Single-base resolution quantitative genome methylation analysis in the model bacterium Helicobacter pylori by enzymatic methyl sequencing (EM-Seq) reveals influence of strain, growth phase, and methyl homeostasis.

BACKGROUND: Bacterial epigenetics is a rapidly expanding research field. DNA methylation by diverse bacterial methyltransferases (MTases) contributes to genomic integrity and replication, and many recent studies extended MTase function also to global transcript regulation and phenotypic variation. Helicobacter pylori is currently one of those bacterial species which possess the highest number and the most variably expressed set of DNA MTases. Next-generation sequencing technologies can directly detect DNA base methylation. However, they still have limitations in their quantitative and qualitative performance, in particular for cytosine methylation. RESULTS: As a complementing approach, we used enzymatic methyl sequencing (EM-Seq), a technology recently established that has not yet been fully evaluated for bacteria. Thereby, we assessed quantitatively, at single-base resolution, whole genome cytosine methylation for all methylated cytosine motifs in two different H. pylori strains and isogenic MTase mutants. EM-Seq reliably detected both m5C and m4C methylation. We demonstrated that three different active cytosine MTases in H. pylori provide considerably different levels of average genome-wide single-base methylation, in contrast to isogenic mutants which completely lost specific motif methylation. We found that strain identity and changed environmental conditions, such as growth phase and interference with methyl donor homeostasis, significantly influenced quantitative global and local genome-wide methylation in H. pylori at specific motifs. We also identified significantly hyper- or hypo-methylated cytosines, partially linked to overlapping MTase target motifs. Notably, we revealed differentially methylated cytosines in genome-wide coding regions under conditions of methionine depletion, which can be linked to transcript regulation. CONCLUSIONS: This study offers new knowledge on H. pylori global and local genome-wide methylation and establishes EM-Seq for quantitative single-site resolution analyses of bacterial cytosine methylation.

Role of epigenetic regulatory mechanisms in age-related bone homeostasis imbalance.

Alterations to the human organism that are brought about by aging are comprehensive and detrimental. Of these, an imbalance in bone homeostasis is a major outward manifestation of aging. In older adults, the decreased osteogenic activity of bone marrow mesenchymal stem cells and the inhibition of bone marrow mesenchymal stem cell differentiation lead to decreased bone mass, increased risk of fracture, and impaired bone injury healing. In the past decades, numerous studies have reported the epigenetic alterations that occur during aging, such as decreased core histones, altered DNA methylation patterns, and abnormalities in noncoding RNAs, which ultimately lead to genomic abnormalities and affect the expression of downstream signaling osteoporosis treatment and promoter of fracture healing in older adults. The current review summarizes the impact of epigenetic regulation mechanisms on age-related bone homeostasis imbalance.

HSDL2 links nutritional cues to bile acid and cholesterol homeostasis.

In response to energy and nutrient shortage, the liver triggers several catabolic processes to promote survival. Despite recent progress, the precise molecular mechanisms regulating the hepatic adaptation to fasting remain incompletely characterized. Here, we report the identification of hydroxysteroid dehydrogenase-like 2 (HSDL2) as a mitochondrial protein highly induced by fasting. We show that the activation of PGC1α-PPARα and the inhibition of the PI3K-mTORC1 axis stimulate HSDL2 expression in hepatocytes. We found that HSDL2 depletion decreases cholesterol conversion to bile acids (BAs) and impairs FXR activity. HSDL2 knockdown also reduces mitochondrial respiration, fatty acid oxidation, and TCA cycle activity. Bioinformatics analyses revealed that hepatic Hsdl2 expression positively associates with the postprandial excursion of various BA species in mice. We show that liver-specific HSDL2 depletion affects BA metabolism and decreases circulating cholesterol levels upon refeeding. Overall, our report identifies HSDL2 as a fasting-induced mitochondrial protein that links nutritional signals to BAs and cholesterol homeostasis.

Differential regulation of lung homeostasis and silicosis by the TAM receptors MerTk and Axl.

