AU2021271499A1

AU2021271499A1 - Nicotinamide adenine dinucleotide (NAD) concentration increasing agent

Info

Publication number: AU2021271499A1
Application number: AU2021271499A
Authority: AU
Inventors: Daisuke Takemoto
Original assignee: Suntory Holdings Ltd
Current assignee: Suntory Holdings Ltd
Priority date: 2020-05-11
Filing date: 2021-05-07
Publication date: 2022-12-15
Also published as: TW202200129A; WO2021230145A1; TWI879956B; CN115867270A; JPWO2021230145A1; JP7633238B2; KR20230009417A

Abstract

The purpose of the present invention is to provide a nicotinamide adenine dinucleotide (NAD) concentration increasing agent that is safe and derived from a food-containing component. The present invention pertains to a nicotinamide adenine dinucleotide (NAD) concentration increasing agent that includes one or more sesamins as active ingredients.

Description

DESCRIPTION TITLE OF INVENTION: NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) CONCENTRATION INCREASING AGENT TECHNICAL FIELD

[0001] The present invention relates to a nicotinamide adenine dinucleotide (NAD) concentration increasing agent.

BACKGROUND ART

[0002] In recent years, countries with a high proportion of elderly people have faced the challenge of extending healthy life expectancy. One of the factors of shorter healthy life expectancy is a decline in physical function or the like caused by an age-related decline in nicotinamide adenine dinucleotide (NAD+) production in the body.

[0003] Nicotinamide adenine dinucleotide (NAD+, (hereafter also referred to as NAD)) is a coenzyme that mediates many redox reactions in the body. The NAD level is known to decrease in the aging process, which causes defects in nuclear and mitochondrial function, leading to many age related pathologies. For example, Non-Patent Literature 1 suggests that aging and age-related diseases are associated with a decline in nicotinamide adenine dinucleotide (NAD+) level in cells and a decline in enzymatic activity of sirtuins, the longevity genes, which are NAD+-dependent deacetylases. A recent report says that increasing NAD+ activates sirtuins, resulting in anti-aging effects (Non Patent Literature 2). Vigorous research is therefore being conducted to search for ingredients that are effective in preventing or ameliorating an age-related decline in NAD+ and are applicable to pharmaceutical products, foods for specified health uses, foods with function claims, and other products.

[0004] Specifically, Non-Patent Literature 2 says that the extracellular nicotinamide phosphoribosyltransferase (eNAMPT) level decreases with age in mice and humans, and discloses that an increase in eNAMPT increases the NAD level to inhibit aging and prolong life. Non-Patent Literature 2 also says that supplementation with extracellular vesicles (EVs) containing eNAMPT ameliorates physical activity to extend the life of mice, suggesting that the supplementation could be a potential intervention in inhibition of aging.

[0005] Non-Patent Literature 2 however includes no suggestion or disclosure about any action of sesamin and/or episesamin to increase nicotinamide adenine dinucleotide (NAD) in vivo.

CITATION LIST - Non-Patent Literature

[0006] Non-Patent Literature 1: Imai, S. & Guarente, L. (2014) Trends Cell Biol., 24, 464-471. "NAD+ and sirtuins in aging and disease" Non-Patent Literature 2: Yoshida M, Satoh A, Lin JB, Mills KF, Sasaki Y, Rensing N, Wong M, Apte RS, Imai SI., Cell Metab. (2019) 30(2): 329-342. e5. "Extracellular Vesicle Contained eNAMPT Delays Aging and Extends Lifespan in Mice"

SUMMARY OF INVENTION - Technical Problem

[0007] The present invention aims to provide a safe nicotinamide adenine dinucleotide (NAD) concentration increasing agent derived from food ingredients.

- Solution to Problem

[00081 The present inventor made intensive studies to solve the above problem to find out that sesamin-class compounds have an effect of increasing nicotinamide adenine dinucleotide (NAD) concentration.

