exposure. Moreover, CBG and CBD have superior tolerability compared to other anti-aging actives namely vitamin C, retinoids, and exfoliating acids.

UV radiation is a form of energy most commonly produced by the sun. Even though there are three types of UV radiation, it is only UVB and UVA that reach earth’s surface²⁹. Having a smaller wavelength, UVB can only penetrate the outer layers of the skin (i.e. the epidermis) and is responsible for sunburns and causing earlier signs of photoaging^30,31. UVB radiation can also cause DNA damage, which overtime may lead to skin cancer. On the other hand, the longer-wavelength UVA rays are capable of penetrating into the deeper skin layers, such as the dermis, causing changes to collagen, elastin, and also DNA^32,33. As UV radiation can travel through clouds and reflect off surfaces such as snow, water, sand and grass, UV exposure is essentially a guarantee of life on earth³⁴.

The structural changes that occur following chronic UV exposure are generally tied to the extracellular matrix (ECM), which is a non-cellular and heterogeneous network of connective tissues that provides an array of functions, including structural support, tissue segregation, biochemical functioning, as well as cellular adhesion, communication and differentiation³⁵. The ECM found in human skin is primarily composed of proteins such as collagens, elastins, fibronectins and laminins which create a fibrous network that provides structure to the ECM and skin. The interstitial space within this protein network is occupied by proteoglycans, which are molecules containing a protein core covalentlylinked to a polysaccharide chain known as a glycosaminoglycan^36,37. Proteoglycans provide organisational direction to the ECM proteins while also maintaining hydration and supporting mechanical strength of the skin^38,39. Deterioration of the ECM components inevitably leads to a loss of structure, elasticity, firmness, and hydration⁴⁰.

Inflammaging

Inflammation is part of our body's natural immune response and serves as an essential defense mechanism to protect against injury and infection caused by a range of aggressors, including pathogens, toxic compounds, damaged cells, allergens and radiation⁶⁴. While inflammation is also an essential part of the healing process, chronic inflammation can create a persistent and exhaustive state of chaos for the body²².

There is a growing body of evidence which indicates that chronic inflammation can accelerate cellular aging. This process has recently been coined by the term “inflammaging”. Inflammaging generally involves cumulative tissue damage that can lead to a range of diseases, such as diabetes, atherosclerosis, macular degeneration and skin aging, suggesting that inflammation is a major determinant of overall health and wellness^21-24.

In the context of skincare, acute inflammation may cause redness and sensitivity while also compromising the integrity of our skin barrier. With skin being the body’s largest and most critical organ responsible for keeping foreign and potentially harmful invaders out, a compromised skin barrier is a slippery slope to experiencing other issues such as dryness, blemishes, and other infections.

UV exposure triggers a series of inflammatory events involving the release of ROS, inflammatory mediators such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8), alongside MMPs which induce their own localized destructive effects^22,23,65. Interestingly, UV exposure also induces the activation of macrophages and neutrophils which have been shown to infiltrate into the epidermis to remove cellular debris and other cells affected by UV exposure²¹. This suggests that inflammaging and photoaging are intertwined with an innate immune response.

Cosmetic solutions for aging prevention

Anti-aging strategies can be divided into two categories, the first of which aims to prevent damage caused by external aggressors (i.e. proactive), while the second category addresses skin damage that has already occurred (i.e. reactive). As there is unfortunately no “one size fits all” solution for addressing signs of aging skin, a combination approach is often the most effective. Generally, the beauty industry has utilised retinoids, exfoliating acids and vitamin C as a means of reversing signs of aging, but these may cause irritation and photosensitivity. There is a need for ingredients that are as effective yet better tolerated than the current industry standards.

The best strategy for preventing skin damage is the use of sunscreens and other products with validated Sun Protection Factors (SPF) given that UV exposure is the main contributor to extrinsic aging. As SPF is a measure of UVB protection, dermatologists recommend products with broad spectrum coverage to defend against both UVA and UVB radiation^78,79. A secondary approach includes the use of topical antioxidants, such as vitamin C, to neutralize radicals generated during real-time sun exposure^80,81.

