Use of active ingredients for treatment and / or prevention of skin aging

Abstract

Compositions may include the cosmetic use of an active agent for the treatment and / or prevention of skin aging, wherein the agent is capable of inhibiting aging-related secretion phenotypes by i) reducing the release of IL-6, IL-8, TNF-alpha, and matrix metallopeptidase-1 (MMP1); ii) reducing the activity of b-galactosidase, iii) reducing the biosynthesis of secretory crimp-associated protein 4 (SFRP 4), and iv) reducing the expression of p21 in fibroblasts.

Description

Priority Statement

[0001] This patent application claims priority to U.S. Provisional Application No. 63 / 500,417, filed May 5, 2023; U.S. Provisional Application No. 63 / 626,823, filed January 30, 2024; and French Application No. 2313018, filed November 24, 2023, all of which are incorporated herein by reference in their entirety. Background Technology

[0002] The present invention generally relates to active ingredients capable of combating intrinsic aging of the dermis and its manifestations, compositions containing said active ingredients, and their use as cosmetic or pharmaceutical (e.g., dermatological) dermal compositions.

[0003] The skin is the largest organ in the human body: it provides a barrier against harmful organisms and substances, protects against UV radiation, and regulates water loss and body temperature. The skin is a complex organ composed of several compartments with different functions. The outermost layer, the epidermis, is divided into four sublayers (stratum basale, stratum spinosum, stratum granulosum, and stratum corneum), in which keratinocytes are the main cell type. Melanocytes, which produce pigment, are located in the stratum basale of the epidermis, determining skin color and providing photoprotective properties. The dermal-epidermal junction (DEJ) connects the epidermis to the underlying dermis, which contains dermal fibroblasts and appendages such as hair follicles, sebaceous glands, and sweat glands (1).

[0004] Skin aging is a multifactorial process that affects almost every aspect of its biology and function; it is driven by both internal (e.g., time, genetic factors, hormones) and external (e.g., UV exposure, pollution) factors. Visible signs of internal aging include loss and sagging of subcutaneous fat, leading to sunken cheeks and eye sockets; and loss of firmness and sagging due to bone loss causing separation of bone from the skin. Other visible signs include thin, dry skin, fine lines, decreased elasticity, abnormal pigmentation, graying hair, and hair loss.

[0005] Internal and external aging are partly due to the aging process and represent inevitable changes caused solely by the passage of time. They are primarily physiological changes that have subtle but undeniably significant effects on both healthy and diseased skin and are largely determined by genetics. Aging, and especially skin aging, is an ongoing process that typically begins in the mid-twenties but may not become apparent for decades. In a person's twenties, collagen production begins to slow and elastin becomes slightly less elastic. Dead skin cells do not shed quickly, and the turnover of new skin cells decreases. The process of internal skin aging is similar to that seen in most internal organs, and one explanation is that it involves a reduced proliferative capacity, leading to cellular senescence, and altered biosynthetic activity of skin-derived cells. The rate of internal skin aging in any individual can be significantly influenced by personal and environmental factors, particularly the amount of ultraviolet light exposure. For example, photodamage that significantly accelerates visible skin aging also greatly increases the risk of skin tumors: internal and external aging processes are additive. However, it must be emphasized that the terms aging and cellular senescence are not interchangeable: aging is a gradual decline that occurs over time, while senescence occurs throughout life, including during embryonic development. The number of senescent cells increases with age, but senescence also plays an important role during development (2).

[0006] Aging doesn't just occur in the skin. Its role in all tissues is to prevent the replication of cells carrying damaged DNA, which plays a crucial anti-tumor function. Aging typically occurs in response to damaging stimuli, including telomere shortening (replicative aging), DNA damage (DNA damage-induced aging), and oncogenic signaling (oncogene-induced aging).

[0007] Replicative senescence refers to the phenomenon where normal, non-malignant cells cease dividing in vitro after approximately fifty divisions; this is known as the Hayflick limit. Replicative senescence is induced by telomere shortening. With each round of DNA replication, telomeres gradually shorten, eventually reaching a critical length that prevents further replication, thus stopping cell division. Extremely short, uncapped telomeres trigger a DNA damage response, thereby initiating senescence.

[0008] DNA damage triggers DNA repair mechanisms, apoptosis, or senescence depending on the degree of damage and the physiological environment. Senescent cells are characterized by a persistent DNA damage response (DDR), including chronic ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) kinase signaling, which ultimately leads to cell cycle arrest and senescence by activating the p53 / p21 and p16 / pRb pathways. Persistent DNA damage and subsequent senescence can also be induced by ionizing radiation, chemotherapy agents, genotoxic stress, and oxidative stress.

[0009] In response to oncogenic signaling, cellular senescence is induced as an effective cell-autonomous anti-cancer mechanism. Senescence occurring in cells with oncogenic signaling is a response designed to prevent them from transforming into malignant cells. Oncogene-induced senescence (OIS) is caused by the overactivation of oncogenes (such as H-Ras) or the inactivation of tumor inhibitors (such as PTEN). For example, the expression of H-RASV12 (an oncogenic form of the GTPase H-RAS) triggers OIS by inducing chronic p38 mitogen-activated protein kinase (p38 MAPK) signaling. Strong mitogenic signaling can also induce DNA damage through replication stress, thereby triggering the collapse of the replication fork (2).

