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Ergothioneine (EGT) is a sulfur-containing amino acid with strong antioxidant activity. In this study, a D-galactose induced mouse aging model was used to investigate the anti-aging effects of EGT. EGT intervention could significantly improve the recognition memory of aging mice. Additionally, it improved the D-galactose induced decrease in the number of neurones, enhanced the levels of cAMP and BDNF in the brain, and increased the density and expression of PSD95 in aging mice. Meanwhile, EGT could attenuate oxidative stress by reducing the content of MDA and enhancing T-SOD activity via the Nrf2/HO-1 pathway. In addition, EGT could alleviate mitochondrial function by regulating the AMPK/SIRT1/PGC-1α pathway, which in turn attenuated D-galactose induced hippocampal neuronal injury and improved the learning and memory abilities in mice. This study provides a potential dietary strategy to improve age-induced memory impairment.

Background: Oxidative damage to the ovaries is the primary cause of impaired reproductive functions in female animals. This study aimed to investigate the protective role of N-Acetyl-L-cysteine (NAC) in reducing oxidative damage in the ovaries of female rabbits., Methods and Results: Female rabbit ovaries were treated in vitro with varying concentrations of D-galactose (D-gal): 0, 5, 10, and 15 mg/mL, and it was found that 10 mg/mL D-gal significantly disrupted follicular structures, causing disarray in granulosa cell arrangements and significantly reducing T-SOD and GSH levels (p < 0.01). Consequently, we selected 10 mg/mL D-gal to establish an ovarian failure model. These models were treated with multiple doses of NAC (0, 0.1, 0.3, 0.5 mg/mL). The results revealed that the disruption in granulosa cell arrangement caused by 10 mg/mL D-gal was effectively alleviated by 0.1 mg/mL NAC compared to the D-gal treatment group. Furthermore, 10 mg/mL D-gal significantly (p < 0.01) reduced GSH, T-SOD, and catalase (CAT) levels in the ovaries. However, 0.1 mg/mL NAC effectively (p < 0.01) suppressed these adverse effects. Moreover, the current results showed that 10 mg/mL D-gal alone significantly (p < 0.01) downregulated the expression of Nrf2, GPX, PRDX4, GSR, SOD1, and TAF4B, whereas 0.1 mg/mL NAC counteracted these suppressive effects (p < 0.01)., Conclusions: It could be concluded that NAC may delay ovarian failure by reducing D-gal-induced ovarian oxidative damage in female rabbit, suggested NAC could be a promising therapeutic agent for protecting against ovarian failure and potentially delaying ovarian failure in female rabbits., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aging is a natural and inevitable process of organisms. With the intensification of population aging, research on aging has become a hot topic of global attention. The most obvious manifestation of human aging is the aging of brain function, which has been linked to the development of neurodegenerative diseases. In this study, COP-22, a mono-carbonyl curcumin derivative, was evaluated for its anti-aging ability, especially its ability to resist brain aging induced by D-galactose (D-gal) in mice. For brain protection, COP-22 could resist D-gal-induced oxidative stress by increasing the activity of antioxidative defense enzymes and enhancing antioxidant capacity in the brain tissue; COP-22 could improve the dysfunction of the cholinergic system by decreasing the increased activity of acetylcholinesterase and increasing the reduced content of acetylcholine induced by D-gal; and COP-22 could protect nerve cells of the brain. Further, western blot was used to determine related proteins of the brain. We found that COP-22 could effectively protect against brain injury (SIRT1, p53, p21, and p16) by inhibiting oxidative stress (Nrf2 and HO-1), inflammation (IL-6 and TNF-α), and apoptosis (Bax and caspase-3) in D-gal-induced aging mice. Additionally, COP-22 demonstrated the ability to reduce oxidative stress in serum and liver caused by D-gal, as well as relieve the damages in the liver and kidney induced by D-gal. These results indicated that COP-22 had potential anti-aging activity and could be used in the therapy of aging and aging-associated diseases like Alzheimer disease., (© 2024. The Author(s).)

Objective: Icariin (ICA) has a good neuroprotective effect and can upregulate neuronal basal autophagy in naturally aging rats. Mitochondrial dysfunction is associated with brain aging-related neurodegenerative diseases. Abnormal opening of the mitochondrial permeability transition pore (mPTP) is a crucial factor in mitochondrial dysfunction and is associated with excessive autophagy. This study aimed to explore that ICA protects against neuronal injury by blocking the mPTP opening and down-regulating autophagy levels in a D-galactose (D-gal)-induced cell injury model., Methods: A cell model of neuronal injury was established in rat pheochromocytoma cells (PC12 cells) treated with 200 mmol/L D-gal for 48 h. In this cell model, PC12 cells were pre-treated with different concentrations of ICA for 24 h. MTT was used to detect cell viability. Senescence associated β-galactosidase (SA-β-Gal) staining was used to observe cell senescence. Western blot analysis was performed to detect the expression levels of a senescence-related protein (p21), autophagy markers (LC3B, p62, Atg7, Atg5 and Beclin 1), mitochondrial fission and fusion-related proteins (Drp1, Mfn2 and Opa1), and mitophagy markers (Pink1 and Parkin). The changes of autophagic flow were detected by using mRFP-GFP-LC3 adenovirus. The intracellular ultrastructure was observed by transmission electron microscopy. Immunofluorescence was used to detect mPTP, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS) and ROS levels. ROS and apoptosis levels were detected by flow cytometry., Results: D-gal treatment significantly decreased the viability of PC12 cells, and markedly increased the SA-β-Gal positive cells as compared to the control group. With the D-gal stimulation, the expression of p21 was significantly up-regulated. Furthermore, D-gal stimulation resulted in an elevated LC3B II/I ratio and decreased p62 expression. Meanwhile, autophagosomes and autolysosomes were significantly increased, indicating abnormal activation of autophagy levels. In addition, in this D-gal-induced model of cell injury, the mPTP was abnormally open, the ROS generation was continuously increased, the MMP was gradually decreased, and the apoptosis was increased. ICA effectively improved mitochondrial dysfunction to protect against D-gal-induced cell injury and apoptosis. It strongly inhibited excessive autophagy by blocking the opening of the mPTP. Cotreatment with ICA and an mPTP inhibitor (cyclosporin A) did not ameliorate mitochondrial dysfunction. However, the protective effects were attenuated by cotreatment with ICA and an mPTP activator (lonidamine)., Conclusion: ICA inhibits the activation of excessive autophagy and thus improves mitochondrial dysfunction by blocking the mPTP opening., (© 2024. Huazhong University of Science and Technology.)

Diet adjustment will affect the health of gut microbiota, which in turn influences the development and function of the organism's brain through the gut-brain axis. Walnut oil (WO), peony seed oil (PSO) and camellia seed oil (CSO), as typical representatives of woody plant oils, have been shown to have the potential to improve cognitive impairment in mice, but the function mechanisms are not clear. In this study, we comparatively investigated the neuroprotective effects of these three oils on D-galactose (D-gal)-induced cognitive impairment in mice, and found that the ameliorative effect of WO was more prominent. During the behavioral experiments, supplementation with all three oils would improve spatial learning and memory functions in D-gal mice, with a significant reduction in the error times ( p < 0.001) and a significant increase in step-down latency ( p < 0.001); walnut oil supplementation also significantly increased the number of hidden platform traversals, the target quadrant spent times and percentage of distance ( p < 0.05). The results of biomarker analysis showed that WO, in addition to significantly inhibiting D-gal-induced oxidative stress and neuroinflammation as did PSO, significantly increased the ACh content in the mouse brain ( p < 0.05) and modulated neurotransmitter levels. The results of further microbiota diversity sequencing experiments also confirmed that dietary supplementation with all three oils affected the diversity and composition of the gut microbiota in mice. Among them, WO significantly restored the balance of the mouse gut microbiota by increasing the abundance of beneficial bacteria ( Bacteroidetes , Actinobacteria , Firmicutes ) and decreasing the abundance of harmful bacteria ( Clostridium , Shigella , Serratia ), which was consistent with the results of behavioral experiments and biomarker analyses. Based on the analysis of the fatty acid composition of the three oils and changes in the gut microbiota, it is hypothesized that there is a correlation between the fatty acid composition of the dietary supplement oils and neuroprotective effects. The superiority of WO over PSO and CSO in improving cognitive impairment is mainly attributed to its balanced composition of omega-6 and omega-3 fatty acids.

The efficacy and safety of galacto-oligosaccharides (GOS) in treating functional constipation were evaluated in a four-week randomized, double-blind clinical trial on 63 patients who met Rome IV criteria (34 GOS, 29 placebo group). The number of bowel movements per day and changes in the shape of bowel movements in the treatment group significantly improved compared to those in the control group after four weeks. The Patient Assessment Constipation Quality of Life questionnaire showed that satisfaction with constipation significantly increased in the treatment group. The levels of Bifidobacterium sp. and Lactobacillus sp. significantly increased after four weeks of GOS treatment compared to those measured at baseline. No significant adverse drug reactions were identified in any indicator except for pulse rate. Thus, the prebiotic GOS can be safely used in foods and pharmaceuticals to alleviate symptoms of functional constipation by improving the intestinal flora.

