Aging and Disease最新文献

Growing evidence has highlighted that the same biological pathways implicated in oncogenesis also regulate the aging process, by influencing the organism's capacity to surveil and respond to cellular aberrations. Emerging therapeutic strategies, including senolytic agents, metabolic modulators and immunotherapies, not only hold promises for cancer treatment, but offer possibilities for mitigating the degenerative consequences of aging. This review seeks to integrate recent developments, provides insights into the overlapping molecular pathways that underlie both cancer and age-related disorders, while offering an in-depth exploration of the subtle dynamics in immune system, and explores how certain cancer therapies can be leveraged for managing age-related conditions. Furthermore, it illustrates the critical role of immune restoration as a therapeutic mechanism and examines the key considerations and potential pitfalls when adapting cancer treatments to age-related diseases.

Alzheimer's disease (AD) is a progressive neurological disease characterized by a decline in cognitive abilities and memory loss. Mitochondrial dysfunction is a major factor in early pathological changes; however, its precise pathogenic mechanisms are not yet fully understood. Mitochondria are essential for neuronal energy generation, calcium ion balance regulation, apoptosis control, and production of reactive oxygen species. Among the various mitochondrial changes, the imbalance between fission and fusion is closely linked to β-amyloid deposition and tau pathology, forming a vicious cycle. The electron transport chain (ETC) produces more than 90% of cellular ATP and is damaged in AD. However, most studies simply refer to "mitochondrial dysfunction" in general terms without detailing specific changes in ETC complexes and their subunits. This review aims to provide a detailed overview of the dynamics and ETC complex dysfunction observed in AD for therapeutic targets.

Aging is accompanied by a marked increase in cancer incidence and mortality, yet most studies still consider cellular senescence, the tumor microenvironment, and the microbiome as largely separate axes. Here, we propose an integrative triad framework in aging-related cancers in which cellular senescence, tumor microenvironment (conceptualized here as part of a broader tumor microecology), and the microbiome dynamically interact to shape tumor initiation, evolution, and treatment response. We summarize how senescent cells, via context-dependent senescence-associated secretory phenotypes (SASPs), remodel stromal, immune, and metabolic niches in aging hosts and how gut and intratumoral microbiota both induce and are reshaped by senescence. Focusing on colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC), together with pan-cancer transcriptomic and microbiome analyses. We highlight disease and subtype-specific patterns in which senescence signatures, immune contexture, and microbial features co-stratify prognosis and therapeutic outcomes, and integrate pan-cancer transcriptomic and microbiome analyses to illustrate shared and divergent triad configurations across tumor types. Finally, we discuss the therapeutic implications of this triad, including timing-dependent use of senolytics and senomorphics, diet and microbiome-targeted interventions, fecal microbiota transplantation (FMT), and the ecological risks of antibiotics, particularly in multimorbid older patients. We argue that triad-informed biomarkers and trial designs integrating senescence, microenvironment, and microbiome readouts will be important for mechanism-based, age-adapted cancer prevention and therapy in older adults, especially those with CRC, HCC, and PDAC.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ⁹-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ⁹-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ⁹-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ⁹-THC-induced neuroinflammatory responses. Furthermore, Δ⁹-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ⁹-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ⁹-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.

Coronary artery disease (CAD), the leading cause of mortality worldwide, is increasingly recognized for its impact on brain health and cognition, yet the mechanisms linking CAD to vascular and metabolic alterations in the brain remain poorly understood. Prior work has identified regional deficits in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR), a measure of vascular reserve, in patients with CAD, but the consequences of these impairments for cognition and cerebral metabolism have not been established. This study investigated how CAD influences cerebral vascular and metabolic health, and how these alterations relate to cognitive function across multiple domains. Using quantitative magnetic resonance imaging (MRI), we measured CBF, CVR, cerebral metabolic rate of oxygen (CMRO₂), and oxygen extraction fraction (OEF), alongside a validated neuropsychological battery yielding composite scores of executive functions, working memory, processing speed, and verbal episodic memory. The final sample included 35 CAD patients (CAD; n = 35, 66 ± 9 years, 6 females) and 37 healthy controls (n = 37, 65 ± 8 years, 10 females). Compared with controls, CAD patients demonstrated widespread vascular and metabolic impairments, including lower CBF, CVR, and CMRO₂, and elevated OEF, consistent with insufficient oxygen delivery. CBF deficits were more pronounced in patients with prior myocardial infarction. Importantly, lower CVR was associated with poorer performance in the cognitive domain of executive function, while higher OEF related to poorer working memory, underscoring the role of vascular reserve and oxygen consumption in cognition. These findings demonstrate that CAD impairs cerebral vascular and metabolic health, highlighting CVR and OEF as sensitive biomarkers linking brain health to cognitive outcomes and as promising targets for interventions to preserve cognition in CAD.

