Age-related Degenerative Diseases Research Articles

Unveiling the Gut-Disc Axis: How Microbiome Dysbiosis Accelerates Intervertebral Disc Degeneration.

The gut microbiome (GM), often referred to as the second genome of the human body, plays a crucial role in various metabolic processes and mediates the development of numerous diseases. Intervertebral disc degeneration (IDD) is an age-related degenerative spinal disease characterized by the loss of disc height, hydration, and integrity, leading to pain and reduced mobility. Although the pathogenesis of IDD is not fully understood, recent studies suggest that dysbiosis of the gut microbiome may accelerate the progression of IDD through multiple mechanisms. This article begins by discussing the potential relationship between GM dysbiosis and human diseases, followed by a comprehensive review of the regulatory mechanisms of GM in skeletal diseases within the gut-disc axis framework. Furthermore, it explores three potential pathways through which GM dysbiosis may mediate the development of IDD: immunomodulation, bacterial translocation and colonization, and the decomposition and absorption of intestinal metabolites. These pathways can disrupt disc cell homeostasis and promote degenerative changes. Finally, this paper summarizes for the first time the potential therapeutic approaches for delaying IDD by targeting the gut-disc axis, providing new insights into the pathogenesis and regenerative repair strategies for IDD.

Various Strategies of Tendon Stem/Progenitor Cell Reprogramming for Tendon Regeneration.

Rotator cuff tears (RCT) are the most common cause of shoulder pain among adults. "Rotator cuff" refers to the four muscles that cover the shoulder joint: supraspinatus, infraspinatus, subscapularis, and teres minor. These muscles help maintain the rotational movement and stability of the shoulder joint. RCT is a condition in which one or more of these four muscles become ruptured or damaged, causing pain in the arms and shoulders. RCT results from degenerative changes caused by chronic inflammation of the tendons and consequent tendon tissue defects. This phenomenon occurs because of the exhaustion of endogenous tendon stem cells. Tendon regeneration requires rejuvenation of these endogenous tendon stem/progenitor cells (TSPCs) prior to their growth phase. TSPCs exhibit clonogenicity, multipotency, and self-renewal properties; they express classical stem cell markers and genes associated with the tendon lineage. However, specific markers for TSPC are yet to be identified. In this review, we introduce novel TSPC markers and discuss various strategies for TSPC reprogramming. With further research, TSPC reprogramming technology could be adapted to treat age-related degenerative diseases, providing a new strategy for regenerative medicine.

TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport

Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.

Identifying critical modules and biomarkers of intervertebral disc degeneration by using weighted gene co-expression network.

Intervertebral disc degeneration (IVDD) is an age-related orthopedic degenerative disease characterized by recurrent episodes of lower back pain, the pathogenesis of which is not fully understood. This study aimed to identify key biomarkers of IVDD and its causes. We acquired three gene expression profiles from the Gene Expression Omnibus (GEO) database, GSE56081, GSE124272, and GSE153761, and used limma fast differential analysis to identify differentially expressed genes (DEGs) between normal and IVDD samples after removing batch effects. We applied weighted gene co-expression network (WGCNA) to identify the key modular genes in GSE124272 and intersected these with DEGs. Next, A protein-protein interaction network (PPI) was constructed, and Cytoscape was used to identify the Top 10 hub genes. Functional enrichment analyses were performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Three key genes were validated using Western Blot (WB) and qRT-PCR. Additionally, we predicted miRNAs involved in hub gene co-regulation and analyzed miRNA microarray data from GSE116726 to identify four differentially expressed miRNAs. We identified 10 hub genes using bioinformatics analysis, gene function enrichment analysis revealed that they were primarily enriched in pathways, such as the TNF signaling pathway. We chose JUNB, SOCS3, and CEBPB as hub genes and used WB and qRT-PCR to confirm their expression. All three genes were overexpressed in the IVDD model group compared to the control group. Furthermore, we identified four miRNAs involved in the co-regulation of the hub genes using miRNet prediction: mir-191-5p, mir-20a-5p, mir-155-5p, and mir-124-3p. Using limma difference analysis, we discovered that mir-191-5p, mir-20a-5p, and mir-155-5p were all down-regulated and expressed in IVDD samples, but mir-124-3p showed no significant change. JUNB, SOCS3, and CEBPB were identified as key genes in IVDD, regulated by specific miRNAs, providing potential biomarkers for early diagnosis and therapeutic targets.