Age-related structural and functional changes in the kidney can eventually lead to development of chronic kidney disease, which is one of the leading causes of mortality among elderly people. For effective management of age-related kidney complications, it is important to identify new therapeutic interventions with minimal side-effects. The present study was designed to evaluate the synergistic effect of a traditional Chinese herb, Alpinate Oxyphyllae Fructus (AOF), and adipose-derived mesenchymal stem cells (ADMSCs) in ameliorating D-galactose (D-gal)-induced renal aging phenotypes in WKY rats. The study findings showed that D-gal-induced alteration in the kidney morphology was partly recovered by the AOF and ADMSC co-treatment. Moreover, the AOF and ADMSC co-treatment reduced the expression of proinflammatory mediators (NFkB, IL-6, and Cox2) and increased the expression of redox regulators (Nrf2 and HO-1) in the kidney, which were otherwise augmented by the D-gal treatment. Regarding kidney cell death, the AOF and ADMSC co-treatment was found to abolish the proapoptotic effects of D-gal by downregulating Bax and Bad expressions and inhibiting caspase 3 activation. Taken together, the study findings indicate that the AOF and ADMSC co-treatment protect the kidney from D-gal-induced aging by reducing cellular inflammation and oxidative stress and inhibiting renal cell death. This study can open up a new path toward developing novel therapeutic interventions using both AOF and ADMSC to effectively manage age-related renal deterioration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Erigeron bonariensis is widely distributed throughout the world's tropics and subtropics. In folk medicine, E. bonariensis has historically been used to treat head and brain diseases. Alzheimer's disease (AD) is the most widespread form of dementia initiated via disturbances in brain function. Herein, the neuroprotective effect of the chemically characterized E. bonariensis ethanolic extract is reported for the first time in an AD animal model. Chemical profiling was conducted using UPLC-ESI-MS analysis. Female rats underwent ovariectomy (OVX) followed by 42 days of D-galactose (D-Gal) administration (150 mg/kg/day, i.p) to induce AD. The OVX/D-Gal-subjected rats received either donepezil (5 mg/kg/day) or E. bonariensis at 50, 100, and 200 mg/kg/day, given 1 h prior to D-Gal. UPLC-ESI-MS analysis identified 42 chemicals, including flavonoids, phenolic acids, terpenes, and nitrogenous constituents. Several metabolites, such as isoschaftoside, casticin, velutin, pantothenic acid, xanthurenic acid, C18-sphingosine, linoleamide, and erucamide, were reported herein for the first time in Erigeron genus. Treatment with E. bonariensis extract mitigated the cognitive decline in the Morris Water Maze test and the histopathological alterations in cortical and hippocampal tissues of OVX/D-Gal-subjected rats. Moreover, E. bonariensis extract mitigated OVX/D-Gal-induced Aβ aggregation, Tau hyperphosphorylation, AChE activity, neuroinflammation (NF-κBp65, TNF-α, IL-1β), and apoptosis (Cytc, BAX). Additionally, E. bonariensis extract ameliorated AD by increasing α7-nAChRs expression, down-regulating GSK-3β and FOXO3a expression, and modulating Jak2/STAT3/NF-ĸB p65 and PI3K/AKT signaling cascades. These findings demonstrate the neuroprotective and memory-enhancing effects of E. bonariensis extract in the OVX/D-Gal rat model, highlighting its potential as a promising candidate for AD management., (© 2024. The Author(s).)

Que Zui tea (QT) is an important herbal tea in the diet of the 'Yi' people, an ethnic group in China, and it has shown significant antioxidant, anti-inflammatory, and hepatoprotective effects in vitro. This study aims to explore the protective effects of the aqueous-ethanol extract (QE) taken from QT against ᴅ-galactose (ᴅ-gal)-induced oxidative stress damage in mice and its potential mechanisms. QE was identified as UHPLC-HRMS/MS for its chemical composition and possible bioactive substances. Thus, QE is rich in phenolic and flavonoid compounds. Twelve compounds were identified, the main components of which were chlorogenic acid, quinic acid, and 6'- O -caffeoylarbutin. Histopathological and biochemical analysis revealed that QE significantly alleviated brain, liver, and kidney damage in ᴅ-gal-treated mice. Moreover, QE remarkably attenuated oxidative stress by activating the Nrf2/HO-1 pathway to increase the expression of antioxidant indexes, including GSH, GSH-Px, CAT, SOD, and T-AOC. In addition, QE administration could inhibit the IL-1β and IL-6 levels, which suppress the inflammatory response. QE could noticeably alleviate apoptosis by inhibiting the expressions of Caspase-3 and Bax proteins in the brains, livers, and kidneys of mice. The anti-apoptosis mechanism may be related to the upregulation of the SIRT1 protein and the downregulation of the p53 protein induced by QE in the brain, liver, and kidney tissues of mice. Molecular docking analysis demonstrated that the main components of QE, 6'- O -caffeoylarbutin, chlorogenic acid, quinic acid, and robustaside A, had good binding ability with Nrf2 and SIRT1 proteins. The present study indicated that QE could alleviate ᴅ-gal-induced brain, liver and kidney damage in mice by inhibiting the oxidative stress and cell apoptosis; additionally, the potential mechanism may be associated with the SIRT1/Nrf2 signaling pathway.

Physical exercise reduces the effects of aging and cognitive decline by improving synaptic plasticity and spatial learning. However, the underlying neurobiological mechanisms are unclear. A total of 45 Male SPF Sprague-Dawley rats were acclimatized and then allocated into three groups, 15 in each group: the saline control (DC) group, D-gal-induced aging (DA) group, and D-gal-induced aging + exercise (DE) group. Six weeks of intraperitoneal injections of D-gal at a concentration of 100 mg/kg body weight/d was injected to establish model of aging in the DA and DE groups. Morris water maze test was implemented to evaluate the hippocampus related cognition. SOD activity and MDA was tested to assess the aging in all groups. H&E and Nissl staining was used to observe the histopathological changes of hippocampal neurons in aging rats. Quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining techniques were used to investigate the expression of synaptic genes and proteins in the hippocampus. Massarray methylation system was employed to measure the PDE-4 gene methylation level in rat hippocampal tissues. Our results demonstrated that exercise intervention improves cognitive function in D-gal-induced aging rats. The methylation of CpG sites in PDE-4 in the hippocampus was significantly increased. The physical exercise significantly increased PDE-4 gene methylation and effectively decreased PDE-4 gene and protein expression. These beneficial behavioral and morphological effects were attributed to PDE-4 methylation, which was activated cAMP/PKA/CREB pathway and improved synaptic plasticity. Exercise induced PDE-4 methylation is key mechanism underpinning the amelioration of learning/memory impairment, suggesting the potential efficacy of physical exercise training in delaying brain aging., (© 2023. The Author(s).)

Research Question: Is there a protective effect of the humanin derivative [Gly14]-humanin (HNG) on a D-gal-induced mouse model of primary ovarian insufficiency (POI), and what is the underlying mechanism?, Design: D-gal (200 mg/kg/day) was injected subcutaneously for 6 weeks to induce the mouse POI model. Mice treated with HNG were injected intraperitoneally with different concentrations for 6 weeks. Ovarian morphology, function, levels of sex hormones and states of oxidative stress in the ovary and body were evaluated., Results: Compared with the D-gal group, 10 mg/kg HNG improved the abnormal ovarian morphology and oestrous cycle (P = 0.0036), increased the number of ovarian follicles (P = 0.0016) and litters (P = 0.0127), and increased the levels of oestrogen (P = 0.0043) and AMH (P = 0.0147). Antioxidant indicators in the ovaries and serum of mice, including total antioxidant capacity (P = 0.0004 and P = 0.0032, respectively), catalase (P = 0.0173 and P = 0.0103, respectively) and glutathione (both P < 0.0001) were significantly increased. The oxidation indicator malondialdehyde decreased significantly (all P < 0.01). Apoptosis of ovarian granulosa cells was significantly reduced (P = 0.0140) as was the expression of senescence-related proteins p53, p21 and p16 (all P < 0.01). The level of autophagy in ovarian tissue of mice treated with high increased (significantly increased LC3 protein [P < 0.0001] and significantly reduced p62 protein [P = 0.0007])., Conclusions: HNG inhibited D-gal-induced oxidative stress, apoptosis and ovarian damage, promoting ovarian autophagy. HNG may be a potential prophylactic agent against POI., (Copyright © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Osthole, a natural coumarin found in various medicinal plants, has been previously reported to have neuroprotective effects. However, the specific mechanism by which Osthole alleviates dysmnesia associated with Alzheimer's disease (AD) remains unclear. This study aimed to investigate the neuroprotective properties of Osthole against cognitive impairment in rats induced by D-galactose and elucidate its pharmacological mechanism. The rat model was established by subcutaneously injecting D-galactose at a dose of 150 mg/kg/day for 56 days. The effect of Osthole on cognitive impairment was evaluated by behavior and biochemical analysis. Subsequently, a combination of in silico prediction and experimental validation was performed to verify the network-based predictions, using western blot, Nissl staining, and immunofluorescence. The results demonstrate that Osthole could improve memory dysfunction induced by D-galactose in Sprague Dawley male rats. A network proximity-based approach and integrated pathways analysis highlight two key AD-related pathological processes that may be regulated by Osthole, including neuronal apoptosis, i.e., neuroinflammation. Among them, the pro-apoptotic markers (Bax), anti-apoptotic protein (Bcl-2), the microgliosis (Iba-1), Astro-cytosis (GFAP), and inflammatory cytokines (TNF-R1) were evaluated in both hippocampus and cortex. The results indicated that Osthole significantly ameliorated neuronal apoptosis and neuroinflammation in D-galactose-induced cognitive impairment rats. In conclusion, this study sheds light on the pharmacological mechanism of Osthole in mitigating D-galactose-induced memory impairment and identifies Osthole as a potential drug candidate for AD treatment, targeting multiple signaling pathways through network proximity and integrated pathways analysis.

