Composition

Abstract

The present invention relates to compositions, particularly topical compositions comprising a urolithin, cosmetic compositions comprising a urolithin, cosmetic compositions comprising a urolithin and trehalose, and compositions comprising a urolithin and niacinamide (nicotinamide), as well as compositions comprising a urolithin, trehalose, niacinamide and caffeine. Additionally, the present invention relates to urolithins for use in improving skin barrier function, for example, maintaining skin hydration, improving skin elasticity and firmness, and / or increasing or maintaining the thickness of the skin layer.

Description

[Technical field]

[0001] The present invention relates to compositions, particularly topical compositions comprising a urolithin, cosmetic compositions comprising a urolithin, and cosmetic compositions comprising a urolithin and trehalose, compositions comprising a urolithin and niacinamide (nicotinamide), and compositions comprising a urolithin, trehalose, niacinamide and caffeine. Furthermore, the present invention relates to urolithins for use in improving skin barrier function, for example, maintaining skin hydration, improving skin elasticity and firmness, and / or increasing or maintaining the thickness of the skin layer. Prior Art

[0002] The main function of the skin is to form a barrier between the host's internal environment and environmental insults such as chemicals, ultraviolet light, mechanical injury, and pathogenic microorganisms. The structure of the skin is composed of layers of cells and tissue derived from cells, with the outermost set of layers being the epidermis. The superficial layer is called the stratum corneum, followed inwards by the stratum granulosum, stratum spinosum, stratum basale, and stratum dermis. In addition, on the palms of the hands and soles of the feet, there is an additional layer between the stratum corneum and stratum granulosum, called the stratum lucidum. Numerous products have been developed to improve the function and / or appearance of skin and hair.

[0003] For example, in 2016, the beauty and personal care market was a nearly $500 billion industry. Repeated exposure to environmental insults such as the sun causes thinning, fragility and wrinkling of the skin. More severe sun exposure can cause loss of skin elasticity, deep wrinkles, increased roughness and dryness, and changes in pigmentation (age spots, skin blemishes). The skin can also become leathery and thick in appearance, which is characterized by deep grooves. Other environmental insults, such as chemicals causing burns and / or injuries, acne or viral infections (e.g., chickenpox), can cause scarring and lead to even more severe and permanent damage to the skin.

[0004] Additionally, the disease can also change the appearance of the skin. For example, lupus patients often exhibit a distinctive rash called a "butterfly rash" that spreads across the patient's face.

[0005] Furthermore, the strength and integrity of the skin, particularly with respect to its ability to respond to environmental stresses and / or resist disease, generally declines with age.

[0006] Urolithins have been proposed as treatments for a variety of conditions associated with insufficient mitochondrial activity, such as obesity, reduced metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive disorders, mood disorders, stress, and anxiety disorders, for weight management, or to enhance muscle or mental performance, see WO2012 / 088519 (Amazentis SA).

[0007] US Patent Publication No. 2013 / 0133666 (derived from Application No. PCT / US2013 / 48310) discloses a method of increasing autophagy, particularly including mitophagy, in a cell comprising contacting a cell with an effective amount of a urolithin or a pharma- ceutically acceptable salt thereof, thereby increasing autophagy, particularly including mitophagy, in the cell. Administration may be to a subject having a disease or condition selected from metabolic stress, cardiovascular disease, endothelial cell dysfunction, sarcopenia, muscle degenerative disease, Duchenne muscular dystrophy, alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver damage or muscle injury, alpha 1-antitrypsin deficiency, ischemia / reperfusion injury, inflammation, skin aging, inflammatory bowel disease, Crohn's disease, obesity, metabolic syndrome, type II diabetes, hyperlipidemia, osteoarthritis, neurodegenerative disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, age-related macular degeneration, mitochondrial disease (e.g., poor growth, muscle weakness, muscle weakness, vision problems, hearing problems, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory diseases, neurological problems, autonomic dysfunction, sometimes learning disabilities, and dementia (as a result of mitochondrial disease), muscle disease, cancer, cognitive disorders, stress, and mood disorders.

[0008] There are many different skin care formulations that are advertised to improve the appearance of skin, regardless of the type of skin damage. Examples of such formulations include retinol, hydroxyl acids, and coenzyme Q. 10 These include, but are not limited to, urolithins, copper peptides, kinetin and / or tea extracts. Numerous creams, oils, topicals and oral preparations are launched every month, but new regimens that are safe and effective for improving the function of the subject's largest organ, the skin, are constantly sought. For example, retinoids show promise in treating skin aging, but irritant reactions such as burning, scaling or dermatitis associated with retinoid therapy limit patient acceptance. Although several uses of urolithins have been disclosed for the skin, the inventors have discovered improved formulations and combinations for use on the skin, particularly for cosmetic applications, as well as novel uses of urolithins for improving skin barrier function. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2014 / 004902 Summary of the Invention

[0010] (1) Composition containing trehalose and / or NAD precursor The present invention relates to a) trehalose, b) a composition comprising a compound of formula (I) or a salt thereof. [ka] During the ceremony, A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; Z is selected from H and OH.

[0011] In a further embodiment of the present invention, there is provided a composition comprising niacinamide (nicotinamide) and a compound of formula (I) above or a salt thereof.

[0012] In a further embodiment of the invention, there is provided a composition comprising an NAD precursor and a compound of formula (I) above or a salt thereof, wherein the NAD precursor is selected from nicotinic acid (niacin), niacinamide (nicotinamide), tryptophan, nicotinamide mononucleotide and nicotinamide riboside.

[0013] In a further embodiment of the present invention, there is provided a composition comprising trehalose, niacinamide (nicotinamide) and a compound of formula (I) above or a salt thereof.

[0014] In a further embodiment, there is provided a composition comprising trehalose, an NAD precursor, and a compound of formula (I) above or a salt thereof.

[0015] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor, such as a cream or lotion, comprising about 0.8% to about 2.0% of a compound of formula (I), such as urolithin A.

[0016] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor, such as a cream or lotion, comprising about 0.8% to about 1.5% of a compound of formula (I), such as urolithin A.

[0017] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor, such as a cream or lotion, comprising about 0.8% to about 1.2% of a compound of formula (I), such as urolithin A.

[0018] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor, such as a cream or lotion, comprising about 1% of a compound of formula (I), such as urolithin A.

[0019] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor for use in the treatment of one or more of the indications described herein.

[0020] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor for use as a cosmetic.

[0021] In a further embodiment, there is provided a method of cosmetically treating the skin using a composition of the invention comprising a compound of formula (I) and trehalose and / or an NAD precursor.

[0022] A method for the cosmetic treatment of the skin using an effective amount of a cosmetic composition comprising a compound of formula (I) and trehalose and / or an NAD precursor.

[0023] Use of a compound of formula (I) and trehalose and / or an NAD precursor as a cosmetic.

[0024] A non-therapeutic use of a cosmetic formulation comprising a compound of formula (I) and trehalose and / or an NAD precursor.

[0025] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) a NAD precursor, such as niacinamide, and

[0026] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; and d) caffeine.

[0027] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; d) a B vitamin, such as D-panthenol, is provided.

[0028] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; d) Nopah flower extract (Opuntia ficus indica).

[0029] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; and d) isomerized sugar syrup.

[0030] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; d) a Nicotiana sylvestris leaf cell culture.

[0031] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; d) Nicotiana sylvestris leaf cell cultures; and e) isomerized sugar.

[0032] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; d) Nopah flower extract (Opuntia ficus-indica); e) caffeine, f) isomerized sugar; g) a B vitamin, such as D-panthenol, is provided.

[0033] In a further embodiment, a) a compound of formula (I), such as urolithin A; b) trehalose, c) an NAD precursor, such as niacinamide; d) caffeine, e) a B vitamin, such as D-panthenol, is provided.

[0034] In a further embodiment, a) a compound of formula (I), such as urolithin A, said compound of formula (I) comprising 0.8% to 5% (w / w) of the composition; b) trehalose, said trehalose comprising 0.05% to 6% (w / w) of the composition; c) an NAD precursor, such as niacinamide, wherein the niacinamide constitutes 0.1% to 10% (w / w) of the composition.

[0035] In a further embodiment, a) a compound of formula (I), such as urolithin A, said compound of formula (I) comprising 0.8% to 4% (w / w) of the composition; b) trehalose, said trehalose comprising 0.1% to 0.8% (w / w) of the composition; c) an NAD precursor, such as niacinamide, wherein the niacinamide constitutes 0.5% to 8% (w / w) of the composition.

[0036] In a further embodiment, a) a compound of formula (I), such as urolithin A, said compound of formula (I) comprising 0.8% to 3% (w / w) of the composition; b) trehalose, the trehalose comprising 0.1% to 0.7% (w / w) of the composition; c) an NAD precursor, such as niacinamide, wherein the niacinamide constitutes 0.5% to 6% (w / w) of the composition.

[0037] In a further embodiment, a) a compound of formula (I), e.g. urolithin A, said compound of formula (I) comprising 0.8% to 2% (w / w) of the composition; b) trehalose, said trehalose comprising 0.1% to 0.5% (w / w) of the composition; c) an NAD precursor, such as niacinamide, wherein the niacinamide constitutes 0.5% to 5% (w / w) of the composition.

[0038] In a further embodiment, a) a compound of formula (I), e.g. urolithin A, wherein said compound of formula (I) comprises about 1% (w / w) of the composition; b) trehalose, said trehalose comprising about 0.25% (w / w) of the composition; c) an NAD precursor, such as niacinamide, wherein the niacinamide constitutes about 1% to 3% (w / w) of the composition.

[0039] In a further embodiment, a) a compound of formula (I), such as urolithin A, said compound of formula (I) comprising 0.8% to 5% (w / w) of the composition; b) trehalose, said trehalose comprising 0.05% to 1% (w / w) of the composition; c) an NAD precursor, such as niacinamide, comprising 0.1% to 10% (w / w) of the composition; d) an antioxidant / blood circulation enhancer, e.g. caffeine, wherein the antioxidant / blood circulation enhancer, e.g. caffeine, constitutes 0.1% to 5% (w / w) of the composition.

[0040] In a further embodiment, a) a compound of formula (I), such as urolithin A, said compound of formula (I) comprising 0.8% to 4% (w / w) of the composition; b) trehalose, said trehalose comprising 0.1% to 0.8% (w / w) of the composition; c) an NAD precursor, such as niacinamide, comprising 0.5% to 8% (w / w) of the composition; d) an antioxidant / blood circulation enhancer, e.g. caffeine, wherein the antioxidant / blood circulation enhancer, e.g. caffeine, constitutes 0.1% to 3% (w / w) of the composition.

[0041] In a further embodiment, a) a compound of formula (I), such as urolithin A, said compound of formula (I) comprising 0.8% to 3% (w / w) of the composition; b) trehalose, the trehalose comprising 0.1% to 0.7% (w / w) of the composition; c) an NAD precursor, such as niacinamide, comprising 0.5% to 6% (w / w) of the composition; d) an antioxidant / blood circulation enhancer, e.g. caffeine, wherein the antioxidant / blood circulation enhancer, e.g. caffeine, constitutes 0.1% to 2% (w / w) of the composition.

[0042] In a further embodiment, a) a compound of formula (I), e.g. urolithin A, said compound of formula (I) comprising 0.8% to 2% (w / w) of the composition; b) trehalose, said trehalose comprising 0.1% to 0.5% (w / w) of the composition; c) an NAD precursor, such as niacinamide, comprising 0.5% to 5% (w / w) of the composition; d) an antioxidant / blood circulation enhancer, e.g. caffeine, wherein the antioxidant / blood circulation enhancer, e.g. caffeine, constitutes 0.1% to 1% (w / w) of the composition.

[0043] In a further embodiment, a) a compound of formula (I), e.g. urolithin A, wherein said compound of formula (I) comprises about 1% (w / w) of the composition; b) trehalose, said trehalose comprising about 0.25% (w / w) of the composition; c) an NAD precursor, such as niacinamide, comprising about 1% to 3% (w / w) of the composition; and d) an antioxidant / blood circulation enhancer, such as caffeine, wherein the antioxidant / blood circulation enhancer, such as caffeine, constitutes about 0.5% (w / w) of the composition.

[0044] Examples of antioxidants / blood circulation enhancers include caffeine, green tea (Camellia japonica leaf extract), Vitamin C, Vitamin K, and Vitamin E. In further embodiments, the compositions of the present invention contain Vitamin C in an amount of about 0.1% to about 5% (w / w), about 0.5% to about 2% (w / w), about 0.7% to 1.5% (w / w), or about 1% of the composition. In further embodiments, the compositions of the present invention contain Vitamin K in an amount of about 0.5% to about 10% (w / w), about 1% to about 8% (w / w), about 2% to 7% (w / w), about 4% to about 6% (w / w), or about 5% (w / w) of the composition. In further embodiments, the compositions of the present invention contain Vitamin E in an amount of about 0.5% to about 10% (w / w), about 1% to about 8% (w / w), about 2% to 7% (w / w), about 4% to about 6% (w / w), or about 5% (w / w) of the composition.

[0045] In further embodiments, the compositions of the invention comprise a compound of formula (1) in an amount of about 0.8% to about 5% (w / w), about 0.8% to about 4% (w / w), about 0.8% to about 3% (w / w), about 0.8% to about 2% (w / w), about 0.8% to about 1% (w / w), or about 1% (w / w).

[0046] In further embodiments, the compositions of the present invention are from about 0.05% to about 8% (w / w), from about 0.1% to about 6% (w / w), from about 0.1% to about 5% (w / w), from about 0.1% to about 4% (w / w), from about 0.1% to about 3% (w / w), from about 0.1% (w / w) to about 2% (w / w), from about 0.1% to about 0.9% (w / w), from about 0.1% to about 0.8% (w / w), from about 0.1% to about 0. The composition contains trehalose in an amount of about 7% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.2% to about 0.3% (w / w), or about 0.25% (w / w), or about 0.5% (w / w), about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), or about 5% (w / w).

[0047] In further embodiments, the compositions of the invention comprise an NAD precursor in an amount of about 0.1% to about 10% (w / w), 0.25% to about 9% (w / w), 0.25% to about 8% (w / w), 0.5% to about 7% (w / w), 0.5% to about 6% (w / w), 0.5% to about 5% (w / w), 0.5% to about 4% (w / w), 1% to about 4% (w / w), 1% to about 3% (w / w), about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), or about 5% (w / w).

[0048] In further embodiments, the compositions of the present invention comprise an antioxidant / blood circulation enhancer, such as caffeine, in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 3% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1% (w / w), about 0.2% to about 0.9% (w / w), about 0.3% to about 0.8% (w / w), about 0.3% to about 0.7% (w / w), about 0.3% to about 0.6% (w / w), about 0.4% to about 0.6% (w / w), or about 0.5% (w / w).

[0049] In further embodiments, the compositions of the present invention comprise a B vitamin, such as D-panthenol, in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 3% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 2% (w / w), about 1% (w / w), or about 0.5% (w / w).

[0050] In further embodiments, the compositions of the present invention include nopa flower extract (Opuntia ficus-indica) in an amount of about 0.05% to about 0.2% (w / w), about 0.05% to about 0.15% (w / w), about 0.075 to about 0.125% (w / w), about 0.075 to about 0.1% (w / w), or about 0.1% (w / w). The nopa flower extract can include one or more of hydrolyzed Opuntia ficus-indica flower extract, Opuntia ficus-indica stem extract, and Opuntia ficus-indica callus culture extract.

[0051] In further embodiments, the compositions of the present invention contain isomerized sugar in an amount of about 0.5% to about 5% (w / w), about 0.5% to about 4% (w / w), 0.5% to about 3% (w / w), 0.5% to about 2% (w / w), about 0.825% (w / w), about 1.65% (w / w), or about 2.75% (w / w).

[0052] In further embodiments, the compositions of the invention comprise Nicotiana sylvestris leaf cell culture in an amount of about 0.0005% to about 0.005% (w / w), about 0.0005% to about 0.004% (w / w), about 0.0005% to about 0.004% (w / w), about 0.0005% to about 0.003% (w / w), about 0.001% to about 0.002% (w / w), or about 0.0015% (w / w).

[0053] (2) A composition comprising a compound of formula (I), a further autophagy inducer, and a mitochondrial biogenesis promoter. In a further embodiment of the invention, (a) a compound of formula (I) as defined above or a salt thereof, such as urolithin A; (b) a further autophagy inducer, e.g., trehalose; (c) Compositions are provided that include a combination with a mitochondrial biogenesis enhancer, such as a nicotinamide adenine dinucleotide precursor, such as niacinamide.

[0054] In a further embodiment of the invention, (a) a compound of formula (I) as defined above or a salt thereof; (b) Further autophagy inducers, (c) a mitochondrial biogenesis promoter.

[0055] In a further embodiment of the invention, (a) a compound of formula (I) as defined above or a salt thereof, such as urolithin A; (b) a further autophagy inducer, e.g., trehalose; (c) a mitochondrial biogenesis promoter, such as a nicotinamide adenine dinucleotide precursor, such as niacinamide; (d) Compositions are provided that include a combination with an antioxidant / blood circulation enhancer, such as caffeine.

[0056] In a further embodiment of the invention, (a) a compound of formula (I) or a salt thereof, such as urolithin A, in which the compound of formula (I) accounts for 0.8% to 5% (w / w) of the composition; (b) a further autophagy inducer, e.g., trehalose, wherein the autophagy inducer comprises 0.05% to 1% (w / w) of the composition; and (c) A composition is provided comprising a combination of a mitochondrial biogenesis enhancer, such as a nicotinamide adenine dinucleotide precursor, such as niacinamide, wherein the mitochondrial biogenesis enhancer comprises 0.1% to 10% (w / w) of the composition.

[0057] In a further embodiment of the invention, (a) a compound of formula (I) or a salt thereof, such as urolithin A, in which the compound of formula (I) accounts for 0.8% to 5% (w / w) of the composition; (b) a further autophagy inducer, e.g., trehalose, wherein the autophagy inducer comprises 0.05% to 1% (w / w) of the composition; and (c) a mitochondrial biogenesis enhancer, such as a nicotinamide adenine dinucleotide precursor, such as niacinamide, the mitochondrial biogenesis enhancer comprising 0.1% to 10% (w / w) of the composition; (d) There is provided a composition comprising a combination of an antioxidant / blood circulation enhancer, such as caffeine, wherein the antioxidant / blood circulation enhancer comprises 0.1% to 5% (w / w) of the composition.

[0058] Examples of autophagy inducers include, but are not limited to, carbamazepine, clonidine, lithium, metformin, rapamycin (and rapalogs), rilmenidine, sodium valproate, verapamil, trifluoperazine, statins, tyrosine kinase inhibitors (e.g., Akt-mTOR signaling inhibitors and Beclin 1 tyrosine phosphorylation inhibitors), BH3 mimetics, caffeine, omega-3 polyunsaturated fatty acids, resveratrol, spermidine, vitamin D pterostilbene, physteine, genistein, quercetin, apigenin, kaempferol, minoxidil, actinonin, kinetin triphosphate, pifithrin-a, deferiprone, 1,10'-phenanthroline, and trehalose, such as trehalose.

[0059] Examples of mitochondrial biogenesis promoters include PPAR-PGC-1α axis activators (e.g., bezafibrate), AMPK activators (e.g., resveratrol), Sirt1 agonists (e.g., quercetin, resveratrol), antioxidants (L-carnitine, coenzyme Q 10 , MitoQ 10and other mitochondrially targeted antioxidants, such as N-acetylcysteine ​​(NAC), vitamin C, vitamin E, vitamin K1, vitamin B, sodium pyruvate and alpha-lipoic acid, and NAD precursors (e.g., niacinamide).