Study of impacts of two types of cellular aging on the yeast bud morphogenesis.

Understanding the mechanisms of the cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short cell cycle, and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. By analyzing experimental data, this study shows that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional multiscale chemical-mechanical model was developed and used to suggest and test hypothesized impacts of aging on bud morphogenesis. Experimentally calibrated model simulations showed that during the early stage of budding, tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip, a process guided by the polarized Cdc42 signal. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage as observed in experiments in this work. The model simulation results suggest that the localization of new cell surface material insertion, regulated by chemical signal polarization, could be weakened due to cellular aging in yeast and other cell types, leading to the change and stabilization of the bud aspect ratio.

Research advances in the function and anti-aging effects of nicotinamide mononucleotide.

Aging and age-related ailments have emerged as critical challenges and great burdens within the global contemporary society. Addressing these concerns is an imperative task, with the aims of postponing the aging process and finding effective treatments for age-related degenerative diseases. Recent investigations have highlighted the significant roles of nicotinamide adenine dinucleotide (NAD+) in the realm of anti-aging. It has been empirically evidenced that supplementation with nicotinamide mononucleotide (NMN) can elevate NAD+ levels in the body, thereby ameliorating certain age-related degenerative diseases. The principal anti-aging mechanisms of NMN essentially lie in its impact on cellular energy metabolism, inhibition of cell apoptosis, modulation of immune function, and preservation of genomic stability, which collectively contribute to the deferral of the aging process. This paper critically reviews and evaluates existing research on the anti-aging mechanisms of NMN, elucidates the inherent limitations of current research, and proposes novel avenues for anti-aging investigations.

Impaired degradation of PLCG1 by chaperone-mediated autophagy promotes cellular senescence and intervertebral disc degeneration

ABSTRACT Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1. Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value. Abbreviation: ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.

Phytochemical Composition and Toxicological Screening of Anise Myrtle and Lemon Myrtle Using Zebrafish Larvae.

Plants are an immense source of drugs, and 50% of modern pharmacopeia has a plant origin. With increasing life expectancy in humans, many age-related degenerative diseases converge on oxidative cellular stress pathways. This provides an opportunity to develop broad treatments by targeting the cause of common pathologic cell degeneration. Toxicological effects can be readily assessed in a live animal model system to establish potential fauna for clinical use. Here, we characterized and evaluated the antioxidant potential and toxicological effects of anise myrtle (Syzygium anisatum) and lemon myrtle (Backhousia citriodora) leaves. Using zebrafish larvae, a model for high-throughput pre-clinical in vivo toxicology screening, we identified safe levels of extract exposures for development of future therapeutics. The antioxidant capacity and toxicity were very similar in these two myrtles. The LC50-96h for anise myrtle was 284 mg/L, and for lemon myrtle, it was 270 mg/L. These measurements are comparable to ongoing studies we are performing using the same criteria in zebrafish, which allow for robust testing and prioritization of natural fauna for drug development.

Prebiotics improve frailty status in community-dwelling older individuals in a double-blind, randomized, controlled trial.

BACKGROUNDFrailty significantly affects morbidity and mortality rates in the older population (age >65 years). Age-related degenerative diseases are influenced by the intestinal microbiota. However, limited research exists on alterations in the intestinal microbiota in frail older individuals, and the effectiveness of prebiotic intervention for treating frailty remains uncertain.OBJECTIVEWe sought to examine the biological characteristics of the intestinal microbiome in frail older individuals and assess changes in both frailty status and gut microbiota following intervention with a prebiotic blend consisting of inulin and oligofructose.METHODSThe study consisted of 3 components: an observational analysis with a sample size of 1,693, a cross-sectional analysis (n = 300), and a multicenter double-blind, randomized, placebo-controlled trial (n = 200). Body composition, commonly used scales, biochemical markers, intestinal microbiota, and metabolites were examined in 3 groups of older individuals (nonfrail, prefrail, and frail). Subsequently, changes in these indicators were reevaluated after a 3-month intervention using the prebiotic mixture for the prefrail and frail groups.RESULTSThe intervention utilizing a combination of prebiotics significantly improved frailty and renal function among the older population, leading to notable increases in protein levels, body fat percentage, walking speed, and grip strength. Additionally, it stimulated an elevation in gut probiotic count and induced alterations in microbial metabolite expression levels as well as corresponding metabolic pathways.CONCLUSIONSThe findings suggest a potential link between changes in the gut microbiota and frailty in older adults. Prebiotics have the potential to modify the gut microbiota and metabolome, resulting in improved frailty status and prevention of its occurrence.TRIAL REGISTRATIONClinicalTrials.gov NCT03995342.