Introduction: TAM receptor-mediated efferocytosis plays an important function in immune regulation and may contribute to antigen tolerance in the lungs, a site with continuous cellular turnover and generation of apoptotic cells. Some studies have identified failures in efferocytosis as a common driver of inflammation and tissue destruction in lung diseases. Our study is the first to characterize the in vivo function of the TAM receptors, Axl and MerTk, in the innate immune cell compartment, cytokine and chemokine production, as well as the alveolar macrophage (AM) phenotype in different settings in the airways and lung parenchyma. Methods: We employed MerTk and Axl defective mice to induce acute silicosis by a single exposure to crystalline silica particles (20 mg/50 µL). Although both mRNA levels of Axl and MerTk receptors were constitutively expressed by lung cells and isolated AMs, we found that MerTk was critical for maintaining lung homeostasis, whereas Axl played a role in the regulation of silica-induced inflammation. Our findings imply that MerTk and Axl differently modulated inflammatory tone via AM and neutrophil recruitment, phenotype and function by flow cytometry, and TGF-ß and CXCL1 protein levels, respectively. Finally, Axl expression was upregulated in both MerTk-/- and WT AMs, confirming its importance during inflammation. Conclusion: This study provides strong evidence that MerTk and Axl are specialized to orchestrate apoptotic cell clearance across different circumstances and may have important implications for the understanding of pulmonary inflammatory disorders as well as for the development of new approaches to therapy.

BR regulates wheat root salt tolerance by maintaining ROS homeostasis.

MAIN CONCLUSION: Trace amounts of epibrassinolide (EpiBL) could partially rescue wheat root length inhibition in salt-stressed situation by scavenging ROS, and ectopic expression of TaDWF4 or TaBAK1 enhances root salt tolerance in Arabidopsis by balancing ROS level. Salt stress often leads to ion toxicity and oxidative stress, causing cell structure damage and root development inhibition in plants. While prior research indicated the involvement of exogenous brassinosteroid (BR) in plant responses to salt stress, the precise cytological role and the function of BR in wheat root development under salt stress remain elusive. Our study demonstrates that 100 mM NaCl solution inhibits wheat root development, but 5 nM EpiBL partially rescues root length inhibition by decreasing H2O2 content, oxygen free radical (OFR) content, along with increasing the peroxidase (POD) and catalase (CAT) activities in salt-stressed roots. The qRT-PCR experiment also shows that expression of the ROS-scavenging genes (GPX2 and CAT2) increased in roots after applying BR, especially during salt stress situation. Transcriptional analysis reveals decreased expression of BR synthesis and root meristem development genes under salt stress in wheat roots. Differential expression gene (DEG) enrichment analysis highlights the significant impact of salt stress on various biological processes, particularly "hydrogen peroxide catabolic process" and "response to oxidative stress". Additionally, the BR biosynthesis pathway is enriched under salt stress conditions. Therefore, we investigated the involvement of wheat BR synthesis gene TaDWF4 and BR signaling gene TaBAK1 in salt stress responses in roots. Our results demonstrate that ectopic expression of TaDWF4 or TaBAK1 enhances salt tolerance in Arabidopsis by balancing ROS (Reactive oxygen species) levels in roots.

Melatonin restores hepatic lipid metabolic homeostasis disrupted by blue light at night in high-fat diet-fed mice.

Artificial light at night (ALAN) is an emerging environmental pollutant that threatens public health. Recently, ALAN has been identified as a risk factor for obesity; however, the role of ALAN and its light wavelength in hepatic lipid metabolic homeostasis remains undetermined. We showed that chronic dim (~5 lx) ALAN (dLAN) exposure significantly promoted hepatic lipid accumulation in obese or diabetic mice, with the most severe effect of blue light and little effect of green or red light. These metabolic phenotypes were attributed to blue rather than green or red dLAN interfering with hepatic lipid metabolism, especially lipogenesis and lipolysis. Further studies found that blue dLAN disrupted hepatic lipogenesis and lipolysis processes by inhibiting hepatic REV-ERBs. Mechanistically, feeding behavior mediated the regulation of dLAN on hepatic REV-ERBs. In addition, different effects of light wavelengths at night on liver REV-ERBs depended on the activation of the corticosterone (CORT)/glucocorticoid receptor (GR) axis. Blue dLAN could activate the CORT/GR axis significantly while other wavelengths could not. Notably, we demonstrated that exogenous melatonin could effectively inhibit hepatic lipid accumulation and restore the hepatic GR/REV-ERBs axis disrupted by blue dLAN. These findings demonstrate that dLAN promotes hepatic lipid accumulation in mice via a short-wavelength-dependent manner, and exogenous melatonin is a potential therapeutic approach. This study strengthens the relationship between ALAN and hepatic lipid metabolism and provides insights into directing ambient light.

