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Excess exogenous supplementation of D-galactose (D-gal), a monosaccharide and reducing sugar, generates reactive oxygen species (ROS), leading to cell damage and death. ROS accumulation is critical in aging. Therefore, D-gal-induced aging mouse models are used in aging studies. Herein, we evaluated D-gal's effect on neonatal testis development using an in vitro organ culture method. Mouse testicular fragments (MTFs) derived from neonatal testes (postnatal day 5) were cultured with 500 mM D-gal for 5 days. D-gal-treated MTFs showed a significantly increased and decreased expression of undifferentiated and differentiated germ cell markers, respectively, with a substantial reduction in meiotic cells. In D-gal-exposed MTFs, expression levels of Sertoli cell markers (Sox9 and Wt1) increased, while those of StAR and 17β-HSD3, whose expressions are abundant in D-Gal treated adult Leydig cells, decreased. Additionally, the enzyme 3 β-HSD1, essential for steroidogenesis in Leydig cells, was significantly reduced in D-gal-exposed MTFs compared to that in controls.D-gal significantly increased the expression of Bad, Bax, and cleaved caspase-3 and -8. Via oxidative stress in MTF. Overall, D-gal negatively regulates germ cell and Leydig cell development in neonatal testes through pro-apoptotic mechanisms and ROS., (© 2024. The Author(s).)

Herpes simplex virus (HSV) infections can occur throughout life, thereby allowing transmission to new hosts, with an impact on public health. Acyclovir remains the treatment of choice for these infections; however, an increase in resistant strains in recent years has been observed. In this study, the activity of a native Delonix regia galactomannan (NDr) against HSV-1 was investigated in vitro. NDr was characterized using infrared spectroscopy and NMR. Evaluation of cytotoxicity and the antiviral effect was determined, respectively, by MTT and plaque reduction assays. The NDr concentrations that inhibited cell viability (CC 50 ) and viral infection (IC 50 ) by 50% were above 2000 and 64 μg/mL, respectively. Thus, the polysaccharide showed a high selectivity index (> 31.25). When NDr was added at different stages of HSV-1 replication, a strong inhibitory effect was found by direct interaction with the virus (71-67%, virucidal effect) or previously with the cell, 6 h before infection (99.8-68.4%, prophylactic effect) at concentrations from 200 to 50 μg/mL. NDr showed similar effects in prophylactic 1 h (52%) and adsorption inhibition (55%) assays at 200 μg/mL. A reduction in the antiherpetic effect was observed after infection. These results suggest that NDr is effective in the early stages of HSV-1 infection and is a promising agent for controlling herpetic infections., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

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.)

Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of Ca2+ release-activated Ca2+ (CRAC) channels has been proposed as a potential treatment, and currently, a novel selective CRAC channel inhibitor CM4620 (Auxora, CalciMedica) is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here, we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 n m, have been studied against necrosis induced by bile acids, palmitoleic acid, or l-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 n m and palmitoleic acid starting from 1 n m. Combining CM4620 and galactose (1 m m) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acid-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced edema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 m m) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)

Enhancement of oxidative stress and resultant neuronal injury play important roles in initiating cognitive impairment during the aging process. Thus, attenuating oxidative injury is regarded as a profitable therapeutic strategy for age-associated cognitive impairment. Previous studies showed that gliclazide (Gli) had a protective role in neuronal injury from cerebral ischemia/reperfusion (I/R) injury. However, whether Gli has a profitable effect on age-associated cognitive impairment remains largely unclear. The present study showed that Gli held the potential to attenuate neuronal apoptosis in D-gal-induced senescent cells and aging mice. Additionally, Gli could alleviate synaptic injury and cognitive function in D-gal-induced aging mice. Further study showed that Gli could attenuate oxidative stress in D-gal-induced senescent cells and aging mice. The p38 MAPK pathway was predicted as the downstream target of Gli retarding oxidative stress using in silico analysis. Further studies revealed that Gli attenuated D-gal-induced phosphorylation of p38 and facilitated Nrf2 nuclear expression, indicating that the anti-oxidative property of Gli may be associated with the p38 MAPK pathway. The study demonstrates that Gli has a beneficial effect on ameliorating D-gal-induced neuronal injury and cognitive impairment, making this compound a promising agent for the prevention and treatment of age-associated cognitive impairment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Herein, four silver(I) complexes bearing acetylated d-galactopyranoside-based N-heterocyclic carbene ligands were synthesized and fully characterized by elemental analysis, NMR, and X-ray photoelectron spectroscopy. All complexes were obtained with an anomeric β-configuration and as monocarbene species. In this study, we investigated the biological effects of the silver(I) complexes 2a-d on the human rhabdomyosarcoma cell line, RD. Our results show concentration-dependent effects on cell density, growth inhibition, and activation of key signaling pathways such as Akt 1/2, ERK 1/2, and p38-MAPK, indicating their potential as anticancer agents. Notably, at 35.5 µM, the complexes induced mitochondrial network disruption, as observed with 2b and 2c, whereas with 2a, this disruption was accompanied by nuclear content release. These results provide insight into the utility of carbohydrate incorporated NHC complexes of silver(I) as new agents in cancer therapy., 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 © 2024 Elsevier Ltd. All rights reserved.)

Background: Curcumin (Curcuma longa) is a well-known medicinal plant that induces autophagy in various model species, helping maintain cellular homeostasis. Its role as a caloric restriction mimetic (CRM) is being investigated. This study explores the potential of curcumin (CUR), as a CRM, to provide neuroprotection in D galactose induced accelerated senescence model of rats through modulation of autophagy. For six weeks, male rats received simultaneous supplementation of D-gal (300 mg/kg b.w., subcutaneously) and CUR (200 mg/kg b.w., oral)., Method and Results: The oxidative stress indices, antioxidants, and electron transport chain complexes in brain tissues were measured using standard methods. Reverse transcriptase-polymerase chain reaction (RT-PCR) gene expression analysis was used to evaluate the expression of autophagy, neuroprotection, and aging marker genes. Our results show that curcumin significantly (p ≤ 0.05) enhanced the level of antioxidants and considerably lowered the level of oxidative stress markers. Supplementing with CUR also increased the activity of electron transport chain complexes in the mitochondria of aged brain tissue, demonstrating the antioxidant potential of CUR at the mitochondrial level. CUR was found to upregulate the expression of the aging marker gene (SIRT-1) and the genes associated with autophagy (Beclin-1 and ULK-1), as well as neuroprotection (NSE) in the brain. The expression of IL-6 and TNF-α was downregulated., Conclusion: Our findings demonstrate that CUR suppresses oxidative damage brought on by aging by modulating autophagy. These findings imply that curcumin might be beneficial for neuroprotection in aging and age-related disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Although the selective and effective clearance of senescent cancer cells can improve cancer treatment, their development is confronted by many challenges. As part of efforts designed to overcome these problems, prodrugs, whose design is based on senescence-associated β-galactosidase (SA-β-gal), have been developed to selectively eliminate senescent cells. However, chemotherapies relying on targeted molecular inhibitors as senolytic drugs can induce drug resistance. In the current investigation, we devised a new strategy for selective degradation of target proteins in senescent cancer cells that utilizes a prodrug composed of the SA-β-gal substrate galactose (galacto) and the proteolysis-targeting chimeras (PROTACs) as senolytic agents. Prodrugs Gal-ARV-771 and Gal-MS99 were found to display senolytic indexes higher than those of ARV-771 and MS99. Significantly, results of in vivo studies utilizing a human lung A549 xenograft mouse model demonstrated that concomitant treatment with etoposide and Gal-ARV-771 leads to a significant inhibition of tumor growth without eliciting significant toxicity.

