Age-related Neurodegenerative Diseases Research Articles

Macrophage co-culture promotes cell reprogramming and prevents ferroptosis in aging fibroblasts for neurodegeneration therapy.

Ferroptosis, a form of programmed cell death associated with lipid peroxidation and iron dependency, plays a critical role in affecting neuronal function in the aging-related neurodegenerative diseases. Macrophages, influenced by these changes, contribute significantly to the progression of aging nerve diseases. Induced neuronal reprogramming is an advanced technology, which can direct convert somatic cells, such as fibroblasts, into neurons, and offers a promising approach for drug screening aimed at correcting ferroptosis and combating aging-related nerve diseases. However, the efficiency of this reprogramming process remains a significant challenge. In this study, we aimed to manipulate macrophage phenotypes to enhance the direct conversion of fibroblasts into neurons. Specifically, we sought to correct ferroptosis through screening natural compounds using aged fibroblasts and utilizing macrophages to promote induced neuronal (iN) reprogramming. Our findings demonstrate that M2 macrophages effectively promote the direct reprogramming of fibroblasts into iNs. In a novel macrophage-fibroblast co-culture system, M2 macrophages facilitate iN reprogramming by reducing fibroblast adhesion forces and promoting asymmetric cell division. Furthermore, we discovered that manipulating matrix stiffness can induce polarization of macrophages towards the M2 phenotype, thereby enhancing fibroblast reprogramming into iNs. To facilitate these findings, we developed a mechano-cue-based drug screening chip, where soft hydrogels induced and maintained the phenotype of M2 macrophages and effectively promoted cell reprogramming. Using a combinatorial approach with 36 such chips, we screened natural compounds for their anti-aging properties, focusing on reversing fibroblast aging and inducing their conversion into neuronal cells. Notably, Vitexin, an apigenin flavone glycoside with a role as a platelet aggregation inhibitor, emerged as a promising candidate to achieve our therapeutic goals. This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases. KEY MESSAGE: This study highlights the potential of macrophage-mediated modulation of fibroblast reprogramming as a strategy to address ferroptosis-induced neuronal dysfunction in aging-related nerve diseases.

Extracellular vesicles contribute to the beneficial effects of exercise training in APP/PS1 mice.

Exercise improves cognitive function in Alzheimer's disease (AD) via mechanism that are not fully clear. Here, we first examined the effect of voluntary exercise training (VET) on energy metabolism and cognitive function in the APP/PS1 transgenic mouse (Tg) model of familial AD. Next, we profiled extracellular vesicles (EVs) and examined whether they may play a role in the protective effects of VET via intranasal administration of EVs, purified from the blood of sedentary (sEV) and/or acutely exercised (eEV) donor wild-type mice into APP/PS1Tg mice. We show that VET reduced resting energy expenditure (REE) and improved cognition in APP/PS1 Tg mice. Administration of eEV, but not sEV, also reduced REE, but had no effect on cognition. Taken together, these data show that exercise is effective intervention to improve symptoms of AD in APP/PS1Tg mice. In addition, eEVs mediate some of these effects, implicating EVs in the treatment of age-related neurodegenerative diseases.

Advances in neural stem cells in aging and age-related neurodegenerative diseases

With aging, neural stem cells (NSCs) undergo age-related changes, including metabolic abnormalities, disrupted protein homeostasis, mitochondrial dysfunction, reduced genetic stability, and more notably, a diminished capacity for proliferation and differentiation. These changes may contribute to the development of age-related neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In these conditions, disease-specific pathological changes may interact with age-related alterations of NSCs, resulting in impairment of neurogenesis, which further leads to cognitive, mood, and motor decline. Based on these changes, potential therapeutics targeting neurogenesis and stem cell-based therapies may restore the functions of NSCs and replace the degenerated neurons, aiming to ameliorate functional decline in these neurodegenerative diseases. While stem cell-based therapies, including stem cell transplantation and stem cell secretome therapy, show great potential in the treatment of neurodegenerative diseases, challenges in tumorigenesis, immune rejection, and extraction or storage of the stem cell secretome need to be further addressed. A better understanding of age- and disease-related changes in NSCs, the underlying mechanism driving these changes, and the benefits and drawbacks of the therapeutic approaches may provide insights for novel disease-modifying interventions for the future treatment of these diseases.