Prototyping an Ontological Framework for Cellular Senescence Mechanisms: A Homeostasis Imbalance Perspective.

Although cellular senescence is a key factor in organismal aging, with both positive and negative effects on individuals, its mechanisms remain largely unknown. Thus, integrating knowledge is essential to explain how cellular senescence manifests in tissue damage and age-related diseases. Here, we propose an ontological model that organizes knowledge of cellular senescence in a computer-readable form. We manually annotated and defined cellular senescence processes, molecules, anatomical structures, phenotypes, and other entities based on the Homeostasis Imbalance Process ontology (HOIP). We described the mechanisms as causal relationships of processes and modelled a homeostatic imbalance between stress and stress response in cellular senescence for a unified framework. HOIP was assessed formally, and the relationships between cellular senescence and diseases were inferred for higher-order knowledge processing. We visualized cellular senescence processes to support knowledge utilization. Our study provides a knowledge base to help elucidate mechanisms linking cellular and organismal aging.

Intracellular Protective Functions and Therapeutical Potential of Trehalose.

Trehalose is a naturally occurring, non-reducing saccharide widely distributed in nature. Over the years, research on trehalose has revealed that this initially thought simple storage molecule is a multifunctional and multitasking compound protecting cells against various stress factors. This review presents data on the role of trehalose in maintaining cellular homeostasis under stress conditions and in the virulence of bacteria and fungi. Numerous studies have demonstrated that trehalose acts in the cell as an osmoprotectant, chemical chaperone, free radical scavenger, carbon source, virulence factor, and metabolic regulator. The increasingly researched medical and therapeutic applications of trehalose are also discussed.

Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis.

Micro- and nano-plastics (NPs) are found in human milk, blood, tissues, and organs and associate with aberrant health outcomes including inflammation, genotoxicity, developmental disorders, onset of chronic diseases, and autoimmune disorders. Yet, interfacial interactions between plastics and biomolecular systems remain underexplored. Here, we have examined experimentally, in vitro, in vivo, and by computation, the impact of polystyrene (PS) NPs on a host of biomolecular systems and assemblies. Our results reveal that PS NPs essentially abolished the helix-content of the milk protein ß-lactoglobulin (BLG) in a dose-dependent manner. Helix loss is corelated with the near stoichiometric formation of ß-sheet elements in the protein. Structural alterations in BLG are also likely responsible for the nanoparticle-dependent attrition in binding affinity and weaker on-rate constant of retinol, its physiological ligand (compromising its nutritional role). PS NP-driven helix-to-sheet conversion was also observed in the amyloid-forming trajectory of hen egg-white lysozyme (accelerated fibril formation and reduced helical content in fibrils). Caenorhabditis elegans exposed to PS NPs exhibited a decrease in the fluorescence of green fluorescent protein-tagged dopaminergic neurons and locomotory deficits (akin to the neurotoxin paraquat exposure). Finally, in silico analyses revealed that the most favorable PS/BLG docking score and binding energies corresponded to a pose near the hydrophobic ligand binding pocket (calyx) of the protein where the NP fragment was found to make nonpolar contacts with side-chain residues via the hydrophobic effect and van der Waals forces, compromising side chain/retinol contacts. Binding energetics indicate that PS/BLG interactions destabilize the binding of retinol to the protein and can potentially displace retinol from the calyx region of BLG, thereby impairing its biological function. Collectively, the experimental and high-resolution in silico data provide new insights into the mechanism(s) by which PS NPs corrupt the bimolecular structure and function, induce amyloidosis and onset neuronal injury, and drive aberrant physiological and behavioral outcomes.