This study aimed to determine whether trimethylamine N-oxide (TMAO) was involved in sympathetic activation in aging and the underlying mechanisms. Our hypothesis is TMAO reduces P2Y12 receptor (P2Y12R) and induces microglia-mediated inflammation in the paraventricular nucleus (PVN), then leading to sympathetic activation in aging. This study involved 18 young adults and 16 old adults. Aging rats were established by injecting D-galactose (D-gal, 200 mg/kg/d) subcutaneously for 12 weeks. TMAO (120 mg/kg/d) or 1% 3, 3-dimethyl-l-butanol (DMB) was administrated via drinking water for 12 weeks to investigate their effects on neuroinflammation and sympathetic activation in aging rats. Plasma TMAO, NE and IL-1β levels were higher in old adults than in young adults. In addition, standard deviation of all normal to normal intervals (SDNN) and standard deviation of the average of normal to normal intervals (SDANN) were lower in old adults and negatively correlated with TMAO, indicating sympathetic activation in old adults, which is associated with an increase in TMAO levels. Treatment of rats with D-gal showed increased senescence-associated protein levels and microglia-mediated inflammation, as well as decreased P2Y12R protein levels in PVN. Plasma TMAO, NE and IL-1β levels were increased, accompanied by enhanced renal sympathetic nerve activity (RSNA). While TMAO treatment exacerbated the above phenomenon, DMB mitigated it. These findings suggest that TMAO contributes to sympathetic hyperactivity in aging by downregulating P2Y12R in microglia and increasing inflammation in the PVN. These results may provide promising new target for the prevention and treatment of aging and aging-related diseases., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cardiac aging is defined as mitochondrial dysfunction of the heart. Vitamin D (VitD) is an effective agent in ameliorating cardiovascular disorders. In this study, we indicated the protective effects of VitD against cardiac aging. Male Wistar rats were randomly divided into four groups: control (CONT), D-galactose (D-GAL): aged rats induced by D-GAL, D-GAL + Ethanol: aged rats treated with ethanol, and D-GAL + VitD aged rats treated with VitD. Aging was induced by D-GAL at 150 mg/kg via intraperitoneal injection for 8 weeks. Aged rats were treated with VitD (D-GAL + VitD) by gavage for 8 weeks. The serum samples were used to evaluate biochemical factors, and heart tissues were assessed to determine oxidative stress and gene expression. The D-GAL rats exhibited cardiac hypertrophy, which was associated with decreased antioxidant enzyme activity, enhanced oxidative marker, and changes in the expression of mitochondrial genes in comparison with the control rats. Co-treatment with VitD ameliorated all these changes. In conclusion, VitD could protect the heart against D-GAL-induced aging via enhancin g antioxidant effects, and the expression of mitochondrial genes.

Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1's neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.

A decline in immune response, exhibited in the form of immunosenescence and inflammaging, is an age-associated disturbance of the immune system known to predispose the elderly to a greater susceptibility to infection and poor vaccine response. Polysaccharides and polyphenols from botanicals are known for their immune modulation effects. Here we evaluated a standardized mushroom-based composition, UP360, from Aloe barbadensis , Poria co cos, and Rosmarinus officinalis , as a natural nutritional supplement for a balanced immune response in an accelerated aging mouse model. Immunosenescence was induced by continual subcutaneous injection of D-galactose (D-gal) at a dose of 500 mg/kg/day to CD-1 mice. UP360 was administered at oral doses of 200 and 400 mg/kg to the mice starting on the 5 th week of D-gal injection. The study lasted for a total of 9 weeks. All mice were given a quadrivalent influenza vaccine at 3  µ g/animal via intramuscular injection 14 days before the end of the study. A group of D-gal-treated mice treated at 400 mg/kg/day UP360 was kept without vaccination. Whole blood, serum, spleen homogenate, and thymus tissues were used for analysis. UP360 was found to improve the immune response as evidenced by stimulation of innate and adaptive immune responses, increase antioxidant capacity as reflected by augmented SOD and Nrf2, and preserve vital immune organs, such as the thymus, from aging-associated damage. The findings depicted in this report show the effect of the composition in activating and maintaining homeostasis of the immune system both during active infections and as a preventive measure to help prime the immune system. These data warrant further clinical study to explore the potential application of the mushroom-based composition as an adjunct nutritional supplement for a balanced immune response., Competing Interests: All authors are current Unigen employees, therefore, they have competing financial interests., (Copyright © 2024 Mesfin Yimam et al.)

Many of the cancer cells produce energy with accelerated glycolysis and perform lactic acid production even under normoxic conditions called the "Warburg effect". Metabolism can directly or indirectly regulate the apoptotic mechanism so that cancer cells take advantage of reprogrammed metabolism to avoid apoptosis. The aim of this study is to examine the mechanism of apoptosis by incubating human lung carcinoma cells (A549) under different metabolic conditions in hypoxia or normoxia environments. A549 cells were incubated in the normoxic or hypoxic condition that contained 5 mM glucose (Glc 5), 25 mM glucose (Glc 25), or 10 mM galactose (OXPHOS/aglycemic), and the mechanism of apoptosis was investigated. In the hypoxia condition, the rate of early apoptosis in aglycemic OXPHOS cells was increased (15.5% ±7.1). In addition, the activity of caspase-3 (6.1% ± 0.9), caspase-9 (30.4% ± 0.9), and cytochrome c expression level increased; however, the mitochondrial membrane potential (51.9% ± 0.4) was found to be decreased. Changing the amount of oxygen in glycolytic cells had no effect on apoptosis. However, it has been determined that apoptosis is stimulated under hypoxia conditions in aglycemic cells in which galactose is used instead of glucose. Considering that the majority of cancer cells are hypoxic, these data are important in determining targets in therapeutic intervention., (© 2024 John Wiley & Sons Ltd.)

The accumulation of senescent cells in bone during aging contributes to senile osteoporosis, and clearance of senescent cells by senolytics could effectively alleviate bone loss. However, the applications of senolytics are limited due to their potential toxicities. Herein, small extracellular vesicles (sEVs) have been modified by incorporating bone-targeting peptide, specifically (AspSerSer) 6 , to encapsulate galactose-modified Maytansinoids (DM1). These modified vesicles are referred to as (AspSerSer) 6 -sEVs/DM1-Gal, and they have been designed to specifically clear the senescent osteocytes in bone tissue. In addition, the elevated activity of lysosomal β-galactosidase in senescent osteocytes, but not normal cells in bone tissue, could break down DM1-Gal to release free DM1 for selective elimination of senescent osteocytes. Mechanically, DM1 could disrupt tubulin polymerization, subsequently inducing senescent osteocytes apoptosis. Further, administration of bone-targeting senolytics to aged mice could alleviate aged-related bone loss without non-obvious toxicity. Overall, this bone-targeting senolytics could act as a novel candidate for specific clearance of senescent osteocytes, ameliorating age-related bone loss, with a promising therapeutic potential for senile osteoporosis., (© 2023 Wiley‐VCH GmbH.)

Eggs, with their high nutritional value, are great carriers for enriching nutrients. In this study, selenium- and/or zinc-enriched eggs (SZE) were obtained and their effects on ameliorating oxidative stress injury, alleviating cognitive impairment, and maintaining intestinal flora balance in a D-gal-induced aging mice model were investigated. As determined by the Y-maze test, SZE restored the learning and memory abilities and increased the Ach level and AChE activity of aging mice ( p < 0.05). Meanwhile, supplementation of low-dose SZE increased antioxidant levels and decreased inflammation levels ( p < 0.05). High-dose SZE increased anti-inflammatory levels but were less effective than low dose. Additionally, SZE maintained the intestinal flora balance and significantly increased the ratio of Firmicutes and Bacteroidota . Blautia , as a probiotic, was negatively correlated with pro-inflammatory factors and positively correlated with antioxidant levels ( p < 0.05). These results suggest that SZE might improve organ damage and cognitive function by attenuating oxidative stress and inflammatory response and maintaining healthy gut flora.

Sperm survival and activity depend on the provision of energy and nutrients from seminal plasma (SP). This study aimed to investigate the variations of metabolites within SP before and after freezing and subsequently explore the potential regulatory mechanisms affecting yak sperm cryodamage due to changes in metabolites in the SP. Untargeted metabolomics analysis was performed to screen for differential metabolites, followed by KEGG analysis to identify enriched signaling pathways. The combinatorial analysis of metabolomics and sperm proteomics revealed the influence of key SP metabolites on sperm proteins. Subsequently, the relevant differentially expressed proteins were verified by Western blot analysis. Finally, the mechanism underlying the positive effect of galactose on sperm motility was determined by assessing the change in ATP content in sperm before and after freezing and thawing. The data showed that a total of 425 and 269 metabolites were identified in the positive and negative ion modes, respectively. Freezing and thawing resulted in the up-regulation of 70 metabolites and the down-regulation of 29 metabolites in SP. The primary impact of freezing and thawing was observed in carbohydrate metabolism, including pyruvate metabolism, pentose phosphate pathway, galactose metabolism, the TCA cycle, and butanoate metabolism. In the combined analysis and Western blot results, a significant positive correlation was observed between galactose and Aldo-keto reductase family 1 member B1 (AKR1B1) (P < 0.05), which has the ability to convert galactose into galactol. Furthermore, the addition of galactose to thawed semen improved sperm motility by increasing AKR1B1 protein in sperm and was associated with the content of ATP. These data identify differential metabolites between fresh and frozen-thawed SP and suggest that galactose is a valuable additive for cryopreserved sperm, providing a theoretical basis for further exploration of the refrigerant formula for yak sperm cryopreservation., (Copyright © 2023. Published by Elsevier Inc.)