Improving brain health via the central executive network.

Cognitive and physical stress have significant effects on brain health, particularly through their influence on the central executive network (CEN). The CEN, which includes regions such as the dorsolateral prefrontal cortex, anterior cingulate cortex and inferior parietal lobe, is central to managing the demands of cognitively challenging motor tasks. Acute stress can temporarily reduce connectivity within the CEN, leading to impaired cognitive function and emotional states. However a rebound in these states often follows, driven by motivational signals through the mesocortical and mesolimbic pathways, which help sustain inhibitory control and task execution. Chronic exposure to physical and cognitive challenges leads to long-term improvements in CEN functionality. These changes are supported by neurochemical, structural and systemic adaptations, including mechanisms of tissue crosstalk. Myokines, adipokines, anti-inflammatory cytokines and gut-derived metabolites contribute to a biochemical environment that enhances neuroplasticity, reduces neuroinflammation and supports neurotransmitters such as serotonin and dopamine. These processes strengthen CEN connectivity, improve self-regulation and enable individuals to adopt and sustain health-optimizing behaviours. Long-term physical activity not only enhances inhibitory control but also reduces the risk of age-related cognitive decline and neurodegenerative diseases. This review highlights the role of progressive physical stress through exercise as a practical approach to strengthening the CEN and promoting brain health, offering a strategy to improve cognitive resilience and emotional well-being across the lifespan.

Targeting natural antioxidant polyphenols to protect neuroinflammation and neurodegenerative diseases: a comprehensive review

Polyphenols, naturally occurring phytonutrients found in plant-based foods, have attracted significant attention for their potential therapeutic effects in neurological diseases and neuroinflammation. These compounds possess diverse neuroprotective capabilities, including antioxidant, anti-inflammatory, and anti-amyloid properties, which contribute to mitigating the progression of neurodegenerative conditions such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Dementia, Multiple Sclerosis (MS), Stroke, and Huntington’s Disease (HD). Polyphenols have been extensively studied for their ability to regulate inflammatory responses by modulating the activity of pro-inflammatory genes and influencing signal transduction pathways, thereby reducing neuroinflammation and neuronal death. Additionally, polyphenols have shown promise in modulating various cellular signaling pathways associated with neuronal viability, synaptic plasticity, and cognitive function. Epidemiological and clinical studies highlight the potential of polyphenol-rich diets to decrease the risk and alleviate symptoms of neurodegenerative disorders and neuroinflammation. Furthermore, polyphenols have demonstrated their therapeutic potential through the regulation of key signaling pathways such as Akt, Nrf2, STAT, and MAPK, which play critical roles in neuroprotection and the body’s immune response. This review emphasizes the growing body of evidence supporting the therapeutic potential of polyphenols in combating neurodegeneration and neuroinflammation, as well as enhancing brain health. Despite the substantial evidence and promising hypotheses, further research and clinical investigations are necessary to fully understand the role of polyphenols and establish them as advanced therapeutic targets for age-related neurodegenerative diseases and neuroinflammatory conditions.

Multiple synergistic anti-aging effects of vascular cell adhesion molecule 1 functionalized nanoplatform to improve age-related neurodegenerative diseases.

