Progeria is a genetic disease in which premature aging-like symptoms appear at a younger age, earlier than actual age. Molecular genetic studies of hereditary progeria have identified the causative genes and genes that contribute to DNA repair or genomic stability. Cells derived from patients with progeria also exhibit cellular senescence traits, indicating the contribution of DNA damage and cellular senescence. Despite the development of various models for Werner syndrome, which is common in the Japanese population, there is still no suitable model system that exhibits signs of aging. Recently, we have attempted to create a new mouse model of Werner syndrome and have shown that the mouse model can reproduce some of the symptoms of the patient and that the tissue cells exhibit cellular senescence traits. Cells derived from the mouse model are sensitive to senolytic drugs and can be evaluated for their senolytic effects. In this review, we will give an overview of hereditary progeria, introduce the latest mouse models of progeria, and discuss the possibility of controlling aging with functional foods.

In Japan, the number of the centenarians, continuously renewed for more than half a century since the late 20th century, exceed 90,000 by September 2022. We grow frequently aware of the era of the 100-year lifespan with life extension. Accordingly, to improve the quality of life (QOL) of the elderly and extend their healthy lifespan, the various biological functional changes declining with aging has been discussed in a multidisciplinary and comprehensive manner. Conversely, the factors of aging have been well studied, and the secret of healthy longevity is considered to be consist of a regular diet, with balanced "nutrition" and abstemious eating, moderate and habitual "exercise", and improvement of sleep quality and "communication" in a stress-free environment. Alternatively, chronic inflammation quietly accumulated with aging or the decline of physiological functions, including immunosenescence, is also important aging factors. In this issue, the transition of life span and aging research studied on various organisms is introduced, and geroscience research will be briefly reviewed, in which evidence from the unveiled life span genes and aging mechanisms will be brought geriatrics closer to human medicine. I will also introduce the possibility and impact of alleviation of chronic inflammation by functional foods and nutritional interventions on individual aging process, which are closely linked to the healthy life span extension. As an example, the results of long-term feeding of prebiotic lactobacillus to model mice to introduce the possibility of suppressing chronic inflammation by nutritional interventions with functional foods on aging linked to extending healthy lifespan.

Evolutionary biology has predicted that the effects of dietary calorie restriction (DR) arise from adaptive mechanisms that allow animals to survive when food resources are scarce in the natural environment. We focused on neuropeptide Y (Npy), which is involved in this physiological adaptation. We found that Npy deficient mice exhibit reduced lifespan extension, tumor suppression, and stress tolerance, demonstrating the critical role of Npy in the effects of DR. Furthermore, we found that Npy antagonizes β-adrenergic signaling and suppresses DR-induced reduction of excess body fat. Mutations in single genes that attenuate growth hormone (GH)-IGF-1 signaling consistently prolong the lifespan of experimental animals in the AL environment. Since the GH-IGF-1 system is also repressed in DR animals, this signal appears to be an evolutionarily conserved signal that controls aging and lifespan in a variety of animals. The family of FoxO transcription factors, which stays downstream of IGF1 signaling, may be involved in the effects of DR. We tested the requirement for the transcription factors in the impact of DR by conducting lifespan studies in mice heterozygously deleted for the Foxo1 or Foxo3 gene. Our results suggest that FoxO1 is essential for the tumor suppressive effects of DR and FoxO3 for lifespan extension. Subsequent studies showed that FoxO3 is critical in liver metabolism and mitochondrial bioenergetics. Since genotypic analyses of human longevity have also demonstrated an association with FOXO3 gene polymorphisms in several races, the search for genes associated with the effects of DR may have applications in the control of human aging.

Due to the global increase in population aging, anti-aging research has been vigorously conducted. Nicotinamide adenine dinucleotide (NAD⁺) is an essential cofactor for maintaining vital cellular functions and has attracted attention as an anti-aging molecule. Demand for NAD⁺ increases due to irregular lifestyle habits and aging. On the other hand, it is believed that NAD⁺ supplementation with NAD⁺ precursors is effective in preventing and treating lifestyle-related diseases and age-related disorders. Among the NAD⁺ precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have been confirmed to have health-promoting effects in a wide range of animal models. In recent years, clinical trials using NR and NMN have been actively conducted. However, at present, NAD⁺ precursors in clinical trials have not shown effects as expected from the results of animal models. Meanwhile, basic research targeting NAD⁺ metabolism itself is being actively continued to achieve more efficient increase in NAD⁺ levels, and new aspects of NAD⁺ metabolism are being revealed. Based on these latest findings, we will describe the current status and challenges of NAD⁺ research and share the path to health promotion through the regulation of NAD⁺ metabolism.