This study aims to explore the effect of preventive administration of Yigong Powder on the learning and memory abilities of the mouse model of aging induced by D-galactose and decipher the underlying mechanism, so as to provide a basis for the application of Yigong Powder in the prevention and treatment of cognitive decline. Forty KM mice were randomized into control, model, donepezil(1.5 mg·kg~(-1)), and high-dose(7.5 g·kg~(-1)) and low-dose(3.75 g·kg~(-1)) Yigong Powder groups. The mice in other groups except the control group were injected with D-galactose(200 g·kg~(-1)) at the back of the neck for the modeling of aging. At the same time, the mice were administrated with corresponding drugs by gavage for one month. Morris water maze was used to examine the learning and memory abilities of the mice. Hematoxylin-eosin staining was employed to observe the pathological and morphological changes of the hippocampus. The immunofluorescence assay was employed to detect the expression of ionized calcium-binding adapter molecule 1(IBA1), glial fibrillary acidic protein(GFAP), chemokine C-X-C-motif ligand 12(CXCL12), chemokine C-X-C-motif receptor 4(CXCR4) in the hippocampus and observe the positional relationship between IBA1, GFAP, and CXCR4. Western blot was employed to determine the protein levels of extracellular regulated kinase(ERK), p-ERK, and tumor necrosis factor receptor 1(TNFR1). Enzyme-linked immunosorbent assay was employed to measure the levels of glutamate and tumor necrosis factor(TNF-α) in the brain tissue and the level of TNF-α in the serum and spleen. Yigong Powder significantly shortened the escape latency, increased the times crossing platforms, and prolonged the cumulative time in quadrants of the aging mice. It alleviated the nerve cell disarrangement, increased intercellular space, and cell degeneration or death in the hippocampus and reduced the pathology score of the damaged nerve. Moreover, Yigong Powder reduced the positive area of IBA1 and GFAP, reduced the levels of TNF-α in the brain tissue, serum, and spleen, and decreased spleen index. Furthermore, Yigong Powder decreased the average fluorescence intensity of CXCL12 and CXCR4, reduced CXCR4-positive astrocytes and microglia, down-regulated the protein levels of p-ERK/ERK and TNFR1, and lowered the level of glutamate in the brain tissue. This study showed that the preventive administration of Yigong Powder can ameliorate the learning and memory decline of the D-galactose-induced aging mice by regulating the immune function of the spleen and the CXCL12/CXCR4 signaling in the brain to reduce glutamate release. However, the mechanism of Yigong San in preventing and treating dementia via regulating spleen and stomach function remains to be studied.

Aging is characterized by a decline in biological functions, leading to various health issues. There is significant interest in mitigating age and age-related health issues. Gut microbiota has emerged as a crucial target for combating aging and influencing host health. This study evaluated the anti-aging effects of Lactiplantibacillus plantarum CCFM8661 in mice and the role of the gut microbiota in mediating its effects. Aging was induced in mice using D-galactose, and L. plantarum CCFM8661 was orally administered for 8 weeks to evaluate its effects on age-related decline and the gut microbiota. The results demonstrated that supplementation with L. plantarum CCFM8661 effectively alleviated cognitive impairment and oxidative stress in the aging brain, as well as liver oxidation and bone damage, and impaired intestinal barrier function in aging mice. Furthermore, L. plantarum CCFM8661 modulated the gut microbiota of aging mice, increasing the abundance of beneficial bacteria, such as Ruminococcaceae, and influenced the functionality of the gut microbiota to promote the production of active metabolites. These findings suggest that L. plantarum CCFM8661 has a mitigating effect on organismal aging, especially brain aging.

Dysregulation of protein homeostasis, proteostasis, is a distinctive hallmark of many neurodegenerative disorders and aging. Deleteriously, the accumulation of aberrant proteins in Alzheimer's disease (AD) is accompanied with a marked collapse in proteostasis network. The current study explored the potential therapeutic effect of vardenafil (VAR), a phosphodiesterase-5 inhibitor, in AlCl 3 /D-galactose (D-gal)-induced AD in rats and its possible underlying mechanisms. The impact of VAR treatment on neurobehavioral function, hippocampal tissue architecture, and the activity of the cholinergic system main enzymes were assessed utilizing VAR at doses of 0.3 mg/kg and 1 mg/kg. Additionally, the expression level of amyloid-beta and phosphorylated tau proteins in the hippocampus were figured out. Accordingly, VAR higher dose was selected to contemplate the possible underlying mechanisms. Intriguingly, VAR elevated the cyclic guanosine monophosphate level in the hippocampus and averted the repressed proteasome activity by AlCl 3 /D-gal; hence, VAR might alleviate the burden of toxic protein aggregates in AD. In addition, a substantial reduction in the activating transcription factor 6-mediated endoplasmic reticulum stress was demonstrated with VAR treatment. Notably, VAR counteracted the AlCl 3 /D-gal-induced depletion of nuclear factor erythroid 2-related factor 2 level. Moreover, the anti-senescence activity of VAR was demonstrated via its ability to restore the balance of the redox circuit. The modulation of phosphatidylinositol-3-kinase/protein kinase B/p53 pathway and the reduction of nuclear factor kappa B level, the key regulator of senescence-associated secretory phenotype mediators release, with VAR treatment were also elucidated. Altogether, these findings insinuate the possible therapeutic benefits of VAR in AD management., (© 2023. The Author(s).)

Acteoside, an important phenylethanol glycoside, is the main active component in Osmanthus fragrans flower. Our previous study found that acteoside showed high antiaging effect but its absorption rate was low. We speculated acteoside palliated aging-related cognitive impairment before being absorbed, that was intestinal homeostasis underlie the antiaging effect of acteoside. In this study, acteoside was confirmed to palliate cognitive impairment in d-galactose induced aging mice. Acteoside treatment dramatically reduced oxidative stress, alleviated intestinal inflammation, restored intestinal mucosal barrier, rebuilt gut microbiome structure and upregulated gut microbiome metabolites short-chain fatty acids (SCFAs) and amino acids (AAs). Furthermore, antibiotic treatment revealed that the antiaging ability of acteoside was abolished in microbiota depleted mice, which offered direct evidence for the essential role of gut microbiota in the attenuation of cognitive impairment of acteoside. Together, our study indicated that acteoside palliated cognitive impairment by regulating intestinal homeostasisand acteoside intake might be a promising nutritional intervention in prevention of neurodegenerative diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

The onset and progression of Alzheimer's disease (AD) are influenced by a variety of factors. These include oxidative stress, overexpression of acetylcholinesterase (AChE), depletion of acetylcholine levels, increased beta-secretase mediated conversion of Amyloid Precursor Protein (APP) to Amyloid Beta (Abeta), accumulation of Abeta oligomers, decrease in Brain Derived Neurotrophic factor (BDNF) and accelerated neuronal apoptosis due to elevated levels of caspase-3. The currently available therapeutic approaches are inadequate in affecting these pathological processes except maybe the overexpression of AChE (AChE inhibitors like donepezil, rivastigmine). There is an urgent need to develop disease modifying pharmacotherapeutic interventions which have appreciable safety and cost effectiveness. From previously reported in vitro studies and a preliminary assessment of neuroprotective effect in scopolamine induced dementia-like cognitive impairment in mice, vanillin has been used as the compound of interest in the present study. Vanillin, a phytoconstituent, has been used in humans, safely, in the form of a flavouring agent for various foods, beverages, and cosmetics. Owing to its chemical nature i.e. being a phenolic aldehyde, it has an additional antioxidant property that is congruent to the desirable characteristics that are sought in a suitable novel anti-AD agent. In our study, vanillin proved to have a nootropic effect in healthy Swiss albino mice as well as an ameliorative effect in aluminium chloride and D-galactose induced AD model in mice. Apart from tackling oxidative stress, vanillin was found to reduce the levels of AChE, beta secretase, caspase-3, enhance degradation of Abeta plaques and elevate the levels of BDNF, in cortical and hippocampal regions. Vanillin is a promising candidate for being incorporated into the search for safe and effective anti-AD molecules. However, further research might be needed to warrant its application clinically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: We previously showed that aging accelerates after 3 months of exposure to hypoxia and environmental change but not genetic modifications. Here, we aimed to simply induce early-onset age-related hearing loss within a short period based on our previous method., Methods: We randomly divided 16 C57BL/6 mice into four groups that were maintained under conditions of normoxia and hypoxia with or without injected D-galactose for 2 months. Deteriorated hearing, the expression of age-related factors, and oxidative stress responses were detected using the click and tone burst auditory brainstem response test, reverse transcription-polymerase chain reaction, and by measuring superoxide dismutase (SOD)., Results: The group maintained under hypoxia combined with D-galactose lost hearing particularly at 24 Hz and 32 Hz at 6 weeks compared with the other groups. Aging-related factors were also significantly decreased in the hypoxia and D-galactose groups. However, SOD levels did not significantly differ among the groups., Conclusion: Age-related hearing loss is an environmental disorder induced by chronic oxidative stress associated with genetic backgrounds. Our findings suggested that D-galactose and hypoxia can induce the phenotypes of age-related hearing loss and aging-associated molecules in a murine model within a short time with environmental stimulation alone., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C. A. Meyer exerted obvious memory-enhancing and antiaging effects, and the simpler the structure of ginsenosides, the better the biological activity. In this work, we aimed to explore the therapeutic effect and underlying molecular mechanism of 20(S)-protopanaxatriol (PPT), the aglycone of panaxatriol-type ginsenosides, by establishing D-galactose (D-gal)-induced subacute brain aging model in mice. The results showed that PPT treatment (10 and 20 mg/kg) for 4 weeks could significantly restore the D-gal (800 mg/kg for 8 weeks)-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Meanwhile, PPT also significantly reduced the histopathological changes caused by D-gal exposure. Moreover, PPT could increase TFEB/LAMP2 protein expression to promote mitochondrial autophagic flow. Importantly, the results from molecular docking showed that PPT had good binding ability with LAMP2 and TFEB, suggesting that TFEB/LAMP2 might play an important role in PPT to alleviate D-gal-caused brain aging., (© 2023 John Wiley & Sons Ltd.)

