Senescence-accelerated Mouse Prone 8 Research Articles

Erinacine A-Enriched Hericium erinaceus Mycelium Delays Progression of Age-Related Cognitive Decline in Senescence Accelerated Mouse Prone 8 (SAMP8) Mice.

There have been many reports on the neuroprotective effects of Hericium erinaceus mycelium, in which the most well-known active compounds found are diterpenoids, such as erinacine A. Previously, erinacine A-enriched Hericeum erinaceus mycelium (EAHEM) was shown to decrease amyloid plaque aggregation and improve cognitive disability in Alzheimer’s disease model APP/PS1 mice. However, its effects on brain aging have not yet been touched upon. Here, we used senescence accelerated mouse prone 8 (SAMP8) mice as a model to elucidate the mechanism by which EAHEM delays the aging of the brain. Three-month-old SAMP8 mice were divided into three EAHEM dosage groups, administered at 108, 215 and 431 mg/kg/BW/day, respectively. During the 12th week of EAHEM feeding, learning and memory of the mice were evaluated by single-trial passive avoidance and active avoidance test. After sacrifice, the amyloid plaques, induced nitric oxidase synthase (iNOS) activity, thiobarbituric acid-reactive substances (TBARS) and 8-OHdG levels were analyzed. We found that the lowest dose of 108 mg/kg/BW EAHEM was sufficient to significantly improve learning and memory in the passive and active avoidance tests. In all three EAHEM dose groups, iNOS, TBARS and 8-OHdG levels all decreased significantly and showed a dose-dependent response. The results indicate that EAHEM improved learning and memory and delayed degenerative aging in mice brains.

Coffeeberry Activates the CaMKII/CREB/BDNF Pathway, Normalizes Autophagy and Apoptosis Signaling in Nonalcoholic Fatty Liver Rodent Model.

Nonalcoholic fatty liver disease (NAFLD) shows extensive liver cell destruction with lipid accumulation, which is frequently accompanied by metabolic comorbidities and increases mortality. This study aimed to investigate the effects of coffeeberry (CB) on regulating the redox status, the CaMKII/CREB/BDNF pathway, autophagy, and apoptosis signaling by a NAFLD rodent model senescence-accelerated mice prone 8 (SAMP8). Three-month-old male SAMP8 mice were divided into a control group and three CB groups (50, 100, and 200 mg/kg BW), and fed for 12 weeks. The results show that CB reduced hepatic malondialdehyde and carbonyl protein levels. CB significantly enhanced Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) and reduced the phospho-cAMP response element-binding protein (p-CREB)/CREB ratio. In addition, CB increased the silent information regulator T1 level, promoted Beclin 1 and microtubule-associated protein light chain 3 II expressions, and reduced phosphorylated mammalian target of rapamycin and its downstream p-p70s6k levels. CB also inhibited the expressions of apoptosis-related factors poly (ADP-ribose) polymerase-1 and the apoptosis-inducing factor. In conclusion, CB might protect the liver by reducing oxidative stress, activating the CaMKII/CREB/BDNF pathway, and improving autophagic and apoptotic expressions in a dose-dependent manner.

An enriched environment delays the progression from mild cognitive impairment to Alzheimer's disease in senescence-accelerated mouse prone 8 mice.

A previous study demonstrated that middle-aged (5-6 months of age) senescence-accelerated mouse prone 8 (SAMP8) mice can be used as animal models of mild cognitive impairment (MCI). An enriched environment (EE) can mitigate cognitive decline and decrease the pathological changes associated with various neurodegenerative diseases. In the present study, the learning-memory abilities of SAMP8 mice during the MCI phase (5 months of age) was evaluated and neuropathological changes in the hippocampus were examined after the mice were exposed to an EE for 60 days. In the Morris water maze test, EE-exposed mice demonstrated significantly decreased escape latency and increased time spent in the target quadrant and number of platform crossings compared with control mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling and Nissl staining showed that EE-exposed mice had reduced neuronal apoptosis and increased number of surviving neurons compared with control mice. Golgi staining, transmission electron microscopy, and immunohistochemical staining demonstrated that EE-exposed mice exhibited increased dendritic spine densities among secondary and tertiary apical dendrites; increases in synaptic numerical density, synaptic surface density, and expression of synaptophysin; and reduced deposition of amyloid-β (Aβ) and expression of amyloid-precursor protein (APP) in the hippocampal CA1 region compared with control mice. These results demonstrate that EE exposure effectively decreases neuronal loss and regulates neuronal synaptic plasticity by reducing the expression of APP and the deposition of Aβ in the hippocampal CA1 region, thereby mitigating cognitive decline in SAMP8 mice during the MCI phase and delaying the progression from MCI to Alzheimer's disease.

