Hippocampus Of Aged Mice Research Articles

Aged hippocampal single-cell atlas screening unveils disrupted neuroglial system in postoperative cognitive impairment.

Glia-neuron interaction is a crucial feature in aged hippocampus during the occurrence of postoperative cognitive impairment. However, the regulatory effects of microglia, astrocytes, and oligodendrocytes in this glia-neuron interaction, the potential mechanisms and gene targets are still to be elucidated. Here, single-cell RNA sequencing was performed to detect the perioperative genomic expression characteristics of neuroglial system in the hippocampus of aged mice, and to investigate the potential cross-cellular mechanisms and valuable treatment options for glia-neuron interaction-related cognitive impairment. We found that postoperative neurons and glia cells exhibited protein dysmetabolism and mitochondrial electron misrouting. Impaired autophagy and circadian rhythm worsened microglia activation/neuroinflammation, and exacerbated these metabolic alterations. Reactive microglia also aggravated astrocyte and oligodendrocyte cytotoxicity through the PGD2/DP and complement pathways, altering glutamate level and synaptic function via the "tripartite synapses" model, and affecting neuronal myelination. Ligand-receptor communication also indicated these synaptic and axonal dysfunctions via enhanced MDK and PTN pathways. Additionally, we found that anesthetic dexmedetomidine hold therapeutic potential within the disrupted neuroglial system. It enhanced neuronal metabolic rebalance (Atf3-related) and reduced neuroinflammation from a multicellular perspective, therefore improving postoperative cognitive impairment. Together, our study proposes an aged hippocampal cell atlas and provides insights into the role of disrupted glia-neuron cycle in postoperative cognitive impairment. Our findings also elucidate the therapeutic potential and mechanism of dexmedetomidine intervention.

ACSL3 is a promising therapeutic target for alleviating anxiety and depression in Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, affects over 55 million people worldwide and is often accompanied by depression and anxiety. Both significantly impact patients' quality of life and impose substantial societal and economic burdens on healthcare systems. Identifying the complex regulatory mechanisms that contribute to the psychological and emotional deficits in AD will provide promising therapeutic targets. Biosynthesis of omega-3 (ω3) and omega-6 fatty acids (ω6-FA) through long-chain acyl-CoA synthetases (ACSL) is crucial for cell function and survival. This is due to ω3/6-FA's imperative role in modulating the plasma membrane, energy production, and inflammation. While ACSL dysfunction is known to cause heart, liver, and kidney diseases, the role of ACSL in pathological conditions in the central nervous system (e.g., depression and anxiety) remains largely unexplored. The impact of ACSLs on AD-related depression and anxiety was investigated in a mouse model of Alzheimer's disease (3xTg-AD). ACSL3 levels were significantly reduced in the hippocampus of aged 3xTg-AD mice (via capillary-based immunoassay). This reduction in ACAL3 was closely associated with increased depression and anxiety-like behavior (via forced swim, tail suspension, elevated plus maze, and sucrose preference test). Upregulation of ACSL3 via adenovirus in aged 3xTg-AD mice led to increased protein levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor C (VEGF-C) (via brain histology, capillary-based immunoassay), resulting in alleviation of depression and anxiety symptoms. The present study highlights a novel neuroprotective role of ACSL3 in the brain. Targeting ACSL3 will offer an innovative approach for treating AD-related depression and anxiety.

Multi-Protective Effects of Petunidin-3-O-(trans-p-coumaroylrutinoside)-5-O-glucoside on D-Gal-Induced Aging Mice

