Aging and Disease最新文献

Aging research seeks to understand the progressive decline in physiological function throughout adulthood. Frailty is a significant clinical manifestation of aging. Recent discoveries of global hallmarks of aging have paved the way for deeper insight into its molecular mechanisms. Proteomics has emerged as a powerful approach, given the proteome's sensitivity to environmental changes. This study aimed to uncover novel biological insights into aging by analyzing proteins that are significantly associated with chronological age or frailty. We conducted a systematic review of Medline and Embase up to August 2024 to find studies involving adults that used proteomic analyses. From each study, we compiled the significant proteins consistently reported across age-related or frailty-related studies by extracting statistical outcomes and expression patterns. Significant proteins were compared, and pathway enrichment analysis was performed using STRING software. Our analysis included 2,630 age-associated proteins from 27 studies and 194 frailty-associated proteins from 8 studies. We identified 177 shared proteins for both age and frailty, including nine with opposite expression trends. Meta-regression and pathway analyses revealed convergence on key biological processes, including immunity, inflammation, metabolism, homeostasis, coagulation, and neurology. These findings suggest that age- and frailty-related proteomic studies provide complementary insights into understanding the overall complexity of the biology of aging. This integrative approach emphasizes the potential of proteomics not only for biomarker discovery but also for advancing our understanding of our functional capacities. Future multi-omics studies will be essential for further elucidating the complex molecular landscape of aging.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and memory decline. Current therapeutic strategies largely provide symptomatic relief and remain limited in their capacity to halt or reverse disease progression. Accordingly, increasing efforts seek to reexamine AD pathophysiology from a systemic perspective and to identify novel therapeutic targets. Although classical AD research has focused primarily on intrinsic brain pathology, accumulating evidence indicates that disease progression reflects complex interactions among multiple cellular and systemic mechanisms. The central nervous system (CNS) is now recognized as functionally interconnected with peripheral organs through immune-mediated and neural communication networks. Within this framework, the concept of the organ-brain axis has emerged, proposing that organ-specific immune microenvironments and inflammation-derived mediators originating from peripheral tissues may modulate immune homeostasis in the brain, neuronal survival, and neurodegenerative processes. In patients with AD, immunological alterations are observed not only within the CNS but also in peripheral organs including the gut, lung, liver, and bladder, and these changes are associated with disease progression. Peripheral immune dysregulation extends beyond localized inflammatory responses, potentially contributing to sustained neuroinflammation, disruption of blood-brain barrier integrity, and pathological activation of microglia and astrocytes. Rather than viewing AD as a disorder confined to the brain, this review adopts a systemic perspective in which peripheral immune environments dynamically interact with central neuroinflammatory pathways. We comprehensively summarize immune cell alterations across major peripheral organs under AD pathology, their interactions with neuronal cells, and the potential signaling mechanisms that mediate organ-brain immune crosstalk.

The measurement of fluid biomarkers such as phosphorylated tau at threonine 181 (pTAU181), amyloid-β 40 (Aβ40), and Aβ42 is a routine medical examination that contributes to achieving an accurate diagnosis within the Alzheimer's disease (AD) clinical continuum. The aim of this study is to compare the concentration of these biomarkers in CSF and plasma and determine their relationship with the patients' clinical variant and profile. Patients were diagnosed following the NIA-AA criteria. Plasma and CSF were obtained from healthy controls (HC), mild cognitive impairment (MCI non-AD), MCI displaying positive AD markers (MCI-AD), and AD patients. Biomarker levels were assessed using the LUMIPULSE® G600II instrument (Fujirebio, Japan). Data showed a significant increase in pTAU181 concentration, specifically in the progression from MCI non-AD to AD conditions. The opposite trend was observed for Aβ42 and Aβ42/Aβ40. Furthermore, these biomarker trends appeared to change consistently with variations in the MMSE score, highlighting the relevance of plasma in detecting changes in patients' cognitive function. Considering the clinical variant, atypical patients displayed the highest pTAU181 and lowest Aβ42 levels, consistent with their lower MMSE scores. Lastly, the posterior cortical atrophy (PCA) profile showed higher pTAU181 and lower Aβ42 levels when compared to other profiles. Nevertheless, these last results are to be cautiously interpreted given the limited number of samples included in the analysis. Hence, further analyses on larger cohorts are needed to better define the role of these biomarkers in distinguishing between patients' clinical variants.