[0060] The compound of formula (I) is a member of the urolithin family, in particular, the compound of formula (I) may be urolithin A, urolithin B, urolithin C or urolithin D. In one embodiment, the compound of formula (I) is urolithin A.

[0061] In further embodiments, the compositions of the invention comprise a compound of formula (1) in an amount of about 0.8% to about 5% (w / w), about 0.8% to about 4% (w / w), about 0.8% to about 3% (w / w), about 0.8% to about 2% (w / w), about 0.8% to about 1% (w / w), or about 1% (w / w).

[0062] In further embodiments, compositions of the invention comprise an autophagy inhibitor in an amount of about 0.05% to about 1%, about 0.1% to about 0.9%, about 0.1% to about 0.8%, about 0.1% to about 0.7%, about 0.1% to about 0.5%, about 0.1% to about 0.4%, about 0.1% to about 0.35%, about 0.2% to about 0.3%, or about 0.25%.

[0063] In further embodiments, the compositions of the present invention comprise a mitochondrial biogenesis enhancer in an amount of about 0.1% to about 10% (w / w), about 0.25% to about 9% (w / w), about 0.25% to about 8% (w / w), about 0.5% to about 7% (w / w), about 0.5% to about 6% (w / w), about 0.5% to about 5% (w / w), about 0.5% to about 4% (w / w), about 1% to about 4% (w / w), about 1% to about 3% (w / w), about 1% (w / w), about 2% (w / w), about 3% (w / w), about 4% (w / w), or about 5% (w / w).

[0064] In further embodiments, the compositions of the invention comprise a central nervous system stimulant, e.g., caffeine, in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 3% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1% (w / w), about 0.2% to about 0.9% (w / w), about 0.3% to about 0.8% (w / w), about 0.3% to about 0.7% (w / w), about 0.3% to about 0.6% (w / w), about 0.4% to about 0.6% (w / w), or about 0.5% (w / w).

[0065] The compositions of the present invention are suitable for both cosmetic and medical applications.

[0066] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I), an additional autophagy inducer, and a mitochondrial biogenesis enhancer, such as a cream or lotion, comprising about 0.8 to about 2.0% of a compound of formula (I), such as urolithin A.

[0067] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I), an additional autophagy inducer, and a mitochondrial biogenesis enhancer, such as a cream or lotion, comprising about 0.8 to about 1.5% of a compound of formula (I), such as urolithin A.

[0068] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I), an additional autophagy inducer, and a mitochondrial biogenesis enhancer, such as a cream or lotion, comprising about 0.8 to about 1.2% of a compound of formula (I), such as urolithin A.

[0069] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I) and an additional autophagy inducer and a mitochondrial biogenesis enhancer, e.g., a cream or lotion, comprising about 1% of a compound of formula (I), e.g., urolithin A.

[0070] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising a compound of formula (I), an additional autophagy inducer, and a mitochondrial biogenesis enhancer, for use in the treatment of one or more of the indications described herein.

[0071] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising a compound of formula (I), a further autophagy inducer, and a mitochondrial biogenesis enhancer, for use in the treatment of one or more of the indications described herein, said one or more indications being: (a) Acne, (b) Contact dermatitis (c) eczema; (d) psoriasis; (e) Rosacea, (f) lupus erythematosus, (g) warts, (h) Shingles, (i) hives, (j) brown spots; (k) Melasma, (l) Kuroko, (m) dermatitis; (n) skin infection; (o) skin inflammation; (p) seborrheic dermatitis, (q) fungal skin infections (e.g., candidiasis, tinea pedis), (r) skin cancer; (s) Diaper rash is selected.

[0072] In a further embodiment, there is provided a composition of the invention which is injectable and further comprises collagen and / or hyaluronic acid.

[0073] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising a compound of formula (I), such as urolithin A, and a further autophagy inducer, such as trehalose, and a mitochondrial biogenesis enhancer, such as an NAD precursor, for use to enhance anti-wrinkle efficacy.

[0074] For the avoidance of doubt, compositions of the present invention may comprise one or more autophagy inducers and one or more mitochondrial biogenesis enhancers.

[0075] In a further embodiment, there is provided a method of cosmetically treating the skin using a composition of the invention comprising a compound of formula (I), an additional autophagy inducer, and a mitochondrial biogenesis enhancer.

[0076] A method for the cosmetic treatment of the skin using an effective amount of a cosmetic composition comprising a compound of formula (I), a further autophagy inducer, and a mitochondrial biogenesis promoter.

[0077] The use of a compound of formula (I) together with further autophagy inducers and mitochondrial biogenesis promoters as a cosmetic agent.

[0078] A non-therapeutic use of a cosmetic formulation comprising a compound of formula (I) and a further autophagy inducer and a mitochondrial biogenesis promoter.

[0079] 4) Use of the compounds of formula (I) In a further embodiment of the invention, (a) To improve or maintain skin barrier function, (b) To limit transepidermal water loss, (c) To improve skin elasticity and firmness, (d) to increase or maintain the thickness of the skin layer; (e) increasing or maintaining the topographic index of the dermal-epidermal junction of the skin; (f) to increase or maintain hydration of the skin; (g) To reduce biological aging of the skin; (h) reducing the appearance of fine lines and wrinkles; (i) To reduce radiation-induced skin damage, e.g. UV radiation-induced skin damage, (j) to protect the skin against damage caused by radiation, such as UV, beta or gamma radiation, including during the medical treatment of conditions such as cancer; (k) To reduce hair damage caused by radiation, e.g., skin damage caused by UV radiation, (l) to protect hair from damage caused by radiation, such as UV, beta or gamma radiation, including during medical treatment of conditions such as cancer; (m) To improve collagen tissue in the skin; (n) To improve the skin matrix, (o) To improve the physical properties of the skin; (p) To reduce redness of the skin caused by sunlight, (q) / To protect against photoaging caused by sunlight, (r) to treat or prevent skin infections; and / or (s) Compositions of the invention, such as compositions comprising Urolithin A, are provided for one or more of the following uses for treating or preventing skin cancer.

[0080] In a further embodiment of the invention, (a) regenerating and / or revitalizing the appearance of the skin; (b) enhancing the skin's energy supply; (c) improving skin texture; (d) improved skin radiance; (e) skin rejuvenation, (f) reduced visibility of pores and fine lines; (g) Improved skin respiration, (h) supporting optimal cellular function in the skin; (i) Promoting / activating the skin's detoxification processes; (j) promoting collagen repair; and / or (k) There is provided a composition of the invention, such as a composition comprising Urolithin A, for one or more uses in improving skin stem cell health.

[0081] In a further embodiment of the invention, (a) regenerating and / or revitalizing the appearance of the skin; (b) enhancing the skin's energy supply; (c) improving skin texture; (d) improved skin radiance; (e) skin rejuvenation / regeneration; (f) reduced visibility of pores and fine lines; (g) Improved skin respiration, (h) supporting optimal cellular function in the skin; (i) Promoting / activating the skin's detoxification processes; (j) promoting collagen repair; and / or (k) There is provided a composition of the invention, such as a composition comprising Urolithin A, for one or more uses in improving skin stem cell health.

[0082] In a further embodiment of the invention, a) To maintain the skin barrier function b) To limit transepidermal water loss c) To improve skin elasticity and firmness, d) To increase or maintain the thickness of the skin layer e) to increase or maintain skin hydration; f) To improve the anti-wrinkle effect, g) To improve collagen tissue in the skin; h) To promote collagen production i) To maintain plump, youthful looking skin j) To reduce biological aging of the skin k) Improve skin health; l) To reduce puffiness of the skin and dark circles under the eyes; and / or m) there is provided a composition of the invention, e.g. a composition comprising urolithin A, for one or more of the following uses for improving the microstructure of the skin;

[0083] In a further embodiment of the invention, a) improve skin healthspan; and / or b) There is provided a composition of the invention, e.g. a composition comprising urolithin A, for one or more of the following uses: improving the longevity of skin;

[0084] In a further embodiment of the invention, (a) Maintaining or increasing hair thickness, (b) regeneration of hair root cells; (c) survival of root hair cells; (d) hair stem cell growth and / or regeneration; (e) hair cell survival, (f) prevention of hair loss, (g) Hair maintenance, (h) improving scalp health; (i) improving or maintaining hair strength, and / or (j) There is provided a composition of the invention, for example a composition comprising Urolithin A, for one or more uses in promoting hair growth restoration.

[0085] In a further embodiment of the invention, a) Maintaining or increasing hair thickness, b) regeneration of hair root cells, c) survival of root hair cells; d) hair stem cell growth and / or regeneration; e) hair cell survival, f) Hair loss prevention, g) Improved scalp health, and / or h) a composition of the invention, e.g. a composition comprising urolithin A, for one or more of the following uses: promoting hair growth restoration

[0086] In a further embodiment, a) Maintaining or increasing hair thickness, b) regeneration of hair root cells, c) survival of root hair cells; d) hair stem cell growth and / or regeneration; e) hair cell survival, f) Hair loss prevention, g) promoting the growth of new hair; h) Improved scalp health, i) improving hair transplant survival; and / or j) A method for promoting hair growth restoration is provided.

[0087] In a further embodiment of the invention, a) Enhancement of hair stem cell function, b) Enhancement of hair follicle elongation; c) promoting hair matrix cell proliferation, e.g., as measured by Ki67 levels; d) Prolongation of the hair growth phase (prolongation of the duration of the later phase), e) Hair matrix cell proliferation, f) inhibition of hair matrix cell apoptosis, and g) There is provided a composition of the invention, e.g. a composition comprising urolithin A, for one or more of the following uses: reducing melanin aggregation in pigmentary units, such as hair follicular pigmentary units.

[0088] In a further embodiment of the present invention, there is provided a method for reducing biological aging of the skin, thus providing a composition of the present invention for reducing the biological age of the skin by 5 years or more, such as 2 years or more, such as 3 years or more, such as 4 years or more, such as 8 years or more, or such as 10 years or more.

[0089] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 2.0% of a compound of formula (I), such as Urolithin A, for one or more of the applications described herein.

[0090] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.5% of a compound of formula (I), such as urolithin A, for one or more of the applications described herein.

[0091] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.2% of a compound of formula (I), such as urolithin A, for one or more of the applications described herein.

[0092] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 1% of a compound of formula (I), such as Urolithin A, for one or more of the applications described herein.

[0093] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 2.0% of a compound of formula (I), such as Urolithin A, which use is to reduce intrinsic and / or extrinsic aging.

[0094] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.5% of a compound of formula (I), such as Urolithin A, which use is to reduce intrinsic and / or extrinsic aging.

[0095] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.2% of a compound of formula (I), such as Urolithin A, which use is to reduce intrinsic and / or extrinsic aging.

[0096] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 1% of a compound of formula (I), such as Urolithin A, which use is to reduce intrinsic and / or extrinsic ageing.

[0097] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 2.0% of a compound of formula (I), such as Urolithin A, which use is to reduce photoaging.

[0098] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.5% of a compound of formula (I), such as urolithin A, which use is to reduce photoaging.

[0099] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.2% of a compound of formula (I), such as Urolithin A, which use is to reduce photoaging.

[0100] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 1% of a compound of formula (I), such as Urolithin A, which use is to reduce photoageing.

[0101] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 2.0% of a compound of formula (I), such as Urolithin A, to reduce skin inflammation caused by ultraviolet light exposure, such as ultraviolet B light (UVB).

[0102] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.5% of a compound of formula (I), such as Urolithin A, in reducing skin inflammation caused by ultraviolet light exposure, such as ultraviolet B light (UVB).

[0103] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.2% of a compound of formula (I), such as Urolithin A, in reducing skin inflammation caused by ultraviolet light exposure, such as ultraviolet B light (UVB).

[0104] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 1% of a compound of formula (I), such as Urolithin A, in reducing skin inflammation caused by ultraviolet light exposure, such as ultraviolet B light (UVB).

[0105] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 2.0% of a compound of formula (I), such as Urolithin A, which use is to reduce oxidative stress in the skin.

[0106] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.5% of a compound of formula (I), such as Urolithin A, which use is to reduce oxidative stress in the skin.

[0107] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), such as a cream or lotion comprising about 0.8 to about 1.2% of a compound of formula (I), such as Urolithin A, which use is to reduce oxidative stress in the skin.

[0108] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), for example a cream or lotion comprising about 1% of a compound of formula (I), such as Urolithin A, which use is to reduce oxidative stress in the skin.

[0109] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), for example a cream or lotion comprising about 0.8 to about 2.0% of a compound of formula (I), such as Urolithin A, which use is to improve skin health.

[0110] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), for example a cream or lotion comprising about 0.8 to about 1.5% of a compound of formula (I), such as Urolithin A, which use is to improve skin health.

[0111] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), for example a cream or lotion comprising about 0.8 to about 1.2% of a compound of formula (I), such as Urolithin A, which use is to improve skin health.

[0112] In a further embodiment, there is provided the use of a composition of the invention comprising a compound of formula (I), for example a cream or lotion comprising about 1% of a compound of formula (I), such as Urolithin A, which use is to improve skin health.

[0113] The present invention further provides a novel use for improving skin barrier function.

[0114] In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in improving or maintaining skin barrier function.

[0115] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for improving or maintaining skin barrier function.

[0116] In a further embodiment, there is provided a method of improving or maintaining skin barrier function comprising administering an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0117] In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the treatment of a disease or condition associated with disruption of the skin barrier.

[0118] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for the treatment of a disease or condition associated with disruption of the skin barrier.

[0119] In a further embodiment, there is provided a method of use for treating a disease or condition associated with disruption of the skin barrier comprising administering an effective amount of a compound of formula (I) or a salt thereof, such as Urolithin A.

[0120] Examples of diseases or conditions associated with the breakdown of the skin barrier include, but are not limited to, atopic eczema, atopic dermatitis, acne, aging skin, dry skin, cutaneous side effects of certain chronic medications, and pruritus.

[0121] In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in increasing or maintaining skin hydration.

[0122] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for increasing or maintaining skin hydration.

[0123] In a further embodiment, there is provided a method for use in increasing or maintaining skin hydration comprising administering an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0124] In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the prevention and / or treatment of transepidermal water loss (TEWL).

[0125] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for the prevention and / or treatment of transepidermal water loss.

[0126] In a further embodiment, there is provided a method of preventing and / or treating transepidermal water loss comprising administering an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0127] In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in improving skin elasticity and / or firmness.

[0128] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for improving skin elasticity and / or firmness.

[0129] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a cosmetic product for improving skin elasticity and / or firmness.

[0130] In a further embodiment, there is provided a composition of the invention comprising a compound of formula (I), such as urolithin A, for use as a cosmetic for one or more of the applications described herein.

[0131] In a further embodiment, there is provided a method of cosmetically treating the skin using a composition of the invention comprising a compound of formula (I) for use in one or more applications as described herein.

[0132] A method of cosmetic treatment of the skin using an effective amount of a cosmetic composition comprising a compound of formula (I) for use in one or more of the applications described herein.

[0133] The use of a compound of formula (I) as a cosmetic for use in one or more of the applications described herein.

[0134] The non-therapeutic use of a cosmetic formulation comprising a compound of formula (I) for use in one or more of the applications described herein.

[0135] In a further embodiment, there is provided a method of improving skin elasticity and / or firmness comprising administering an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0136] In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in increasing or maintaining the thickness of the skin layer.

[0137] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for increasing or maintaining the thickness of the skin layer.

[0138] In a further embodiment, there is provided a method of increasing or maintaining the thickness of the skin layer comprising administering an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0139] In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in increasing or maintaining the topographic index of the dermal-epidermal junction of the skin.

[0140] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a medicament for increasing or maintaining the topographic index of the dermal-epidermal junction of the skin.

[0141] In a further embodiment, the present invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for use in the manufacture of a cosmetic product for increasing or maintaining the shape index of the dermal-epidermal junction of the skin.

[0142] In a further embodiment, there is provided a method of increasing or maintaining the shape index of the dermal-epidermal junction comprising administering to the skin an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0143] In another embodiment of the present invention, there is provided a compound of formula (I) or its salt as defined above for reducing wrinkle depth, particularly facial wrinkle depth, for example, the reduction in wrinkle depth is at least about 15% below baseline.In some embodiments, the wrinkle depth is at least 3.5%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15%.For example, after a period of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0144] In another embodiment of the present invention, there is provided a compound of formula (I) or its salt as defined above for reducing the visible area of ​​wrinkles, particularly the visible area of ​​facial wrinkles, for example, the reduction in visible area is at least about 4% below baseline.In a further embodiment, the visible area is at least 5%, at least 6%, or at least 7%.For example, after a period of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks has elapsed.

[0145] In another embodiment of the present invention, there is provided a compound of formula (I) or its salt as defined above for reducing the visible length of wrinkles, particularly the visible length of facial wrinkles, for example, the reduction in visible length is at least about 6% below baseline.In a further embodiment, the visible length is at least 7%, at least 8%, at least 9%, or at least 10%.For example, after a period of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks has elapsed.

[0146] In another embodiment of the present invention, there is provided a compound of formula (I) or its salt as defined above for reducing the visible depth of wrinkles, particularly the visible depth of facial wrinkles, for example, the reduction in the visible depth is at least about 3.5% below baseline.In a further embodiment, the visible depth is at least 4%, at least 5%, or at least 6%, for example after a period of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0147] In another embodiment of the present invention, there is provided a compound of formula (I) or its salt as defined above for reducing the visible volume of wrinkles, particularly the visible volume of facial wrinkles, for example, the reduction in visible volume is at least about 4% below baseline.In a further embodiment, the visible volume is at least 5%, at least 6%, or at least 7%, for example after a period of about 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0148] In another embodiment of the invention, one of the facial wrinkle parameters is selected, in particular the following facial wrinkle parameters: (a) Conspicuous area; (b) noticeable length; (c) noticeable depth; and / or (d) To reduce one or more of the noticeable volumes, a compound of formula (I) as defined above or a salt thereof is provided.

[0149] For example, use the percentage below baseline and time periods listed for each integer above.

[0150] In a further embodiment, (a) Conspicuous area; (b) noticeable length; (c) noticeable depth; and / or (d) There is provided a composition of the invention comprising a compound of formula (I), e.g. urolithin A, for use as a cosmetic to reduce one of the facial wrinkle parameters: visible volume.

[0151] For example, use the percentage below baseline and time periods listed for each integer above.

[0152] In a further embodiment, (a) Conspicuous area; (b) noticeable length; (c) noticeable depth; and / or (d) There is provided a method for cosmetically treating facial wrinkles using a composition of the invention comprising a compound of formula (I) to reduce one of the parameters of facial wrinkles: visible volume.

[0153] For example, use the percentage below baseline and time periods listed for each integer above.

[0154] (a) Conspicuous area; (b) noticeable length; (c) noticeable depth; and / or (d) A method for cosmetically treating facial wrinkles using an effective amount of a cosmetic composition comprising a compound of formula (I) to reduce one of the parameters of facial wrinkles: visible volume.

[0155] For example, using the percentage below baseline and time periods recited for each integer above. In one embodiment, the invention provides a compound of formula (I) or a salt thereof, such as Urolithin A, for administration to the head, scalp or hair.

[0156] In a further embodiment, the invention provides a compound of formula (I), or a salt thereof, such as Urolithin A, for the manufacture of a medicament for administration to the head, scalp or hair, e.g. for use in any one of the uses described herein.

[0157] In a further embodiment, there is provided a method comprising administering an effective amount of a compound of formula (I), or a salt thereof, such as Urolithin A, to the head, scalp and hair, e.g. for use in any one of the uses described herein.

[0158] In a further embodiment, there is provided a cosmetic method comprising administering an effective amount of a compound of formula (I), or a salt thereof, such as Urolithin A, to the head, scalp and hair, e.g. for use in any one of the applications described herein.

