Process for selecting cosmetic active agents

Abstract

The present invention relates to a process for selecting cosmetic active agents used in the formulation of a composition, including the steps consisting in a) providing a structured database and b) for a list of candidate cosmetic active agents with known effects on biomarkers and, optionally, cofactors and / or metabolites listed in said database, identifying with the aid of said database at least one cosmetic active agent having a beneficial effect on at least two hallmarks belonging to at least two different predefined clusters. The invention also relates to a process for manufacturing a composition, including the step consisting in selecting one or more cosmetic active agents by performing the selection process according to the invention, and the manufacture of said composition by integrating the selected cosmetic active agent(s) into a physiologically acceptable medium. The invention also relates to the cosmetic use of a composition obtained via the process according to the invention, for its application to keratin materials.

Description

[0001] Description

[0002] Title: Process for selecting cosmetic active agents

[0003] Technical field

[0004] The present invention relates to a process for selecting cosmetic active agents included in the formulation of a composition using a structured database.

[0005] The invention also relates to a process for manufacturing a composition, notably a cosmetic composition, comprising the step consisting in selecting one or more cosmetic active agents by performing the selection process according to the invention, and the manufacture of said composition by integrating the selected cosmetic active agent(s) into a physiologically acceptable medium.

[0006] Finally, the invention relates to the cosmetic use, in particular topical use, of a composition obtained according to the manufacturing process according to the invention, for its application to human keratin materials, in particular to the skin.

[0007] Prior art

[0008] The selection of cosmetic active agents represents a crucial step in the development of innovative cosmetic products, especially when it comes to antiaging formulations. This process is very complex, as it must incorporate several key criteria to ensure not only the efficiency of the active agents, but also their relevance to the varied needs of consumers. One of the first criteria to consider is the age of the consumer. This is because the skin evolves over time, and the biological mechanisms responsible for skin aging differ according to the periods of life. At age 25, skin needs focus more on preventing damage caused by environmental factors, while at age 50 or 70, concerns often include repairing accumulated damage, loss of elasticity, or reducing deep wrinkles.

[0009] To meet these specific needs, it is essential to understand in depth the biological mechanisms involved in skin aging. These mechanisms notably include the gradual decrease in collagen and elastin production, which leads to a loss of firmness and elasticity of the skin. Added to this is the increase in oxidative stress, caused by the accumulation of free radicals, which damage skin cells and accelerate the appearance of visible signs of aging. The skin barrier, which protects the skin from external aggressions and maintains its hydration, also becomesmore fragile with age, worsening skin dehydration and sensitivity. In addition, the reduction of cell renewal contributes to a dull complexion and irregular texture.

[0010] Today, several processes are used to select active agents capable of responding to these multiple problems. Scientific research is based notably on sophisticated biological screening, where hundreds of molecules are tested in vitro to assess their ability to stimulate key skin functions, such as collagen production or reducing oxidative damage. Skin tissues reconstructed in the laboratory can simulate aging and enable study of the effects of active agents under controlled conditions.

[0011] Despite this progress, current processes have significant limitations. Individual variability, linked to factors such as genetics, lifestyle or environmental conditions, complicates predicting the effectiveness of active agents for each consumer. In addition, existing methods are often costly and time-consuming, which hinders rapid innovation in an ever-changing sector.

[0012] There is thus a need to develop new tools and methods that are more effective and rapid for the selection of cosmetic active agents, particularly in the field of antiaging. In particular, there is a need for a process for the selection of cosmetic active agents, particularly in the field of antiaging, which is multidimensional and allows a more accurate and personalized response to the expectations of users, while accelerating the development process of cosmetic products.

[0013] Disclosure of the invention

[0014] The object of the present invention is to meet at least one of the above needs.

[0015] In particular, the invention provides a novel process based on the creation of a structured database that lists various biological causes of skin aging, called hallmarks, as well as intracellular and extracellular biomarkers, biological functions and, optionally, cofactors, metabolites and root causes of skin aging. The database also includes cause and effect relationships between these elements, allowing for in-depth analysis of biological interactions.

[0016] Summary of the inventionAs mentioned above, the present invention thus relates to a process for selecting cosmetic active agents included in the formulation of a composition, in particular an antiaging cosmetic composition, comprising the steps consisting in:

[0017] a) providing a structured database, listing:

[0018] (1) a set of biological causes of skin aging, known as hallmarks, each hallmark being in a single cluster according to the nature of a biological dysfunction, in particular in a cluster chosen from structural dysfunctions, functional dysfunctions and communication pathway dysfunctions,

[0019] (2) a list of intracellular biomarkers associated with one or more hallmarks, (3) a list of extracellular biomarkers associated with one or more hallmarks, (4) a list of biological functions associated with one or more hallmarks,

[0020] (5) a list of relationships reflecting a cause and effect relationship, notably an activation or inhibition relationship, between at least two elements of the database chosen from the biomarkers and the biological functions,

[0021] each hallmark being in a single cluster according to the nature of a biological dysfunction, in particular in a cluster chosen from structural dysfunctions, functional dysfunctions and communication pathway dysfunctions, and

[0022] b) for a list of candidate cosmetic active agents with known effects on biomarkers and, optionally, cofactors and / or metabolites listed in said database, identifying with the aid of said database at least one cosmetic active agent having a beneficial effect on at least two hallmarks belonging to at least two different predefined clusters.

[0023] In particular, the structured database further includes:

[0024] (6) a list of cofactors and metabolites, and / or

[0025] (7) a list of root causes of skin aging.

[0026] According to a particular embodiment, step b) is carried out to identify at least one cosmetic active agent having a beneficial effect on at least three hallmarks belonging to at least two different predefined clusters, in particular belonging to at least three different predefined clusters.In particular, step b) is carried out to identify a combination of at least two active agents, said combination having a beneficial effect on at least two hallmarks belonging to two different predefined clusters, better still having a beneficial effect on at least three hallmarks belonging to at least two different predefined clusters, even better still having a beneficial effect on at least three hallmarks belonging to three different predefined clusters.

[0027] In particular, step b) is performed by computer, the structured database being stored in a computer memory.

[0028] According to a particular embodiment, the process includes, after step b), an in vitro and / or in vivo test phase of the selected cosmetic active agent(s).

[0029] According to one embodiment, the process comprises the step of generating a topogram from all or part of the data of the database.

