JP2022046831A - Agent for extending life of mammal - Google Patents

Abstract

To provide an agent for extending the life of a mammal.SOLUTION: The present invention discloses an agent for extending a life of a mammal (life extender) that includes an agent to inhibit expression or functions of synoviolin.SELECTED DRAWING: Figure 1

Description

The present invention relates to agents for extending the lifespan of mammals.

Japanese Patent No. 62164943 describes a sweetener for extending the life of an active ingredient of D-psicose. It is a long-standing desire of mankind to extend lifespan, including immortality and longevity.

Japanese Patent No. 62164943

It is an object of the present invention to provide an agent for extending the life span of a mammal.

The present invention is basically based on the findings of Examples that inhibition of Synoviolin expression or function can significantly prolong the lifespan of mammals, especially those carrying the obesity gene.

One of the embodiments described herein relates to an agent for prolonging the lifespan of a mammal (life-prolonging agent), including an agent that inhibits the expression or function of Synoviolin.

A preferred embodiment of the life-prolonging agent is that the mammal expresses the obesity gene.

In a preferred embodiment of the life-prolonging agent, the agent that inhibits the expression or function of Synoviolin is one or more selected from the siRNA of Synoviolin, the decoy nucleic acid of Synoviolin, and the antisense nucleic acid of Synoviolin.

A preferred embodiment of the life-prolonging agent is that the agent that inhibits the expression or function of Synoviolin is an extract of walnut branches, shells or leaves.

（Ｒ^１～Ｒ^４は，同一でも異なってもよく，水素原子，水酸基，Ｃ_１－３アルキル基，Ｃ_１－３アルコキシ基，及びハロゲン原子のいずれかを表わし，Ｒ^１～Ｒ^４の少なくともひとつは水酸基であり，
Ｒ^５及びＲ^６は，同一でも異なってもよく，水素原子，Ｃ_１－３アルキル基，及びハロゲン原子のいずれかを表わし，
Ｘ^１及びＸ^２は，同一でも異なってもよく，酸素原子又は硫黄原子を表し，
Ａ^１－Ａ^２は，Ｃ－Ｃ，又はＣ＝Ｃを表す。） A preferred embodiment of the life-prolonging agent is that the agent that inhibits the expression or function of noviolin is plumbagin, quercetin, a naphthalene derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. It is a solvate.

(R ¹ to R ⁴ may be the same or different, and represent any one of a hydrogen atom, a hydroxyl group, a C _1-3 alkyl group, a C _1-3 alkoxy group, and a halogen atom, and at least of R ¹ to R ⁴ . One is the hydroxyl group,
R ⁵ and R ⁶ may be the same or different and represent either a hydrogen atom, a _C1-3 alkyl group, or a halogen atom.
X ¹ and X ² may be the same or different and represent an oxygen atom or a sulfur atom.
A ¹ -A ² represents C-C or C = C. )

A preferred embodiment of the life-prolonging agent is to prolong the lifespan of a mammal by promoting the expression of beige or brown cells.

An embodiment different from the above of the present invention relates to an agent that promotes the expression of beige cells or brown cells, including an agent that inhibits the expression or function of Synoviolin. The composition and manufacturing method of this agent may be the same as that of the above-mentioned life extension agent.

According to the present invention, it is possible to provide an agent for extending the life span of a mammal.

FIG. 1 is a graph that replaces the drawing showing the cumulative survival rates of wild-type mice and Synoviolin knockout mice. FIG. 2-1 is a graph that replaces the drawing showing the expression analysis results of various markers. FIG. 2-2 is a graph that replaces the drawing showing the expression analysis results of various markers.

Hereinafter, embodiments for carrying out the present invention will be described. The present invention is not limited to the forms described below, and includes those modified appropriately by those skilled in the art from the following forms.