[0010] Senescent cells are characterized by stable cell cycle arrest, morphological and metabolic changes, chromatin reorganization, altered gene expression, and the acquisition of the senescence-associated secretory phenotype (SASP). A key characteristic of senescent cells is their ability to contaminate healthy cells, transforming them into senescent cells and accelerating their aging process. Newly formed senescent cells employ the same communication patterns as healthy cells, perpetuating a vicious cycle. If left unchecked, these cells can multiply up to three times by age 65.

[0011] Applied to the skin, this knowledge could overturn the concept of beauty from the inside out, suggesting that our largest organ, the skin, may influence how we age overall. This could be a completely new way of looking at the healthy lifespan of the skin.

[0012] As mentioned above, the hallmark of senescent cells is the presence of senescence-associated secretory phenotype (SASP). SASP includes several families of soluble and insoluble factors, which can be broadly classified into the following main categories: soluble signaling factors (interleukins, chemokines, and growth factors), secretory proteases, and secretory insoluble protein / extracellular matrix (ECM) components (4).

[0013] Because they may be involved in many aging and disease processes, eliminating senescent cells and reducing the age-associated secretory phenotype (SASP) has become an attractive therapeutic and cosmetic strategy; however, translating these findings into relevant human applications is currently limited by the following fragmented understanding: the fundamental molecular cell biology of senescent cells in vivo and the overall importance of aging for age-related diseases (3).

[0014] Known SASP inhibitors belong to one of the following pharmacological categories:

[0015] a. Glucocorticoids, as effective inhibitors of selected components of SASP;

[0016] b. Statins, such as simvastatin, can reduce the expression of pro-inflammatory cytokines (IL-6, IL-8, and MCP-1);

[0017] c. JAK1 / 2 inhibitors, such as ruxolitinib.

[0018] d. NF-κB and p38 inhibitors;

[0019] e. In Mitochondrial autophagy Mitochondrial depletion agents in damaged conditions.

[0020] However, there is a need to develop new SASP inhibitors to meet the expectation of shifting the focus of dermatology from improving cosmetic outcomes of aging skin to reducing the actual disease associated with aging skin problems in the face of an aging population.

[0021] There is also a need to develop new SASP inhibitors to selectively eliminate senescent cells in the body, thereby reducing inflammation, enhancing immune system function, and slowing the progression of age-related diseases, all of which can lead to increased health and lifespan.

[0022] WO2023 / 012115 discloses an active ingredient comprising at least one Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa. Preferably, the extract consists of a cytoplasmic fraction of Saccharomyces cerevisiae (INCI: Saccharomyces cerevisiae extract). The ingredient is proposed for improving skin regeneration and treating skin aging, particularly wrinkles, dark circles, and skin tone. The ingredient is described as being able to improve the interaction between the skin, blood vessels, and the immune system by increasing the synthesis and secretion of growth factors (KGF, EGF, IGF, FGF, PDGF, TGF-β, and VEGF). Summary of the Invention

[0023] This invention provides an active ingredient that can inhibit aging-related secretory phenotypes by inhibiting or reducing the following: i) the release of IL-6, IL-8, TNF-α, and matrix metallopeptidase-1 (MMP1); ii) β-galactosidase activity; iii) the biosynthesis of secreted frizzled-related protein 4 (SFRP 4); and iv) p21 expression in fibroblasts. Specifically, the active ingredient comprises at least one Saccharomyces cerevisiae extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa, preferably and adenosine and / or Schisandra sphenanthera fruit extract.

[0024] The reduction in the sense of this invention means, preferably, at least about -20%, about -25%, about -30%, about -35%, about -40%, about -45%, about -50%, about -55%, about -60%, about -65%, about -70%, about -75%, about -80%, about -85%, about -90%, or about -95% compared to the level of the corresponding marker in untreated senescent cells. All ranges between any of the above pairs of values ​​are explicitly disclosed herein.

[0025] By inhibiting age-related secretory phenotypes, the ingredients treat visible signs of intrinsic skin aging, such as sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning and dry skin; fine wrinkles; reduced elasticity; abnormal pigmentation; and graying and hair loss.

[0026] The present invention also provides a cosmetic use of a brewer's yeast extract for treating and / or preventing skin aging, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa, specifically wherein skin aging includes apparent signs of intrinsic skin aging, such as sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning and dry skin; fine wrinkles; decreased elasticity; abnormal pigmentation; and graying and hair loss.

[0027] The present invention also provides compositions comprising Saccharomyces cerevisiae extract for cosmetic use in treating and / or preventing skin aging, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa for treating and / or preventing skin aging.

[0028] The present invention also provides a therapeutically effective amount of *Saccharomyces cerevisiae* extract for treating and / or preventing aging, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa, particularly wherein aging can be, in particular, replicative aging, DNA damage-induced aging, or oncogene-induced aging. More particularly, aging can be skin aging, such as apparent signs of intrinsic skin aging.

[0029] This invention also provides a therapeutically effective amount of *Saccharomyces cerevisiae* extract for the treatment and / or prevention of age-related diseases in humans, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa. Age-related diseases can be, in particular, cancer, heart disease, or dementia.