[0159] A non-therapeutic use of a cosmetic formulation for administration to the head, scalp or hair comprising a compound of formula (I) for use in one or more of the applications described herein.

[0160] The use of a compound of formula (I) as a cosmetic for administration to the head, scalp or hair for one or more of the uses described herein.

[0161] In one embodiment, the present invention provides (a) Maintaining or increasing hair thickness, (b) regeneration of hair root cells; (c) survival of root hair cells; (d) hair stem cell growth and / or regeneration; (e) hair cell survival, (f) prevention of hair loss, (g) Hair maintenance, maintaining or repairing hair strength; (h) improving scalp health, and / or (i) To provide a compound of formula (I) or a salt thereof, such as Urolithin A, for use in promoting hair growth restoration, such as for use in cosmetics.

[0162] In a further embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: a) Maintaining or increasing hair thickness, b) regeneration of hair root cells, c) survival of root hair cells; d) hair stem cell growth and / or regeneration; e) hair cell survival, f) Hair loss prevention, g) Improved scalp health, and / or h) providing a compound of formula (I) or a salt thereof, e.g. Urolithin A, for use in the manufacture of a medicament or for use in the manufacture of a cosmetic product, for promoting hair growth restoration.

[0163] In a further embodiment, a) Maintaining or increasing hair thickness, b) regeneration of hair root cells, c) survival of root hair cells; d) hair stem cell growth and / or regeneration; e) hair cell survival, f) Hair loss prevention, g) Improved scalp health, and / or h) A method for promoting hair growth recovery, such as a cosmetic method, Methods are provided which include administering an effective amount of a compound of formula (I) or a salt thereof, such as urolithin A.

[0164] In one embodiment, administration for use in the invention is by topical administration of the compound of formula (I) or a salt thereof, such as Urolithin A. In a further embodiment, administration for use in the invention is by injection of the compound of formula (I), such as Urolithin A.

[0165] International patent applications WO2018 / 162650 (Amazentis) and WO2018 / 162651 (Amazentis) disclose optimized dosage ranges for oral administration of urolithins. The present application includes topical administration of compounds of formula (I), such as urolithin A, which requires optimized dosage ranges different from those required for oral administration. Thus, the present invention also provides optimized dosage ranges for topical administration of compounds of formula (I) to the skin. Thus, there is provided a compound of formula (I) or a salt thereof, [ka] During the ceremony, A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; Z is selected from H and OH; For topical administration, the concentration ranges from 0.1 to 5% w / w.

[0166] In another embodiment, the concentration range of the compound of formula (I) or salt thereof is 0.8% to 4% of the composition, such as 0.8% to 3% of the composition, such as 0.8% to 2% w / w, for example 1% to 2% w / w of the composition, for example 1% to 1.5% w / w, such as 0.8%, 0.9%, 1%, 1.5% or 2% w / w of the composition, for example about 1% w / w. In a further embodiment of the invention, the concentration range of the compound of formula (I) or salt thereof is 1% to 5% w / w, such as 2% to 5% w / w, for example 3% to 5% w / w, such as 4% to 5% w / w.

[0167] In another embodiment of the present invention there is provided a compound of formula (I) or a salt thereof as defined above for topical administration for cosmetic use in a concentration ranging from 0.8% to 5%.

[0168] In another embodiment of the present invention there is provided a compound of formula (I) or a salt thereof as defined above for topical administration in a concentration ranging from 0.8% to 5% for the treatment and / or prevention of a skin condition, skin disease or skin disorder in a subject.

[0169] In another embodiment of the present invention, (a) To improve or maintain skin barrier function, (b) to prevent and / or treat transepidermal water loss; (c) To improve skin elasticity and firmness, (d) to increase or maintain the thickness of the skin layer; (e) increasing or maintaining the topographic index of the dermal-epidermal junction of the skin; (f) to increase or maintain hydration of the skin; (g) To reduce biological aging of the skin; (h) reducing the appearance of fine lines and wrinkles; (i) To reduce radiation-induced skin damage, e.g. UV radiation-induced skin damage, (j) to protect the skin against damage caused by radiation, such as UV, beta or gamma radiation, including during the medical treatment of conditions such as cancer; (k) to reduce hair damage due to radiation, e.g., skin damage due to UV radiation, and / or (l) There is provided a compound of formula (I) as defined above or a salt thereof for topical administration in a concentration in the range of 0.8% to 5%, for one or more of the following uses, for example for protecting hair from damage caused by radiation, such as UV, beta or gamma radiation, including during the medical treatment of a condition such as cancer.

[0170] (3) Compositions containing micronized compounds of formula (I) and uses thereof An important aspect of topical skin formulations, particularly cosmetic topical skin formulations, is the sensory impact and user experience. In addition to developing new skin formulations containing urolithins, it has been discovered that a particular particle size distribution provides an optimized sensory impact and user experience. Thus, in a further embodiment of the present invention, there is provided a compound of formula (I) or a salt thereof: [ka] During the ceremony, A, B, C and D are each independently selected from H and OH; W, X and Y are each independently selected from H and OH; Z is selected from H and OH; The compound or salt has a D50 size in the range of 1 to 10 μm and a D90 size in the range of 4 to 25 μm.

[0171] In a further embodiment of the invention there is provided a composition of the invention comprising a compound of formula (I) as defined above or a salt thereof, said compound or salt having a D50 size in the range of 1 to 10 μm and a D90 size in the range of 4 to 25 μm.

[0172] In a further embodiment of the invention there is provided a composition of the invention comprising a compound of formula (I) as defined above or a salt thereof, said compound or salt having a D10 size of greater than or equal to 0.1 μm, a D50 size in the range of 2 to 8 μm and a D90 size in the range of 6 to 20 μm.

[0173] In a further embodiment of the present invention there is provided a composition of the invention comprising a compound of formula (I) as defined above or a salt thereof, wherein said compound or salt has a D50 size in the range of 2 to 8 μm and a D90 size in the range of 6 to 20 μm.

[0174] In a further embodiment of the invention there is provided a composition of the invention comprising a compound of formula (I) as defined above or a salt thereof, wherein said compound or salt has a D10 size of equal to or greater than 0.1 μm, a D50 size of equal to or less than 15 μm and a D90 size of equal to or less than 25 μm.

[0175] In a further embodiment of the present invention there is provided a composition of the invention comprising a compound of formula (I) as defined above or a salt thereof, said compound or salt having a D10 size in the range of 0.1 to 2 μm, a D50 in the range of 5 to 12 μm and a D90 size in the range of 12 to 25 μm.

[0176] In a further embodiment of the invention there is provided a composition according to the invention comprising a compound of formula (I) as defined above or a salt thereof, said compound or salt having a D50 size in the range of 1 to 10 μm and a D90 size in the range of 4 to 25 μm, The composition may be topically administered at a concentration ranging from 0.1% to 20%, 0.1% to 10%, 0.1% to 5%, for example, about 0.1% to about 2%, about 0.125%, about 0.5%, about 1.0%, about 1.5%, about 2%, about 5%, about 10%, about 12%, about 15%, or about 20% for cosmetic applications.

[0177] In another embodiment of the invention there is provided a composition comprising a compound of formula (I) or a compound of formula (I) as defined above or a salt thereof, said compound or salt having a D in the range of 1 to 10 μm for one or more of the following applications: 50 Size and D in the range of 4 to 25 μm 90 Size: (a) To improve or maintain skin barrier function, (b) to prevent and / or treat transepidermal water loss; (c) To improve skin elasticity and firmness, (d) to increase or maintain the thickness of the skin layer; (e) increasing or maintaining the topographic index of the dermal-epidermal junction of the skin; (f) to increase or maintain hydration of the skin; (g) To reduce biological aging of the skin; (h) reducing the appearance of fine lines and wrinkles; (i) To reduce radiation-induced skin damage, e.g. UV radiation-induced skin damage, (j) to protect the skin against damage caused by radiation, such as UV, beta or gamma radiation, including during the medical treatment of conditions such as cancer; (k) To reduce hair damage caused by radiation, e.g., skin damage caused by UV radiation, (l) To protect hair from damage caused by radiation, such as UV, beta or gamma radiation, including during the medical treatment of conditions such as cancer. (m) To improve collagen tissue in the skin; (n) To improve the skin matrix, (o) To improve the physical properties of the skin; (p) to reduce redness of the skin due to sunlight; and / or (q) To protect against photoaging caused by sunlight.

[0178] Urolithins have low solubility in aqueous media, which leads to poor dispersion and aggregation of the urolithins, resulting in low bioavailability in topical formulations. Thus, in addition to compositions comprising a compound of formula (I), trehalose and / or an NAD precursor, and optionally caffeine, the present invention also provides topical compositions comprising a compound of formula (I) and good solubility of a urolithin resulting in high bioavailability. Thus, according to a further embodiment of the present invention, (a) a compound of formula (I) or a salt thereof, (b) i) aqueous phase; ii) water-soluble emollients and moisturizers; iii) co-solvents / wetting agents; iv) occlusive moisturizers and barrier repair ingredients, such as vitamin-rich occlusive moisturizers and barrier repair ingredients; v) C 8-14 Carrier oils / emollients such as medium chain monoesthetes, vi) emulsifiers, vii) structuring agents, viii) polymeric thickeners and emulsifiers, for example C15-19 alkanes; ix) polymeric anionic thickeners, and / or x) A topical composition is provided which includes a preservative.

[0179] According to a further embodiment of the present invention, (a) a compound of formula (I) or a salt thereof; (b)C 8-14 Carrier oils / emollients such as medium chain monoesters, (c) an emulsifier, and a topical composition comprising the same is provided.

[0180] According to a further embodiment of the present invention, (a) a compound of formula (I) or a salt thereof; (b) a water-soluble emollient and moisturizer; (b)C 8-14 Carrier oils / emollients such as medium chain monoesters, (c) an emulsifying agent.

[0181] According to a further embodiment of the present invention, (a) a compound of formula (I) or a salt thereof; (b) a water-soluble emollient and moisturizer; (c)C 8-14 Carrier oils / emollients such as medium chain monoesters, (d) an emulsifier; (e) a structuring agent; and (f) a polymeric thickening agent.

[0182] Examples of water-soluble emollients and moisturizers include glycerin, butylene glycol, and 1,2-hexanediol.

[0183] Examples of co-solvents / humectants include ethanol, glycols (such as butylene glycol), glycerin, ethoxydiglycol, and dimethylisosorbide.

[0184] An example of an occlusive moisturizer and barrier repair ingredient is Butyrospermum Parkii (Shea) Butter.

[0185] Examples of carrier oils / emollients include cococaprylic / capric acids, such as mono-, di-, and triesters ranging from C1 to C22, natural or synthetic fats and oils (defined as triesters of glycerol), lamella forming structures such as those mentioned above, cholesterol, phytosterols, etc.

[0186] Examples of emulsifiers include sorbitan oleate and PEG-100 stearate.

[0187] Examples of structuring agents include stearic acid.

[0188] Examples of polymeric thickeners and emulsifiers include hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymers;

[0189] Examples of polymeric anionic thickeners include carbomers.

[0190] An example of a preservative is phenoxyethanol.

[0191] Examples of surfactants include C8-C22 ionic or non-ionic. Those that are more water soluble (higher hydrophilic lipophilic balance or HLB) tend to disrupt the skin barrier, allowing materials to cross more easily.

[0192] Some surfactants can also form micelles or liposomes that cross the stratum corneum more easily.

[0193] In a further aspect of the invention, there is provided a method for preparing a topical composition of the invention, the method comprising: (a) heating water in a first vessel, e.g., to about 80°C; (b) adding to a second container an oil, an emulsifier, and a compound of formula (I); (c) heating the second container to a temperature, for example, about 80° C.; (d) adding the contents of the second receptacle to the first receptacle; (e) cooling the resulting mixture, for example to about 40°C.

[0194] In a further embodiment of the invention, there is provided a composition comprising one or more ingredients listed in column A of Table 1 in the concentration ranges listed in column C of Table 1.

[0195] In a further embodiment of the invention, there is provided a composition comprising one or more ingredients listed in column B of Table 1 in the concentration ranges listed in column C of Table 1.

[0196] For the avoidance of doubt, the components of the compositions defined in Table 1 add up to 100%. [Table 1-1] [Table 1-2]

[0197] The present invention provides a topical composition comprising a compound of formula (I). However, there may be advantages to a dual administration regimen for the delivery of a compound of formula (I), combining topical administration of a composition comprising a compound of formula (1) with oral administration of a composition comprising a compound of formula (1). For example, administering a topical composition having a concentration of 0.8%-5% of the compound of formula (I) and an oral composition comprising 250 mg-2000 mg of the compound of formula (I), for example administering a topical composition having a concentration of 0.8%-2% w / w of the compound of formula (I) and an oral composition comprising 500 mg, 1000 mg, 1500 mg or 2000 mg of the compound of formula (I).

[0198] As mentioned above, the present invention provides compositions comprising trehalose and a urolithin.

[0199] Trehalose usually comprises at least 0.1% w / w of the composition of the invention, such as at least 0.2% w / w of the composition, at least 0.3% w / w, at least 0.4% w / w, for example 0.5% w / w. For example, trehalose comprises 0.1% to 20% w / w of the composition, such as 0.1% to 15% w / w, for example 0.1% to 10% w / w, for example 0.5% to 5% w / w, for example 0.1% to 5% w / w, for example 0.1% to 2% of the composition, for example 0.1% to 1% of the composition, for example 0.2% to 0.8% w / w of the composition, for example 0.3% to 0.7% w / w of the composition, for example 0.4% to 0.6% w / w of the composition.

[0200] Additionally, the present invention provides compositions comprising niacinamide and a urolithin, or trehalose, niacinamide, and a urolithin.

[0201] Niacinamide typically comprises at least 0.1% w / w of the composition of the invention, such as at least 0.5% w / w, at least 1% w / w, at least 2% w / w, such as 1%, 3% or 5% w / w of the composition. For example, niacinamide comprises 0.1% to 10% w / w of the composition, such as 0.5% to 8% of the composition, such as 0.5% to 7% of the composition, such as 0.5% to 6% w / w, such as 0.5% to 5% w / w of the composition, such as 1% to 3% of the composition, such as 1%, 2%, 3%, 4% or 5% w / w of the composition.

[0202] The compound of formula (I) typically comprises at least 0.5% of the composition, for example 0.5% w / w or 1% of the composition, for example the compound of formula (I) comprises 0.5%-2% w / w of the composition, such as 0.5% or 1% w / w of the composition.

[0203] The compound of formula (I) usually comprises at least 0.8% w / w of the composition of the invention, for example at least 0.9% w / w, at least 1.0% w / w, at least 1.1% w / w, at least 1.2% w / w, at least 1.3% w / w, at least 1.4% w / w, at least 1.5%, at least 1.6%, at least 1.7%, at least 1.8%, at least 1.9% of the composition. For example, the compound of formula (I) comprises 0.8% to 2% w / w of the composition, for example 0.1% to 1.8% w / w, for example 0.8% to 1.5% w / w, for example 0.8% to 1.3% of the composition, for example 1.0% to 1.5% of the composition, for example 1% to 1.3% w / w of the composition, for example 1% or 1.5% w / w, 2.0% of the composition.

[0204] The weight ratio (w / w) of urolithin to trehalose is generally in the range of 10:1 to 1:1, for example, 5:1 to 1:1, for example, 4:1 to 1:1.

[0205] The weight ratio (w / w) of urolithin to niacinamide is generally in the range of 1:200 to 1:1, such as 1:10 to 1:1, such as 1:5 to 1:1, such as 1:3 to 1:1, such as 1:1.

[0206] The weight ratio of trehalose to niacinamide is generally in the range of 1:20 to 1:1, such as 1:10 to 1:1, such as 1:5 to 1:1, such as 1:4 to 1:1, such as 1:5 to 1:1.

[0207] Urolithins: Urolithins are metabolites produced by the action of the gut microbiota of mammals, including humans, on ellagitannins and ellagic acid. Ellagitannins and ellagic acid are compounds commonly found in foods such as pomegranates, nuts, and berries. Ellagitannins are minimally absorbed in the gut itself. Urolithins are a class of compounds having the representative structure (I) shown above. The structures of some particularly common urolithins are set out in Table 2 below with reference to structure (I). [Table 2]

[0208] Indeed, for commercial scale production, it is advantageous to synthesize urolithins, synthetic routes being described, for example, in WO2014 / 004902, WO2015 / 100213 and WO2019 / 168972.

[0209] Urolithins of any structure according to structure (I) may be used in the compositions of the invention. Particularly suitable compounds for use in the compositions of the invention are naturally occurring urolithins. Thus, Z is preferably OH, and W, X and Y are preferably all H. When W, X and Y are all H, A and B are both H, and C, D and Z are all OH, the compound is urolithin C. When W, X and Y are all H, A, B and C are all H, and D and Z are both OH, the compound is urolithin A. Preferably, the urolithin used in the formulations of the invention is urolithin A, urolithin B, urolithin C or urolithin D. Most preferably, the urolithin used in the formulations of the invention is urolithin A. [ka]

[0210] Urolithin A In one embodiment, the urolithin used in the compositions of the invention is micronized. Micronization allows the urolithin to disperse in the formulation or dissolve more rapidly. If micronized urolithin is used, preferably the urolithin has a D of less than 8 μm. 50 More preferably, the urolithin has a particle size of less than 7 μm, such as less than 6 μm, for example less than 5 μm, such as less than 4 μm, for example less than 2.5 μm. 50 More preferably, the urolithin has a size in the range of 1.5 to 8.5 μm, such as 2 to 8 μm, for example 1.5 to 3.5 μm, for example 1.5 to 2.5 μm, such as 3 to 8 μm, for example 3 to 6 μm. 50 Preferably, the urolithin has a D of less than 25 μm. 90 More preferably, the urolithin has a D of less than 15 μm, for example less than 12 μm. 90 The urolithins preferably have a D in the range of 5 to 25 μm, such as 9 to 25 μm, for example 10 to 25 μm, for example 10 to 20 μm, for example 5 to 15 μm. 90 Preferably, the urolithin has a D in the range of 0.5 to 3 μm, such as 0.5 to 2.5 μm, for example 0.5 to 2.0 μm, for example 0.5 to 1.5 μm. 10 Preferably, the urolithin has a D in the range of 5 to 25 μm. 90 , D in the range of 1.5 to 8.5 μm 50 , and D in the range of 0.5 to 3 μm 10 It is preferred that the compound has the formula:

[0211] Micronization can be achieved by methods established in the art, such as, for example, compression force milling, hammer milling, universal or pin milling, or jet milling (e.g., spiral jet milling or fluidized bed jet milling). Jet milling is particularly suitable.

[0212] Form of composition: The compositions of the present invention may be provided in a variety of forms, for example, forms suitable for topical administration. Such compositions for topical administration include makeup, lotions, creams, shampoos, serums, sprays, gels, masks, toners, micellar waters, soaps, balms, mousses, oils, sunscreens, emulsions, exfoliants, hair treatments, lotions, and cleansers.

[0213] In one embodiment of the present invention, there is provided a composition of the present invention in combination with a pharma- ceutically or cosmetically acceptable carrier.

[0214] "Pharmaceutically acceptable carrier" or "cosmetically acceptable carrier" refers to any carrier, diluent, or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient. The active agent may be formulated into a dosage form according to standard practices in the field of pharmaceutical formulation. See Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Edition (1990), Mack Publishing Co., Easton, Pa.