An agent for extending the lifespan of a mammal (lifespan extending agent) is an agent intended to extend the lifespan by ingesting the target mammal. This agent may be a drug, drug or pharmaceutical composition that normally requires clinical trials or regulatory approval, may be a supplement, or may be a food additive. The life-prolonging agent does not have to be effective for all subjects, but may be effective with a certain probability. The life-prolonging agents described herein include agents (ingredients) that inhibit the expression or function of Synoviolin. As shown in the examples, this life-prolonging agent has been shown to be able to prolong the life of the subject with a statistically significant difference.

The target of life-prolonging agents is mammals. Examples of mammals are humans or non-human mammals (non-human mammals). Preferred mammals are mammals that express the obesity gene. An example of a person expressing the obesity gene is a subject having a gene polymorphism related to obesity.

Examples of gene polymorphisms involved in obesity include the gene encoding the β-2 adrenergic receptor (β2AR) (β2AR gene), the gene encoding the β-3 adrenergic receptor (B3AR) (β3AR gene), and the deconjugated protein. It is a polymorphism of the gene encoding (UCP) (UCP1 gene).

β2AR is mainly distributed in the heart, bronchial smooth muscle, etc., and is also present in adipose tissue and is involved in lipolysis. The β2AR gene encoding this includes a polymorphism (Arg16Gly) in which arginine (Arg) at the 16th amino acid position becomes glycine (Gly). It has been reported that those with this polymorphism (16% present in Japanese) have an increased amount of metabolism at rest as compared with those without the polymorphism (Arg16Gly).

β3AR is present in brown adipose tissue and white adipocyte tissue, and binding of noradrenaline initiates heat production in brown adipocyte tissue and lipolysis in white adipocyte tissue. The β3AR gene encoding this includes a polymorphism (Trp64Arg) in which tryptophan (Trp) at the 64th amino acid position becomes arginine (Arg). It has been reported that subjects with this polymorphism (34% present in Japanese) have a reduced amount of metabolism at rest compared to subjects without the polymorphism. ..

UCP1 is a protein that plays a central role in heat production in brown adipose tissue when the exchange nerve is in an excited state. The UCP1 gene encoding this includes a polymorphism (A3826G) in which adenine (A) at position -3826 of mRNA (position upstream of the translation initiation point of the UCP1 gene in the genomic sequence is position 3826) becomes guanine (G). .. It has been reported that subjects with this polymorphism (24% present in obese Japanese women) have a reduced amount of systemic metabolism compared to subjects without the polymorphism.

Subjects with such polymorphisms that reduce the amount of metabolism (for example, polymorphisms of β2AR gene, β3AR gene, and UCP1 gene, such as the above-mentioned Arg16Gly, Trp64Arg, and A3826G, respectively) are examples of mammals expressing the obesity gene. be. These can be analyzed using, for example, Direct Sequencing method using PCR, RFLP analysis, ASP-PCR method, or Tm analysis.

In a preferred embodiment of the life-prolonging agent, the agent that inhibits the expression or function of Synoviolin is one or more selected from the siRNA of Synoviolin, the decoy nucleic acid of Synoviolin, and the antisense nucleic acid of Synoviolin. Synoviolin siRNA, Synoviolin decoy nucleic acid and Synoviolin antisense nucleic acid are known, for example, as described in Japanese Patent No. 6230546.

Synoviolin siRNA
An example of siRNA of sinoviolin is one base sequence selected from SEQ ID NOs: 1 to 5, a base sequence complementary to these base sequences, or one or two bases substituted or inserted from any of these base sequences. , RNA with a deleted or added base sequence. The RNA having the base sequence shown in SEQ ID NOs: 1 to 3 is Synoviolin siRNA, as described by Izumi T, et al. , Artristis Rheum. 2009; 60 (1): 63-72., Yamasaki S, et al. , EMBO J. 2007; 26 (1): 113-22. Is known as disclosed experimentally. It is known that the RNA having the base sequence shown in SEQ ID NOs: 4 and 5 is Synoviolin siRNA, as disclosed experimentally in WO2005 / 0794988 pamphlet.