Osteoporosis (OP) is a major public health challenge affecting over 200 million individuals worldwide. While pharmacological interventions represent mainstream treatment, concerns regarding long-term side effects and patient compliance have driven the exploration of alternative therapies. Exercise interventions have emerged as promising complementary approaches due to their excellent safety profiles, cost-effectiveness, and high adherence rates. Diverse exercise modalities, including aerobic, resistance, and balance exercises, effectively modulate bone homeostasis by promoting osteogenesis, inhibiting osteoclastogenesis, enhancing muscle-bone crosstalk, regulating the vascular/lymphatic systems, and modulating inflammation. This review synthesizes current knowledge on exercise-based therapies for musculoskeletal disorders, with a particular emphasis on their anti-OP mechanisms, which target osteoblast- and osteoclast-mediated bone homeostasis, endocrine regulation, immune function, and muscle performance. Furthermore, we explore the potential of combining exercise with other therapies and systematically compare the clinical efficacy of various exercise types. This review provides deeper mechanistic insights into exercise-mediated bone protection and offers evidence-based perspectives for developing innovative therapeutic strategies in OP management.

For more than three decades, the amyloid cascade hypothesis has framed Alzheimer's disease (AD) as a disorder in which amyloid-β (Aβ) accumulation initiates a pathological cascade leading to neurodegeneration and cognitive decline. Aβ plaque deposition is a robust pathological feature of AD and a useful biomarker target, yet plaques alone do not explain disease onset, clinical heterogeneity, or the pace of symptomatic change. We propose that fibrillar amyloid plaques do not drive AD pathogenesis and instead represent intermediate products of a broader disease process. This amyloid-centered emphasis has shaped research priorities and drug development aimed at lowering amyloid burden. However, amyloid lowering has not produced consistent, clinically meaningful cognitive benefits, exposing a gap between target engagement and patient-centered outcomes. Here, we reevaluate the evidentiary basis and translational performance of the amyloid model using contemporary trial results, biomarker trajectories, and neuropathological observations. We also analyze the scientific, regulatory, and structural forces that sustained amyloid-centered strategies. We advance an integrative view of AD as a staged process involving tau pathology, neuroimmune dysfunction, vascular injury, and aging biology. Progress will depend on earlier and stage-matched intervention, mechanism-informed combination strategies, and regulatory standards anchored to outcomes patients value.

The neutrophil-to-lymphocyte ratio (NLR) is an inexpensive biomarker of systemic inflammation. Although widely studied in acute and chronic conditions, evidence on long-term outcomes in hospitalized older adults is limited. We assessed whether admission NLR predicts in-hospital and post-discharge all-cause mortality in geriatric patients. We performed a retrospective multicenter cohort study of acute medical admissions across IRCCS INRCA geriatric hospitals in Italy (January 2020-December 2024). Data were retrieved from electronic health records and laboratory databases. We analyzed 16,099 hospitalizations from 10,826 patients aged ≥65 years (median 84, 48% male). For long-term outcomes, 9,812 patients discharged alive after their first admission were followed up to 48 months. Admission NLR was calculated from complete blood counts; thresholds were defined by ROC analysis. Outcomes were in-hospital and 48-month mortality. Discrimination was assessed using AUC, Kaplan-Meier curves, and Cox proportional hazards models adjusted for demographics, comorbidities, and laboratory variables. In-hospital mortality occurred in 1,744 cases (11%). An NLR ≥5.36 was associated with higher in-hospital mortality (HR: 2.287; 95% CI: 2.025-2.582; p&;lt0.001). For long-term outcomes, an NLR ≥5.05 predicted increased 48-month mortality (51.6% vs 26.3% for NLR &;lt5.05; adjusted HR: 1.423; 95% CI: 1.302-1.556; p&;lt0.001). NLR values increased with age and were higher in males ≥80 years. A dynamic rise in NLR was observed before in-hospital death, suggesting utility as a marker of deterioration. Admission NLR is a strong, independent predictor of short- and long-term mortality in older adults. Its simplicity supports risk stratification, though optimal cut-offs require validation.