[0030] In one embodiment, the intracellular and extracellular biomarkers are selected from a list comprising the biomarkers involved in: DNA damage repair, such as poly(ADP-ribose) polymerase (PARP), apoptosis inducing factor (AIF) and Ku80 protein (Ku80); protection against telomer shortening, such as cyclin-dependent kinase inhibitor 2 A (pl 6), cell cycle regulator p21 (p21) and tumor suppressor protein p53 (p53); protection of genome integrity, such as DNA methyltransferase (DNMT), ten-eleven translocation methylcytosine dioxygenase (TET) and nuclear factor kappa B (NFKB); protection against histone alterations, such as histone acetyltransferase (HAT), histone deacetylase 1 (HDAC1) and histone demethylase (HDM); protection against chromatin remodeling, such as chromobox protein homolog 4 (CBX4), transcriptional coactivator p300 (p300) and heterochromatin protein 1 (HP1); protection of messenger RNA (mRNA) such as microRNA-377 (mIR-377), microRNA-181b (mIR-181b) and microRNA-138 (mIR-138); autophagy such as microtubule-associated protein LC3 (LC3), autophagy gene 5 (Atg5) and autophagy gene 7 (Atg7); proteasome such as ubiquitin (ubiquitin), proteasome 26S (proteasome 26S), proteasome core 20S (proteasome CORE 20S); protection against extracellular matrix degradation, such as mitogen-activated kinase (MAPK), protein activator complex 1 (AP-1) and protein p38 (p38); cell differentiation such as filaggrin (filaggrin), loricrin (loricrin) and involucrin (involucrin); cell proliferation such as keratin 1 (KI), keratin 16 (KI 6) and keratin 6 (K6); cell migration and / or adhesion such as Rho protein (Rho), integrin family (integrins) and Rac protein (Rac); skin microbiome diversityand skin homeostasis such as Cutibacterium, S. aureus and Clostridium bacteria; senescence-associated secretory phenotype (SASP) and senomorphism such as NOD-like receptor pyrin domain containing protein 3 (NRLP3), microRNA-377 (mIR-377) and lamin Bl (LMNB1); apoptosis such as cell death-associated protein (BAD), caspase-9 (caspase-9), and mammalian rapamycin target (mTOR); cell cycle such as cyclin-dependent kinase inhibitor 2 A (pl 6), cell cycle regulator p21 (p21) and cyclin-dependent kinase inhibitor IB (p27); regulation of DNA such as binding factor-associated protein TAB-1 (TAB-1), microRNA-767 (mIR-767), and protein kinase B (Akt); biogenesis of mitochondria such as peroxisome proliferator-activated gamma receptor 1 -alpha coactivator (PGC-la), AMP-activated protein kinase (AMPK) and sirtuin (SIRT); mitochondrial DNA such as mitochondrial DNA polymerase gamma (polG mtDNA) and mitochondrial transcription factor A (Tfam); mitophagy such as PTEN-induced putative kinase 1 protein (PINK1), Parkin protein (parkin) and translocase of outer membrane 20 (TOM); mitochondrial metabolism such as sirtuin (SIRT), complex II (CII) and ATP synthase (ATP synthase); oxidative stress such as NADPH oxidase (NOX), protein phosphatase 2A (PP2A) or protein tyrosine phosphatase activator (PTPA); reprogramming and differentiation of stem cells such as octamer-linked transcription factor 4 (Oct-4), myelocytomatosis viral oncogene homolog (Myc) and protein expressed by Sry-linked HMG box gene 2 (SOX2); cellular communication of exosomes such as microRNA-767 (mIR-767), microRNA-302-3p (mIR-302-3p) and microRNA-138 (mIR-138); cellular communication of growth factors such as fibroblast growth factor (FGF), keratinocyte growth factor (KGF) and epidermal growth factor (EGF); cellular communication of hormones such as 1 ip-hydroxy steroid dehydrogenase (HSDlip), estrogen (estrogen) and progesterone (progesterone); intracellular trafficking such as the soluble NSF attachment protein receptor complex (SNARE), Rab protein (Rab) or ABCA protein (ABCA); cytokine and chemokine inflammation such as cyclooxygenase-2 (COX2), Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway or mitogen-regulated kinase MAP3 (MAP3K); immune regulation such as forkhead box P3 protein (FOXP3), histamine (histamine) or C-X-C motif chemokine receptor 2 (CXCR2); and induction of senescence-associated secretory phenotype (SASP) such as NOD-like receptor, pyrin domaincontaining protein 3 (NRLP3), microRNA-377 (mIR-377) and nuclear factor kappa B (NFKB).In a particular embodiment, the biological functions are selected from a list including repair of DNA damage, protection against telomer shortening, protection of genome integrity, protection against histone alteration, protection against chromatin remodeling, protection of messenger RNA (mRNA), autophagy, proteasome, protection against extracellular matrix degradation, cell differentiation, cell proliferation, cell migration and / or adhesion, skin microbiome diversity and homeostasis, senescence-associated secretory phenotype (SASP) and senomorphism, apoptosis, cell cycle; DNA regulation, mitochondrial biogenesis, mitochondrial DNA, mitophagy, mitochondrial metabolism, oxidative stress, stem cell reprogramming and differentiation, exosomal cell communication, growth factor cell communication, hormone cell communication, intracellular trafficking, cytokine and chemokine inflammation, immune regulation, and induction of senescence-associated secretory phenotype (SASP).

[0031] According to a particular embodiment, the cofactors and metabolites are chosen from a list comprising nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FADH2), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), dioxygen (O2), vitamin B3, vitamin D3, vitamin A, vitamin C, calcium ion (Ca2+), potassium ion (K+), sodium ion (Na+), chloride ion (CF), glutathione (GSH), nitric oxide (NO), inositol trisphosphate (IP3), diacylglycerol (DAG), amino acids, cysteine, propionate and monosaccharides.

[0032] According to a particular embodiment, the root causes of skin aging are chosen from a list comprising infrared (IR) radiation, ultraviolet (UV) radiation, xenobiotics, sleep disorders, circadian cycle, air pollutants, poor diet, lifestyle, stress, endogenous causes related to chronological aging, fragility of mitochondrial DNA, specificity and changes in hormone levels and changes in gene expression.

[0033] According to a particular embodiment, the relationships include activation or inhibition links connecting elements (1) to (4), in particular elements (1) to (4), (6) and (7), in pairs.

[0034] According to a particular embodiment, the cosmetic active agents are chosen from a list comprising resveratrol; capryloylsalicylic acid; niacinamide (vitamin B3); azelaic acid; ectoin; Zingiber officinale root or rhizome extract; Ginkgo biloba leaf extract; a combination of maltodextrin and Saccharomyces fermentation filtrate; N-acetyl-phytosphingosine (NaP); Bifidobacterium longum: 2-ethoxyethyl (2Z)-cyano{3-[(3-methoxypropyl)amino]cyclohex-2-en-l-ylidene} ethanoate); Calendula officinalis flower extract; tocopherol (vitamin E); ascorbic acid (vitamin C); C-beta-D-xylopyranoside-2-hydroxypropane; Grifola frondosa extract; rhamnose; and Centella asiatica extract titrated with asiaticoside, asiatic acid and madecassic acid.

[0035] The present invention also relates to a process for manufacturing a composition, notably a cosmetic composition, comprising the step consisting in selecting one or more cosmetic active agents by performing the selection process according to the invention, and the manufacture of said composition by integrating the selected cosmetic active agent(s) into a physiologically acceptable medium.

[0036] The invention also relates to the cosmetic use, in particular topical use, of a composition obtained according to the manufacturing process according to the invention, for its application to human keratin materials, in particular to the skin.

[0037] Description of the figures

[0038] Figure 1 shows a topogram representing part of the database listing the hallmark “microchronic inflammation” as well as intracellular and extracellular biomarkers, cofactors, metabolites and relationships between these different elements.

[0039] Detailed description

[0040] The term “cosmetic” means a composition that is compatible with keratin materials, in particular the skin, mucous membranes and skin integuments. The composition according to the invention is non-therapeutic. The composition of the invention comprises in particular a “cosmetically acceptable” medium, also known as a “physiologically acceptable” medium, i.e. a medium that is compatible with all keratin materials, in particular the skin.

[0041] The term “keratin materials” denotes the skin, mucous membranes, keratin fibers such as the eyelashes, eyebrows, bodily hair and head hair, and skin integuments.