Petunidin-3-O-(trans-p-coumaroylrutinoside)-5-O-glucoside (PtCG), the primary anthocyanin ingredient in Lycium ruthenicum Murr., possesses a range of biological activities, including antioxidative properties and melanin inhibition. This study aimed to investigate the protective effect of PtCG on D-galactose (D-gal)-induced aging in female mice and elucidate the underlying molecular pathways. Behavioral experiments, including the MWW and Y-maze tests, revealed that PtCG significantly ameliorated cognitive decline and enhanced learning and memory abilities in aging mice. Regarding biochemical indicators, PtCG considerably improved superoxide dismutase (SOD) and glutathione (GSH) activity while reducing malondialdehyde (MDA) and acetylcholinesterase (AChE) levels in the hippocampus and serum. Furthermore, PtCG ingestion alleviated liver injury by decreasing alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (AKP) levels, and attenuated renal damage by reducing blood urea nitrogen (BUN) and uric acid (UA) levels. Transmission electron microscopy (TEM) results demonstrated that PtCG restored the function and quantity of synapses in the hippocampus. Hematoxylin and eosin (H&E), Masson’s trichrome, and Nissl staining revealed that PtCG significantly improved the relevant pathological characteristics of liver and hippocampal tissues in aging mice. The molecular mechanism investigation showed that PtCG downregulated the protein expression of microglial marker ionized calcium-binding adapter molecule 1 (Iba1), astrocytic marker glial fibrillary acidic protein (GFAP), β-secretase 1 (BACE-1), and amyloid-beta1–42 (Aβ1–42) in the hippocampus of aging mice. The protein expression of inflammatory pathway components, including nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), and interleukin-1 beta (IL-1β), was also suppressed. These findings suggest that PtCG may possess anti-aging properties, with its mechanism of action potentially linked to the attenuation of neuroinflammation, oxidative stress, and liver and kidney damage. PtCG may have future applications as a functional food for the treatment of aging-related disorders.

CaMKIIα-TARPγ8 signaling mediates hippocampal synaptic impairment in aging.

Aging-related decline in memory and synaptic function are associated with the dysregulation of calcium homeostasis, attributed to the overexpression of voltage-gated calcium channels (VGCC). The membrane insertion of AMPAR governed by the AMPAR auxiliary proteins is essential for synaptic transmission and plasticity (LTP). In this study, we demonstrated the hippocampal expression of the transmembrane AMPAR regulatory proteins γ-8 (TARPγ8) was reduced in aged mice along with the reduced CaMKIIα activity and memory impairment. We further showed that TARPγ8 expression was dependent on CaMKIIα activity. Inhibition of CaMKIIα activity significantly reduced the hippocampal TARPγ8 expression and CA3-CA1 LTP in young mice to a similar level to that of the aged mice. Furthermore, the knockdown of hippocampal TARPγ8 impaired LTP and memory in young mice, which mimicked the aging-related changes. We confirmed the enhanced hippocampal VGCC (Cav-1.3) expression in aged mice and found that inhibition of VGCC activity largely increased both p-CaMKIIα and TARPγ8 expression in aged mice, whereas inhibition of NMDAR or Calpains had no effect. In addition, we found that the exogenous expression of human TARPγ8 in the hippocampus in aged mice restored LTP and memory function. Collectively, these results indicate that the synaptic and cognitive impairment in aging is associated with the downregulation of CaMKIIα-TARPγ8 signaling caused by VGCC activation. Our results suggest that TARPγ8 may be a key molecular biomarker for brain aging and that boosting CaMKIIα-TARPγ8 signaling may be critical for the restoration of synaptic plasticity of aging and aging-related diseases.

Role of Hippocampal Glutamatergic Synaptic Alterations in Sevoflurane-Induced Cognitive Dysfunction in Aged Mice.

Perioperative neurocognitive disorders (PND), including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common following anesthesia and surgery in older patients and significantly increase morbidity and mortality. However, the underlying mechanism of PND is unclear. Our study aims to analyze the differentially expressed genes (DEGs) in excitatory neurons and investigate the role of hippocampal glutamatergic synaptic alterations in sevoflurane-induced cognitive dysfunction in aged mice. We performed single-nucleus RNA sequencing (snRNA-seq) technology to examine the alterations of excitatory neurons in hippocampus induced by sevoflurane in aged mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DEGs were performed in excitatory neurons. At last, immunofluorescence staining was used to validate sevoflurane-induced alternation of glutamatergic synapses in the hippocampus of aged mice. This study demonstrates that DEGs in excitatory neurons are associated with reduction of glutamatergic synapses and cognitive dysfunction. After immunofluorescence staining validation, we also confirmed that sevoflurane anesthesia decreased the density of glutamatergic synapses in the hippocampus of aged mice. Our findings demonstrated a key role of hippocampal glutamatergic synaptic alterations in sevoflurane-induced cognitive dysfunction in aged mice.