SEQ ID NO: 1: 5'-GCUGUGACAGAUGCCAUCA-3'
SEQ ID NO: 2: 5'-GGUGUUCUUGGGCAACUG-3'
SEQ ID NO: 3: 5'-GGUUCUGCUGUACAUGGCC-3'
SEQ ID NO: 4: 5'-CGUCCUGGGUACCGCCGUCA-3'
SEQ ID NO: 5: 5'-GUUUTGGUGACUGGUGCUA-3'

"RNA having a base sequence in which one or two bases are substituted, inserted, deleted or added from any of these base sequences" is one base sequence selected from SEQ ID NOs: 2 to 6 and these bases. An RNA having a base sequence in which one or two bases are substituted, inserted, deleted or added from any base sequence of a base sequence complementary to the sequence. Any one type of substitution, insertion, deletion or addition may occur, or two or more may occur. These function as the siRNA of Synoviolin.

Synobiolin Decoy Nucleic Acid An example of a synobiolin decoy nucleic acid has a base sequence in which one or two bases are substituted, inserted, deleted or added from the base sequence shown by SEQ ID NO: 7 or the base sequence shown by SEQ ID NO: 7. It is a decoy nucleic acid of synobiolin. The nucleic acid having the base sequence shown by SEQ ID NO: 7 is a decoy nucleic acid of Synoviolin, for example, using Examples in Tsuchimochi K, et al., Mol Cell Biol. 2005; 25 (16): 7344-56. It is known as shown in the above.
SEQ ID NO: 7: 5'-AUGGUGACUGGUGACUAAGA-3'

Synoviolin decoy nucleic acids and methods for confirming them are known, for example, as disclosed in International Publication WO2005-093067 Pamphlet and International Publication WO2005-074988 Pamphlet.

Synoviolin Antisense Nucleic Acids Methods for screening Synoviolin antisense nucleic acids and Synoviolin antisense nucleic acids are disclosed, for example, in JP2009-155204A, Retable 2006-137514 and Retable 2005-074988. .. The Synoviolin antisense nucleic acid means a nucleic acid that has a sequence complementary to the Synoviolin gene and can inhibit the expression of the Synoviolin gene by hybridizing to the gene. The antisense nucleic acid can be prepared by a synthetic chemical method or the like, which is a nucleic acid compound complementary to the partial base sequence of the gene encoding Synoviolin. In order to evaluate whether or not the nucleic acid compound efficiently inhibits the production of Synoviolin, a screening test using the gene expression level as an index may be performed. As the antisense nucleic acid compound, for example, the expression of Synoviolin can be suppressed to at least 50% or less as compared with the control.

As a method of inhibiting the expression of a specific endogenous gene, a method using antisense technology is well known to those skilled in the art. There are multiple factors as the action of antisense nucleic acid to inhibit the expression of the target gene as follows. That is, transcription initiation inhibition by triple-strand formation, transcription inhibition by hybrid formation with a site where an open loop structure is locally formed by RNA polymerase, transcription inhibition by hybrid formation with RNA whose synthesis is progressing, intron and exson. Inhibition of splicing by hybrid formation at the junction with and inhibition of splicing by hybrid formation with sprisosome formation site, inhibition of transcription from nucleus to cytoplasm by hybrid formation with mRNA, hybrid formation with capping site and poly (A) addition site Inhibition of splicing by, inhibition of translation initiation by hybrid formation with translation initiation factor binding site, translation inhibition by hybrid formation with ribosome binding site near the initiation codon, elongation of peptide chain by hybrid formation with RNA translation region or polysome binding site Inhibition and inhibition of gene expression by the formation of hybrids between nucleic acid and protein interaction sites. In this way, antisense nucleic acids inhibit the expression of target genes by inhibiting various processes such as transcription, splicing or translation (Hirashima and Inoue, Neochemical Experiment Course 2 Nucleic Acid IV Gene Replication and Expression, Japanese Biochemistry). Society ed., Tokyo Chemicals, 1993, 319-347.).