[0042] The term “the skin” means all the skin of the body, and preferably the skin of the face, the scalp, the neckline, the neck, the arms and forearms, the eyelids, around the mouth or behind the ears, the hollow of the elbow, the back of the knees, the hands, the wrists and the ankles, or even more preferably the skin of the face (in particular the forehead, the nose, the cheeks and the chin), the neckline and the neck.A composition according to the invention may comprise a physiologically acceptable medium, i.e. one which has a pleasant color, odor and feel and which does not give rise to any unacceptable discomfort, i.e. tingling, tautness or redness, that is liable to discourage the user from applying this composition. Needless to say, a person skilled in the art will take care to choose a physiologically acceptable medium such that the advantageous properties of the cosmetic active agent(s) of the invention are not, or are not substantially, adversely affected.

[0043] The term “protecting the stability of DNA” refers to the use of a set of mechanisms, actions or interventions aimed at preserving the structural and functional integrity of DNA within cells, by limiting or preventing alterations such as strand breaks, mutations, chemical changes (such as oxidation or abnormal methylation), or dysfunctions in DNA repair processes. This protection may be ensured by agents acting directly or indirectly on DNA or on the cellular pathways involved in its maintenance.

[0044] The term “decrease" or “reduction" is understood in the context of the present invention to mean the reduction of the risk or probability of occurrence of a given phenomenon, in particular with respect to a “normal” reference situation, that is to say in the absence of application of the composition according to the invention.

[0045] In the context of the present invention, the terms “prevent” and “prevention" denote the reduction to a lesser degree of the risk or probability of occurrence of a given phenomenon. “Cell longevity” is understood to mean the ability of cells to maintain their functions and viability over time, despite environmental or metabolic damage and stresses. This longevity depends on specific biological mechanisms that protect cells from aging, premature death or dysfunction. However, cellular aging is inevitable and is associated with progressive changes in cellular structure and functions.

[0046] In that which follows and unless otherwise indicated, the limits of a range of values are included within that range, notably in the expressions “between...” and “ranging from ... to

[0047] Moreover, the expression “at least one” used in the present description is equivalent to the expression “one or more” .

[0048] Process for selecting cosmetic active agentsAccording to one aspect, the present invention thus relates to a process for selecting cosmetic active agents used in the formulation of a composition, in particular an antiaging cosmetic composition, comprising the steps of a) providing a structured database and b) for a list of candidate cosmetic active agents with known effects on biomarkers and, optionally, cofactors and / or metabolites listed in said database, identifying with the aid of said database at least one cosmetic active agent having a beneficial effect on at least two hallmarks belonging to at least two different predefined clusters.

[0049] A structured database is a database in which data are linked to other information within the database.

[0050] The structured database according to the invention can be chosen from relational databases, hierarchical databases, networked databases and object-oriented databases, among others. The structured database according to the invention can in particular be a relational database, where the data are organized in tables, each table representing an entity, each table including columns that define the attributes of the entities, and the rows of the table contain the individual records. Keys are used to uniquely identify records and establish relationships between tables.

[0051] A database query language, such as Structured Query Language (SQL), can be used to manipulate the data.

[0052] Any visualization tool can be used (for example visualization libraries of a programming language or specialized software) to generate topograms from the extracted data.

[0053] The structured database according to the invention first lists a set of biological causes of skin aging. These biological causes are also called hallmarks.

[0054] In particular, nine aging hallmarks have been identified and associated with molecular and cellular mechanisms that are potentially targets of aging and implicated in skin alteration (Lopez-Otin et al., The hallmarks of aging, Cell. 2013 Jun 6; 153(6): 1194-217. doi: 10.1016 / j.cell.2013.05.039).

[0055] Hallmarks suitable for use according to the invention are chosen from the list comprising: o (i) mitochondrial dysfunction,

[0056] o (ii) senescence of cells,

[0057] o (iii) alterations to the skin microbiome,o (iv) DNA instability,

[0058] o (v) epigenetic modifications,

[0059] o (vi) loss of proteostasis,

[0060] o (vii) chronic micro-inflammation,

[0061] o (viii) stem cell depletion, and

[0062] o (ix) cellular communication.

[0063] In particular, hallmarks suitable for use according to the invention are chosen from the list comprising:

[0064] o (i) mitochondrial dysfunction,

[0065] o (ii) senescence of cells,

[0066] o (iii) alterations to the skin microbiome,

[0067] o (iv) DNA instability,

[0068] o (v) epigenetic modifications,

[0069] o (vi) loss of proteostasis,

[0070] o (vii) chronic micro-inflammation,

[0071] o (viii) stem cell depletion, and

[0072] o (ix) cellular communication.

[0073] o (x) extracellular matrix (ECM) changes.

[0074] Each hallmark is in a single cluster, depending on the nature of a biological dysfunction. In particular, the biological dysfunctions are chosen from structural dysfunctions, functional dysfunctions and communication pathway dysfunctions.

[0075] Structural dysfunctions include the following hallmarks: DNA instability, epigenetic modifications and loss of proteostasis.

[0076] DNA instability corresponds to the accumulation of mutations or structural damage in the genome of cells, reducing their viability and increasing the risk of cell dysfunction or premature death.

[0077] Epigenetic modifications involve reversible changes in gene expression, such as DNA methylation or histone modifications, without altering the genetic sequence. These modifications can disrupt cellular functions in response to aging.Proteostasis refers to the balance of proteins in a cell, involving their production, folding and degradation. Loss of this control leads to the accumulation of misfolded or damaged proteins, which disrupts cellular and tissue functions.

[0078] Metabolic dysfunctions include the following hallmarks: alteration of the skin microbiome, mitochondrial dysfunctions, and senescence of cells.

[0079] The skin microbiome, composed of protective microorganisms, can be unbalanced by age or environmental factors. This imbalance weakens the skin barrier and increases susceptibility to inflammation and infection.

[0080] Mitochondria, responsible for the production of cellular energy in the form of ATP, can undergo alterations that decrease their efficiency and increase the generation of free radicals. These dysfunctions contribute to cellular aging and tissue damage.

[0081] Cellular senescence is an irreversible state in which a cell stops dividing but remains metabolically active. These cells accumulate inflammatory factors and degrading enzymes that alter the function of surrounding tissues.

[0082] Dysfunctions in communication pathways include the following hallmarks: chronic microinflammation, stem cell depletion, and impaired cellular communication.

[0083] According to a particular embodiment, dysfunctions in communication pathways include the following hallmarks: chronic microinflammation, stem cell depletion, impaired cellular communication and extracellular matrix (ECM) changes.

[0084] Chronic microinflammation is persistent low-grade inflammation that results from continuous inflammatory signals. This condition aggravates cell damage and interferes with skin regeneration, contributing to skin aging.

[0085] Cutaneous stem cells, essential for tissue renewal and repair, undergo a decrease in their activity and number with age, which is known as stem cell depletion. This limits cell regeneration and accelerates skin aging.

[0086] Cellular communication, essential for coordinating functions between cells, can deteriorate with age. This disrupts regulatory signals such as those related to tissue repair, inflammation or collagen production.

[0087] Extracellular Matrix (ECM) changes refer to the degradation and / or disorganization of fundamental structural components of tissues such as collagen, elastin, glycosaminoglycans(especially hyaluronic acid) and / or proteoglycan. These changes alter mechanobiological signaling impacting plumpness, firmness and elasticity.

[0088] Thus, a first cluster includes hallmarks belonging to structural dysfunctions, i.e. DNA instability, epigenetic modifications and loss of proteostasis.

[0089] A second cluster includes hallmarks belonging to metabolic dysfunctions, i.e. alteration of the cutaneous microbiome, mitochondrial dysfunctions and senescence of cells.