[00091 The present invention relates to the following nicotinamide adenine dinucleotide (NAD) concentration increasing agent. (1) A nicotinamide adenine dinucleotide (NAD) concentration increasing agent, containing at least one sesamin-class compound as an active ingredient. (2) The agent according to (1) above, wherein the at least one sesamin-class compound includes at least one of sesamin or episesamin. (3) The agent according to (1) or (2) above, wherein the agent improves, maintains, or ameliorates NAD concentration or reduces a decline in NAD concentration. (4) The agent according to any one of (1) to (3) above, wherein the agent improves, maintains, or ameliorates mitochondrial function or reduces a decline in mitochondrial function through an increase in NAD concentration. (5) The agent according to any one of (1) to (3) above, wherein the agent improves, maintains, or ameliorates mitochondrial energy production capacity or reduces a decline in mitochondrial energy production capacity through an increase in NAD concentration. (6) The agent according to any one of (1) to (5) above, wherein the agent is used to inhibit and/or delay aging associated with a decline in NAD concentration.

(7) The agent according to any one of (1) to (6) above, wherein the agent is an oral composition. (8) The agent according to any one of (1) to (7) above, wherein the agent is a food or beverage. (9) The agent according to any one of (1) to (8) above, wherein the agent is labeled with at least one of "inhibiting and/or delaying aging associated with a decline in NAD concentration" or "inhibiting and/or delaying cellular senescence". (10) A method of increasing nicotinamide adenine dinucleotide (NAD) concentration, including administering at least one sesamin-class compound. (11) A method of improving, maintaining, or ameliorating nicotinamide adenine dinucleotide (NAD) concentration or reducing a decline in NAD concentration, including administering at least one sesamin-class compound. (12) Use of at least one sesamin-class compound for increasing nicotinamide adenine dinucleotide (NAD) concentration. (13) Use of at least one sesamin-class compound for improving, maintaining, or ameliorating nicotinamide adenine dinucleotide (NAD) concentration or reducing a decline in NAD concentration.

- Advantageous Effects of Invention

[0010] The present invention can provide a nicotinamide adenine dinucleotide (NAD) concentration increasing agent. Ingestion of at least one sesamin-class compound gives an effect of increasing nicotinamide adenine dinucleotide (NAD) concentration. The sesamin-class compounds used in the present invention have long been consumed as food, and are advantageous in that they are highly safe and can be ingested continuously.

BRIEF DESCRIPTION OF DRAWINGS

[0011] FIG. 1 is a graph showing effects of a sesamin episesamin mixture (SE) (sesamin:episesamin (weight ratio =

1:1) on the increase in intracellular NAD level.

DESCRIPTION OF EMBODIMENTS

[0012] The nicotinamide adenine dinucleotide (NAD) concentration increasing agent of the present invention contains at least one sesamin-class compound. The at least one sesamin-class compound is used to increase nicotinamide adenine dinucleotide (NAD) concentration. The at least one sesamin-class compound has an effect of improving, maintaining, or ameliorating nicotinamide adenine dinucleotide (NAD) concentration or reducing a decline in NAD concentration, and therefore is used to improve NAD concentration, to reduce a decline in NAD concentration, to maintain NAD concentration, or to ameliorate NAD concentration. The agent of the present invention is suitably used for improving, maintaining, or ameliorating NAD concentration that has declined with age or for reducing a decline in NAD concentration associated with aging. The nicotinamide adenine dinucleotide concentration increasing agent can also be referred to as a nicotinamide adenine dinucleotide (NAD) level increasing agent. The NAD concentration refers to the intracellular NAD concentration.

[0013] Sesamin-class compounds have an effect of increasing nicotinamide adenine dinucleotide (NAD) concentration and are expected to contribute to inhibition or amelioration of aging associated with a decline in NAD concentration by the effect of improving, maintaining, or ameliorating NAD concentration or reducing a decline in NAD concentration. Aging is understood to be a phenomenon in which physical, physiological, and mental functions decline. The physical changes associated with aging begin at about age 40, after reaching maturity. The physical changes include skin wrinkling, loss of head hair and teeth, graying of hair, fatigue accumulation and slow recovery from fatigue, loss of vision and hearing, loss of motor function, loss of muscle strength and activity, loss of sleep quality, and loss of bone mass. Although aging itself is not a disease, the decline in physical and physiological functions increases the risk of so-called geriatric diseases such as arteriosclerosis, abnormal glucose and lipid metabolism, neurodegeneration, osteoporosis, and cataracts. Also, aging with respect to mental functions such as memory and learning occurs along with the decline in physical functions. Increasing nicotinamide adenine dinucleotide (NAD) concentration is effective in inhibition or amelioration of aging associated with a decline in NAD concentration.