Ginsenoside Rg1 ameliorates aging‑induced liver fibrosis by inhibiting the NOX4/NLRP3 inflammasome in SAMP8 mice.

Aging is often accompanied by liver injury and fibrosis, eventually leading to the decline in liver function. However, the mechanism of aging-induced liver injury and fibrosis is still not fully understood, to the best of our knowledge, and there are currently no effective treatment options available for liver aging. Ginsenoside Rg1 (Rg1) has been reported to exert potent anti-aging effects due to its potential antioxidant and anti-inflammatory activity. The present study aimed to investigate the protective effect and underlying mechanism of action of Rg1 in aging-induced liver injury and fibrosis in senescence-accelerated mouse prone 8 (SAMP8) mice treated for 9 weeks. The histopathological results showed that the arrangement of hepatocytes was disordered, vacuole-like degeneration occurred in the majority of cells, and collagen IV and TGF-β1 expression levels, that were detected via immunohistochemistry, were also significantly upregulated in the SAMP8 group. Rg1 treatment markedly improved aging-induced liver injury and fibrosis, and significantly downregulated the expression levels of collagen IV and TGF-β1. In addition, the dihydroethylene staining and western blotting results showed that Rg1 treatment significantly reduced the levels of reactive oxygen species (ROS) and IL-1β, and downregulated the expression levels of NADPH oxidase 4 (NOX4), p47phox, p22phox, phosphorylated-NF-κB, caspase-1, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain and the NLR family pyrin domain containing 3 (NLRP3) inflammasome, which were significantly upregulated in the liver tissues of elderly SAMP8 mice. In conclusion, the findings of the present study suggested that Rg1 may attenuate aging-induced liver injury and fibrosis by reducing NOX4-mediated ROS oxidative stress and inhibiting NLRP3 inflammasome activation.

Combined Neuroprotective Strategies Blocked Neurodegeneration and Improved Brain Function in Senescence-Accelerated Mice.

Increase in the quality of life, combined with drug strategies, has been studied as possibilities for improving memory and delaying the onset of neurodegenerative diseases. A previous study published by the group of the authors has shown that microdose lithium and enriched environment can improve memory in both mice and humans. To elucidate this relationship better, this study aimed to evaluate whether the chronic combination of these two strategies could increase healthy aging in Senescence Accelerated Mouse-Prone 8 (SAMP8). Animals were submitted to either one or both of these strategies until the age of 10 months when they were anesthetized and killed and their hippocampus was extracted. The untreated SAMP-8 group exhibited worse memory and reduced neuronal density with greater neurodegeneration and increased amyloid-β plaque density compared with the control group. Moreover, significant alterations in proteins related to long-term potentiation, such as, synaptophysin and brain-derived neurotrophic factor (BDNF), were observed in this group. The strategies used in the study maintained long-term memory, reduced anxiety, and increased neuroprotection. Both strategies were efficient in reducing neurodegeneration and increasing parameters related to memory maintenance. In many experiments, the combination of the two strategies was more effective in improving healthy aging. This study sheds light on the combination of strategies that choose to improve the quality of life and drugs with low side effects. Moreover, it opens perspectives for a new field of study for healthy aging.

Cornel Iridoid Glycoside Ameliorated Alzheimer's Disease-Like Pathologies and Necroptosis through RIPK1/MLKL Pathway in Young and Aged SAMP8 Mice.