Copper Homeostasis in the Model Organism C. elegans.

Cellular and organismic copper (Cu) homeostasis is regulated by Cu transporters and Cu chaperones to ensure the controlled uptake, distribution and export of Cu ions. Many of these processes have been extensively investigated in mammalian cell culture, as well as in humans and in mammalian model organisms. Most of the human genes encoding proteins involved in Cu homeostasis have orthologs in the model organism, Caenorhabditis elegans (C. elegans). Starting with a compilation of human Cu proteins and their orthologs, this review presents an overview of Cu homeostasis in C. elegans, comparing it to the human system, thereby establishing the basis for an assessment of the suitability of C. elegans as a model to answer mechanistic questions relating to human Cu homeostasis.

Extracellular Vesicles in Pathophysiology: A Prudent Target That Requires Careful Consideration.

Extracellular vesicles (EVs) are membrane-bound particles released by cells to perform multitudes of biological functions. Owing to their significant implications in diseases, the pathophysiological role of EVs continues to be extensively studied, leading research to neglect the need to explore their role in normal physiology. Despite this, many identified physiological functions of EVs, including, but not limited to, tissue repair, early development and aging, are attributed to their modulatory role in various signaling pathways via intercellular communication. EVs are widely perceived as a potential therapeutic strategy for better prognosis, primarily through utilization as a mode of delivery vehicle. Moreover, disease-associated EVs serve as candidates for the targeted inhibition by pharmacological or genetic means. However, these attempts are often accompanied by major challenges, such as off-target effects, which may result in adverse phenotypes. This renders the clinical efficacy of EVs elusive, indicating that further understanding of the specific role of EVs in physiology may enhance their utility. This review highlights the essential role of EVs in maintaining cellular homeostasis under different physiological settings, and also discusses the various aspects that may potentially hinder the robust utility of EV-based therapeutics.

A new superhero, the intraepithelial mast cell, joins the "Guardians of the Gut".

The intestinal epithelium interacts with immune cells to support tissue homeostasis and coordinate responses against pathogens. In this issue of Immunity, Yang et al. unveil a central role for mast cell-epithelial cell interactions in orchestrating protective type 2 immune responses following intestinal helminth infection.

Roles of airway and intestinal epithelia in responding to pathogens and maintaining tissue homeostasis.

Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positioned where the body interfaces with the outside world. We review the many signaling pathways and mechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate with macrophages, Tregs and epithelial stem cells to mount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease.

An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis.

Pyroptosis has garnered increasing attention because of its ability to trigger robust antitumor immunity. Pyroptosis is initiated by the activation of inflammasomes, which are regulated by various organelles. The collaboration among organelles offers several protective mechanisms to prevent activation of the inflammasome, thereby limiting the induction of efficient pyroptosis. Herein, a multiorganelle homeostasis disruptor (denoted BLL) is constructed by encapsulating liposomes and bortezomib (BTZ) within a layered double hydroxide (LDH) nanocage to continuously activate inflammasomes for inducing efficient pyroptosis. In lysosomes, the negatively charged liposomes are released to recruit the NLRP3 inflammasomes through electrostatic interactions. ER stress is induced by BTZ to enhance the activation of the NLRP3 inflammasome. Meanwhile, the BLL nanocage exhibited H+-scavenging ability due to the weak alkalinity of LDH, thus disrupting the homeostasis of the lysosome and alleviating the degradation of the NLRP3 inflammasome by lysosomal-associated autophagy. Our results suggest that the BLL nanocage induces homeostatic imbalance in various organelles and efficient pyroptosis. We hope this work can provide new insights into the design of an efficient pyroptosis inducer by disrupting the homeostatic balance of multiple organelles and promote the development of novel antineoplastic platforms.

Persistent organic pollutants dysregulate energy homeostasis in human ovaries in vitro.