[0014] In one embodiment, the nicotinamide adenine dinucleotide (NAD) concentration increasing agent of the present invention improves, maintains, or ameliorates NAD concentration or reduces a decline in NAD concentration, and is suitably used for improving, maintaining, or ameliorating NAD concentration that has declined with age or for reducing a decline in NAD concentration associated with aging. In one embodiment, the agent of the present invention is suitably used for improving, maintaining, or ameliorating NAD concentration that has declined with age in middle-aged or older people or for reducing a decline in NAD concentration associated with aging in middle-aged or older people. The middle-aged and older people include the elderly. The middle-aged and older people may be those who are 40 years old and older, for example. The elderly may be those who are 60 years old and older or 65 years old and older, for example. The NAD concentration in humans and other animals can be measured by a common method in the technical field to which the present invention belongs, such as measurement of the intracellular NAD concentration using NAD+/NADH Quantification Colorimetric Kit (BioVision Inc.) or Amplite@ Colorimetric NAD/NADH Ratio Assay Kit (AAT Bioquest).

[0015] The nicotinamide adenine dinucleotide (NAD) concentration increasing agent of the present invention can be used for the treatment of conditions or diseases that are expected to be prevented or alleviated by improving, maintaining, or ameliorating NAD concentration or reducing a decline in NAD concentration. Examples of such conditions or diseases include age-related declines in physical, physiological, and mental functions. Specific examples thereof include the occurrence of skin aging symptoms (wrinkles, sagging, loss of skin firmness, etc.), dry skin due to aging (reduced skin moisture retention), skin blotches, freckles, rough skin, decreased or increased secretion of hormones (growth hormone, thyroid hormone, adrenal cortical hormone, sex hormone, prolactin, antidiuretic hormone, parathyroid hormone, melatonin, etc.), damage to cells (brain cells, cardiac muscle cells, etc.) due to active oxygen, loss of head hair and teeth, loss of vision and hearing, loss of motor function, loss of bone mass, loss of physical fitness, memory decline, loss of learning ability, loss of immune function, and onset of geriatric diseases. The term "preventing" as used herein encompasses preventing disease or symptom onset, delaying disease or symptom onset, decreasing disease or symptom incidence, decreasing risk of disease or symptom onset, and the like. The phrase "alleviating conditions or diseases" encompasses helping the subject recover from conditions or diseases, alleviating conditions or disease symptoms, making positive changes in conditions or disease symptoms, delaying or preventing progression of conditions or diseases, and the like.

[0016] In the present invention, the term "the sesamin-class compound" is a collective term for compounds including sesamin and its analogs. Sesamin is one of main lignan compounds found in sesame. Examples of the sesamin analogs include episesamin and dioxabicyclo[3.3.0]octane derivatives described in JP H04-9331 A. The at least one sesamin-class compound may include a single compound alone or two or more of these compounds above. Specific examples of the sesamin-class compound include sesamin, episesamin, sesaminol, episesaminol, sesamol, and sesamolin. Stereoisomers or racemates of these compounds may be used alone or in mixture. In addition, metabolites of the sesamin-class compound (e.g., those described in JP 2001 139579 A) are also sesamin analogs included in the sesamin class compound of the present invention, and can also be used in the present invention, as long as they exhibit the effect(s) of the present invention. In the present invention, sesamin and/or episesamin can be suitably used as the at least one sesamin-class compound. Sesamin and episesamin can be more suitably used. When sesamin and episesamin are used, the ratio of these components is not limited. For example, the ratio of sesamin to episesamin by weight is preferably 1:0.1 to 1:9, more preferably 1:0.3 to 1:3, still more preferably 1:0.5 to 1:2.