The antisense nucleic acid used in the present invention may inhibit the expression and / or function of the Synoviolin gene by any of the above actions. As one embodiment, designing an antisense sequence complementary to the untranslated region near the 5'end of the mRNA of the Synoviolin gene is considered to be effective in inhibiting the translation of the gene. In addition, sequences complementary to the coding region or the untranslated region on the 3'side can also be used. As described above, the nucleic acid containing the antisense sequence of the sequence of the untranslated region as well as the translated region of the Synoviolin gene is included in the antisense nucleic acid used in the present invention. The antisense nucleic acid used is ligated downstream of the appropriate promoter, preferably the sequence containing the transcription termination signal on the 3'side. The nucleic acid thus prepared can be transformed into a desired animal (cell) by using a known method. The sequence of the antisense nucleic acid is preferably a sequence complementary to the endogenous Synoviolin gene of the transformed animal (cell) or a part thereof, but it is complete as long as the expression of the gene can be effectively suppressed. It does not have to be complementary to. The transcribed RNA has preferably 90% or more, most preferably 95% or more complementarity to the transcript of the target gene. In order to effectively inhibit the expression of the target gene (synoviolin) using the antisense nucleic acid, the length of the antisense nucleic acid is preferably at least 15 bases or more and less than 25 bases. The length is not necessarily limited to this, and may be, for example, 100 bases or more, or 500 bases or more.

In addition, the expression of the Synoviolin gene can be inhibited by using ribozyme or DNA encoding ribozyme. Ribozyme refers to an RNA molecule having catalytic activity. There are various ribozymes with various activities. Among them, research focusing on ribozyme as an enzyme that cleaves RNA has made it possible to design a ribozyme that cleaves RNA in a site-specific manner. Some ribozymes have a size of 400 nucleotides or more, such as Group I intron type and M1 RNA contained in RNase P, but some have an active domain of about 40 nucleotides called hammerhead type and hairpin type. (Makoto Koizumi and Eiko Otsuka, Protein Nucleic Acid Enzyme, 1990, 35, 2191.).

For example, the self-cleaving domain of a hammerhead ribozyme cleaves the 3'side of C15 in the sequence G13U14C15, but base pairing between U14 and A9 is important for its activity, and instead of C15, A15 or U15. However, it has been shown that it can be cleaved (Koizumi, M. et al., FEBS Lett, 1988, 228, 228.). By designing a ribozyme in which the substrate binding site is complementary to the RNA sequence near the target site, it is possible to create a restriction enzyme RNA-cleaving ribozyme that recognizes the UC, UU, or UA sequence in the target RNA (Koizumi, M. et al., FEBS Lett, 1988, 239, 285., Makoto Koizumi and Eiko Otsuka, Protein Nucleic Acid Enzymes, 1990, 35, 2191., Koizumi, M. et al., Nucl Acids Res, 1989, 17, 7059. .).

Hairpin-type ribozymes are also useful for the purposes of the present invention. This ribozyme is found, for example, in the negative strand of the satellite RNA of the tobacco ring spot virus (Buzayan, JM., Nature, 1986, 323, 349.). Hairpin-type ribozymes have also been shown to produce target-specific RNA-cleaving ribozymes (Kikuchi, Y. & Sasaki, N., Nucl Acids Res, 1991, 19, 6751., Hiroshi Kikuchi, Chemistry and Biology, 1992, 30, 112.). Thus, by specifically cleaving the transcript of the Synoviolin gene in the present invention using a ribozyme, the expression of the gene can be inhibited.

Suppression of the expression of the endogenous gene can also be performed by RNA interference (hereinafter abbreviated as "RNAi") using double-stranded RNA having the same or similar sequence as the target gene sequence.

A preferred embodiment of the life-prolonging agent is that the agent that inhibits the expression or function of Synoviolin is an extract of walnut branches, shells or leaves. Examples of walnut branch, shell or leaf extracts are walnut branch extracts, especially walnut branch alcohol extracts. Extracts of walnut branches, shells or leaves are agents that inhibit the expression or function of Synoviolin, as described, for example, in WO 2015/129895.