Background Aging is an important risk factor for sporadic Alzheimer's disease (AD) and other neurodegenerative diseases. Senescence-accelerated mouse-prone 8 (SAMP8) is used as an animal model for brain aging and sporadic AD research studies. The aim of the current study was to investigate the pharmacological effects of cornel iridoid glycoside (CIG), an active ingredient of Cornus officinalis, on AD-type pathological changes in young and aged SAMP8 mice. Methods Locomotor activity test was used to detect the aging process of SAMP8 mice. Nissl staining and immunohistochemical staining were applied to detect neurons and myelin basic protein-labelled myelin sheath. Western blotting was used to detect the expression levels of related proteins of synapse, APP processing, and necroptosis. Results The results showed that SAMP8 mice at the age of 6 and 14 months exhibited lower locomotor activity, age-related neuronal loss, demyelination, synaptic damage, and APP amyloidogenic processing. In addition, the increased levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL), and p-MLKL indicating necroptosis were found in the brain of SAMP8 mice. Intragastric administration of CIG for 2 months improved locomotor activity; alleviated neuronal loss and demyelination; increased the expression of synaptophysin, postsynaptic density protein 95, and AMPA receptor subunit 1; elevated the levels of soluble APPα fragment and disintegrin and metalloproteinase 10 (ADAM10); and decreased the levels of RIPK1, p-MLKL, and MLKL in the brain of young and aged SAMP8 mice. Conclusion This study denoted that CIG might be a potential drug for aging-related neurodegenerative diseases such as AD.

Lamivudine improves cognitive decline in SAMP8 mice: Integrating in vivo pharmacological evaluation and network pharmacology.

The reverse transcriptase inhibitors such as lamivudine (3TC) play important roles in anti‐ageing, but their effects on neurodegenerative diseases caused by ageing are not clear, especially on the functions of the nervous system such as cognition. In this study, we administered 3TC to senescence‐accelerated mouse prone 8 (SAMP8) mice by gastric perfusion (100 mg/kg) for 4 weeks. Our results showed that 3TC significantly improved the ageing status of SAMP8 mice, especially the decline of cognitive ability evaluated by the Morris water maze test. To further investigate the molecular mechanisms of improving the ageing status of SAMP8 mice by 3TC, the qPCR and tissue staining methods were used to study the brain tissues (i.e., hippocampus and cortex) of mice, while the network pharmacology analysis was applied to investigate the potential targets of 3TC. The results showed that the mRNA levels of genes related to long interspersed element‐1, type 1 interferon response, the senescence‐associated secretion phenotype and the Alzheimer's disease in the hippocampus and cortex of SAMP8 mice were increased due to senescence, but this trend was reversed partially by 3TC. Results of histological studies showed that 3TC reduced the death of hippocampal neurons, while the results of network pharmacology analysis indicated that 3TC may exert its influence through multiple pathways, including the oestrogen signalling and the PI3K/Akt and neuroactive ligand‐receptor interaction signalling pathways, which we have verified through in vitro experiments. These findings provide evidence for the therapeutic potential of 3TC in the treatment of neurodegenerative diseases.

A candidate gene of Alzheimer diseases was mutated in senescence-accelerated mouse prone (SAMP) 8 mice

The senescence-accelerated mouse prone (SAMP) 8 strain exhibits age-related learning and memory deficits (LMD) at 2 months of age. We have found strong association of chromosome 12 locus with learning memory deficit (LMD) phenotype in SAMP8 strain. In the course of searching candidate gene, here we identified solute carrier family 24 sodium/potassium/calcium exchanger member 4 (Slc24a4) in SAMP8 chromosome 12 LMD possessing one single nucleotide polymorphism causing amino acid replacement of Threonine at 413 position with Methionine. Since SLC24A4 has been postulated as a candidate of late onset Alzheimer's diseases (LOAD), we further analyze the functional importance of this polymorphism. By expressing Slc24a4 protein in HEK293 cells, here we showed polymorphic SAMP8 type Slc24a4-T413 M causing significant loss of calcium ion (Ca2+) transporter activity in cells compared with that of wild type mouse (Slc24a4-WT). However, no study yet shows any functional association of human SLC24A4 polymorphism with the onset of LOAD pathogenesis. Thus, our present finding may further help to clarify the importance of this ion exchanger with age related cognitive dysfunction.

Long Non-coding RNA Signatures Associated With Liver Aging in Senescence-Accelerated Mouse Prone 8 Model.