Sarcopenia is a process of progressive aging-associated loss of skeletal muscle mass (SMM) recognized as a serious global health issue contributing to frailty and increased all-cause mortality. Exercise and nutritional interventions (particularly intake of dairy products and milk) demonstrate good efficacy, safety, and broad applicability. Here, we propose that at least some of the well-documented favorable effects of milk and milk-derived protein supplements on SMM might be mediated by D-galactose, a monosaccharide present in large quantities in milk in the form of disaccharide lactose (milk sugar). We suggest that ingestion of dairy products results in exposure to D-galactose in concentrations metabolized primarily via the Leloir pathway with the potential to (i) promote anabolic signaling via maintenance of growth factor (e.g., insulin-like growth factor 1 [IGF-1]) receptor mature glycosylation patterns; and (ii) provide extracellular (liver glycogen) and intracellular substrates for short (muscle glycolysis) and long-term (muscle glycogen, intramyocellular lipids) energy availability. Additionally, D-galactose might optimize the metabolic function of skeletal muscles by increasing mitochondrial content and stimulating glucose and fatty acid utilization. The proposed potential of D-galactose to promote the accretion of SMM is discussed in the context of its therapeutic potential in sarcopenia., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)

The aim of this study was to evaluate the effects of galacto-oligosaccharides (GOS) on faecal parameters in healthy dogs and cats. To this end, 20 dogs and 20 Domestic shorthair cats were fed a commercially available adult dog food, or cat food, respectively, with either syrup containing GOS (at 1% w galacto-oligosaccharides/w formulated feed) on top (test group) or no topping (control group) for 56 days in a cross-over design. The study consisted of 2 periods of 24 days adaptation, followed by 4 days of collection of faeces. Faecal samples were tested for moisture, nitrogen, pH, macronutrients, enzymes, and fermentation products. The faecal microbiota were analysed by 16S rDNA profiling. It appeared that GOS have different effects in dogs compared to cats. In dogs, the addition of GOS resulted in increased carbohydrate fermentation (increase of acetic and butyric acid), whereas in cats GOS resulted in increased amino acid fermentation (increase of isovaleric acid). The α-diversity of the canine faecal microbiota was reduced by dietary GOS (Inverse Simpson Index, p = 0.063; Shannon index, p = 0.035) whereas the α-diversity of cat faecal microbiota was unaffected (Inverse Simpson Index, p = 0.539; Shannon index, p = 0.872). Lachnospiraceae spp. and Bifidobacterium spp. positively responded to GOS in both cats and dogs. Lactobacillus spp. and Enterobacteriaceae spp. positively responded to GOS in dogs. In both dogs and cats, GOS may therefore improve stool microbiota and result in the production of specific metabolites that are beneficial to gut health., Competing Interests: Declaration of Competing Interest The author declares no conflict of interest, the study was funded by Saputo Dairy UK LTD., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

The liver is one of the most important organs responsible for detoxifying biomolecules and xenobiotics. Herein, we report the isolation, characterization, and hepatoprotective effect of the Boerhavia procumbens-derived eupalitin-3-O-β-D-galactopyranoside (EGP) compound. The structure of the EGP compound was deduced by using NMR spectroscopic techniques and mass spectrometry. The EGP hepatoprotective activities were evaluated with HepG2 cell viability and LDH assays in vitro, and CCl 4 -induced toxicity was investigated in vivo in the rat model. Compared to the CCl 4 -treated group, cells exposed to the EGP compound at 200 µg/ml showed increased cell viability (60.52 ± 1.22 %) and decreased LDH levels (23.81 ± 1.89 U/ml). The serum levels of SGPT, SGOT, ALP, and total bilirubin in the CCl4-treated group were substantially higher than those in the control group (64 ± 1.89 U/ml, 86 ± 1.47 U/ml, 252.6 ± 2.96 U/ml, and 5.45 ± 0.32 mg/dl, respectively). When compared to animals treated with CCl 4 alone, the EGP compound's in vivo hepatoprotective effect at 60 mg/kg with CCl 4 significantly (p < 0.01) decreased the levels of SGPT and SGOT (26 ± 1.34 U/ml and 42.92 ± 1.6 U/ml) respectively. Furthermore, our histological study showed a significant response in restoring and maintaining the normal morphological appearance of the liver. Thus, our results show that the EGP compound is a promising and novel lead molecule for better hepatotoxicity control and therapy., 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 B.V.)

Astaxanthin is a keto-based carotenoid mainly obtained from marine organisms, like Haematococcus pluvialis (H. pluvialis). Previous studies indicated the protective effects of Astaxanthin and H. pluvialis on aging related oxidative injury in liver, while the potential mechanisms are largely unknown. In addition, H. pluvialis residue is a by-product after astaxanthin extraction, which is rarely studied and utilized. The present study aimed to compare the effects of astaxanthin, H. pluvialis and H. pluvialis residue on the oxidant injury of liver in D-galactose-induced aging mice and explore the potential mechanisms through gut-liver axis. The results showed that all the three supplements prevented D-galactose-induced tissue injury, oxidative stress and chronic inflammation in liver and improved liver function. Gut microbiota analysis indicated that astaxanthin notably increased fecal levels of Bacteroidetes, unclassified&#95;f&#95;&#95; Lachnospiraceae, norank&#95;f&#95;&#95;Lachnospiraceae, norank&#95;f&#95;&#95;norank&#95;o&#95;&#95;Clostridia&#95;UCG-014, Prevotellaceae&#95; UCG-001, unclassified&#95;f&#95;&#95;Prevotellaceae in D-galactose-fed mice (p < 0.05). Compared to aging mice, H. pluvialis group had higher fecal levels of norank&#95;f&#95;&#95;Lachnospiraceae and Lachnospiraceae&#95;UCG-006 (p < 0.05). H. pluvialis residue group displayed higher relative levels of Bacteroidetes, Streptococcus, and Rikenellaceae&#95;RC9&#95;gut&#95;group (p < 0.05). Moreover, the production of fecal microbial metabolites, like SCFAs and LPS was also differently restored by the three supplements. Overall, our results suggest astaxanthin, H. pluvialis and H. pluvialis residue could prevent aging related hepatic injury through gutliver axis and provide evidence for exploiting of H. pluvialis residue as a functional ingredient for the treatment of liver diseases. Future studies are needed to further clarify the effect and mechanism of dominant components of H. pluvialis residue on liver injury, which is expected to provide a reference for the high-value utilization of H. pluvialis resources.

It was reported that LAMMER kinase in Schizosaccharomyces pombe plays an important role in cation-dependent and galactose-specific flocculation. Analogous to other flocculating yeasts, when cell wall extracts of the Δlkh1 strain were treated to the wild-type strain, it displayed flocculation. Gas2, a 1,3-β-glucanosyl transferase, was isolated from the EDTA-extracted cell-surface proteins in the Δlkh1 strain. While disruption of the gas2 + gene was not lethal and reduced the flocculation activity of the ∆lkh1 strain, the expression of a secreted form of Gas2, in which the GPI anchor addition sequences had been removed, conferred the ability to flocculate upon the WT strain. The Gas2-mediated flocculation was strongly inhibited by galactose but not by glucose. Immunostaining analysis showed that the cell surface localization of Gas2 was crucial for the flocculation of fission yeast. In addition, we identified the regulation of mbx2 + expression by Lkh1 using RT-qPCR. Taken together, we found that Lkh1 induces asexual flocculation by regulating not only the localization of Gas2 but also the transcription of gas2 + through Mbx2., (© 2024. The Author(s), under exclusive licence to Microbiological Society of Korea.)