[0030] According to the present invention, the composition can be applied topically, particularly in the following forms: oil-in-water emulsion, water-in-oil emulsion, multiple emulsion (water / oil / water or oil / water / oil), microemulsion, nanoemulsion, solution, suspension, aqueous dispersion, gel, ointment, paste, aerosol foam, spray, hydrogel, powder, foundation, transdermal patch, cream or mask.

[0031] The composition is also suitable for intravenous or parenteral administration, particularly intradermal or subcutaneous administration.

[0032] According to the present invention, the extract may be present in cosmetic or pharmaceutically applicable amounts. For example, the cosmetic or therapeutic composition comprises at least 0.00025% by weight of the whole composition, preferably between 0.001% and 2%, more preferably between 0.01% and 1%, even more preferably between 0.025% and 0.5%, even more preferably between 0.05% and 0.1%, and most preferably 0.0625%. Attached Figure Description

[0033] In drawings that are not necessarily drawn to scale, similar labels in several views describe substantially similar components. The drawings illustrate various aspects of the invention generally by way of example rather than limitation.

[0034] Figures 1A to 1C This is an overview of the release of aging-related IL6, IL8, and TNFα in the presence or absence of active ingredients containing oligo-β-glucan derived from the cytoplasmic fraction of Saccharomyces cerevisiae.

[0035] Figure 2 This is an overview of the expression of SASP-associated matrix metalloproteinase MMP1 in the presence or absence of an active ingredient containing oligo-β-glucan derived from the cytoplasmic fraction of Saccharomyces cerevisiae.

[0036] Figure 3 This is an overview of aging-related β-galactosidase activity, with or without active ingredients containing oligo-β-glucan derived from the cytoplasmic fraction of Saccharomyces cerevisiae.

[0037] Figure 4 This is an overview of immunostaining of secretory coil-associated protein 4 (SFRP4) with or without the presence of an active ingredient containing oligo-β-glucan derived from the cytoplasmic fraction of Saccharomyces cerevisiae. Detailed Implementation

[0038] Reference will now be made in detail to certain aspects of the disclosed subject matter, with examples of said aspects partially illustrated in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it should be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0039] Throughout this document, values ​​expressed in range format should be interpreted flexibly to include not only the values ​​explicitly stated as the limits of the range, but also all individual values ​​or subranges covered within the range, as if each value and subrange were explicitly stated. For example, the range “about 0.1% to about 5%” or “about 0.1% to 5%” should be understood to include not only about 0.1% to about 5%, but also the individual values ​​within the range shown (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise indicated, the statement “about X to Y” has the same meaning as “about X to about Y”. Similarly, unless otherwise indicated, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z”.

[0040] In this document, unless the context clearly indicates otherwise, the terms “a / an” or “the” are used to include one or more, or one or more kinds of. Unless otherwise indicated, the term “or” is used to mean a non-exclusive “or”. The statements “at least one of A and B” or “at least one of A or B” have the same meaning as “A, B, or A and B”. Furthermore, it should be understood that the wording or terms used herein and not otherwise defined are for descriptive purposes only and not restrictive. Any use of section headings is to aid in the reading of this document and should not be construed as restrictive; information relating to a section heading may appear within or outside the specific section mentioned. Commas may be used as delimiters to the left or right of a decimal point or as separators for groups of numbers; for example, “0.000,1” is equivalent to “0.0001”. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety as if they were individually cited. If there is any inconsistency between the usage in this document and those documents which are incorporated by reference, the usage in the incorporated references shall be considered as supplementary to the usage in this document; in the case of irreconcilable inconsistencies, the usage in this document shall prevail.

[0041] As used herein, the term “about” may allow for a degree of variability in the value or range, for example, within 10%, 5%, or 1% of the stated value or range limits, and includes the exact stated value or range. As used herein, the term “substantially” means most or more than, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the term “substantially free” may mean having no or very small amounts of material such that the amount of material present does not affect the material properties of the composition comprising the material, such that about 0% to about 5% by weight of the composition is the material, or about 0% to about 1% by weight, or about 5% by weight or less, or less than or equal to about 4.5% by weight, 4% by weight, 3.5% by weight, 3% by weight, 2.5% by weight, 2% by weight, 1.5% by weight, 1% by weight, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, 0.3% by weight, 0.2% by weight, 0.1% by weight, 0.01% by weight, or about 0.001% by weight or less, or about 0% by weight.

[0042] Standard error applies when indicating the percentage of an ingredient in a composition. For example, 3.0% should be interpreted as 2.9% to 3.1%.

[0043] The term “comprises” and its variations should be interpreted as meaning “includes”, “substantially consists of”, and “consists of”, as well as their variations.

[0044] This invention provides an active ingredient that can inhibit aging-related secretory phenotypes by reducing the release of IL-6, IL-8, TNF-α, and matrix metallopeptidase-1 (MMP1). Specifically, the active ingredient comprises at least one Saccharomyces cerevisiae extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa.

[0045] The present invention also provides at least one Saccharomyces cerevisiae extract for cosmetic use in treating and / or preventing skin aging, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa. The extract may be present in cosmetically effective amounts.

[0046] Specifically, the present invention provides at least one Saccharomyces cerevisiae extract for cosmetic use in treating and / or preventing apparent signs of intrinsic skin aging, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa, such apparent signs as sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning, and dry skin; fine wrinkles; decreased elasticity; abnormal pigmentation; and graying and hair loss. The extract may be present in cosmetically effective amounts.

