Aging and Disease最新文献

Nutritional supplementation is emerging as a promising strategy to support clinical management of early Alzheimer's disease (AD), partly through modulation of the intestinal microbiome via the microbiota-gut-brain axis. This study investigated the impact of Fortasyn Connect (Souvenaid^®), a multinutrient formulation, on gut microbiota using a dual approach: i) a dynamic gastrointestinal simulator (simgi^®) inoculated with feces from AD patients, and ii) an observational study involving early-stage AD patients (n = 22) receiving or not the supplement. The in vitro model provided a direct, host-independent assessment of microbiota responses, showing increased Bifidobacterium and Lactobacillus levels, alongside enhanced short-chain fatty acid (SCFA) production. In patients, supplementation was associated with higher fecal abundance of Bifidobacterium and Christensenellaceae, reduced inflammatory markers (calprotectin and myeloperoxidase), and increased butyrate levels. Fecal lipidomic and proteomic analyses indicated improved lipid digestion, increased secretory IgA, and modulation of host proteins linked to gut-brain homeostasis. Systemically, elevated levels of iron, folate, and vitamin B12 were also observed. For the first time, this study shows that supplements such as Fortasyn Connect can beneficially modulate the gut ecosystem and related immune-metabolic pathways in early AD, thereby targeting disease-relevant mechanisms through the gut-brain axis, in the context of aging.

To synthesize current evidence on structural, cellular, metabolic, and neuro-immune mechanisms of lacrimal gland (LG) aging in humans and animal models, and to map translational strategies for age-related aqueous-deficient dry eye (ADDE). Narrative synthesis of clinical tear-function studies; human histopathology/biobank data; and mechanistic experiments in mouse, rabbit, and non-human primates, with emphasis on single-cell and spatial omics, autonomic regulation, and immune remodeling. LG aging is characterized by acinar attrition, ductal-stromal fibrosis, mitochondrial fragmentation with lipofuscin accumulation; and diminished parasympathetic and sympathetic innervation. Convergent mechanisms-oxidative stress, mitochondrial insufficiency, cellular senescence, immunosenescence with low-grade inflammation, and disrupted cholinergic/catecholaminergic signaling-jointly depress tear volume and alter composition. Cross-species comparisons reveal conserved pathways alongside species-specific susceptibilities that inform model selection. Therapeutic avenues under investigation include anti-inflammatory and metabolic modulators, senolytics, hormone/secretagogue approaches, and regenerative platforms leveraging stem cells, lacrimal organoids, and bioengineered scaffolds. Emerging organoid and ex vivo secretion assays hold potential for mechanism-based screening and phenotyping that bridge preclinical and clinical endpoints. LG aging is a tractable, multifactorial driver of ADDE. Priorities for translation include standardizing functional readouts, aligning cross-species endpoints, and testing mechanism-selected cohorts in early-phase trials with objective measures of tear secretion and ocular-surface integrity. Integrating multi-omics with advanced models and regeneration-focused strategies offers a path from symptomatic relief to durable restoration of gland function.

Successful postural control depends on the integration of visual, vestibular, and proprioceptive inputs. With age, postural control degrades, leading to impaired balance and greater fall risk. Understanding how this integration changes over the lifespan is invaluable for designing more effective interventions that enable healthy postural control in older age. Earlier studies measured visual dependence using perceptual tasks or spontaneous sway comparisons across visual conditions. This study evaluates how visual dependence differs between younger and older adults within the postural control mechanism using a Central Sensorimotor Integration (CSMI) test. Eighty healthy adults (n = 40, 60-87 years, n = 40, 21-52 years) were exposed to small pseudorandom visual scene movements implemented in virtual reality while standing on a compliant surface. Sway responses were measured using virtual reality trackers and interpreted using an established frequency domain balance control model. Model parameters included visual weight, proportional and derivative feedback gains, time delay, and torque feedback gain. Test-retest reliability was assessed in a subgroup (n = 40) and showed excellent intra-class correlation coefficients for visual weight, proportional and derivative feedback gains (ICC = 0.90-0.97), and lower ICCs for time delay (ICC = 0.60) and torque parameters (ICC = 0.30). The main difference between age groups was visual dependence, with older adults relying 40% on vision, compared to 33% for the younger group (p = 0.042). No significant group differences were found in other model parameters. The results provide direct evidence of an increase in visual contribution to posture control with age.