[0017] The sesamin-class compound for use in the present invention is not limited in any way by its form, production method, or the like. For example, when the sesamin-class compound is sesamin, sesamin extracted from sesame oil by a known method (e.g., the method described in JP H04-9331 A) can be used (hereinafter, such sesamin is called a sesamin extract or purified sesamin). Commercially available sesame oil (in liquid form) can also be used as is. However, when sesame oil is used, the characteristic flavor of sesame oil is sometimes evaluated as being organoleptically undesirable. Thus, a tasteless and odorless sesamin extract (or purified sesamin) from sesame oil is preferably used. In addition, since sesame oil has a low sesamin content, use of sesame oil to incorporate a desirable amount of sesamin results in excess volume per unit dose of a composition to be prescribed. This sometimes causes inconvenience in ingestion. In particular, in the case where the composition is formulated for oral administration, the preparation (e.g., tablet or capsule) becomes so bulky that it causes trouble in ingestion. Thus, use of sesamin extract (or purified sesamin) from sesame oil is preferred because it does not require a large amount of ingestion. The sesamin-class compound can also be obtained by synthesis. For example, sesamin and episesamin can be synthesized by the method of Beroza et al. (J. Am. Chem. Soc., 78, 1242 (1956)). Metabolites of sesamin and episesamin can be synthesized by the method of Urata et al. (Chem. Pharm. Bull. (Tokyo), 56(11), 1611-2 (2008)).

[0018] The sesamin-class compound is found in natural products and food and beverages. It is a compound with a long history of consumption and recognized high levels of safety. The sesamin-class compound with secured safety is ideal for continuous and long-term ingestion. The present invention can provide a nicotinamide adenine dinucleotide (NAD) concentration increasing agent that contains a highly safe substance as an active ingredient.

[0019] NAD in vivo plays an important role in activating sirtuins to deacetylate downstream enzymes or transcription factors, thereby promoting the expression and synthesis of molecules involved in mitochondrial function and mitochondrial energy production. Therefore, an increase in NAD concentration has an effect of improving, maintaining, or ameliorating mitochondrial function or reducing a decline in mitochondrial function. The agent of the present invention can improve, maintain, or ameliorate mitochondrial function or reduce a decline in mitochondrial function through an increase in NAD concentration. The agent of the present invention can also improve, maintain, or ameliorate mitochondrial energy production capacity or reduce a decline in mitochondrial energy production capacity through an increase in NAD concentration. Thus, the agent of the present invention achieves an anti cellular senescence effect.

[0020] Herein, the mitochondrial function and mitochondrial energy production capacity only need to be evaluated based on common knowledge in the technical field to which the present invention belongs. Any method may be used for evaluation. For example, the mitochondrial function can be evaluated by continuously evaluating the oxygen consumption rate (hereinafter also described as "OCR") of mitochondria during ATP synthesis in cells as the measurement target, using an extracellular flux analyzer, while adding ATP synthase inhibitors (e.g., oligomycin and rotenone) and an uncoupler (e.g., carbonyl cyanide-p-trifluoromethoxy phenylhydrazone (FCCP)) thereto. Evaluation items may be, for example, basal respiration, ATP production capacity, and maximal respiration, which are considered to be major indices for evaluation of mitochondrial function. The mitochondrial function can be evaluated by analyzing these evaluation items.

[0021] The agent of the present invention can be used to inhibit and/or delay aging associated with a decline in NAD concentration.

[0022] The agent of the present invention is applicable for therapeutic use (medical use) and non-therapeutic use (non medical use). The "non-therapeutic" is a concept that does not include medical activities, i.e., a concept that does not include methods of surgery, therapy, or diagnosis of humans. The agent of the present invention can be provided, for example, in the form of a food or beverage, a pharmaceutical product, a quasi-pharmaceutical product, feed, or the like. The agent of the present invention may be a food or beverage, a pharmaceutical product, a quasi pharmaceutical product, feed, or the like to be used for increasing nicotinamide adenine dinucleotide (NAD) concentration, improving, maintaining, or ameliorating NAD concentration, or reducing a decline in NAD concentration by itself; or the agent may be a material, a formulation, or the like to be added to these products. The agent of the present invention may be a food or beverage, a pharmaceutical product, a quasi-pharmaceutical product, feed, or the like by itself for improving, maintaining, or ameliorating mitochondrial function or reducing a decline in mitochondrial function through an increase in NAD concentration or for improving, maintaining, or ameliorating mitochondrial energy production capacity or reducing a decline in mitochondrial energy production capacity through an increase in NAD concentration; or the agent may be a material, a formulation, or the like to be added to these products.