Aging is a critical factor in the onset and progression of neurodegenerative diseases and cognitive decline, with aging-related neuroinflammation and cellular senescence being major contributors. In the aging brain, the cerebral vascular endothelium overexpresses vascular cell adhesion molecule 1 (VCAM1), activating microglia and leading to neuroinflammation and cognitive impairment. Quercetin, a natural neuroprotective agent widely used for treating neurodegenerative diseases, their therapeutic efficacy, however, is limited by its poor water solubility and inability to penetrate the blood-brain barrier (BBB). To address these challenges, we developed a multifunctional micellar platform (Anti-VCAM1-GM1@Q) to improve age-related neurodegenerative diseases. The micelles incorporate anti-VCAM1 antibodies to target cerebral vascular endothelial cells and block VCAM1. Additionally, monosialoganglioside (GM1) was utilized to deliver quercetin due to its biparental properties, high BBB permeability, and neuroprotective effects. Anti-VCAM1-GM1@Q micelles demonstrated strong anti-aging properties. They improved quercetin's bioavailability, effectively penetrated the BBB, targeted cerebral vascular endothelial cells, and reduced neuroinflammation. In animal models, these micelles provided effective neuroprotection, improved memory function and age-related cognitive impairment, and mitigated age-related neurodegeneration. Notably, this system exhibited remarkable treatment efficacy and high safety, indicating substantial potential for clinical translational applications.

The Brain's Aging Resting State Functional Connectivity.

Resting state networks (RSNs) of the brain are characterized as correlated spontaneous time-varying fluctuations in the absence of goal-directed tasks. These networks can be local or large-scale spanning the brain. The study of the spatiotemporal properties of such networks has helped understand the brain's fundamental functional organization under healthy and diseased states. As we age, these spatiotemporal properties change. Moreover, RSNs exhibit neural plasticity to compensate for the loss of cognitive functions. This narrative review aims to summarize current knowledge from functional magnetic resonance imaging (fMRI) studies on age-related alterations in RSNs. Underlying mechanisms influencing such changes are discussed. Methodological challenges and future directions are also addressed. By providing an overview of the current state of knowledge in this field, this review aims to guide future research endeavors aimed at promoting healthy brain aging and developing effective interventions for age-related cognitive impairment and neurodegenerative diseases.

Oxidative Stress Promotes Axonal Atrophy through Alterations in Microtubules and EB1 Function.

Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence, aged axons are more susceptible to damage or dysfunction. Understanding how aging causes axonal vulnerability is crucial for developing strategies to enhance overall resilience of neurons and prevent neuronal deterioration during aging and in age-related neurodegenerative diseases. Increasing levels of reactive oxygen species (ROS) causes oxidative stress - a hallmark of aging and age-related diseases. Despite this association, a causal relationship between oxidative stress and neuronal aging remains unclear, particularly in how subcellular physiology may be affected by ROS. By using Drosophila-derived primary neuronal cultures and a recently developed in vivo neuronal model of aging, which involves the visualisation of Drosophila medulla neurons, we investigated the interplay between oxidative stress, neuronal aging and the microtubule cytoskeleton. Our results showed that oxidative stress is a key driver of axonal and synaptic decay, as shown by an enhanced appearance of axonal swellings, microtubule alterations (in both axons and synapses) and morphological transformation of axonal terminals during aging. We demonstrated that increasing the levels of ROS sensitises microtubule plus end-binding protein 1 (EB1), leading to microtubule defects that effect neuronal integrity. Furthermore, manipulating EB1 proved to be a valuable therapeutic strategy to prevent aging hallmarks enhanced in conditions of elevated ROS. In summary, we demonstrate a mechanistic pathway linking cellular oxidative stress with changes in the microtubule cytoskeleton leading to axonal deterioration during aging and provide evidence of the therapeutic potential of enhancing microtubule plus-end physiology to improve the resilience of axons.

Multi-omics analysis reveals the genetic aging landscape of Parkinson’s disease

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer’s disease. Despite numerous studies, specific age-related factors remain unidentified. This study employed a multi-omics approach to investigate the link between PD and aging. We integrated blood gene expression profiles, expression quantitative trait loci, genome-wide association studies, predictive models, and conducted clinical validation.By analyzing PD datasets, a total of 953 differentially expressed genes (DEGs) and 10 intersecting aging differentially expressed genes (ADEGs) were identified. Enrichment analysis revealed that the regulatory pathways of these ADEGs involve the classical Wnt signaling pathway, endoplasmic reticulum stress, and neuronal apoptosis. Mendelian randomization (MR) analysis showed that the MAP3K5 gene significantly reduces the risk of PD. Multivariate regression analysis identified MXD1, CREB1, and SIRT3 as key diagnostic genes and constructed a predictive model to aid clinical decision-making. Enzyme-linked immunosorbent assay experiments validated the expression levels of these genes in the serum of PD patients.This study utilized a multi-omics approach to identify key ADEGs and their regulatory mechanisms in PD, leading to the establishment of a diagnostic model. The resource is accessible at this link: https://yunhaihupo.shinyapps.io/DynNomapp. This web application can be used as a standalone resource to explore changes in blood transcription profiles in PD and their relationship to clinical and aging aspects, generating new research hypotheses.

