The use of food and beverage ingredients to prevent and / or improve the decline in memory and learning ability that accompanies aging.

Abstract

[The technical problem to be solved] The subject of this invention is to provide medicines, food products and feeds that effectively prevent and / or improve the decline in memory and learning ability that accompanies aging. Technical means to solve the problem The solution of this invention is to provide a novel microorganism that has the effect of preventing and / or improving the decline in memory and learning ability caused by aging. More specifically, the microorganism is characterized by belonging to the genera *Lactobacillus*, *Bifidobacterium*, *Streptococcus*, *Candida albicans*, and *Micrococcus*. More specifically, the microorganism is characterized by belonging to any one of the following: *Lactobacillus acidophilus*, *Lactobacillus gasseri*, *Lactobacillus johnsonii*, *Lactobacillus delbruekii* subsp. *delbruekii*, *Bifidobacterium chainiensis*, *Bifidobacterium pseudolongum*, *Bifidobacterium bifidum*, *Bifidobacterium breve*, *Bifidobacterium longum*, *Streptococcus thermophilus*, *Leuconostoc dextranicum* subsp. *dextranicum*, *Leuconostoc*, *Pediococcus lactis*, and *Pediococcus pentosaceus*.

Description

[Technical Field] This invention relates to preventive and improving agents for the decline in memory and learning ability that occurs with aging, and / or dietary products that have the effect of preventing and improving the decline in memory and learning ability that occurs with aging. [Previous Technology] In 2010, Japan entered a super-aged society as its population aged 65 and over exceeded 21% of the total population. The proportion of the elderly is expected to continue to increase, reaching 40% by 2060. In this context, issues such as healthcare and welfare in response to the growing elderly population have become urgent problems. With the increasing aging population, the rise in cognitive impairments or dementia, such as decreased memory and learning abilities, among middle-aged and older adults is considered a problem. Generally, it is believed that with age, the fine structure of brain nerve cells changes; through the deposition of abnormal proteins or cell shedding, the brain shrinks, leading to a decline in cognitive function. Besides these age-related changes, other causes include cerebral infarction, cerebral hemorrhage, and excessive accumulation of abnormal proteins. A pathological decline in cognitive function is termed dementia. As of 2012, it was estimated that 15% of people aged 65 and over had dementia, approximately 4.62 million people. It was also said that there were about 4 million people with mild cognitive impairment, who were considered at risk of dementia. Japan is now referred to as the "era of 8 million people with dementia". While drugs for treating dementia are being developed, their current purpose is primarily to delay disease progression, not to achieve a fundamental cure. On the other hand, in healthy elderly individuals or those with mild cognitive impairment considered a precursor to dementia, appropriate interventions such as dietary review and exercise have shown the potential to prevent or improve cognitive decline, including memory and learning abilities, thereby further reducing the risk of developing dementia (Journal of Neuropsychiatry 111, 26-30, (2009)). Considering this, there is increased interest in dietary options that can be sustainably consumed in daily life and are safe with few side effects. Microorganisms used in foods such as lactic acid bacteria are widely used in fermented foods such as cheese or yogurt, pickles, and lactic acid bacteria beverages. Because they are readily available at a low price and have high affinity for lactic acid bacteria, they have been produced in large quantities worldwide since ancient times. Recently, they have gained attention as health foods with excellent health benefits, including preventing constipation, improving diarrhea, preventing infectious diseases, and stimulating the immune system. Regarding their effects on aging or cognitive function, studies have shown that *Lactobacillus gasseri* or *Bifidobacterium longum* are effective against age-related metabolic abnormalities (Japanese Patent 5155961, Japanese Patent 5155960), and that *Lactobacillus reuteri* DSM 17938 strain is effective in promoting cognitive development in young mammals (Japanese Patent No. 2015-503913). However, the role of microorganisms in the decline of memory and learning abilities that accompanies aging remains unclear. The nematode *Caenorhabditis elegans* (hereinafter referred to as *C. elegans*) uses a simple neural circuit composed of 302 neurons to sense various external stimuli and take various coping behaviors. If the nematode is raised at a certain temperature, it will remember that temperature as its comfortable temperature, and therefore will exhibit a habit of