The agent of the present invention can be provided in the form of an agent as is, for example, but the form is not limited thereto. Such an agent may be provided as a composition directly, or as a composition containing the agent. The agent of the present invention may be an oral agent or a parenteral agent, and is preferably an oral agent. The oral agent may be as is a food or beverage, an oral pharmaceutical product, an oral quasi-pharmaceutical product, oral feed, or the like, or may be contained in these products. The agent of the present invention is preferably a food or beverage or an oral pharmaceutical product, more preferably a food or beverage.

[0023] The agent of the present invention may contain optional additives and optional components, in addition to the at least one sesamin-class compound, as long as the effect(s) of the present invention is/are not impaired. Such additives and components can be selected according to the form of the agent or composition or the like. Those that can be used generally in foods, beverages, pharmaceutical products, quasi-pharmaceutical products, feed, and the like can be used. When the agent of the present invention is provided as a food or beverage, a pharmaceutical product, a quasi-pharmaceutical product, feed, or the like, any common method can be used for production.

[0024] For example, when the agent of the present invention is provided as a food or beverage, a component usable in food or beverages (e.g., a food material or an optional food additive) can be added to the at least one sesamin class compound to provide various types of foods or beverages. Non-limiting examples of the foods or beverages include general foods and beverages, health foods, health beverages, foods with function claims, foods for specified health uses, and foods and beverages for the sick. The health foods, the foods with function claims, the foods for specified health uses, and the like can be used, for example, in various forms of preparations such as fine granules, tablets, granules, powders, capsules, chewable tablets, dry syrups, syrups, liquids, beverages, and liquid foods.

[0025] When the agent of the present invention is provided as a pharmaceutical product or a quasi-pharmaceutical product, for example, a pharmacologically acceptable carrier, an optional additive, or the like can be added to the at least one sesamin-class compound to provide various dosage forms of pharmaceutical products or quasi pharmaceutical products. Such a carrier, additive, or the like may be any pharmacologically acceptable one that can be used in pharmaceutical products or quasi-pharmaceutical products. Examples thereof include excipients, binders, disintegrants, lubricants, antioxidants, and colorants. One or more of these can be used. The form of administration (ingestion) of the pharmaceutical product or the quasi-pharmaceutical product may be oral or parenteral (e.g., transdermal, transmucosal, enteral, or injection) administration. When the agent of the present invention is provided as a pharmaceutical product or a quasi pharmaceutical product, it is preferably an oral pharmaceutical product or an oral quasi-pharmaceutical product. Examples of the dosage form for oral administration include liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, and chewable tablets. The pharmaceutical product may be for non-human animals.

[0026] When the agent of the present invention is provided as feed, at least one sesamin-class compound is simply added to feed. The feed includes feed additives. Examples of the feed include feed for farm animals such as cows, pigs, chickens, sheep, and horses; feed for small animals such as rabbits, rats, and mice; and pet food for animals such as dogs, cats, and birds.

[0027] The amount of the sesamin-class compound in the agent of the present invention is not limited. The amount can be set depending on the form of the agent or the like. The total amount of the sesamin-class compound in the agent of the present invention is, for example, preferably 0.001 wt% or more, more preferably 0.01 wt% or more, still more preferably 0.05 wt% or more, and is preferably 10 wt% or less, more preferably 5 wt% or less. In one embodiment, the total amount of the sesamin-class compound in the agent is preferably 0.001 to 10 wt%, more preferably 0.01 to 5 wt%, still more preferably 0.05 to 5 wt%. When the agent contains two or more sesamin-class compounds, the total amount is the sum of the amounts of these compounds.