[0215] For topical administration, the compositions of the present invention may be mixed with a suitable carrier or diluent, such as water, aqueous buffer, oil (especially vegetable oil), ethanol, saline, aqueous dextrose (glucose) and related sugar solutions, glycerol, or glycols, such as propylene glycol or polyethylene glycol. Solutions for topical administration preferably contain a water-soluble salt of the active agent. Stabilizers, antioxidants and preservatives may also be added. Suitable antioxidants include sulfites, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl or propyl paraben, and chlorbutanol. Compositions for topical administration may take the form of an aqueous or non-aqueous solution, dispersion, suspension, or emulsion.

[0216] The topical formulation may also be combined with at least one excipient such as a filler, binder, humectant, disintegrant, solution retarder, absorption enhancer, wetting agent, absorbent, or lubricant.

[0217] Topical compositions including the low-dose formulations of the present invention may further include ceramides, which are well known in the art. See, for example, Meckfessel and Brandt, "The Structure Function and Importance of Ceramides in Skin and Their Use as Therapeutic Agents in Skin-Care Products," J Am Acad Dermatol 2014;71:177-84, which is incorporated herein by reference in its entirety. In further preferred embodiments, the topical formulations are administered over a period of time and used several times, for example, once a day or twice a day treatment for a week or more.

[0218] Examples of ceramides that can be formulated as described herein include, but are not limited to, ceramide EOS, ceramide NS, ceramide NP, ceramide EOH, ceramide AS, ceramide NH, ceramide AP, ceramide AH, ceramide EOP, ceramide NdS, ceramide AdS, and / or ceramide EOdS.

[0219] According to a further aspect of the present invention, (a) a compound of formula (I), such as urolithin A; (b) trehalose, (c) optionally, an NAD precursor, such as niacinamide; and (d) a cosmetically acceptable carrier.

[0220] According to a further aspect of the present invention, (a) a compound of formula (I), such as urolithin A; (b) an NAD precursor, such as niacinamide; (c) optionally trehalose, and (d) a cosmetically acceptable carrier.

[0221] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising about 0.8 to about 2.0% Urolithin A.

[0222] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising about 0.8 to about 1.5% Urolithin A.

[0223] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising about 0.8 to about 1.2% Urolithin A.

[0224] In a further embodiment, there is provided a composition of the invention, such as a cream or lotion, comprising about 1% Urolithin A.

[0225] Additional ingredients in the composition of the present invention: The compositions according to the invention may contain additional ingredients other than urolithin, trehalose and / or NAD precursors, such as resveratrol, coenzyme Q, etc. 10 The compound providing the health benefit may be selected from vitamin C, retinol, caffeine and aminopeptides.

[0226] dose The effective amount of the composition to be ingested will vary depending on the method of administration, the age, weight, and general health of the subject. Factors such as the medical condition, age, and weight of the subject may be important, and the dosing regimen may be adjusted to obtain the optimal response. For example, for topical formulations, 0.5 mg / cm2 to 10 mg / cm2 2 in the morning and evening, e.g., 2 mg / cm 2 is administered in the morning and evening.

[0227] Representative topical compositions are shown in Table 3: [Table 3]

[0228] Treatment: The composition of the present invention can be taken as a single treatment or, more generally, as a series of treatments.For a subject, the dose of the composition can be taken, for example, once, twice or three times a day, or once, twice, three, four, five, six or seven times a week.It will also be understood that the effective dose of the compound may increase or decrease over the course of a particular treatment.

[0229] Medical and Non-medical Treatments: The composition of the present invention can be used as a cosmetic or pharmaceutical product.

[0230] The term "about" refers to a tolerance of ±20% of the relevant value, such as ±15% of the relevant value, such as ±10% of the relevant value or ±5% of the relevant value.

[0231] The phrase "extrinsic aging factors" includes factors related to the environment, such as sun exposure, smoking, hydration, diet, skin care products, and environmental pollution.

[0232] The phrase "intrinsic aging factors" refers to the natural biological process of aging, including slowed stem cell production, loss of estrogen, reduced collagen and elastin, and deterioration of facial tissues, all of which are part of intrinsic aging. The natural biological process of aging also includes a decline in cellular function and metabolism due to impaired metabolism or mitochondrial function.

[0233] The term "NAD" refers to nicotinamide adenine dinucleotide.

[0234] The phrase "NAD precursor" refers to any compound that is an intermediate in the synthesis of NAD in vivo. Examples of NAD precursors include nicotinic acid (niacin), niacinamide (nicotinamide), nicotinamide riboside, tryptophan, and nicotinamide mononucleotide.

[0235] The term "photoaging" refers to the characteristic changes in the skin induced by chronic exposure to ultraviolet A and / or ultraviolet B light.

[0236] The phrase "transepidermal water loss" (TEWL) refers to the loss of water from the body through the epidermal layer (skin) to the surrounding atmosphere via the processes of diffusion and evaporation.

[0237] A further advantage of the formulations and uses of the invention is that the compounds of formula (1), such as Urolithin A, are safe and non-irritating to the skin, unlike current skin treatments such as retinoids, which have many side effects, such as dryness and irritation, changes in skin color, sensitivity to sunlight and redness, swelling, scabbing, or blistering.

[0238] A further advantage of the formulations and uses of the invention is that the compounds of formula (1), such as Urolithin A, reduce skin redness, protect the skin from the sun, prevent photoaging, improve anti-wrinkle efficacy, improve skin hydration, and / or improve collagen organization of the skin.

[0239] How to use Certain compositions and methods described herein may provide beneficial effects on the skin. Certain compositions and methods described herein may treat and / or prevent skin disorders. Certain compositions described herein may be oral compositions to provide oral formulations for treating and / or preventing skin disorders. Certain compositions and methods described herein may improve and / or maintain the aesthetic appearance of the skin.

[0240] The skin diseases to be treated include, but are not limited to, those caused by sun exposure, inflammation, and / or autoimmune diseases. The skin diseases to be treated may include erythematotelangiectatic rosacea, telangiectasia, papulopustular rosacea, and / or pustular rosacea.

[0241] i. Skin diseases related to sun exposure Skin disorders associated with sun exposure that may be treated using the described compositions and methods include, but are not limited to, actinic keratosis, lentigines or age spots, seborrheic keratosis, sunburn, photosensitivity, moles, polymorphous light eruption, solar elastosis or wrinkles, skin cancers (such as melanoma, squamous cell carcinoma, basal cell carcinoma, etc.), and freckles.

[0242] ii. Inflammatory skin diseases Inflammatory skin diseases treated using the described compositions and methods include, but are not limited to, psoriasis, contact dermatitis, atopic dermatitis, seborrheic dermatitis, asteatotic eczema, discoid eczema, hand eczema, gravitational / varicose eczema, eczematous drug eruption, lichen simplex, acne, lichen planus, pityriasis lichenoides, chronic lichenoid keratosis, lichen nitidus, lichen linearis, mycosis fungoides, erythroderma, erythema multiforme, Stevens-Johnson syndrome, vasculitis, and toxic epidermal necrolysis.

[0243] iii. Autoimmune skin diseases Autoimmune skin diseases treated with the described compositions and methods include, but are not limited to, pyoderma gangrenosum, systemic lupus erythematosus, eosinophilic fasciitis, scleroderma, pemphigus vulgaris, bullous pemphigoid, alopecia areata, vitiligo, psoriasis, dermatomyositis, and dystrophic epidermolysis bullosa.

[0244] The invention will be further understood with reference to the following non-limiting examples.

[0245] The following examples illustrate the invention. [Brief description of the drawings]

[0246] [Figure 1] FIG. 1 shows prostaglandin E2 (PGE2) levels measured by ELISA kit in the supernatants of reconstituted human epidermis (RHE) under the indicated conditions. Data are shown as PGE2 concentrations expressed in pg / mL. [Diagram 2]Normalized enrichment scores (NES) for the gene set “collagen fiber organization” in a published skin aging study (Glass et al (2013) Genome Biol 14(7), R75) and in a study applying a product containing Mitopure 1%. [Diagram 3] Bar graph showing some collagen genes that are downregulated with skin aging, indicated by negative aging beta values. Data analyzed from the study: [Glass et al(2013)Genome Biology Article number:R75] [Figure 4] FIG. 1 is a bar graph showing several collagen genes that are upregulated after 8 weeks of Mitopure application to the skin, calculated as the change in expression comparing the end of application to baseline, and values ​​are normalized to the change in expression levels in the placebo control group. [Diagram 5] Heatmap of genes associated with improved skin health following Urolithin A treatment. [Figure 6] Selected genes associated with improved mitophagy and reduced collagen degradation following Urolithin A treatment in human keratinocytes and dermal fibroblasts. [Figure 7] A comparison of the anti-wrinkle effect of a cream containing Urolithin A alone and a cream containing Urolithin A, trehalose and niacinamide. [Figure 8] Changes in skin hydration with a cream containing Urolithin A alone and a cream containing Urolithin A, trehalose, and niacinamide [Figure 9] Reduction in skin wrinkle depth 2 and 8 weeks after application of 1% Urolithin A (Mitopure). [Figure 10] Showing reduction at 1.6 MED dose (moderate sunburn) with 1% Urolithin A. [Figure 11]CONSORT diagram, 55 participants were screened in a placebo-controlled initial aging study, and n=48 middle-aged female subjects with a mean age of 58.6±6.6 years were randomized into two study arms in a split-face / arm study design consisting of a low-dose active group compared with placebo and a second high-dose active group compared with placebo. Skin biopsies were performed on adjacent areas of the volar forearm at the beginning and end of the 8-week intervention. All participants completed the study and were included in the final analysis. [Figure 12] 1% UA applied topically in a basic skin cream (A) in the first aging study or in a matrix of more specific day (B) and night (C) skin cream formulations in the second aging study showed significant anti-wrinkle effects in middle-aged subjects with moderate facial wrinkles after 8 weeks of topical application (p<0.05). Skin barrier function was not significantly affected (D). Skin hydration was improved with topical application of various UA-containing creams (E, F). [Figure 13A] Mitopure positively impacts biomarkers associated with improved skin health. GSEA results from RNA-seq on skin biopsies showing the most important Gene Ontology Biological Process (GO-BP) pathways significantly enriched with Mitopure compared to vehicle. Terms with positive and negative normalized enrichment scores (NES) are classified as "activating" and "repressing", respectively. Pathways are sorted by gene ratio, dot size is scaled by the number of core enriched genes, and dot color reflects the statistical significance of the enrichment (Benjamini-Hochberg adjusted p-value, P-adj). [Figure 13B] Mitopure positively impacts biomarkers associated with improved skin health. Bar plot (top) showing increased expression in core genes of the "collagen fiber organization" pathway in skin biopsies exposed to Mitopure compared to the vehicle group. Bar graph (bottom) of aging beta values ​​for the same genes from a skin aging study. Only core enriched genes common between Mitopure and skin aging datasets are shown. [Figure 13C] Mitopure positively impacts biomarkers associated with improved skin health: expression of genes encoding collagen-degrading enzymes (MMP1, MMP3) and autophagy / mitophagy proteins (PINK1, PARK2, SQSTM1, ULK1) in human dermal fibroblasts (C) treated for 24 h with DMSO or the indicated doses of Mitopure. [Figure 13D] Mitopure positively impacts biomarkers associated with improved skin health, namely the expression of genes encoding collagen-degrading enzymes (MMP1, MMP3) and autophagy / mitophagy proteins (PINK1, PARK2, SQSTM1, ULK1) in human keratinocytes (D) treated for 24 h with DMSO or the indicated doses of Mitopure. [Figure 13E] Mitopure positively impacts biomarkers associated with improved skin health. Expression of genes encoding autophagy / mitophagy proteins (PINK1, PARK2, SQSTM1, ULK1) in reconstructed human epidermis following daily 72-hour application of vehicle or moisturizer containing 1% Mitopure. Data are expressed as fold change relative to vehicle + / - standard error. *p<0.05, **P<0.01, ***P<0.005, ***P<0.001 one-way ANOVA. [Figure 14A] This is the CONSORT flow diagram for Aging Study 2. [Figure 14B] CONSORT flow diagram for UVB erythema testing [Figure 15] The effect of Urolithin A on wrinkles [Figure 16A] Effect of Mitopure on biomarkers associated with improved skin health. Heatmap of log2 fold change from core enriched genes in the "collagen fiber organization" pathway in Mitopure skin biopsies at end of study vs. baseline after normalization to vehicle control. Only subjects present in both visits and both treatments are considered in the visualization. Rows (genes) were hierarchically clustered with a Euclidean distance metric using complete linkage. [Figure 16B] Figure 1. Effect of Mitopure on biomarkers associated with improved skin health. Normalized enrichment scores (NES) for the Mitopure "collagen fiber organization" pathway normalized for vehicle comparison and "aging" dataset. The significance level of BP enrichment for each comparison / dataset is indicated accordingly. [Figure 16C] Effect of Mitopure on biomarkers associated with improved skin health. Expression of the gene encoding collagen type I alpha 1 chain (COL1A1) in human dermal fibroblasts treated for 24 hours with DMSO or the indicated doses of Mitopure. [Figure 16D] Effect of Mitopure on biomarkers associated with improved skin health. Expression of genes encoding collagen degrading enzymes (MMP1, MMP3) in reconstructed human epidermis following daily 72-hour application of vehicle or moisturizer containing 1% Mitopure. Data are expressed as fold change relative to vehicle + / - standard error. [Figure 17] The anti-wrinkle effect of 1% Urolithin A on wrinkles. [Figure 18] Lack of anti-wrinkle effect of 0.5% Urolithin A on wrinkles. [Figure 19] Effect of day and night creams on wrinkles after 8 weeks [Figure 20] Effect of day cream, night cream, and serum on skin hydration after 8 weeks [Figure 21] FIG. 1 is a table summarizing the effects of Urolithin A cream on skin parameters. [Figure 22] Effect of day and night creams on skin hydration after 8 weeks [Diagram 23] Test site allocation DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0247] compound Urolithin A was prepared as follows.

[0248] Urolithin A (4) was prepared in two steps starting from 2-bromo-5-methoxybenzoic acid 1 and resorcinol 2. The pure compound was obtained as a pale yellow powder. [ka]

[0249] Step 1: A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g, 119 mmol, 1.0 equiv.), resorcinol 2 (26.3 g, 239 mmol, 2.0 equiv.), and sodium hydroxide (10.5 g, 263 mmol, 2.2 equiv.) was heated to reflux in water (120 mL) for 1 h. Then, a 5% aqueous solution of copper sulfate (3.88 g CuSO in 50 mL water) was added. 4 5H 2 2H 2 O, 15.5 mmol, 0.1 equiv) was added and the mixture was refluxed for an additional 30 min. The mixture was cooled to room temperature and the solid was filtered through a Buchner filter. The residue was washed with cold water to give a pale red solid, which was triturated in hot MeOH. The suspension was left at 4° C. overnight. The resulting precipitate was filtered and washed with cold MeOH to give the title compound 3 as a pale brown solid.

[0250] Step 2: A suspension of 3 (10.0 g, 41 mmol, 1.0 equiv) in dry dichloromethane (100 mL) was added to a 0 °C solution of 1 M solution of boron tribromide in dry dichloromethane (11.93 mL of pure BBr in 110 mL of anhydrous dichloromethane). 3 , 124 mmol, 3.0 equiv) was added dropwise. The mixture was left at 0° C. for 1 h and then allowed to warm to room temperature. The solution was stirred at that temperature for 17 h. Then, plenty of ice was added to the mixture. The yellow precipitate was filtered and washed with cold water to give a yellow solid, which was heated to reflux in acetic acid for 3 h. The hot solution was quickly filtered and the precipitate was washed with acetic acid and then diethyl ether to give the title compound 4 as a yellow solid. 1 H and 13 C NMR was consistent with the structure of 4.

[0251] Example 1 PGE in reconstituted human epidermis under UV stimulation 2 Release of This study shows the effect of a moisturizing cream containing different concentrations of urolithin A (UA) on the secretion of the pro-inflammatory marker prostaglandin E2 (PGE2) in the supernatant of reconstructed human epidermis.

[0252] method Culture and treatment method Ten-day-old reconstituted human epidermis (RHE) was placed in maintenance medium. RHE was topically treated with or without moisturizing cream containing different concentrations of urolithin A active and incubated for 24 hours. RHE was then rinsed with PBS and sun-sun-stimulated with UVB (+UVA) -850mJ / cm using a SOL500 sun simulator equipped with an H2 filter (Dr. Honle, AG). 2 (+6J / cm 2 ) was irradiated. After irradiation, the treatment was resumed and the RHE were incubated for 24 h. Concurrently, a non-irradiated condition was performed and kept in the dark during the irradiation period. All experimental conditions were performed with n=3.

[0253] PGE2 released into the culture supernatant was measured using a specific ELISA kit according to the supplier's instructions (Enzo Life Sciences, ref. ADI-900-001). Statistical analysis performed by one-way ANOVA. [Table 4]

[0254] conditions See Figure 1 A: Non-irradiated RHE without cream B: Irradiated RHE without cream C: RHE irradiated with a basic cream formulation (without urolithin A). D: RHE irradiated with a cream containing 0.25% urolithin A E: RHE irradiated with cream containing 0.5% urolithin A F: RHE irradiated with cream containing 0.1% urolithin A G: RHE irradiated with cream containing 0.2% urolithin A

[0255] result Figure 1 summarizes the levels of PGE2 secreted by RHE as measured in the supernatant, i.e., cell culture medium. A summary of the statistics for all conditions is provided below. The data show that: a) UV irradiation significantly increases PGE2 levels b) Interestingly, the basic cream formulation (containing no urolithin A) induced a significant increase in secreted PGE2 c) UA significantly reduced PGE2 secretion at concentrations of 0.5%, 1%, and 2% compared to irradiated untreated skin. d) and shows that UA significantly reduces PGE2 secretion at all concentrations tested compared to irradiated skin treated with the basic cream formulation without UA (0% UA). [Table 5]

[0256] conclusion Surprisingly, application of the basic cream formulation has a negative effect on skin protection against UV-induced inflammation. In addition to treating the effects of UV irradiation, we observed an unexpected protective effect of Urolithin A on UV-irradiated skin, attenuating the negative effects of the basic cream.

[0257] Example 2: Effect of a cream containing Mitopure (Urolithin A) on ageing of human skin after 8 weeks of application Biological pathways and genes whose expression decreases with age in human skin and is upregulated after application of a cosmetic product containing Mitopure were identified.

[0258] Pathways (i.e., gene sets) and genes that are downregulated with skin aging were inferred from a publicly available dataset in female twins ranging in age from 39 to 85 years (Glass et al (2013) Genome Biology 3,14:Article number:R752).

[0259] The pathways (i.e., gene sets) and genes upregulated by Mitopure were identified from a clinical study in female subjects aged 50 to 75 years. In the study, a cosmetic product containing a 1% concentration of the active ingredient Mitopure or a placebo product was tested on skin aging over an 8-week period.

[0260] In both studies, skin biopsies were collected and used to (i) extract RNA, (ii) perform high-throughput transcriptomics, i.e., gene expression analysis, and (iii) perform pathway enrichment analysis to identify significantly regulated gene sets.

[0261] The gene set "collagen fiber organization" was found to be significantly downregulated in skin aging studies and significantly upregulated in studies following application of the Mitopure product.

[0262] Figure 2 represents the normalized enrichment score (NES) for the "collagen fiber organization" gene set in both studies. The NES indicates the enrichment of the gene set. Negative values ​​indicate that the pathway is downregulated, whereas positive NES values ​​indicate that the pathway is upregulated. The NES for "collagen fiber organization" is negative in the skin study, indicating a decrease in this gene set with skin aging. The NES for "collagen fiber organization" is positive in the Mitopure study, indicating that application of Mitopure at a concentration of 1% on human skin for one month increases the same pathway that decreases with skin aging.