Natural products with biological activities are promising drug seeds. Functional foods and herbal medicines are useful screening sources for natural products. Aggregation of amyloid β protein (Aβ42) induced neurotoxicity in the pathogenesis of Alzheimer's disease (AD). Therefore, reagents that inhibit the aggregation of Aβ42 are useful to develop anti-AD drugs. Fruitful anti-aggregative natural products have been ever reported by many research groups including us. In general, it is necessary to repeat the purification of the active components from extracts. We have developed an efficient method, using LC-MS combined with principal component analysis (PCA), to search for activity-dependent compounds that prevent the aggregation of Aβ42 from 46 herbal medicine extracts originating from 18 plants (380 extracts in total). Only lotus-derived 5 extracts (Kakou, Kayou, Gusetsu, Rensu, and Renbou) showed differentially inhibitory activities depending on the part of the plant from which they are derived (e.g. petiole, leaf, root node, stamen, and receptacle, respectively). To compare the anti-aggregative properties of compounds of active crude drugs with those of inactive crude drugs, these extracts were subjected to LC-MS, followed by PCA. From 22 candidate compound lists identified from the analysis, glucuronized and glucosidized quercetin, as well as 6 flavonoids (datiscetin, kaempferol, morin, robinetin, quercetin, and myricitrin), including catechol and/or flatness moiety suppressed Aβ42 aggregation, whereas curcumol, a sesquiterpene, did not. These methods offer an activity-differential methodology to identify bioactive compounds with anti-aggregation activity. This review focuses on this cutting-edge knowledge on the exploration of natural products that could be applied to future disease therapeutics and prevention.

Soybeans, especially soybean proteins, are rich in several beneficial effects such as an improvement of energy metabolism. β-conglycinin, approximately 20% of soy protein, is known to regulate lipid metabolism through an activation of lipolysis and an inhibition of lipid absorption. To elucidate a mechanism how β-conglycinin regulates lipid metabolism, molecular anad nutritional analyses were performed. To identify a target molecule which responds to an ingestion of β-conglycinin, we performed transcriptome analysis using hepatic RNA from mice fed with β-conglycinin. We found that FGF21 (fibroblast growth factor 21) was induced by β-conglycinin. FGF21, known as a fasting-induced hormone, is highly expressed in the liver. Secreted FGF21 acts on target tissues including adipose tissue, liver, and the nervous system. FGF21 have several beneficial effects such as the anti-obese effect and the improvement of lipid metabolism. Overexpression of FGF21 in mice extends life span, suggesting the anti-aging effects of FGF21. Using FGF21 knockout mice, we found that β-conglycinin improved lipid metabolism through FGF21. Serial analysis revealed that β-conglycinin induced FGF21 expression through transcriptional factor ATF4 which is activated by amino acid deprivation. We found that methionine in the portal vein was decreased by β-conglycinin. These findings showed that β-conglycinin improve energy metabolism through activation of the ATF4-FGF21 axis. This review summaries function of soybean, especially a relationship between FGF21 and soybean proteins.

Both glucosamine (GlcN) and its derivative N-acetyl-d-glucosamine (NAG) are amino monosaccharides, widely used to treat osteoarthritis (OA) as dietary supplements. Recent clinical trials such as MOVES and LEGS confirmed the efficacy of glucosamine for knee OA. In addition, PROOF trial showed the efficacy of GlcN to prevent knee OA. Regarding COVID-19, it was reported that habitual use of glucosamine was associated with a lower risk of hospital admission and mortality with COVID-19, but not the risk of SARSCoV-2 infection. In this review, the clinical significance of GlcN and NAG for COVID-19 prophylaxis were discussed.