[0028] The agent of the present invention is preferably an oral composition (a composition to be ingested orally (orally administered)). The dosage (which can also be referred to as "intake") of the agent of the present invention is not limited. The dosage of the agent of the present invention may be any amount that achieves an effect of increasing nicotinamide adenine dinucleotide concentration or an effect of improving, maintaining, or ameliorating NAD concentration or reducing a decline in NAD concentration. The dosage may be appropriately set according to the administration form, administration method, body weight of a subject, and the like.

[0029] In one embodiment, when the agent of the present invention is orally ingested by or administered to a human (adult), the total intake of the sesamin-class compound is preferably 0.5 mg or more, more preferably 1 mg or more, still more preferably 3 mg or more, and is preferably 200 mg or less, more preferably 100 mg or less, still more preferably 80 mg or less per 60 kg body weight per day. In one embodiment, the total intake of the sesamin-class compound is preferably 0.5 to 200 mg, more preferably 1 to 100 mg, still more preferably 3 to 80 mg per 60 kg body weight per day for a human (adult). Preferably, the sesamin-class compound in the above amount is ingested or administered in one or more portions per day, for example, in one to several portions (e.g., two or three portions) per day. In one embodiment, preferably, the sesamin-class compound in the above amount is orally ingested by or administered to a human. In one embodiment, the agent of the present invention can be used to allow the sesamin class compound in the above amount to be ingested by or administered to a human per 60 kg body weight per day. When the agent contains two or more sesamin-class compounds, the total intake is the sum of these compounds. In one embodiment, sesamin and/or episesamin is orally ingested by or administered to a human (adult) in an amount of preferably 0.5 to 200 mg, more preferably 1 to 100 mg, still more preferably 3 to 80 mg per 60 kg body weight per day as the total intake of sesamin and episesamin.

[00301 Preferably, the agent of the present invention is continuously ingested or administered. Continuous ingestion or administration of the sesamin-class compound is likely to enhance the above effects. In one embodiment, the agent of the present invention is continuously ingested or administered for preferably one week or more, more preferably four weeks or more, still more preferably eight weeks or more, particularly preferably 12 weeks or more.

[00311 The nicotinamide adenine dinucleotide (NAD) concentration increasing agent of the present invention may be labeled with a function claim of a function exerted by increasing nicotinamide adenine dinucleotide (NAD) concentration or a function exerted by improving, maintaining, or ameliorating NAD concentration or reducing a decline in NAD concentration. The agent of the present invention may be labeled with one or more function claims selected from the group consisting of "improving, maintaining, or ameliorating mitochondrial function or reducing a decline in mitochondrial function through an increase in NAD concentration", "improving, maintaining, or ameliorating mitochondrial energy production capacity or reducing a decline in mitochondrial energy production capacity through an increase in NAD concentration", "inhibiting and/or delaying aging associated with a decline in NAD concentration", "inhibiting aging through an increase in NAD concentration", and "inhibiting and/or delaying cellular senescence". In one embodiment of the present invention, the agent of the present invention is preferably a food or beverage labeled with one or more of the above function claims. The label may be one indicating use for obtaining one or more of these functions.

[0032] The subject (which can also be referred to as "administration subject") subjected to ingestion or administration of the agent of the present invention is not limited. Humans and non-human animals can be subjected to ingestion. Examples of the non-human animals include industrial animals, pets, and laboratory animals. Specifically, the term "industrial animals" refers to animals that are bred for industrial purposes. Examples include farm animals such as cows, horses, pigs, goats, and sheep; poultry such as chickens, ducks, quals, turkeys, and ostriches; and fish such as yellowtail, young yellowtail, red seabream, Japanese horse mackerel, carp, rainbow trout, and eel. The term "pets" refers to pet animals or companion animals such as dogs, cats, common marmosets, birds, and hamsters. The term "laboratory animals" refers to mice, rats, guinea pigs, beagles, miniature pigs, rhesus monkeys, crab-eating monkeys, and other animals that are used in research in fields of medicine, biology, agronomy, pharmacy, and the like.