Oxidative stress results from the imbalance between reactive oxygen species (ROS) production and antioxidant defence and is primarily involved in aging. The current study investigated the antioxidant activity of rutin in aging in rats induced by D-galactose (D-gal) for 42 days. Rutin was orally used at doses of 50 and 100 mg kg -1 daily. Results showed that D-gal induced oxidative alterations in the brain and liver recognized via upregulation of aging and oxidative markers. In contrast, rutin ameliorated the oxidative stress induced by D-gal by enhancing antioxidant markers such as superoxide dismutase-1, glutathione peroxidase-1, and glutathione S-transferase- α . Also, rutin significantly decreased the accumulation of β -galactosidase and reduced the expression of p53 , p21 , Bcl-2-associated X protein ( Bax ), caspase-3 ( CASP3 ), and mammalian target of rapamycin ( mTOR ) in brain and hepatic tissues. Rutin potentially attenuated these aging-related oxidative alterations in a dose-dependent manner. Moreover, rutin markedly reduced the increased immunohistochemical expression of β -galactosidase, 8-hydroxy-2'-deoxyguanosine, calcium-binding adapter molecule 1, glial fibrillary acidic protein, Bax, and interleukin-6 and significantly increased Bcl2, synaptophysin, and Ki67. Furthermore, a molecular docking study revealed that rutin exhibited high affinity to rat and human caspases, PI3K/AKT/mTOR, and the IL-6 receptor. Finally, we can conclude that rutin supplementation can be a promising natural protective compound that could delay aging and maintain health.

Mitochondrial inflammation triggered by abnormal mitochondrial division and regulated by the Drp1/HK1/NLRP3 pathway is correlated with the progression of aging-associated cognitive impairment (AACI). Alpinetin is a novel flavonoid derived from Zingiberaceae that has many bioactivities such as antiinflammation and anti-oxidation. However, whether alpinetin alleviates AACI by suppressing Drp1/HK1/NLRP3 pathway-inhibited mitochondrial inflammation is still unknown. In the present study, D-galactose (D-gal)-induced aging mice and BV-2 cells were used, and the effects of alpinetin on learning and memory function, neuroprotection and activation of the Drp1/HK1/NLRP3 pathway were investigated. Our data indicated that alpinetin significantly alleviated cognitive dysfunction and neuronal damage in the CA1 and CA3 regions of D-gal-treated mice. Moreover, D-gal-induced microglial activation was markedly reduced by alpinetin by inhibiting the Drp1/HK1/NLRP3 pathway-suppressed mitochondrial inflammation, down-regulating the levels of p-Drp1 (s616), VDAC, NLRP3, ASC, Cleaved-caspase 1, IL-18, and IL-1β, and up-regulating the expression of HK1. Furthermore, after Drp1 inhibition by Mdivi-1 in vitro, the inhibitory effect of alpinetin on Drp1/HK1/NLRP3 pathway was more evident. In summary, the current results implied that alpinetin attenuated aging-related cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation, suggesting that the inhibition of the Drp1/HK1/NLRP3 pathway is one of the mechanisms by which alpinetin attenuates AACI., (© 2023 John Wiley & Sons Ltd.)

Anti-Alzheimer's disease (AD) drugs can only change the symptoms of cognitive impairment in a short time but cannot prevent or completely cure AD. Thus, a more effective drug is urgently needed. Cornuside is extracted from Corni Fructus, a traditional Chinese medicine that plays an important role in treating dementia and other age-related diseases. Thus, the study aimed to explore the effects and mechanisms of Cornuside on the D-galactose (D-Gal) induced aging mice accompanied by cognitive decline. Initially, we found that Cornuside improved the learning and memory abilities of D-Gal-treated mice in behavioral experiments. Pharmacological experiments indicated that Cornuside acted on anti-oxidant and anti-inflammatory effects. Cornuside also reversed acetylcholin esterase (AChE) activity. Meanwhile, pathology tests showed that Cornuside had a protective effect on neuron damage. Cornuside increased the expression of brain-derived neurotrophic factor (BDNF), and down-regulated the expression of receptor for advanced glycosylation end products (RAGE), ionized calcium binding adapter molecule 1 (Iba1), and glial fibrillary acidic protein (GFAP) respectively. Further studies claimed that Cornuside had important effects on the expression of IκBα and extracellular signal-regulated kinases 1/2 (ERK1/2). These effects might be achieved through regulating the AGEs-RAGE-IκBα-ERK1/2 signaling pathway, among which, ERK1/2 might be the key protein. The study provides direct preclinical evidence for the research of Cornuside, which may become an excellent candidate drug for the treatment of aging-related AD., (© 2023 John Wiley & Sons Ltd.)

In this work, RLWPF (Arg-Leu-Trp-Pro-Phe) and VLRLF (Val-Leu-Arg-Leu-Phe) were investigated for the effects against D-galactose (D-gal) induced cognitive impairment by modulating the gut microbiota composition. The effects on serum metabolite production were further investigated. The two novel peptides derived from walnut protein alkaline protease hydrolysates were predicted by docking to acetylcholinesterase (AChE) with the highest binding affinities, -10.3 and -9.9 kcal mol -1 , considered as the potential neuroprotective peptides. In behavioral experiments, RLWPF and VLRLF treatment significantly restored spatial learning and memory impairment induced by D-gal. The results showed that RLWPF and VLRLF could alleviate cholinergic dysfunction, oxidative stress, and inflammation to varying degrees caused by D-gal-induced aging. Furthermore, 16S rRNA analysis revealed that RLWPF and VLRLF treatment improved cognitive impairment by regulating the composition of the gut microbiota and the abundance of harmful bacteria, including the ratio of Firmicutes to Bacteroidetes , Helicobacter , Allobaculum , Alistipes , Mucispirillum , and Odoribacter . In addition to the same regulation, RLWPF and VLRLF had their marker and regulatory flora. Studies based on the gut microbiota would allow a better understanding of the neuroprotective effects of walnut-derived peptides, supporting that walnut-derived peptides could be potential functional ingredients in foods and nutraceuticals or drug candidates in the treatment of cognitive dysfunction.

Objective: To investigate the efficacy of Gouqizi () seed oil (FLSO) on D-gal induced inflammation in testis of rats and ., Methods: In aging Sertoli cells (TM4 cells) induced by D-galactose (D-gal), the expression of upregulated aging-related proteins. The number of cells counted by cell counting kit (CCK)-8 assay showed a high number of cells disposed with FLSO at 50, 100 and 150 μg/mL compared to that for the aging model. , male Sprague-Dawley rats ( = 50, 8-week-old, 230-255 g) were randomly categorized into control, aging model, and FLSO (low-, medium-, and high-dose) groups. The expression of nuclear factor-κB (NF-κB) and its upstream factors [Janus kinase 1 (JAK1) and signal transducerand activator of transcription 1 (STAT1)] was detected by Western blot and immunofluorescence, related inflammatory factors quantified by enzyme-linked immunosorbent assay. Evaluation of testicular tissue by Johnsen score, the spermatogenic function was explored., Results: The expression of interleukin-1β (IL-1β) ( < 0.05), IL-6 ( < 0.001), and tumor necrosis factor α (TNF-α) ( < 0.05) was decreased significantly, while that of heme oxygenase-1 (HO-1) ( < 0.001) and IL-10 ( < 0.05) was increased in cells disposed with FLSO 100 μg/mL. FLSO inhibited the expression of NF-B and declined p-p65/p65 ( < 0.01), as detected by Western blotting. In, the levels in serum of IL-1β ( < 0.001), IL-6 ( < 0.05), and TNF-( < 0.01) declined while IL-10 ( < 0.05) was upregulated post-FLSO treatment. In addition, the expression of JAK-1 and STAT1 increased significantly in testicular tissue of rats treated with FLSO as compared to the aging model of rats ( < 0.001), while the expression of NF-κB ( < 0.001) declined in the testis in the FLSO group, as assessed by immunofluorescence. The levels of inhibor B and testosterone in serum both increased (< 0.05)., Conclusions: In conclusion, this study determined the protective effects of FLSO to tolerate inflammatory injury in the testis, indicating that FLSO alleviates inflammation JAK-1/STAT1/NF-κB pathway.

Chlorogenic acid (CGA) and epigallocatechin-3-gallate (EGCG) are major polyphenolic constituents of coffee and green tea with beneficial health properties. In this study, we evaluated the gut protecting effect of CGA and EGCG, alone or in combination, on D-galactose-induced aging mice. CGA plus EGCG more effectively improved the cognition deficits and protected the gut barrier function, compared with the agents alone. Specifically, CGA plus EGCG prevented the D-galactose mediated reactive oxygen species accumulation by increasing the total antioxidant capacity, reducing the levels of malondialdehyde, and suppressing the activity of the antioxidant enzymes superoxide dismutase and catalase. In addition, supplementation of CGA and EGCG suppressed gut inflammation by reducing the levels of the proinflammatory cytokines TNFα, IFNγ, IL-1β and IL-6. Moreover, CGA and EGCG modulated the gut microbiome altered by D-galactose. For instance, CGA plus EGCG restored the Firmicutes/Bacteroidetes ratio of the aging mice to control levels. Furthermore, CGA plus EGCG decreased the abundance of Lactobacillaceae, Erysipelotrichaceae, and Deferribacteraceae, while increased the abundance of Lachnospiraceae, Muribaculaceae, and Rikenellaceae, at the family level. In conclusion, CGA in combination with EGCG ameliorated the gut alterations induced by aging, in part, through antioxidant and anti-inflammatory effects, along with its gut microbiota modulatory capacity.