However, the use of sunscreens and antioxidants does not provide complete protection against photoaging, nor are they solutions to combat signs of aging caused by intrinsic factors, such as hormonal changes and genetics. Fortunately, there is a growing menu of ingredients that can help keep skin in good condition by mitigating the effects of pre-existing skin damage and the degenerative effects of the intrinsic aging processes.

Historically, this arsenal has included ingredients such as retinoids and exfoliating acids (specifically, glycolic and lactic acid). More recently, vitamin C and various peptides (specifically matrikines, which are peptide chains made from fragments of ECM proteins like collagen and elastin that can regulate a range of cellular functions related to growth and repair) have also proved to be efficacious for reversing signs of aging skin^82,83. While these ingredients provide a range of anti-aging benefits, their common mechanisms of action involve the promotion of collagen synthesis and cellular turnover.

A common yet significant drawback to these ingredients (with the exception of peptides) is their irritation potential and risk of photosensitivity. These negative side effects are especially problematic for retinoids and exfoliating acids for reasons yet to be fully elucidated. Some evidence suggests that the increased risk of irritation and photosensitivity are tied to structural changes in the stratum corneum and epidermis that impact the absorption and scattering of UV rays, while another mechanism could be related to the enhanced cellular turnover which results in the formation of a new and delicate layer of skin^95,102.

Despite these limitations, many consumers trudge onwards with using popular exfoliating acid, vitamin C and retinoid for the sake of healthy and youthful-looking skin. The adoption of retinoids and exfoliating acids is often a slow and painful process. In the case of retinoids, consumers are advised to “start low and go slow” while also avoiding the simultaneous use of other skincare ingredients with irritation potential (such as vitamin C). It can often take several weeks for the skin to adjust to new retinoid-based products, during which time erythema, dryness, and flaking may occur^89,103.

The guidance on exfoliating acids is somewhat similar to retinoids in that consumers are advised to limit their use of exfoliating acids to a few times a week while alternating the use of these products with other irritating ingredients and avoiding sun exposure^93,104. Products intended for at-home use generally contain between 5 - 20 % acids, while in-clinic treatments such as chemical peels contain much higher concentrations.

In the case of vitamin C, the minimum effective concentration for desired aging-related outcomes is 8%. However, many products contain upwards of 10%, furthering the risk of irritation as a trial- and-error approach may be required to identify products containing a tolerable yet effective concentration, particularly amongst consumers with sensitive skin or those who are using products containing retinoids and exfoliating acids^97,105,106.

The guidance on the use of these ingredients can be confusing, which can pose challenges to the safe and long-term adoption of products containing these ingredients. More importantly, the risk of irritation and (in the case of retinoids and exfoliating acids) photosensitivity limits the concentration and frequency of use of these ingredients, which in turn may impact their overall efficacy. This is particularly problematic for the growing number of individuals with sensitive or reactive skin, rendering most forms of ingredients such as retinoids, vitamin C, and exfoliating acids as incompatible options for skincare routines requiring the daily or frequent use of these ingredients to address signs of aging skin.

These limitations point to the need for non-irritating ingredients with multifaceted benefits that can address the many harmful aging effects of UV exposure and inflammation. Cannabinoids can effectively fill this gap given their established anti-inflammatory and antioxidant properties, presenting a new frontier for active aging prevention solutions.

Cannabinoids as multifaceted aging prevention actives

Cannabinoids are fascinating molecules with immense promise in the context of health, wellness and aging. Most notably, cannabinoids such as Cannabigerol (CBG) and Cannabidiol (CBD) have been shown to counteract the inflammatory effects of UVA, UVB bacterial pathogens and chemical irritants, while also possessing superior antioxidant capacity to ascorbic acid (vitamin C) and the ability to inhibit lipid peroxidation caused by UVB exposure. These combined properties open the door to an entirely new range of active skincare solutions that, unlike traditional treatments, do not pose risks for irritation and photosensitivity.

Inhibition of UVB-induced lipid peroxidation

Lipid peroxidation is a well-established outcome of UV exposure that is linked to ECM breakdown and premature signs of photoaging. For this reason, the ability of CBG and CBD to inhibit lipid peroxidation alone and in combination was evaluated in a study involving 3D cultured human epidermal skin tissues (EpiDermTM) pre-treated with test materials. 4-Hydroxynonenal (4-HNE) formation as an indicator of lipid peroxidation was measured from tissue lysates following exposure to UVB radiation (200 mJ/cm2, 280-340 nm). Ascorbic acid was used as a positive control for lipid peroxidation.