Gut microbiota-brain bile acid axis orchestrates aging-related neuroinflammation and behavior impairment in mice

Emerging evidence shows that disrupted gut microbiota-bile acid (BA) axis is critically involved in the development of neurodegenerative diseases. However, the alterations in spatial distribution of BAs among different brain regions that command important functions during aging and their exact roles in aging-related neurodegenerative diseases are poorly understood. Here, we analyzed the BA profiles in cerebral cortex, hippocampus, and hypothalamus of young and natural aging mice of both sexes. The results showed that aging altered brain BA profiles sex- and region- dependently, in which TβMCA was consistently elevated in aging mice of both sexes, particularly in the hippocampus and hypothalamus. Furthermore, we found that aging accumulated-TβMCA stimulated microglia inflammation in vitro and shortened the lifespan of C. elegans, as well as behavioral impairment and neuroinflammation in mice. In addition, metagenomic analysis suggested that the accumulation of brain TβMCA during aging was partially attributed to reduction in BSH-carrying bacteria. Finally, rejuvenation of gut microbiota by co-housing aged mice with young mice restored brain BA homeostasis and improved neurological dysfunctions in natural aging mice. In conclusion, our current study highlighted the potential of improving aging-related neuro-impairment by targeting gut microbiota-brain BA axis.

Acute changes in hippocampal metabolism after anesthesia and surgery: Implications for perioperative neurocognitive disorder

BackgroundThe risk of developing dementia is higher in individuals who suffer from perioperative neurocognitive disorder (PND), including postoperative cognitive dysfunction (POCD) and delirium. Recent studies have indicated correlations between anesthesia, surgery and PND. Acute metabolic changes induced by anesthesia and surgery may be related to cognitive impairments. Despite a paucity of research on acute metabolic changes in the hippocampus during surgery, there are conflicting about specific metabolites. MethodsWe developed a mouse model of cognitive impairment induced by isoflurane anesthesia and unilateral nephrectomy. Cognition was evaluated by Y maze and fear conditioning test (FCT). The hippocampus was harvested after the surgery. LC-MS (liquid chromatography-mass spectrometry) was performed. The differential metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were analyzed. ResultsAnesthesia and surgery exposure induced cognition decline. A total of 49 metabolites were significantly up-regulated and 122 down-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the metabolites identified purine, glutathione, nicotinate and nicotinamide metabolism. Metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were identified including nicotinamide adenine dinucleotide (NAD), 1-Methylnicotinamide, propionic acid, histidine, adenosine, and guanosine cyclic monophosphate. Some metabolites exhibited a consistent change trend in the hippocampus of aging mice. ConclusionsThe study indicates that anesthesia and surgery can induce acute alterations in hippocampal metabolomics, including metabolites involved in lipid, amino acid, nucleotide, and carbohydrate metabolism. These metabolites may play a role in modulating PND through the regulation of neuroinflammation, oxidative stress, blood-brain barrier (BBB) permeability.

Physical Exercise Inhibits Cognitive Impairment and Memory Loss in Aged Mice, and Enhances Pre- and Post-Synaptic Proteins in the Hippocampus of Young and Aged Mice.

The aim of this study was to evaluate the effects of swimming in the brain and behavior of young and aged mice. Forty-eight male C57BL/6J mice were randomly distributed into 4 groups (n = 12 per group, 3 and 18months old). The subdivision of the groups was: 3months-SED, 18months-SED, 3months-EXE, and 18months-EXE. SED mice did not swim, while EXE mice performed the physical exercise protocol. Training was initiated 48h after the adaptation week. Swimming sessions consisted of 30min, with no overload, 5days per week, for 4weeks. After the exercise protocol, it was revealed working and spatial memory were impaired in the 18months-SED group. Pre- and post-synaptic proteins were enhanced in the groups that swam when compared to the 3- and 8months-SED groups. Lipid peroxidation was greater in the aged mice that did not perform the physical exercise protocol and might have contributed to the cognitive impairment in this group. In conclusion, an aerobic physical exercise protocol, performed through regular swimming sessions, inhibited cognitive impairment, memory loss and lipid peroxidation in the aged mice, while pre- and post-synaptic proteins were enhanced in the hippocampus of young and aged mice.

