Sequential Targeted Enzyme‐Instructed Self‐Assembly Supramolecular Nanofibers to Attenuate Intervertebral Disc Degeneration

Advanced Materials, Год журнала: 2024, Номер 36(41)

Опубликована: Сен. 2, 2024

Abstract As an age‐related disease, intervertebral disc degeneration is closely related to inflammation and aging. Inflammatory cytokines cellular senescence collectively contribute the degradation of disc. Blocking this synergy reduces extracellular matrix damage caused by In study, drug‐loaded nanofibers with sequential targeting functions are constructed through intelligent response, hydrophilicity, in situ self‐assembly empowerment flurbiprofen. The peptide precursor responds cleavage overexpressed MMP‐2 degenerative microenvironment (intracellular extracellular), resulting formation self‐assembled that enable on‐demand release flurbiprofen COX‐2 response. vitro, Comp. 1 (Flurbiprofen‐GFFYPLGLAGEEEERGD) expression inflammation‐related genes proteins polarization M1 macrophages competitively inhibiting increases COL‐2 aggrecan. Additionally, it can reduce Senescence‐Associated Secretory Phenotype DNA aged nucleus pulposus cells promote recovery proliferation cell cycle. vivo, delay preventing accumulation senescent cells. Therefore, sequentially targeted blocking synergistic effect inflammatory senescence.

Язык: Английский

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Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases

Mechanisms of Ageing and Development, Год журнала: 2024, Номер 222, С. 111995 - 111995

Опубликована: Окт. 9, 2024

Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as senotherapeutic agent the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age disease, both circulating immune cell populations solid organs tissues. Senescent cells contribute to development many diseases, primarily by eliciting systemic inflammation through their senescence-associated secretory phenotype. Here, we explore whether fisetin can eliminate thereby alleviate examining current evidence from vitro studies animal models that investigate fisetin's impact on well phase I/II trials various patient populations. We discuss application humans, including challenges future directions. Our review available data suggests targeting offers promising strategy managing multiple potentially transforming healthcare older multimorbid patients. However, further are needed establish safety, pharmacokinetics, efficacy senotherapeutic, identify relevant reliable outcome measures human trials, optimize dosing, better understand possible limitations agent.

Язык: Английский

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Circadian Rhythm, Hypoxia, and Cellular Senescence: From Molecular Mechanisms to Targeted Strategies

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177290 - 177290

Опубликована: Янв. 1, 2025

Язык: Английский

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Causal Associations of Inflammatory Cytokines With Osteosarcopenia: Insights From Mendelian Randomization and Single Cell Analysis

Mediators of Inflammation, Год журнала: 2025, Номер 2025(1)

Опубликована: Янв. 1, 2025

Background: Osteosarcopenia, the coexistence of osteoporosis and sarcopenia, poses significant challenges in aging populations due to its dual impact on bone muscle health. Inflammation, mediated by specific cytokines, is thought play a crucial role development osteosarcopenia, though underlying mechanisms are not fully understood. Objective: This study aimed clarify causal circulating cytokines pathogenesis osteosarcopenia employing mendelian randomization (MR) single-cell RNA sequencing (scRNA-seq) identify cell-specific cytokine expression patterns. The ultimate objective was uncover potential pathological therapeutic targets for treating osteosarcopenia. Methods: A two-sample MR approach employed, leveraging publicly available genome-wide association (GWAS) data from multiple cohorts. total 91 were examined using genetic instruments, their effects traits related sarcopenia evaluated. Various complementary sensitivity analyses performed ensure robust findings. Additionally, scRNA-seq datasets human marrow analyzed validate profiles candidate cytokines. Results: analysis identified several with traits, including LTA, CD40, CXCL6, CXCL10, DNER (delta notch-like epidermal growth factor-related receptor), VEGFA (vascular endothelial factor A). LTA CD40 protective both muscle, while posed risk. Other demonstrated opposite muscle. Single cell revealed distinct patterns, highly expressed lymphocytes, immune cells, various musculoskeletal types. Age-related differences also noted, more younger individuals, older individuals. Conclusion: offers preliminary insights into inflammatory potentially driving identifying key that may be involved pathogenesis. By integrating data, we highlight targets, further research needed confirm these findings implications

Язык: Английский

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The associations between skin advanced glycation end-products and Framingham cardiovascular risk in different age groups

Frontiers in Cardiovascular Medicine, Год журнала: 2025, Номер 12

Опубликована: Апрель 8, 2025

Advanced glycation end-products (AGEs) may contribute to the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), potentially influencing its development and progression differently at various life stages. This study aimed elucidate associations between AGEs risk ASCVD across different age groups. In this cross-sectional study, 1,240 subjects were enrolled divided into three groups (Group Ⅰ, 20-39 years old, n = 468; Group Ⅱ, 40-59 471; Ⅲ, 60-79 301). Skin measured by skin autofluorescence (SAF). was assessed a validated Framingham score calculator. Other proven factors also measured, including glycosylated hemoglobin, uric acid, lipid profile, homocysteine, cystatin C. An increasing trend in observed from Ⅰ Ⅲ. significantly associated with all (OR 1.029, 95% CI 1.003-1.056, P 0.018), independent some factors. association particularly significant individuals aged 1.047, CI: 1.025-1.069; OR 1.022, 1.002-1.042; both < 0.05). ROC analysis showed that predicted diagnosis medium or high pooled group, Our substantiates play an important role as factor for ASCVD, highlighting their significance beyond traditional assessment models, middle-aged older populations.