Studies regarding age-related erectile dysfunction (ED) based on naturally aging models are limited by their high costs, especially for the acquisition of primary cells from the corpus cavernosum. Herein, d-galactose ( d-gal) was employed to accelerate cell senescence, and the underlying mechanism was explored. As predominant functional cells involved in the erectile response, corpus cavernosum smooth muscle cells (CCSMCs) were isolated from 2-month-old rats. Following this, d-gal was introduced to induce cell senescence, which was verified via β-galactosidase staining. The effects of d-gal on CCSMCs were evaluated by terminal deoxynucleoitidyl transferase dUTP nick-end labeling (TUNEL), immunofluorescence staining, flow cytometry, western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, RNA interference (RNAi) was carried out for rescue experiments. Subsequently, the influence of senescence on the corpus cavernosum was determined via scanning electron microscopy, qRT-PCR, immunohistochemistry, TUNEL, and Masson stainings. The results revealed that the accelerated senescence of CCSMCs was promoted by d-gal. Simultaneously, smooth muscle alpha-actin (alpha-SMA) expression was inhibited, while that of osteopontin (OPN) and Krüppel-like factor 4 (KLF4), as well as fibrotic and apoptotic levels, were elevated. After knocking down KLF4 expression in d-gal-induced CCSMCs by RNAi, the expression level of cellular alpha-SMA increased. Contrastingly, the OPN expression, apoptotic and fibrotic levels declined. In addition, cellular senescence acquired partial remission. Accordingly, in the aged corpus cavernosum, the fibrotic and apoptotic rates were increased, followed by downregulation in the expression of alpha-SMA and the concurrent upregulation in the expression of OPN and KLF4. Overall, our results signaled that d-gal-induced accelerated senescence of CCSMCs could trigger fibrosis, apoptosis and phenotypic switch to the synthetic state, potentially attributed to the upregulation of KLF4 expression, which may be a multipotential therapeutic target of age-related ED., (© 2023 Wiley Periodicals LLC.)

Background: The prevalence of cardiac fibrosis, intricately linked to various cardiovascular diseases, continues to rise. Aconite, a traditional Chinese herb renowned for its cardiovascular benefits, holds promise in treating heart ailments. However, the mechanisms underlying its anti-fibrotic effects, particularly in cardiac fibrosis, remain elusive., Hypothesis/purpose: This study aims to shed light on aconite's potential as an anti-fibrotic agent and elucidate its mechanisms in a rat model of isoproterenol (ISO)-induced cardiac fibrosis., Methods: By inducing cardiac fibrosis through ISO injection, the study investigates the role of decoction of white aconite (DWA) in mitigating fibrotic processes. Techniques including metabolomics, RT-qPCR, western blot, and immunofluorescence were employed to unveil the molecular changes induced by DWA., Results: DWA exhibited a remarkable reduction in echocardiographic parameters, cardiac weight increase, myocardial infarction extent, inflammatory cell infiltration, collagen deposition in heart tissue, and serum CK-MB, cTnT, cTnI levels post ISO injection. Metabolomic analysis unveiled DWA's modulation of 27 metabolites, especially in galactose metabolism, addressing metabolic disturbances in cardiac fibrosis. Additionally, DWA suppressed mRNA expression of fibrosis markers (Collagen I, CTGF, TGF-β), inhibited protein levels of MMP-9, α-SMA, and Galectin-3, while elevating TIMP1 expression., Conclusion: DWA demonstrated potent anti-fibrotic effects by curbing collagen deposition and alleviating metabolic disruptions in cardiac fibrosis via the galactose metabolism pathway, possibly mediated by the Gal-3/TGF-β/Smad signaling pathway., 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 GmbH.)

This study aims to investigate the protective effect of a freeze-dried powder prepared from a fermentation milk whey containing a high-yield GABA strain (FDH-GABA) against D-galactose-induced brain injury and gut microbiota imbalances in mice by probing changes to the PI3K/AKT/mTOR signaling pathway. A prematurely aged mouse model was established by performing the subcutaneous injection of D-galactose. Subsequently, the effects of FDH-GABA on the nervous system and intestinal microenvironment of the mice were explored by measuring their antioxidant activities, anti-inflammatory state, autophagy, pathway-related target protein expression levels, and intestinal microorganisms. Compared to the D-gal group, FDH-GABA improved the levels of SOD, T-AOC, IL-10, and neurotransmitters, while it reduced the contents of MDA and TNF-α. FDH-GABA also promoted autophagy and inhibited the PI3K/AKT/mTOR signaling pathway in the brains of the aged mice. Moreover, FDH-GABA restored the diversity of their intestinal flora. Pathological observations indicated that FDH-GABA was protective against damage to the brain and intestine of D-galactose-induced aging mice. These results reveal that FDH-GABA not only improved antioxidant stress, attenuated inflammation, restored the neurotransmitter content, and protected the tissue structure of the intestine and brain, but also effectively improved their intestinal microenvironment. The ameliorative effect of FDH-GABA on premature aging showed a clear dose-response relationship, and at the same time, the changes of intestinal microorganisms showed a certain correlation with the relevant indexes of nervous system. These findings provide insight into the effect of the FDH-GABA intervention on aging, providing a novel means for alleviating detrimental neurodegenerative changes in the aging population., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the positing presented in, or the review of, the manuscript entitled “Beneficial effect of GABA-rich fermented milk whey on nervous system and intestinal microenvironment of aging mice induced by D-galactose”., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Intestinal stem cells (ISCs) are the reservoir source of various types of intestinal cells, and the decline of stem cell function in the gut may be a potential factor for aging-related disease. The present study aimed to explore the regulatory mechanisms of Panax ginseng C.A.Meyer (Araliaceae, Panax genus) that could restore gut aging by enhancing intestinal function and regulating ISCs in aging mice based on the Wnt/β-catenin signaling pathway., Methods: A total of 60 ICR male mice were randomly divided into control, model, metformin, and ginseng water decoction (GWD) 3.6, 1.8, and 0.9 g/kg groups. The aging model was induced by 1 % D-galactose (s.c. 0.1 mL/10 g) for 28 days. Moreover, GWD was given to aging mice intragastrically (i.g.) once a day for 28 successive days. The learning memory ability, pathological status, and function in the ileum tissue, the activity of digestive enzymes, and short-chain fatty acid (SCFA) content in the colon were evaluated, and the related mechanism was investigated., Results: Ginseng can decrease the escape latency time and increase the swimming speed and the number of crossing platforms in aging mice. Moreover, the pathology of ileum tissue improved, the length of the intestinal villi increased, and the width of the villi and the depth of the crypts decreased. The activities of trypsin, α-amylase, and lipase increased in duodenal content and intestinal mucosa. In the colon, the content of SCFA, such as acetic acid, propionic acid and butyric acid, increased, indicating that ginseng significantly improves intestinal function impairment. The mRNA expressions and protein levels of β-catenin, C-myc, GSK-3β, Lgr5, and Olfm4 were upregulated in the ginseng group., Conclusions: Ginseng improves intestinal function and regulates the function of ISCs in order to protect intestinal health by activating the Wnt/β-catenin signaling pathway in aging mice., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Milk fat globule epidermal growth factor 8 (MFG-E8) and whey protein have emerged as promising bionutrient supplements for enhancing skeletal muscle mass and function. In the present study, aging-related sarcopenia rat model was employed to elucidate the effects of the combined administration of MFG-E8 and whey protein on the catabolism and anabolism of gastrocnemius protein. Combined intervention led to notable enhancements in the antioxidative stress status and mitochondrial biogenesis capacity of gastrocnemius muscle fibers in the aging rats, concomitant with a significant inhibition of lipid accumulation. Moreover, the synergistic effect of MFG-E8 and whey protein was found to exert modulatory effects on key signaling pathways, including PI3K/Akt/PGC-1α pathway and MAPK/ERK signaling pathways in the gastrocnemius muscle of the aging rats. Specifically, this combined intervention was observed to promote mitochondrial biogenesis and regulate the expression of protein anabolism and catabolism-related regulators, thereby facilitating the alleviation of mitochondrial oxidative stress and enhancing biogenesis in gastrocnemius tissues. The findings of our study provide compelling evidence for the potential of MFG-E8 as a promising dietary supplement with antisarcopenic properties to ameliorate muscle protein metabolism disorders and mitigate mitochondrial-mediated myoblast apoptosis induced by oxidative stress., (© 2024, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

A new lectin from marine sponge Ircinia strobilina, denominated IsL, was isolated by combination of affinity chromatography in Guar gum matrix followed by size exclusion chromatography. IsL was able to agglutinate native and enzymatically treated rabbit erythrocytes, being inhibited by galactosides, such as α-methyl-D-galactopyranoside, β-methyl-D-galactopyranoside and α-lactose. IsL hemagglutinating activity was stable at neutral to alkaline pH, however the lectin loses its activity at 40° C. The molecular mass determinated by mass spectrometry was 13.655 ± 5 Da. Approximately 40% of the primary structure of IsL was determined by mass spectrometry, but no similarity was observed with any protein. The secondary structure of IsL consists of 28% α-helix, 26% β-sheet, and 46% random region, as determined by dichroism circular. IsL was a calcium-dependent lectin, but no significant variations were observed by circular dichroism when IsL was incubated in presence of calcium and EDTA. IsL was not toxic against Artemia nauplii and did not have antimicrobial activity against bacterial cells. However, the IsL was able to significantly inhibit the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis.