GluN2A or GluN2B subunits of the NMDA receptor contribute to changes in neuronal excitability and impairments in LTP in the hippocampus of aging mice but do not mediate detrimental effects of oligomeric Aβ (1-42).

Studies in rodent models have revealed that oligomeric beta-amyloid protein [Aβ (1-42)] plays an important role in the pathogenesis of Alzheimer's disease. Early elevations in hippocampal neuronal excitability caused by Aβ (1-42) have been proposed to be mediated via enhanced activation of GluN2B-containing N-methyl-D-aspartate receptors (NMDAR). To what extent GluN2A or GluN2B-containing NMDAR contribute to Aβ (1-42)-mediated impairments of hippocampal function in advanced rodent age is unclear. Here, we assessed hippocampal long-term potentiation (LTP) and neuronal responses 4-5 weeks after bilateral intracerebral inoculation of 8-15 month old GluN2A+/- or GluN2B+/- transgenic mice with oligomeric Aβ (1-42), or control peptide. Whole-cell patch-clamp recordings in CA1 pyramidal neurons revealed a more positive resting membrane potential and increased total spike time in GluN2A+/-, but not GluN2B+/--hippocampi following treatment with Aβ (1-42) compared to controls. Action potential 20%-width was increased, and the descending slope was reduced, in Aβ-treated GluN2A+/-, but not GluN2B+/- hippocampi. Sag ratio was increased in Aβ-treated GluN2B+/--mice. Firing frequency was unchanged in wt, GluN2A+/-, and GluN2B+/-hippocampi after Aβ-treatment. Effects were not significantly different from responses detected under the same conditions in wt littermates, however. LTP that lasted for over 2 h in wt hippocampal slices was significantly reduced in GluN2A+/- and was impaired for 15 min in GluN2B+/--hippocampi compared to wt littermates. Furthermore, LTP (>2 h) was significantly impaired in Aβ-treated hippocampi of wt littermates compared to wt treated with control peptide. LTP induced in Aβ-treated GluN2A+/- and GluN2B+/--hippocampi was equivalent to LTP in control peptide-treated transgenic and Aβ-treated wt animals. Taken together, our data indicate that knockdown of GluN2A subunits subtly alters membrane properties of hippocampal neurons and reduces the magnitude of LTP. GluN2B knockdown reduces the early phase of LTP but leaves later phases intact. Aβ (1-42)-treatment slightly exacerbates changes in action potential properties in GluN2A+/--mice. However, the vulnerability of the aging hippocampus to Aβ-mediated impairments of LTP is not mediated by GluN2A or GluN2B-containing NMDAR.

Trilobatin suppresses aging-induced cognitive impairment by targeting SIRT2: Involvement of remodeling gut microbiota to mediate the brain-gut axis

BackgroundAging is associated with learning and memory disorder, affecting multiple brain areas, especially the hippocampus. Previous studies have demonstrated trilobatin (TLB), as a natural food additive, can extend the life of Caenorhabditis elegans and exhibit neuroprotection in Alzheimer's disease mice. However, the possible significance of TLB in anti-aging remains elusive. PurposeThis study aimed to delve into the physiological mechanism by which TLB ameliorated aging-induced cognitive impairment in senescence-accelerated mouse prone 8 (SAMP8) mice. Methods6-month-old SAMP8 mice were administrated with TLB (5, 10, 20 mg/kg/day, i.g.) for 3 months. The therapeutic effect of TLB on aging-induced cognitive impairment was assessed in mice using behavioral tests and aging score. The gut microbiota composition in fecal samples was analyzed by metagenomic analysis. The protective effects of TLB on blood-brain barrier (BBB) and intestinal barrier were detected by transmission electron microscope, H&E staining and western blot (WB) assay. The inhibitive effects of TLB on inflammation in brain and intestine were assessed using immunofluorescence, WB and ELISA assay. Molecular docking and surface plasma resonance (SPR) assay were utilized to investigate interaction between TLB and sirtuin 2 (SIRT2). ResultsHerein, the findings exhibited TLB mitigated aging-induced cognitive impairment, neuron injury and neuroinflammation in hippocampus of aged SAMP8 mice. Moreover, TLB treatment repaired imbalance of gut microbiota in aged SAMP8 mice. Furthermore, TLB alleviated the damage to BBB and intestinal barrier, concomitant with reducing the expression of SIRT2, phosphorylated levels of c-Jun NH2 terminal kinases (JNK) and c-Jun, and expression of MMP9 protein in aged SAMP8 mice. Molecular docking and SPR unveiled TLB combined with SIRT2 and down-regulated SIRT2 protein expression. Mechanistically, the potential mechanism of SIRT2 in TLB that exerted anti-aging effect was validated in vitro. As expected, SIRT2 deficiency attenuated phosphorylated level of JNK in HT22 cells treated with d-galactose. ConclusionThese findings reveal, for the first time, SIRT2-mediated brain-gut barriers contribute to aging and aging-related diseases, and TLB can rescue aging-induced cognitive impairment by targeting SIRT2 and restoring gut microbiota disturbance to mediate the brain-gut axis. Overall, this work extends the potential application of TLB as a natural food additive in aging-related diseases.