[0090] A third cluster includes hallmarks belonging to dysfunctions in communication pathways, i.e. chronic microinflammation, stem cell depletion, impaired cellular communication and optionally extracellular matrix (ECM) changes.

[0091] According to one embodiment, step b) is carried out to identify at least one cosmetic active agent having a beneficial effect on at least three hallmarks belonging to at least two different predefined clusters, in particular belonging to at least three different predefined clusters. The term “beneficial effect” is understood to mean an effect that has the consequence of slowing down or even preventing the effects of a biological cause of skin aging. For example, a cosmetic active agent with a beneficial effect on the loss of proteostasis could be an active agent that promotes the proper folding of proteins by stimulating cellular repair mechanisms, such as the activity of molecular chaperones. It may also work by reducing the accumulation of misfolded or damaged proteins through the activation of degradation systems, such as proteasome or autophagy.

[0092] According to a particular embodiment, step b) is carried out to identify a combination of at least two cosmetic active agents, said combination having a beneficial effect on at least two hallmarks belonging to two different predefined clusters, better still having a beneficial effect on at least three hallmarks belonging to at least two different predefined clusters, even better still having a beneficial effect on at least three hallmarks belonging to three different predefined clusters.

[0093] A structured database according to the invention also provides a list of intracellular biomarkers associated with one or more hallmarks and a list of extracellular biomarkers associated with one or more hallmarks.

[0094] According to a particular embodiment, the intracellular and extracellular biomarkers are selected from a list comprising the biomarkers involved in: DNA damage repair, such as poly(ADP-ribose) polymerase (PARP), apoptosis inducing factor (AIF) and Ku80 protein(Ku80); protection against telomer shortening, such as cyclin-dependent kinase inhibitor 2A (pl6), cell cycle regulator p21 (p21) and tumor suppressor protein p53 (p53); protection of genome integrity, such as DNA methyltransferase (DNMT), ten-eleven translocation methylcytosine dioxygenase (TET) and nuclear factor kappa B (NFKB); protection against histone alterations, such as histone acetyltransferase (HAT), histone deacetylase 1 (HDAC1) and histone demethylase (HDM); protection against chromatin remodeling, such as chromobox protein homolog 4 (CBX4), transcriptional coactivator p300 (p300) and heterochromatin protein 1 (HP1); protection of messenger RNA (mRNA) such as microRNA-377 (mIR-377), microRNA-181b (mIR-181b) and microRNA-138 (mIR-138); autophagy such as microtubule-associated protein LC3 (LC3), autophagy gene 5 (Atg5) and autophagy gene 7 (Atg7); proteasome such as ubiquitin (ubiquitin), proteasome 26S (proteasome 26S), proteasome core 20S (proteasome core 20S); protection against extracellular matrix degradation, such as mitogen-activated kinase (MAPK), protein activator complex 1 (AP-1) and protein p38 (p38); cell differentiation such as filaggrin (filaggrin), loricrin (loricrin) and involucrin (involucrin); cell proliferation such as keratin 1 (KI), keratin 16 (K16) and keratin 6 (K6); cell migration and / or adhesion such as Rho protein (Rho), integrin family (integrins) and Rac protein (Rac); skin microbiome diversity and skin homeostasis such as Cutibacterium, S. aureus and Clostridium bacteria; senescence-associated secretory phenotype (SASP) and senomorphism such as NOD-like receptor pyrin domain containing protein 3 (NRLP3), microRNA-377 (mIR-377) and lamin Bl (LMNB1); apoptosis such as cell death-associated protein (BAD), caspase-9 (caspase-9), and mammalian rapamycin target (mTOR); cell cycle such as cyclin-dependent kinase inhibitor 2A (pl6), cell cycle regulator p21 (p21) and cyclin-dependent kinase inhibitor IB (p27); regulation of DNA such as binding factor-associated protein TAB-1 (TAB-1), microRNA-767 (mIR-767), and protein kinase B (Akt); biogenesis of mitochondria such as peroxisome proliferator-activated gamma receptor 1 -alpha coactivator (PGC-la), AMP-activated protein kinase (AMPK) and sirtuin (SIRT); mitochondrial DNA such as mitochondrial DNA polymerase gamma (polG mtDNA) and mitochondrial transcription factor A (Tfam); mitophagy such as PTEN-induced putative kinase 1 protein (PINK1), Parkin protein (parkin) and translocase of outer membrane 20 (TOM); mitochondrial metabolism such as sirtuin (SIRT), complex II (CII) and ATP synthase (ATP synthase); oxidative stress such as NADPH oxidase (NOX), protein phosphatase 2A (PP2A) or protein tyrosine phosphataseactivator (PTPA); reprogramming and differentiation of stem cells such as octamer-linked transcription factor 4 (Oct-4), myelocytomatosis viral oncogene homolog (Myc) and protein expressed by Sry-linked HMG box gene 2 (SOX2); cellular communication of exosomes such as microRNA-767 (mIR-767), microRNA-302-3p (mIR-302-3p) and microRNA-138 (mIR-138); cellular communication of growth factors such as fibroblast growth factor (FGF), keratinocyte growth factor (KGF) and epidermal growth factor (EGF); cellular communication of hormones such as 1 ip-hydroxy steroid dehydrogenase (HSDlip), estrogen (estrogen) and progesterone (progesterone); intracellular trafficking such as the soluble NSF attachment protein receptor complex (SNARE), Rab protein (Rab) or ABC A protein (ABCA); cytokine and chemokine inflammation such as cyclooxygenase-2 (COX2), Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway or mitogen-regulated kinase MAP3 (MAP3K); immune regulation such as forkhead box P3 protein (FOXP3), histamine (histamine) or C-X-C motif chemokine receptor 2 (CXCR2); and induction of senescence-associated secretory phenotype (SASP) such as NOD-like receptor, pyrin domain-containing protein 3 (NRLP3), microRNA-377 (mIR-377) and nuclear factor kappa B (NFKB).

[0095] A structured database according to the invention also provides a list of biological functions associated with one or more hallmarks.

[0096] In a particular embodiment, the biological functions are selected from a list including repair of DNA damage, protection against telomer shortening, protection of genome integrity, protection against histone alteration, protection against chromatin remodeling, protection of messenger RNA (mRNA), autophagy, proteasome, protection against extracellular matrix degradation, cell differentiation, cell proliferation, cell migration and / or adhesion, skin microbiome diversity and homeostasis, senescence-associated secretory phenotype (SASP) and senomorphism, apoptosis, cell cycle, DNA regulation, mitochondrial biogenesis, mitochondrial DNA, mitophagy, mitochondrial metabolism, oxidative stress, stem cell reprogramming and differentiation, exosomal cell communication, growth factor cell communication, hormone cell communication, intracellular trafficking, cytokine and chemokine inflammation, immune regulation, and induction of senescence-associated secretory phenotype (SASP).In particular, the biological functions DNA damage repair and protection against telomer shortening are related to the hallmark DNA instability.

[0097] In particular, the biological functions protection of genome integrity, protection against histone modifications, protection against chromatin remodeling and protection of messenger RNA (mRNA) are related to the hallmark epigenetic modifications.

[0098] In particular, the biological functions autophagy, proteasome, protection against extracellular matrix degradation, cell differentiation, cell proliferation, and cell migration and / or adhesion are related to the hallmark loss of proteostasis.

[0099] In particular, the biological function diversity of the cutaneous microbiome and homeostasis of the skin is related to the hallmark alterations of the cutaneous microbiome.