[0263] The gene set "collagen fiber organization" is related to biological pathways related to skin firmness, strength, and youthfulness. Genes in this gene set "collagen fiber organization" are collagen genes that code for collagen proteins. These genes include COL1A1, COL5A1, COL5A2, COL14A1, and COL3A1.

[0264] Figure 3 shows that all of these genes are downregulated in human skin with age, as indicated by the negative aging beta scores. In fact, the aging beta score uses a linear mixed model to calculate how much gene expression changes with age in subjects of various ages. The negative beta values ​​indicate that expression of these genes is reduced with age in human skin.

[0265] The same collagen genes that are downregulated with skin aging are also all upregulated after application of Mitopure, as shown in Figure 4. The increase in expression of these genes is calculated as the change in expression at the end of application compared to baseline, and values ​​are normalized to the change in expression levels in the placebo control group.

[0266] Collagen genes code for collagen proteins that play an important role in supporting skin health with aging. Indeed, the extracellular matrix of the dermis is composed primarily of collagen fibers (types I and III), elastin, and proteoglycans (Ross MH, Kaye GI, Pawlina W: Connective Tissue in Histology: A text and Atlas. Lippincott Williams & Wilkins; Pennsylvania, PA: 2003). The mechanical properties of the skin depend largely on the nature and organization of dermal collagen, which is responsible for the mechanical strength of the skin (Agache et al (1980) Archives of Dermatological Research volume 269, pages 221-232).

[0267] These results suggest that Mitopure enhances skin strength by improving collagen-related gene expression and collagen assembly in human skin.

[0268] method Clinical studies, and sample processing and analysis were performed as described in Glass et al. (2013) Genome Biology Article number: R75.

[0269] Gene set enrichment analysis (GSEA) was performed using the R package ClusterProfiler [Yu et al., 2012]. Briefly, in each comparison, genes were ranked by their age beta score value, and enrichment of specific gene sets among up- or down-regulated genes was statistically tested. The minimum and maximum gene set sizes were set to 10 and 500, respectively. The resulting p-values ​​were adjusted using the BH method. Terms with adjusted p-values ​​below 0.05 were considered statistically significant.

[0270] Example 3: Effects of Urolithin A (Mitopure) on primary human fibroblast and keratinocyte cells result

[0271] This experiment compared the expression of genes associated with biological processes involved in skin homeostasis / health in human primary keratinocytes treated with 2.5uM or 10uM Urolithin A in DMSO (control).

[0272] The heat map in Figure 5 shows that UA supports skin cells against the harmful effects of photoaging / environmental pollutants / toxins in human primary keratinocytes. In particular: -Urolithin A reduces the expression of several genes that code for enzymes involved in collagen degradation. These genes belong to the categories of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinase (ADAM). ○MMPs are induced by UV skin irradiation and contribute to collagen degradation and skin photoaging (Quan et al. (2013) J Invest Dermatol ○.2013 May;133(5):1362-6). In fact, about 80% of skin aging is thought to be caused by UV exposure, and most of the studies describing changes affecting ECM components refer to the photoaging process. In the case of collagen, these biochemical and molecular changes caused by photoaging are well defined, one of its distinguishing features being the decrease in the amount of fibrillar collagen mediated by various secreted proteases such as MMPs (Rodriuquez et al(2017)Biochimica et Biophysica Acta-Molecular Cell Research 1864(11A),2015-2025). Increase in MMP1MMP-1 may be important in the aging effects of smoking on the skin (Lahmann et al(2001)Lancet 24;357(9260),935-6) ADAM is upregulated in several skin diseases, in skin with impaired healing ability, and in skin after UV irradiation, i.e. photoaging (Kawaguchi & Hearing (2011) Enzyme Research Article 482498) -Urolithin A reduces the expression of several genes encoding pro-inflammatory cytokines, namely interleukins (IL1A, IL1B), which are induced in skin exposed to UV and environmental pollutants (Kim & Park 2016) Molecular Mechanisms of the Aging Process and Rejuvenation. Editor Naofumi Shiomi. ISBN: 978-953-51-2568-6). -Urolithin A increases the expression of several genes encoding proteins associated with autophagy / mitophagy and improved mitochondrial function. This is significant as mitochondria are the main organelles affected during chronological and UV-induced skin aging, the phenotypic manifestations of which are a direct consequence of mitochondrial dysfunction (Sreedhar et al (2020) Cell Death & Disease 11, Article No: 444).

[0273] Figure 6 shows gene expression levels in both human primary keratinocytes and dermal fibroblasts treated with 2.5uM or 10uM Urolithin A DMSO (control). The data show that Urolithin A increased the mitophagy marker PINK1 in both cell types, and Urolithin A reduced matrix metalloproteinase MMP1, a marker that is increased in association with skin chronological and photoaging, in both cell types.

[0274] method The study was performed with normal adult human dermal fibroblasts (NHDF-Ad) from two pooled donors (catalog number: CC-2511) and normal adult human epidermal keratinocytes (NHEK-Ad) from two pooled donors (catalog number: 00192627, Lonza). The cell batches are shown in the table below (Table 3).

[0275] The study was performed using five technical replicates for each experimental condition (Figure 1). [Table 6]

[0276] Primary skin cells were expanded in flasks and seeded into 12-well cell culture plates, filled with 1 mL of medium, and incubated at 37 °C for 24 h at 5% CO 2The cells were incubated at 37° C. with 0.1% insulin, 0.1% hFGF-B, 0.1% GA-1000, and 2% FBS in a basal medium for human dermal fibroblasts. The basal culture medium for human keratinocytes consisted of KBM™ Gold medium (keratinocyte basal medium) supplemented with hydrocortisone, transferrin, epinephrine, gentamicin, amphotericin B, BPE, hEGF, and insulin.

[0277] RNA sequencing Primary cells were treated with 0.1% DMSO (control), 2.5 μM and 10 μM Urolithin A at confluence (approximately 250,000 cells per well) for 24 hours and harvested for RNA sequencing and expression profiling using an NGS platform. Significantly up- and down-regulated mRNAs were analyzed with bioinformatics tools (Figure 2).

[0278] RNA extraction and quality control RNA was extracted from cell lysates using the RNeasy mini kit (Qiagen) according to the manufacturer's protocol. Lysate buffer from the extraction kit was added to the cell pellets and samples were stored at -80°C until RNA extraction. Enzymatic DNase digestion was performed to remove DNA during extraction.

[0279] After extraction, RNA was quantified using Qubit™ RNA BR Assay Kit. RNA integrity was also assessed by defining the RNA Integrity Number (RIN) and DV200 (percentage of fragments >200 nucleotides) using RNA ScreenTape and associated reagents. RNA quantification results and RIN values ​​were sent via email to the sponsor to validate the samples used for library preparation.

[0280] Library preparation and sequencing Libraries were prepared using the Illumina Stranded mRNA Prep kit according to the manufacturer's protocol. Briefly, polyA RNA was captured and fragmented. cDNA was synthesized and index anchors were ligated. Libraries were then amplified and cleaned up. Prepared libraries were quantified using the Qubit™ dsDNA BR Assay Kit and size verified with the Agilent High Sensitivity DNA kit.

[0281] All libraries were normalized, pooled, and denatured. PhiX was included in the libraries as a sequencing control. The libraries and pools containing PhiX were then loaded onto a flow cell from the NextSeq 500 / 550 High Output Kit v2.5.

[0282] Data processing and analysis Demultiplexing of raw sequencing data was performed using bcl2fastq software. Sequencing quality control was performed using FastQC software. Reads were mapped to the human genome (Hg38) and quality control metrics such as the percentage of uniquely mapped reads were generated. Exploratory data analysis was performed to validate the quality of the data. Data were normalized and differential gene expression analysis was performed to compare biological groups of interest.

[0283] Data Acquisition, Processing and Analysis Software The following systems were used for electronic capture, processing and archiving of data: [Table 7]

[0284] Example 4: Clinical trial: Efficacy study of a new cosmetic product to reduce UVB-induced erythema the purpose The objective of this exploratory study was to determine the erythema-reducing efficacy of two strengths of the test product against mild sunburn induced by a sun simulator, compared with an untreated control and a placebo product.

[0285] The subjects in this study were women and men with healthy back skin and an ITA° >28°.

[0286] Irradiation with a sun simulator induced a minimum erythema dose (MED) of 1.25 sunburn in one set of test sites and 1.6 MED in the other set of test sites. Three test sites in each set had the product applied 24 hours before irradiation, and the other three test sites in each set had the product applied immediately after irradiation. Irradiated but untreated test sites served as controls.

[0287] The efficacy of the test products was assessed by visual assessment of erythema before and after irradiation and by instrumental color measurement with a Chromameter.The study was reviewed by an independent Institutional Review Board (IRB) for ethical approval.

[0288] Efficacy evaluation The following efficacy evaluation(s) are performed: Erythema (a*) by Chromameter (see Figure 10) Visual erythema assessment (trained graders)

[0289] Type of product(s) Face care products (two different concentrations of active ingredient (Urolithin A) and placebo).

[0290] research design Randomization Double-blind placebo vs. product study Placebo control Intra-individual comparison

[0291] Statistics type -Compared to untreated

[0292] Evaluation Time Chroma Meter: Baseline (before irradiation and application) 24 hours after irradiation Visual assessment: 24 hours after irradiation [Table 8]

[0293] The test material(s) will be cosmetic products provided by the Sponsor. Test materials will be used undiluted or diluted as specified on the delivery form. Test materials will be stored at room temperature.

[0294] Test site The subject's back, in the area between the shoulder blades and the lower back, excluding the spine area.

[0295] Test site allocation Application sites are arranged in four vertical columns (two blocks of four and three). Test products are assigned to sites by rotating permutation in each block of three test sites to minimize anatomical selection bias. The same assignment is used for all four columns so that all products are placed in the same row on the dorsal surface of all four columns. Pre- and post-treatment sites are arranged in opposite columns on either side of the spine (sites 1-4 and 11-14, or 5-7 and 8-10. Untreated sites will be at the top or bottom of a row of four sites (sites 1 or 4 and sites 11 or 14), but will be centered between the two columns.

[0296] The radiation dose was 1.25 on the right side (sites 8-14) for even subject numbers and 1.25 on the left side (sites 1-7) for odd subject numbers. The radiation dose was 1.6 on the contralateral side.

[0297] Coating amount 75μl

[0298] Coating Style The test article is applied to the assigned test site on the erythematous patch using a skin patch test system (see "Patch Test System").

[0299] Patch Test System The following patch test system(s) are used: Occlusive patch test systems: Finn chambers®, large, lined with Scanpor®. Filter discs are used when the test material is highly fluid.

[0300] Study population A minimum of 22 subjects will be recruited for this study from the general population of the study site and nearby communities, with approximately 20 subjects expected to complete the study. Subjects who drop out after randomization into the study will not be replaced. All subjects will fully understand the study procedures.

[0301] All inclusion and exclusion criteria and subject instructions mentioned below will be checked by questionnaire before the start of the study and during the study. Symptoms occurring during the course of the study as well as deviations from the protocol described in the exclusion criteria and instructions will not necessarily lead to the exclusion of the subject. The investigator will decide if the subject is still eligible or not.

[0302] Inclusion criteria Written informed consent to participate in the study Willingness to actively participate in the study and attend scheduled visits Female and / or Male 18 to 65 years old - Skin color is uniform and there is no erythema or black pigmentation at the test site. -ITA°>28 at test site

[0303] Exclusion criteria Female subjects: Pregnant or breastfeeding Drug addicts, alcoholics AIDS, HIV positive or infectious hepatitis Any condition that may preclude participation or affect study response / evaluation - Participating in or waiting to participate in a cosmetic and / or pharmaceutical study related to the test site Any of the following illnesses that reduce physical ability / stamina: asthma (asymptomatic allergic asthma is not an exclusion criterion), hypertension, cardiovascular disease - Not diagnosed with cured cancer and have required chemotherapy, radiation therapy, and / or hormone therapy within the past two years Insulin-dependent diabetes mellitus Electronic implants that cannot be removed during irradiation (e.g. pacemakers, insulin pumps, hearing aids, etc.) · Records of allergies to cosmetics and / or ingredients -Active skin disease at the test site Irregularly tanned skin at the test site History of dysplastic nevi, melanoma, or other skin cancer History of abnormal reactions to sunlight Regular use of tanning beds (10 or more times in the past 6 months) Any marks, such as scars, moles, tattoos, irritated skin, or excessive hair growth at the test site that may affect the study. Use of medications known to have phototoxic and / or photosensitizing potential (e.g., some antibiotics, blood pressure regulators, and antidepressants, St. John's wort) within the last 14 days prior to the start of the study and / or throughout the course of the study Application of any topical medication to the test site within the last 7 days prior to the start of the study and / or throughout the course of the study Systemic therapy with immunosuppressants (e.g., corticosteroids) and / or antihistamines (e.g., antiallergic drugs) within the last 7 days prior to the start of the study and / or throughout the course of the study Systemic therapy with anti-inflammatory or analgesic drugs (e.g., diclofenac), except for mild analgesics such as acetylsalicylic acid or paracetamol, within the last 3 days prior to the start of the study and / or throughout the course of the study

[0304] Instructions for subjects Instructions before starting the study: Subjects are instructed not to: - Application of any leave-on cosmetic product (e.g., cream, lotion) to the test site within 3 days prior to the start of the study Apply cleansing products (e.g., soap, shampoo, bath and shower products) to the test site the morning before starting the study. -Smoking within the last 2 hours before starting the study Exposure of the test site to excessive sunlight, UV therapy, and / or artificial tanning within the last 7 days prior to the start of the study

[0305] Instructions throughout the study: Subjects are instructed not to: Applying any leave-on cosmetic products (e.g., creams, lotions) to the test sites throughout the course of the study Applying any cleansing agent (e.g., soap, shampoo, bath and shower products) to the test sites throughout the course of the study -Smoking within the last 2 hours before the measurement Exposure of test sites to excessive sunlight, UV therapy, and / or artificial tanning throughout the course of the study Apply water to the test area (e.g., do not bathe, shower carefully, do not go to the pool)

[0306] Test procedure Day 1: Subjects will come to the study site. They will be informed about the study and will provide written consent. The subjects' skin type will be classified using colorimetric skin typing.

[0307] Test sites are outlined on the subject's back with a skin marker, after which a baseline measurement is taken at all test sites using a Chromameter.

[0308] The back is then irradiated with six 0.9 cm diameter spots for measuring MED, with the UV-B dose increasing by 25% for each spot.

[0309] Application is to be made to previously treated areas (codes B-D and l-L).

[0310] Day 2: Subjects return to the study site 24±4 hours after exposure. Minimal erythema dose (MED) readings are taken and the exposure time for 1 MED is determined. The correct exposure dose at the test site is calculated by multiplying the 1 MED exposure dose by the exposure factors (1.25 and 1.6).

[0311] Patches from pre-treated test sites (codes B-G) are removed. Test article residue is carefully removed with dry soft tissue.

[0312] All test sites are irradiated at least 1 hour after patch removal according to the exposure factor (1.25 or 1.6). After irradiation, the test product is applied to the irradiated spots that will be treated after irradiation (codes E-G and M-O). Untreated irradiated control sites serve as negative controls.

[0313] Day 3: 23±2 hours after exposure, subjects return to the study site and the patches are removed. Test article residue is carefully removed with dry soft tissue. After a waiting period of at least 1 hour and up to 2 hours, a final visual evaluation and chromameter reading is made.

[0314] A time deviation of ±10% is allowed for patch removal.

[0315] Exam Schedule A scheme of the test procedure is given as Appendix 1 to the protocol.

[0316] Climate conditions Room temperature without additional air conditioning will be used during the study(s).

[0317] Instrument measurement(s) The following instrumental measurement(s) are performed: · Chromameter CR400 (Minolta, Devices D-Langenhagen, Germany): Skin color can be objectively quantified by reflectance measurements with a tristimulus chromameter. The measurement principle is based on the reflection of a xenon flash that diffusely brightens the skin at a site of 8 mm diameter. The light reflected perpendicularly from the skin is then detected by a highly sensitive silica photodiode that provides a color analysis of the detected light. The chromameter defines the measured color in the L*a*b* color coordinate system. The L* value defines the brightness. The color is defined by the parameters a* (red-green axis, negative a* values: green, positive a* values: red) and b* (blue-yellow axis, negative b* values: blue, positive b* values: yellow). The a* value correlates well with the visual assessment of skin redness (erythema), and a* is a measure of erythema. An increase in the a* value corresponds to an increase in the degree of skin redness. o Parameter: a* Skin redness o Three measurements were taken for each test site and evaluation time. · SOLAR SIMULATOR multiport 300W (SOLAR Light Co, Philadelphia, USA, with appropriate filters and light guides). This system is used with a UV transparent flexible fiber optic bundle to illuminate the test site with the required irradiance in a 1 cm diameter spot. The illuminated spots can be illuminated simultaneously. The spectrum complies with the SPF test method of ISO 24444. o One exposure per test site

[0318] Visual evaluation At the assessment times described above, trained graders will assess skin erythema for each group of radiation doses at the various test sites according to the following scale: Scoring Scale -2 = Significantly increased redness compared to negative control (untreated) -1 = slight increase in redness compared to negative control (untreated) 0 = No difference in redness compared to negative control (untreated) (no effect) 1 = slight reduction in redness compared to negative control (untreated) 2 = Significantly reduced redness compared to negative control (untreated) 3 = Completely suppresses redness

[0319] Untreated areas are set to 0.

[0320] The scores are entered directly into a PC system using an appropriate computer program.

[0321] Expected local effects using patch test system The use of tape to secure the chamber to the skin may result in a tape reaction (erythema and pruritus). This is usually limited to the area of ​​direct contact with the tape and usually resolves within a few hours. As this reaction is expected and considered a normal reaction after prolonged application of tape to the skin, tape reactions will not be documented.

[0322] In the event of severe tape reactions that may affect the scoring of the test sites, these reactions and the results of the evaluation of each test site will be documented.

[0323] Potential local effects of UV radiation When the skin is exposed to UV radiation, a sunburn (erythema) may occur. This is usually limited to the area that was in direct contact with the UV radiation. This reaction is expected and is considered a normal reaction after a given period of exposure. It is documented in the study along with the reading score. Only if there are abnormal reactions are these reactions and the consequences for the performance of each test site documented.

[0324] side effects According to ICH GCP, an adverse reaction (AR) is defined as "any adverse and unintended reaction to a medicinal product associated with any dose." In clinical studies with cosmetics, consumer products, or medical devices, the following interpretation is adopted: the phrase "reaction to a medicinal product" means that there is at least a reasonable possibility of a causal relationship between the test material and the adverse event (AE), i.e., the relationship cannot be excluded. Thus, an AE that the physician classifies as having at least a "possible" (i.e., possible, probable) causal relationship with the test material is defined as an AR.

[0325] All adverse events (except for parameters scored as part of the protocol) will be recorded in the study records. The obligation to document ARs runs from the time the subject is enrolled in the study until 5 days after the last dose of test article (if reported by the subject).

[0326] In case of an AR, it is the investigator's responsibility to notify the sponsor within three business days at the latest. ARs will also be reported in the final report.

[0327] Analyzing data In this study, the following analyses are defined:

[0328] Statistical data analysis A significance level of 0.05 (alpha) will be selected for statistical analysis. Due to the exploratory nature of this study, no adjustment for multiplicity will be performed.

[0329] Equipment measurement: Pairwise comparisons of treatments will be performed by paired t-tests for differences from baseline. In each of the four groups: (A, B, C, D), (A, E, F, G), (H, I, K, L) and (FI, M, N, 0). Before / after within the erythema dose: (B, E) (C, F), (D, G), (l, M), (K, N), (L, 0) Between erythema doses: (A,H), (B,l), (C,K), (D,L), (E,M), (F,N), (G,0).