The liver is sensitive to aging because the risk of hepatopathy, including fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, increases dramatically with age. Long non-coding RNAs (lncRNAs) are >200 nucleotides long and affect many pathological and physiological processes. A potential link was recently discovered between lncRNAs and liver aging; however, comprehensive and systematic research on this topic is still limited. In this study, the mouse liver genome-wide lncRNA profiles of 8-month-old SAMP8 and SAMR1 models were explored through deep RNA sequencing. A total of 605,801,688 clean reads were generated. Among the 2,182 identified lncRNAs, 28 were differentially expressed between SAMP8 and SAMR1 mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) surveys showed that these substantially dysregulated lncRNAs participated in liver aging from different aspects, such as lipid catabolic (GO: 0016042) and metabolic pathways. Further assessment was conducted on lncRNAs that are most likely to be involved in liver aging and related diseases, such as LNC_000027, LNC_000204E, NSMUST00000144661.1, and ENSMUST00000181906.1 acted on Ces1g. This study provided the first comprehensive dissection of lncRNA landscape in SAMP8 mouse liver. These lncRNAs could be exploited as potential targets for the molecular-based diagnosis and therapy of age-related liver diseases.

Synergistic Neuroprotective Effects of a Natural Product Mixture against AD Hallmarks and Cognitive Decline in Caenorhabditis elegans and an SAMP8 Mice Model

The study of different natural products can provide a wealth of bioactive compounds, and more interestingly, their combination can exert a new strategy for several neurodegenerative diseases with major public health importance, such as Alzheimer’s disease (AD). Here, we investigated the synergistic neuroprotective effects of a mixed extract composed of docosahexaenoic acid, Ginkgo biloba, D-pinitol, and ursolic acid in several transgenic Caenorhabditis elegans (C. elegans) and a senescence-accelerated prone mice 8 (SAMP8) model. First, we found a significantly higher survival percentage in the C. elegans group treated with the natural product mixture compared to the single extract-treated groups. Likewise, we found a significantly increased lifespan in group of C. elegans treated with the natural product mixture compared to the other groups, suggesting synergistic effects. Remarkably, we determined a significant reduction in Aβ plaque accumulation in the group of C. elegans treated with the natural product mixture compared to the other groups, confirming synergy. Finally, we demonstrated better cognitive performance in the group treated with the natural product mixture in both AD models (neuronal Aβ C. elegans strain CL2355 and the SAMP8 mice model), confirming the molecular results and unraveling the synergist effects of this combination. Therefore, our results proved the potential of this new natural product mixture for AD therapeutic strategies.

Folic Acid Inhibits Aging-Induced Telomere Attrition and Apoptosis in Astrocytes In Vivo and In Vitro.

Folic acid (FA) has been reported to inhibit astrocyte apoptosis and improve aging-induced disorders; however, its role in telomere attrition remains unclear. In present study, 4-month-old senescence-accelerated mouse prone 8 (SAMP8) mice were assigned to four treatment groups for the in vivo experiment: FA-deficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group, and high FA-supplemented diet (FA-H) group. These mice were euthanized when 10months old. There was also a young SAMP8 (4 months old) control group (Con-Y) fed with FA-normal diet. In in vitro study, primary cultures of astrocytes from hippocampus and cerebral cortex were incubated for five generations with various concentrations of FA (0-40μM) and were assigned to five groups: FA 0μM (generation 5), FA 10μM (generation 5), FA 20μM (generation 5), FA 40μM (generation 5), and FA 10μM (generation 1). The results showed that FA supplementation inhibited aging-induced astrocytosis, astrocyte apoptosis, neurodegeneration, and prevented telomere attrition in hippocampus and cortex of SAMP8 mice. FA supplementation also decreased apoptosis and telomere attrition, and increased telomerase activity, in primary cultures of astrocytes. These results showed that it may be one of the mechanisms that FA inhibiting aging-induced apoptosis of astrocyte by alleviating telomere attrition.

Effects of two kinds of Kampo‐hozai, ninjinyoeito and kamikihito, on mental disorder‐like behaviors in senescence‐accelerated mouse‐prone 8 mice