[0047] The present invention also provides a therapeutically effective amount of an active agent for treating and / or preventing skin aging, said active agent comprising at least one Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa. The extract may be present in a pharmaceutically effective amount.

[0048] Specifically, the present invention provides a therapeutically effective amount of an active agent for treating and / or preventing apparent signs of intrinsic skin aging, said active agent comprising at least one Saccharomyces cerevisiae extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa, such apparent signs as sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning and dry skin; fine wrinkles; decreased elasticity; abnormal pigmentation; and graying and hair loss.

[0049] The present invention also provides a composition for cosmetic use in treating and / or preventing skin aging, said composition comprising at least one Saccharomyces cerevisiae extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa. The extract may be present in the composition in a cosmetically effective amount.

[0050] In particular, the present invention provides a cosmetic use of a composition for treating and / or preventing apparent signs of intrinsic skin aging, said composition comprising at least one Saccharomyces cerevisiae extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa, such apparent signs as sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning, and dry skin; fine wrinkles; decreased elasticity; abnormal pigmentation; and graying and hair loss. The extract may be present in a cosmetically effective amount in the composition.

[0051] The present invention also provides a therapeutically effective amount of a composition for treating and / or preventing skin aging, said composition comprising at least one *Saccharomyces cerevisiae* extract, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa. The extract may be present in the composition in a pharmaceutically effective amount.

[0052] Specifically, the present invention provides a therapeutically effective amount of a composition for treating and / or preventing apparent signs of intrinsic skin aging, said composition comprising at least one *Saccharomyces cerevisiae* extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa, such apparent signs as sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning, and dry skin; fine wrinkles; decreased elasticity; abnormal pigmentation; and graying and hair loss. The extract may be present in the composition in a pharmaceutically effective amount.

[0053] According to the present invention, the extract may be present in cosmetic or pharmaceutically applicable amounts. For example, the cosmetic or therapeutic composition comprises at least 0.00025% by weight of the whole composition, preferably between 0.001% and 2%, more preferably between 0.01% and 1%, even more preferably between 0.025% and 0.5%, even more preferably between 0.05% and 0.1%, and most preferably 0.0625%.

[0054] The compositions of the present invention may contain other active agents for treating or preventing aging, particularly adenosine and / or Schisandra chinensis fruit extract (INCI). Saccharomyces cerevisiae extract corresponding to cytoplasmic fractions containing oligo-β-glucan with a molar mass between 2 and 5 kDa, together with adenosine and / or Schisandra chinensis fruit extract, may produce a synergistic effect in the cosmetic and / or therapeutic treatments of the present invention.

[0055] The topical compositions according to the invention may contain at least one other ingredient typically found in topical cosmetic and / or pharmaceutical (e.g., dermatological) compositions, selected from: water, oil (particularly selected from volatile and / or non-volatile linear or cyclic silicone oils), wax (e.g., cerescargot, ozokerite, beeswax, or carnauba wax), silicone elastomers, nonionic, anionic, cationic, and / or amphoteric surfactants, co-surfactants (e.g., linear fatty alcohols), thickeners, gelling agents, humectants (e.g., polyols such as glycerin), colorants, preservatives, fillers, tensors, chelating agents, fragrances, and mixtures thereof.

[0056] These compositions may be, in particular, in the form of oil-in-water emulsions, water-in-oil emulsions, multiple emulsions (water / oil / water or oil / water / oil), optionally microemulsions or nanoemulsions, or in the form of solutions, suspensions, aqueous dispersions, gels, ointments, pastes, aerosol foams or sprays, hydrogels, powders or foundations or transdermal patches. They may be more or less fluid and have the appearance of creams, emulsions, gels, masks or any other aspect of healthy skin care and beauty. Those skilled in the art are familiar with the procedures, ingredients and forms commonly used in the preparation of dermal formulations.

[0057] A gel is a colloid in which a dispersed phase has been combined with a continuous phase to produce a semi-solid material, such as a gel.

[0058] "Oil" is a composition containing at least 95 wt% lipophilic substances. Examples of lipophilic substances include, but are not limited to, naturally occurring and synthetic oils, fats, fatty acids, lecithin, triglycerides, and combinations thereof.

[0059] A "continuous phase" refers to a liquid in which solids are suspended or droplets of another liquid are dispersed, and is sometimes referred to as the external phase. A continuous phase can also refer to a colloidal fluid phase in which solid or fluid particles are internally distributed. If the continuous phase is water (or another hydrophilic solvent), then water-soluble or hydrophilic drugs will dissolve in the continuous phase (as opposed to dispersion). In multiphase formulations (e.g., emulsions), the discrete phase is suspended or dispersed within the continuous phase. Excipients for topical application may include antimicrobial compounds such as parabens; antioxidants, such as sodium ascorbate and α-tocopherol; stabilizers, such as sorbitol; and / or emulsifiers to produce a stable emulsion having both a hydrophilic and a hydrophobic phase.

[0060] "Diluent" can be included in a formulation to dissolve, disperse, or otherwise incorporate into a carrier. Examples of diluents include, but are not limited to, water, buffered aqueous solutions, organic hydrophilic diluents such as monovalent alcohols, and low molecular weight diols and polyols (e.g., propylene glycol, polypropylene glycol, glycerol, butanediol).