Cardiovascular diseases (CVDs) have long been the leading cause of mortality among the elderly worldwide. Despite substantial progress, a complete understanding of the initiation and progression of CVDs remains elusive. Emerging evidence suggests that the risk of developing CVDs increases with aging and prolonged insulin resistance (IR). Insulin is a key metabolic hormone crucial for regulating glucose and lipid metabolism in various tissues. An impaired tissue response to insulin stimulation results in IR. With aging, pathological changes such as visceral obesity, chronic inflammation, and oxidative stress collectively exacerbate IR, leading to dyslipidemia, hyperglycemia, and hypertension. These conditions highlight IR as a critical factor linking aging to various CVDs, including atherosclerosis, heart failure, and hypertension. Thus, preventing IR is essential for preserving cardiac function. In this review, the pathological mechanisms of IR in elderly individuals are summarized, emphasizing their association with aging-related CVDs. Additionally, potential therapeutic targets associated with IR for treating CVDs are discussed, along with current limitations and future directions for cardiac recovery strategies.

Cellular senescence is a state of stable growth arrest that is accompanied by a characteristic phenotype. The senescent phenotype is dynamic and heterogeneous, and it depends on both the type of cell and the factors that trigger senescence. There is no single biomarker that is shared by all senescent cell types. Therefore, our studies aimed to define a set of biomarkers that can discriminate among proliferating, senescent and temporally growth-arrested (quiescent) cells. We analysed vascular smooth muscle cells (VSMCs) derived from healthy aortae that underwent senescence in vitro but also VSMCs isolated from human atherosclerotic plaques that underwent senescence in vivo. Our results demonstrate that changes in the levels of nuclear proteins (Lamin B1, HMGB1, PARP1) are the most consistent, stable and widespread in cells senescing in vitro while changes in the levels of signalling proteins implicated in senescence (p53, p21^CIP, p16^INK4A) appeared to be more variable. VSMCs derived from atherosclerotic plaques reflects pattern of senescence biomarker expression observed in VSMCs undergoing in vitro senescence but some differences were revealed. There was a gradual decrease in p21^CIP level and an increase in p16^INK4A level as VSMCs cultured in vitro progressed toward late senescence or entered replicative senescence, whereas plaque-derived senescent VSMCs showed increased p21^CIP and p16^INK4A protein expression compared with proliferating VSMCs from healthy aortas. Overall, we have defined a set of biomarkers that is common for VSMCs undergoing in vitro and in vivo senescence and enable to recognize senescent cells with high confidence, regardless of senescence trigger and senescence phase (early versus late).

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited targeted therapies and a substantial unmet clinical need. Immunotherapy has emerged as a transformative frontier in TNBC, with immune checkpoint inhibitors (ICIs) representing a major category of this approach. The KEYNOTE-522 trial established pembrolizumab, an ICI, combined with chemotherapy as a standard neoadjuvant regimen for TNBC. However, the clinical outcomes of neoadjuvant immunotherapy-containing regimens are influenced by multiple factors, including the specific immunotherapeutic agents employed, companion strategies (such as distinct chemotherapy backbones or antibody-drug conjugates), patient characteristics, and trial design. Therefore, the implementation of neoadjuvant immunotherapy in broader clinical practice should be approached with caution. Elderly patients (≥65 years, over one-quarter of all breast cancer cases) may experience reduced efficacy from immunotherapy due to immunosenescence and are more susceptible to treatment-associated toxicity. Leveraging the neoadjuvant setting for biomarker-driven risk stratification will be essential to guide age-tailored treatment optimization and minimize unnecessary toxicity. This perspective highlights the opportunities and challenges associated with neoadjuvant immunotherapy in TNBC and outlines future directions for optimizing its clinical application.

Aging of skeletal muscles is accompanied by a progressive deposition of adipose and fibrotic tissue within the interstitial compartment. This process profoundly disrupts the structural integrity and contractile function of the muscle. Such maladaptive remodeling not only compromises muscle performance but also impairs its regenerative capacity, predisposing old individuals to frailty and sarcopenia. Fibro-adipogenic progenitors (FAPs) have been identified as the principal cellular source of the pathological adipogenic and fibrogenic remodeling. These stromal cells integrate mechanical, biochemical, and immune signals within the muscle niche, ultimately determining whether muscle repair leads to effective regeneration or maladaptive remodeling. In young muscle, transient FAP activation supports satellite cell-mediated myogenesis through extracellular matrix remodeling and pro-regenerative signaling. However, in aging muscle, this precise regulation is disrupted. The aged niche is characterized by chronic inflammatory stress, altered matrix composition, and impaired immune-stromal communication. These changes drive FAPs toward maladaptive phenotypes that promote fibrosis, intramuscular fat accumulation, and regenerative failure. FAP dysfunction is increasingly recognized as a central mechanism contributing to age-related sarcopenia, increased susceptibility to injury, and delayed recovery. Given their dual ability to promote both regeneration and degeneration, understanding how aging reprograms FAP fate and function offers a promising avenue to rejuvenating the aged muscle niche. Here, we summarize current insights into the roles and dynamics of FAPs in aged muscle and discusses their potential as therapeutic targets to restore regenerative capacity and mitigating muscle aging.