Aims: To investigate whether transient dietary restriction or aerobic exercise in young adulthood exert long-lasting protection against brain aging later in life., Main Methods: Seven-week-old male Wistar rats were divided into 2 groups and given either normal saline as a vehicle (n = 8) or 150 mg/kg/day of D-galactose (n = 40) for 28 weeks, the D-galactose being used to induce aging. At week 13 of the experiment, D-galactose-treated rats were further divided into 5 groups, 1) no intervention, 2) transient dietary restriction for 6 weeks (week 13-18), 3) transient exercise for 6 weeks (week 13-18), 4) long-term dietary restriction for 16 weeks (week 13-28), and 5) long-term exercise for 16 weeks (week 13-28). At the end of week 28, cognitive function was examined, followed by molecular studies in the hippocampus., Key Findings: Our results showed that either long-term dietary restriction or aerobic exercise effectively attenuated cognitive function in D-galactose-treated rats via the attenuation of oxidative stress, cellular senescence, Alzheimer's-like pathology, neuroinflammation, and improvements in mitochondria, brain metabolism, adult neurogenesis, and synaptic integrity. Although transient interventions provided benefits in some brain parameters in D-galactose-treated rats, an improvement in cognitive function was not observed., Significance: Our findings suggested that transient lifestyle interventions failed to exert a long-lasting protective effect against brain aging. Hence, novel drugs mimicking the neuroprotective effect of long-term dietary restriction or exercise and the combination of the two since young age appear to be more appropriate treatments for the elderly who are unable to engage in long-term dietary restriction or exercise., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Cardiac apoptosis plays a key role in increased morbidity associated with aging-induced-cardiac disorder. Mitochondria play an important role in cardiac apoptosis, and dynamin-related protein 1 (Drp1), as a main mediator of mitochondrial fission, can trigger the mitophagy process to sustain the mitochondrial quality. The present study was done to determine the effect of vitamin D (VitD) treatment on cardiac hypertrophy through mitophagy regulation in aged animals induced by D-galactose (D-GAL)., Methods and Results: Male Wistar rats were randomly divided into four groups: control, D-GAL (aging group), D-GAL co-injected with VitD (D-GAL ± VitD), and D-GAL plus ethanol (D-GAL ± Ethanol). Aging was induced by an intraperitoneal (i.p.) administration of D-GAL at 150 mg/kg daily for eight weeks and also VitD (400 IU/kg) or ethanol was injected (i.p.) into aging rats. Then, the levels of cardiac mitophagy and cardiac apoptosis were determined by measuring the expression of tensin homologue (PTEN)-induced putative kinase 1 (PINK1), Drp1, Bcl2-Associated X (Bax), and B-cell lymphoma 2 (Bcl2) genes. Aging in rats was associated with a reduction in mitophagy and also an increase in apoptosis of the heart through down-regulation of Drp1, PINK1, and Bcl2 genes and also up-regulation of Bax. However, VitD improved cardiac hypertrophy through cardiac mitophagy in D-GAL-induced aging rats., Conclusion: VitD can inhibit cardiac hypertrophy by an increase in mitophagy and a decrease in apoptosis in the aging heart. The illustration of the suggested mechanism underlying of Vitamin D in cardiac hypertrophy induced by aging., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Prolonged lactation provides substantial health benefits, possibly because of galactose as part of milk sugar lactose. Isocaloric replacement of dietary glucose [16 energy%(en%)] with galactose within a normal diet (64en% carbohydrates) during a 3-wk postweaning period provided substantial benefits on short- and long-term physiologic and metabolic parameters at the whole-body level and liver in female mice, which might be attributable to intestinal function., Objectives: This study aimed to investigate if partial dietary replacement of glucose with galactose alters intestinal metabolism underlying hepatic health effects., Methods: Proximal intestinal mucosa gene profiles in female mice were analyzed using RNAseq technology, validated, and correlated with hepatic health parameters., Results: Transcriptome analysis revealed that the presence of galactose primarily affected the pathways involved in energy metabolism. A consistently higher expression was observed in the subset of mitochondrial transcripts (78 of 80, all P.adj < 0.1). Oxidative phosphorylation (OXPHOS) represented the most upregulated process (all top 10 pathways) independent of the total mitochondrial mass (P = 0.75). Moreover, galactose consistently upregulated carbohydrate metabolism pathways, specifically glycolysis till acetyl-CoA production and fructose metabolism. Also, the expression of transcripts involved in these pathways was negatively correlated with circulating serum amyloid A3 protein, a marker of hepatic inflammation [R (-0.61, -0.5), P (0.002, 0.01)]. Accordingly, CD163 + cells were decreased in the liver. Additionally, the expression of key fructolytic enzymes in the small intestinal mucosa was negatively correlated with triglyceride accumulation in the liver [R (-0.45, -0.4), P (0.03, 0.05)]., Conclusions: To our knowledge, our results show for the first time the role of galactose as an OXPHOS activator in vivo. Moreover, the concept of intestinal cells acting as the body's metabolic gatekeeper is strongly supported, as they alter substrate availability and thereby contribute to the maintenance of metabolic homeostasis, protecting other organs, as evidenced by their potential ability to shield the liver from the potentially detrimental effects of fructose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Liver aging, marked by cellular senescence and low-grade inflammation, heightens susceptibility to chronic liver disease and worsens its prognosis. Insulin-like growth factor 2 (IGF2) has been implicated in numerous aging-related diseases. Nevertheless, its role and underlying molecular mechanisms in liver aging remain largely unexplored., Methods: The expression of IGF2 was examined in the liver of young (2-4 months), middle-aged (9-12 months), and old (24-26 months) C57BL/6 mice. In vivo, we used transgenic IGF2 f/f ; Alb-Cre mice and D-galactose-induced aging model to explore the role of IGF2 in liver aging. In vitro, we used specific short hairpin RNA against IGF2 to knock down IGF2 in AML12 cells. D-galactose and hydrogen peroxide treatment were used to induce AML12 cell senescence., Results: We observed a significant reduction of IGF2 levels in the livers of aged mice. Subsequently, we demonstrated that IGF2 deficiency promoted senescence phenotypes and senescence-associated secretory phenotypes (SASPs), both in vitro and in vivo aging models. Moreover, IGF2 deficiency impaired mitochondrial function, reducing mitochondrial respiratory capacity, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD) + /NADH ratio, increasing intracellular and mitochondrial reactive oxygen species levels, and disrupting mitochondrial membrane structure. Additionally, IGF2 deficiency markedly upregulated CCAAT/enhancer-binding protein beta (CEBPB). Notably, inhibiting CEBPB reversed the senescence phenotypes and reduced SASPs induced by IGF2 deficiency., Conclusions: In summary, our findings strongly suggest that IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling. These results provide compelling evidence for considering IGF2 as a potential target for interventions aimed at slowing down the process of liver aging., (© 2023. The Author(s).)

The gut might play an important role in the etiopathogenesis of Alzheimer's disease (AD) as gastrointestinal alterations often precede the development of neuropathological changes in the brain and correlate with disease progression in animal models. The gut has an immense capacity to generate free radicals whose role in the etiopathogenesis of AD is well-known; however, it remains to be clarified whether gastrointestinal redox homeostasis is associated with the development of AD. The aim was to (i) examine gastrointestinal redox homeostasis in the presymptomatic and symptomatic Tg2576 mouse model of AD; (ii) investigate the effects of oral d-galactose previously shown to alleviate cognitive deficits and metabolic changes in animal models of AD and reduce gastrointestinal oxidative stress; and (iii) investigate the association between gastrointestinal redox biomarkers and behavioral alterations in Tg2576 mice. In the presymptomatic stage, Tg2576 mice displayed an increased gastrointestinal electrophilic tone, characterized by higher lipid peroxidation and elevated Mn/Fe-SOD activity. In the symptomatic stage, these alterations are rectified, but the total antioxidant capacity is decreased. Chronic oral d-galactose increased the antioxidant capacity and reduced lipid peroxidation in the Tg2576 but had the opposite effects in the wild-type animals. The total antioxidant capacity of the gastrointestinal tract was associated with greater spatial memory. Gut redox homeostasis might be involved in the development and progression of AD pathophysiology and should be further explored in this context.