[0330] Visual assessment: Pairwise comparisons of treatments will be performed by Wilcoxon signed-rank tests on raw data. In each of the four groups: (A, B, C, D), (A, E, F, G), (H, I, K, L) and (H, M, N, 0). Before / after within the erythema dose: (B,E) (C,F), (D,G), (l,M), (K,N), (1,0) Between erythema doses: (A,H), (B,l), (C,K), (D,L), (E,M), (F,N), (G,0).

[0331] Statistical data calculations are performed using commercially available statistical software (SAS for Windows). [Table 9]

[0332] result As expected, all erythema (a*) values ​​measured 24 hours after irradiation were higher than baseline for all treatment codes, indicating that sunburn occurred at all sites tested. The study showed that skin cream containing 1% Urolithin A caused significantly less skin redness at 1.6 MED UVB dose compared to the respective untreated sites as measured by the Chromameter (p=0.02, Figure 10). Skin redness / erythema was reduced by approximately 14.3%. This is consistent with the reduction in pro-inflammatory mediators (PGE2 levels) observed in Figure 1 in reconstituted human epidermis after UVB exposure. In this clinical study, skin cream containing a 0.5% dose of Urolithin A or placebo showed no significant effect on skin redness / erythema

[0333] Example 5 (Aging Study 1) Clinical trial: Evaluation of the anti-aging effect of a new cosmetic product containing only Urolithin A 1.1 Purpose The aim of this proof-of-concept study was to investigate the effect of a cosmetic product containing two different concentrations of the active ingredient on skin ageing and its effect on mitochondrial function compared to a placebo product.

[0334] The study will enroll female subjects between the ages of 50 and 75 who have visible facial wrinkles.

[0335] To analyze mitochondrial effects, biopsies will be taken from a sub-panel of the volar forearm before and after 8 weeks of product application and analyzed for biomarkers by a third party (see Figures 2 and 4).

[0336] The effect of the test article on the skin barrier function is evaluated by transepidermal water loss (TEWL) at the beginning, after 2 weeks, and after 8 weeks of product application. In addition, the effect on the facial skin on skin hydration (by Corneometer), skin elasticity and firmness (by Cutometer), and skin color (by Spectrophotometer) is investigated. Furthermore, the thickness of the skin layer and the shape index of the dermal-epidermal junction (DEJ) are measured by line-field confocal optical coherence tomography (LC-OCT). Images for wrinkle analysis and documentation purposes are taken on the color face. A questionnaire on product characteristics is completed after 2 weeks of product application and at the end of the study.

[0337] Primary endpoints: Change from baseline in skin mitochondrial health after 8 weeks (assessed by skin biopsy) Change from baseline in skin barrier function (assessed by transepidermal water loss) after 8 weeks

[0338] Additional achievements: -Change from baseline in skin barrier function after 2 weeks (transepidermal water loss assessment) Change from baseline in skin hydration (assessed by skin volume) after 2 and 8 weeks Change from baseline in pigmentation (assessed as skin color) after 2 and 8 weeks Change from baseline in skin firmness after 2 and 8 weeks Change from baseline in skin elasticity after 2 and 8 weeks Changes from baseline in skinfold thickness and DEJ waviness index (assessed by LC OCT imaging analysis) after 8 weeks for both groups, or after 2 and 8 weeks for only one group* Change from baseline in wrinkles and fine lines after 2 and 8 weeks (assessed by color face image analysis) Subjective evaluation of product characteristics assessed by questionnaire after 2 and 8 weeks *At the discretion of the sponsor depending on the results of other instrumental measurements

[0339] 1.2 Evaluation of efficacy The following efficacy evaluation(s) are performed: Sponsor / third-party biomarker analysis of 3mm punch biopsies from 30 subjects (15 per group) · Transepidermal water loss (TEWL) by Tevameter [g / (m2h)j Skin hydration - Skin capacitance [auj] by corneometer (see Figure 8) ·Skin color by spectrophotometer Skin hardness - R0(Uf)[mm] by cutometer Skin Elasticity - R7 (Ur / Uf) by Cutometer ·Image analysis by Damae** using line-field confocal optical coherence tomography (LC-OCT): (a) Thickness of skin layers (epidermis and stratum corneum) (b) Shape index of the dermo-epidermal junction (DEJ) - Image analysis of color face images using Newtone (a) Analysis of wrinkles and fine lines (see Figure 7) (b) Creating an average face Product characteristics questionnaire ** Depending on the results of other instrumental measurements, analyses will be performed at three time points for one group or at two time points for two groups, as determined by the sponsor

[0340] 1.3 Tolerability assessment Not applicable

[0341] 1.4 Type of product(s) Face care products (two different concentrations of active ingredient (Urolithin A) and placebo)

[0342] 1.5 Research overview ·Exploratory purpose Randomization Double Blind Intra-individual comparisons (before and after treatment) Placebo control

[0343] 1.6 Types of Statistics Comparison between treatments Evaluation time comparison

[0344] 1.7 Evaluation Time Baseline (Day 1) Day 15 (2 weeks after application) Day 57 (8 weeks after application) [Table 10]

[0345] The test material(s) are cosmetic products, and the test materials are used undiluted or diluted as specified in the delivery form. The test materials are stored at room temperature.

[0346] 2.2 Test site The face and volar forearm (for biopsy), which are shown in Figure 23.

[0347] 2.3 Test site allocation Site 1 is on the right side of the face and site 2 is on the left side. Sites 1 and 2 are used for instrumental measurements. For the biopsy subpanel, site 3 is on the right forearm and site 4 is on the left forearm.

[0348] The study items will be randomly and balanced between the right and left sides of the face (and the left and right volar forearm for the biopsy subpanel). For the biopsy subpanel, the treatment code assignment (right vs. left) will be the same for the face and the volar forearm.

[0349] Each group of 24 subjects will receive either the test product or a placebo.

[0350] Fifteen subjects from each group will be randomly selected to be included in the biopsy subpanel.

[0351] 2.4 Application amount Approximately 2mg / cm2 Face: The amount needed for half the face (including the eye area) is approximately the size of a hazelnut of the test product. Volar Forearm: The amount needed for each volar forearm is approximately equivalent to a pea-sized amount of test article.

[0352] 2.5 Application type and frequency If the test article(s) is to be used by the subject himself / herself, appropriate instructions will be given to the subject verbally and, if deemed necessary, in writing.

[0353] Correct application of the product will be demonstrated by the technician during the first application on Day 1. Application training will then be followed by subjects applying the test material(s) at home twice daily, in the morning and evening, for 8 weeks.

[0354] Subjects are instructed to use the test product in the morning and evening each day.

[0355] On day 15, subjects will be instructed not to apply the test article in the morning before visiting the study center; morning application will occur on-site after all evaluations.

[0356] 2.6 Accountability and Subversion Accountability for the test item(s) at the study site rests with ProDerm. Records of receipt of test items and disposition of unused product(s) or alternate return to Sponsor will be kept, and ProDerm will ensure that the test item(s) are used as directed in this protocol. Test materials remaining at the conclusion of the study will be destroyed at least 6 weeks after issuance of the final report, unless otherwise requested.

[0357] 2.7 Duration of treatment 8 weeks per subject

[0358] 2.8 Post-treatment products After completion of the study, the subpanel who underwent biopsy will be given a post-treatment product (sunscreen for sensitive skin, SPF50+) to use when exposing the biopsy wound to sunlight.

[0359] 3 Study population 3.1 Subject number A minimum of 48 subjects (24 subjects per group) will be recruited for this study from the general population of the study site and nearby communities, and approximately 40 subjects (20 per group) are expected to complete the study. Subjects who drop out after randomization into the study will not be replaced. All subjects will fully understand the study procedures.

[0360] 3.2 Subject Selection All inclusion and exclusion criteria and subject instructions mentioned below will be checked by questionnaire before the start of the study. Symptoms occurring during the course of the study as well as deviations from the protocol described in the exclusion criteria and instructions will not necessarily lead to the exclusion of the subject. The investigator will decide if the subject is still eligible or not.

[0361] Subjects will be instructed to inform the study site of any medical problems or changes in treatment.

[0362] Inclusion criteria Written informed consent to participate in the study Willingness to actively participate in the study and attend scheduled visits ·woman 50 to 75 years old Visible facial wrinkles (ProDerm Scale grades 3-6) See Appendix 2 The skin at the test site is healthy. - Having received a tetanus vaccination within the past 10 years (for the biopsy subgroup)

[0363] Exclusion criteria Female subjects: Pregnant or breastfeeding Drug addicts, alcoholics AIDS, HIV positive or infectious hepatitis Any condition that may preclude participation or affect study response / evaluation - Participating in or waiting to participate in a cosmetic and / or pharmaceutical study related to the test site - Not diagnosed with cured cancer and have required chemotherapy, radiation therapy, and / or hormone therapy within the past two years Diabetes (type 1 and type 2) Any of the following illnesses that reduce physical ability / stamina: asthma (asymptomatic allergic asthma is not an exclusion criterion), hypertension, cardiovascular disease · Records of allergies to cosmetics and / or ingredients, skin care and / or skin cleansing products Intolerance to adhesive dressings (e.g. acrylates) -Active skin disease at the test site Regular use of tanning beds Any marks, such as scars, moles, tattoos, irritated skin, or excessive hair growth at the test site that may affect the study. - Application of topical medication to the test site within the last 3 days prior to starting the study Medical treatment to reduce facial wrinkles (e.g., peeling with vitamin A or fruit acids) within the last 2 weeks prior to the start of the study Systemic therapy with immunosuppressants (e.g., corticosteroids) and / or antihistamines (e.g., antiallergic drugs) within the last 7 days prior to study initiation - Systemic therapy with anti-inflammatory or analgesic drugs (e.g., diclofenac) within the last 3 days prior to the start of the study, except for mild analgesics such as paracetamol -Having received antibiotic treatment within the past 2 weeks prior to the start of the study Regularly taking anticoagulants (e.g., for thrombosis prevention), such as Aspirin or Macular, within 15 days prior to the biopsy Previous cosmetic surgery in the test area (e.g., laser, facelift) History of wound healing complications (e.g., keloids, hypertrophic scars, contracture scars)

[0364] Instructions throughout the study: Subjects are instructed not to: -Smoking within the last 2 hours before the measurement Drinking caffeinated beverages (e.g., coffee, cola, tea) within the last 2 hours prior to device measurement - The test area must have been in contact with water within the last 2 hours prior to the device measurement (e.g., no bathing or swimming, only careful showering except for the test area). Any product with the same indication as the test product may be applied to the test site throughout the course of the study. Applying any leave-on cosmetic products (e.g., creams, lotions) to the test sites throughout the course of the study Applying any cosmetic products (e.g., mascara, eye shadow, make-up, powder, and other covering products) to the test site at the scheduled visit Removal of hair from test sites throughout the course of the study (e.g., shaving, depilating, waxing) Exposure of test sites to excessive sunlight, UV therapy, and / or artificial tanning throughout the course of the study After biopsy sampling, apply water to the test site until the wound heals (e.g., no bathing, careful showering, no swimming pools, no saunas)

[0365] Subjects are instructed to: If the test area is exposed to artificial or natural UV rays, use the provided sunscreen on the wound for 8 weeks after the wound has healed. After biopsy sampling, wear a wound dressing on the biopsy wound for approximately 5 days. - Wear a long-sleeved shirt or hat if the test site is exposed to strong sunlight throughout the study. - The final application of the test product(s) should be done the evening before the scheduled visit. Apply the test product(s) to the test site(s) as follows (per ProDerm instructions): twice daily throughout the course of the study Continue to use routine cleaning products (e.g., soap, shampoo, bath and shower products) at the test sites, but do not change brands or use new products throughout the course of the study. Continue to use cosmetic products (e.g., mascara, eye shadow, make-up, powder, and other covering products) that you normally use at the test site, but do not change brands or use new products throughout the course of the study.

[0366] 5. Test Procedure 5.1 Description of test procedure screening: Subjects arrive at the study site. Subjects are informed about the study both verbally and in writing and give written consent. The suitability of each subject is assessed according to the inclusion / exclusion criteria. Prior / concurrent diagnoses and prior / concomitant medications relevant to the study are recorded. Subjects who meet the inclusion / exclusion criteria are enrolled in the study.

[0367] Day 1: Subjects arrive at the study site and after an acclimation period, images are taken and instrumental measurements (baseline) of the test sites are performed. Biopsy involves subpanel biopsies on the volar aspects of both forearms.

[0368] The test product(s) will be issued to the subject with instructions for use at the assigned test site and a diary will be provided to record product application. Allocation of test product(s) will be made according to a randomization scheme provided by ProDerm. The first product application will be made under the guidance of a technician. The subject will make one further application at home.

[0369] Days 2-14: Subjects will use the test product(s) as described above (see Application Modality) and record product application in the diary. The final product application will occur the evening before the next study site visit.

[0370] For the biopsy subpanel: If the biopsy wound has not healed by day 8, you will be instructed to notify the study site.

[0371] Day 15: Subjects return to the study site. After an acclimation period, images and instrumental measurements of the test sites are repeated. Diaries are checked by a technician, a questionnaire regarding product characteristics is completed by the subject, and biopsy wounds are followed up, if applicable. Product application is then performed under the guidance of a technician. Subjects perform one further application at home.

[0372] Days 16-56: Subjects will use the test product(s) as described above (see Application Modality) and record product application in their diary. The final product application will occur the evening before the next study site visit.

[0373] Day 57: Subjects return to the study site. After an acclimation period, imaging and instrumental measurements of the test sites are repeated and subjects complete a questionnaire regarding the test material properties of the test article. The remaining test materials and diary are returned. Biopsy involves repeat subpanel biopsies on the volar sides of both forearms.

[0374] Biopsy subpanel follow-up visit (7 / ±2 days after last biopsy sampling) Subjects will return to the study site for follow-up of their wounds. Subjects will be provided with sunscreen and instructed to continue using it on the test areas for the next 8 weeks.

[0375] A deviation of ±2 days is acceptable as it is not expected to have any substantial effect on the study results.

[0376] 5.2 Climatic conditions The instrumental measurement(s) will be performed in an air-conditioned room with a temperature of 22+2°C and a relative humidity of 50±7.5%. Prior to the measurements, subjects will stay in the climate-controlled room for at least 30 minutes.

[0377] 5.3 Test Schedule A scheme of the test procedure is given as Appendix 1 to the protocol.

[0378] 5.4 Instrumental measurement(s) The following instrumental measurement(s) are performed:

[0379] Tevameter® TM300 (Courage & Khazaka, Cologne, Germany): Transepidermal water loss (TEWL) is a non-invasive method to measure skin barrier function and is considered a sensitive parameter to quantify damage to the skin barrier. Briefly, the insensible evaporation of water from the skin is It is measured by placing a cylindrical open chamber containing two humidity sensors at a given distance from the skin.

[0380] The probe is kept in place for 30 seconds for each measurement to ensure that a stable value is established. The first part of the measurement belongs to this equilibration phase. The values ​​from the last 10 seconds (=10 values) are averaged as the actual measurement. -One measurement per test site and evaluation time

[0381] Spectrophotometer (CM700d, Minolta, Langenhagen, Germany): Skin reactions are objectively quantified using reflectance measurements with a tristimulus spectrophotometer. The spectrophotometer allows reflected color measurements in CIE L*a*b* units (CIE1976). The measurement principle is based on the reflection of a xenon flash that illuminates the object diffusely and uniformly.

[0382] The CIE L*a*b* color space is device independent. The L* value defines the lightness. The color is defined by the parameters a* (red-green axis, negative a* values: green, positive a* values: red) and b* (blue-yellow axis, negative b* values: blue, positive b* values: yellow). - Three replicate measurements per test site

[0383] Cutometer MPA 580 (Courage&Khazaka, Cologne, Germany). The measurement principle is based on sucking the skin into an opening with a diameter of 2 mm. A defined vacuum of 300 mbar is introduced into the measuring head. The measuring head is placed on the skin with a defined pressure and the skin is sucked into the measuring head opening for 5 seconds, then released and measured for another 5 seconds. Using an optical measuring system, the extent to which the skin has been sucked into the measuring head is detected contactlessly and this value together with the ability of the skin to return to its original state gives a measure of the skin's elasticity.

[0384] Parameters: R0 total elasticity (=Uf=first maximum amplitude, highest point of the first curve) R7 Quotient of elastic relaxation and total elasticity (=Ur / Uf= the part of elasticity compared to the perfect curve, the closer the value is to 1 (100%), the more elastic the curve is -One measurement per test site and evaluation time

[0385] Corneometer CM 825 (Courage & Khazaka, Cologne, Germany): The measurement of the hydration of the stratum corneum is carried out by the capacitance method with the Corneometer. The measurement principle is based on the change in capacitance of the measuring head, which acts as a capacitor. An electric field is created between the conductors made of gold. By these means the dielectric constant of the upper skin layers is measured. Since the dielectric constant changes as a function of the water content of the skin, the hydration of the stratum corneum can be measured. -Five measurements per test site and evaluation time

[0386] LC-OCT 800 3D (DAMAE Medical, Paris, France): Line-field confocal optical coherence tomography is a technique that combines the principles of time-domain optical coherence tomography and confocal microscopy. With this technique, skin can be imaged in vivo in its live state without further preparation. This method allows in vivo mapping of the skin by measuring the echo time delay and amplitude of light backscattered from the skin microstructure through low-coherence interferometry associated with confocal spatial filtering. Using the live vertical, live horizontal, and 3D modes, the various layers of the epidermis, dermis, and dermo-epidermal junction can be clearly imaged. For the 3D mode, a 3D stack with a size of 1.2mmx0.5mmx0.5mm is generated with a resolution of 1.3pmx1.3pmx1.1pm. · Two 3D acquisitions will be evaluated at each test site.

[0387] Parameters: -Thickness of skin layers (epidermis and stratum corneum) - Shape index of the dermo-epidermal junction

[0388] Colorface® PHOTOBOX (Newtone Technologies, Lyon, France): Colorface® is used for standardized computer-controlled facial photography. It is equipped with a 24-megapixel Nikon camera and various LED flashes at fixed positions in the booth. Facial lighting is The acquisition of the fluorescence images is carried out using TIFF2025510123000017.tif20114. The color face acquisition software is used as the image database, but also defines the settings for each study. All settings are fixed to avoid unnecessary changes of the image capture parameters. The equipment allows the photographing of the face with high quality and the same lighting at different evaluation times. Images are taken for the following face positions: TIFF2025510123000018.tif15114 - one image per configuration, face position and evaluation time -Data is stored in the Newtone Imaging Access Cloud -Images will be provided to Sponsor in an anonymized manner where possible (e.g. black bars covering the eyes).

[0389] 5.5 Research method(s) The following investigative method(s) will be performed: Biopsy Removal: The room used to take the biopsy is disinfected. The subject is asked to lie on a bench in an appropriate position to ensure the biopsy site is accessible. A medical professional cleanses the area of ​​the skin where the biopsy will be performed with an antiseptic spray (e.g., Octenisept®). A local anesthetic (e.g., 1% Skandicain®) is administered subcutaneously to the biopsy site using a sterile syringe fitted with an appropriate sterile needle prior to the biopsy removal. A punch biopsy (3 mm) is sampled by the physician using a punch biopsy instrument. The biopsy includes the epidermis and dermis. Each biopsy sample is appropriately labeled (e.g., study number, subject number).

[0390] This procedure induces only small wounds. This procedure induces only small wounds. After the biopsy excision, the wound is closed with SteriStrips® or sutured with stitches as needed and covered with a protective dressing. The subject is provided with a waterproof dressing to cover the wound after the skin biopsy is taken. The wound should be kept dry until it heals. Instructions for changing the dressing and for spare dressings are provided to the subject.