Exposure to persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), has historically been linked to population collapses in wildlife. Despite international regulations, these legacy chemicals are still currently detected in women of reproductive age, and their levels correlate with reduced ovarian reserve, longer time-to-pregnancy, and higher risk of infertility. However, the specific modes of action underlying these associations remain unclear. Here, we examined the effects of five commonly occurring POPs - hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethylene (DDE), 2,3,3',4,4',5-hexachlorobiphenyl (PCB156), 2,2',3,4,4',5,5'-heptachlorobiphenyl (PCB180), perfluorooctane sulfonate (PFOS) - and their mixture on human ovaries in vitro. We exposed human ovarian cancer cell lines COV434, KGN, and PA1 as well as primary ovarian cells for 24 h, and ovarian tissue containing unilaminar follicles for 6 days. RNA-sequencing of samples exposed to concentrations covering epidemiologically relevant levels revealed significant gene expression changes related to central energy metabolism in the exposed cells, indicating glycolysis, oxidative phosphorylation, fatty acid metabolism, and reactive oxygen species as potential shared targets of POP exposures in ovarian cells. Alpha-enolase (ENO1), lactate dehydrogenase A (LDHA), cytochrome C oxidase subunit 4I1 (COX4I1), ATP synthase F1 subunit alpha (ATP5A), and glutathione peroxidase 4 (GPX4) were validated as targets through qPCR in additional cell culture experiments in KGN. In ovarian tissue cultures, we observed significant effects of exposure on follicle growth and atresia as well as protein expression. All POP exposures, except PCB180, decreased unilaminar follicle proportion and increased follicle atresia. Immunostaining confirmed altered expression of LDHA, ATP5A, and GPX4 in the exposed tissues. Moreover, POP exposures modified ATP production in KGN and tissue culture. In conclusion, our results demonstrate the disruption of cellular energy metabolism as a novel mode of action underlying POP-mediated interference of follicle growth in human ovaries.

Anticancer efficacy triggered by synergistically modulating the homeostasis of anions and iron: Design, synthesis and biological evaluation of dual-functional squaramide-hydroxamic acid conjugates.

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.

Disruption of the c-terminal serine protease domain of Fam111a does not alter calcium homeostasis in mice.

FAM111A gene mutations cause Kenney-Caffey syndrome (KCS) and Osteocraniostenosis (OCS), conditions characterized by short stature, low serum ionized calcium (Ca2+), low parathyroid hormone (PTH), and bony abnormalities. The molecular mechanism mediating this phenotype is unknown. The c-terminal domain of FAM111A harbors all the known disease-causing variations and encodes a domain with high homology to serine proteases. However, whether this serine protease domain contributes to the maintenance of Ca2+ homeostasis is not known. We hypothesized the disruption of the serine protease domain of FAM111A would disrupt Ca2+ homeostasis. To test this hypothesis, we generated with CRISPR/Cas9, mice with a frameshift insertion (c.1450insA) or large deletion (c.1253-1464del) mutation in the Fam111a serine protease domain. Serum-ionized Ca2+ and PTH levels were not significantly different between wild type, heterozygous, or homozygous Fam111a mutant mice. Additionally, there were no significant differences in fecal or urine Ca2+ excretion, intestinal Ca2+ absorption or overall Ca2+ balance. Only female homozygous (c.1450insA), but not heterozygous mice displayed differences in bone microarchitecture and mineral density compared to wild-type animals. We conclude that frameshift mutations that disrupt the c-terminal serine protease domain do not induce a KCS or OCS phenotype in mice nor alter Ca2+ homeostasis.

Heterogeneity and plasticity of tissue-resident memory T cells in skin diseases and homeostasis: a review.

Skin tissue-resident memory T (Trm) cells are produced by antigenic stimulation and remain in the skin for a long time without entering the peripheral circulation. In the healthy state Trm cells can play a patrolling and surveillance role, but in the disease state Trm cells differentiate into various phenotypes associated with different diseases, exhibit different localizations, and consequently have local protective or pathogenic roles, such as disease recurrence in vitiligo and maintenance of immune homeostasis in melanoma. The most common surface marker of Trm cells is CD69/CD103. However, the plasticity of tissue-resident memory T cells after colonization remains somewhat uncertain. This ambiguity is largely due to the variation in the functionality and ultimate destination of Trm cells produced from memory cells differentiated from diverse precursors. Notably, the presence of Trm cells is not stationary across numerous non-lymphoid tissues, most notably in the skin. These cells may reenter the blood and distant tissue sites during the recall response, revealing the recycling and migration potential of the Trm cell progeny. This review focuses on the origin and function of skin Trm cells, and provides new insights into the role of skin Trm cells in the treatment of autoimmune skin diseases, infectious skin diseases, and tumors.