[0100] In particular, the biological functions secretory phenotype associated with senescence (SASP) and senomorphism, apoptosis, cell cycle and DNA regulation are related to the hallmark senescence of cells.

[0101] In particular, the biological functions mitochondrial biogenesis, mitochondrial DNA; mitophagy; mitochondrial metabolism and oxidative stress are related to the hallmark mitochondrial dysfunctions.

[0102] In particular, the biological function reprogramming and differentiation of stem cells is related to the hallmark depletion of stem cells.

[0103] In particular, the biological functions exosome cellular communication, growth factor cellular communication, hormone cellular communication and intracellular trafficking are related to the hallmark cellular communication.

[0104] In particular, the biological functions cytokine and chemokine inflammation, immune regulation and induction of senescence-associated secretory phenotype (SASP) are related to the hallmark chronic microinflammation.

[0105] A structured database according to the invention also provides a list of relationships reflecting a cause and effect relationship, notably an activation or inhibition relationship, between at least two elements of the database chosen from the biomarkers and the biological functions.

[0106] According to one embodiment, where the structured database additionally provides a list of cofactors and metabolites, and / or a list of root causes of skin aging, the relationship list may also reflect a cause and effect relationship, notably an activation or inhibition relationship,between at least two elements of the database selected from biomarkers, biological functions, cofactors and metabolites, and / or root causes of aging.

[0107] According to one embodiment, relationships including activation or inhibition links linking in pairs the elements: hallmarks, intracellular biomarkers, extracellular biomarkers and biological functions, in particular the elements: hallmarks, intracellular biomarkers, extracellular biomarkers, biological functions, cofactors and metabolites and root causes of skin aging.

[0108] In a particular embodiment, the structured database may also provide (6) a list of cofactors and metabolites.

[0109] In particular, the cofactors and metabolites may be chosen from a list comprising nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FADH2), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), di oxygen (O2), vitamin B3, vitamin D3, vitamin A, vitamin C, calcium ion (Ca2+), potassium ion (K+), sodium ion (Na+), chloride ion (CF), glutathione (GSH), nitric oxide (NO), inositol trisphosphate (IP3), diacylglycerol (DAG), amino acids, cysteine, propionate and monosaccharides.

[0110] According to a particular embodiment, the structured database may also provide (7) a list of root causes of skin aging.

[0111] In particular, the root causes of skin aging are chosen from a list comprising infrared (IR) radiation, ultraviolet (UV) radiation, xenobiotics, sleep disorders, circadian cycle, air pollutants, poor diet, lifestyle, stress, endogenous causes related to chronological aging, fragility of mitochondrial DNA, specificity and changes in hormone levels and changes in gene expression.

[0112] Step b) of the process according to the invention comprises, for a list of candidate cosmetic active agents with known effects on biomarkers and, optionally, cofactors and / or metabolites listed in said database, identifying with the aid of said database at least one cosmetic active agent having a beneficial effect on at least two hallmarks belonging to at least two different predefined clusters.The structured database may be stored in a computer memory.

[0113] Step b) can be performed manually, for example by querying the database, which is stored in a computer memory, using one or more keywords related to the hallmarks and / or effects, or by consulting a topogram generated from the database.

[0114] According to a particular embodiment, step b) is carried out by computer.

[0115] The term “carried out by computer” means that a computer system of any type is used, for example a personal computer, workstation, server, smartphone or tablet, the processing being performed locally or at several remote locations between computing units exchanging data.

[0116] Where appropriate, the active agent identification is done in an automated way, for example by scanning a list of candidate active agents and determining from the database whether there are beneficial effects on associated biomarkers, biological functions, and predefined hallmarks.

[0117] According to a particular embodiment, the process includes, after step b), an in vitro and / or in vivo test phase of the selected cosmetic active agent(s).

[0118] In particular, this test phase comprises at least one test adapted to an antiaging cosmetic active agent.

[0119] To evaluate antiaging cosmetic active agents, several in vitro tests can be carried out. It is possible to measure their antioxidant capacity by evaluating the neutralization of free radicals (DPPH, ORAC, etc. tests) and to test the stimulation of collagen synthesis by fibroblasts in culture. It is also possible to analyze the inhibition of metalloproteinases (MMPs), responsible for the degradation of the extracellular matrix, as well as cell renewal by the proliferation of keratinocytes. DNA protection tests assess the ability of the active agent to limit oxidative or UV damage. Hydration efficiency can be studied by measuring the expression of proteins such as aquaporin-3 or hyaluronic acid production. Finally, the analysis of senescence markers, such as senescent P-galactosidase, complements these evaluations to characterize the antiaging effects of the active agents.

[0120] To evaluate antiaging cosmetic active agents, several in vivo tests can be carried out directly on human volunteers. The effectiveness on skin hydration can be measured using comeometry, which quantifies the water level in the stratum corneum. The improvement inskin elasticity and firmness can be evaluated with a cutometer, while the effect on fine lines and wrinkles is analyzed by 3D imaging techniques or profilometry methods. The ability of an active agent to unify the complexion can be studied by measuring the pigmentation and radiance of the skin using a colorimeter or a spectrophotometer. To evaluate tolerance and possible anti-inflammatory effects, clinical observations and redness or irritation measurements are carried out. Finally, questionnaires filled out by the volunteers complement these evaluations with subjective data regarding the perception of the efficacy and comfort of the product.

[0121] According to one embodiment, the cosmetic active agents can be chosen from a list comprising resveratrol; capryloylsalicylic acid; niacinamide (vitamin B3); azelaic acid; ectoin; Zingiber officinale root or rhizome extract; Ginkgo biloba leaf extract; a combination of maltodextrin and Saccharomyces fermentation filtrate; N-acetyl-phytosphingosine (NaP); Bifidobacterium longum: 2-ethoxyethyl (2Z)-cyano{3-[(3-methoxypropyl)amino]cyclohex-2-en-l-ylidene} ethanoate); Calendula officinalis flower extract; tocopherol (vitamin E); ascorbic acid (vitamin C); C-beta-D-xylopyranoside-2-hydroxypropane; Grifola frondosa extract; rhamnose; and Centella asiatica extract titrated with asiaticoside, asiatic acid and madecassic acid.

[0122] According to a particular embodiment, the process also includes the step of generating a topogram from all or part of the data of the database.

[0123] In the context of the present text, a topogram can be interpreted as a graphical or schematic representation of the relationships between the various tables of the database. It illustrates connections between entities (tables), often using entity-relationship diagrams (ERDs), where tables are represented by rectangles and relationships by lines or arrows. Such a “topogram” helps to visualize the structure and interactions of the data, facilitating the understanding of the organization of the database and the dependencies between the tables. Examples of topograms are the entity-relationship diagram (ERD) (which represents tables and relationships between them using rectangles and lines), the graph diagram (which uses nodes and edges to show relationships between tables organically), the hierarchy diagram (which organizes tables in a tree structure, often used for parent-child relationships), the matrix diagram (which shows relationships between tables in a grid where intersectionsindicate connections), and the textual relationships table (which describes the relationships between tables in list or table form.)

[0124] A topogram can be obtained manually or using software tools.

[0125] A topogram can be obtained by using database modeling tools such as Microsoft Visio, MySQL Workbench or specialized software such as ER / Studio, which make it possible to visualize relationships between tables in a database using entity-relationship diagrams or other graphical formats.