A preferred embodiment of the life-prolonging agent is that the agent that inhibits the expression or function of Synoviolin is purmbagin, quercetin, or a naphthalene derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. It is a solvated product. Plumbagin and quercetin inhibit the expression or function of Synoviolin as described in Japanese Patent No. 580932. It is patent No. 6280050 that the naphthalene derivative represented by the formula (I) (particularly 5,8-dihydroxy-4a, 8a-dihydro- [1,4] naphthoquinone or a salt thereof) inhibits the expression or function of Synoviolin. As described in.

（Ｒ^１～Ｒ^４は，同一でも異なってもよく，水素原子，水酸基，Ｃ_１－３アルキル基，Ｃ_１－３アルコキシ基，及びハロゲン原子のいずれかを表わし，Ｒ^１～Ｒ^４の少なくともひとつは水酸基であり，
Ｒ^５及びＲ^６は，同一でも異なってもよく，水素原子，Ｃ_１－３アルキル基，及びハロゲン原子のいずれかを表わし，
Ｘ^１及びＸ^２は，同一でも異なってもよく，酸素原子又は硫黄原子を表し，
Ａ^１－Ａ^２は，Ｃ－Ｃ，又はＣ＝Ｃを表す。）

(R ¹ to R ⁴ may be the same or different, and represent any one of a hydrogen atom, a hydroxyl group, a C _1-3 alkyl group, a C _1-3 alkoxy group, and a halogen atom, and at least of R ¹ to R ⁴ . One is the hydroxyl group,
R ⁵ and R ⁶ may be the same or different and represent either a hydrogen atom, a _C1-3 alkyl group, or a halogen atom.
X ¹ and X ² may be the same or different and represent an oxygen atom or a sulfur atom.
A ¹ -A ² represents C-C or C = C. )

A preferred embodiment of the compound represented by the formula (I) is
In the general formula (I)
R ¹ to R ⁴ may be the same or different, and represent a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, or a chlorine atom, and at least one of R ¹ and R ⁴ is a hydroxyl group.
R5 and ^R6 may be the ^same or different and represent a hydrogen atom or a methyl group.
Both X ¹ and X ² represent oxygen atoms.
A ¹ -A ² represents C = C.

A preferred embodiment of the compound represented by the formula (I) is
R ¹ and R ⁴ may be the same or different, at least one of R ¹ and R ⁴ is a hydroxyl group, and the remaining groups represent a hydrogen atom, a hydroxyl group, a methyl group, a methoxy group, or a chlorine atom.
R ² and R ³ represent a hydrogen atom.
Both R ⁵ and R ⁶ represent hydrogen atoms.
Both X ¹ and X ² represent oxygen atoms.
A ¹ -A ² represents C = C.

A preferred embodiment of the compound represented by the formula (I) is
The naphthalene derivative represented by the general formula (I) is
5,8-Dihydroxy-4a, 8a-dihydro- [1,4] naphthoquinone,
5-Hydroxy-4a, 8a-dihydro- [1,4] naphthoquinone,
5-Hydroxy-2,3,4a,8a-Tetrahydro- [1,4] naphthoquinone,
5-Hydroxy-7-methoxy-4a, 8a-dihydro- [1,4] naphthoquinone,
5-Hydroxy-8-methoxy-4a, 8a-dihydro- [1,4] naphthoquinone, and
One or more of 5-chloro-8-hydroxy-4a, 8a-dihydro- [1,4] naphthoquinone.

The pharmaceutically acceptable salt means a pharmaceutically acceptable salt of the naphthalene derivative represented by the general formula (I). The pharmaceutically acceptable solvate means a pharmaceutically acceptable solvate of the naphthalene derivative represented by the general formula (I). Examples of pharmaceutically acceptable salts are inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts. Examples of inorganic acid salts are hydrochlorides, hydrobromides, sulfates, nitrates and phosphates. Examples of organic acid salts are acetates, succinates, fumarates, maleates, tartrates, citrates, lactates, stearate, benzoates, methanesulfonates, and p-toluenesulfonates. It is a salt salt. Examples of inorganic base salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salts, and ammonium salts. Examples of organic base salts are diethylamine salts, diethanolamine salts, meglumine salts, and N, N'-dibenzylethylenediamine salts. Examples of acidic amino acid salts are aspartate and glutamate. Examples of basic amino acid salts are arginine, lysine, and ornithine. An example of a solvate is a hydrate.