Results measured by 4-HNE showed that UVB radiation exposure significantly increased lipid peroxidation in epidermal tissue (Figure 1).

CBD (0.5%), CBG (0.75%, 1%) and combinations (0.25% CBD + 0.25% CBG, 0.375% CBD + 0.375% CBG) provided statistically significant (p<0.05) inhibition of lipid peroxidation compared to the UVB- exposed vehicle control. Additionally, 0.5% CBD was more effective than CBG. Interestingly, different dose-dependent activities were observed for CBD and CBG. Specifically, there was a dose- dependent increase in activity for CBG, meaning that higher doses resulted in less lipid peroxidation, whereas CBD had a dose-dependent decrease in activity whereby lipid peroxidation increased with CBD concentration. The combination of CBD and CBG produced a similar effect to CBD treatments, with a dose-dependent decrease in inhibition activity observed.

Based on these data, it was concluded that both CBD and CBG protected against significant UVB- induced lipid peroxidation in 3D skin tissue models. Furthermore, the differentiated dose-response suggests that less may sometimes be more, which is an important consideration in the context of cannabinoid product development.

Inhibition of inflammation caused by UVB exposure

UVB exposure is known to cause sunburns, which is associated with an inflammatory response within the skin that involves the release of a range of inflammatory cytokines, including Interleukin 8 (IL-8)^107,108. IL-8 has also been linked to inflammaging of skin as discussed previously, making this another highly relevant target in the context of aging prevention^21-23.

Therefore, the anti-inflammatory activity of CBG, CBD and select combinations of both cannabinoids was evaluated in a study involving pre-treated 3D cultured human epidermal skin tissues (EpiDerm^TM), whereby IL-8 formation was quantified using enzyme-linked immunosorbent assay (ELISA) after 24 hours post-UVB irradiation and incubation with test materials. Clobestasol propionate was used as a positive control for anti-inflammatory activity.

UVB irradiation (200 mJ/cm2, 280-340 nm) produced a significant increase in IL-8 release in culture media suggesting a pro-inflammatory response by UVB (Figure 2). Clobetasol propionate showed a complete decrease (100%) in IL-8. All cannabinoid treatments provided a statistically significant (p<0.05) inhibitory effect for IL-8 compared to the vehicle control that was comparable (i.e. >100%) to Clobestasol as the positive anti-inflammatory control. Based on these data, it was concluded that both CBD and CBG protect against significant UVB-induced pro-inflammatory cytokine (IL-8) release associated with photo- and inflammaging.

Further research on cannabinoids' anti-inflammatory & antioxidant activity

Recent findings reported by Willow Biosciences Inc., a biotechnology company that uses its proprietary FutureGrown^TM platform to manufacture pure, consistent and sustainable Cannabigerol (CBG), provide further evidence that both CBG and CBD possess notable antioxidant activity¹⁰⁹. Using a cell-free model, they reported that the antioxidantcapacity of CBG was approximately double that of CBD, with both cannabinoids being less potent compared to ascorbic acid. However, when tested using a cell-based model involving human dermal fibroblasts induced with hydrogen peroxide, both CBG and CBD inhibited the intracellular formation of free radicals and were observed to be 1,800-fold more potent compared to ascorbic acid. Taken together, these findings reveal that CBG and CBD are potent antioxidants that are capable of scavenging ROS present within dermal cells.

Willow also probed the anti-inflammatory activity of CBD and CBG against UV-induced inflammation¹⁰⁹. They found that CBG was twice as effective when compared to CBD at inhibiting the release of TNF-α from normal human epidermal keratinocytes exposed to UVB, and that both cannabinoids were significantly more effective than the positive anti-inflammatory control, clobetasol propionate. Similarly, treatment of human dermal fibroblasts with CBG resulted in a significant inhibition of IL-6 following UVA radiation, while a lesser and non-statistically significant inhibitory effect was observed for CBD. Both cannabinoids offered significant improvement in IL-6 inhibition compared to ascorbic acid.