Major depressive disorder (MDD) affects hundreds of millions worldwide and remains a major unmet clinical need because conventional monoaminergic agents achieve remission in fewer than half of patients and leave a substantial treatment-resistant subgroup. To address this gap, integrative multi-omics approaches, combined with computational systems biology, are being used to dissect its multifactorial etiology. Here, we review key findings from large Genome-wide association studies (GWAS), single-cell and spatial transcriptomics, proteomics, and metabolomics that converge on disrupted neuroplasticity, immune-inflammatory signaling, HPA-axis dysregulation, mitochondrial metabolism, and gut-brain interactions. We describe how AI-driven network modeling and structure-based drug design (SBDD) are translating multi-omics signals into candidate biomarkers and mechanism-based therapeutics, for example, N-methyl-D-aspartate/glutamatergic modulators, kappa opioid antagonists, anti-inflammatory agents, and epigenetic modulators. We highlighted the clinical implications, specifically molecularly stratified biomarkers for patient selection, trial enrichment, and structure-guided optimization of rapid-acting antidepressants and microbiome-based interventions. Finally, we discuss the limitations and immediate translational priorities that emphasize the trajectory from multi-omics discovery to precision psychiatry for MDD.

Vascular dementia (VD) is the second most prevalent form of dementia, yet no disease-modifying treatments are available. Proteins in the brain, cerebrospinal fluid (CSF), and plasma with strong genetic associations represent promising therapeutic targets. However, a comprehensive, proteome-wide screening for VD-associated proteins has not been conducted. We employed a cross-tissue proteomic Mendelian randomization (MR) framework, integrating pQTL data from brain, CSF, and plasma with VD GWAS. We identified causal VD-associated proteins, assessed their consistency across VD subtypes, explored metabolite-mediated effects via metabolomic MR, determined cell-type specificity using single-nucleus RNA sequencing (snRNA-seq), and prioritized therapeutics through drug-target interaction analysis and molecular modeling. MR analysis identified APOE as the strongest VD-associated protein in both CSF and plasma, indicating systemic relevance. Several proteins, including the 14-3-3 family, AREG, SMOC1, and UBE2G2, were exclusively associated in CSF, suggesting CNS-specific roles. Metabolomic MR revealed key APOE-mediated metabolites linked to disease progression. snRNA-seq showed APOE upregulation in excitatory neurons of VD patients. Drug screening highlighted benserazide and puromycin as top candidates, validated by molecular simulations. This study systematically identifies genetically validated proteomic targets for VD, establishing APOE as a central molecular driver. By integrating proteomics, genomics, metabolomics, and drug discovery, we propose a comprehensive framework for targeted therapeutic development, supporting precision medicine in VD treatment.

Neurodegenerative diseases represent an escalating global health crisis affecting more than 55 million people worldwide; however, underlying mechanisms remain unclear, and therapeutic breakthroughs are elusive. Emerging evidence indicates that hexokinase (HK), the rate-limiting glycolytic enzyme, functions as a master regulator orchestrating neuronal survival through metabolic‒mitochondrial coupling. This review consolidates emerging paradigms revealing that HK maintains neuronal viability through its obligate interaction with mitochondrial VDAC1, forming a metabolic checkpoint that integrates energy status with survival signaling. Disease-specific HK dysfunction patterns precede clinical manifestations and drive pathological cascades across primary neurodegenerative conditions. Pathological proteins characteristic of neurodegeneration-amyloid-β in AD, α-synuclein in PD, mutant SOD1 in ALS, and huntingtin in HD-converge to disrupt the HK-VDAC1 axis through distinct molecular mechanisms, triggering mitochondrial permeabilization, bioenergetic collapse, and inflammatory activation. This uncoupling event promotes VDAC1 oligomerization, enabling the cytosolic release of mtDNA, which in turn activates the NLRP3 inflammasome while depleting antioxidant capacity, establishing self-perpetuating neuroinflammatory cycles. The literature reveals that HK functions as a molecular rheostat, determining neuronal fate through glucose-6-phosphate-mediated feedback control, modulation of growth factor signaling, and regulation of apoptosis/survival pathways. Therapeutic targeting of HK through peptide interventions, enzymatic modulation, and gene therapy demonstrates robust neuroprotective effects across multiple disease models. Meanwhile, combination strategies addressing metabolic-inflammatory networks show synergistic efficacy. These insights position HK as a convergent therapeutic nexus offering unprecedented opportunities for precision intervention in neurodegeneration, with potential for early diagnostic applications and preventive strategies that could transform treatment paradigms for conditions affecting millions worldwide.