Aging and age-related diseases are important study topics due to their associations with progressive physiological damage to genes, cells, tissues, and the entire organism, which ultimately affects the functional efficiency of organs. Lycium ruthenicum Murr. is a functional food that is known for its high contents of anthocyanins and spermidines, both of which have been demonstrated to have positive effects on anti-aging activity and anti-oxidation. In this study, we used HPLC-MS to analyze the constituents of L. ruthenicum Murr. Extract (LRM) and investigated their potential mechanism for exerting antioxidative effects in D-galactose (D-Gal) aging model mice. LRM (25 mg/kg, 50 mg/kg, and 100 mg/kg) improved cognitive function in D-Gal-treated mice, as shown by reduced escape latencies and increased platform crossings in behavioral tests. We measured the contents of lipid peroxidation (LPO) and malondialdehyde (MDA) and the enzyme activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in mice serum and brain after 6 weeks of D-Gal treatment. LRM decreased the contents of LPO and MDA and increased the enzyme activities of SOD and GSH-Px, indicating the protection effect of LRM against D-Gal-induced oxidative stress. Additionally, LRM can inhibit oxidative stress in cells by reducing intracellular ROS levels and restoring mitochondrial membrane potential, thereby inhibiting paraquat (PQ)-induced cellular senescence and delaying cell aging. Therefore, LRM has the potential to be a healthcare product for the treatment of age-related diseases.

With the ageing of society's population, neurodegenerative diseases have become an important factor affecting the quality of life and mortality in the elderly. Since its physiopathological processes are complex and the authorized medications have recently been shown to have several adverse effects, the development of safe and efficient medications is urgently needed. In this study, we looked at how ginsenoside Rg1 works to postpone neural stem cell ageing and brain ageing, giving it a solid scientific foundation for use as a therapeutic therapy for neurodegenerative diseases., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Adenosine monophosphate kinase/liver kinase B1/peroxisome proliferator-activated receptor-γ coactivator 1-α (AMPK/LKB1/PGC1α) pathway has a vital role in regulating age-related diseases. It controls neurogenesis, cell proliferation, axon outgrowth, and cellular energy homeostasis. AMPK pathway also regulates mitochondrial synthesis. The current study evaluated the effect of chrysin on D-galactose (D-gal) induced-aging, neuron degeneration, mitochondrial dysfunction, oxidative stress, and neuroinflammation in mice. The mice were allocated randomly into four groups (10 each group): Group 1: normal control group, Group 2: D-gal group, Groups 3 and 4: chrysin (125 and 250 mg/kg, respectively). Groups 2-4 were injected with D-gal (200 mg/kg/day; s.c) for 8 weeks to induce aging. Groups 3 and 4 were orally gavaged every day concurrent with D-gal. At the end of experiment, behavioral, brain biochemical and histopathological changes were monitored. Chrysin administration elevated discrimination ratio in object recognition, Y Maze percentage alternation, locomotor activity and brain contents of AMPK, LKB1, PGC1α, NAD (P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), nerve growth factor (NGF) (neurotrophin-3; NT-3), and seretonin as well as reduced brain contents of tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), advanced glycation end products (AGEs) and glial fibrillary acidic protein (GFAP) compared to D-gal-treated mice. Chrysin also alleviated cerebral cortex and white matter neurons degeneration. Chrysin protects against neurodegeneration, improves mitochondrial autophagy and biogenesis as well as activates antioxidant genes expression. In addition, chrysin ameliorates neuroinflammation and stimulates the release of NGF and serotonin neurotransmitter. So, chrysin has a neuroprotective effect in D-gal induced-aging in mice., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Brain aging is the most important risk factor for neurodegenerative disorders, and abnormal apoptosis is linked to neuronal dysfunction. Specifically, studies have found that exercise effectively inhibits hippocampal neuronal apoptosis, while the molecular mechanism remains unclear. In the present study, we investigated the impact of aerobic exercise on hippocampal neuronal apoptosis in aging mice and the potential involvement of DAPK1 and its downstream pathways based on recent data that DAPK1 may be associated with neuronal death in neurodegenerative diseases. Senescent mice were subjected to 8 weeks of Aerobic training. Following behavioral testing, hippocampal samples were examined histologically and biochemically to detect pathological changes, neuronal apoptosis, and mRNA and protein levels. We found that the exercise intervention improved spatial memory and alleviated neuronal apoptosis in the brain. Notably, exercise down-regulated DAPK1 expression and inhibited Fas death receptor transactivation and the mitochondrial apoptotic pathway in the hippocampus. These results shed new light on the protective effect of regular exercise against brain aging though modulating the DAPK1 pathway., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Aging is a highly complicated natural process. Brain aging is associated with remarkable neurodegenerative changes and oxidative damage. Whey protein (WP) has been mentioned to have an antioxidant property. Nuclear factor erythrogen-2 associated factor 2 (Nrf2) signaling pathway is an antioxidant defense system. Nrf2 activity declines with age so, its activation could be a promising therapeutic strategy for aging. This study aimed to explore the anti-aging role of WP against D-galactose (D-gal) induced age-related degenerative changes and oxidative damage in the prefrontal cortex (PFC) and investigate its underlying mechanisms. Forty adult male rats were divided into 4 groups; control, WP group received WP (28.77 mg/kg/day) by gastric tube on the 4 th experimental week; D-gal (model group) received D-gal (300 mg/kg/day) intraperitoneally for 8 weeks and D-gal +WP group received WP on the 4 th week of D-gal treatment. Specimens from PFC were obtained for biochemical, histological, immunohistochemical and western blot analysis. WP treatment in D-gal +WP group reduced lipid peroxidation, enhanced antioxidant enzyme activities, decreased advanced glycation end products level and improved the histological and ultrastructural alterations. Moreover, the number of neurons expressed the senescence marker; p21 and percentage area of the astrocytic marker; glial fibrillary acidic protein were significantly reduced. WP also enhanced Nrf2 pathway and its downstream targets; heme oxygenase-1 and NADPH quinone oxidoreductase 1. In conclusion WP alleviates the D-gal-induced PFC aging through activating Nrf2 pathway, reducing cell senescence and gliosis. So, it may be a potential therapeutic target to retard the aging process., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received widespread attention because of their significant protective effects on the kidney. Previous studies have shown that Sirt1, as which is an antiaging protein, is closely related to the maintenance of redox homeostasis. The goal of this study was to determine whether empagliflozin could ameliorate D-galactose-induced renal senescence in mice, and examine the possible mechanisms of Sirt1. We constructed a rapid ageing model in mice by administering D-galactose. An ageing model was constructed by treating cells with high glucose. Treadmill and Y-maze tests were used to assess exercise tolerance and learning memory ability. Pathologically stained sections were used to assess kidney injury. Tissue and cell senescence were evaluated by senescence-associated β-galactosidase staining. The expression levels of P16, SOD1, SOD2 and Sirt1 were detected by immunoblotting. D-gal-treated mice exhibited significant age-related changes, as measured by behavioural tests and ageing marker protein levels. empagliflozin alleviated these ageing manifestations. In addition, Sirt1, SOD1 and SOD2 levels were downregulated in model mice and upregulated by empagliflozin treatment. Empagliflozin had similar protective effects at the cellular level, and these effects were reduced by the Sirt1 inhibitor. Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Studies have shown that lidocaine has antioxidative stress, anti-inflammatory, and nerve-protective effects. The current study investigated the effects of lidocaine on cognitive function in rats with cognitive dysfunction., Methods: A total of 48 rats were randomly assigned to four groups of 12 rats each: control group; L (lidocaine) + D (d-galactose) group, d-galactose group (D group); and D + L group. We assessed cognitive function using a Morris water maze (MWM) and pathologic changes of hippocampal sections. An enzyme-linked immunosorbent assay (ELIZA) was used to detect serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels in rats, and protein immunoblotting (western blot) was used to detect brain tissue proteins (collapsing response mediator protein-2 [CRMP2], phosphorylated-collapsing response mediator protein-2 [P-CRMP2], and β-amyloid protein [Aβ])., Results: The MWM showed that the d-gal group (284.09 ± 20.46, 5.20 ± 0.793) performed worse than the L + D (265.37 ± 22.34, 4.170 ± 0.577; p = .000) and D + L groups (254.72 ± 27.87, 3.750; p = .000) in escape latency and number of platform crossings, respectively. The L + D group (44.94 ± 2.92 pg/mL, 6.22 ± 0.50 pg/mL, and 460.02 ± 8.26 nmol/mL) and D + L group (46.88 ± 2.63 pg/mL, 5.90 ± 0.38 pg/mL, and 465.6 ± 16.07 nmol/mL) had significantly lower serum inflammatory levels of interleukin-6, tumor necrosis factor-α, and MDA than the d-gal group (57.79 ± 3.96 pg/mL, 11.25 ± 1.70 pg/mL, and 564.9 ± 15.90 nmol/mL), respectively. The L + D group (3.17 ± 0.41 μg/mL) and D + L group (3.08 ± 0.09 μg/mL) had significantly higher serum inflammatory levels of SOD than the d-gal group (2.20 ± 0.13 μg/mL) (all p = .000). The levels of CRMP2, P-CRMP2, and Aβ in the brain tissue homogenates of the L + D group (0.87 ± 0.04, 0.57 ± 0.0, and 0.16 ± 0.02) and the D + L group (0.82 ± 0.05, 0.58 ± 0.09, and 0.15 ± 0.02) were significantly different than the d-gal group (0.67 ± 0.03, 0.96 ± 0.040, and 0.29 ± 0.05)., Conclusions: Lidocaine was shown to reduce cognitive impairment in rats with cognitive dysfunction through anti-inflammatory and antioxidative stress mechanisms in combination with CRMP2 antiphosphorylation., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Necroptosis, a programmed form of necrotic cell death carried out by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3, has been found to be implicated in the pathogenesis of Alzheimer's disease (AD). An FDA-approved anti-cancer drug, pazopanib, is reported to possess potent inhibitory effect against necroptosis via interfering with RIPK1. So far, there are no existing data on the influence of pazopanib on necroptotic pathway in AD. Thus, this study was designed to explore the impact of pazopanib on cognitive impairment provoked by ovariectomy (OVX) together with D-galactose (D-Gal) administration in rats and to scrutinize the putative signaling pathways underlying pazopanib-induced effects. Animals were allocated into four groups; the first and second groups were exposed to sham operation and administered normal saline and pazopanib (5 mg/kg/day, i.p.), respectively, for 6 weeks, while the third and fourth groups underwent OVX then were injected with D-Gal (150 mg/kg/day, i.p.); concomitantly with pazopanib in the fourth group for 6 weeks. Pazopanib ameliorated cognitive deficits as manifested by improved performance in the Morris water maze besides reversing the histological abnormalities. Pazopanib produced a significant decline in p-Tau and amyloid beta (Aβ) plaques. The neuroprotective effect of pazopanib was revealed by hampering neuroinflammation, mitigating neuronal death and suppressing RIPK1/RIPK3/MLKL necroptosis signaling pathway. Accordingly, hindering neuroinflammation and the necroptotic RIPK1/RIPK3/MLKL pathway could contribute to the neuroprotective effect of pazopanib in D-Gal/OVX rat model. Therefore, this study reveals pazopanib as a valuable therapeutic agent in AD that warrants future inspection to provide further data regarding its neuroprotective effect., (© 2023. The Author(s).)