Oxidative stress and neuroinflammation play crucial roles in aging. S-adenosylmethionine (SAM), a popular supplement, is a potential antioxidant and candidate therapy for depression. This study aimed to evaluate the neuroprotective effects of SAM on D-galactose-induced brain aging and explore its underlying mechanisms. Brain aging model was established with D-galactose (180 mg/kg/day) for 8 weeks. During the last 4 weeks, SAM (16 mg/kg) was co-administrated with D-galactose. Behavior tests were used to assess cognitive function and depression-like behaviors of rats. Results showed that cognitive impairment and depression-like behaviors were reversed by SAM. SAM reduced neuronal cell loss, increased brain-derived neurotrophic factor level in the hippocampus, inhibited amyloid-β level and microglia activation, as well as pro-inflammatory factors levels in the hippocampus and serum. Further, SAM enhanced antioxidant capacity and attenuated cholinergic damage by reducing malondialdehyde levels, increasing acetylcholine levels, expression levels of α7 nicotinic acetylcholine receptor (α7nAChR), nuclear factor erythrocyte 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the hippocampus. Above all, SAM has a potential neuroprotective effect on ameliorating cognitive impairment in brain aging, which is related to inhibition of oxidative stress and neuroinflammation, as well as α7nAChR signals. DATA AVAILABILITY: Data will be made available on request., Competing Interests: Declaration of Competing Interest All the authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Polygonatum cyrtonema Hua is cultivated for its edible and medical value. The steam-processed rhizome of P. cyrtonema is the main form for daily consumption and it has been used traditionally in tonics for treating various age-related disorders. The aim of our study was to compare the physicochemical properties and antioxidant activity of polysaccharides respectively extracted from crude P. Cyrtonema (PCPC), and steam-processed P. cyrtonema (PCPS), and to explore a possible underlying antioxidant mechanism., Results: The PCPC with a molecular weight of 4.35 × 10 3  Da mainly consisted of fructose and trace amounts of glucose, whereas PCPS with 4.24 × 10 4  Da was composed of fructose, arabinose, glucose, xylose, mannose, galacturonic acid and glucuronic acid. The PCPC had a triple-helical conformation whereas PCPS was a random coil. Both exhibited free radicals- scavenging activity in vitro. In a mouse model of oxidative damage, PCPC or PCPS treatment significantly reversed histopathological alterations, reactive oxygen species (ROS) accumulation and the reduction of antioxidant enzyme activity. They both also promoted Nrf2 nuclear transport by decreasing Keap-1 expression and increasing HO-1 expression. Both in vitro and in vivo, PCPS exhibited more potent antioxidant activity than PCPC., Conclusion: Overall, the results suggest that PCPS has a stronger effect on the prevention of oxidative damage by activating Nrf2/HO-1 antioxidant signaling. This study demonstrates the role of steam-processed P. cyrtonema rhizome and provides valuable perspective for PCPS as a functional agent. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Background: To thoroughly explore the values of Cinnamomum cassia leaf residues (CcLR), their antioxidant activity in vivo and the relationship with gut microbiota were investigated using d-galactose-induced aging mice., Results: Results showed that CcLR extract treatment exerted antioxidant activity by increasing the levels of superoxide dismutase (P < 0.01) and glutathione peroxidase (P < 0.05), as well as inhibiting the formation of malondialdehyde (P < 0.01). Meanwhile, the inflammatory response was also alleviated as the ratio of pro-inflammatory tumor necrosis factor-α (P < 0.01) and interleukin-1β (P < 0.01))/anti-inflammatory cytokines (interleukin-10; P < 0.05) in serum was decreased and the contents of inflammatory markers (induced nitrogen monoxide synthase and nitric oxide) in brain and liver tissues (P < 0.01) were reduced. Moreover, through inhibiting acetylcholinesterase activity and improving choline acetyltransferase activity, the cholinergic system in aging mice recovered to levels comparable to the normal control group. In addition, 16S rRNA sequencing results demonstrated that CcLR extract promoted the growth of beneficial bacteria. In particular, Spearman correlation analysis revealed that the abundance of Colidextribacter was negatively correlated with serum superoxide dismutase (P < 0.05, R = -0.943), and Helicobacter displayed a positive correlation with the content of brain nitric oxide (P < 0.05, R = 0.899), suggesting that regulating gut microbiota might be one of the mechanisms for reducing oxidative stress, thus postponing the aging process., Conclusion: It is suggested that CcLR extract could be used as a novel antioxidant and anti-aging resource in the pharmaceutical and food industries. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Background: The link between immediate hypersensitivity reactions (HSR) following the first cetuximab infusion and the IgE sensitization against anti-galactose-α-1,3-galactose (α-Gal) is now well-established. An automated Fluoroenzyme-Immunoassay (FEIA) is available and may facilitate the screening of patients with anti-α-Gal IgE before treatment., Methods: This study aimed to evaluate its performances as compared to a previously validated anti-cetuximab IgE ELISA, using 185 samples from two previously studied cohorts., Results: Despite 21.1% of discrepancies between the two techniques, FEIA discriminated better positive patients and similarly negative ones with a ≥ 0.525 kU A /L threshold. Sensitivity was 87.5% for both tests, specificity was better for FEIA (96.3% vs ELISA: 82.1%). FEIA had a higher positive likelihood ratio (23.9 vs ELISA: 4.89) and a similar negative likelihood ratio (0.13 vs ELISA: 0.15). In our population, the risk of severe HSR following a positive test was higher with FEIA (56.7% vs ELISA: 19.6%) and similar following a negative test (0.7% vs ELISA: 0.8%)., Conclusion: Although the predictive value of the IgE screening before cetuximab infusion remains discussed, this automated commercial test can identify high-risk patients and is suitable for routine use in laboratories. It could help avoiding cetuximab-induced HSR by a systematic anti-α-Gal IgE screening before treatment., (© 2023. The Author(s).)

Dietary methionine restriction (MR) has been shown to delay aging and ameliorate age-related cognitive impairments. We hypothesized that changes in the gut microbiota may mediate these effects. To test this hypothesis, ICR mice subcutaneously injected with 150 mg kg -1 day -1 D-galactose were fed a normal (0.86% methionine) or an MR (0.17% methionine) diet for 2 months. Multiple behavioral experiments were performed, and the gut microbiota composition, metabolite profiles related to short-chain fatty acids (SCFAs) in the feces, and indicators related to the redox and inflammatory states in the hippocampus were further analyzed. Our results indicated that MR alleviated cognitive impairment (including non-spatial memory deficits, working memory deficits, and hippocampus-dependent spatial memory deficits) and anxiety-like behavior in D-Gal-induced aging mice. Furthermore, MR increased the abundance of putative SCFA-producing bacteria such as Lachnospiraceae, Turicibacter , Roseburia , Ruminococcaceae&#95;UCG-014 , Intestinimonas , Rikenellaceae, Tyzzerella , and H 2 S-producing bacteria such as Desulfovibrio in feces. Moreover, MR reversed and normalized the levels of intestinal SCFAs (acetate, propionate, and butyrate) and important intermediate metabolites of the SCFAs (pyruvate, lactate, malate, fumarate, and succinate), abolished aging-induced oxidative stress and inflammatory responses, increased the levels of H 2 S in the plasma and hippocampus, and selectively modulated the expression of multiple learning- and memory-related genes in the hippocampus. These findings suggest that MR improved the gut microbiota composition and SCFA production and alleviated oxidative stress and inflammatory responses in the hippocampus, which might prevent cognitive impairment in D-galactose-induced aging mice.

Dendrobium huoshanense C. Z. Tang et S. J. Cheng polysaccharide (DHP) is the essential active ingredient of D.huoshanense and has high medicinal value. A high dose of D-galactose (D-gal) is commonly utilized in the aging model establishment. In this study, we explored whether DHP shields PC12 cells and aging mice from D-gal caused damage and the possible mechanism. In vitro experiments, D-gal induced PC12 cells were used to investigate, and then DHP was used for treatment. In vivo experiments, 72 SPF ICR male mice were randomly divided into six groups (control: normal saline; model: D-gal (400 mg/kg); VE group: VE (50 μg/ml); DHP groups: D-gal + DHP (15.6 mg/ml; 31.2 mg/ml; 62.4 mg/ml)). The results showed that DHP could enhance the viability of D-gal injured PC12 cells and prevent cell apoptosis. DHP effectively promoted the transition from phase G0/G1 to phase S and inhibited cell cycle arrest. DHP has a potential neuroprotective effect on D-gal caused cognitive and memory disorders in mice. On the one hand, DHP protects the antioxidant enzymes SOD, GSH-PX, and CAT from excessive ROS buildup. On the other hand, DHP was demonstrated to block the expression of the P53/P21 signaling pathway-related proteins P53, P21, and P16. These results imply that DHP could be a potential neuroprotective agent against aging. PRACTICAL APPLICATIONS: Cognitive and memory decline caused by aging problems has become a problem in recent years. There are many theories about aging, among which oxidative stress is considered to be one of the important pathophysiological parts of various diseases in the aging process. In this study, DHP could not only improve the damage of D-Gal to PC12 cells, but also improve the cognitive and memory impairment caused by D-Gal in mice. In conclusion, this study verified the anti-aging effect of DHP from in vitro and in vivo experiments, and its mechanism may involve the P53/P21 pathway. Therefore, this study indicated that polysaccharides from Dendrobium huoshanense, a traditional Chinese medicine of homologous medicine and food, had potential and industrial value as potential anti-aging drugs., (© 2022 The Authors. Journal of Food Biochemistry published by Wiley Periodicals LLC.)

