Microglial response to aging and neuroinflammation in the development of neurodegenerative diseases

Cellular senescence and chronic inflammation in response to aging are considered to be indicators of brain aging;they have a great impact on the aging process and are the main risk factors for neurodegeneration.Reviewing the microglial response to aging and neuroinflammation in neurodegenerative diseases will help understand the importance of microglia in neurodegenerative diseases.This review describes the origin and function of microglia and focuses on the role of different states of the microglial response to aging and chronic inflammation on the occurrence and development of neurodegenerative diseases,including Alzheimer's disease,Huntington's chorea,and Parkinson's disease.This review also describes the potential benefits of treating neurodegenerative diseases by modulating changes in microglial states.Therefore,inducing a shift from the neurotoxic to neuroprotective microglial state in neurodegenerative diseases induced by aging and chronic inflammation holds promise for the treatment of neurodegenerative diseases in the future.

Influence of aging,mitochondrial dysfunction,and inflammation on Parkinson's disease

Aging is associated with chronic form of inflammation called inflammaging,which results from immune system changes.Inflammaging plays a crucial role in the pathogenesis of various neurodegenerative diseases(Dabravolski et al.,2022).Moreove r,aging-related inflammation can be triggered by disrupted mitophagy.

Synthetic high-density lipoprotein(sHDL):a bioinspired nanotherapeutics for managing periapical bone inflammation

Apical periodontitis(AP)is a dental-driven condition caused by pathogens and their toxins infecting the inner portion of the tooth(i.e.,dental pulp tissue),resulting in inflammation and apical bone resorption affecting 50%of the worldwide population,with more than 15 million root canals performed annually in the United States.Current treatment involves cleaning and decontaminating the infected tissue with chemo-mechanical approaches and materials introduced years ago,such as calcium hydroxide,zinc oxide–eugenol,or even formalin products.Here,we present,for the first time,a nanotherapeutics based on using synthetic highdensity lipoprotein(sHDL)as an innovative and safe strategy to manage dental bone inflammation.sHDL application in concentrations ranging from 25μg to 100μg/mL decreases nuclear factor Kappa B(NF-κB)activation promoted by an inflammatory stimulus(lipopolysaccharide,LPS).Moreover,sHDL at 500μg/mL concentration markedly decreases in vitro osteoclastogenesis(P<0.001),and inhibits IL-1α(P=0.027),TNF-α(P=0.004),and IL-6(P<0.001)production in an inflammatory state.Notably,sHDL strongly dampens the Toll-Like Receptor signaling pathway facing LPS stimulation,mainly by downregulating at least 3-fold the pro-inflammatory genes,such as Il1b,Il1a,Il6,Ptgs2,and Tnf.In vivo,the lipoprotein nanoparticle applied after NaOCl reduced bone resorption volume to(1.3±0.05)mm^(3) and attenuated the inflammatory reaction after treatment to(1090±184)cells compared to non-treated animals that had(2.9±0.6)mm^(3)(P=0.0123)and(2443±931)cells(P=0.004),thus highlighting its promising clinical potential as an alternative therapeutic for managing dental bone inflammation.

Myotis bat STING attenuates aging-related inflammation in female mice

Bats,notable as the only flying mammals,serve as natural reservoir hosts for various highly pathogenic viruses in humans(e.g.,SARS-CoV and Ebola virus).Furthermore,bats exhibit an unparalleled longevity among mammals relative to their size,particularly the Myotis bats,which can live up to 40 years.However,the mechanisms underlying these distinctive traits remain incompletely understood.In our prior research,we demonstrated that bats exhibit dampened STING-interferon activation,potentially conferring upon them the capacity to mitigate virus-or aging-induced inflammation.To substantiate this hypothesis,we established the first in vivo bat-mouse model for aging studies by integrating Myotis davidii bat STING(MdSTING)into the mouse genome.We monitored the genotypes of these mice and performed a longitudinal comparative transcriptomic analysis on MdSTING and wild-type mice over a 3-year aging process.Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice,as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines,immunopathology,and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo.These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner.Although the underlying mechanism awaits further study,this research has critical implications for bat longevity research,potentially contributing to our comprehension of healthy aging in humans.