[0061] The appropriate excipients are selected based on the type of formulation. Standard excipients include gelatin, casein, lecithin, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetearyl alcohol, cetomacrogol emulsifying wax, sorbitol esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitol fatty acid esters, polyethylene glycol, polyoxyethylene stearate, colloidal silica, phosphates, sodium lauryl sulfate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, sugars, and starches.

[0062] An emulsion is a formulation in which a liquid is distributed in the form of droplets throughout a bulk of a second liquid. The dispersed liquid is a discontinuous phase, and the dispersion medium is a continuous phase. When the oil is the dispersed liquid and the aqueous solution is the continuous phase, it is called an oil-in-water emulsion, and when water or an aqueous solution is the dispersed phase and the oil or oily substance is the continuous phase, it is called a water-in-oil emulsion. The oil phase may consist at least partially of a propellant (such as an HFA propellant). Either or both of the oil and aqueous phases may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially nonionic surfactants; emulsifiers, especially emulsifying waxes; and liquid nonvolatile nonaqueous materials, especially diols, such as propylene glycol. The oil phase may contain other pharmaceutically approved oily excipients. For example, materials such as hydroxylated castor oil or sesame oil can be used as surfactants or emulsifiers in the oil phase.

[0063] "Emollients" are external coatings that soften or lubricate the skin and are generally known in the art and are broadly listed, for example, in "Handbook of Pharmaceutical Excipients," 4th edition, Pharmaceutical Press, 2003. These emollients include, but are not limited to, almond oil, castor oil, carob extract, cetylstearoyl alcohol, cetyl alcohol, cetyl ester wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitate stearate, glycerin, glyceryl monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohol, paraffin oil, paraffin oil and lanolin alcohol, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol, and combinations thereof. In one embodiment, the emollient is ethylhexyl stearate and ethylhexyl palmitate.

[0064] A surfactant is a surface-active agent that reduces surface tension and thereby increases the emulsifying, foaming, dispersing, diffusing, and wetting properties of a product. Suitable nonionic surfactants include emulsifying waxes, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbates, sorbitol esters, benzyl alcohol, methyl benzoate, cyclodextrin, glyceryl monostearate, poloxamer, povidone, and combinations thereof. In one embodiment, the nonionic surfactant is stearyl alcohol.

[0065] Emulsifiers are surfactants that promote the suspension of one liquid in another and facilitate the formation of stable mixtures or emulsions of oil and water. Common emulsifiers include metallic soaps, certain animal and vegetable oils, and various polar compounds. Suitable emulsifiers include gum arabic, anionic emulsifying waxes, calcium stearate, carbomer, cetearyl stearate, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitate stearate, glyceryl monostearate, glyceryl monooleate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lanolin, hydrous lanolin alcohol, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohol, sodium dihydrogen phosphate, monoethanolamine, nonionic emulsifying waxes, oleic acid, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, astragalus gum, triethanolamine, xanthan gum, and combinations thereof. In one embodiment, the emulsifier is glyceryl stearate.

[0066] "Lotion" is a liquid formulation with low to medium viscosity. Lotions may contain fine powdery substances soluble in a dispersion medium using suspending and dispersing agents. Alternatively, a lotion may have a liquid substance as the dispersed phase that is immiscible with a mordant and is typically dispersed by means of an emulsifier or other suitable stabilizer. In one embodiment, the lotion is in the form of an emulsion with a viscosity between 100 and 1000 centistokes. The fluidity of the lotion allows for rapid and uniform application over a wide surface area. Lotions are generally intended to dry on the skin, leaving a thin coating of their medicinal components on the skin surface.

[0067] "Cream" is a viscous liquid or semi-solid emulsion that is "water-in-oil" or "oil-in-water". Creams may contain emulsifiers and / or other stabilizers. In one embodiment, the formulation is in the form of a cream with a viscosity greater than 1,000 centistokes, typically in the range of 20,000 to 50,000 centistokes. Creams are generally preferred over ointments because they are generally easier to spread and easier to remove.

[0068] "Ointment" is a semi-solid formulation containing an ointment base and optionally one or more active agents. Examples of suitable ointment bases include hydrocarbon bases (e.g., paraffin oil, white paraffin oil, yellow ointment, and mineral oil); absorbent bases (hydrophilic paraffin oil, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointments); and water-soluble bases (e.g., polyethylene glycol ointments). Pastes typically differ from ointments because they contain a greater percentage of solids. Pastes are typically more absorbent and less greasy than ointments prepared with the same components.

[0069] A "gel" is a semi-solid system containing a dispersion of small or large molecules in a liquid medium, which is semi-solid due to the action of a thickener or polymeric material dissolved or suspended in the liquid medium. The liquid may include lipophilic, aqueous, or both components. Some emulsions may be gels or otherwise include gel components. However, some gels are not emulsions because they do not contain homogenized blends of immiscible components. Suitable gelling agents include, but are not limited to, modified celluloses such as hydroxypropyl cellulose and hydroxyethyl cellulose; carbomer homopolymers and copolymers; and combinations thereof. Suitable solvents in liquid mediums include, but are not limited to, diethylene glycol monoethyl ether; alkyl glycols such as propylene glycol; dimethyl isosorbide anhydride; and alcohols such as isopropanol and ethanol. Solvents are typically selected based on their ability to dissolve the drug. Other additives that improve the skin feel and / or emollient properties of the formulation may also be incorporated. Examples of such additives include, but are not limited to, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoate, mineral oil, squalane, cyclomethicone, decanoic acid / caprylic acid triglyceride, and combinations thereof.