Язык: Английский

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Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6793 - 6793

Опубликована: Июнь 20, 2024

Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings aging crucial identify geroprotectors, precisely quantify biological age, propose healthy longevity approaches. This review explores pathways are currently being investigated as intervention targets biomarkers spanning molecular, cellular, systemic dimensions. Interventions target these hallmarks may ameliorate process, with some progressing clinical trials. Biomarkers used estimate aging-associated disease. Utilizing biomarkers, clocks can be constructed predict state abnormal aging, diseases, mortality. Biological age estimation therefore provide basis for fine-grained stratification by predicting all-cause mortality well ahead onset specific thus offering window intervention. Yet, despite technological advancements, challenges persist due individual variability dynamic nature biomarkers. Addressing this requires longitudinal studies robust biomarker identification. Overall, utilizing discover new drug develop opens frontiers medicine. Prospects involve multi-omics integration, machine learning, personalized approaches targeted interventions, promising healthier population.

Язык: Английский

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Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta‐analyses: The Long Life Family Study

Aging Cell, Год журнала: 2024, Номер 23(10)

Опубликована: Июнь 26, 2024

Abstract Patients with chronic kidney disease (CKD) have increased oxidative stress and inflammation, which may escalate the production of advanced glycation end‐products (AGEs). High soluble receptor for AGE (sRAGE) low estimated glomerular filtration rate (eGFR) levels are associated CKD aging. We evaluated whether eGFR calculated from creatinine cystatin C share pleiotropic genetic factors sRAGE. employed whole‐genome sequencing correlated meta‐analyses on combined genome‐wide association study (GWAS) p ‐values in 4182 individuals (age range: 24–110) Long Life Family Study (LLFS). also conducted transcriptome‐wide studies (TWAS) whole blood a subset 1209 individuals. identified 59 GWAS loci ( < 5 × 10 −8 ) 17 TWAS genes (Bonferroni‐ 2.73 −6 traits genes, LSP1 MIR23AHG , were sRAGE located within loci, lncRNA‐ KCNQ1OT1 CACNA1A/CCDC130 respectively. variants eQTLs glomeruli tubules, predicted carcinoma. harbored kidney, carcinoma, connected enhancer‐promoter function‐related phenotypes at . Additionally, higher allele frequencies protective detected LLFS than ALFA‐Europeans TOPMed, suggesting better function healthy‐aging general populations. Integrating genomic annotation transcriptional gene activity revealed enrichment elements aging‐ related processes. The expressions suggest their underlying shared effects highlight roles kidney‐ aging‐related signaling pathways.

Язык: Английский

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Decoding senescence of aging single cells at the nexus of biomaterials, microfluidics, and spatial omics

npj Aging, Год журнала: 2024, Номер 10(1)

Опубликована: Ноя. 26, 2024

Aging has profound effects on the body, most notably an increase in prevalence of several diseases. An important aging hallmark is presence senescent cells that no longer multiply nor die off properly. Another characteristic altered immune system fails to properly self-surveil. In this multi-player process, cellular senescence induces a change secretory phenotype, known as senescence-associated phenotype (SASP), many with intention recruiting accelerate clearance these damaged cells. However, SASP results inducing secondary nearby cells, resulting those becoming senescent, and improper activation state chronic inflammation, called inflammaging, Senescence termed immunosenescence, further dysregulation system. interdisciplinary approach needed physiologically assess changes at tissue level. Thus, intersection biomaterials, microfluidics, spatial omics great potential collectively model immunosenescence. Each approaches mimics unique aspects body undergoes part aging. This perspective highlights key how biomaterials provide non-cellular cues cell aging, microfluidics recapitulate flow-induced multi-cellular dynamics, analyses dissect coordination biomarkers function interactions distinct environments. overview play role organ cancer, wound healing, Alzheimer's, osteoporosis included. To illuminate societal impact increasing trend anti-senescence anti-aging interventions, including pharmacological medical procedures, lifestyle discussed, context senescence.