Interleukin-35: A key player managing pre-diabetes and chronic inflammatory type 1 autoimmune diabetes

Interleukin-35(IL-35)is a novel protein comprising IL-12αand IL-27βchains.The IL12A and EBI3 genes are responsible for its production.The study of IL-35 has experienced a substantial increase in interest in recent years,as demonstrated by many research papers.Recent clinical studies have shown that individuals who do not have a C-peptide have notably reduced amounts of IL-35 in their blood serum.This is accompanied by a drop in the percentage of IL-35+Treg cells,regulatory B cells,and CD8+FOXP3+cells that produce IL-35.This article em-phasizes the potential significance of IL-35 expression in governing the immune response and its involvement in chronic inflammatory autoimmune diabetes in pancreatic inflammation.It demonstrates IL-35's ability to regulate cytokine proportions,modulate B cells,and protect against autoimmune diabetes.However,further investigation is necessary to ascertain the precise mechanism of IL-35,and meticulous planning is essential for clinical studies.

Effects of Maillard reaction and its product AGEs on aging and age-related diseases

Maillard reaction(MR)is a non-enzymatic browning reaction commonly seen in food processing,which occurs between reducing sugars and compounds with amino groups.Despite certain advantages based on Maillard reaction products(MRPs)found in some food for health and storage application have appeared,however,the MR occurring in human physiological environment can produce advanced glycation end products(AGEs)by non-enzymatic modification of macromolecules such as proteins,lipids and nucleic acid,which could change the structure and functional activity of the molecules themselves.In this review,we take AGEs as our main object,on the one hand,discuss physiologic aging,that is,age-dependent covalent cross-linking and modification of proteins such as collagen that occur in eyes and skin containing connective tissue.On the other hand,pathological aging associated with autoimmune and inflammatory diseases,neurodegenerative diseases,diabetes and diabetic nephropathy,cardiovascular diseases and bone degenerative diseases have been mainly proposed.Based on the series of adverse effects of accelerated aging and disease pathologies caused by MRPs,the possible harm caused by some MR can be slowed down or inhibited by artificial drug intervention,dietary pattern and lifestyle control.It also stimulates people's curiosity to continue to explore the potential link between the MR and human aging and health,which should be paid more attention to for the development of life sciences.

How do neurons age?A focused review on the aging of the microtubular cytoskeleton

Aging is the leading risk factor for Alzheimer’s disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer’s disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer’s disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease.

Single-cell transcriptomic atlas of goat ovarian aging

Background The ovaries are one of the first organs that undergo degenerative changes earlier in the aging process,and ovarian aging is shown by a decrease in the number and quality of oocytes.However,little is known about the molecular mechanisms of female age-related fertility decline in different types of ovarian cells during aging,especially in goats.Therefore,the aim of this study was to reveal the mechanisms driving ovarian aging in goats at single-cell resolution.Results For the first time,we surveyed the single-cell transcriptomic landscape of over 27,000 ovarian cells from newborn,young and aging goats,and identified nine ovarian cell types with distinct gene-expression signatures.Functional enrichment analysis showed that ovarian cell types were involved in their own unique biological processes,such as Wnt beta-catenin signalling was enriched in germ cells,whereas ovarian steroidogenesis was enriched in granulosa cells(GCs).Further analysis showed that ovarian aging was linked to GCs-specific changes in the antioxidant system,oxidative phosphorylation,and apoptosis.Subsequently,we identified a series of dynamic genes,such as AMH,CRABP2,THBS1 and TIMP1,which determined the fate of GCs.Additionally,FOXO1,SOX4,and HIF1A were identified as significant regulons that instructed the differentiation of GCs in a distinct manner during ovarian aging.Conclusions This study revealed a comprehensive aging-associated transcriptomic atlas characterizing the cell typespecific mechanisms during ovarian aging at the single-cell level and offers new diagnostic biomarkers and potential therapeutic targets for age-related goat ovarian diseases.

Biochanin A attenuates spinal cord injury in rats during early stages by inhibiting oxidative stress and inflammasome activation

Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.