Knee osteoarthritis (KOA) is a degenerative disorder that affects the joint in a non-uniform and focal manner. It is characterized by the loss of hyaline articular cartilage, along with bony remodeling, capsular stretching, and weakness of periarticular muscles. It could be ascribed to etiological factors that are modifiable (obesity, joint injury, occupational hazards, physical inactivity), non-modifiable (age, female gender, and genetic predisposition, racial/ethnic differences), or emerging, such as high blood pressure, vitamin D deficiency, and metabolic syndrome, which might contribute to KOA pathophysiology. KOA treatment is multimodal, and recent years have witnessed a shift from primarily pharmacologic, surgical to regenerative therapies ones, due to limited advantages of the former and evidence that advanced approaches are more likely to suppress pathological symptoms in the long term and to delay or prevent functional decline. Minimally invasive stem cell-based alternatives such as adipose-derived stem cells (ADSCs) are being explored owing to their differentiation potential towards chondro-, osteo-, and adipogenic lineages for osteochondral reparative regeneration. ADSC-derived extracellular vesicles, particularly exosomes (ADSC-exo), are gaining prominence in the treatment of KOA due to their unique regenerative and anti-inflammatory properties. These exosomes offer several advantages compared to cellular interventions, being a cell-free therapeutic strategy, low immunogenicity, and potential to deliver bioactive molecules, promote anti-inflammatory effects, and cartilage repair and regeneration. ADSC-exo expresses miRNA and improved safety by regulating various pathways such as PI3K/AKT/mTOR signaling or Wnt/β-catenin signalling. Combinatorial approaches have also been applied with ADSCs, such as platelet-rich plasma, shockwave therapy, xanthan gum, hyperbaric oxygenation, and nanoparticles, which have shown significant improvements in alleviating KOA. Based on the above evidence, we have reviewed the advances in epidemiology, emerging etiopathologies, and ADSCs-based revitalization strategies for the osteoarthritic knee joint.

This perspective article synthesizes contemporary evidence on advancing thrombolytic strategies for acute ischemic stroke, focusing on extended-window intravenous thrombolysis (IVT) and adjunctive intra-arterial thrombolysis (IAT) during thrombectomy. Future directions for extended-window thrombolysis should integrate artificial intelligence (AI)-powered neuroimaging interpretation to precisely identify the tissue window and quantify hemorrhage risk, while a simplified paradigm based on non-contrast CT and AI collaboration is critical for expanding IVT access in resource-limited settings. For adjunctive IAT, candidate selection should be refined by integrating residual thrombus burden with perfusion status. Collectively, these precision strategies are poised to enhance reperfusion benefits and alleviate the global stroke burden.

Neurodegenerative diseases (NDs), which affect millions globally, are characterized by progressive motor and non-motor deficits and currently lack a cure. Molecular chaperones, particularly heat shock proteins (HSPs), have emerged as promising therapeutic candidates to combat these conditions. HSPs are classified into six major families and have been extensively studied in contexts ranging from autoimmune diseases to cancer and viral infections. Their broad functional repertoire-which includes preventing protein aggregation, correcting misfolding, regulating apoptosis, mediating autophagy, and maintaining proteostasis-positions them as potent modulators of the pathological processes underlying NDs. This review will explore the mechanisms of different HSP classes and critically assess their therapeutic potential for NDs.