Musculoskeletal disease can be a serious condition associated with aging that may lead to fractures and a bedridden state due to decreased motor function. In addition to exercise training to increase muscle mass, increasing muscle function with the intake of functional foods is an effective treatment strategy for musculoskeletal disease. The redox imbalance caused by increased reactive oxygen species (ROS) induce muscle hypofunction. Mammals have various antioxidants systems that protect tissue and cells from ROS. Superoxide dismutase (SOD) is an antioxidant enzyme that converts superoxide to hydrogen peroxide, which is further detoxified to water and O2 by catalase and GPx enzymes. SOD2 is constitutively and ubiquitously expressed in the mitochondria to regulate the redox balance in the cells of tissues. The loss of SOD2 induces mitochondrial redox imbalance by increasing the generation of superoxide, resulting in mitochondrial dysfunction in cells and several tissues, indicating important role of SOD2 for living body. Previously, we demonstrated that, musclespecific SOD2-deficient mice (muscle-Sod2^-/-) show a severe disturbance in exercise in association with increased mitochondrial reactive oxygen species, as well as mitochondrial dysfunction and muscle damage. Muscle-Sod2^-/- mice are expected to be used as a muscle fatigue model for research applications for elucidating the mechanism of muscle dysfunction and improving motor function. In this review, we describe the pathology of skeletal muscle in muscle-Sod2^-/- mice and introduce the search for functional foods that enhance motor function using these deficient mice.

Hyaluronan (HA) is a large glycosaminoglycan which exists in the human body as a component of the extra-cellular matrices. HA is an essential molecule for matrix assembly and fluid viscosity in cartilage. Currently, intraarticular injection of HA is widely used for the treatment of pain in the rheumatoid arthritis and osteoarthritis, however, the roles of HA in bone metabolism remain unknown. We have reported that HA showed the inhibitory effects on inflammatory bone resorption. HA inhibited interleukin (IL)-1-induced bone resorbing activity associated with decreasing the production of matrix metalloproteinase (MMP)-2 and -9 in organ cultures of mouse calvariae. In cocultures of mouse primary osteoblasts and bone marrow cells, HA suppressed IL-1-induced osteoclast differentiation. Mechanistically, in osteoblasts, HA blocked PG (prostaglandin) E2 production through the downregulating mRNA expression of cyclooxygenase (COX)-2, membrane-bound PGE synthase (mPGES)-1, receptor activator of NF-κB ligand (RANKL), and MMP-13. We further demonstrated that HA attenuates NF-κB transcriptional activity in osteoblasts. In this review, we summarized the recent studies regarding the roles of HA in bone tissues as the preventive component for bone resorption. HA could be a one of the candidates for maintaining bone health.

Arabinogalactan-protein (AGP) contained in plants is a plant proteoglycan with a structure in which a branched chain of arabinogalactan (AG) consisting of galactose and arabinose is bound to a hydroxyproline (Hyp) core protein. AGP is known to have physiological functions related to plant differentiation and growth. However, it was difficult to completely separate AGP and AG by conventional methods. In this study, we fractionated AGP (PGn) from gum arabic by hydrophobic chromatography, and examined its effects on skin cells. It was difficult to completely separate AGP and AG by conventional methods. Gum arabic dissolved in a saturated saline solution was adsorbed on a hydrophobic carrier and eluted with a solution having a stepwise lower NaCl concentration to obtain an AGP fraction. It was suggested that hydrophobic chromatography can extract AGP more efficiently than ion-exchange chromatography. Next, PGn and PG were added to human epidermal keratinocytes (HaCaT) and human dermal fibroblasts (HFB), and the effects on gene expression and hyaluronic acid (HA) production were investigated. In epidermal cells, it was confirmed that the expression of hyaluronan synthase gene (HAS2) increased and the amount of hyaluronan production increased. Therefore, it was suggested that samples with high AGP content may increase the amount of HA in the skin and improve the skin moisture content.