ABSTRACTAimNinjinyoeito (NYT) and kamikihito (KKT) are two types of a group of Japanese herbal medicines called ‘Kampo‐hozai’, which can improve depleted mental and physical energy in a variety of patients. NYT and KKT are therefore also expected to improve the symptoms of aging. However, evidence of the therapeutic effects of NYT and KKT on age‐related mental disorders in basic research remains scarce. The present study examined the effects of NYT and KKT on mental disorder‐like behaviors in senescence‐accelerated mouse‐prone 8 (SAMP8) mice, a model of accelerated aging.MethodsSAMP8 mice were orally administered NYT or KKT (300 or 1000 mg/kg/d) starting from 12 weeks of age. A splash test was conducted at 21 weeks of age. An open‐field test was conducted at 20 and 33–34 weeks of age.ResultsTreatment with NYT, but not KKT, increased the grooming time of SAMP8 mice in the splash test at 21 weeks of age, suggesting that NYT ameliorates apathy‐like behavior. In contrast, treatment with KKT, but not NYT, increased the time spent by SAMP8 mice in the inner zone of the open‐field test at 33–34 weeks of age, suggesting that KKT ameliorates anxiety‐like behavior.ConclusionNYT and KKT may be useful for treating apathy and anxiety, respectively, in older individuals.

Folic acid alleviates age-related cognitive decline and inhibits apoptosis of neurocytes in senescence-accelerated mouse prone 8: deoxythymidine triphosphate biosynthesis as a potential mechanism

Disturbed deoxythymidine triphosphate biosynthesis due to the inhibition of thymidylate synthase (TS) can lead to uracil accumulation in DNA, eventually, lead to neurocytes apoptosis and cognitive decline. Folic acid supplementation delayed cognitive decline and neurodegeneration in senescence-accelerated mouse prone 8 (SAMP8). Whether folic acid, one of nutrition factor, the effect on the expression of TS is unknown. The study aimed to determine if folic acid supplementation could alleviate age-related cognitive decline and apoptosis of neurocytes by increasing TS expression in SAMP8 mice. According to folic acid concentration in diet, four-month-old male SAMP8 mice were randomly divided into three different diet groups by baseline body weight in equal numbers. Moreover, to evaluate the role of TS, a TS inhibitor was injected intraperitoneal. Cognitive test, apoptosis rates of neurocytes, expression of TS, relative uracil level in telomere, and telomere length in brain tissue were detected. The results showed that folic acid supplementation decreased deoxyuridine monophosphate accumulation, uracil misincorporation in telomere, alleviated telomere length shorting, increased expression of TS, then decreased apoptosis rates of neurocytes, and alleviated cognitive performance in SAMP8 mice. Moreover, at the same concentration of folic acid, TS inhibitor raltitrexed increased deoxyuridine monophosphate accumulation, uracil misincorporation in telomere, and exacerbated telomere length shorting, decreased expression of TS, then increased apoptosis rates of neurocytes, and decreased cognitive performance in SAMP8 mice. In conclusion, folic acid supplementation alleviated age-related cognitive decline and inhibited apoptosis of neurocytes by increasing TS expression in SAMP8 mice.

The Search for Citrus Components with Neuroprotective and Anti-dementia Effects in the Mouse Brain

Citrus kawachiensis (Kawachi Bankan), is a citrus species grown in Ehime, Japan, and its peel is abundant in 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF). We have recently revealed that HMF, one of the citrus flavonoids, has anti-inflammatory activity and neuroprotective abilities in the brain against global cerebral ischemia. HMF rescued neuronal cell death in the hippocampus and suppressed the activation of microglia, whose activation have been shown to significantly aggravate neurological deficit scores for ischemic mice. In the Y-maze test, HMF showed protection against ischemia-induced short-term memory dysfunction; in addition, HMF enhanced the expression of brain-derived neurotrophic factor and accelerated neurogenesis in the hippocampus. Similarly, the powder of the peel of C. kawachiensis showed anti-inflammatory activity and neuroprotective abilities in the ischemic brain. To further examine the effect of the peel of C. kawachiensis, we administered it to senescence-accelerated-mouse prone 8 (SAMP8) mice, which show memory impairment and brain inflammation, tau hyperphosphorylation, and neuronal dysfunction. The C. kawachiensis treatment inhibited microglial activation and the hyperphosphorylation of tau protein in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in SAMP8. These results suggest that HMF and the peel of C. kawachiensis have potential effects as neuroprotective and anti-dementia agents.

A UPLC-Q-TOF/MS-Based Metabolomics Study on the Effect of Corallodiscus flabellatus (Craib) B. L. Burtt Extract on Alzheimer's Disease.