Disruption of the blood-brain barrier (BBB) has been observed in several neurological diseases. This study explored the protective effect of the walnut-derived peptide TWLPLPR (TW-7) against d-galactose (d-gal)-induced cognitive disturbance in mice and its potential protection mechanism in β-amyloid 25-35 (Aβ 25-35 )-injured bEnd.3 cells. TW-7 improved the learning ability and memory of the cognitive impairment mice. Transmission electron microscopy showed that the BBB integrity in the hippocampus was restored; while immunofluorescence analysis and western blotting indicated that the protection of BBB integrity was associated with increased expression levels of tight junction (TJ) proteins. In Aβ 25-35 -damaged bEnd.3 cells, treatment with a matrix metalloproteinase 9 (MMP-9) activator and inhibitor confirmed that TW-7 partially reduced MMP-9 expression and increased zonula occludin-1 (ZO-1) and Claudin-5 expression. Furthermore, TW-7 reduced MMP-9 levels by forming stable complexes with it and by inhibiting the NF-κB p65/iNos pathway. These data suggested that TW-7 maintains BBB integrity by inhibiting the expression and activity of MMP-9, and TW-7 improves learning and memory ability in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To investigate the effects of RRT (Rosa roxburghii Tratt) glucosides and quercetin on oxidative stress and chronic inflammation in D-galactose-induced aging mice, 90 mice (8 weeks old) were randomly divided into the normal group (NC), aging model group (D-gal), isoquercitrin group (D-gal+isoquercitrin), quercitrin group (D-gal+quercitrin), quercetin group (D-gal+quercetin) and positive control group (D-gal+Metformin). The aging model was established by subcutaneous injection of D-galactose (100 mg/kg). After 42 days of the administration, antioxidant and inflammatory indexes were measured, HE staining was used to investigate pathological changes in liver and brain tissue, and Western blot was used to determine the protein abundance of nuclear factor E2-related factor (Nrf2) and heme oxygenase (HO-1) in the brain. The results showed that, when compared to the NC group, the D-gal group had a significantly lower brain, liver, kidney, and spleen indexes; the contents of MDA, L-1β, IL-6, and TNF-α in serum, liver, and brain were significantly higher, but the levels of CAT, SOD, and GSH-Px were significantly lower. Isoquercitrin, quercitrin, and quercetin significantly increased organ indexes and activities of CAT, SOD, and GSH-Px while decreasing MDA, IL-1β, IL-6, and TNF-α levels in serum, liver, and brain tissues compared to the D-gal group. The morphological changes in the brain and liver tissue were significantly restored by glycosides and quercetin, as observed in HE staining. Furthermore, Western blot results revealed that glycosides and quercetin increased the protein levels of Nrf2, HO-1, and NQO1. Finally, the antioxidant and anti-inflammatory effects of RRT glycoside and quercetin in aging may be attributed to an activated Nrf2/HO-1 signaling pathway. PRACTICAL APPLICATIONS: Aging is characterized by physical changes and dysfunction of numerous biological systems caused by a variety of factors. The oxidative stress and inflammatory effects of RRT glycosides and quercetin on D-galactose-induced aging mice were investigated in this study. RRT glycosides and quercetin were found to protect organ atrophy, liver, and brain tissue in aging mice by regulating oxidative stress and chronic inflammation. It served as the theoretical foundation for the investigation of Rosa roxburghii Tratt as a health product and pharmaceutical raw material., (© 2022 Wiley Periodicals LLC.)

Background: Aging causes decreased antioxidant capacity and chronic inflammation and may even elevate cancer risks. Previous studies reported that flaxseed oil (FO) can alleviate age-related diseases, including improving alcoholic liver disease, atherosclerosis and diabetes. However, whether the intestinal microbiota accountable for this alleviation is still unknown. This study aims to study the antioxidant effects of FO in an aging rat model and the underlying mechanism between the intestinal microbiota and aging., Results: Our results presented that serum and liver antioxidant capacities in FO group were up-regulated, and liver inflammation in FO group was reduced. The 16S rDNA sequencing showed that FO regulated the microbial community, including up-regulation of four families of Lactobacillus and six families of Clostridium. In addition, FO had also adjusted the relative abundance of several genera such as Ruminococcaceae&#95;UCG-005 and Prevotella&#95;9, which may be the key bacteria associated with the aging process. Colonic transcriptome analysis showed that there were 1679 differentially expressed genes (DEGs) in the Model group and the FO group (134 up-regulated and 1545 down-regulated). Gene set enrichment analysis (GSEA) revealed FO down-regulates the expression of the upstream genes Ptprc, Lck, Zap70, Lat and Lcp2 in the T cell receptor signaling pathway., Conclusion: In conclusion, FO improved antioxidant capacity and reduced intestinal microbial disturbances caused by aging damage, indicating that dietary FO has the potential to fight aging damage. This study provides a more comprehensive view of dietary intervention to improve aging. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

The study aimed to determine whether gut-brain communication could be modulated by epigallocatechin-3-gallate (EGCG) in a mouse aging model that was established by daily injection of D-galactose (D-gal) for 10 weeks. Our results showed that EGCG could improve aging-associated changes by increasing the immune organ indexes, brain index, and learning and memory ability in vivo . EGCG-triggered aging prevention was associated with the reduction of lipid peroxidation and elevation of enzymatic and non-enzymatic antioxidant activities in the brain. Concomitantly, treatment of D-gal-induced aging in mice with EGCG significantly reduced corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone, suggesting that EGCG-exerted protection of the aging brain was involved in the inhibition of the hypothalamic-pituitary-adrenal (HPA) axis. Further data concerning intestinal function showed that EGCG could enhance fecal moisture in vitro and reduce the pH value of feces in aging mice when compared to the D-gal group, suggesting that EGCG played beneficial roles in the intestine of aging mice. Moreover, short-chain fatty acids (SCFAs), the mediators of gut-brain communication, were significantly increased in the intestinal contents of aging mice by treatment with EGCG. Therefore, the tea polyphenol EGCG showing anti-aging properties was demonstrated to be implicated in modulating gut-brain communication by attenuating the HPA axis and enhancing the content of SCFAs.

We aimed to compare the ovarian reserve of rats exposed to oral D-galactose during prenatal and early life with rats exposed to D-galactose only during the prenatal period. Fifteen female pregnant Wistar rats were randomly divided into three groups. The first and second groups were fed a D-galactose enriched diet (35%) from the third day of pregnancy to parturition (PP) and the third day to the end of lactation (PL), respectively. The control group (C group) was fed a standard diet. The study population was the female offspring of three groups (PP', PL', and C'), in which some reproductive factors were examined between 45 and 50 days of age. When compared with the PP' group, the number of primordial follicles was significantly higher in the PL' group at PND 45-50 (40 vs. 30; p = .01); however, the antimullerian hormone level was significantly reduced in the PL' group versus control group (-2.2, 95% confidence interval [CI]: -2.83, -1.53 ng/ml p = .000), and follicle-stimulating hormone level significantly increased in PP' group versus control (4.5 mIU/ml, 95% CI: 1.40-7.62, p = .005). There was no significant difference in leukocyte infiltration or antiovarian antibody among the groups. Continued exposure to D-galactose during the lactation period inhibits the primordial follicle loss in rats in terms of producing fewer atretic follicles., (© 2022 Wiley Periodicals LLC.)

Age-associated loss of skeletal muscle mass and function is one of the main causes of the loss of independence and physical incapacitation in the geriatric population. This study used the D-galactose-induced C2C12 myoblast aging model to explore whether nobiletin (Nob) could delay skeletal muscle aging and determine the associated mechanism. The results showed that Nob intervention improved mitochondrial function, increased ATP production, reduced reactive oxygen species (ROS) production, inhibited inflammation, and prevented apoptosis as well as aging. In addition, Nob improved autophagy function, removed misfolded proteins and damaged organelles, cleared ROS, reduced mitochondrial damage, and improved skeletal muscle atrophy. Moreover, our results illustrated that Nob can not only enhance mitochondrial function, but can also enhance autophagy function and the protein synthesis pathway to inhibit skeletal muscle atrophy. Therefore, Nob may be a potential candidate for the prevention and treatment of age-related muscle decline.