Emerging Medical Technologies and Their Use in Bionic Repair and Human Augmentation.

As both the proportion of older people and the length of life increases globally, a rise in age-related degenerative diseases, disability, and prolonged dependency is projected. However, more sophisticated biomedical materials, as well as an improved understanding of human disease, is forecast to revolutionize the diagnosis and treatment of conditions ranging from osteoarthritis to Alzheimer's disease as well as impact disease prevention. Another, albeit quieter, revolution is also taking place within society: human augmentation. In this context, humans seek to improve themselves, metamorphosing through self-discipline or more recently, through use of emerging medical technologies, with the goal of transcending aging and mortality. In this review, and in the pursuit of improved medical care following aging, disease, disability, or injury, we first highlight cutting-edge and emerging materials-based neuroprosthetic technologies designed to restore limb or organ function. We highlight the potential for these technologies to be utilized to augment human performance beyond the range of natural performance. We discuss and explore the growing social movement of human augmentation and the idea that it is possible and desirable to use emerging technologies to push the boundaries of what it means to be a healthy human into the realm of superhuman performance and intelligence. This potential future capability is contrasted with limitations in the right-to-repair legislation, which may create challenges for patients. Now is the time for continued discussion of the ethical strategies for research, implementation, and long-term device sustainability or repair.

Biological resilience in health and disease.

All living organisms - from single-celled prokaryotes through to invertebrates and humans - are frequently exposed to numerous challenges during their lifetime, which could damage their molecular and cellular contents and threaten their survival. Nevertheless, these diverse organisms are, on the whole, remarkably resilient to potential threats. Recent years have seen rapid advances in our mechanistic understanding of this emerging phenomenon of biological resilience, which enables cells, tissues and whole organisms to bounce back from challenges or stress. In this At a Glance article, I discuss current knowledge on the diverse molecular mechanisms driving biological resilience across scales, with particular focus on its dynamic and adaptive nature. I highlight emerging evidence that loss of biological resilience could underly numerous pathologies, including age-related frailty and degenerative disease. Finally, I present the multi-disciplinary experimental approaches that are helping to unravel the causal mechanisms of resilience and how this emerging knowledge could be harnessed therapeutically in the clinic.

A mechanism for telomere-specific telomere length regulation.

Telomeric DNA, composed of short, direct repeats, is of crucial importance for chromosome stability. Due to intrinsic problems with replicating this DNA, the repeat tracts shorten at each cell division. Once repeat tracts become critically short, a telomeric stress signal induces cellular senescence and division arrest, which eventually may lead to devastating age-related degenerative diseases associated with dysfunctional telomers. Conversely, maintenance of telomere length by telomerase upregulation is a hallmark of cancer. Therefore, telomere length is a critical determinant of telomere function. How telomere length is established and molecular mechanisms for telomere-specific length regulation remained unknown. Here we show that subtelomeric chromatin is a determinant for how telomere equilibrium set-length is established in cis. The results demonstrate that telomerase recruitment mediated by the telomere-associated Sir4 protein is modulated on chromosome 3L in a telomere-specific way. Increased Sir4 abundance on subtelomeric heterochromatin of this specific telomere leads to telomere lengthening of only that telomere in cis, but not at other telomeres. Therefore, this work describes a mechanism for a how telomere-specific repeat tract length can be established. Further, our results will force the evaluation of telomere length away from a generalized view to a more telomere-specific consideration.

Association of leukocyte telomere length with cardiac conduction disease and sick sinus syndrome

Abstract Background Cardiac conduction disease (CCD) and sick sinus syndrome (SSS) may be related to a degenerative process. Leukocyte telomere length (LTL) is associated with the aging process and age-related degenerative diseases. We aimed to investigate the association between LTL and the risks of CCD/SS, and to explore whether LTL is related with cardiovascular imaging and electrocardiographic (ECG) changes. Methods This is a population-based cross-sectional study of UK Biobank participants without history of CCD/SSS recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging and ECG measurements and incident CCD/SSS were evaluated by multivariable regression models. Results Among the 412,452 white participants, 188,891 (45.8%) were male, with a mean age of 57.3 years. Longer LTL was independently associated with positive cardiac remodeling, including higher left ventricular mass, larger atrial volume, and increased atrial stroke volumes. However, no significant associations were observed with ECG findings including PR interval and P-wave duration. 11991 (2.6%) participants developed CCD and 984 (0.2%) developed SSS. Longer LTL was not associated with younger age. However, longer LTL was not associated with a lower risk of incident CCD (LTL fourth quartile vs. first quartile: hazard ratio, 0.98; 95% CI, 0.97-1.0; P = 0.057) or SSS (LTL fourth quartile vs. first quartile: hazard ratio, 0.98; 95% CI, 0.92-1.05; P = 0.554). Conclusions In this cross-sectional study, longer LTL was associated with a larger atrial size with better atrial function in middle age, but not with ECG changes. However, longer LTL was not associated with a lower risk of incident CCD and SSS.