moving towards the previously raised temperature when placed on a temperature gradient. For example, *C. elegans* raised at 23°C placed on a temperature gradient from 17°C to 23°C without food will move to around 23°C after one hour. Furthermore, if *C. elegans* that have memorized a temperature of 23°C are raised at a new temperature of 17°C, they will acquire a new memory of 17°C after about 4 hours and begin to move towards the vicinity of 17°C along the temperature gradient (Proc. Natl. Acad. Sci. USA, 72, 4061-4065 (1975); Genetics, 169, 1437-1450 (2005); J. Neurosci. Methods, 154, 45-52 (2006)). This behavior is called thermotaxis and is known as a model system reflecting the plasticity of neural functions such as memory or learning (Curr. Opin. Neurobiol., 17, 712-719 (2007)). The inventors, through previous experiments using lasers to destroy neurons, clarified the neurons necessary for thermotaxis, which is known to be based on very simple neural circuits (Nature, 376, 344-348 (1995)). Furthermore, their research team analyzed the process of temperature memory formation using whole-genome microarray analysis, molecular genetics, and imaging techniques. The results showed that *C. elegans* receives ambient temperature throughout the body via the transcription factor HSF-1 during temperature reception. This temperature reception induces changes in gene expression, revealing that temperature signals are stored as memory through estrogen (a female hormone) in AFD neurons, the temperature-receiving neurons within the neural circuit (Nat. Neurosci., 14, 984-92 (2011)). Furthermore, the inventors, in their investigation of the function of the ortholog of CREB, a representative transcription factor responsible for memory, in *C. elegans*, discovered that there is only one ortholog of CREB, which functions exclusively in AFD neurons (EMBO Rep., 12, 855-862 (2011)). That is, among all neurons in *C. elegans*, AFD neurons are the only neurons with temperature memory via CREB. Based on these studies, part of the molecular mechanism involved in the formation of temperature memory can be understood. Although nematodes and mammals are evolutionarily distant, they share many common molecular structures at the cellular level. There are reports that molecules known to be related to memory in mammals are also associated with thermotropism in nematodes. Several studies have reported that, for example, the mammalian memory factor CREB (CRH-1 in nematodes) is associated with the acquisition of temperature memory in nematodes (EMBO Rep., 12, 855-862 (2011)); serotonin, a brain-mediated memory neurotransmitter in mammals, controls thermotropism in nematodes (PLoS One., 8, 1-10 (2013)); and calcineurin (RCAN-1 in nematodes), a mammalian memory factor, is associated with thermotropic behavior in nematodes (J. Mol. Biol., 427, 3457-3468 (2015)). Furthermore, components reported to have effects on the nervous system in nematodes have also shown effects on the brain-nervous system in mammals. Specifically, oral ingestion of α-lipoic acid has been reported to improve age-related decline in associative learning in nematodes and mammals (Neurobiol. Aging., 26, 899-905 (2005); J. Med. Food., 15, 713-7 (2012)), and oral ingestion of curcumin has been reported to improve age-related cognitive impairment in nematodes and mammals (Neurobiol. Aging., 39, 69-81 (2016); Geroscience., 40, 73-95 (2018)). Considering these factors, the thermotropic behavior of *C. elegans* is considered a suitable model system for analyzing the molecular mechanisms of temperature acceptance and memory. [Previous Art Documents] [Patent Documents] [Patent Document 1] Japanese Patent 5155961 [Patent Document 2] Japanese Patent 5155960 [Patent Document 3] Japanese Patent Publication No. 2015-503913 [Non-Patent Documents] [Non-Patent Literature] Katsuyoshi Mizukami, Journal of Neuropsychiatry 111, 26-30, (2009) [Non-Patent Literature 2] Hedgecock, EM & Russell, RL: Normal and mutant thermotaxis in the nematode Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA, 72, 4061-4065 (1975) [Non-Patent Literature 3] Mohri, A., Kodama, E., Kimura, KD et al.: Genetic control of temperature preference in the nematode Caenorhabditis elegans. Genetics, 169, 1437-1450 (2005) [Non-Patent Literature 4] Ito, H., Inada, H. & Mori, I.: Quantitative analysis of thermotaxis in the nematode Caenorhabditis elegans. J. Neurosci. Methods, 154, 45-52 (2006) [Non-Patent Literature 5] Mori, I., Sasakura, H. & Kuhara, A.: Worm thermotaxis: a model system for analyzing thermosensation and neural plasticity. Curr. Opin. Neurobiol., 17, 712-719 (2007) [Non-Patent Literature 6] Mori, I. & Ohshima, Y.: Neural regulation of thermotaxis in Caenorhabditis elegans. Nature, 376, 344-348 (1995) [Non-Patent Literature 7] Sugi, T., Nishida, Y., & Mori, I.: Regulation of behavioral plasticity by systemic temperature signaling in Caenorhabditis elegans. Nat. Neurosci., 14, 984-92 (2011) [Non-Patent