[00331 The subject (which can be also referred to as "administration subject") subjected to ingestion or administration of the agent of the present invention is preferably a human or non-human mammal, more preferably a human. In one embodiment, the administration subject may be one needing or wanting to increase nicotinamide adenine dinucleotide (NAD) concentration, one needing or wanting to improve, maintain, or ameliorate NAD concentration or reduce a decline in NAD concentration, and the like. Examples of the subjects include middle-aged and older people, one needing or wanting to improve, maintain, or ameliorate mitochondrial function or reducing a decline in mitochondrial function through an increase in NAD concentration, one needing or wanting to improve, maintain, or ameliorate mitochondrial energy production capacity or reducing a decline in mitochondrial energy production capacity through an increase in NAD concentration, one needing or wanting to inhibit and/or delay cellular senescence through an increase in NAD concentration, and the like. The middle-aged and older people may be those who are 40 years old and older, for example. In one embodiment, the elderly are preferred subjects among the middle-aged and older people. The elderly may be those who are 60 years old and older or 65 years old and older, for example. The agent of the present invention can be used by healthy people for purposes such as preventing conditions or diseases that are likely to be prevented or alleviated by increasing nicotinamide adenine dinucleotide (NAD) concentration, improving, maintaining, or ameliorating NAD concentration, or reducing a decline in NAD concentration.

[0034] The present invention also encompasses the following methods. A method of increasing nicotinamide adenine dinucleotide (NAD) concentration, including administering at least one sesamin-class compound. A method of improving, maintaining, or ameliorating NAD concentration or reducing a decline in NAD concentration, including administering at least one sesamin-class compound. A method of improving, maintaining, or ameliorating NAD concentration that has declined with age or reducing a decline in NAD concentration associated with aging, including administering at least one sesamin-class compound.

[0035] The present invention also encompasses the following uses. Use of at least one sesamin-class compound for increasing nicotinamide adenine dinucleotide (NAD) concentration. Use of at least one sesamin-class compound for improving, maintaining, or ameliorating NAD concentration or reducing a decline in NAD concentration. Use of at least one sesamin-class compound for improving, maintaining, or ameliorating NAD concentration that has declined with age, or reducing a decline in NAD concentration associated with aging.

The above methods and uses may be therapeutic or non therapeutic. Administration of at least one sesamin-class compound can increase nicotinamide adenine dinucleotide (NAD) concentration. In other words, administration of at least one sesamin-class compound can improve, maintain, or ameliorate NAD concentration or reduce a decline in NAD concentration. In addition, administration of at least one sesamin-class compound can improve, maintain, or ameliorate NAD concentration that has declined with age or reduce a decline in NAD concentration associated with aging. Thus, administration of at least one sesamin-class compound enables: improvement, maintenance, or amelioration of mitochondrial function or reduction of a decline in mitochondrial function through an increase in NAD concentration; improvement, maintenance, or amelioration of mitochondrial energy production capacity or reduction of a decline in mitochondrial energy production capacity through an increase in NAD concentration; and inhibition and/or delay of cellular senescence through an increase in NAD concentration.

[00361 In the methods and uses, the sesamin-class compound and its preferred embodiments are the same as those of the agent of the present invention. The at least one sesamin class compound may include one sesamin-class compound or two or more sesamin-class compounds. In the above methods and uses, preferably, the at least one sesamin-class compound is administered to (injected by) a subject at least once per day, for example, one to several times (e.g., two or three times) per day. In the above methods and uses, preferably, the sesamin-class compound is orally administered (orally ingested). The above uses are preferably for humans or non-human mammals, more preferably for humans.

[0037] The above methods and uses only require use of the at least one sesamin-class compound in an amount (which can also be referred to as "effective amount") that achieves a desired effect (i.e., effect of improving, maintaining, or ameliorating mitochondrial function or reducing a decline in mitochondrial function through an increase in nicotinamide adenine dinucleotide (NAD) concentration, effect of improving, or maintaining mitochondrial energy production capacity or reducing a decline in mitochondrial energy production capacity through an increase in NAD concentration, and/or effect of inhibiting and/or delaying cellular senescence through an increase in NAD concentration). Preferred dosage, preferred administration subjects, and the like of the sesamin-class compound are as described above for the agent or composition of the present invention. The sesamin-class compound may be administered directly or may be administered in the form of an agent or composition containing the sesamin-class compound. For example, the agent or composition of the present invention described above may be used.