A Cross-Sectional Analysis of the Readability of Online Information Regarding Hip Osteoarthritis.

Introduction Osteoarthritis (OA) is an age-related degenerative joint disease. There is a 25% risk of symptomatic hip OA in patients who live up to 85 years of age. It can impair a person's daily activities and increase their reliance on healthcare services. It is primarily managed with education, weight loss and exercise, supplemented with pharmacological interventions. Poor health literacy is associated with negative treatment outcomes and patient dissatisfaction. A literature search found there are no previously published studies examining the readability of online information about hip OA. Objectives To assess the readability of healthcare websites regarding hip OA. Methods The terms "hip pain", "hip osteoarthritis", "hip arthritis", and "hip OA" were searched on Google and Bing. Of 240 websites initially considered, 74 unique websites underwent evaluation using the WebFX online readability software (WebFX®, Harrisburg, USA). Readability was determined using the Flesch Reading Ease Score (FRES), Flesch-Kincaid Reading Grade Level (FKGL), Gunning Fog Index (GFI), Simple Measure of Gobbledygook (SMOG), Coleman-Liau Index (CLI), and Automated Readability Index (ARI). In line with recommended guidelines and previous studies, FRES >65 or a grade level score of sixth grade and under was considered acceptable. Results The average FRES was 56.74±8.18 (range 29.5-79.4). Only nine (12.16%) websites had a FRES score >65. The average FKGL score was 7.62±1.69 (range 4.2-12.9). Only seven (9.46%) websites were written at or below a sixth-grade level according to the FKGL score. The average GFI score was 9.20±2.09 (range 5.6-16.5). Only one (1.35%) website was written at or below a sixth-grade level according to the GFI score.The average SMOG score was 7.29±1.41 (range 5.4-12.0). Only eight (10.81%) websites were written at or below a sixth-grade level according to the SMOG score. The average CLI score was 13.86±1.75 (range 9.6-19.7). All 36 websites were written above a sixth-grade level according to the CLI score. The average ARI score was 6.91±2.06 (range 3.1-14.0). Twenty-eight(37.84%) websites were written at or below a sixth-grade level according to the ARI score. One-sample t-tests showed that FRES (p<0.001, CI -10.2 to -6.37), FKGL (p<0.001, CI 1.23 to 2.01), GFI (p<0.001, CI 2.72 to 3.69), SMOG (p<0.001, CI 0.97 to 1.62), CLI (p<0.001, CI 7.46 to 8.27), and ARI (p<0.001, CI 0.43 to 1.39) scores were significantly different from the accepted standard. One-way analysis of variance (ANOVA) testing of FRES scores (p=0.009) and CLI scores (p=0.009) showed a significant difference between categories. Post hoc testing showed a significant difference between academic and non-profit categories for FRES scores (p=0.010, CI -15.17 to -1.47) and CLI scores (p=0.008, CI 0.35 to 3.29). Conclusions Most websites regarding hip OA are written above recommended reading levels, hence exceeding the comprehension levels of the average patient. Readability of these resources must be improved to improve patient access to online healthcare information which can lead to improved patient understanding of their own condition and treatment outcomes.