Hypothalamic circuits and aging:keeping the circadian clock updated

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

Strengthening Active Aging through Older People’s Association and Economic Activity of the Older People in Nepal

Aging is a natural lifelong process ending in death. Many older people are living in poverty. Older people are generally considered dependent on others as they grow older. The purpose of this article is to explore the entrepreneurship activities of Nepalese older adults. Data for this study were collected from the project Help Age International (HAI) implemented in Nepal. Qualitative data observations and interviews were used to collect data. The findings of this study show the formation of the Older People’s Association (OPA) has supported many older people to participate outside the home in various social activities. Moreover, regular deposits through OPAs offer little help. OPAs support older people in their need of financial support to implement minor entrepreneurship. Older people who received support were pleased and were actively involved in their activities and also regularly deposited money in them. Subsequently, older people’s participation in social activities has increased and also helped to lower elderly abuse, loneliness, and depression. Local governments should promote such activities which will help with healthy aging.

Polygenic Profile and Magnitude Impact of Inflammatory Response in Soccer Athletes

The practice of soccer involves carrying-out actions of high intensity, which demand a great generation of eccentric strength, which in turn results in an increase in the inflammatory response after training practice and game matches. The study aimed to investigate, in combination and individually, the association of 28 polymorphisms with the inflammatory responses of soccer athletes. The sample consisted of 47 male under-20 soccer athletes who belong to clubs in the first division of Brazilian soccer. Blood samples were collected at Pre, and 03, 24, and 48 hours after the training session to evaluate the inflammatory responses (hematological analyzes (hemogram), creatine phosphokinase (CK), high sensitivity quantitative C-reactive protein (CRP), tumor necrosis factor-alpha, (TNFα), interleukin 6 (IL-6) and insulin-like growth factor 1 (IGF-1)). DNA was obtained through scraping of buccal cells, where a sterile swab was rubbed on the inner side of the mouth of each participant 06 times. The database was built using the TruSeq DNA PCRFree kit (Illumina®) and the Covaris equipment for shearing genomic DNA (gDNA) by ultrasound. Of the analyzed SNPs, 09 (ACTN3 rs1815739, COL5A1 rs12722, COL5A1 rs3196378, HGF rs5745697, IGF1 rs35767, IL-6 rs1800795, MMP3 rs679620, SLC30A8 rs13266634, SOX15 rs4227) were individually associated with biomarkers and 07 SNPs, (COL5A1 rs12722, COL5A1 rs3196378, COL5A1 rs1800012, HGF rs5745697, IGF1 rs35767, IL-6 rs1800795 and MMP3 rs679620) analyzed in combination, explained 16% to 40% of the variation of inflammatory responses in soccer athletes. The results suggest that the genotypic profile can be taken into account for a more individualized distribution of the training load, along with the elaboration of recovery strategies for high-level athletes between training sessions and games of high physical and physiological demand.

Skeletal phenotypes and molecular mechanisms in aging mice

Aging is an inevitable physiological process,often accompanied by age-related bone loss and subsequent bone-related diseases that pose serious health risks.Research on skeletal diseases caused by aging in humans is challenging due to lengthy study durations,difficulties in sampling,regional variability,and substantial investment.Consequently,mice are preferred for such studies due to their similar motor system structure and function to humans,ease of handling and care,low cost,and short generation time.In this review,we present a comprehensive overview of the characteristics,limitations,applicability,bone phenotypes,and treatment methods in naturally aging mice and prematurely aging mouse models(including SAMP6,POLG mutant,LMNA,SIRT6,ZMPSTE24,TFAM,ERCC1,WERNER,and KL/KL-deficient mice).We also summarize the molecular mechanisms of these aging mouse models,including cellular DNA damage response,senescence-related secretory phenotype,telomere shortening,oxidative stress,bone marrow mesenchymal stem cell(BMSC)abnormalities,and mitochondrial dysfunction.Overall,this review aims to enhance our understanding of the pathogenesis of aging-related bone diseases.

Brain endothelial cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway in aging and neurodegeneration

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a key mediator of neuroinflammation.While current studies primarily attribute its effects to neurons and glial cells,emerging research suggests that cGAS-STING signaling may play a critical role in cerebral vasculature,particularly in brain endothelial cells.Therefore,studying the role 7of inflammation caused by the cGAS-STING pathway in brain endothelial cells could provide a more comprehensive understanding of neuroinflammatory disease and new avenues for therapeutic interventions.Here,we review the multifaceted role of global cGAS-STING signaling in various neurological and neuroinflammatory diseases and the potential contribution of cGAS-STING in brain endothelial cells.