Changes in the cortical GABAergic inhibitory system with ageing and ageing-related neurodegenerative diseases.

The human cortical inhibitory system is known to play a vital role for normal brain development, function, and plasticity. GABA is the most prominent inhibitory neurotransmitter in the CNS and is a key regulator not only for motor control and motor learning, but also for cognitive processes. With ageing and many neurodegenerative pathologies, a decline in GABAergic function in several cortical regions together with a reduced ability to task-specifically modulate and increase inhibition in the primary motor cortex has been observed. This decline in intracortical inhibition is associated with impaired motor control but also with diminished motor-cognitive (i.e. dual-tasking) and cognitive performance (e.g. executive functions). Furthermore, more general well-being such as sleep quality, stress resistance or non-specific pain perception are also associated with reduced GABA functioning. The current review highlights the interplay between changes in GABAergic function and changes in motor control, motor-cognitive and cognitive performance associated with healthy ageing, as well as in seniors with neurodegenerative diseases such as mild cognitive impairment. Furthermore, recent evidence highlighting the ability to up- or downregulate cortical inhibition by means of physical exercise programs is presented and discussed.

A comprehensive review on neurotrophic receptors and their implications in brain health: Exploring the neuroprotective potential of berries

Neurotrophic receptors are specialized proteins on the surface of neurons that regulate the growth, development, and survival of nerve cells, interacting with specific neurotrophic factors to support neuronal function and overall brain health. Key examples include the tropomyosin receptor kinase (Trk) family and the p75 neurotrophin receptor. This review highlights the neuroprotective potential of berries such as blueberries, strawberries, raspberries, and blackberries known for their rich content of bioactive compounds, including polyphenols, flavonoids, and anthocyanins. These phytochemicals possess antioxidant and anti-inflammatory properties that may play a critical role in neuroprotection. Emerging evidence from clinical trials suggests that berry consumption can enhance cognitive function and provide protection against age-related neurodegenerative diseases. Notably, the modulation of signaling pathways related to neurotransmission, cell survival, inflammation, and neuroplasticity underscores the significance of these fruits in neuroprotection. This review uniquely synthesizes recent findings on the specific neurotrophic factors influenced by berry-derived phytochemicals, providing insights into their mechanisms of action. Furthermore, we explore the implications of these compounds in developing functional foods aimed at preventing neurodegeneration and promoting cognitive health, thereby contributing to the growing body of research on dietary interventions for brain health.

Fundamental research and practical application of GDNF as a neuroprotective agent in neurodegenerative diseases

Glial cell line-derived neurotrophic factor (GDNF) is under extensive investigation as a therapeutic agent for treating age-related neurodegenerative diseases and traumatic neuronal injury. The compelling results from preclinical studies contrast with the disappointing outcomes of phase II clinical trials in Parkinson’s disease, highlighting the need for further fundamental research. Several hypotheses have been proposed to explain these discrepancies, including challenges with the delivery of high molecular weight drugs, GDNF’s high affinity for heparin and heparin-like molecules, which limits its biodistribution in the brain parenchyma, the use of protein forms differing from the native GDNF, and the existence of multiple isoforms of the protein. These issues underscore the necessity for further investigation into GDNF at the genetic, RNA, and protein levels. This review aims to consolidate the latest data on GDNF, address the challenges identified, and explore its potential for therapeutic application in human neurodegenerative diseases.

Dietary Strategies to Mitigate Alzheimer's Disease: Insights into Antioxidant Vitamin Intake and Supplementation with Microbiota-Gut-Brain Axis Cross-Talk.