Aim: Alzheimer's disease (AD) is the most prevalent form of dementia with multiple etiology and no effective remedy. Statins are a group of medicines that are basically used to lower cholesterol. However, several studies have recently done to assess the potential relationship between statins use and dementia but presented controversial results., Methods: In this study, using ovariectomy and D-galactose injection, a model of AD was induced in female rats, and then the protective effects of oral administration of simvastatin were investigated. shuttle box and Y-maze tests were done to assess the animals' learning and memory performance. Using GC-MC, ELISA, Immunohistochemistry and tissue staining techniques, changes in the amount of short-chain fatty acids (SCFAs), plasma and hippocampus neuroinflammatory markers and histological changes in the intestine and hippocampus were assessed in sham, disease and treatment groups., Key Findings: Oral administration of simvastatin improved the gut microbiome activity (increased the amount of SCFAs in fecal samples) and strengthened the tight junctions of intestinal cells. Moreover, simvastatin reduced the amount of TNF-α and IL-1β in plasma and hippocampus. Also, cell death and Amyloid plaques notably decreased in the simvastatin-treated hippocampal tissue. All these physiological changes led to better performance in behavioral tasks in the treatment group in comparison to the disease group., Significance: These findings provide evidence that simvastatin may improve gut-brain axis followed by improvement in learning and memory via an anti-inflammatory effect., Competing Interests: Declaration of Competing Interest We declare that this work has not been published previously, that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright holder., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Age-related hearing loss, known as presbycusis, is the result of auditory system degeneration. Numerous studies have suggested that reactive oxygen species (ROS) and mitochondrial oxidative damage play important roles in the occurrence and progression of aging. The D-galactose (D-gal)-induced aging model is well known and widely utilized in aging research. Our previous studies demonstrate that administration of D-gal causes mitochondrial oxidative damage and causes subsequent dysfunction in the cochlear ribbon synapses, which in turn leads to hearing changes and early stage presbycusis. Stria vascularis (SV) cells are vital for hearing function. However, it is unclear to what extent D-gal induces oxidative damage and apoptosis in the cochlear SV of mice. In addition, the source of the causative ROS in the cochlear SV has not been fully investigated., Methods: In this study, we investigated ROS generation in the cochlear SV of mice treated with D-gal. Hearing function was measured using the auditory brainstem response (ABR). Immunofluorescence was used to examine apoptosis and oxidative damage. Transmission electron microscopy was also used to investigate the mitochondrial ultrastructure. DNA fragmentation was determined using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. Mitochondrial membrane potential (MMP) and ATP were also measured., Results: We found that D-gal-treated mice exhibited a significant shift in the mean amplitude and latency of the ABR; a remarkable increase in the levels of NADPH oxidase (NOX-2), Uncoupling protein 2 (UCP2) and cleaved caspase-3 (c-Cas3) was observed, as well as an increase in the number of TUNEL-positive cells were observed in the SV of mice. Both the expression of the DNA oxidative damage biomarker 8-hydroxy-2-deoxyguanosine (8-OHdG) and a commonly occurring mitochondrial DNA deletion were markedly elevated in the SV of mice that had been treated with D-gal to induce aging. Conversely, the ATP level and MMP were significantly reduced in D-gal-induced aging mice. We also found alterations in the mitochondrial ultrastructure in the SV of aging mice, which include swollen and distorted mitochondrial shape, shortened and thickened microvilli, and the accumulation of lysosomes in the SV., Conclusion: Our findings suggest that the impairment of cochlear SV during presbycusis may be caused by mitochondrial oxidative damage and subsequent apoptosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In this study, a highly branched polysaccharide (GPF, 112.0 kDa) was isolated and purified from Gomphus clavatus Gray fruiting bodies. GPF was primarily composed of mannose, galactose, arabinose, xylose, and glucose at a molar ratio of 3.2:1.9:1.6:1.2:1.0. GPF was a highly branched heteropolysaccharide composed of 13 glucosidic bonds, with a degree of branching (DB) of 48.85 %. GPF exhibited anti-aging activity in vivo, significantly increased antioxidant enzymes activities (SOD, CAT and GSH-Px), improved total antioxidant capability (T-AOC) and decreased MDA level in the serum and brain of d-Gal induced aging mice. Behavioral experiments showed that GPF effectively improved learning and memory deficits in d-Gal induced aging mice. Mechanistic studies indicated that GPF could activate AMPK by increasing AMPK phosphorylation and upregulating SIRT1 and PGC-1α expression. These findings suggest that GPF has significant potential as a natural candidate to slow down aging and prevent aging-related 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 B.V.)

Red ginseng is a classical processed product from Panax ginseng. C.A Meyer with many bioactive components formed through the Maillard reaction called Maillard reaction products. Maillard reaction refers to complex reversible reactions between amino acids or proteins and glycosides, which are used in food processing and storage, as well as in tobacco development, traditional Chinese medicine processing, and wine brewing. Arginyl-fructosyl-glucose (AFG) is a main non-saponin (ginsenoside) component produced in red ginseng processing, with high antioxidant, anti-apoptotic and neuroprotective efficiencies. However, its effects and mechanisms against oxidation stress in on the brain remain elusive. Therefore, this study aimed at exploring the therapeutic effect exerted by AFG on murine subacute brain aging induced by D-galactose (D-gal) and its potential molecular mechanism in the murine model, finding that AFG (40 and 80 mg/kg) significantly ameliorated D-gal-resulted changes in pathology. Besides, according to the transmission electron microscopy (TEM) and Western blot, AFG corrected the mitochondrial dysfunction resulted from ROS, thereby delaying the mice brain aging caused by D-gal., 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 B.V.)