Literature 8] Nishida, Y., Sugi, T., Nonomura, M. et al.: Identification of the AFD neuron as the site of action of the CREB protein in Caenorhabditis elegans thermotaxis. EMBO Rep., 12, 855-862 (2011) [Non-Patent Literature 9] Li, Y., Zhao, Y., Huang, X., et al.: Serotonin control of thermotaxis memory behavior in nematode Caenorhabditis elegans. PLoS One., 8, 1-10 (2013) [Non-Patent Literature 10] Li, W., Bell, HW, Ahnn, J., Lee, SK: Regulator of Calcineurin (RCAN-1) Regulates Thermotaxis Behavior in Caenorhabditis elegans. J. Mol. Biol., 427, 3457-3468 (2015) [Non-Patent Literature 11] Murakami, S., Murakami, H.: The effects of aging and oxidative stress on learning behavior in C. elegans. Neurobiol. Aging., 26, 899-905 (2005) [Non-Patent Literature 12] Cui, Y., Shu, Y., Zhu, Y., Shi, Y., Le, G.: High-fat diets impair spatial learning of mice in the Y-maze paradigm: ameliorative potential of α-lipoic acid. J. Med. Food., 15, 713-7 (2012) [Non-Patent Literature 13] Miyasaka, T., Xie, C., Yoshimura, S., et al.: Curcumin improves tau-induced neuronal dysfunction of nematodes. Neurobiol. Aging., 39, 69-81 (2016) [Non-patent document 14] Sarker, MR, Franks, SF.: Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies. Geroscience., 40, 73-95 (2018). [Summary of the Invention] [The problem that the invention aims to solve] This invention relates to providing a novel microorganism that has the effect of preventing and / or improving the decline in memory and learning ability that accompanies aging. [Means of the Problem] The inventors of this case, focusing on the possibility of preventing or improving various functional abnormalities of organisms through food materials that can be ingested daily, conducted in-depth research on microorganisms used in food and their components. As a result, they discovered that the cells or cultures of several different genera of microorganisms have the effect of preventing and / or improving the decline in memory-learning ability associated with aging, and thus completed this invention. That is, this invention has the following structure: (1) A composition for maintaining and / or improving memory-learning ability, containing the cells or cultures of one or more microorganisms belonging to the genera Lactobacillus, Bifidobacterium, Streptococcus, Leuconostoc, and Pediococcus. (2) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the Lactobacillus genus is selected from one or more of Lactobacillus acidophilus, Lactobacillus gasseri, Lactobacillus gallinarum, Lactobacillus johnsonii, and Lactobacillus delbruekii subsp. delbruekii.(3) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the Lactobacillus genus is selected from Lactobacillus acidophilus, Lactobacillus gallinarum, Lactobacillus brevis, Lactobacillus casei, Lactobacillus crispatus, Lactobacillus delbrueckii, Lactobacillus delbruekii subsp. delbruekii, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus johnsonii, Lactobacillus lactis, and Lactobacillus reye's. The *Lactobacillus* species must be one of the following: *Lactobacillus leichmannii*, *Lactobacillus paracasei*, *Lactobacillus pentosus*, *Lactobacillus plantarum*, *Lactobacillus reuteri*, *Lactobacillus rhamnosus*, *Lactobacillus sakei*, or *Lactobacillus salivarius*. (4) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the Bifidobacterium genus is selected from one or more of Bifidobacterium catenulatum, Bifidobacterium pseudolongum, Bifidobacterium bifidum, Bifidobacterium breve, and Bifidobacterium longum.(5) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the Bifidobacterium genus is selected from no more than one of the following: Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium catenulatum, Bifidobacterium pseudocatenulatum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium pseudolongum, Bifidobacterium longum, and Bifidobacterium longum subspecies infantis. (6) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the Streptococcus genus is Streptococcus thermophilus.(7) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the streptococcus species is selected from Streptococcus agalactiae, Streptococcus anginosus, Streptococcus iniae, Streptococcus intermedius, Streptococcus equi, Streptococcus oralis, Streptococcus gallolyticus, Streptococcus gallolyticus subspecies gallolyticus, Streptococcus constellatus, Streptococcus gordonii, Streptococcus salivarius, Streptococcus sanguis, Streptococcus thermophilus The bacteria must be one or more of the following: *Thermophilus*, *Streptococcus suis*, *Streptococcus zooepidemicus*, *Streptococcus sobrinus*, *Streptococcus pneumoniae*, *Streptococcus pyogenes*, *Streptococcus phage*, *Streptococcus faecalis*, *Streptococcus faecium*, *Streptococcus bovis*, *Streptococcus mitis*, and *Streptococcus mutans*. (8) A composition for maintaining and / or improving memory-learning ability as in (1), wherein the Candida albicans is selected from one or more of Leuconostoc mesenteroides subsp. dextranicum and Leuconostoc lactis.