[0391] Pigmentation may occur after healing of the lesions. Patients are informed of this and further possible side effects. To reduce the risk of pigmentation, patients will be instructed to avoid sunlight on the test sites and / or use sunscreen after the study is performed.

[0392] Number of biopsies Days 1 and 57: One biopsy per study site and evaluation time (a total of four biopsies per subject)

[0393] Handling of biopsy After biopsy sampling, the biopsy is cut into two parts and the parts are stored separately in sterile Eppendorf tubes. One part is collected in a tube without buffer. The second part is stored in a tube with 1 ml of RNA-later (RNAIater™ Solution AM7024, Thermo Fisher Scientific) buffer to prevent RNA degradation. · Samples will be flash frozen in liquid nitrogen until further processing, stored on dry ice until the end of the study day, and stored at -80°C until shipment. · To minimize cross-contamination of samples, individuals preparing samples should wear fresh gloves.

[0394] Biopsy storage and shipping Biopsies will be stored at -80°C. Samples will be shipped on dry ice by appropriate World Courier upon completion of the study (next business day unless otherwise requested).

[0395] Analysis of biopsies (next step without contacting the subject) Analysis of the biopsies will be performed by the sponsor and selected third parties.

[0396] The following evaluations are performed: -Transcriptomics of skin biopsies -Analysis of protein biomarkers of cell health

[0397] Gene set enrichment analysis (GSEA) is employed to look for overrepresentation of known mitochondrial pathways and gene function categories among regulatory genes expressed in human skin. Genes are ranked and filtered by fold change (high to low) in GSEA analysis to reduce the risk of false positives (unadjusted P-value 0.1 before use). Gene sets defined by the Gene Ontology (GO) Consortium (http: / / www.geneontology.org / ) are analyzed.

[0398] 5.6 Image analysis The analysis is performed by an external partner and a separate report is produced by the external partner (Newtone).

[0399] Color facial images of the test sites are evaluated for:

[0400] Crow's Feet Analysis: Parameters: Visible Length, Visible Surface, Visible Depth, Visible Volume Lighting: STD60 View: Profile: Right and Left Part: Crow's feet

[0401] Average 2D face: On average, one face per group One application of crow's feet to each half face (best case per group as selected by sponsor), one view, face or profile to D1, D15 and D57

[0402] 5.7 Survey on subject acceptance of product Product characteristics are evaluated by subjects and checked with predefined identical options It consists of closed questions including: -2 = Strongly disagree -1 = Somewhat disagree 1=Somewhat agree 2=I completely agree

[0403] In this study, a skin cream containing a high dose of 1% Urolithin A showed a significant effect in reducing wrinkle depth after 8 weeks of topical application (see Figure 7). This anti-wrinkle effect was not observed with lower doses of Urolithin A, as was the case with the 0.5% skin cream (Figure 12), which did not affect the same parameters. The effect was time-dependent, with effects observed as early as 2 weeks after topical application and significantly enhanced by week 8 (Figures 13, 14). The anti-wrinkle effect of 1% Urolithin A administration is supported by the molecular signature observed in skin biopsies, suggesting that a 1% dose of Urolithin A has a significant impact on collagen organization in aged skin, showing a significant upregulation of collagen genes (Figures 2 and 4). Age-related collagen degradation and decreased collagen synthesis are key features of skin aging (Figures 2 and 3). The observation that precise local administration of 1% Urolithin A may have a wrinkle-reducing effect via its effect on collagen tissue is a unique finding from this study.

[0404] Example 6 (Aging Study 2) Clinical trial: Evaluation of the anti-aging effects of a new cosmetic product containing Urolithin A, trehalose and niacinamide the purpose The objective of this exploratory study was to evaluate the anti-wrinkle efficacy of a cosmetic product compared to an untreated control.

[0405] The study will enroll female and male subjects between the ages of 40 and 65 with healthy skin and visible wrinkles in the periorbital area.

[0406] After a washout period, the test product is applied to one half of the face for 8 weeks. Evaluations are conducted before and after 2, 4, and 8 weeks of product application.

[0407] Anti-wrinkle efficacy will be evaluated in the periorbital area by investigating the three-dimensional structure of wrinkles (DermaTOP). Skin hydration, skin elasticity efficacy and skin barrier function will be investigated by Corneometer, Cutometer and Tevameter measurements. In a subgroup of 12 subjects, the ceramide content, including barrier lipids, in the stratum corneum will be measured by Raman spectroscopy.

[0408] Additionally, images are taken (USR-Clip) and then evaluated by trained graders for anti-wrinkle and skin radiance benefits.

[0409] In addition, subjects will complete a questionnaire regarding product characteristics 2, 4 and 8 weeks after product application.

[0410] The study will be reviewed by an independent Institutional Review Board (IRB) for ethical approval.

[0411] Efficacy evaluation The following efficacy evaluation(s) are performed: Skin roughness - Ra [μm] by DermaTOP Skin Roughness - Rz [μm] by DermaTOP Skin hardness - R0(Uf)[mm] by cutometer Skin Elasticity - R7 (Ur / Uf) by Cutometer Skin hydration - Corneometer skin capacitance [au] Transepidermal water loss (TEWL) by Tevameter [g / (m 2 h)] Ceramide [au] by Raman spectroscopy in a subgroup of subjects (n=12 per test group) Photo documentation with USR-Clip (Hasselblad) Image scoring for skin radiance and wrinkle improvement [trained scorers] Product characteristics questionnaire

[0412] Type of product(s) Face care products (1 day cream, 1 night cream, 1 eye cream, 1 serum)

[0413] (Day cream, night cream, eye cream, serum) ingredients Day Cream 1% Urolithin A 3% Niacinamide 0.25% trehalose 0.0015% Nicotiana sylvestris leaf cell culture 1.65% isomerized sugar

[0414] Other ingredients in the day cream: Aqua (Water), Glycerin, Butylene Glycol, Dicaprylyl Carbonate, Glyceryl Stearate Citrate, Squalane, Cetyl Alcohol, Ammonium Acryloyldimethyltaurate / Vp Copolymer, Butyrospermum Parkii (Shea) Butter, Hydroxyacetophenone, Xanthan Gum, 1,2-Hexanediol, Caprylyl Glycol, Tocopheryl Acetate, Sodium Phytate, Camellia Japonica Leaf Extract, Hydrolyzed Opuntia Ficus-Indica Flower Extract, Alcohol, Sodium Lactate, Carbomer, Citric Acid, Sodium Citrate, Coco-Glucoside, Sodium Hyaluronate, Tocopherol, Palmitoyl Tripeptide-1, Palmitoyl Tetrapeptide-7.

[0415] Night Cream 1% Urolithin A 3% Niacinamide 0.25% trehalose 0.5% caffeine 0.5% D-panthenol 2.75% high fructose sugar 0.0875% Hydrolyzed Opuntia Ficus-Indica Flower Extract 0.002% Opuntia ficus-indica stem extract 0.0002% Opuntia ficus-indica callus culture extract

[0416] Other ingredients in the night cream: Aqua (Water), Glycerin, Butylene Glycol, Diglycerin, Dicaprylyl Carbonate, Saccharide Isomerate, Glyceryl Stearate Citrate, Ammonium Acryloyldimethyltaurate / vp Copolymer, Squalane, Sorbitol, Behenyl Alcohol, Cellulose, Undecane, Hydroxyacetophenone, Tridecane, Sodium Stearoyl Glutamate, 1,2-Hexanediol, Caprylyl Glycol, Camellia Sinensis Leaf Extract, Alcohol, Citric Acid, Sodium Lactate, Sodium Citrate, Carbomer, Coco-glucoside, Sodium Hyaluronate, Tocopherol, Palmitoyl Tripeptide-1, Palmitoyl Tetrapeptide-7,

[0417] Eye cream 1% Urolithin A 1% Niacinamide 0.25% trehalose

[0418] Other ingredients in the eye cream: Aqua (Water), Glycerin, Dicaprylyl Carbonate, Propanediol, Squalane, Undecane, Caprylic / Capric Triglyceride, Glyceryl Stearate Citrate, 1,2-Hexanediol, Behenyl Alcohol, Cetyl Alcohol, Butylene Glycol, Tridecane, Sodium Polyacrylate, Pullulan, Hydroxyacetophenone, Ethylhexylglycerin, Caprylyl Glycol, Xanthan Gum, Camellia Sinensis Leaf Extract, Nannochloropsis Oculata Extract, Pentylene Glycol, Sodium Hydroxide, Trumpet Halibut Flower / Leaf / Stem Extract, Alcohol, Sodium Lactate, Carbomer, Coco-Glucoside, Sodium Hyaluronate, Tocopherol Citric Acid, Capsicum Annuum Leaf Extract, Palmitoyl Tripeptide-1, Palmitoyl Tetrapeptide-7.

[0419] Serum 1% Urolithin A 5% Niacinamide 0.25% trehalose 0.5% caffeine 0.825% isomerized sugar 1% D-Panthenol 0.0875% Hydrolyzed Opuntia Ficus-Indica Flower Extract

[0420] Other ingredients in the serum: Aqua (Water), Glycerin, Butylene Glycol, Caprylic / Capric Triglyceride, Hydrogenated Lecithin, Hydroxyacetophenone, Ammonium Acryloyldimethyltaurate / VP Copolymer, Xanthan Gum, 1,2-Hexanediol, Caprylyl Glycol, Sodium PCA, Camellia Sinensis Leaf Extract, Alcohol, Erythritol, Phytic Acid, Sodium Lactate, Sodium Hydroxide, Chondrus Crispus (Carrageenan), Pentylene Glycol, Citric Acid, Carbomer, Coco-Glucoside, Sodium Hyaluronate, Benzoic Acid, Sodium Citrate, Sorbic Acid, Palmitoyl Tripeptide-1, Palmitoyl Tetrapeptide-7, Nicotiana Benthamiana Hexapeptide-40 SH-Polypeptide-47

[0421] research design ·exploratory Randomization · Blinding of sponsor labels (unbranded products) Intra-individual comparison

[0422] Statistics type Comparison of each group / subgroup (n=12) with untreated subjects in terms of Raman measurements Comparison of evaluation times for each group / subgroup (n=12) in Raman measurements

[0423] Evaluation Time Baseline (Day 1) Day 15 (2 weeks after application) Day 29 (4 weeks after application) Day 57 (8 weeks after application)

[0424] Test materials Study group code / ProDerm → product / code / sponsor / concentration Group 1 A untreated B Day Cream Group 2 A untreated C Night Cream Group 3 A untreated D Eye Cream Group 4 A untreated E Serum

[0425] The test material(s) will be cosmetic products provided by the sponsor. If applicable, test and control materials will be identified by a proderm code (e.g., "A", "B", etc.) and / or sponsor identification code for the separate delivery form. Test materials will be used undiluted or diluted as specified on the delivery form. The sponsor will identify the potential hazards of test materials provided by the sponsor or its designee(s) in connection with this study. It will be the sponsor's responsibility to determine the identity, strength, purity, composition, and other characteristics that adequately define the test material for each batch of product prior to use in the study. Determination of the stability of the test material and documentation of the method of synthesis or derivation are also the sponsor's responsibility. Test materials will be stored at room temperature in the container in which they were received unless otherwise specified on the delivery form. Test materials remaining at the conclusion of the study will be destroyed at least six weeks after issuance of the final report, unless otherwise requested.

[0426] Test site Face (Split Face) Measuring area: Crow's feet areas: DermaTOP Cheekbones: Cutemeter, Corneometer, Tevameter, Raman

[0427] Test site allocation Randomization: Subjects are divided equally into four groups: Group 1 receives treatments A and B, Group 2 receives A and C, Group 3 receives A and D, and Group 4 receives A and E. Treatments are randomly assigned in a balanced manner to the left and right test areas within each group.

[0428] Washout Products ISANA MED, Wash Lotion for Sensitive Skin

[0429] Length of washout period At least 7 days.

[0430] Standard Cleaning Procedure Subjects will receive washout products (silicone-free, soap / alkali-free, paraben-free) provided by the study site, which will be used according to the following instructions beginning 7 days prior to the start of the study and continuing throughout the duration of the study.

[0431] The washout product is used once daily in the evening, with water only being used in the morning during the washout period and during the study period (just prior to application of the test article).

[0432] Coating amount Approximately 2mg / cm 2 Under normal use conditions, a hazelnut-sized amount is applied to one half of the face for day creams, night creams and serums, and a pea-sized amount is applied around the eye area for eye cream. The correct amount of test product applied is verified by a technician on-site.

[0433] Application type and frequency The test article will be applied by the subject at home once or twice daily. If the subject is to use the test article himself, appropriate verbal and written instructions will be given to the subject.

[0434] The following application frequencies are carried out for each test article over an 8 week period: Code B: Day cream: once a day in the morning Code C: Night cream: once a day in the evening Code D: Eye cream: twice a day in the morning and evening (pat lightly around the eyes) Code E: Serum: twice a day, morning and evening

[0435] The first application of the test article will occur at the study site under the supervision of a technician on Day 1, leaving one area untreated. The test material will then be applied by subjects at home over a period of 8 weeks, following application training.

[0436] On days 15, 29, and 57, subjects will be instructed not to apply the test article in the morning before visiting the study center; morning applications will occur on-site after all evaluations.

[0437] Length of washout period At least 7 days.

[0438] Standard Cleaning Procedure Subjects will receive washout products (silicone-free, soap / alkali-free, paraben-free) provided by the study site, which will be used according to the following instructions beginning 7 days prior to the start of the study and continuing throughout the duration of the study.

[0439] The washout product is used once daily in the evening, with water only being used in the morning during the washout period and during the study period (just prior to application of the test article).

[0440] Washout Products ISANA MED, Wash Lotion for Sensitive Skin

[0441] Study population A minimum of 144 subjects will be recruited for this study from the study site location and nearby communities, with approximately 120 subjects expected to complete the study. Subjects who drop out after randomization into the study will not be replaced. All subjects will fully understand the study procedures.

[0442] All inclusion and exclusion criteria and subject instructions mentioned below will be checked by questionnaire before the start of the study and during the study. Symptoms occurring during the course of the study as well as deviations from the protocol described in the exclusion criteria and instructions will not necessarily lead to the exclusion of the subject. The investigator will decide if the subject is still eligible or not.

[0443] Inclusion criteria Written informed consent to participate in the study Willingness to actively participate in the study and attend scheduled visits · Women and men Between 40 and 65 years old BMI<30kg / m2 The skin at the test site is healthy. · Skin at the test site is of uniform color and free of erythema or black pigmentation (except for subjects of black ethnicity) Visible facial wrinkles (ProDerm Scale grades 3-6) See Appendix 2 Ethnicity: At least one Black, Asian, and Hispanic subject per study arm

[0444] Exclusion criteria Female subjects: Pregnant or breastfeeding Drug addicts, alcoholics AIDS, HIV positive or infectious hepatitis Any condition that may preclude participation or affect study response / evaluation - Participating in or waiting to participate in a cosmetic and / or pharmaceutical study related to the test site -Active skin disease at the test site Documentation of allergies to face / eye care products ·Diabetes - Not diagnosed with cured cancer and have required chemotherapy, radiation therapy, and / or hormone therapy within the past two years Any of the following illnesses associated with reduced physical ability / stamina: asthma (asymptomatic allergic asthma is not an exclusion criterion), hypertension (uncontrolled by medication), cardiovascular disease Epilepsy Any marks, such as scars, moles, tattoos, scars, irritated skin, excessive hair growth, or freckles at the test site that may affect the study. Sun-tanned skin (important for the subgroup of subjects for whom Raman measurements are planned) Regular use of tanning beds - Application of topical medications to the test site within the last 7 days prior to starting the study Patients who have received systemic therapy with immunosuppressants (e.g., corticosteroids) and / or antihistamines (e.g., antiallergic drugs) within the last 7 days prior to study initiation Previous cosmetic surgery in the test area (e.g., laser, facelift) - Have had cosmetic surgery, such as IPL (intense pulsed light), Botox, chemical peels, or dermabrasion, in the study area within the last 2 years prior to the start of the study and / or throughout the course of the study Medical treatment to reduce facial wrinkles (e.g., peeling with vitamin A or fruit acids) within the last 2 weeks prior to the start of the study

[0445] Instructions for subjects Instructions before starting the study: Subjects are instructed not to: Not applicable Subjects are instructed to: Not applicable

[0446] Instructions throughout the study: Subjects are instructed not to: Applying any cleansing products (e.g., soap, shampoo, bath and shower products) other than the washout product provided to the test site throughout the washout period Apply any cleansing agent (e.g., soap, shampoo, bath and shower products) to the test site the morning before the scheduled visit. Applying leave-on cosmetic products (e.g., creams, lotions) other than the test product to the test sites throughout the course of the study Applying cosmetic products (e.g., mascara, eye shadow, makeup, powder, and other covering products) to the test site the morning before the scheduled visit. - Contact the test area with water within the last 2 hours prior to device measurement (e.g., no bathing or swimming, only careful showering except for the test area). · Visiting saunas or receiving massages at the test sites throughout the course of the study Excessive exposure of test areas to sunlight, UV therapy, and / or artificial tanning throughout the course of the study. - Apply moisturizing and anti-aging cover cream, tinted day cream, and face powder to the test areas throughout the study. Drinking caffeinated beverages (e.g., coffee, cola, tea) within the last 2 hours prior to device measurement -Smoking within the last 2 hours before the measurement Subjects are instructed to: Use ProDerm-provided washout products on the test sites from Day -7 through the end of the study as directed. Apply the test product(s) to the test site on the appropriate side (as directed by ProDerm) at the following frequency: once daily for Groups 1 and 2, twice daily for Groups 3 and 4 throughout the course of the study. Continue to use regularly used cosmetic products (e.g., mascara, eyeshadow, powder) at the test sites, but avoid changing brands or using new products throughout the course of the study. - The final application of the test product(s) must be performed the day before the scheduled clinic visit.

[0447] Informed consent For studies involving human subjects, the following procedures are effective: Each subject must provide written informed consent to the investigator / researcher's designee prior to enrollment in the study. Subjects will receive a copy of the informed consent statement upon request.

[0448] An original signed copy of each subject participating in the study will be kept in the Investigator's study records. The consent statement must meet the requirements of applicable regulations. The Investigator or the Investigator's designee will inform each subject of the purpose and nature of the study in accordance with applicable regulations.

[0449] Subjects will be informed that they may withdraw their consent at any time and may discontinue their participation in the study at any time without repercussion, and that ProDerm may terminate their participation in the study prematurely for administrative or other reasons.

[0450] If images are taken for marketing purposes, subjects are asked whether they consent to having their images taken that may be used by the sponsor for marketing and promotional purposes. Each subject who consents will sign the relevant specific informed consent form. Only images of subjects who have given informed consent may be used for marketing and promotional purposes.

[0451] Test procedure -Day 7 (washout): Subjects arrive at the study site. Subjects are informed about the study and provide written consent. Subjects are provided with washout products. Subjects are instructed to use only washout products at the test sites until their next study site visit.

[0452] Day -7 to Day -1: Subjects apply the washout product as instructed.

[0453] Day 1: Subjects return to the study site and standardized images of the face (USR-CliP) are taken. After at least 30 minutes of acclimatization, instrumental measurements (baseline) are performed at the test sites. Raman measurements are performed on a randomly selected subpanel of 12 subjects. The test product(s) are issued to the subjects with instructions for use at the assigned test site. Allocation of the test product(s) is made according to a randomization scheme provided by ProDerm. The first product application is made under the guidance of a technician. Further application(s) are made by the subject at home.