Alzheimer's disease (AD), which is characterized by deterioration in cognitive function and neuronal death, is the most prevalent age-related progressive neurodegenerative disease. Clinical and experimental research has revealed that gut microbiota dysbiosis may be present in AD patients. The changed gut microbiota affects brain function and behavior through several mechanisms, including tau phosphorylation and increased amyloid deposits, neuroinflammation, metabolic abnormalities, and persistent oxidative stress. The lack of effective treatments to halt or reverse the progression of this disease has prompted a search for non-pharmaceutical tools. Modulation of the gut microbiota may be a promising strategy in this regard. This review aims to determine whether specific dietary interventions, particularly antioxidant vitamins, either obtained from the diet or as supplements, may support the formation of beneficial microbiota in order to prevent AD development by contributing to the systemic reduction of chronic inflammation or by acting locally in the gut. Understanding their roles would be beneficial as it may have the potential to be used as a future therapy option for AD patients.

A New Insight into the Mechanism of Atrazine-Induced Neurotoxicity: Triggering Neural Stem Cell Senescence by Activating the Integrated Stress Response Pathway.

Atrazine (AT), a widely utilized chemical herbicide, causes widespread contamination of agricultural water bodies. Recently, exposure to AT has been linked to the development of age-related neurodegenerative diseases (NDs), suggesting its neurotoxicity potential. As an endocrine disruptor, AT targets the hypothalamus, a crucial part of the neuroendocrine system. However, the toxicological mechanism of AT exposure to the hypothalamus and its correlation with ND development remain unexplored. Our results indicated that AT exposure caused significant morphological and structural damage to the hypothalamus, leading to the loss of mature and intact neurons and microglial activation. Furthermore, hypothalamic neural stem cells (HtNSCs) were recruited to areas of neuronal damage caused by AT. Through invivo and invitro experiments, we clarified the outcomes of AT-induced HtNSC recruitment alongside the loss of mature/intact neurons. Mechanistically, AT induces senescence in these recruited HtNSCs by activating integrated stress response signaling. This consequently hinders the repair of damaged neurons by inhibiting HtNSC proliferation and differentiation. Overall, our findings underscore the pivotal role of the integrated stress response pathway in AT-induced HtNSC senescence and hypothalamic damage. Additionally, the present study offers novel perspectives to understand the mechanisms of AT-induced neurotoxicity and provides preliminary evidence linking AT contamination to the development of NDs.

Do Alzheimer Disease genetic loci influence the risk of Age‐Related Macular Degeneration?

AbstractBackgroundAlzheimer’s Disease (AD) and Age‐Related Macular Degeneration (AMD) are two age related neurodegenerative diseases that share multiple characteristics, including deposition of amyloid beta. In AD, amyloid plaque accumulation contributes to neurological dysfunction, while in AMD amyloid is a component of the hallmark retinal drusen complexes that lead to degeneration of central vision. Both diseases have significant and opposite risk due to the APOE e4 and e2 alleles. Investigation into other potential genetic similarities between the two diseases is warranted.MethodsVariants from the recent AMD meta‐analysis (Fritsche et al., 2016) and AD meta‐analysis (Bellenguez et al., 2022) were utilized to generate genetic risk scores (GRS) in an Amish founder population. 1293 individuals (1120 controls and 173 cases) were included in the AD analysis and 654 individuals were included in the AMD analysis (334 controls and 320 cases). AMD‐only and AD‐only GRSs were applied separately to both AMD and AD. We then combined both the AMD and AD variants into a single GRS applied to each disease. We subsequently removed AD SNPs sequentially from the GRS to identify any AD variants that might improve the association with AMD.ResultsAs expected, the AD‐only GRS successfully predicted AD (p = 0.01). However, the AMD‐only GRS was less successful in predicting AMD (p = 0.145). The combined AD/AMD GRS was more successful in predicting AMD (p = 0.12) than the AMD‐only GRS, while AD prediction decreased in performance (p = 0.67) compared to the AD‐only GRS. The sequential analysis identified thirteen AD variants that improved the AMD‐only GRS when combined with the AMD variants (p = 0.06).ConclusionsWhile the AD‐only GRS was most successful in predicting AD, the AD/AMD GRS outperformed the AMD‐only GRS in predicting AMD. These results suggest that several AD loci in addition to APOE may also influence AMD.