[0070] The “foaming agent” consists of a combination of an emulsion and a gaseous propellant. The gaseous propellant is primarily composed of hydrofluorocarbons (HFAs). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and blends of these substances with other HFAs currently approved or potentially approved for medical use are suitable. The propellant is preferably not a hydrocarbon propellant gas that may produce flammable or explosive vapors during spraying. Furthermore, the composition preferably does not contain volatile alcohols that may produce flammable or explosive vapors during use.

[0071] The pH of the composition is controlled using a buffer. Preferably, the buffer buffers the composition from pH about 4 to pH about 7.5, more preferably from pH about 4 to pH about 7, and most preferably from pH about 5 to pH about 7. In a preferred embodiment, the buffer is based on triethanolamine, citric acid, sodium hydroxide, disodium phosphate, and potassium phosphate.

[0072] Preservatives can be used to prevent the growth of fungi and microorganisms. Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzyl alcohol, hexadecylpyridinium chloride, chlorobutanol, phenol, phenethyl alcohol, potassium sorbate, octanoyl alcohol, 1,2-hexanediol, and thimerosal.

[0073] Antioxidants can be used in the compositions of the present invention. Examples of antioxidants are tocopherol, hydroxyacetophenone, dimethylmethoxychromoyl alcohol, and phenylethyl alcohol.

[0074] Other viscosity modifiers may be present, such as potassium chloride and natural gums, such as xanthan gum, gum arabic, astragalus gum, carrageenan, chitosan, guar gum, konjac gum, fungal gums, dextrin, and starch.

[0075] Chelating agents, such as sodium glucuronide, may also be present.

[0076] Fragrances can be added to the compositions of the present invention.

[0077] Permeation enhancers are often used to facilitate transdermal drug delivery across the skin, especially across the stratum corneum. More commonly used reinforcing agents include urea, carbonyl diamine, imidulazolium urea, N,N-diethylformamide, N-methyl-2-pyrrolidine, 1-dodecyl-azacycloheptan-2-one, calcium mercaptoacetate, 2-pyrrolidine, N,N-diethyl-m-toluamide, oleic acid and its ester derivatives (e.g., methyl monooleate, ethyl monooleate, propyl monooleate, isopropyl monooleate, butyl monooleate, vinyl monooleate, and glyceryl monooleate), sorbitan esters (e.g., sorbitan monolaurate and sorbitan monooleate), other fatty acid esters (e.g., isopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleate), and nonionic detergents (e.g., BRIJ® 76 (stearoyl poly(deoxyethylene ether)), BRIJ® 78 (stearyl poly(20)oxyethylene ether), BRIJ® 96 (oil-based poly(10)oxyethylene ether) and BRIJ® 721 (stearyl poly(21)oxyethylene ether)) (ICI Americas Inc. Corp.).

[0078] Emulsion stabilizers, surfactants, and emulsifiers may also be present, such as sorbitan isostearate, hydroxyethyl acrylate / acryloyloxydiethyl taurate copolymer, and sorbitan isostearate.

[0079] Moisturizers are essential for skincare by providing necessary skin hydration and maintaining the skin's moisture balance. Exemplary moisturizers include glycerin, hyaluronic acid, aloe vera, honey, hydrolyzed protein, panthenol, allantoin, seaweed and algae, sodium PCA (sodium pyrrolidone carboxylate), glycoisomers, sugar alcohols (e.g., sorbitol), hydroxy acids (e.g., lactic acid and gluconolactone), agave nectar, betaine, chitosan, trehalose, beta-glucan, topical collagen, galactoarabinogalactan, and propylene glycol.

[0080] The solvents used in the compositions of the present invention may include water, alcohols (e.g., ethanol and isopropanol), alkanes (e.g., C15-19 alkanes), silicone oils, and mineral oils.

[0081] Skin conditioning agents can be added to the compositions of the present invention, such as caprylic / capric triglyceride, α-glucan triglyceride, palmitoyl tripeptide-5, glycerol, disacchariyl gallic acid, panthenol, pantothenic acid lactone, sodium stearoyl glutamate, lactic acid, hydrolyzed hyaluronic acid, sodium hyaluronate, and maltodextrin.

[0082] Other natural extracts may be present in the compositions of the present invention, such as yeast / acetobacterium / black tea ferment, daisy (Bellis perennis) flower extract, Thermus Thermophillus ferment, and Sphingomonas ferment extract.

[0083] After preparation, the product is filled into appropriate dispensers and delivered to the end user. Examples of final containers may include pump bottles, squeeze bottles, wide-mouth bottles, tubes, or vials.

[0084] The present invention will now be illustrated by non-limiting examples of compositions according to the invention and by test results.