The polysaccharides from Balanophora polyandra enhanced neuronal autophagy to ameliorate brain function decline in natural aging mice through the PI3K/AKT/mTOR signaling pathway.

The decline of aging brain neurons is the main cause of various neurodegenerative disease. This study aimed to examine the impact of Balanophora polyandra polysaccharides (BPP) against aging related neuronal deterioration. C57BL/6 mice were fed with regular feed for 27 months to establish a natural aging mouse model. From 3 months of age, mice in the drug-treated group were respectively fed with feed containing 0.05 or 0.18% BPP until 27 months of age. The effects of BPP treatment on the pathological changes of neurons in mice brain were evaluated, as well as autophagy-related and signaling pathway proteins. BPP treatment had a notable positive impact on the pathological injury of cortical and hippocampal neurons, alleviated neuronal degeneration, and enhanced the staining of Nissl bodies in natural aging mice. Furthermore, BPP upregulated autophagy-related proteins LC3 II/I, Parkin, and PINK1 in the cortex and hippocampus of aging mice, and significantly decreased the expression of p62, PI3K, p-protein Kinase B (AKT), and p-mTOR. Immunofluorescence results showed a reduction in the brightness of LC3, which mainly coexpressed with NeuN in natural aging mice brain, and increased LC3-positive neurons were observed after BPP treatment. Collectively, BPP treatment enhanced neuronal autophagy to improve brain functional degradation through the PI3K/AKT/mTOR signaling in natural aging mice. These finding suggested that BPP has potential to mitigate or delay the neurodegeneration associated with aging and further investigation was needed to validate its efficacy in elderly populations.

Euonymus alatus Leaf Extract Attenuates Effects of Aging on Oxidative Stress, Neuroinflammation, and Cognitive Impairment.

Our study aimed to explore the impact and mechanism of Euonymus alatus leaf extract on age-dependent oxidative stress, neuroinflammation, and progressive memory impairments in aged mice. Twenty-four-month-old mice received EA-L3 (300 mg/kg/day) or the reference drug, donepezil (DPZ, 5 mg/kg/day), for 6 weeks, and learning and memory functions were detected using the Passive Avoidance Test (PAT). As expected, cognitive function deficits were detected in aged mice compared with young mice, and these deficits were significantly mitigated by dietary treatments with EA-L3. In parallel, it upregulated the brain-derived neurotrophic factor (BDNF) and subsequently activated the extracellular-signal-regulated kinase (ERK)/cAMP response element-binding (CREB) signaling in the mouse hippocampus and scopolamine-induced B35 and SH-SY5Y neuroblastoma cells. EA-L3 showed strong anti-inflammatory effects with decreased NF-κBp65, cyclooxygenase 2 (COX-2), and tumor necrosis factor alpha (TNF-α), increased interleukin (IL)-10, and doublecortin (DCX) protein expression in the hippocampus of aged mice. Similar results were also confirmed in LPS-induced BV-2 microglia and neuroblastoma cells upon treatment with EA-L3 extract. In addition, EA-L3 notably dose-dependently decreased ROS in BV2 cells after exposure to LPS. Taken together, EA-L3 might be used as a dietary supplement to alleviate oxidative stress, the deterioration of hippocampal-based memory tasks, and neuroinflammation in elderly people.

CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer’s diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

Abstract WP318: Increased Synapse Elimination by Inflammatory Cells Contribute to Lon-Lasting Post-Stroke Memory Dysfunction in Aged Mice

Background and Purpose: Memory impairments are common after stroke. Memory dysfunction lasted longer in aged than in young mice, but the mechanisms are still unclear. Microglia maintain normal memory via removing excessive synapses and increase turnover of synaptic connections after stroke. Long-term memory deficits in aged mice may be associated with increased microglia in the brain. Hypothesis: Increased synapse removal by inflammatory cells contribute to the long-lasting post-stroke memory dysfunction of aged mice. Methods: Permanent distal middle cerebral artery occlusion (pMCAO) was induced in young and aged mice. The memory functions were analyzed weekly for 8 weeks by Y-maze test and at 8 weeks post stroke by novel objective recognition (NOR) test. Brain samples were collected 8 weeks after pMCAO induction. RNAseq analysis was performed to study gene expression profiles in peri-infarct area and hippocampus. Nissl staining was used to measure infarct volume and immunostaining was done to detect CD68 + and GFAP + cells and synapse in peri-infarct region and hippocampus. Results: RNAseq data shown up-regulation of CD68, GFAP, pro-inflammatory cytokines, immune response, microglia chemotaxins and phagocytosis genes; and down-regulation of synaptic assembly and transmission, synaptic plasticity, and long-term potentiation genes in aged mice at peri-infarct region and ipsilateral hippocampi. Aged mice had larger infarct volumes, more CD68 + and GFAP + cells in the peri-infarct region and ipsilateral hippocampi than young mice and had more CD68 + cells in the ipsilateral than the contralateral hippocampi. In Y-maze test, aged stroke mice made fewer spontaneous alternations from 3 to 8 weeks after pMCAO than young stroke and sham operated aged mice. In the NOR test, aged stroke mice spent less time on the novel objects than young stroke and sham aged mice. Increased synaptophysin positive CD68 + cells were detected in the hippocampi of aged stroke mice. Conclusions: Increase of synaptic elements by inflammatory cells contribute to the long-lasting post-stroke memory deficit in the aged mice, and reduction of neuroinflammation may improve their memory function.

Melatonin Ameliorates Sevoflurane Anesthesia-Induced Deficits in Learning and Memory of Aged Mice Through Nrf2 Signaling Related Ferroptosis.

Our research aimed at investigating the protective effects in aged mice exposed to sevoflurane anesthesia. To assess learning and memory abilities and exploratory behavior, the novel object recognition (NOR) test, Morris water maze (MWM) test, and open field test were employed. Commercial kits were used to measure levels of malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase activity, superoxide dismutase activity, catalase activity, and iron. The messenger RNA and protein levels of ferritin heavy chain 1, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, and glutathione peroxidase 4 in the hippocampus were detected. Treatment with melatonin significantly ameliorated the decrease in exploration time of novel objects and the discrimination index induced by sevoflurane anesthesia. Melatonin also reduced escape latencies and increased the time spent in the target quadrant in the MWM test. In the open field test, melatonin-treated mice exhibited greater exploratory activity, including longer distances traveled and a higher number of rearing events. Further, melatonin treatment markedly decreased the levels of oxidative stress markers and iron in the hippocampus of aged mice exposed to sevoflurane anesthesia. However, the beneficial effects of melatonin were significantly attenuated following treatment with the Nrf2 inhibitor ML385. Our results suggest that melatonin could alleviate learning and memory impairment induced by sevoflurane anesthesia in aged mice through its antioxidant properties, partially through the Nrf2 pathway.

Aging differentially alters the transcriptome and landscape of chromatin accessibility in the male and female mouse hippocampus.