The above compounds can be isolated and purified using known methods by applying conventional chemical procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various chromatographies.

A preferred embodiment of the life-prolonging agent is to prolong the lifespan of a mammal by promoting the expression of beige or brown cells. As shown in the examples described later, by inhibiting the expression or function of Synoviolin, the expression of white adipocytes can be suppressed and the expression of beige cells and brown cells can be promoted.

That is, an embodiment different from the above of the present invention relates to an agent that promotes the expression of beige cells or brown cells, including an agent that inhibits the expression or function of Synoviolin. The composition and manufacturing method of this agent may be the same as that of the above-mentioned life extension agent.

Certain embodiments of the agents disclosed herein can be administered orally or parenterally. In the case of parenteral administration, pulmonary dosage forms (for example, those using a nephrizer), nasal dosage forms, transdermal dosage forms (eg, ointments, creams), injection formulations and the like can be mentioned. In the case of the injection type, it can be administered systemically or locally by, for example, intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, or the like.

The administration method should be selected as appropriate according to the patient's age and symptoms. The effective dose is 0.1 μg to 100 mg, preferably 1 to 10 μg per 1 kg of body weight at a time. However, the above-mentioned therapeutic agents are not limited to these doses. When a nucleic acid such as siRNA is mixed, an example of the dose of the nucleic acid is 0.01 to 10 μg / ml, preferably 0.1 to 1 μg / ml.

The agents of certain embodiments disclosed herein can be formulated according to conventional methods and may include pharmaceutically acceptable carriers and additives. Such carriers and additives include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, carboxymethyl. Starch sodium, pectin, methyl cellulose, ethyl cellulose, xanthan gum, arabic rubber, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, vaseline, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, pharmaceuticals. Examples thereof include acceptable surfactants and the like as additives. The above-mentioned additive is selected from the above alone or in combination as appropriate depending on the dosage form of the therapeutic agent of the present invention. For example, when used as an injectable preparation, a purified ER stress inducer is dissolved in a solvent (for example, physiological saline, buffer solution, glucose solution, etc.), and Tween80, Tween20, gelatin, human serum albumin, etc. are added thereto. Can be used. Alternatively, it may be freeze-dried to form a dosage form that dissolves before use. As the excipient for freeze-drying, for example, sugar alcohols such as mannitol and glucose and sugars can be used.

This specification discloses the use of agents that inhibit the expression or function of Synoviolin to produce agents for prolonging the lifespan of mammals (lifespan prolonging agents). This use is a method for producing a life-prolonging agent using a known formulation method or a known processing method using an agent that inhibits the expression or function of Synoviolin as an active ingredient.

This specification also discloses a method for extending the life span of a target mammal, which comprises the step of administering to the target mammal an agent that inhibits the expression or function of Synoviolin. It is expected that the subject's life span will be extended by ingesting a life-prolonging agent containing an agent that inhibits the expression or function of Synoviolin as an active ingredient.

The cumulative survival rates of wild-type and fat-specific Synoviolin knockout mice were investigated. First, fat-specific Synoviolin knockout mice (Adiponectin-Cre; Syvn1flox / flox mice) were prepared. In order to produce a fat-specific Synoviolin knockout mouse, first, a Sivn1flox / flox mouse and an adiponectin (Adiponectin) -Cre mouse (The Jackson Laboratory) are crossed to form a heterozygote containing Adipoq-Cre; Synn1flox / mouse. Obtained. Next, as a secondary mating, Adiponq-Cre; Sivn1flox / + mice were mated with Sivn1flox / flox mice to obtain Adiponq-Cre; Sivn1flox / flox mice. PCR confirmed that Cre recombinase-mediated Sivn1 knockout occurred in the WAT (white adipose tissue) and BAT (brown adipose tissue) of the obtained Adiponectin-Cre; Synn1flox / flox mice.