[0454] Days 2-14: Subjects will use the test product(s) as described above (see Application Mode). The final product application will occur on Day 14.

[0455] Day 15: The subject returns to the study site. A standardized image of the face (USR-CliP) is taken. After acclimatization, the instrumental measurements of the test sites are repeated. In addition, the subject completes a questionnaire regarding the test material properties of the test article.

[0456] The product will then be applied under the supervision of a technician, and if applicable, subjects will apply one additional application at home.

[0457] Days 16-28: Subjects will use the test product(s) as described above (see Application Mode). The final product application will occur on Day 28.

[0458] Day 29: The subject returns to the study site. A standardized image of the face (USR-CliP) is taken. After acclimatization, the instrumental measurements of the test sites are repeated. In addition, the subject completes a questionnaire regarding the test material properties of the test article.

[0459] The product will then be applied under the supervision of a technician, and if applicable, subjects will apply one additional application at home.

[0460] Days 29-56: Subjects will use the test product(s) as described above (see Application Mode). The last product application will occur on Day 56.

[0461] Day 57: The subject returns to the study site. A standardized image of the face (USR-CliP) is taken. After acclimatization, the instrumental measurements of the test sites are repeated. In addition, the subject completes a questionnaire regarding the test material properties of the test article.

[0462] The remaining test materials will be returned.

[0463] A deviation of ±2 days during the application step is acceptable as it is not expected to have a substantial effect on the outcome of the study.

[0464] After completion of the study, the images are further evaluated for anti-wrinkle efficacy by three trained graders who, in a blinded and randomized manner, rank each pair of images (before and after 2, 4, and 8 weeks of product application, respectively) for all subjects in terms of wrinkle improvement.

[0465] Climate conditions The instrumental measurement(s) will be performed in an air-conditioned room with a temperature of 22 ± 2 °C and a relative humidity of 50 ± 7.5%. Prior to the measurements, subjects will stay in the climate-controlled room for at least 30 min.

[0466] Exam Schedule A scheme of the test procedure is given as Appendix 1 to the protocol.

[0467] Instrument measurement(s) The following instrumental measurement(s) are performed:

[0468] DERMATOP blue (Eo Tech SA, Marcouxis, France): uses phase-shift and gray-coded measurements of human skin to capture the three-dimensional surface structure of the investigated skin site. The measurement principle is based on digital fringe projection. Under a defined triangulation angle, fringes projected with a sinusoidal-like intensity on the measured surface are detected by a CCD camera. The three-dimensional skin surface profile is calculated from the combination of the fringe position and the gray value of each pixel. From the captured three-dimensional structure, the roughness parameters are calculated. The parameters: Rz and Ra are chosen and represent mainly the coarse structure (Rz) or the finer skin structure (Ra). A decrease in the roughness parameters Rz and Ra corresponds to a decrease in the degree of skin roughness. -One measurement per test site and evaluation time

[0469] Cutometer MPA 580 (Courage&Khazaka, Cologne, Germany). The measurement principle is based on sucking the skin into an opening with a diameter of 2 mm. A defined vacuum of 300 mbar is introduced into the measuring head. The measuring head is placed on the skin with a defined pressure and the skin is sucked into the measuring head opening for 5 seconds, then released and measured for another 5 seconds. Using an optical measuring system, the extent to which the skin has been sucked into the measuring head is detected contactlessly and this value together with the ability of the skin to return to its original state gives a measure of the skin's elasticity.

[0470] Parameters: R0 total elasticity (=Uf=first maximum amplitude, highest point of the first curve,) R7 Quotient of elastic relaxation and total elasticity (=Ur / Uf= the part of elasticity compared to the perfect curve, the closer the value is to 1 (100%), the more elastic the curve is -One measurement per test site and evaluation time

[0471] Corneometer CM 825 (Courage&Khazaka, Cologne, Germany): The measurement of the hydration of the stratum corneum is carried out by the capacitance method with the Corneometer. The measurement principle is based on the change in capacitance of the measuring head, which acts as a capacitor. An electric field is created between the conductors made of gold. By these means the dielectric constant of the upper skin layers is measured. Since the dielectric constant changes as a function of the water content of the skin, the hydration of the stratum corneum can be measured. -Five measurements per test site and evaluation time

[0472] TEWAMETER® TM300 (Courage & Khazaka, Cologne, Germany): Transepidermal water loss (TEWL) is a non-invasive method to measure skin barrier function and is considered a sensitive parameter to quantify skin barrier damage. Briefly, insensible water evaporation from the skin is measured by placing a cylindrical open chamber equipped with two humidity sensors at a defined distance from the skin.

[0473] The probe is kept in place for 30 seconds for each measurement to ensure that a stable value is established. The first part of the measurement belongs to this equilibration phase. The values ​​from the last 10 seconds (=10 values) are averaged as the actual measurement. -One measurement per test site and evaluation time

[0474] USR-CLIP (proderm, Schönefeld, Germany): Photo documentation is performed using a high-resolution digital camera unit for standardized and reproducible clinical photography (USR-CliP) equipped with a high-resolution 50 megapixel Hasselblad camera H5D-50c.

[0475] In photography, the corrected colors are used so that further evaluation can be performed at a later stage. -One image(s) per test site and evaluation time

[0476] Pseudonymized images may be used for marketing purposes provided a corresponding informed consent is signed by the subject.

[0477] Raman spectrometer model gen2-SCA Skin Analyzer (River Diagnostics, Rotterdam, The Netherlands): Raman spectra are obtained by focusing a low-power laser light onto the skin and measuring the Raman scattered light from the laser focus. A small portion of the scattered light is found at higher wavelengths than the incident laser light. This portion of the scattered light provides information about the molecular composition of the skin. Raman spectra are combined to display a concentration profile of molecular species.

[0478] Fingerprint profile for NMF detection in SC: The fingerprint profile is calculated from Raman spectra (wavenumber range 400-1800 cm-1) acquired at various depths. The amount may vary depending on the skin depth and measurement conditions.

[0479] For NMF, the detection profile was defined at epidermal depths of 0, 4, 8, 12 + / - 4 μm from the skin surface, with 4 μm increments, an integration time of 5 seconds, and one frame per depth. - Approximately 6 profiles per test site and evaluation time -50μm pinhole

[0480] Investigators manually curate all fingerprint profiles: invalid curves (e.g., clearly inconsistent keratin curve patterns) are filtered out.

[0481] The following parameters are evaluated from the acquired fingerprint profile by means of Raman software (Skin Tools3, RiverD): -Ceramide [au]

[0482] Research method(s) The following research methods are carried out: Product acceptance survey by subjects The product attributes are evaluated by the subjects and consist of closed questions with identical predefined options to be checked. -2 = Strongly disagree -1 = Somewhat disagree 1=Somewhat agree 2=I completely agree

[0483] The scheme of the questionnaire is given as Appendix 3 of the protocol.

[0484] Image evaluation Subsequent ranking of images by trained graders: Visual evaluation of images captured as above. A computerized system randomizes the images of one subject, allowing for blind visual ranking of images. Images are evaluated on a color-calibrated monitor. The NEC SpectraView Reference271 is a professional wide-gamut 10-bit P-IPS LCD monitor with high image quality and color accuracy for color-critical applications.

[0485] Three trained raters rank each pair of images in a blinded and randomized manner with respect to the parameters "skin radiance" (taking into account skin color, clarity, brightness and luminosity) and "anti-wrinkle effectiveness" (crow's feet area).

[0486] For evaluation of code D eye creams, the image is cropped to show only the area of ​​the eye where only the test product has been applied and evaluation is performed there only.

[0487] For each subject, test area and evaluation time, images before (baseline) and after (days 15, 29 and 57) product application are presented simultaneously and separately for each post-treatment to a grader based on the following visual analogue scale: -50 = the left image is better, +50 = the right image is better. Both images cannot be ranked equally.

[0488] After the study was completed, the values ​​were derandomized. Decoded as -50 = better baseline ~ +50 = better after treatment (days 15, 29, 57)

[0489] In this study, a better wrinkle reduction profile (13-15% reduction in wrinkles) was observed with topical products containing a mixture of 1% Urolithin A, trehalose (0.25%) and niacinamide (1-5%) compared to creams containing only 1% Urolithin A (4-6% reduction) - see Figure 7. Furthermore, topical application of the skin care products for 8 weeks also improved the skin hydration profile (Figure 8). As shown in the figure, the significant effect on wrinkle reduction and improved hydration was maintained across a range of products containing the three ingredients Urolithin A, trehalose and niacinamide. The effect of the combination of these active ingredients was independent of the model of application and the timing of the application day, which also differed in that the day cream was applied once every morning and the night cream was applied once in the evening before going to bed.

[0490] Results of Aging Study 1 (Example 5) and Aging Study 2 (Example 6) demographics Fifty-five participants were screened in the first placebo-controlled aging study. Of those, n=48 middle-aged female subjects with a mean age of 58.6 ± 6.6 years were randomized into two study arms in a split-face / arm study design that included a lower dose of active compared to placebo and a second higher dose of active compared to placebo (Figure 11). All participants completed the study and none dropped out. The ethnicity of all participants was Caucasian. In the second aging study, n=144 middle-aged subjects with a mean age of 55.4 ± 6.6 years were randomized using a split-face study design comparing the treated side with the untreated side. In this study, n=142 subjects completed the study protocol and two subjects dropped out (Figure 14). At final analysis, there were 35 men (25%) and 107 women (75%), including n=2 (1%) Black, 125 (88%) White, n=4 (3%) East Asian, n=3 (2%) Hispanic, and n=8 (6%) West Asian ethnicities. In the UVB-Mediated Erythema Study (Example 4) (placebo-controlled, photodamage study), n=22 subjects were enrolled (10 men (48%), 11 women (52%), mean age 44.0±14.1 years, Caucasian ethnicity). One subject dropped out, leaving n=21 subjects who completed the study protocol (FIG. 14B).

[0491] In all cases, the dosage of the affected test article was not changed and all subjects recovered without sequelae. In the UVB erythema study, one subject experienced two adverse reactions related to skin irritation with erythema. The reactions were mild in severity and resolved without sequelae.

[0492] Wrinkle reduction with topical application of 1% UA In the aging study 1, the reduction in wrinkles was measured after 2 and 8 weeks of application of the test treatment (Figure 15A). The 1% UA treatment group showed a significant reduction in wrinkle depth at 8 weeks compared to the placebo-treated side (p=0.04, Figure 12A). 0.5% UA showed no significant effect compared to placebo. In the second aging study, 1% UA was found to have a significant effect on the reduction of wrinkles (finer and coarser skin structures, calculated as Ra and Rz, respectively) compared to the untreated side, an effect that was already present after 2 weeks of application and maintained after 4 and 8 weeks of application (Table 5). [Table 11]

[0493] This effect was independent of application timing and product matrix, as application of both day and night creams containing 1% UA produced similar wrinkle-reducing effects (Figure 12B, C).

[0494] Impact on skin barrier and skin hydration in aging research Daily application of a cream (day or night cream) containing 1% UA significantly improved skin hydration after 2 weeks of use compared to pre-treatment levels. The improved skin hydration levels observed were maintained even 8 weeks after application of the night cream compared to the untreated side (Figure 12E, F).

[0495] Supportive Biomarkers We performed RNA-seq transcriptomics of forearm skin biopsies from aging study I to investigate biological pathways affected by topical UA application. Gene set enrichment analysis (GSEA) was applied to identify significant pathways altered by UA, comparing baseline to end of study, and normalizing results to vehicle. “Collagen fiber organization” was the pathway most significantly activated by UA (Figures S13A and S16A), and UA application also reduced gene sets related to chemokine responses (Figure S13A). We further studied which UA-regulated pathways are involved in the natural skin aging process. Analyzing published skin aging clinical studies12, “collagen fiber organization” is a common feature, induced by UA and downregulated with skin aging (Figure S16B). This gene set includes collagen genes encoding fibrillar type I and III collagens (Figure S13B), which are known to be reduced in skin with chronological aging13, photoaging, and smoking14. UA also reversed the age-related decline in genes involved in skin homeostasis, including EMILIN-1, which regulates 3D structure and elasticity15, and AEBP (Figure 13B), which encodes a collagen-interacting protein required for optimal tissue repair16. These data are consistent with the positive impact of UA on reducing wrinkles, a process caused by impaired collagen production and organization in the skin.

[0496] The GSEA results suggest an effect of UA on the dermis, the skin layer that produces and secretes collagen. To better understand the mechanism of action of UA in skin cells, primary human dermal fibroblasts were treated with either 2.5 μM or 10 μM UA or vehicle for 24 h. Surprisingly, this short-term exposure to UA did not alter collagen gene expression (Figure 16C). However, it suppressed the expression of matrix metalloproteinase (MMP1), a gene involved in collagen degradation (Figure 13C). Furthermore, UA induced a dose-dependent increase in the expression of mitophagy genes PARKIN and PINK1, and autophagy genes MAP1LC3 and ULK1, compared to vehicle-treated cells (Figure 13C).

[0497] Human primary keratinocytes treated with UA or vehicle for 24 h showed a similar gene expression signature as dermal cells. UA led to a dramatic downregulation of both MMP1 and MMP3, another important collagen degrading enzyme (Figure 13D). And, similar to dermal fibroblasts, it upregulated the expression of autophagy and mitophagy genes (Figure 13D). Finally, we employed a 3D reconstituted human epidermis (RHE) model in which 1% UA moisturizing cream was applied daily for 3 days. No changes were observed in MMP1 and MMP3 gene expression (Figure 16D). However, consistent with the data from primary cells, the results confirm the early activation of mitophagy and autophagy genes in RHE with UA application compared to vehicle (Figure 13E).

[0498] Example 7 Product Acceptance Survey Participants in the study completed a product acceptance questionnaire, as described in the protocol in Example 6. In this questionnaire, a value of more than 60% is considered a significant improvement. Table 6 summarizes the results of the questionnaire, which shows that all listed parameters showed significant improvement at 8 weeks, and most of the listed parameters showed significant improvement at 4 weeks. [Table 12]

[0499] Example 8 3-week user test A three-week user study was conducted on 30 healthy women between the ages of 40 and 65. Participants used the day cream, night cream, and serum as described in Example 6. The following important benefits were observed: [Table 13] [Table 14] [Table 15]

Claims

1. a) A compound of formula (I), 【Chemistry 1】 During the ceremony, A, B, C, and D are each independently selected from H and OH. W, X, and Y are each independently selected from H and OH. Z is selected from H and OH. Compounds and, b) Trehalose and, A composition containing the following:

2. a) The compound of formula (I), b) Trehalose and, c) NAD precursor and The composition according to claim 1, comprising:

3. d) The compound of formula (I), e) Trehalose and, f) NAD precursor and g) Nicotiana sylvestris leaf cell culture and, h) Isomerized sugar and, The composition according to claim 1, comprising:

4. a) The compound of formula (I), b) Trehalose and, c) NAD precursor and d) Nopa flower extract, e) Caffeine and, f) Isomerized sugar and, g) Vitamin B and, The composition according to claim 1, comprising:

5. a) The compound of formula (I), b) Trehalose and, c) NAD precursor and d) Caffeine and, e) Vitamin B and, The composition according to claim 1, comprising:

6. a) The compound of formula (I), b) Trehalose and, c) NAD precursor and d) Caffeine and, The composition according to claim 1, comprising:

7. a) A compound of formula (I) comprising 0.8% to 5% (w / w) of the composition, b) Trehalose comprising 0.05% to 1% (w / w) of the composition, c) An NAD precursor comprising 0.1% to 10% (w / w) of the composition, d) Caffeine, optionally comprising 0.1% to 5% (w / w) of the composition, The composition according to claim 1, comprising:

8. a) The compound of formula (I) comprises 0.8% to 2% (w / w) of the composition, b) The trehalose constitutes 0.1% to 0.5% (w / w) of the composition, c) The NAD precursor accounts for 0.5% to 5% (w / w) of the composition, d) The caffeine comprises 0.1% to 1% (w / w) of the composition. The composition according to claim 7.

9. (a) A compound of formula (I) or a salt thereof as described in Claim 1, (b) Autophagy-inducing substances, (c) Optionally, a mitochondrial biosynthesis promoter and A composition containing the following:

10. The composition according to claim 9, wherein the composition comprises a mitochondrial biosynthesis promoter.

11. The composition according to claim 8, wherein the compound of formula (I) is urolithin A.

12. The composition according to claim 9, wherein the autophagy-inducing substance is selected from carbamazepine, clonidine, lithium, metformin, rapamycin, rilmenidine, sodium valproate, verapamil, trifluoperazine, statins, tyrosine kinase inhibitors, BH3 mimetic drugs, caffeine, omega-3 polyunsaturated fatty acids, resveratrol, spermidine, vitamin D pterostilbene, phistein, genistein, quercetin, apigenin, kaempferol, minoxidil, actinonine, kinetin triphosphate, pifislin-a, deferipron, 1,10'-phenanthroline, and trehalose.

13. The composition according to claim 10, wherein the mitochondrial biosynthesis promoter is selected from a PPAR-PGC-1α axis activator, an AMPK activator, a Sirt1 agonist, an antioxidant, and an NAD precursor.

14. (a) In order to improve or maintain the skin barrier function, (b) To prevent and / or treat transcutaneous water loss, (c) To improve skin elasticity and firmness, (d) In order to increase or maintain the thickness of the skin layer, (e) In order to increase or maintain the shape index of the dermal epidermal junction of the skin, (f) In order to increase or maintain skin hydration, (g) To combat the signs of skin aging, (h) To reduce the biological aging of the skin, (i) To reduce fine lines and wrinkles, (j) To delay and / or reduce and / or prevent signs of aging selected from the group consisting of loss of skin firmness and / or elasticity, thinning of the skin, wrinkles and fineness, patterns, dullness of the skin, hyperpigmentation of the skin, or hyperpigmentation and hyperpigmentation of pigmentation, (k) To reduce skin damage caused by irradiation, (l) To protect the skin from damage caused by radiation, (m) In order to reduce hair damage caused by irradiation, (n) To protect hair from damage caused by radiation, (o) In order to improve the collagen tissue of the skin, (p) To improve irritation caused by dry skin (q) To reduce sunburn on the skin, and / or (r) The composition according to any one of claims 1 to 13 for one or more uses for protection from photoaging caused by sunlight.

15. (a) Maintaining or increasing the thickness of hair, (b) Regeneration of hair follicle cells, (c) Survival of hair follicle cells, (d) Growth and / or regeneration of hair stem cells, (e) Survival of hair cells, (f) Prevention of hair loss, (g) Promoting the growth of new hair, (h) Improvement of scalp health, and / or (i) The composition according to any one of claims 1 to 13 for one or more uses of promoting hair growth and restoration.

16. (a) regeneration and / or activation of the appearance of the skin, (b) Strengthening the energy supply of the skin, (c) Improvement of skin texture, (d) Improvement of skin radiance, (e) Skin rejuvenation, (f) Reduced visibility of pores and fine lines, (g) Improvement of skin respiration, (h) Support for optimal skin cell function, (i) Promoting / activating the skin's detoxification process, (j) Promotion of collagen repair, and / or (k) The composition according to any one of claims 1 to 13 for one or more uses of improving the health of skin stem cells.

17. (a) acne, (b) Contact dermatitis (c) eczema; (d) psoriasis; (e) rosacea, (f) Lupus, (g) warts, (h) Herpes zoster, (i) hives, (j) brown spots, (k) Melasma, (l) Kuroko, (m) dermatitis; (n) skin infection; (o) skin inflammation; (p) seborrheic dermatitis, (q) skin fungal infections; (r) skin cancer, and (s) A composition according to any one of claims 1 to 13 for use in the treatment of one or more indications selected from diaper rash.

Images