A UPLC-Q-TOF/MS-based metabolomics study was carried out to explore the intervening mechanism of Corallodiscus flabellatus (Craib) B. L. Burtt (CF) extract on Alzheimer's disease (AD). The AD model group consisted of senescence-accelerated mouse prone 8 (SAMP8) mice, and the control group consisted of senescence-accelerated mouse resistant 1 (SAMR1) mice. UPLC-Q-TOF/MS detection, multivariate statistical analysis, and pathway enrichment were jointly performed to research the change in metabolite profiling in the urine of AD mice. The result suggested that the metabolite profiling of SAMP8 mice significantly changed at the sixth month compared with SAMR1 mice of the same age, and the principal component analysis (PCA) score scatter plots of the CF group closely resembled those of the control and positive drug (huperzine A, HA) group. A total of 28 metabolites were considered potential biomarkers associated with the metabolism of beta-alanine, glycine, serine, threonine, cysteine, methionine, arginine, proline, and purines in AD mice. Furthermore, the CF group was clustered with the control and positive group and was clearly separated from the model group in the heat map. In conclusion, significant anti-AD effects were firstly observed in mice after treatment with the CF extract, and the urinary metabolomics approach assisted with dissecting the underlying mechanism.

Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit reduced entoconid in the lower second molar

ObjectiveThe position and size of the major cusps in mammalian molars are arranged in a characteristic pattern that depends on taxonomy. In humans, the cusp which locates distally within each molar is smaller than the mesially located cusp, which is referred to as “distal reduction”. Although this concept has been well-recognized, it is still unclear how this reduction occurs. Current study examined whether senescence-accelerating mouse prone 8 (SAMP8) mice could be a possible animal model for studying how the mammalian molar cusp size is determined. DesignSAMP8 mice were compared with parental control (SAMR1) mice. Microcomputed tomography images of young and aged mice were captured to observe molar cusp morphologies. Cusp height from cement-enamel junction and mesio-distal length of molars were measured. The statistical comparison of the measurements was performed by Mann-Whitney U test. ResultsSAMP8 mice showed reduced development of the disto-lingual cusp (entoconid) of lower second molar when compared with SAMR1 mice. The enamel thickness and structure was disturbed at entoconid, and aged SAMP8 mice displayed severe wear of the entoconid in lower second molar. These phenotypes were observed on both sides of the lower second molar. ConclusionsIn addition to the general senescence phenotype observed in SAMP8 mice, this strain may genetically possess molar cusp phenotypes which is determined prenatally. Further, SAMP8 mice would be a potential model strain to study the genetic causes of the distal reduction of molar cusp size.

Anti-Fatigue Effect of a Dietary Supplement from the Fermented By-Products of Taiwan Tilapia Aquatic Waste and Monostroma nitidum Oligosaccharide Complex.

The Taiwan Tilapia is an important aquaculture product in Taiwan. The aquatic by-products generated during Tilapia processing, such as fish bones and skin, are rich in minerals and protein. We aimed to explore the effect of a dietary supplement, comprising a mixture of fermented Tilapia by-products and Monostroma nitidum oligosaccharides as the raw materials, combined with physical training on exercise performance and fatigue. We used a mouse model that displays a phenotype of accelerated aging. Male senescence-accelerated mouse prone-8 (SAMP8) mice were divided into two control groups—with or without physical training—and supplemented with different doses (0.5 times: 412 mg/kg body weight (BW)/day; 1 time: 824 mg/kg BW/day; 2 times: 1648 mg/kg BW/day) of fermented Tilapia by-products and Monostroma nitidum oligosaccharide-containing mixture and combined with exercise training groups. Exercise performance was determined by testing forelimb grip strength and with a weight-bearing exhaustive swimming test. Animals were sacrificed to collect physical fatigue-related biomarkers. Mice dosed at 824 or 1648 mg/kg BW/day showed improvement in their exercise performance (p < 0.05). In terms of biochemical fatigue indicators, supplementation of 824 or 1648 mg/kg BW/day doses of test substances could effectively reduce blood urea nitrogen concentration and lactate concentration and increase the lactate ratio (p < 0.05) and liver glycogen content post-exercise (p < 0.05). Based on the above results, the combination of physical training and consumption of a dietary supplementation mixture of fermented Tilapia by-products and Monostroma nitidum oligosaccharides could improve the exercise performance of mice and help achieve an anti-fatigue effect.