Discussion

The above results provide valuable insight into the antioxidant and broad-spectrum anti- inflammatory activity of cannabinoids as novel ingredients for aging prevention. First and foremost, the anti-inflammatory activity against UVA (IL-6) and UVB (IL-8, TNF-α) exposure indicates that CBG followed by CBD are able to protect skin from the photoaging and inflammaging effects associated with UV exposure. CBG shows particular promise on this front against UVA exposure, demonstrating significantly superior results compared to vitamin C.

Secondly, CBD and unique cannabinoid blends showed significant activity against UVB-induced lipid peroxidation. The dose-response effects of CBD and CBG suggest that formulators should take into account the unique properties of each cannabinoid when developing products intended to provide antioxidant benefits, as higher concentrations may not translate into enhanced efficacy. However, this requires a thorough understanding of the properties and functionality of these interesting compounds while further highlighting the importance of research aimed at characterising these molecules using tissue models that are relevant for cosmetic research and development.

These results, coupled with the improved tolerability of cannabinoids compared to vitamin C, position cannabinoids like CBG and CBD as compelling and tolerable solutions for protecting skin against the oxidative and inflammatory aging effects of UV exposure.

Harnessing the aging prevention power of cannabinoids

Cellular Goods is committed to bringing the science of wellbeing to consumers’ daily lives. To this end, a range of skincare solutions incorporating high purity lab-made cannabinoids has been developed. By harnessing the anti-inflammatory and antioxidant properties of cannabinoids, Cellular Goods’ offerings provide targeted solutions for aging prevention that are suitable for sensitive skin.

The first product in this range is Cellular Goods’ Cannabinoid Serum, a breakthrough formula designed to prevent signs of aging by combating the various effects of intrinsic and extrinsic aging factors:

Extrinsic Aging: Lab-made high-purity CBG counteracts the aging effects of UV exposure and inflammation.

Intrinsic Aging: As one of the most research-backed peptides, palmitoyl pentapeptide-4 promotes collagen synthesis, smooths skin and reduces the appearance of fine lines and wrinkles. The serum also contains sodium lactate, glycerin, and sodium PCA as skin-identical natural moisturising factors (NMFs) with substanciated efficacy towards supporting a healthy and hydrated skin barrier.

Cellular Goods’ Age Prevention Serum has been dermatologically tested and proven suitable for sensitive skin.

With the introduction of Cellular Goods’ Cannabinoid Serum, Cellular Goods will be the first manufacturer of CBG-powered skincare in the UK. Their products are made exclusively with lab- made cannabinoids, which offer superior purity, safety, consistency, and sustainability compared to their plant-derived counterparts. This breakthrough serum will be the first product in Cellular Goods’ line of highly potent age-preventive skincare solutions.

Conclusion

Skin aging is an inevitable process driven by a range of factors dominated by UV exposure and chronic inflammation. Solutions aimed at preventing signs of aging should therefore directly address the deleterious impacts of these aggressors by reducing inflammation and preventing lipid peroxidation and further damage caused by reactive oxygen species, all of which lead to degradation of the extracellular matrix, a loss of elasticity, the formation of fine lines and wrinkles, a dull and uneven skin tone, and dry skin.

While the current catalogue of aging prevention ingredients, namely vitamin C, retinoids and exfoliating acids, can provide some protection against photo- and inflammaging while imparting other aging benefits by way of collagen synthesis, their use is often limited due to their irritancy potential and photosensitivity. This points to the need for well-tolerated active ingredients that can proactively mitigate UV and inflammation-induced damage responsible for signs of aging.

To this end, cannabinoids such as CBG and CBD are well positioned to fill this gap due to their potent anti-inflammatory and antioxidant properties. Scientific research has revealed that CBG and CBD are capable of preventing inflammation caused by UVA and UVB exposure equally if not more effectively than vitamin C. These cannabinoids and their blends can also prevent lipid peroxidation caused by UVB exposure, which is a significant feat considering their improved tolerability compared to vitamin C.

Taken together, these results indicate that cannabinoids are compelling ingredients that provide multiple mechanisms against photo- and inflammaging, qualifying them as novel ingredients with immense potential for aging prevention solutions. Cellular Goods is the first to offer science-backed skincare solutions that leverage the potent anti-inflammatory and antioxidant properties of high- purity lab-made cannabinoids to provide consumers with targeted solutions for aging prevention.

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