Aging-related memory impairment and pathological memory disorders such as Alzheimer's disease differ between males and females, and yet little is known about how aging-related changes in the transcriptome and chromatin environment differ between sexes in the hippocampus. To investigate this question, we compared the chromatin accessibility landscape and gene expression/alternative splicing pattern of young adult and aged mouse hippocampus in both males and females using ATAC-seq and RNA-seq. We detected significant aging-dependent changes in the expression of genes involved in immune response and synaptic function and aging-dependent changes in the alternative splicing of myelin sheath genes. We found significant sex-bias in the expression and alternative splicing of hundreds of genes, including aging-dependent female-biased expression of myelin sheath genes and aging-dependent male-biased expression of genes involved in synaptic function. Aging was associated with increased chromatin accessibility in both male and female hippocampus, especially in repetitive elements, and with an increase in LINE-1 transcription. We detected significant sex-bias in chromatin accessibility in both autosomes and the X chromosome, with male-biased accessibility enriched at promoters and CpG-rich regions. Sex differences in gene expression and chromatin accessibility were amplified with aging, findings that may shed light on sex differences in aging-related and pathological memory loss.

The effects of long-term lactate and high-intensity interval training (HIIT) on brain neuroplasticity of aged mice

Extensive research has confirmed numerous advantages of exercise for promoting brain health. More recent studies have proposed the potential benefits of lactate, the by-product of exercise, in various aspects of brain function and disorders. However, there remains a gap in understanding the effects of lactate dosage and its impact on aged rodents. The present study first examined the long-term effects of three different doses of lactate intervention (2000 mg/kg, 1000 mg/kg, and 500 mg/kg) and high-intensity interval training (HIIT) on aging mice (20–22 months) as the 1st experiment. Subsequently, in the 2nd experiment, we investigated the long-term effects of 500 mg/kg lactate intervention and HIIT on brain neuroplasticity in aged mice (25–27 months).The results of the 1st experiment demonstrated that both HIIT and different doses of lactate intervention (500 mg/kg and 2000 mg/kg) positively impacted the neuroplasticity biomarker VEGF in the hippocampus of aging mice. Subsequently, the 2nd experiment revealed that long-term HIIT significantly improved the performance of mice in open-field, novel object recognition, and passive avoidance tests. However, lactate intervention did not significantly affect these behavioral tests. Moreover, compared to the control group, both HIIT and lactate intervention positively influenced the angiogenesis signaling pathway (p/t-AKT/ENOS/VEGF), mitochondrial biomarker (SDHA), and metabolic protein (p/t-CREB, p/t-HSL, and LDH) in the hippocampus of aged mice. Notably, only lactate intervention significantly elevated the BDNF (PGC-1α, SIRT1, and BDNF) signaling pathway and metabolic content (lactate and pyruvate). In the end, long-term HIIT and lactate intervention failed to change the protein expression of p/t-MTOR, iNOS, nNOS, HIF-1α, SYNAPSIN, SIRT3, NAMPT, CS, FNDC5 and Pan Lactic aid-Lysine in the hippocampus of aged mice.In summary, the present study proved that long-term HIIT and lactate treatment have positive effects on the brain functions of aged mice, suggesting the potential usage of lactate as a therapeutic strategy in neurodegenerative diseases in the elderly population.

Bifidobacterium pseudocatenulatum NCU-08 ameliorated senescence via modulation of the AMPK/Sirt1 signaling pathway and gut microbiota in mice.

Aging is a degenerative disease in which organisms and neurological functions decline. Emerging research has underscored the vital role of the gut microbiota in age-related processes. However, the identification of aging-associated core microbiota remains limited. In this investigation, we isolated a strain of B. pseudocatenulatum NCU-08 from the feces of centenarians and assessed its impact on aging using a mouse model induced by D-gal. Our study revealed the exceptional probiotic attributes of B. pseudocatenulatum NCU-08. Administration of B. pseudocatenulatum NCU-08 significantly ameliorated age-related memory impairment, motor dysfunction, and anxiety-like behaviors in aging mice (p < 0.01). Moreover, tissue staining analysis demonstrated that B. pseudocatenulatum NCU-08 reduced the intensity of SA-β-gal-positive in the hippocampus of aging mice. It also reversed pathological damage and structural abnormalities in brain and intestinal tissue. B. pseudocatenulatum NCU-08 inhibited neuroinflammation induced by TLR4/NF-κB (p < 0.01) and preserved the blood-brain barrier integrity by activating the AMPK/Sirt1 pathway (p < 0.05). Furthermore, it mitigated neuronal apoptosis and oxidative stress by upregulating the PI3K/AKT signaling pathway (p < 0.01) and enhancing the activities of antioxidant enzymes, including GSH-Px (p < 0.01), SOD (p < 0.01), and CAT (p < 0.01). Besides, analysis of 16S rRNA sequencing data demonstrated that treatment with B. pseudocatenulatum NCU-08 restored intestinal microbiota homeostasis after senescence. It enhanced the abundance of beneficial bacteria while suppressing the growth of pathogenic microorganisms. In summary, our study unveiled that this novel strain of B. pseudocatenulatum NCU-08 exerts anti-aging effects through regulating the AMPK/Sirt1 pathway and intestinal microbiota. It holds promise as a functional food for promoting anti-aging effects and offers a novel approach to address aging and associated metabolic disorders.