[0085] Example

[0086] Example 1

[0087] Figures 1A to 1C Showing the use of REGENIXIR ®The results of studies on cells using (SiLab) yeast extract (https: / / www.silab.fr / en / products / skincare / 113 / regenixir) and the assessment of SASP preventative efficacy by measuring the levels of TNF-α, IL-6, and IL-8 produced by untreated cells and cells treated with REGENIXIR. Figures 1A to 1C As observed, cells treated with Reginixir exhibited decreased expression levels of TNF-α, IL-6, and IL-8. Normal human fibroblasts were cultured with H2O2 for 1 hour. After H2O2 stress, the medium was removed and replaced with a medium containing the composition, and the cells were cultured at 37°C and 5% CO2 for 24 hours. This stress was repeated for seven days. The aging-associated secretory proteome (SASP) was then quantified using an ELISA kit specific for IL6, IL8, and TNFα. Results were normalized to total protein content.

[0088] Figure 2 This shows the results of a study on cells treated with REGENIXIR® (SiLab) and the assessment of SASP preventative efficacy by measuring the amount of MMP1 released from REGENIXIR-treated and untreated cells. Figure 2 As observed, senescent cells showed increased MMP1 release compared to non-senescent cells. Treatment of senescent cells with REGENIXIR induced a significant decrease in MMP1. Senescence of normal human dermal fibroblasts was induced through replicative senescence, based on the Hayflick model. Senescent cells were treated with the composition for 72 hours. Untreated senescent cells and untreated non-senescent cells were cultured under identical conditions. Matrix metalloproteinase-1 (MMP1) release was measured using a specific ELISA kit.

[0089] Figure 3 This illustrates studies conducted on cells treated with REGENIXIR® (SiLab) and results of testing senescence-related β-galactosidase activity (SA-β-gal) on REGENIXIR-treated and untreated cells. Figure 3 As observed, intracellular senescence-associated β-galactosidase activity was statistically reduced when cells were treated with the composition. Normal human dermal fibroblasts from aged donors were cultured and treated with the composition for 72 hours. Untreated cells were cultured under the same conditions. Intracellular senescence-associated β-galactosidase activity (SA-β-gal) was then quantified using the CellEvent Senescence Green assay kit.

[0090] Figure 4This diagram illustrates studies conducted on cells treated with REGENIXIR® (SiLab) and results testing the expression of secretory coil-associated protein 4 (SFRP4) in REGENIXIR-treated and untreated cells. Figure 4 As observed, a significant decrease in SFRP4 expression was observed in cells treated with the composition. Normal human dermal fibroblasts from aged donors were cultured and treated with the composition for 72 hours. Untreated cells were cultured under the same conditions. Secretory coil-associated protein 4 (SFRP4) was then quantified by immunostaining.

[0091] The effects of REGENIXIR® on cellular senescence were investigated in senescent normal human fibroblasts. Results showed a significant decrease in intracellular SA-β-gal activity and reduced expression of secretory coil-associated protein 4 (SFRP4). The SASP profile was also modulated with a significant decrease in the release of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-1 (MMP-1). REGENIXIR® allows for the treatment and / or prevention of cellular senescence and the modulation of SASP, thereby limiting its adverse effects on neighboring non-senescent cells.

[0092] Example 2

[0093] This study aims to investigate a dual approach of active ingredient blends to address cellular senescence through both inhibiting senostatic (also known as senomorphic) and senolytic cellular action.

[0094] method

[0095] The potential of blends containing biotechnologically active ingredients such as adenosine, Schisandra chinensis, and Saccharomyces cerevisiae extract to inhibit and eliminate senescent cells was tested.

[0096] To evaluate the dual approach, we used different techniques:

[0097] i) For the method of inhibiting senescent cells, artificially aged fibroblasts via the Hayflick method were used: SASP was measured by measuring the release of cytokines and matrix metalloproteinases using enzyme-linked immunosorbent assay (ELISA).

[0098] ii) For the method of eliminating senescent cells, senescent fibroblasts from mature donors were used: SFRP4 in normal human fibroblasts from mature donors was examined by immunostaining. Senescence-associated β-galactosidase activity (SA-β-gal) was quantified using the CellEvent Senescence Green assay kit.

[0099] result

[0100] Following treatment, in vitro results related to the inhibition of senescent cells showed that the SASP profile was significantly modulated as levels of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-1 (MMP-1) decreased.

[0101] Regarding its role in clearing senescent cells, experiments showed a significant decrease in intracellular SA-β-gal activity. There was also downregulation of secretory coil-associated protein 4 (SFRP4).

[0102] Discussion and Conclusion

[0103] This study demonstrates the potential of biotechnologically active compound blends derived from adenosine, Schisandra chinensis, and Saccharomyces cerevisiae extracts to modulate cellular senescence by: reducing the occupancy of senescent cells, as demonstrated by downregulation of β-galactosidase and SFRP4; and reducing SASP, as shown in SASP assays, as revealed by downregulation of SFRP4 in senescent fibroblasts, thereby limiting their adverse effects on neighboring non-senescent fibroblasts.

[0104] By minimizing cellular senescence, these active ingredients can help improve skin texture and slow down the skin aging process.

[0105] This anti-aging approach can be implemented in anti-aging skincare strategies, provided that active ingredients are allowed to work at their best, helping to increase healthy cells (regardless of aging) in their metabolic functions, particularly in collagen synthesis.

[0106] Example 3

[0107] Cosmetic / Dermatological Compositions

[0108] The cosmetic / dermatological composition according to the present invention comprises the following ingredients:

[0109]

[0110] Terms and conditions

[0111] Clause 1: A method for treating and / or preventing aging, comprising administering to a human or animal a therapeutically effective amount of a Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa.