[0038] The present invention also encompasses use of at least one sesamin-class compound for producing the agent or composition of the present invention.

EXAMPLES

[0039] The present invention is described in more detail with reference to examples. The present invention is not limited to these examples.

[0040] <Examples 1 and 2, Comparative Example 1: Evaluation test of effect of sesamin-episesamin mixture (SE) (sesamin:episesamin (weight ratio = 1:1)) on intracellular

NAD+ concentration (NAD concentration) > To examine the effect on intracellular NAD+ concentration, HepG2 cells were seeded in 12-well plates at 1.0 x 105 cells/well, and cultured in a DMEM medium (Nacalali Tesque, Inc., containing 10% FBS) at 370C with C02 (5%) for 24 hours. After 24 hours of culturing, the medium in each well was replaced with a DMEM medium (containing 1% albumin and no FBS (Comparative Example 1: control)) containing no sesamin/episesamin mixture (SE), a DMEM medium (containing 1% albumin and no FBS (Example 1)) containing 1 pM of SE, or a DMEM medium (containing 1% albumin and no FBS (Example 2)) containing 10 pM of SE, followed by culturing for additional 24 hours. The added media were removed, and the cells in the wells were washed with D-PBS (Nacalai Tesque Inc.), followed by collection of cell suspensions by adding NADH/NAD Extraction Buffer (NAD+/NADH Quantification Colorimetric Kit, available from BioVision Inc.). Cell extracts were then obtained according to the manual of the kit and analyzed for intracellular NAD+ concentration. The Intracellular NAD+ concentration was determined by measuring the protein concentration of the cell extract (Pierce@ BCA Protein Assay Kit, available from Thermo Scientific, Inc.), and calculated as a value per protein concentration. FIG. 1 shows the results (average of N = 2).

[0041] FIG. 1 shows that the intracellular NAD+ concentration was increased by 20% in the 1 pM SE group of Example 1 and by 37% in the 10 pM SE group of Example 2, relative to the control group (medium containing no SE) of Comparative Example 1. These results confirm the dose dependent increasing effect of SE treatment on intracellular NAD+ concentration.

Claims

Claim 1. A nicotinamide adenine dinucleotide (NAD) concentration increasing agent, comprising: at least one sesamin-class compound as an active ingredient.
Claim 2. The agent according to claim 1, wherein the at least one sesamin-class compound includes at least one of sesamin or episesamin.
Claim 3. The agent according to claim 1 or 2, wherein the agent improves, maintains, or ameliorates NAD concentration or reduces a decline in NAD concentration.
Claim 4. The agent according to any one of claims 1 to 3, wherein the agent improves, maintains, or ameliorates mitochondrial function or reduces a decline in mitochondrial function through an increase in NAD concentration.
Claim 5 The agent according to any one of claims 1 to 3, wherein the agent improves, maintains, or ameliorates mitochondrial energy production capacity or reduces a decline in mitochondrial energy production capacity through an increase in NAD concentration.
Claim 6. The agent according to any one of claims 1 to 5, wherein the agent is used to inhibit and/or delay aging associated with a decline in NAD concentration.
Claim 7. The agent according to any one of claims 1 to 6, wherein the agent is an oral composition.
Claim 8. The agent according to any one of claims 1 to 7, wherein the agent is a food or beverage.
Claim 9. The agent according to any one of claims 1 to 8, wherein the agent is labeled with at least one of "inhibiting and/or delaying aging associated with a decline in NAD concentration" or "inhibiting and/or delaying cellular senescence".
Claim 10. A method of increasing nicotinamide adenine dinucleotide (NAD) concentration, comprising administering at least one sesamin-class compound.
Claim 11. A method of improving, maintaining, or ameliorating nicotinamide adenine dinucleotide (NAD) concentration or reducing a decline in NAD concentration, comprising administering at least one sesamin-class compound.
Claim 12. Use of at least one sesamin-class compound for increasing nicotinamide adenine dinucleotide (NAD) concentration.
Claim 13. Use of at least one sesamin-class compound for improving, maintaining, or ameliorating nicotinamide adenine dinucleotide (NAD) concentration or reducing a decline in NAD concentration.