[0126] Process for manufacturing a composition

[0127] According to another aspect, the present invention relates to a process for manufacturing a composition, notably a cosmetic composition, comprising the step consisting in selecting one or more cosmetic active agents by performing the selection process according to the invention, and the manufacture of said composition by integrating the selected cosmetic active agent(s) into a physiologically acceptable medium.

[0128] Thus, a process for manufacturing a composition according to the invention may include one or more of the steps of the process for selecting cosmetic active agents according to the invention described previously.

[0129] A composition obtained according to the invention is in particular a cosmetic composition. More particularly, it is a cosmetic care composition, in particular an antiaging cosmetic care composition.

[0130] A composition according to the invention may comprise an aqueous phase and / or a fatty phase.

[0131] For the purposes of the invention, the term 'fatty phase" means a phase comprising at least one oil and all of the liposoluble and lipophilic ingredients and the fatty substances, which are notably liquid at 20°C and atmospheric pressure, used for the formulation of the compositions of the invention.

[0132] A composition according to the invention may comprise water and optionally a water-soluble organic solvent.

[0133] According to the present invention, the term “water-soluble organic solvent' denotes a compound that is liquid at room temperature and water-miscible (miscibility with water of greater than 50% by weight at 25°C and atmospheric pressure).A fatty phase that is suitable for preparing the compositions, especially cosmetic compositions, according to the invention may comprise hydrocarbon-based oils, silicone oils, fluoro oils or non-fluoro oils, or mixtures thereof.

[0134] The oils may be volatile or nonvolatile.

[0135] For the purposes of the invention, the term “volatile oiV means any oil that is capable of evaporating on contact with the skin in less than one hour, at room temperature and atmospheric pressure. The volatile oil is a volatile cosmetic compound that is liquid at room temperature, particularly having a nonzero vapor pressure, at room temperature and atmospheric pressure, particularly having a vapor pressure ranging from 0.13 Pa to 40000 Pa (IO-3to 300 mmHg), in particular ranging from 1.3 Pa to 13 000 Pa (0.01 to 100 mmHg) and more particularly ranging from 1.3 Pa to 1300 Pa (0.01 to 10 mmHg).

[0136] The term "nonvolatile" refers to an oil whose vapor pressure at room temperature and atmospheric pressure is nonzero and is less than 10'3mmHg (0.13 Pa).

[0137] The fatty phase may comprise at least one volatile or nonvolatile hydrocarbon-based oil and / or one volatile and / or nonvolatile silicone oil and / or one volatile and / or nonvolatile fluoro oil.

[0138] For the purposes of the present invention, the term “hydrocarbon-based oil” means an oil mainly containing hydrogen and carbon atoms.

[0139] The term “silicone oiV means an oil comprising at least one silicon atom and notably at least one Si-0 group.

[0140] The term “fluoro oil” means an oil comprising at least one fluorine atom.

[0141] The oils may optionally comprise oxygen, nitrogen, sulfur and / or phosphorus atoms, for example in the form of hydroxyl or acid radicals.

[0142] A fatty phase of a composition according to the invention may also comprise, mixed with or dissolved in an oil, other fatty substances, such as fatty acids containing from 8 to 30 carbon atoms, waxes, silicone resins, silicone elastomers, a gum selected from silicone gums, a pasty compound and mixtures thereof.

[0143] A composition according to the present invention may comprise at least one gelling agent (or thickener) that is hydrophilic, i.e. that is water-soluble or water-dispersible, or lipophilic, i.e. that is soluble or dispersible in the fatty phase.A composition according to the invention may also comprise one or more additional cosmetic active agents. These additional active agents are different from the cosmetic active agents selected from the selection process according to the invention.

[0144] Needless to say, a person skilled in the art will take care to select one or more additional cosmetic active agents such that the advantageous properties of the cosmetic active agents selected by the selection process of the invention are not, or are not substantially, adversely affected.

[0145] Additional active agents that may be mentioned include, for example, moisturizers, depigmenting agents, desquamating agents, different antiaging agents, mattifying agents, cicatrizing agents, preserving agents such as antibacterial agents, UV-screening agents which are notably lipophilic, and mixtures thereof.

[0146] A composition according to the invention may contain one or more adjuvants commonly used in the cosmetic and dermatological fields; emollients; sequestrants; antioxidants; fillers; free-radical scavengers; essential oils; fragrances; film-forming agents; dyes; and mixtures thereof.

[0147] The total amounts of the various ingredients mentioned above are those conventionally used in the fields under consideration, in particular in the field of cosmetics. They may vary according to the type of composition which a person skilled in the art seeks to prepare.

[0148] A composition according to the invention may be in any presentation form normally used in the cosmetics field, in particular in the skincare cosmetics field.

[0149] It may notably be in the form of an aqueous or aqueous-alcoholic solution, which may be gelled, a dispersion of the lotion type, which may be a two-phase dispersion, an oil-in-water or water-in-oil emulsion or a multiple emulsion, a gel, notably an aqueous gel, or even a dispersion of oils in an aqueous phase, notably using spherules, it being possible for these spherules to be polymeric particles or, better still, lipid vesicles of ionic and / or nonionic type. In particular, a composition according to the invention may be in the form of a gel, notably an aqueous gel. It may also be an anhydrous composition. The term “anhydrous composition” means a composition containing less than 10% by weight of water, in particular less than 5% by weight of water, more particularly less than 2% by weight of water or even less than 0.5% of water, and notably free of water, the water not being added duringthe preparation of the composition but corresponding to the residual water provided by the mixed ingredients. The composition may be of more or less fluid liquid consistency.

[0150] A composition according to the invention is in particular suitable for topical administration. Thus, a composition according to the invention may comprise all the constituents usually employed in the envisaged topical application and administration.

[0151] A composition according to the invention may advantageously be in the form of an emulsion, particularly obtained by dispersion of an aqueous phase in a fatty phase (W / O) or of a fatty phase in an aqueous phase (O / W), of liquid or semi-liquid consistency of the milk type, or of soft consistency, or else of a multiple emulsion (W / O / W or O / W / O). These compositions are prepared according to the usual known methods.

[0152] More particularly, a composition according to the invention may be intended for topical application and may in particular be in the form of an emulsion, in particular an oil-in-water emulsion. In particular, such an emulsion is not intended to be rinsed off after application. A composition according to the invention is more particularly intended to be applied to skin. In particular, the skin is the skin of the face, scalp, neckline, neck, arms or forearms, or even more preferably the skin of the face (in particular of the forehead, nose, cheeks and chin), neckline and neck.

[0153] The composition according to the invention may alternatively be in the form of a face and / or body care or makeup product, and may be packaged, for example, in the form of a cream in a jar or a fluid in a tube or a pump bottle or a dropper bottle.

[0154] A composition according to the invention can be manufactured by any known process generally used in the cosmetics field. In particular, the manufacturing process comprises beforehand at least the step consisting in selecting one or more cosmetic active agents by performing the selection process according to the invention.

[0155] The ingredients can be mixed before being formed into shape, in the order and under conditions readily determined by a person skilled in the art.

[0156] According to a particular mode of the invention, other agents intended to enhance the appearance and / or texture of the skin may also be added to the composition according to the invention.

[0157] Cosmetic useAccording to another aspect, the present invention relates to the cosmetic use, in particular the topical use, of a composition obtained via the process according to the invention, for its application to human keratin materials, in particular to the skin.

[0158] The composition used according to the invention may be that described previously.

[0159] The cosmetic use according to the invention is non-therapeutic.

[0160] The cosmetic use according to the invention is more particularly carried out by administering via the topical route a composition obtained via a process according to the invention.