Oudemansiella raphanipies , also called "Edible Queen," is a mushroom that possesses antioxidant, anti-inflammatory, anti-bacterial, anti-tumor and immunity-enhancing properties. The present study aimed to assess the effect of O. raphanipies -derived polysaccharide (ORPS) on the progression of nonalcoholic fatty liver disease (NAFLD) in mice. We studied the structure of ORPS-1 by high-performance gel permeation chromatography (HPGPC), ion chromatography-mass spectrometry (GC-MS), and Fourier transform-infrared spectroscopy (FT-IR). ORPS-1 mainly comprised galactose, fucose, glucose, mannose, and xylose, following an 18:6:6:4:1 molar ratio. In addition, the therapeutic effect as well as a potential mechanism of ORPS-1 in the treatment of high-fat diet (HFD)-induced NAFLD were investigated. The results showed that ORPS-1 improved liver function, ameliorated liver steatosis, and reduced lipid droplet accumulation in HFD mice. A metabolomics approach with GC-MS was utilized to evaluate liver improvement by ORPS-1 treatment. Principal component analysis showed that liver metabolic profiling was significantly altered by HFD feeding or treatment with an intermediate dose of ORPS-1 in mice compared with that of control mice. By investigating the metabolic pathways with identified biomarkers, various pathways such as steroid biosynthesis, valine, leucine, and isoleucine biosynthesis, glycerol phospholipid metabolism, glyceride metabolism, and arginine and proline metabolism in HFD mice were observed to be significantly influenced by ORPS-1 treatment. The results indicate ORPS-1 metabolic effects on liver tissues, provide methods for assessing the molecular impact of ORPS-1 on NAFLD, and suggest the potential mechanism underlying its health benefits.

Polysaccharide from Polygonatum sibiricum (PSP) possesses antioxidant, antiaging, and neuroprotective activities. However, whether and how the steaming process influences the biological activities of PSP, especially against aging-related memory impairment, is not yet known. In this study, Polygonatum sibiricum rhizome was subjected to a "nine steaming and nine drying" process, then PSPs with different steaming times were abstracted. Thereafter, the physicochemical properties were qualified; the antioxidant activities of PSPs were evaluated in a D-gal-induced HT-22 cell model, and the effects of PSPs (PSP0, PSP5 and PSP9) on memory was evaluated using D-gal-injured mice. Our results showed that while the steamed PSPs had a low pH value and a large negative charge, they shared similar main chains and substituents. Cellular experiments showed that the antioxidant activity of steamed PSPs increased. PSP0, PSP5, and PSP9 could significantly ameliorate the memory impairment of D-gal-injured mice, with PSP5 showing the optimal effect. Meanwhile, PSP5 demonstrated the best effect in terms of preventing cell death and synaptic injury in D-gal-injured mice. Additionally, the steamed PSPs increased anti-oxidative stress-related protein expression and decreased inflammation-related protein expression in D-gal-injured mice. Collectively, the steaming process improves the effects of PSPs against D-gal-induced memory impairment in mice, likely by increasing the antioxidant activity of PSPs.

Probiotics and prebiotics have received attention in alleviating neurodegenerative diseases. Lactobacillus plantarum ( L. plantarum ) 69-2 was combined with galactooligosaccharides (GOS) and supplemented in a d-galactose (d-gal)-induced neurodegeneration and memory impairment mice model to explore its effects on the brain and the regulation of short-chain fatty acids. The results showed that the L. plantarum -GOS supplementation inhibited d-gal-induced oxidative stress and increased the brain's nuclear factor erythroid 2-related factor 2 (Nrf2) levels. Butyrate, a metabolite of the gut microbiota regulated by L. plantarum combined with GOS, inhibits p-JNK expression, downregulates pro-apoptotic proteins expression and the activation of inflammatory mediators, and upregulates synaptic protein expression. This might be a potential mechanism for L. plantarum 69-2 combined with GOS supplementation to alleviate d-gal-induced neurodegeneration and memory impairment. This study sheds new light on the development of aging-related neuroprotective dietary supplements based on the gut-brain axis.

Lycopene (LYC) possesses bioactivity to improve the pathogenesis of several chronic diseases via antioxidant-associated mechanisms. The purpose of this study was to investigate whether LYC could attenuate D-galactose (D-gal)-induced mitochondrial dysfunction and insulin signaling impairment in mouse kidneys and livers. Two-month-old CD-1 mice were treated by intraperitoneal injection of 150 mg kg -1 day -1 D-gal for 8 weeks and received 0.03% LYC (w/w, mixed into diet). The results showed that LYC ameliorated oxidative stress triggered by D-gal by enhancing the Nrf2 antioxidant defense pathway and increasing the expression of the antioxidant response genes HO-1 and NQO1 in mouse kidneys and livers. LYC inhibited the MAPK and NFκB pathways and attenuated renal and hepatic inflammatory responses. Moreover, LYC upregulated the expression of genes related to mitochondrial biosynthesis and oxidative phosphorylation and improved insulin signal transduction through the IRS-1/AKT/GSK3β pathway in mouse kidneys and livers.

Age-related diseases, including dementia, are a major health concern affecting daily human life. Strawberry ( Fragaria ananassa Duch.) is the most eaten fruit worldwide due to its exceptional aroma and flavor. However, it's rapid softening and decay limit its shelf-life. Freezing and boiling represent the well-known conservation methods to extend its shelf-life. Therefore, we aimed to discover the phytochemical content differences of fresh and processed strawberries associated with investigating and comparing their neuroprotective effects in a rat model of aging. Female Wistar rats were orally pretreated with fresh, boiled, and frozen F. ananassa methanolic extracts (250 mg kg -1 ) for 2 weeks, and then these extracts were concomitantly exposed to D-galactose [65 mg kg -1 , subcutaneously (S/C)] and AlCl 3 (200 mg kg -1 , orally) for 6 weeks to develop aging-like symptoms. The results of UPLC/ESI-MS phytochemical profiling revealed 36 secondary metabolites, including phenolics, flavonoids, and their glycoside derivatives. Compared with boiled and frozen extracts, the fresh extract ameliorated the behavioral deficits including anxiety and cognitive dysfunction, upregulated brain HO-1 and Nrf2 levels, and markedly reduced caspase-3 and PPAR-γ levels. Moreover, LDH and miRNA-9, 124 and 132 protein expressions were reduced. The histological architecture of the brain hippocampus was restored and glial fibrillary acidic protein (GFAP) immunoexpression was downregulated. In conclusion, the fresh extract has neuroprotective activity that could have a promising role in ameliorating age-related neurodegeneration.

Anti-aging is a challenging and necessary research topic. Momordica charantia L. is a common edible medicinal plant that has various pharmacological activities and is often employed in daily health care. However, its anti-aging effect on mice and the underlying mechanism thereof remain unclear. Our current study mainly focused on the effect of Momordica charantia L. on d-galactose-induced subacute aging in mice and explored the underlying mechanism. UHPLC-Q-Exactive Orbitrap MS was applied to qualitatively analyze the chemical components of Momordica charantia L. ethanol extract (MCE). A subacute aging mice model induced by d-galactose (d-gal) was established to investigate the anti-aging effect and potential mechanism of MCE. The learning and memory ability of aging mice was evaluated using behavioral tests. The biochemical parameters, including antioxidant enzyme activity and the accumulation of lipid peroxides in serum, were measured to explore the effect of MCE on the redox imbalance caused by aging. Pathological changes in the hippocampus were observed using hematoxylin and eosin (H&E) staining, and the levels of aging-related proteins in the PI3K/AKT signaling pathway were assessed using Western blotting. The experimental results demonstrated that a total of 14 triterpenoids were simultaneously identified in MCE. The behavioral assessments results showed that MCE can improve the learning and memory ability of subacute mice. The biochemical parameters determination results showed that MCE can improve the activity of antioxidant enzymes and decrease the accumulation of lipid peroxides in aging mice significantly. Furthermore, aging and injury in the hippocampus were ameliorated. Mechanistically, the results showed a significant upregulation in the protein expression of P-PI3K/PI3K and P-AKT/AKT (p < 0.01), as well as a significant reduction in cleaved caspase-3/caspase-3, Bax and P-mTOR/mTOR (p < 0.01). Our results confirm that MCE could restore the antioxidant status and improve cognitive impairment in aging mice, inhibit d-gal-induced apoptosis by regulating the PI3K/AKT signaling pathway, and rescue the impaired autophagy caused by mTOR overexpression, thereby exerting an anti-aging effect.

Aging is referred to progressive dysfunction of body organs, including the brain. This study aims to explore the anti-aging effect of combing nicotinamide mononucleotide (NMN) and lycopene (Lyco) (NMN + Lyco) on aging rats and senescent PC12 cells. Both in vivo and in vitro aging models were established using D-galactose (D-gal). The combination showed a trend to superiority over monotherapy in preventing aging in vivo and in vitro. Morris water maze test showed that NMN + Lyco effectively improved the ability of spatial location learning and memory of aging model rats. NMN + Lyco mitigated the oxidative stress of rat brains, livers, and PC12 cells by elevating the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), GSH, as well as total antioxidant capacity (T-AOC), and reducing malondialdehyde (MDA) content. CCK-8 assay, senescence-associated β-galactosidase staining, and flow cytometer confirmed the cellular senescence of PC12 cells after exposing D-gal, and indicated the anti-senescence effect of NMN + Lyco in vitro. Moreover, NMN + Lyco effectively down-regulated the expressions of p53, p21, and p16 (senescence-related genes), and activated Keap1-Nrf2 signaling in both in vivo and in vitro aging models. In total, NMN + Lyco protected rats and PC12 cells from cognitive impairment and cellular senescence induced by D-gal, of which effects might be linked to the reduction of oxidative stress and the activation of Keap1-Nrf2 signaling., (Copyright © 2022. Published by Elsevier B.V.)