Homocysteinemia and Depression in Community-Dwelling Older Adults: The Cohort Longitudinal Study “InveCeAb” (Brain Aging in Abbiategrasso)

Depression is a major health problem, especially for elderly people. According to the “homocysteine hypothesis of depression”, high homocysteine levels may cause depression of mood via cerebrovascular diseases. Whilst biologically plausible, such hypothesis needs yet confirmation. We aimed at: 1) studying the relationships between homocysteinemia (HCY) and depression in a community-dwelling cohort of people aged 70 to 75 years at baseline;2) investigating plasma levels of HCY and 3) comparing these levels between males and females, in the same population. We exploited the data from four waves (2010, 2012, 2014 and 2018) of the longitudinal study “InveCeAb”, with specific regard towards mood assessment, by Geriatric Depression Scale (GDS) scoring, and diagnosis of clinically relevant or subthreshold depression. HCY plasma levels were measured in the waves 2012, 2014 and 2018. Sample attrition was due mainly to death or overall worsening. No statistically significant differences were found in plasma homocysteine levels in each wave, according to depressive symptoms. No correlations were found between plasma HCY levels in each wave with their corresponding GDS scores, even after adjustment for folate and cobalamin blood concentrations. Dichotomized levels of HCY (≤15 vs >15 μM/l) were not associated with dichotomized GDS scores (≤4 vs higher), clinically relevant and subthreshold depression diagnosis and any antidepressive use, in any wave. First (2012) HCY levels increased with participants’ increasing age, cross-sectionally. Listwise HCY concentrations decreased along the 3 waves. HCY levels were always higher in males than in females. Our results may challenge the “homocysteine hypothesis” of depression, whilst supporting the role of high homocysteinemia as a marker of overall bad health.

Regulation of aging by NELF-A and RNA polymerase Ⅱ elongation

Epigenetic regulation of aging:Aging is defined as the gradual decline of physiological function and cellular integrity,causing o rganismal vulnerability to age-onset diseases and morbidity.Studies in different animal models have led to the identification of twelve aging hallmarks that shared several features:its age-associated manifestation.

Astrocyte syncytium:from neonatal genesis to aging degeneration

Modern neuroscience began from all reaching and fierce conflict between“neuronismo and reticulismo”——between neuronal and reticular theories of the organization of the nervous system;the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal(the proponent of the neuronal doctrine)and Camillo Golgi(who advocated the syncytial reticular organization of neural networks)delivered their Noble prize lectures(Verkhratsky,2009).

Preventing brain aging by the artificial enforcement of the unfolded protein response:future directions

As the life expectancy of the world’s population increases,age-related diseases are emerging as one of the greatest problems facing modern society.The onset of dementia and neurodegenerative diseases is strictly dependent on aging as a major risk factor and has a profound impact on various aspects of the lives of individuals and their families.

Training muscles to keep the aging brain fit

1.Aging and exercise Aging is associated with the decline of cellular,tissue,and systemic functions and is characterized by at least 7 highly interdependent molecular pillars of aging1(Fig.1).Besides compromised genetic functions(telomer shortening and epigenetic dysregulation),metabolic efficiency(impaired mitochondrial functions and nutrient sensing),and cellular stress responses deteriorate.Consequential disruption of normal protein regulation(proteostasis)in combination with impaired cellular waste clearance leads to the accumulation of macromolecular damage(and in some cases to specific protein aggregation pathologies,like in Alzheimer’s dementia brains).

Dendritic spine degeneration:a primary mechanism in the aging process

Recent reports suggest that aging is not solely a physiological process in living beings;instead, it should be considered a pathological process or disease(Amorim et al., 2022). Consequently, this process involves a wide range of factors, spanning from genetic to environmental factors, and even includes the gut microbiome(GM)(Mayer et al., 2022). All these processes coincide at some point in the inflammatory process, oxidative stress, and apoptosis, at different degrees in various organs and systems that constitute a living organism(Mayer et al., 2022;AguilarHernández et al., 2023).