[0112] Clause 2: A method for treating and / or preventing aging, comprising administering to a human or animal a therapeutically effective amount of a Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa, wherein aging is replicative aging, DNA damage-induced aging, or oncogene-induced aging.

[0113] Clause 3: A method for treating and / or preventing skin aging, comprising administering to a human or animal a therapeutically effective amount of a Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa.

[0114] Clause 4: A method for treating and / or preventing apparent signs of intrinsic skin aging, comprising administering to a human or animal a therapeutically effective amount of a Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa.

[0115] Clause 5: A method for treating and / or preventing age-related diseases in humans, comprising administering to a human or animal a therapeutically effective amount of a Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa.

[0116] Clause 6: The method described in Clause 5, wherein the age-related disease is cancer, heart disease, or dementia.

[0117] Article 7: A method for treating and / or preventing human diseases according to any one of Articles 1 to 6, comprising administering a pharmaceutical composition comprising a pharmaceutically effective amount of a Saccharomyces cerevisiae extract, said extract corresponding to a cytoplasmic fraction comprising an oligo-β-glucan with a molar mass between 2 and 5 kDa.

[0118] Clause 8: The method according to Clause 7, wherein the composition is for intravenous or parenteral administration, particularly intradermal or subcutaneous administration.

[0119] It should be understood that although the invention has been specifically disclosed by way of particular aspects and optional features, modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and such modifications and variations are considered to be within the scope of various aspects of the invention.

Claims

1. An active agent for cosmetic use in treating and / or preventing skin aging, wherein the agent is capable of inhibiting an aging-related secretory phenotype by: i) reducing the release of IL-6, IL-8, TNF-α and matrix metallopeptidase-1 (MMP1); ii) reducing the activity of β-galactosidase; iii) reducing the biosynthesis of secretory coil-associated protein 4 (SFRP4); and iv) reducing the expression of p21 in fibroblasts.

2. The cosmetic use according to claim 1, wherein the active agent is an extract of Saccharomyces cerevisiae, the extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa, and / or a fruit extract of Schisandra chinensis.

3. The cosmetic use according to claim 2, wherein skin aging includes apparent signs of intrinsic skin aging.

4. The cosmetic use according to claim 2, wherein the apparent signs of intrinsic skin aging include sunken cheeks and eye sockets; loss of skin firmness; sagging, thinning and dry skin; fine wrinkles; decreased elasticity; abnormal pigmentation; and graying and hair loss.

5. The cosmetic use according to claim 4, wherein the extract is present in a cosmetically suitable amount.

6. The cosmetic use according to claim 5, wherein the active agent further comprises an amount of adenosine suitable for cosmetic purposes.

7. An active agent for treating and / or preventing skin aging or age-related diseases in humans in a therapeutically effective amount, wherein the agent is capable of inhibiting an aging-related secretory phenotype by: i) reducing the release of IL-6, IL-8, TNF-α and matrix metallopeptidase-1 (MMP1); ii) reducing the activity of β-galactosidase; iii) reducing the biosynthesis of secretory coil-associated protein 4 (SFRP4); and iv) reducing the expression of p21 in fibroblasts.

8. The therapeutically effective amount of the active agent for use according to claim 7, wherein the active agent is an extract of Saccharomyces cerevisiae corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa, and / or a fruit extract of Schisandra chinensis.

9. The therapeutically effective amount of the active agent according to claim 8, wherein the active agent further comprises adenosine.

10. The therapeutically effective amount for use according to any one of claims 7 to 9, wherein aging is replicative aging, DNA damage-induced aging, or oncogene-induced aging.

11. The therapeutically effective amount for use according to any one of claims 7 to 9, wherein the age-related disease is cancer, heart disease, or dementia.

12. A cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of an extract of *Saccharomyces cerevisiae*, said extract corresponding to a cytoplasmic fraction comprising oligo-β-glucan with a molar mass between 2 and 5 kDa, and a fruit extract of *Schisandra chinensis*.

13. The cosmetic or pharmaceutical composition according to claim 12, further comprising adenosine.

14. The cosmetic or pharmaceutical composition according to any one of claims 12 or 13, wherein the Saccharomyces cerevisiae extract is present in an amount of at least 0.00025% by weight, preferably between 0.001% and 2%, more preferably between 0.01% and 1%, even more preferably between 0.025% and 0.5%, even more preferably between 0.05% and 0.1%, and most preferably 0.0625% by weight of the whole composition, the extract corresponding to a cytoplasmic fraction containing oligo-β-glucan with a molar mass between 2 and 5 kDa.

15. The cosmetic or pharmaceutical composition according to any one of claims 12 to 14, wherein the composition is in the form of: oil-in-water emulsion, water-in-oil emulsion, multiple emulsion (water / oil / water or oil / water / oil), microemulsion, nanoemulsion, solution, suspension, aqueous dispersion, gel, ointment, paste, aerosol foam, spray, hydrogel, powder, foundation, transdermal patch, cream, or mask.

16. The cosmetic or pharmaceutical composition according to any one of claims 12 to 15, wherein the composition is for intravenous or parenteral application, particularly intradermal or subcutaneous application.

17. The cosmetic or pharmaceutical composition of claim 13, comprising:

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