Integrating transcriptomic and proteomic data for a comprehensive molecular perspective on the association between sarcopenia and osteoporosis

BackgroundOsteoporosis and sarcopenia are common age-related conditions characterized by the progressive loss of bone density and muscle mass, respectively. Their co-occurrence, often referred to as osteosarcopenia, presents significant challenges in elderly care due to increased fragility and functional impairment. Existing studies have identified shared pathological mechanisms between these conditions, including inflammation, hormonal imbalances, and metabolic dysregulation, but a comprehensive understanding of their molecular interplay remains incomplete. ObjectiveThis study aims to deepen our understanding of the molecular interactions between sarcopenia and osteoporosis through an integrated omics approach, revealing potential therapeutic targets and biomarkers. MethodsEmploying a combination of proteomics and transcriptomics analyses, this study analyzed bone and muscle tissue samples from patients diagnosed with osteoporosis and osteosarcopenia. Techniques included high-throughput sequencing and label-free proteomics, supported by advanced bioinformatics tools for data analysis and functional annotation of genes and proteins. ResultsThe study found marked differences in gene and protein expressions between osteoporosis and osteosarcopenia tissues. Specifically, genes like PDIA5, TUBB1, and CYFIP2 in bone, along with MYH7 and NCAM1 in muscle, exhibited differential expression at both mRNA and protein levels. Pathway analyses revealed the significance of oxidative-reduction balance, cellular metabolism, and immune response in the progression of these conditions. Importantly, the study pinpointed osteoclast differentiation and NF-kappa B signaling pathways as critical in the molecular dynamics of osteosarcopenia, suggesting potential targets for therapy. ConclusionsThis study utilized transcriptomics and proteomics to identify key genes and proteins impacting sarcopenia and osteoporosis, employing advanced network tools to delineate interaction networks and crucial signaling pathways. It highlighted genes like PDIA5 and TUBB1, consistently expressed in both analyses, involved in pathways such as osteoclast differentiation and cytokine interactions. These insights enhance understanding of the molecular interplay in bone and muscle degeneration with aging, suggesting directions for future research into therapeutic interventions and prevention strategies for age-related degenerative diseases.

Hyper-physiologic mechanical cues, as an osteoarthritis disease-relevant environmental perturbation, cause a critical shift in set points of methylation at transcriptionally active CpG sites in neo-cartilage organoids

BackgroundOsteoarthritis (OA) is a complex, age-related multifactorial degenerative disease of diarthrodial joints marked by impaired mobility, joint stiffness, pain, and a significant decrease in quality of life. Among other risk factors, such as genetics and age, hyper-physiological mechanical cues are known to play a critical role in the onset and progression of the disease (Guilak in Best Pract Res Clin Rheumatol 25:815–823, 2011). It has been shown that post-mitotic cells, such as articular chondrocytes, heavily rely on methylation at CpG sites to adapt to environmental cues and maintain phenotypic plasticity. However, these long-lasting adaptations may eventually have a negative impact on cellular performance. We hypothesize that hyper-physiologic mechanical loading leads to the accumulation of altered epigenetic markers in articular chondrocytes, resulting in a loss of the tightly regulated balance of gene expression that leads to a dysregulated state characteristic of the OA disease state.ResultsWe showed that hyper-physiological loading evokes consistent changes in CpGs associated with expression changes (ML-tCpGs) in ITGA5, CAV1, and CD44, among other genes, which together act in pathways such as anatomical structure morphogenesis (GO:0009653) and response to wound healing (GO:0042060). Moreover, by comparing the ML-tCpGs and their associated pathways to tCpGs in OA pathophysiology (OA-tCpGs), we observed a modest but particular interconnected overlap with notable genes such as CD44 and ITGA5. These genes could indeed represent lasting detrimental changes to the phenotypic state of chondrocytes due to mechanical perturbations that occurred earlier in life. The latter is further suggested by the association between methylation levels of ML-tCpGs mapped to CD44 and OA severity.ConclusionOur findings confirm that hyper-physiological mechanical cues evoke changes to the methylome-wide landscape of chondrocytes, concomitant with detrimental changes in positional gene expression levels (ML-tCpGs). Since CAV1, ITGA5, and CD44 are subject to such changes and are central and overlapping with OA-tCpGs of primary chondrocytes, we propose that accumulation of hyper-physiological mechanical cues can evoke long-lasting, detrimental changes in set points of gene expression that influence the phenotypic healthy state of chondrocytes. Future studies are necessary to confirm this hypothesis.