[0161] Topical administration consists in externally applying compositions, notably cosmetic compositions, to the skin according to the usual techniques for the use of these compositions. By way of illustration, the cosmetic use according to the invention may be performed by topical, for example daily, application of at least one composition according to the invention, which may be formulated, for example, in the form of a cream, gel, serum, lotion, emulsion or cleansing milk, in particular in gel form.

[0162] The application may be repeated for example 1 to 2 times daily over a day or more, and generally over an extended period of at least 3 days, at least 4 weeks, or even 4 to 15 weeks, with one or more periods of stoppage, if necessary.

[0163] According to one embodiment, the application is daily (once a day) and generally over an extended period of at least 3 days, at least 4 weeks, or even 4 to 15 weeks, with one or more periods of stoppage, if necessary.

[0164] According to one embodiment, the cosmetic use according to the invention may comprise a single application.

[0165] The examples that follow illustrate the present invention without limiting the scope thereof. The starting materials are referred to by their chemical or INCI name. The amounts are indicated as weight percentages of starting materials relative to the total weight of the composition, unless otherwise mentioned.

[0166] In the examples, unless otherwise specified, the temperature is room temperature (25°C) and is expressed in degrees Celsius, and the pressure is atmospheric pressure.

[0167] Examples

[0168] Example 1:Figure 1 represents a topogram generated from a part of the structured database according to the invention.

[0169] This topogram represents:

[0170] The hallmark “chronic micro-inflammation”, belonging to the cluster “communication pathway dysfunctions”.

[0171] As previously explained, a structured database according to the invention comprises hallmarks, namely biological causes of skin aging, listed and organized in clusters according to their nature, and constitute the basis for the analysis and search for relevant active agents. Each hallmark is associated with intracellular and extracellular biomarkers.

[0172] Intracellular and extracellular biomarkers associated with these hallmarks, and acting directly or indirectly thereon; these biomarkers represent key indicators related to one or more hallmarks. Examples of biomarkers represented in the topogram of figure 1 include MAPK, COX2, p38 and NFKB.

[0173] One or more biological functions associated with the above hallmarks, these biological functions being activated or deactivated by intracellular or extracellular biomarkers. They reflect the functional consequences associated with hallmarks. Biological functions represented in the topogram include cytokine and chemokine inflammation, immune regulation, and induction of senescence-associated secretory phenotype (SASP);

[0174] One or more root causes of aging acting directly or indirectly on biological functions and / or biomarkers. In figure 1, such root causes include UVA and UVB radiation. Cofactors and metabolites may also be involved in the implementation of biological functions and thus in the associated hallmarks. In figure 1, DAG is included.

[0175] Candidate active agents with known effects on biomarkers. In the case of the hallmark “chronic micro-inflammation”, vitamin B3 is a candidate cosmetic active agent, due to its regulatory effect on the transcription factor NFKB (intracellular biomarker) which impacts the expression of the inflammatory cytokines IL1, IL6, IL8 or TNF.

[0176] Causal relationships, which represent the causal links (activation, inhibition) between biomarkers, biological functions and root causes, making it possible tomodel networks of biological interactions between at least two elements of the structured database.

[0177] The selection of relevant cosmetic active agents according to the claimed process is based on a systematic and step-by-step approach, facilitated by a structured database, in particular a relational database.

[0178] 1 , Identification of target hallmarks

[0179] The process commences by identifying two hallmarks specific to skin aging that it is desired to target. These hallmarks are chosen according to their importance and their impact on the skin.

[0180] 2, Database query

[0181] Once the target hallmarks have been identified, the database is queried for biomarkers, cofactors and / or metabolites associated with these hallmarks. The effects of the cosmetic active agents on these biomarkers are listed in the form of activating or inhibiting interactions, and consequently their effect on the different biological functions involved.

[0182] 3, Analysis of the effects of cosmetic active agents

[0183] For each candidate cosmetic active agent, an analysis is carried out to identify its potential effects on the hallmarks identified. The following steps are followed:

[0184] A. The effects of the active agent on intracellular or extracellular biomarkers are linked to the hallmarks with which these biomarkers are associated.

[0185] b. The interactions identified are crossed with the hallmark clusters.

[0186] 4, Validation of affected clusters

[0187] It is verified that the active agent has a significant effect on at least two hallmarks belonging to two different clusters. This guarantees both targeted and extensive action on the biological causes of skin aging of interest.

[0188] 5, Selection of relevant active agents

[0189] The active agents and / or combinations of active agents that meet the above criteria (effects on at least two hallmarks of different clusters) are selected as relevant candidates and can be directly integrated into a cosmetic formulation, in particular antiaging. Their effectiveness can then be confirmed by further biological studies.

Claims

CLAIMS1. A process for selecting cosmetic active agents included in the formulation of a composition, in particular an antiaging cosmetic composition, comprising the steps consisting in:a) providing a structured database, listing:(1) a set of biological causes of skin aging, known as hallmarks, chosen from the list comprising:o (i) mitochondrial dysfunction,o (ii) senescence of cells,o (iii) alterations to the skin microbiome,o (iv) DNA instability,o (v) epigenetic modifications,o (vi) loss of proteostasis,o (vii) chronic micro-inflammation,o (viii) depletion of stem cells, ando (ix) cellular communicationeach hallmark being in a single cluster according to the nature of a biological dysfunction, in particular in a cluster chosen from structural dysfunctions, functional dysfunctions and communication pathway dysfunctions,(2) a list of intracellular biomarkers associated with one or more hallmarks, (3) a list of extracellular biomarkers associated with one or more hallmarks, (4) a list of biological functions associated with one or more hallmarks, and (5) a list of relationships reflecting a cause and effect relationship, notably an activation or inhibition relationship, between at least two elements of the database chosen from the biomarkers and the biological functions, and b) for a list of candidate cosmetic active agents with known effects on biomarkers and, optionally, cofactors and / or metabolites listed in said database, identifying with the aid of said database at least one cosmetic active agent having a beneficial effect on at least two hallmarks belonging to at least two different predefined clusters.

2. The process as claimed in claim 1, wherein said list of hallmarks also includes: (x) extracellular matrix (ECM) changes.

3. The process as claimed in claim 1 or claim 2, the structured database also comprising: (6) a list of cofactors and metabolites, and / or(7) a list of root causes of skin aging.

4. The process as claimed in any one of the preceding claims, step b) being carried out to identify at least one cosmetic active agent having a beneficial effect on at least three hallmarks belonging to at least two different predefined clusters, in particular belonging to at least three different predefined clusters.

5. The process as claimed in any one of the preceding claims, step b) being carried out to identify a combination of at least two active agents, said combination having a beneficial effect on at least two hallmarks belonging to two different predefined clusters, better still having a beneficial effect on at least three hallmarks belonging to at least two different predefined clusters, even better still having a beneficial effect on at least three hallmarks belonging to three different predefined clusters.

6. The process as claimed in any one of the preceding claims, step b) being performed by computer, the structured database being stored in a computer memory.

7. The process as claimed in any one of the preceding claims, including, after step b), an in vitro and / or in vivo test phase of the selected cosmetic active agent(s).

8. The process as claimed in any one of the preceding claims, including the step of generating a topogram from all or part of the data of the database.