Spinal cord injury (SCI) causes not only intraspinal damage but also systemic organ pathology, with aging as a key determinant of outcomes. The mechanisms by which old age aggravate SCI pathology remain unclear. The voltage-gated proton channel Hv1 plays a key role in regulating immune responses. Hv1 increases with aging and SCI, and Hv1 KO provides neuroprotection in young mice. We hypothesized that age-related Hv1 upregulation worsens spinal cord, spleen, and lung pathology and hinders locomotor recovery after SCI via immune modulation. Using aged Hv1 KO and WT male mice subjected to moderate SCI, we assessed behavioral and molecular outcomes. Transcriptomic analysis revealed that Hv1 mRNA expression was higher in the brains of aged sham mice and further upregulated in injured spinal cord tissues. Spinal cord RNA-seq showed acute innate immune and cytokine activation in both genotypes. Hv1 deletion enhanced chromatin remodeling, epigenetic and Wnt signaling, while suppressing NF-κB-driven inflammation and oxidative stress-induced apoptosis. In the spleen, Hv1 depletion enhanced immune responses while suppressing mitosis. T cell and leukocyte activation increased, whereas lung cytokine signaling decreased. Functional recovery improved with reduced tissue damage. After chronic SCI, Hv1 KO mice showed elevated circadian rhythm and T cell proliferation in the spinal cord, increased mitotic gene expression but reduced adaptive immunity in the spleen, and enhanced immune activation with decreased cilium activity in the lungs. Together, our findings reveal how Hv1 contributes to age-related intraspinal damage and peripheral immune dysfunction after SCI, highlighting a potential therapeutic target for elderly patients.

Thyroid hormone (TH) signaling regulates cellular metabolism and stress response in the retina. Increased TH levels in circulation are associated with a higher incidence of age-related macular degeneration. Furthermore, stimulation of TH signaling induces retinal degeneration in mice, which is accompanied by the activation of retinal glial cells. Here, we investigated the transcriptional changes induced by triiodothyronine (T3) in retinal glial cells using single-cell RNA sequencing (scRNAseq) and bioinformatic analyses. One-month-old C57BL/6 mice were given T3 (20 μg/ml in drinking water) for four weeks, after which their retinal cells were collected to assess viability and undergo scRNAseq. The resulting data were analyzed using the Seurat package, visualized by the Loupe Browser, and Ingenuity Pathway Analysis. Analyses of differentially expressed genes (DEGs) in Müller cells, astrocytes, and microglia revealed significant enrichment in pathways associated with stress, immune response, and degeneration. Müller cells exhibited upregulation of mitochondrial dysfunction, acute-phase response, and sirtuin signaling pathways. Astrocytes displayed downregulation of synaptogenesis, neurovascular coupling, cAMP response elements, and calcium signaling. Microglia showed upregulation of coordinated lysosomal expression and regulation signaling, systemic lupus erythematosus in T cells, and multiple sclerosis signaling, and downregulation of actin-binding Rho activating signaling, retinoic acid receptor activation signaling, and IL-17 signaling. The distinct and overlapping transcriptional responses suggest that each retinal glial cell type plays a specific and coordinated role in adapting to stress. This study offers new insights into TH-induced retinal stress and degeneration at the transcriptional and pathway-level responses of retinal glial cells.