Язык: Английский

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Hungry for biomarkers of aging

Aging Cell, Год журнала: 2024, Номер 23(4)

Опубликована: Март 27, 2024

Greater insights into biological mechanisms (hallmarks) of aging, their associations with aging-related diseases and disabilities, early evidence that they can be modified by intervention have generated intense interest in testing the geroscience hypothesis; is, interventions targeting hallmarks aging will delay or even prevent age-related disabilities. This innovative potentially disruptive approach to optimize human health has revealed need, potential, challenges for operationalizing markers, biomarkers, aging. Sensitive specific methods continue progress quantifying loss proteostasis, mitochondrial dysfunction, epigenetic alterations, oxidative damage, cellular senescence, other (Lopez-Otin et al., 2023) at tissue single cell levels, particularly preclinical models. Their utility humans, however, limited accessibility tissues most vulnerable conditions, example, heart, brain, lung, kidney. challenge driven National Institute on Aging (https://predictivebiomarkers.org/), a recently formed Biomarkers Consortium (https://www.agingconsortium.org/), entities develop feasible, valid, and, context hallmarks, modifiable biomarkers (Moqri 2023, 2024; Rutledge 2022). As an we exploited literature secretome several types induced senescence vitro candidate panel comprised cytokines, chemokines, matrix remodeling proteins, growth factors, could reliably measured blood humans (Schafer 2020). We observed expected changes circulating abundance conditions associated increased senescent burden, including advanced chronological age, frailty, disability, chronic disease (Aversa, Atkinson, 2023; Fielding Schafer Most recently, studied biospecimens clinical data from Comprehensive Assessment Long-term Effects Reducing Intake Energy (CALERIE™) study demonstrated participants randomized 2 years calorie restriction had reduced concentrations Year 1 compared those ad libitum diet White, 2023). In thoughtful categorization as response, predictive, surrogate, proposed Cummings Kritchevsky, change senescence-related proteins response would support use (Cummings & Response are critical advancement pharmacological part, such provide confirmation early-phase trials target engagement (e.g., reduction burden secretory phenotype cells reprogramming epigenome more youthful state) guide optimal dose dosing regimens. If field is so fortunate arsenal distinct, albeit interrelated, these may also foster personalized medicine selection right intervention, person, time. However, hurdles track translation persist. For whether reflect average state across all organs strongly influenced age particular organ unclear. Similarly, accessible informative lungs pulmonary disease) remains demonstrated. A recent showing sets linked highlights potential overcome barriers our reflective given (Oh Another key question activity hallmark predictive longer term outcomes regulatory agencies, how one feels, functions, survives. reasonable application but, this stage, largely unanswered. than 1900 relatively healthy older adults either zero condition baseline, was able predict mortality better combination sex, race, presence (St Sauver Moreover, CALERIE™ participants, reported were highly homeostatic model insulin resistance calculation sensitivity suggest serve perhaps surrogate which respond future outcomes. classic example biomarker pressure. restriction, like exercise, undoubtedly mediates improvements metabolic through multiple mechanisms, limiting causal attribution (i.e., elimination suppression responsible benefits restriction). Additional research needed determine specifically cells, genomic instability, deregulated nutrient-sensing, stem exhaustion, etc., recognized metabolic, musculoskeletal, cardiovascular, immunological, cognitive function, line hypothesis. Finally, it should noted offer decision making, absence hallmarks. Individuals presumably heightened vulnerability disabilities poor medical surgical drug toxicity, complications, length hospital stay, rehospitalization). Indeed, DNA methylation, somatic mutations, shown predicting risk adverse events (Fielding Jaiswal Ebert, 2019; Mahapatra McCrory 2021). It plausible used existing calculators, now heavily inform decisions, electing conservative versus aggressive management condition, prescribing prehabilitation prior proactively initiating comprehensive transitional care plans rehospitalization following discharge hospital. Given promise, exciting observe contribute current multidisciplinary collaborative efforts within test The expectation help advance hypothesis compelling premise practice. NKL grateful helpful discussions feedback colleagues Robert Arlene Kogod Center Mayo Clinic Dr. Steve University California San Francisco Pacific Medical Center. supported grants (AG062413, AG055529, AG079754, AG058738, AG044170) Glenn Foundation Research. intellectual property related work licensed commercial entity. been reviewed Conflict Interest Review Board being conducted compliance Clinic's policies.

Язык: Английский

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Bidirectional Two-Sample Mendelian Randomization Study of Immunoglobulin G N-Glycosylation and Senescence-Associated Secretory Phenotype

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6337 - 6337

Опубликована: Июнь 7, 2024

Observational studies revealed changes in Immunoglobulin G (IgG) N-glycosylation during the aging process. However, it lacks causal insights and remains unclear which direction relationships exist. The two-sample bidirectional Mendelian randomization (MR) design was adopted to explore associations between IgG N-glycans senescence-associated secretory phenotype (SASP). Inverse variance weighted (IVW) Wald ratio methods were used as main analyses, supplemented by sensitivity analyses. Forward MR analyses glycan peak (GP) SASP, including GP6 (odds [OR] = 0.428, 95% confidence interval [CI] 0.189–0.969) GP17 (OR 0.709, 95%CI 0.504–0.995) with growth/differentiation factor 15 (GDF15), GP19 an advanced glycosylation end-product-specific receptor (RAGE) 2.142, CI 1.384–3.316), GP15 matrix metalloproteinase 2 (MMP2) 1.136, =1.008–1.282). reverse indicated that genetic liability RAGE associated increased levels of 1.125, 1.003–1.261) GP24 1.222, 1.046–1.428), while pulmonary activation-regulated chemokines (PARC) exhibited GP10 1.269, 1.048–1.537) 1.297, 1.072–1.570). findings provided suggested evidence on causality might reveal potential regulatory mechanisms.

Язык: Английский

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