Lactococcus strains with psychobiotic properties improve cognitive and mood alterations in aged mice.

Aging often accompanies cognitive and mood disturbances. Emerging evidence indicates that specific probiotics mitigate cognitive and mood dysfunctions. Strains within Lactococcus, a subgroup of probiotics, including Lactococcus lactis and Lactococcus cremoris are shown beneficial effects on brain functions via the gut microbiota-brain axis (GBA). Our previous study identified two Lactococcus strains (L. lactis WHH2078 and L. cremoris WHH2080) with the ability to promote the secretion of gut 5-hydroxytryptophan (5-HTP), the precursor of the GBA mediator 5-hydroxytryptamine (5-HT). In this study, the modulatory effects of WHH2078 and WHH2080 on cognitive and mood alternations were investigated in aged mice. Oral administration of WHH2078 and WHH2080 (1 × 109 CFU/mL/day) in aged mice (12-month-old) for 12 weeks significantly improved cognitive and depressive-and anxiety-like behaviors. The neuronal loss, the 5-HT metabolism dysfunction, and the neuroinflammation in the hippocampus of aged mice were restored by WHH2078 and WHH2080. the disturbances in the serum tryptophan metabolism in aged mice were unveiled by metabolomics, notably with decreased levels of 5-HT and 5-HTP, and increased levels of kynurenine, 3-hydroxykynurenine, and indolelactic acid, which were reversed by WHH2078 and WHH2080. Regarding the gut microbial community, WHH2078 and WHH2080 restored the increased abundance of Firmicutes, Desulfobacterota, and Deferribacterota and the decreased abundance of Bacteroidota and Actinobacteriota in aged mice. The beneficial effects of the two strains were linked to the modulation of 5-HT metabolism and gut microbiota. Our findings point to the potential role of Lactococcus strains with 5-HTP-promoting abilities as therapeutic approaches for age-related cognitive and mood disorders.

An enriched environment promotes cognitive recovery and cerebral blood flow in aged mice under sevoflurane anaesthesia.

Sevoflurane is an inhalation anaesthetic agent widely used in clinical settings. Despite good surgical outcomes using sevoflurane, patients frequently develop postoperative cognitive dysfunction (POCD). An enriched environment (EE), as a rehabilitation technique, could provide objects and tools to facilitate neuromotor and visual stimuli and brain activity, and is reported to improve cognitive functions. We aim to investigate the impairments of sevoflurane inhalation on cognitive function in mice and determine the benefits of EE in ameliorating POCD. Eighteen-month-old mice were exposed to sevoflurane inhalation for 2 h and then placed in standard environment (SE) or EE cages. The mice without sevoflurane exposure in standard or EE cages were used as controls. The behavioural tests include Morris water maze, Y maze and novel object recognition. Magnetic resonance imaging (MRI) was used to determine the blood circulation in the brains. The proangiogenic factors (CD31, angiopoietin-1, vascular endothelial growth factor, and N-cadherin) and neurotrophic (brain-derived neurotrophic factor, post-synaptic density protein 95) expression in hippocampus of aged mice were evaluated by Western blotting and RT-PCR analysis. Sevoflurane-exposed mice demonstrated reduced performance in learning, memory and spatial memory tests. Enriched environment improved the behavioural performance of sevoflurane-exposed animals. Sevoflurane exposure reduced the blood flow in the brains, and these effects were ameliorated by EE habitation. The EE also promoted the expression of angiogenic and neurotropic factors in sevoflurane-exposed animals. In summary, EE is effective in ameliorating the side-effects of sevoflurane exposure in aged mice.