Aims: To investigate the effects of hyperbaric oxygen therapy (HBOT) on metabolic disturbance, aging and bone remodeling in D-galactose-induced aging rats with and without obesity by determining the metabolic parameters, aging and oxidative stress markers, bone turnover markers, bone microarchitecture, and bone biomechanical strength., Materials and Methods: Male Wistar rats were fed either a normal diet (ND; n = 18) or a HFD (n = 12) for 22 weeks. At week 13, vehicle (0.9% NaCl) was injected into ND-fed rats (NDV; n = 6), while 150 mg/kg/day of D-galactose was injected into 12 ND-fed rats (NDD) and 12 HFD-fed rats (HFDD) for 10 weeks. At week 21, rats were treated with either sham (NDVS, NDDS, or HFDDS; n = 6/ group) or HBOT (NDDH, or HFDDH; n = 6/group) for 14 days. Rats were then euthanized. Blood samples, femora, and tibiae were collected., Key Findings: Both NDD and HFDD groups developed aging as indicated by increased AGE level, increased inflammation and oxidative stress as shown by raised serum TNF-α and MDA levels, impaired bone remodeling as indicated by an increase in levels of CTX-1, TRACP-5b, and impaired bone structure/strength, when compared with those of the NDVS group. HFD aggravated these indicators of bone dyshomeostasis in D-galactose-treated rats. HBOT restored bone remodeling and bone structure/strength in the NDD group, however HBOT ameliorated bone dyshomeostasis in the HFDD group., Significance: HBOT is a potential intervention to decrease the risk of osteoporosis and bone fracture in aging with or without obesity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The present study investigated the mechanism of the Tibetan patent medicine Ershiwuwei Shanhu Pills(ESP) in alleviating Alzheimer's disease in mice via Akt/mTOR/GSK-3β signaling pathway. BALB/c mice were randomly assigned into a blank control group, a model group, low(200 mg·kg~(-1)), medium(400 mg·kg~(-1)) and high(800 mg·kg~(-1)) dose groups of ESP, and donepezil hydrochloride group. Except the blank control group, the other groups were given 20 mg·kg~(-1) aluminum chloride by gavage and 120 mg·kg~(-1) D-galactose by intraperitoneal injection for 56 days to establish Alzheimer's disease model. Morris water maze was used to detect the learning and memory ability of mice. The level of p-tau protein in mouse hippocampus and the levels of superoxide dismutase(SOD), malondialdehyde(MDA), catalase(CAT), and total antioxidant capacity(T-AOC) in hippocampus and serum were detected. Hematoxylin-eosin staining and Nissl staining were performed for the pathological observation of whole brain in mice. TdT-mediated dUTP nick-end labeling(TUNEL) staining was employed for the observation of apoptosis in mouse cortex. Western blot was adopted to detect the protein levels of p-mTOR, p-Akt, and GSK-3β in the hippocampus. Compared with the model group, the ESP groups showcased alleviated pathological damage of the whole brain, decreased TUNEL positive cells, reduced level of p-tau protein in hippocampus, and risen SOD, CAT, and T-AOC levels and declined MDA level in hippocampus and serum. Furthermore, the ESP groups had up-regulated protein levels of p-mTOR and p-Akt while down-regulated protein level of GSK-3β in hippocampus. Therefore, ESP can alleviate the learning and memory decline and oxidative damage in mice with Alzheimer's disease induced by D-galactose combined with aluminum chloride, which may be related to Akt/mTOR/GSK-3β signaling pathway.

Aging is the primary cause of neurodegenerative diseases, which are mainly characterized by cognitive decline and neuropsychiatric symptoms. Corn embryo, an important component of corn kernels, contains plenty of essential nutrients and bioactive compounds. However, corn embryo is often removed in the process of refining corn. To reveal potential biological benefits of corn embryo, the present study investigated the intervention effects of corn embryo on age-related cognitive decline and neuropsychiatric symptoms. Ninety male Wistar rats were randomly divided into six groups: Control, Corn embryo, Aging model, Low-, Medium- and High-dose intervention group. Aging models induced by an intraperitoneal injection of 60 mg/kg D-galactose plus a gavage of 200 mg/kg aluminum chloride were intervened with a gavage of 0.3, 0.6 or 1 g/kg corn embryo while the Control and Corn embryo groups received saline and 0.6 g/kg corn embryo respectively. Morris water maze and open field test were performed to assess cognitive abilities and anxiety-like behaviors. Brain biochemical parameters including the malondialdehyde, glutathione, glutathione sulfhydryl transferase and γ-glutamylcysteine synthetase were detected to evaluate oxidative stress levels. The mRNA expression of brain-derived neurotrophic factor was determined to estimate neurotrophic factor levels. Besides, histopathological alterations were visualized by hematoxylin-eosin staining and neuronal apoptosis levels were measured by the immunohistochemical staining of Bax and Bcl-2. Ultimately, the mimetic aging rats showed significant cognitive impairment (n = 15, P < 0.01) and anxiety-like behaviors (n = 15, P < 0.01), increased oxidative stress (n = 5, P < 0.001), neurodegeneration (n = 5, P < 0.001) and apoptosis (n = 5, P < 0.01) and reduced neurotrophic factors (n = 5, P = 0.074) in the brain. However, corn embryo effectively prevented the above undesirable neurobehavioral alterations via attenuating oxidative stress (n = 5, P < 0.01), neurodegeneration (n = 5, P < 0.001) and apoptosis (n = 5, P < 0.01) and increasing the levels of neurotrophic factors (n = 5, P < 0.001), suggesting its strong neuroprotective effects., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Crateva unilocularis and C. unilocularis Buch. shoots are traditionally served as a vegetable with many health-promoting benefits. The aim of the current investigation was designed to study the preventive effect of ethanol extract from C. unilocularis shoots (CSE) on D-galactose (D-gal) induced brain and liver injury and cognitive disorders of mice, and to illuminate the potential molecular mechanisms. Results exhibited that CSE, especially at a dose of 600 mg kg -1 b.w., remarkably improved the morphology and number of hippocampal neurons against impairment caused by D-gal ( p < 0.05). Biochemical parameters displayed that CSE, especially at a high dose, substantially increased SOD (by about 35.37%, 24.98% and 45.51%), CAT (by about 45.73%, 31.44% and 30.70%), and GSH-Px (by about 36.47%, 17.68% and 52.87%) activities and decreased the level of MDA (by about 22.58%, 23.38% and 27.69%) in the plasma, liver, and brain, respectively ( p < 0.05). The AChE content in mice administered a high dose of CSE decreased by about 44.48%. Further mechanism results revealed that the prevention by CSE might be achieved by upregulating the expressions of p-PI3K/PI3K, p-Akt/Akt, Nrf2, HO-1, and NQO1 proteins ( p < 0.05). In addition, behavioral experiments showed that CSE at a dose of 600 mg kg -1 could significantly improve the anxiety status and impairment of learning and memory caused by D-gal ( p < 0.05). These results substantially proved that C. unilocularis shoots could effectively attenuate D-gal-induced brain and liver injury and cognitive disorders of mice and could be applied to develop new functional foods to encounter aging-related impairments in brain function.

Scope: Alzheimer's disease (AD) is a neurodegenerative disease with phenomena of cognitive impairments. Oxidative stress and cholinergic system dysfunction are two widely studied pathogenesis of AD. Dihydromyricetin (DMY) is a natural dihydroflavonol with many bioactivities. In this study, it is aimed to investigate the effects of DMY on cognitive impairment in d-galactose (d-gal) induced aging mice., Methods and Results: Mice are intraperitoneally injected with d-gal for 16 weeks, and DMY is supplemented in drinking water. The results show that DMY significantly improves d-gal-induced cognitive impairments in novel object recognition and Y-maze studies. H&E and TUNEL staining show that DMY could improve histopathological changes and cell apoptosis in mice brain. DMY effectively induces the activities of catalase, superoxide dismutase and glutathione peroxidase, and reduces malondialdehyde level in mice brain and liver. Furthermore, DMY reduces cholinergic injury by inhibiting the activity of Acetylcholinesterase (AChE) in mice brain. In vitro studies show that DMY is a non-competitive inhibitor of AChE with IC50 value of 161.2 µg mL -1 ., Conclusion: DMY alleviates the cognitive impairments in d-gal-induced aging mice partly through regulating oxidative stress and inhibition of acetylcholinesterase., (© 2021 Wiley-VCH GmbH.)

Objectives: Age-related hearing loss (ARHL) is much more prevalent with age, affecting not only peripheral but central auditory system. We have previously established an aging model of peripheral auditory system in vitro using cultured cochlear basilar membrane. However, there is no ideal accelerated aging model on central auditory system in vitro. To establish the aging model, auditory cortical neurons (ACNs) were primary cultured and treated with either vehicle or different doses of D-galactose (D-gal). We studied the effect of D-gal on ACNs by evaluating the hallmarks of aging, including cell proliferation, oxidative stress, mitochondrial function, and neuronal apoptosis. Compared with the control group, cell viability was significantly inhibited in the D-gal-treated group in a dose-dependent manner. The production of reactive oxygen species was strongly increased in the D-gal-treated group. Meanwhile, the level of 8-hydroxy-2'-deoxyguanosine, which is a biomarker of DNA oxidative damage, was even higher in the D-gal-treated group than that in the control group. Conversely, the levels of ATP and mitochondrial membrane potential were notably decreased in the D-gal-treated group contrast to that in the control group. Furthermore, the number of neuronal apoptosis in the D-gal-treated group, compared with that in the control group, was dramatically increased in a dose-dependent approach. Together, our results demonstrate that ACNs treated with D-gal in vitro display senescence characteristics by regulating oxidative stress and apoptosis, indicating accelerated aging model on ACNs are successfully established. And the model provides a promising approach for exploring underlying mechanisms of the ARHL., Competing Interests: The authors declare that there is no competing interest in the present article.