Miso is classified into rice miso, barley miso, and soybean miso depending on its ingredients, and its color becomes darker with maturity. The pigment component of miso is melanoidin—a brown-colored substance produced by the reaction of amino acids and sugar. Melanoidin has a high antioxidant effect, which improves with the aging of the miso. Color is often evaluated using the color value—L*a*b*, where L*, a*, and b* represent brightness, redness, and yellowness, respectively. The color of miso is conventionally evaluated mainly by the L value. However, since melanoidin is brown-colored, a and b values must also be considered. In addition, the color of melanoidin depends on the type of amino acids and can be used to identify them, which is essential for evaluating the antioxidant effect of miso. Therefore, in this study, we clarified the interrelations of the antioxidant effect of miso, color value, and amino acid type contained in miso. The highest antioxidant activity and lowest Lab value were observed in soybean miso, and a high negative correlation was confirmed between the antioxidant effect and color value. Furthermore, melanoidins made from each amino acid and glucose were studied. Thermal reactants of cysteine, lysine, arginine, histidine, and glucose showed high antioxidant activity; however, color values of lysine, arginine, and histidine were the highest, while those of cysteine were the lowest. In addition, almost all amino acids showed a high correlation between coloration and antioxidant activity, but the correlation was low in case of glutamic acid. These results indicate that the antioxidant effect of miso showed a high negative correlation with not only the L value but also the a and b values, and that lysine, arginine, and histidine showed high antioxidant effect and color values in the model melanoidin, while cysteine showed high antioxidant effect but low color values, and that the color values and antioxidant effects of miso depend on the content of amino acids in miso and that lysine, arginine, and histidine contribute more to coloration, whereas cysteine, lysine, arginine, and histidine contribute more to the antioxidant effects.

Collagen hydrolyzate (CH) used as a functional food is mostly produced from pig skin, fish scale and fish skin. The purpose of this study was to clarify the difference in the effect of ingestion of different origin of CH using an ovariectomized osteoporosis model and photoaging model induced by UVB irradiation. The amino acid composition of CH derived from different origin with a molecular weight of around 2000 differs in Pro and Hyp contents. Constituent oligopeptides consisted of many Gly-Pro and Hyp-Gly, and tripeptides were more abundant in pig skin CH than in fish CH. The effects of CH intake in the photoaging model improved skin hydration and epidermal thickening, even if the origin was different. The wrinkles were improved by administration of CH derived from fish skin. In addition, as a result of administering CH with different origins to the osteoporosis model, the bone density of the distal femur slightly increased. It was suggested that the administration of CH with different origins had similar effects on the skin and motor organs, but the effects might be different.

The number of people with dementia is increasing worldwide, and it is expected that 130 million people will be affected the disease by 2050 (World Alzheimer's disease Report, 2015). About 70% of dementia patients have been thought to be Alzheimer's disease (AD), therefore, the development of therapeutic agents for AD is urgent issue in our society. Although various drug targets, including β-amyloid (Aβ), have been proposed so far, disease-modifying small compounds capable of suppressing the progress of the pathological condition itself have not been successfully developed. In this study, we constructed a system to quantitatively analyze Aβ toxicity using Drosophila, and attempted to isolate effective therapeutic agents from multiple compounds derived from functional foods, which are thought to have therapeutic effects on dementia. From this analysis, we identified 5 polyphenol compounds, including Quercetin and Kaempferol.

【Purpose】 Cataract, a disease in which the lens becomes cloudy and results in vision loss, is the most common cause of blindness in the world. Oxidative stress is believed to be involved in the cause of lens cloudiness. Patients with diabetes, a major lifestyle-related disease, rapidly develop cataracts. Using the Streptozicin (STZ)induced diabetic cataract rat model, we examined the effects of acerola water (AW), prepared with acerola powder VC30 containing a high vitamin C content and antioxidant properties, on cataract development.

【Methods】 Male SD rats were injected intraperitoneally with 60 mg/kg of STZ to induce hyperglycemia. The following week, blood glucose levels were monitored, and blood glucose levels of 300 mg/dL or higher were considered hyperglycemia and all other blood glucose levels were excluded. Separate control (water), 4% AW, STZ (water), STZ+2% AW, and STZ+4% AW groups were established. After hyperglycemia was confirmed, water or 2% or 4% acerola water was given ad libitum. Blood glucose levels were monitored biweekly and the lens was observed by slit lamp at 8 weeks after AW intake. Both eyes and pancreas were removed for histopathological evaluation after 10 weeks of AW intake.

【Results】The STZ-treated groups remained hyperglycemic and showed no improvement with 2% and 4% AW intake. Islets of Langerhans in the pancreas were smaller and decreased in number in the STZ-treated groups without improvement from 2% or 4% AW intake. Slit-lamp observation showed cloudiness in the STZ-treated groups, and histopathological evaluation showed lens abnormalities including lens fiber swelling, vacuolization, and ectopic nuclei. 2% and 4% AW ingestion did not reduce lens pathological changes.