An overview of the relationship between inflammation and cognitive function in humans, molecular pathways and the impact of nutraceuticals

Inflammation has been associated with cognitive decline, whether in the peripheral or central nervous systems. The primary mechanism involves the response of microglia, an immune cell in the brain, which generates pro-inflammatory mediators such as cytokines, chemokines, and adhesion molecules. The excessive production of pro-inflammatory mediators may accelerate the damage to neurons, contributing to the development of neurodegenerative diseases such as Alzheimer’s disease, mild cognitive impairment, and vascular dementia, as well as a general decline in cognitive function. Various studies have supported the correlation between elevated pro-inflammatory mediators and a decline in cognitive function, particularly in aging and age-related neurodegenerative diseases. Moreover, this association has also been observed in other inflammatory-related conditions, including post-operative cognitive impairment, diabetes, stroke, obesity, and cancer. However, the interaction between inflammatory processes and cognitive function in humans remains unclear and varies according to different health conditions. Therefore, this review aims to consolidate and evaluate the available evidence from original studies as well as meta-analyses in order to provide a greater understanding of the inflammatory process in connection with cognitive function in humans. Furthermore, relevant biological cellular processes, putative inflammatory biomarkers, and the role of nutraceuticals on the interaction between cognitive performance and inflammatory status are outlined.

Exercise alleviates cognitive decline of natural aging rats by upregulating Notch-mediated autophagy signaling.

Notch signaling, a classical signaling pathway of neurogenesis, is downregulated during the aging and age-related neurodegenerative diseases. Exercise has been proposed as an effective lifestyle intervention for delaying cognitive decline. However, it remains unclear whether exercise intervention could alleviate cognitive decline by modulating neurogenesis in naturally aging rats. In this study, 21-month-old natural aging rats were used to study brain aging. The natural aging rats underwent different forms of exercise training (aerobic exercise or strength training or comprehensive exercise with aerobic exercise and strength training) for 12 consecutive weeks. The cognitive function of natural aging rats was determined by Morris Water Maze. Notch signaling, autophagy-related proteins and hippocampal neurogenesis were examined by immunofluorescence, qRT-PCR and Western blot. Results showed that natural aging rats exhibited cognitive decline, accumulation of AD pathological proteins (APP and Aβ), and decreased neurogenesis (decreased DCX, Ki67 and GFAP), compared with the young control rats. Moreover, a significant decline in Notch signaling and autophagy was found in the hippocampus of natural aging rats. However, different forms of exercise upregulated Notch signaling and its downstream target genes, as well as autophagy-related proteins, including LC3, Beclin1, and p62. In summary, our data suggest that different forms of exercise can mitigate brain aging by upregulating Notch signaling and autophagy, thereby increasing hippocampal neurogenesis and improves spatial learning and memory abilities.