[Prdx1 regulates macrophage polarization by maintaining mitochondrial homeostasis].

In order to investigate the role of Prdx1 in macrophage polarization, mouse leukemia cells of monocyte macrophage (RAW264.7) were treated with lipopolysaccharides (LPS)+ interferon gamma (IFNγ) or IL-4 to induce type 1 macrophage (M1) and type 1 macrophage (M2) macrophages, respectively. The Prdx1 gene knockout cells (Prdx1-/-) were used for the study. Flow cytometry was conducted to detect M1/M2 macrophage markers, and ELISA kits were used to measure M1/M2 cytokine levels. Inducible nitric-oxide synthase (iNOS) activity, arginase-1 (Arg-1) activity, and oxidative damage were also assessed. The Seahorse XFe24 Extracellular Flux Analyzer was employed to measure extracellular acidification rate and oxygen consumption rate. The mitochondrial membrane potential was analyzed using the mitochondrial membrane potential dye (JC-1) fluorescent probe, and mitochondrial superoxide was detected through fluorescence staining. Additionally, the impact of adding a mitochondrial reactive oxygen species (ROS) scavenger on RAW264.7 macrophage polarization was examined. The results demonstrated an increase in ROS, hydrogen peroxide, and 8-hydroxy-2 deoxyguanosine (8-OHDG). Cytotoxicity and mitochondrial toxic effects, including mitochondrial superoxide accumulation, decreased adenosine-triphosphate (ATP) production, reduced mitochondrial membrane potential, and decreased mitochondrial DNA copy number, were observed. Furthermore, down-regulation of translocase of inner mitochondrial membrane 23 (TIM23) mitochondrial protein and mitochondrial stress protein heat shock protein 60 (HSP60) was noted. The extra cellular acidification rate (ECAR) in M1 macrophage polarization in RAW264.7 cells was increased, while oxygen consumption rate (OCR) in M2 macrophages was reduced. These findings indicate that Prdx1 knockout in RAW264.7 cells can inhibit M2 macrophage polarization but promote M1 macrophage polarization by impairing mitochondrial function and reducing oxidative phosphorylation.

Fucoidan Improves D-Galactose-Induced Cognitive Dysfunction by Promoting Mitochondrial Biogenesis and Maintaining Gut Microbiome Homeostasis.

Recent studies have indicated that fucoidan has the potential to improve cognitive impairment. The objective of this study was to demonstrate the protective effect and possible mechanisms of fucoidan in D-galactose (D-gal)-induced cognitive dysfunction. Sprague Dawley rats were injected with D-galactose (200 mg/kg, sc) and administrated with fucoidan (100 mg/kg or 200 mg/kg, ig) for 8 weeks. Our results suggested that fucoidan significantly ameliorated cognitive impairment in D-gal-exposed rats and reversed histopathological changes in the hippocampus. Fucoidan reduced D-gal-induced oxidative stress, declined the inflammation level and improved mitochondrial dysfunction in hippocampal. Fucoidan promoted mitochondrial biogenesis by regulating the PGC-1α/NRF1/TFAM pathway, thereby improving D-gal-induced mitochondrial dysfunction. The regulation effect of fucoidan on PGC-1α is linked to the upstream protein of APN/AMPK/SIRT1. Additionally, the neuroprotective action of fucoidan could be related to maintaining intestinal flora homeostasis with up-regulation of Bacteroidota, Muribaculaceae and Akkermansia and down-regulation of Firmicutes. In summary, fucoidan may be a natural, promising candidate active ingredient for age-related cognitive impairment interventions.