Safety and efficacy of autologous adipose tissue-derived stem cell transplantation in aging-related low-grade inflammation patients: a single-group, open-label, phase I clinical trial

BackgroundInflamm-aging is associated with the rate of aging and is significantly related to diseases such as Alzheimer’s disease, Parkinson’s disease, atherosclerosis, heart disease, and age-related degenerative diseases such as type II diabetes and osteoporosis. This study aims to evaluate the safety and efficiency of autologous adipose tissue-derived mesenchymal stem cell (AD-MSC) transplantation in aging-related low-grade inflammation patients.MethodsThis study is a single-group, open-label, phase I clinical trial in which patients treated with 2 infusions (100 million cells i.v) of autologous AD-MSCs were initially evaluated in 12 inflamm-aging patients who concurrently had highly proinflammatory cytokines and 2 of the following 3 diseases: diabetes, dyslipidemia, and obesity. The treatment effects were evaluated based on plasma cytokines.ResultsDuring the study’s follow-up period, no adverse effects were observed in AD-MSC injection patients. Compared to baseline (D-44), the inflammatory cytokines IL-1α, IL-1β, IL-8, IL-6, and TNF-α were significantly reduced after 180 days (D180) of MSC infusion. IL-4/IL-10 at 90 days (D90) and IL-2/IL-10 at D180 increased, reversing the imbalance between proinflammatory and inflammatory ratios in the patients.ConclusionAD-MSCs represent a potential intervention to prevent age-related inflammation in patients.Trial registrationClinicalTrials.gov number is NCT05827757, first registered on 13th Oct 2020

Deep learning-based spinal canal segmentation of computed tomography image for disease diagnosis: A proposed system for spinal stenosis diagnosis.

Lumbar disc herniation was regarded as an age-related degenerative disease. Nevertheless, emerging reports highlight a discernible shift, illustrating the prevalence of these conditions among younger individuals. This study introduces a novel deep learning methodology tailored for spinal canal segmentation and disease diagnosis, emphasizing image processing techniques that delve into essential image attributes such as gray levels, texture, and statistical structures to refine segmentation accuracy. Analysis reveals a progressive increase in the size of vertebrae and intervertebral discs from the cervical to lumbar regions. Vertebrae, bearing weight and safeguarding the spinal cord and nerves, are interconnected by intervertebral discs, resilient structures that counteract spinal pressure. Experimental findings demonstrate a lack of pronounced anteroposterior bending during flexion and extension, maintaining displacement and rotation angles consistently approximating zero. This consistency maintains uniform anterior and posterior vertebrae heights, coupled with parallel intervertebral disc heights, aligning with theoretical expectations. Accuracy assessment employs 2 methods: IoU and Dice, and the average accuracy of IoU is 88% and that of Dice is 96.4%. The proposed deep learning-based system showcases promising results in spinal canal segmentation, laying a foundation for precise stenosis diagnosis in computed tomography images. This contributes significantly to advancements in spinal pathology understanding and treatment.

Exploration beyond osteoarthritis: the association and mechanism of its related comorbidities.

Osteoarthritis is the most prevalent age-related degenerative joint disease and a leading cause of pain and disability in aged people. Its etiology is multifaceted, involving factors such as biomechanics, pro-inflammatory mediators, genetics, and metabolism. Beyond its evident impact on joint functionality and the erosion of patients' quality of life, OA exhibits symbiotic relationships with various systemic diseases, giving rise to various complications. This review reveals OA's extensive impact, encompassing osteoporosis, sarcopenia, cardiovascular diseases, diabetes mellitus, neurological disorders, mental health, and even cancer. Shared inflammatory processes, genetic factors, and lifestyle elements link OA to these systemic conditions. Consequently, recognizing these connections and addressing them offers opportunities to enhance patient care and reduce the burden of associated diseases, emphasizing the need for a holistic approach to managing OA and its complications.

Age-related changes in meningeal lymphatic function are closely associated with vascular endothelial growth factor-C expression

Meningeal lymphatic vessels (MLVs) have crucial roles in removing metabolic waste and toxic proteins from the brain and transporting them to the periphery. Aged mice show impaired meningeal lymphatic function. Nevertheless, as the disease progresses, and significant pathological changes manifest in the brain, treating the condition becomes increasingly challenging. Therefore, investigating the alterations in the structure and function of MLVs in the early stages of aging is critical for preventing age-related central nervous system degenerative diseases. We detected the structure and function of MLVs in young, middle-aged, and aged mice. Middle-aged mice, compared with young and aged mice, showed enhanced meningeal lymphatic function along with MLV expansion and performed better in the Y maze test. Moreover, age-related changes in meningeal lymphatic function were closely associated with vascular endothelial growth factor-C (VEGF-C) expression in the brain cortex. Our data suggested that the cerebral cortex may serve as a target for VEGF-C supplementation to ameliorate meningeal lymphatic dysfunction, thus providing a new strategy for preventing age-related central nervous system diseases.