A011: Effects of Aerobic Exercise on Microbiota

Background/Objective: Gut flora plays an important role in host stress response, anxiety, depression and cognitive function through the gut-brain axis. Microbial diversity decreases with age, which in turn affects the function of the nervous system. The role of exercise in the prevention and treatment of age-related diseases and neurodegenerative diseases has received increasing attention. The purpose of this study was to elucidate the regulatory role of intestinal flora, gut-brain axis and nervous system function in the prevention of nervous system function decline in the elderly. Methods: The sample consisted of 16, 52-week-old SPF C57BL/6 male mice that were randomly divided into two groups: a old control group (OC) and an old treadmill exercise group (OE). The mice underwent 16 W moderate intensity incremental load exercise. ELISA was used to detect 5-Hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA) and Dopamine (DA) in the hippocampus. Serum and hippocampal glutamate and serum Acetylcholine (ACH) were determined by ultraviolet colorimetry. The expression of insulin-like growth factors 1 (IGF1) and brain-derived neurotrophic factor (BDNF) in hippocampus and vascular epithelial growth factor (VEGF) were measured by Western blot. Fecal samples were collected and analyzed by 16S rDNA sequencing. Results: (1) 5-HT and Glu in the hippocampus (P < 0.01), and DA and GABA in the hippocampus were significantly increased (P < 0.05) after aerobic exercise. Serum Glu and serum Ach in aerobic exercise group were significantly higher than those in the control group (P < 0.01). (2) The expression of BDNF, VEGF and IGF1 in the hippocampus of naturally aged mice were significantly increased after aerobic exercise (P < 0.01). (3) The results of Alpha diversity analysis showed that Shannon index, Simpson index and Chao1 in OE group were significantly increased compared with those in OC group (P < 0.01). The relative abundances of Bacteroidetes and Parasicutes were significantly increased, while the relative abundances of Proteobacteria in naturally aged mice were significantly decreased (P < 0.01) after aerobic exercise. Conclusions: The composition of intestinal flora and the expression of central neurotransmitters in elderly mice were significantly improved after 16 weeks of moderate-intensity aerobic exercise with incremental load. The expression of adult hippocampal neurogenesis (AHN)-related proteins in hippocampus: VEGF, IGF1 and BDNF were significantly improved, and neurogenesis was promoted. Intestinal microbiota - gut - brain axis plays an important role in the improvement of hippocampal neurogenesis in elderly mice.

The anti-inflammatory cytokine interferon-gamma as a potential therapeutic target of Alzheimer’s disease: a retrospective observational study

The age-related neurodegenerative disease Alzheimer’s disease is characterized by progressive cognitive decline and neurodegeneration and is often accompanied by inflammation within the central nervous system. This study investigated the role of interferon-gamma, an anti-inflammatory cytokine, in Alzheimer’s disease pathogenesis. Our findings highlight three critical insights: first, there was a significant reduction in interferon-gamma expression at the early stages of Alzheimer’s disease, suggesting an initial impairment in immune function. Second, we identified a novel correlation between the expression levels of interferon-gamma and its receptors, which may indicate a mechanism through which interferon-gamma signaling is altered in Alzheimer’s disease. Third, we observed an increase in entropy and determinant values for interferon-gamma and its receptors, suggesting that systemic dysregulation likely contributes to disease progression. Our study underscores the pivotal role of interferon-gamma in Alzheimer’s disease and highlights its potential as a therapeutic target.

Betaine and aging: A narrative review of findings, possible mechanisms, research perspectives, and practical recommendations.

The rapid aging of the global population necessitates addressing age-related conditions through innovative strategies. Nutritional supplements have emerged as potential interventions for preventing or slowing age-related changes, with betaine being a promising candidate. This systematic review aims to provide a comprehensive analysis of current literature on the impact of betaine on the aging process. Specifically, we summarize the mechanisms through which betaine is proposed to affect aging, we integrate existing findings, we identify gaps in the literature, and we discuss practical implications for promoting healthy aging. Evidence suggests that betaine may counteract aging-related changes in methylation potential by increasing concentration of S-adenosylmethionine, a key methyl donor. Additionally, betaine reduces homocysteine concentrations, potentially mitigating vascular, neurodegenerative, and oxidative damage. Betaine has also been shown to enhance mitochondrial function, to reduce oxidative stress, and to attenuate inflammation. It may serve as a preventive agent against sarcopenia by promoting anabolic signaling pathways and improving muscle strength in younger adults. Betaine may also exert an effect on bone remodeling and adipose tissue metabolism, with animal studies indicating enhanced fat oxidation and reduced fat synthesis. Although certain limited studies have suggested betaine's potential in mitigating age-related neurodegenerative diseases, the currently available evidence does not establish a clear link between dietary betaine intake and the incidence of cardiovascular diseases or type-2 diabetes. In conclusion, emerging evidence highlights the potential of betaine in attenuating age-related changes. However, further research is required to elucidate the efficacy and safety of betaine supplementation in older populations.