A bicyclic α‑iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration

I2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I2-IR. Recently, we described a new imidazoline-structure family which showed high affinity and selectivity for I2-IR. In vivo studies in mice indicated a neuroprotective role and revealed beneficial effects in behaviour and cognition with a murine model of neurodegeneration, senescence-accelerated prone mouse (SAMP8). Herein, we report a novel non-imidazoline-structure of bicyclic α-iminophosphonates family with high affinities for I2-IR. In vivo studies in 5X-FAD mice (a transgenic representative model of AD) and SAMP8 mice (a model of neurodegeneration linked to aging) showed an improvement in behaviour and cognition, a reduction of AD hallmarks and of neuroinflammation markers for the mice treated with the lead compound B06. After evaluating several pathways associated with neurodegeneration, we demonstrated that CaN pathway plays a critical role on the neuroprotective effects of I2-IR ligands on SAMP8 mice model. To rule out warnings of the novel family, we calculated DMPK and physicochemical properties for the novel bicyclic α-iminophosphonates. As well, we carried out drug metabolism, safety studies and in vivo pharmacokinetics for lead compound B06. In summary, we present a novel family of I2-IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.

Anti-aging effects of a functional food via the action of gut microbiota and metabolites in aging mice.

Wushen (WS) is a mixed food containing 55 natural products that is beneficial to human health. This study aimed to reveal the preventive effect of WS on aging via a combined analysis of gut microbiome and metabolome. Senescence-accelerated mouse prone 8 (SAMP8) mice were used as aging model and senescence-accelerated mouse resistant 1 (SAMR1) mice as control. The mice were fed four diet types; control diet (for SAMR1 mice), standard diet (for SAMP8 mice, as SD group), WS diet, and fecal microbiota transplantation (FMT; transplanted from aging-WS mice). Our results showed that the weight, food intake, neurological function, and general physical conditions significantly improved in WS-fed mice compared to those fed with SD. The CA1 hippocampal region in WS-fed aged mice showed fewer shriveled neurons and increased neuronal layers compared to that of the SD group. WS-fed mice showed a decrease in malondialdehyde and an increase in superoxide dismutase levels in the brain; additionally, IL-6 and TNF-α levels significantly decreased, whereas IL-2 levels and the proportion of lymphocytes, CD3+CD8+ T, and CD4+IFNγ+T cells increased in WS-fed mice. After fed with WS, the abundance of Ruminococcus and Butyrivibrio markedly increased, whereas Lachnoclostridium and Ruminiclostridium significantly decreased in the aging mice. In addition, 887 differentially expressed metabolites were identified in fecal samples, among these, Butyrivibrio was positively correlated with D-glucuronic acid and Ruminococcus was positively associated with 5-acetamidovalerate. These findings provide mechanistic insight into the impact of WS on aging, and WS may be a valuable diet for preventing aging.

An Examination of Lactobacillus paracasei GKS6 and Bifidobacterium lactis GKK2 Isolated from Infant Feces in an Aged Mouse Model.

Supplementary which could maintain normal physiological mechanisms and functions while aging has drawn our attention due to the population aging in recent years. Probiotics have been believed with desirable properties such as antioxidation and anti-inflammatory for delaying the aging process. However, the age-related experiments conducted in the mammalian models with probiotics were few. In this study, we demonstrated the effects of administration of probiotics Lactobacillus paracasei GKS6 (GKS6) and Bifidobacterium lactis GKK2 (GKK2), respectively, at the dosage of 5.0 × 109 cfu/kg BW/day for fourteen weeks in senescence-accelerated mouse prone 8 (SAMP8) mice. The three-month-old SAMP8 mice were divided into three groups: control, mice fed with GKS6, and mice fed with GKK2. There were ten females and ten males in each group. The SAMP8 mice fed with probiotics GKS6 and GKK2 showed a significantly lower degree of aging followed by Takeda's grading method on the eleventh week of the experiment. The GKK2 group showed significantly increased forelimb grip strength in male SAMP8 mice and muscle fiber number in both genders. Compared to the control, both GKS6 and GKK2 presented a significant increase in liver superoxide dismutase and catalase activities. In addition, a significant decrease in the levels of liver thiobarbituric acid-reactive substances was observed in the probiotics group. These results suggested that probiotics GKS6 and GKK2 could act as antioxidants in delaying the process of aging and preventing age-related muscle loss.