32 ANTI-AGEING


to explain the anti-ageing activity of the autophagy-stimulating peptide derivatives. Other aspects of skin ageing must be explored.


Inflamm-ageing Among the various ageing theories currently being suggested, inflamm-ageing is one the best-known and most broadly accepted.6


Low-level or micro-


scale inflammation, induced either by external stimuli or by internal factors, can accelerate skin ageing through the deleterious action of pro- inflammatory cytokines. As pro-inflammatory cytokines, interleukin-6


(IL-6), IL-8 and tumour necrosis factor (TNF)-a induce the increased expression of matric metalloproteinases (MMPs) and premature skin ageing. Hence, alleviating inflammation, either by removing external stimuli or blocking the inflammation-induced cellular signals, can hypothetically prevent or slow down the skin ageing process. The development of skin anti- ageing products with skin-soothing activity is based on this hypothesis.7 Previous studies reported that activation of


autophagy signalling under various inflammatory conditions, i.e. the activation of the toll-like receptors (TLR)-2/6, TLR48


or TLR39 in human


epidermal keratinocytes, UV-irradiated keratinocytes4


(2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD)- treated keratinocyte,10


, or environmental pollutant resulted in reduced


expression of inflammatory responses. This suggests that the autophagy activator can mitigate the inflamm-ageing and ultimately provide anti- ageing effects. A recently published study further reported


that attenuated autophagy signalling in chronical inflammatory skin diseases, atopic dermatitis and psoriasis.11


In accordance with these reports, we


also reported the clinical benefits of an autophagy activator for atopic dermatitis. In a double-blind, randomised, placebo-controlled clinical study performed on atopic dermatitis patients, we observed a significant improvement in disease symptoms, skin barrier function and hydration in the group which applied a moisturiser containing autophagy-enhancing peptide.12


Barri-ageing While there are a few potential sources of inflammatory mediators responsible for inflamm- ageing, senescent cells and senescence-associated secretory phenotypes (SASPs) from senescent cells are suggested as major contributors.13


However,


skin barrier function also plays an important role and, in this article, we would like to describe the roles of skin barrier function in ageing process using a new term of ‘barri-ageing’. During the last few decades, significant


knowledge has been accumulated about the roles of the skin barrier function, especially in skin homeostasis. While most skin barrier research has resulted in the development of moisturising products, recent study has highlighted the potential development of anti-ageing cosmetics based on the skin barrier function. The disruption of the skin barrier function


induces complex cellular events, such as an immediate release of pre-formed stratum corneum intercellular lipids, the stimulation of lipid synthesis and the proliferation of epidermal keratinocytes.14


PERSONAL CARE February 2022 A


Increased penetration of exogenous irritants


Autophagy activator


Skin barrier impairment Dry skin


Itching-scratching cycle


Depletion of epidermal ceramides EPIDERMIS


Inflammatory cytokines


Barri-ageing


MICROVESSEL DERMIS


Systemic micro-inflammation Figure 2: Barri-ageing


significant increase in pro-inflammatory cytokines is also accompanied by skin barrier damage. In a recently published study, it was suggested that the micro-inflammation of skin not only induces skin ageing, but also systemic ageing, such as metabolic or cardiovascular diseases.15 An impaired skin barrier function in aged skin was suggested as a major underlying factor responsible for the increased inflammatory cytokines expression in skin, ultimately resulting in elevated levels of cytokines circulating. In a pilot study in older participants, the


long-term application of barrier emollient not only improved skin barrier functions, but also lowered systemic levels of IL-1b, IL-6 and TNF-a.16 These results widen the crucial roles of skin barrier functions as skin hydration and maintenance of epidermal permeability into keeping the skin and the whole body from barri-ageing. The barrier function of mammalian skin


originates from the terminal differentiation of epidermal keratinocytes, which generates the corneocytes and stratum corneum intercellular lipids, including ceramides. Autophagy constitutively participates in the differentiation process and experimental impairment of autophagy resulted in defects in epidermal barrier functions.17 Autophagy-activating peptide derivative


treatment stimulated the expression of differentiation marker proteins in in vitro-cultured human epidermal keratinocytes and ex vivo human skin explant models. An accelerated recovery in the skin barrier function was also observed in a clinical study.18


Sensiti-ageing There are diverse names and definitions explaining sensitive skin. Recently special interest groups on sensitive skin in the International Forum for the Study of Itching suggested that it is a syndrome defined by the occurrence of unpleasant sensations, such as stinging, burning, pain, pruritus and tingling sensations, in response to stimuli that should not normally provoke such sensations.19 As the definition of it as a syndrome implies,


sensitive skin is a collection of symptoms which are ongoing without a specific, identifiable cause. Even with its obscure definition, the prevalence of sensitive skin is quite high, and in many countries including the US, the UK, Korea, and Japan, more than 50% of females said that they have sensitive


skin.20 The unprecedented pandemic situation and


long-term mask-wearing further aggravate the severity of sensitive skin.21 Sensitive skin is not only as an unpleasant


and annoying condition, it can also accelerate skin ageing in several ways. Increased sensitivity prevents people from using conventional anti- ageing products and also exacerbates the damage to common extrinsic factors, such as dry weather, air conditioning, temperature variation, heat, pollution and even water.19


Damage-induced


itching and resultant scratching leads to the vicious ‘itch-scratch’ cycle and induces the expression of pro-inflammatory cytokines in skin, ultimately resulting in inflamm-ageing. Impaired skin barrier function has also been


suggested as one of the major pathophysiologic factors involved in sensitive skin and possibly as a cause of premature skin ageing. While there are many soothing ingredients for sensitive skin, few studies have been reported for using autophagy activators. Recently, through series of in vitro and ex vivo


studies, we were able to show that autophagy signalling is also involved in dermal mast cell activation (or degranulation). A clinical study of the capsaicin test (CAT) with autophagy-activating peptide derivative further showed significant prevention effects on skin erythema and burning sensation. A delay in skin temperature increase was also observed in the same clinical study, which suggests that using this can improve the skin barrier function and retard the transcutaneous penetration of capsaicin.


Summary In addition to the classical intrinsic and extrinsic types of ageing, new terms for skin ageing describing the causal factors or associated symptoms are continuously being introduced. As a core machinery for maintaining skin homeostasis, autophagy signalling is involved in almost every aspect of skin ageing. The application of AquatideTM


can address diverse


types of ageing. While experimental evidence supports the rationale for using it in anti-ageing cosmetics, clinical study further confirmed the beneficial outcomes of anti-ageing.


References: 1 Saha S, Panigrahi DP, Patil S, Bhutia SK. Autophagy in health & disease: A


www.personalcaremagazine.com PC


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