【Conclusion】In this study, there was no inhibitory effect of AW intake on the pathogenesis of diabetes

In this study, we investigated the platelet aggregation-promoting effects of porous chitosan sheet. Chitosan sponge was manufactured as follows, first, chitosan was dissolved in acetic acid aqueous solution, next frozen to as sherbet ice to obtain homogeneous frozen ice, and the sherbet ice was lyophilized, and then heat-treated. Chitosan sheet (chitosan acetate) was a hemostatic material obtained by pressing the chitosan sponge and finally sterilizing by gamma rays. The chitosan sponge had homogeneous porous structure on the surface and cross section with controlled median pore diameter of 97 μm by adding less than 2% ethanol of the final concentration to chitosan acetate solution, While the chitosan sheet had smaller porous structure with the median diameter of 32 μm. Chitosan sponge and chitosan sheet were absorbed quickly, and chitosan sheet showed a decrease in eluted acetic acid and an increase in breaking strength after water absorption by heat treatment at no less than 85 ℃ for 24h. We evaluated the platelet aggregation-promoting activity of chitosan sheet by measuring platelet factor 4 (PF4) and β-thromboglobulin (β-TG) released from aggregated platelets, after contacting with human platelet rich plasma (PRP). Chitosan sheet significantly released the higher amounts of PF4 and β-TG than gauze, hemostatic bandage of chitosan containing acetic acid and chitosan fiber (p < 0.01). These results suggest that chitosan sheet function as a hemostatic material by promoting platelet aggregation.

The high protein (HP) diet is a diet that limits carbohydrate intake and supplements it with protein, and is effective in regulating blood glucose and blood lipids. High-intensity exercise has been reported to have various adverse effects on the body. We investigated the effects of the HP diet during exercise. Male C3H/HeSlc mice were divided into two groups: a normal diet (C) group fed 20％ protein and a HP group fed 40％ protein. Both groups were kept for 10 weeks, with 20 min of swimming exercise daily for the last 10 days. Limiting exercise time was lower in the HP group. Lactate levels decreased after exercise in C group, but increased in HP group. Kidney and intra-abdominal fat weights increased in the HP group. The HP group showed higher plasma CPK activity and BUN concentration, and lower renal O₂^- scavenging activity. The concentrations of Mg, Ca, Mn, Fe (excluding plasma), Cu, Zn, and Se in each organ were lower in the HP group. Plasma Fe concentrations were higher in the HP group. Thus, muscle fatigue, decreased renal function, and enlarged kidneys were observed in the HP group. The results also suggest that the efficiency of lactate utilization may be decreased in the HP group. The results of trace element concentrations indicated that the HP group may excrete more minerals that are excessively consumed and excreted by exercise, and that the mineral balance in the body is disturbed. We believe that these factors may have contributed to the decrease in endurance.

[Purpose] MNU-induced rat cataract model has been used as a screening system for therapeutic effects of new drugs. The involvement of oxidative stress in this model was clarified, and the pathological inhibitory effect of Profine^® (PF) derived from sake lees, which has antioxidant properties, was examined.

[Methods] Experiment 1: 3-week-old female SD rats were given a single intraperitoneal (ip) dose of 75 mg/kg of MNU, and the degree of cataract was observed histologically and immunohistochemically using 8-OHdG, TG, γH2A.X, for up to 7 days. In addition, serum oxidative stress levels were compared between groups using d-ROM test. Experiment 2: Two-week-old female rats received a single ip dose of 50 mg/kg MNU and were fed 2%, 4%, and 8% PF diet from 3 weeks of age. After 4 weeks, the degree of cataracts was observed histologically as well as by naked eye.

[Results] Experiment 1: Single cell death of lens epithelial cells was observed from 48 hours after MNU administration, and loss of lens epithelial cells and swelling of lens fibers were observed on day 7. Oxidative stress markers showed 8-OHdG or thymidine glycol positive signals in some nuclei of lens epithelial cells from 48 hours after MNU administration. Systematic oxidative stress level was high on day 7 after administration. Experiment 2: The incidence of cataracts decreased in a PF concentration-dependent manner (83% in the MNU alone group, 40% in the group with 2% PF, 17% in the group with 4% PF, and 0% in the group with 8% PF) in gross appearance. The same trend was observed in the cataract index based on histological changes.

[Discussion] Oxidative stress in the lens was involved in the progression of MNU-induced cataract. The inhibitory effect of PF on the pathogenesis was also observed. The inhibitory effect may be related to the excellent antioxidant effect of PF.