9. The process as claimed in any one of the preceding claims, the intracellular and extracellular biomarkers being selected from a list comprising the biomarkers involved in:DNA damage repair, such as poly(ADP-ribose) polymerase (PARP), apoptosis inducing factor (AIF) and Ku80 protein (Ku80); protection against telomer shortening, such as cyclin-dependent kinase inhibitor 2 A (pl 6), cell cycle regulator p21 (p21) and tumor suppressor protein p53 (p53); protection of genome integrity, such as DNA methyltransferase (DNMT), ten-eleven translocation methylcytosine dioxygenase (TET) and nuclear factor kappa B (NFKB); protection against histone alterations, such as histone acetyltransferase (HAT), histone deacetylase 1 (HDAC1) and histone demethylase (HDM); protection against chromatin remodeling, such as chromobox protein homolog 4 (CBX4), transcriptional coactivator p300 (p300) and heterochromatin protein 1 (HP1); protection of messenger RNA (mRNA) such as microRNA-377 (mIR-377), microRNA-181b (mIR-181b) and microRNA-138 (mIR-138); autophagy such as microtubule-associated protein LC3 (LC3), autophagy gene 5 (Atg5) and autophagy gene 7 (Atg7); proteasome such as ubiquitin (ubiquitin), proteasome 26S (proteasome 26S), proteasome core 20S (proteasome CORE 20S); protection against extracellular matrix degradation, such as mitogen-activated kinase (MAPK), protein activator complex 1 (AP-1) and protein p38 (p38); cell differentiation such as filaggrin (filaggrin), loricrin (loricrin) and involucrin (involucrin); cell proliferation such as keratin 1 (KI), keratin 16 (KI 6) and keratin 6 (K6); cell migration and / or adhesion such as Rho protein (Rho), integrin family (integrins) and Rac protein (Rac); skin microbiome diversity and skin homeostasis such as Cutibacterium, S. aureus and Clostridium bacteria; senescence-associated secretory phenotype (SASP) and senomorphism such as NOD-like receptor pyrin domain containing protein 3 (NRLP3), microRNA-377 (mIR-377) and lamin Bl (LMNB1); apoptosis such as cell death-associated protein (BAD), caspase-9 (caspase-9), and mammalian rapamycin target (mTOR); cell cycle such as cyclin-dependent kinase inhibitor 2 A (pl 6), cell cycle regulator p21 (p21) and cyclin-dependent kinase inhibitor IB (p27); regulation of DNA such as binding factor-associated protein TAB-1 (TAB-1), microRNA-767 (mIR-767), and protein kinase B (Akt); biogenesis of mitochondria such as peroxisome proliferator-activated gamma receptor 1-alpha coactivator (PGC-la), AMP-activated protein kinase (AMPK) and sirtuin (SIRT); mitochondrial DNA such as mitochondrial DNA polymerase gamma (polG mtDNA) and mitochondrial transcription factor A (Tfam); mitophagy such as PTEN-induced putative kinase 1 protein (PINK1), Parkin protein (parkin) and translocase of outer membrane 20 (TOM); mitochondrial metabolism such as sirtuin (SIRT), complex II (CII) and ATP synthase (ATP synthase); oxidative stress such as NADPH oxidase (NOX), protein phosphatase 2A (PP2A) or protein tyrosine phosphatase activator (PTPA); reprogramming and differentiation of stem cells such as octamer-linked transcription factor 4 (Oct-4), myelocytomatosis viral oncogene homolog (Myc) and protein expressed by Sry-linked HMG box gene 2 (SOX2); cellular communication of exosomes such as microRNA-767 (mIR-767), microRNA-302-3p (mIR-302-3p) and microRNA-138 (mIR-138); cellular communication of growth factors such as fibroblast growth factor (FGF), keratinocyte growth factor (KGF) and epidermal growth factor (EGF); cellular communication of hormones such as 1 ip-hydroxy steroid dehydrogenase (HSDlip), estrogen (estrogen) and progesterone (progesterone); intracellular trafficking such as the soluble NSF attachmentprotein receptor complex (SNARE), Rab protein (Rab) or ABCA protein (ABCA); cytokine and chemokine inflammation such as cyclooxygenase-2 (COX2), Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway or mitogen-regulated kinase MAP3 (MAP3K); immune regulation such as forkhead box P3 protein (FOXP3), histamine (histamine) or C-X-C motif chemokine receptor 2 (CXCR2); and induction of senescence-associated secretory phenotype (SASP) such as NOD-like receptor, pyrin domaincontaining protein 3 (NRLP3), microRNA-377 (mIR-377) and nuclear factor kappa B (NFKB).

10. The process as claimed in any one of the preceding claims, the biological functions being selected from a list comprising repair of DNA damage, protection against telomer shortening, protection of genome integrity, protection against histone alteration, protection against chromatin remodeling, protection of messenger RNA (mRNA), autophagy, proteasome, protection against extracellular matrix degradation, cell differentiation, cell proliferation, cell migration and / or adhesion, skin microbiome diversity and homeostasis, senescence-associated secretory phenotype (SASP) and senomorphism, apoptosis, cell cycle; DNA regulation, mitochondrial biogenesis, mitochondrial DNA, mitophagy, mitochondrial metabolism, oxidative stress, stem cell reprogramming and differentiation, exosomal cell communication, growth factor cell communication, hormone cell communication, intracellular trafficking, cytokine and chemokine inflammation, immune regulation, and induction of senescence-associated secretory phenotype (SASP).

11. The process as claimed in any one of claims 3 to 10, the cofactors and metabolites being chosen from a list comprising nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FADH2), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), dioxygen (O2), vitamin B3, vitamin D3, vitamin A, vitamin C, calcium ion (Ca2+), potassium ion (K+), sodium ion (Na+), chloride ion (CF), glutathione (GSH), nitric oxide (NO), inositol trisphosphate (IP3), diacylglycerol (DAG), amino acids, cysteine, propionate and monosaccharides.

12. The process as claimed in any one of claims 3 to 11, the root causes of skin aging being chosen from a list comprising infrared (IR) radiation, ultraviolet (UV) radiation, xenobiotics, sleep disorders, circadian cycle, air pollutants, poor diet, lifestyle, stress,endogenous causes related to chronological aging, fragility of mitochondrial DNA, specificity and changes in hormone levels and changes in gene expression.

13. The process as claimed in any one of the preceding claims, the relationships including activation or inhibition links connecting elements (1) to (4), in particular elements (1) to (4), (6) and (7), in pairs.

14. The process as claimed in any one of the preceding claims, the cosmetic active agents being chosen from a list comprising resveratrol; capryloylsalicylic acid; niacinamide (vitamin B3); azelaic acid; ectoin; Zingiber officinale root or rhizome extract; Ginkgo biloba leaf extract; a combination of maltodextrin and Saccharomyces fermentation filtrate; N-acetyl-phytosphingosine (NaP); Bifidobacterium longum: 2-ethoxyethyl (2Z)-cyano{3-[(3-methoxypropyl)amino]cyclohex-2-en-l-ylidene} ethanoate); Calendula officinalis flower extract; tocopherol (vitamin E); ascorbic acid (vitamin C); C-beta-D-xylopyranoside-2-hydroxypropane; Grifola frondosa extract; rhamnose; and Centella asiatica extract titrated with asiaticoside, asiatic acid and madecassic acid.

15. A process for manufacturing a composition, notably a cosmetic composition, comprising the step consisting in selecting one or more cosmetic active agents by performing the selection process as claimed in any one of claims 1 to 14, and the manufacture of said composition by integrating the selected cosmetic active agent(s) into a physiologically acceptable medium.

16. The cosmetic use, in particular topical use, of a composition obtained via the process as claimed in claim 15, for its application to human keratin materials, in particular to the skin.

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