FIG. 1 is a graph that replaces the drawing showing the cumulative survival rates of wild-type mice and fat-specific Synoviolin knockout mice. As shown in FIG. 1, it can be seen that the cumulative survival rate of the fat-specific Synoviolin knockout mice is about 1.25 times higher than that of the wild-type mice. This indicates that the lifespan of mammals can be significantly extended by inhibiting the development of Synoviolin or by inhibiting the activity of Synoviolin.

Genetically obese mice (db / db) become shorter-lived when fed a high-fat diet. As the action of Synn1 on the improvement of the pathological condition like metabolic syndrome, qualitative changes are considered in addition to quantitative changes in adipose tissue. Therefore, we performed a comprehensive gene expression analysis of adipocytes. As a result of preliminary experiments, markers for brown adipocytes and beige adipocytes were expressed by comprehensive gene expression analysis of white adipocytes in adipose-specific Synoviolin knockout mice. Analysis of adipocyte differentiation-related factors: White adipose tissue RNA was extracted to express white adipose tissue (Fabp4, etc.), brown adipose tissue (Ucp-1, Cox8b, Cidea, PRDM16, etc.), and beige cell (Tmem26, Cd137, etc.) markers. investigated. Specifically, the fats of wild-type mice and fat-specific Synoviolin knockout mice were sampled, and RNA was purified using the RN Easy mini kit (manufactured by Qiagen). Furthermore, using the purified RNA, microarray analysis was performed using a high-sensitivity DNA chip 3D-Gene manufactured by Toray Industries, Inc. The results are shown in FIGS. 2-1 and 2-2. FIGS. 2-1 and 2-2 show the expression levels of the fat-specific Synoviolin knockout mice when the expression level of the wild-type mice is 1.

FIGS. 2-1 and 2-2 are graphs that replace the drawings showing the results of expression analysis of various markers. From FIGS. 2-1 and 2-2, in the fat-specific Synoviolin knockout mice, the expression of white fat (Fabp4) was suppressed, brown fat (Ucp-1, Cox8b, Cidea) was highly expressed, and beige cells (Csprs). , Ear2) was found to be highly expressed.

It can be used in the present invention, the pharmaceutical industry, the supplement industry, and the food industry.

Claims (7)

Agents for prolonging the lifespan of mammals, including agents that inhibit the expression or function of Synoviolin. The agent for extending the life span of the mammal according to claim 1, wherein the mammal is a mammal expressing an obesity gene. The agent for extending the life span of a mammal according to claim 1, wherein the agent that inhibits the expression or function of Synoviolin is selected from Synoviolin siRNA, Synoviolin decoy nucleic acid, and Synoviolin antisense nucleic acid 1 A species or agent that is more than one. The agent for extending the life span of a mammal according to claim 1, wherein the agent that inhibits the expression or function of Synoviolin is an extract of walnut branches, shells or leaves. The agent for extending the life span of a mammal according to claim 1, wherein the agent that inhibits the expression or function of Synoviolin is plumbagin, quercetin, a naphthalene derivative represented by the formula (I), or a pharmaceutical thereof. An agent that is an acceptable salt or a pharmaceutically acceptable solvate thereof.

(In formula (I),
R ¹ to R ⁴ may be the same or different, and represent any one of a hydrogen atom, a hydroxyl group, a C _1-3 alkyl group, a C _1-3 alkoxy group, and a halogen atom, and at least one of R ¹ to R ⁴ . Is a hydroxyl group
R ⁵ and R ⁶ may be the same or different and represent either a hydrogen atom, a _C1-3 alkyl group, or a halogen atom.
X ¹ and X ² may be the same or different and represent an oxygen atom or a sulfur atom.
A ¹ -A ² represents C-C or C = C. ) The agent for extending the lifespan of a mammal according to claim 1, which is an agent for extending the lifespan of a mammal by promoting the expression of beige cells or brown cells. An agent that promotes the expression of beige or brown cells, including an agent that inhibits the expression or function of Synoviolin.

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