Efferocytosis, the process by which phagocytes clear apoptotic cells, is fundamental for maintaining physiological homeostasis. Inflammaging as a chronic and low-grade inflammatory state characteristic of aging is recognized as a significant contributor to tumor development. As crucial innate immune cells found in various tissues, macrophages are closely involved in both inflammaging and tumor. Accumulating evidence indicates that macrophage-mediated efferocytosis is closely linked to these processes, and its disruption can initiate or accelerate disease. Therefore, it is essential to elucidate the pivotal functions of macrophage efferocytosis in inflammaging and tumor biology to develop potential therapeutic strategies. Herein, this study first aims to uncover the crosstalk between inflammaging and tumor. We then investigate the mechanisms of macrophage efferocytosis, outlining its distinct functional phases and associated metabolic adaptations. The effects of efferocytosis on macrophage functions are also discussed. Furthermore, this study summarizes the prospective therapies treating inflammaging and tumor by modulating macrophage efferocytosis. Collectively, targeting macrophage efferocytosis represents a promising strategy for treating chronic inflammation-associated diseases, including tumor and inflammaging.

Cellular senescence and immunosenescence drive chronic tissue damage via persistent senescence-associated secretory phenotype (SASP)-mediated inflammation, particularly through pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α). In osteoarthritis (OA), senescent chondrocytes promote cartilage degradation, while in rheumatoid arthritis (RA), aged immune cells impair self-tolerance. Emerging therapies targeting these mechanisms - including senolytics and cytokine inhibitors-demonstrate potential to break this pathological cycle. These findings emphasize the necessity of combined anti-inflammatory and anti-aging approaches for managing age-related rheumatic diseases.

As population ages globally, the agenda of healthy aging has emerged as a critical priority. For addressing the evolving needs of the aging population, the World Health Organization (WHO) introduced the concept of Intrinsic Capacity (IC), which is defined as the composite of all physical and mental capacities. IC brings a major paradigm change, shifting the focus from disease to function and optimization of IC through life has been suggested to be required for achieving healthy aging. In parallel, geroscience is an emerging discipline aiming to understand the biology of aging and developing strategies to slow the aging process and thus prevent age-related functional decline and chronic diseases. This narrative review explores the conceptual and translational connection between IC and geroscience, proposing that IC may serve not only as a measurable indicator of global function but also as a potential target for geroscience interventions. We discuss how the hallmarks of aging underlie declines in the domains of IC and summarize emerging gerotherapeutic approaches that may potentially optimize IC. We further discuss the possibility of integrating IC into geroscience-informed clinical and public health frameworks, emphasizing its value in guiding preventive and personalized strategies for healthy aging.

Age-related chronic low-grade inflammation contributes to both frailty and bone loss. One of the key regulators of inflammatory signaling that declines with age is tristetraprolin (TTP), an RNA-binding protein that promotes degradation of pro-inflammatory transcripts. In this study, we investigated whether stabilizing TTP during aging could reduce frailty and enhance bone health by mitigating inflammation and immune dysfunction. We utilized a knock-in mouse model (TTP∆ARE), in which an AU-rich region of the 3' untranslated region was deleted to stabilize TTP mRNA and increase protein expression. Aged TTP∆ARE mice had reduced physical frailty scores, a composite measure based on body weight and physical performance, than age-matched wild-type controls (WT). Since frailty is associated with fracture risk, we examined bone structure. Aged TTP∆ARE males exhibited significantly higher bone mineral density and improved bone microarchitecture relative to WT mice. Our prior work showed that aging elevates myeloid-derived suppressor cells (MDSCs), which possess osteoclastogenic potential. The monocytic MDSCs (M-MDSCs) from the bone marrow of aged TTP∆ARE formed fewer osteoclasts than those from WT mice. Further, transcriptomic analysis of M-MDSCs revealed downregulation of bone resorption and remodeling pathways, along with upregulation of immune activation genes. In addition, immunophenotyping revealed a healthier, youthful-like immune profile in aged TTP∆ARE mice, including increased T-cell reservoirs. These findings signify the critical role of TTP in bone health during aging by regulating osteoimmunological induction of M-MDSCs, which leads to a partial reversal of the age-associated immune senescent phenotype, resulting in increased bone mineral density and improved functional capacity during aging.