(9) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the *Candida* genus is selected from no more than one species of *Leuconostoc mesenteroides* subsp. *dextranicum*, *Leuconostoc mesenteroides*, and *Leuconostoc lactis*. (10) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the *Micrococcus* genus is selected from one or more species of *Pediococcus acidilactici* and *Pediococcus pentosaceus*. (11) The composition for maintaining and / or improving memory-learning ability as in (1), wherein the *Micrococcus* genus is selected from no more than one species of *Pediococcus acidilactici* and *Pediococcus pentosaceus*. (12) The composition for maintaining and / or improving memory-learning ability as in (2), wherein the Lactobacillus strain is selected from one or more of the following strains: Lactobacillus acidophilus SBT1921, Lactobacillus gasseri SBT2056, Lactobacillus avium SBT0316, Lactobacillus johnsonii SBT0307, ​​and Lactobacillus delbruekii subsp. SBT0413. (13) The composition for maintaining and / or improving memory-learning ability as in (4), wherein the Bifidobacterium strain is selected from one or more of the following strains: Bifidobacterium chainratum SBT11114, Bifidobacterium pseudolongum SBT2922, Bifidobacterium bifidum SBT10550, Bifidobacterium breve SBT10532, and Bifidobacterium longum SBT10527. (14) A composition for maintaining and / or improving memory-learning ability as in (6), wherein the Streptococcus genus is Streptococcus thermophilus SBT0118. (15) A composition for maintaining and / or improving memory-learning ability as in (8), wherein the Candida albicans genus is selected from one or more of Leuconostoc dextranicum subsp. SBT0096 and Leuconostoc mollissima SBT2561. (16) A composition for maintaining and / or improving memory-learning ability as in (10), wherein the Micrococcus genus is selected from one or more of Pediococcus lactis SBT3331 and Pediococcus pentosaceus SBT2229. (17) A composition for maintaining and / or improving memory-learning ability as in any one of (1) to (16), wherein the maintenance and / or improvement of memory-learning ability is for the prevention and / or improvement of the decline in memory-learning ability associated with aging.(18) The memory-learning ability maintenance and / or improvement composition as in (17), wherein the decline in memory-learning ability associated with aging does not include the decline in memory-learning ability or memory ability associated with brain diseases, memory impairments and mental illnesses. (19) The memory-learning ability maintenance and / or improvement composition as in any of (1) to (18), wherein the active ingredient is not peptides contained in the culture supernatant of microorganisms, but rather the microbial cells. (20) A food, a medicine, or a feed for maintaining and / or improving memory-learning ability, characterized in that it contains the memory-learning ability maintenance and / or improvement composition as in any of (1) to (19). (21) Lactobacillus acidophilus SBT1921 strain with NITE P-02980, Lactobacillus avium SBT0316 strain with NITE P-02981, Lactobacillus johnsonii SBT0307 strain with NITE P-02982, Bifidobacterium chainratum SBT11114 strain with NITE P-02983, Bifidobacterium pseudolongum SBT2922 strain with NITE P-02984, Bifidobacterium bifidum SBT10550 strain with NITE P-02985, Bifidobacterium breve SBT10532 strain with NITE P-02986, Bifidobacterium longum SBT10527 strain with NITE P-02987, and strains with NITE P-02988... Streptococcus thermophilus strain SBT0118 (P-02988), Leuconostoc dextranicum subsp. SBT0096 (NITE P-02989), Leuconostoc lactis strain SBT2561 (NITE P-02990), Pediococcus lactis strain SBT3331 (NITE BP-02991), or Pediococcus pentosaceus strain SBT2229 (NITE BP-02992). [Effects of the invention]. This invention can prevent and / or improve the decline in memory and learning abilities that accompany aging. This invention is effective in improving the quality of life in daily life for elderly people who are concerned about declining memory and learning abilities.

Implementation Method

Claims

1. A use of a dietary or beverage composition to prevent and / or improve age-related decline in memory and learning abilities, wherein the dietary or beverage composition contains cells of one or more microorganisms belonging to the genus *Lactobacillus*; wherein, The Lactobacillus genus is selected from Lactobacillus gasseri; the decline in memory-learning ability that accompanies aging does not include the decline in memory-learning ability or memory ability that accompanies brain diseases, memory impairments, and mental illnesses.

2. As in claim 1, the use of dietary or beverage ingredients to prevent and / or improve the decline in memory and learning abilities associated with aging, wherein, Lactobacillus gasseri strain SBT2056 with accession number FERM BP-11038.

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