Previously, we observed curcumin improves aging-associated memory impairment in D-galactose (D-gal) and normal-aged (NA) mice. Evidence showed that multiple agents can be used in managing aging-induced memory dysfunction, drawn by the contribution of several pathways. Curcumin and Epigallocatechin 3 gallate (EGCG) combination substantially reduced the oxidative stress that commonly mediates aging. This study examined the combined effect of EGCG and curcumin on memory improvement in two recognized models, D-gal and normal-aged (NA) mice. The co-administration of EGCG and curcumin significantly (p < 0.05) increased retention time detected by passive avoidance (PA) and freezing response determined in contextual fear conditioning (CFC) compared to the discrete administration of EGCG or curcumin. Biochemical studies revealed that the combination of EGCG and curcumin remarkably ameliorated the levels (p < 0.05) of glutathione, superoxide dismutase, catalase, advanced oxidation protein products, nitric oxide, and lipid peroxidation compared to the monotherapy of EGCG or curcumin in mice hippocampi. The behavioral and biochemical studies revealed that the combination of EGCG and curcumin showed better improvement in rescuing aging-associated memory disorders in mice. EGCG and curcumin combination could serve as a better choice in managing aging-related memory disorders., (© 2023. Springer Nature Limited.)

Lonicera japonica polysaccharides (LJPs) exhibit anti-aging effect in nematodes. Here, we further studied the function of LJPs on aging-related disorders in D-galactose (D-gal)-induced ICR mice. Four groups of mice including the control group, the D-gal-treated group, the intervening groups with low and high dose of LJPs (50 and 100 mg/kg/day) were raised for 8 weeks. The results showed that intragastric administration with LJPs improved the organ indexes of D-gal-treated mice. Moreover, LJPs improved the activity of superoxide dismutase (SOD), catalase (CAT) as well as glutathione peroxidase (GSH-Px) and decreased the malondialdehyde (MDA) level in serum, liver and brain. Meanwhile, LJPs restored the content of acetylcholinesterase (AChE) in the brain. Further, LJPs reversed the liver tissue damages in aging mice. Mechanistically, LJPs alleviate oxidative stress at least partially through regulating Nrf2 signaling. Additionally, LJPs restored the gut microbiota composition of D-gal-treated mice by adjusting the Firmicutes/Bacteroidetes ratio at the phylum level and upregulating the relative abundances of Lactobacillaceae and Bifidobacteriacesa. Notably, the KEGG pathways involved in hazardous substances degradation and flavone and flavonol biosynthesis were significantly enhanced by LJPs treatment. Overall, our study uncovers the role of LJPs in modulating oxidative stress and gut microbiota in the D-gal-induced aging mice., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Senescent cells persist and continuously secrete proinflammatory and tissue-remodeling molecules that poison surrounding cells, leading to various age-related diseases, including diabetes, atherosclerosis, and Alzheimer's disease. The underlying mechanism of cellular senescence has not yet been fully explored. Emerging evidence indicates that hypoxia is involved in the regulation of cellular senescence. Hypoxia-inducible factor (HIF)- 1α accumulates under hypoxic conditions and regulates cellular senescence by modulating the levels of the senescence markers p16, p53, lamin B1, and cyclin D1. Hypoxia is a critical condition for maintaining tumor immune evasion, which is promoted by driving the expression of genetic factors (such as p53 and CD47) while triggering immunosenescence. Under hypoxic conditions, autophagy is activated by targeting BCL-2/adenovirus E1B 19-kDa interacting protein 3, which subsequently induces p21 WAF1/CIP1 as well as p16 Ink4a and increases β-galactosidase (β-gal) activity, thereby inducing cellular senescence. Deletion of the p21 gene increases the activity of the hypoxia response regulator poly (ADP-ribose) polymerase-1 (PARP-1) and the level of nonhomologous end joining (NHEJ) proteins, repairs DNA double-strand breaks, and alleviates cellular senescence. Moreover, cellular senescence is associated with intestinal dysbiosis and an accumulation of D-galactose derived from the gut microbiota. Chronic hypoxia leads to a striking reduction in the amount of Lactobacillus and D-galactose-degrading enzymes in the gut, producing excess reactive oxygen species (ROS) and inducing senescence in bone marrow mesenchymal stem cells. Exosomal microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play important roles in cellular senescence. miR-424-5p levels are decreased under hypoxia, whereas lncRNA-MALAT1 levels are increased, both of which induce cellular senescence. The present review focuses on recent advances in understanding the role of hypoxia in cellular senescence. The effects of HIFs, immune evasion, PARP-1, gut microbiota, and exosomal mRNA in hypoxia-mediated cell senescence are specifically discussed. This review increases our understanding of the mechanism of hypoxia-mediated cellular senescence and provides new clues for anti-aging processes and the treatment of aging-related 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pearl oyster shells comprise two layers, a prismatic and nacreous layer, of calcium carbonate. The nacreous layer has been used in Chinese medicine since ancient times. In this study, we investigated the effects of the extract from the nacreous layer of pearl oysters (nacre extract) on D-galactose-induced brain and skin aging. Treatment with nacre extract led to the recovery of D-galactose-induced memory impairment, as examined using the Barnes maze, novel object recognition, and Y-maze tests. A histological study showed that nacre extract suppressed D-galactose-induced neuronal cell death and the expression of B cell lymphoma 2 (Bcl-2)-associated X protein (Bax), which causes apoptosis in the hippocampus. In addition, the expression levels of brain-derived neurotrophic factor, which counteracts age-related brain dysfunction, and nicotinamide adenine dinucleotide-dependent deacetylase (sirtuin 1), which delays aging and extends lifespan, increased after nacre extract treatment. Moreover, the nacre extract showed anti-aging effects against D-galactose-induced skin aging; it suppressed D-galactose-induced wrinkle formation, decreased skin moisture, decreased epidermal thickness, and destroyed collagen arrangement associated with aging. Furthermore, the nacre extract suppressed oxidative stress associated with aging in the brain and skin by upregulating the expression of catalase and superoxide dismutase. The expression level of the cellular senescence marker p16, which is induced by oxidative stress, was elevated in the hippocampus and skin epidermal layer of D-galactose-treated mice, and it was suppressed by the administration of nacre extract. These results show that the nacre extract can suppress D-galactose-induced aging by enhancing anti-oxidant activity and suppressing p16 expression. Thus, the nacre extract may be an effective anti-aging agent., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Premature ovarian insufficiency (POI) has become one of the greatest health threats to the reproduction of women during their fertile age. Lycium barbarum polysaccharides (LBPs) are known for anti-aging and reproductive protective functions. Here, we investigated the protective effect of LBP on POI mice and revealed its possible mechanism by a combination of 16S rRNA sequencing and metabolomics analysis. In the current study, female C57BL/6J mice treated with D-galactose were used as a model to investigate the reversal effect of LBP on the degenerative ovarian function. The ameliorative effect of LBP on POI was evaluated from the estrous cycle, ovarian reserve, serum sex hormone levels, and fertility testing. Additionally, 16S rRNA gene sequencing and untargeted metabolomics were integrated to analyze the effects of LBP on the gut microbiota and fecal metabolic profile in the POI mice. The results showed that LBP administration significantly increased the total number of follicles and the number of follicles at different developmental stages in the POI mice. In addition, LBP was effective in reducing the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), regularizing the disordered estrous cycle, and increasing the number of offspring of the POI mice. The results from 16S rRNA sequencing showed that LBP had beneficial effects on the composition and structure of the gut microbiota in the POI mice. In a metabolomics study, a total of 23 metabolites were finally identified as potential biomarkers of POI, and multiple pathways were regulated after the treatment of LBP, especially the arginine biosynthesis, glycerophospholipid metabolism and steroid hormone biosynthesis pathways. Pearson's correlation analysis showed that the regulation effect of LBP on metabolites was closely related to Faecalibaculum , Bilophila and Anaerofustis in the gut microbiota. In summary, the results demonstrated that LBP could improve the ovarian reserve and provides evidence both on the gut microbiota and metabolism, which provide beneficial support for the applications of LBP in female ovarian function degeneration.