Aging and Disease最新文献

Chronic gastritis (CG) is a highly prevalent, age-associated inflammatory disorder of gastric mucosa and a key precursor of gastric cancer in older adults. Beyond Helicobacter pylori infection and environmental insults, accumulating evidence indicates that chronic, low-grade inflammation coupled with aging biology, "gastric inflammaging", plays a central role in driving mucosal degeneration, atrophy, and malignant transformation. Here, we synthesize current mechanistic and multi-omics evidence to conceptualize CG as a tractable model of organ-specific inflammaging. We first summarize how hallmarks of aging-including cellular senescence and the senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, impaired autophagy, immune exhaustion, and microbiome dysbiosis-converge to create a self-perpetuating inflammatory microenvironment in the stomach. We then review emerging single-cell and spatial multi-omics studies that delineate senescence-inflammation niches and reveal how these molecular neighborhoods relate to disease stage and cancer risk. Finally, we discuss therapeutic implications, highlighting geroscience-guided interventions such as senolytics/senomorphics, inflammasome and cGAS-STING pathway modulators, microbiota- and metabolite-targeted strategies, lifestyle interventions, and natural products, and propose a precision framework linking inflammaging biomarkers to patient stratification and clinical endpoints. Reframing CG as a gastric inflammaging model may provide a prototype for organ-specific healthy aging strategies and near-term gerotherapeutic trials aimed at extending healthspan.

Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1^G93A, TDP43^A315T, and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1^G93A transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1^G93A transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.

Sphingolipids are essential bioactive lipids that play pivotal roles in maintaining the structural integrity of cellular membranes and regulating key signaling pathways in the central nervous system (CNS). In both neuronal and glial cells, sphingolipid metabolism regulates diverse processes, including cell survival, apoptosis, neuroinflammation, and myelination. Increasing evidence implicates dysregulation of sphingolipid pathways in the pathogenesis of various CNS disorders, notably cerebrovascular diseases such as small vessel disease and stroke, as well as neurodegenerative conditions including Alzheimer's disease, cerebral amyloid angiopathy, Parkinson's disease, and multiple sclerosis. This review summarizes the current advances in sphingolipid metabolism and signaling in the brain, with a focus on the functional interplay between neurons and glia, as well as the mechanisms by which disrupted sphingolipid homeostasis contributes to CNS pathology. Key sphingolipid metabolites such as ceramide, ceramide-1-phosphate, and sphingosine-1-phosphate emerge as critical mediators of neuroinflammation, blood-brain barrier disruption, and cognitive impairment. Furthermore, we explore emerging therapeutic strategies targeting sphingolipid pathways and their potential to slow disease progression and improve neurological outcomes. A deeper understanding of the roles of neuronal and glial sphingolipids in brain health and disease may advance the development of novel diagnostic tools and therapeutic strategies for cerebrovascular and neurodegenerative disorders.

Exercise training represents a well-established anti-aging intervention that counteracts the multisystem functional decline. Skeletal muscle, the primary effector of physical activity, functions as a potent secretory organ, releasing myokines and extracellular vesicles into circulation. These muscle-derived factors mediate extensive crosstalk between muscle and distant organs, thereby coordinating the multi-tissue adaptations that underline the systemic benefits of exercise. This review synthesizes current knowledge on how myokine networks counteract aging across key physiological systems-including the metabolic, cardiovascular, musculoskeletal, nervous, and immune systems-by modulating core aging-related processes such as chronic inflammation, metabolic dysregulation, and loss of tissue homeostasis. We highlight how diverse myokines converge on conserved signaling hubs to exert integrated protective effects and discuss the profound influence of sex and age on myokine action. Finally, we outline the translational potential of, and challenges to, harnessing this myokine network in clinical practice, proposing personalized exercise regimens and engineered myokine-based therapies as promising strategies for promoting healthy aging.

The escalating cost, extended timelines, and low success rates in pharmaceutical research demand a rethinking of biotechnology R&D infrastructure to more efficiently discover and deliver novel therapeutics to an increasingly aging population. We introduce the concept of the AI-Integrated Biotechnology Hub, a purpose-built research ecosystem uniting residential, commercial, clinical, and research facilities under a central, AI-driven operating system. The hub functions as a multi-sided platform that unites health data collection, smart living environments, and federated learning to enable secure, privacy-preserving biomedical and longevity research. By integrating real estate, biotechnology facilities, research hospitals, and community services, the model maximizes data utility, accelerates drug discovery, and enhances resident well-being. Transparency, accountability, and ethical stewardship are critical pillars of governance, enacted through dynamic consent, data trusts, and multi-stakeholder oversight. Designed to be scalable across urban and vertical architectures, this paradigm represents a potential approach that may enable more efficient research workflows to improve healthspan, foster innovation, and reshape the economics of global drug development.

The interthalamic adhesion (ITA), located at the center of the brain, may influence ventricular morphology and cerebrospinal fluid (CSF) dynamics. Its role in Hakim's disease, renamed idiopathic normal pressure hydrocephalus (iNPH), remains unclear. To investigate the relationship between ITA morphology and CSF dynamics in the third ventricle using three-dimensional (3D) and four-dimensional (4D) flow MRI in healthy individuals and patients with Hakim's disease. The study participants were 83 patients with Hakim's disease (mean age, 77.0 ± 6.2 years) and 226 healthy volunteers (mean age, 58.2 ± 18.2 years) were analyzed. 3D T1-weighted MRI was used to evaluate the morphology of the third ventricle and ITA, and 4D flow MRI (velocity encoding = 5 cm/sec) was used to assess CSF streamlines and vorticity throughout the cardiac cycle. ITA width increased and ITA area decreased with third ventricle enlargement. Compared with younger healthy volunteers, older volunteers had approximately two-fold greater mean ITA width and one-third smaller mean ITA area, whereas patients with Hakim's disease had four-fold greater width and one-eighth smaller area. ITA absence was more frequent in Hakim's disease (14%) than in healthy volunteers, though this difference was not statistically significant. In healthy volunteers, downward systolic and upward diastolic streamlines with paired vortices behind the ITA were consistently observed, irrespective of age. In contrast, 63 patients with Hakim's disease (81%) lacked these flow patterns and instead exhibited abnormal bidirectional flows in the cerebral aqueduct, with some showing marked upward flow extending into the third ventricle. The ITA functions as a potential structural regulator of third-ventricular morphology and CSF dynamics. In Hakim's disease, physiological streamlines and vortices within the third ventricle are absent, and abnormal aqueductal flow predominates.

Phosphorylated ubiquitin (pS65-Ub) is generated by the kinase-ligase pair PINK1-Parkin to selectively label damaged mitochondria for degradation via the autophagy-lysosome system (mitophagy). Consistent with increasing mitochondrial and lysosomal dysfunctions, pS65-Ub accumulates with aging in human autopsy brain and in mice. pS65-Ub levels are strongly and independently elevated in brains from subjects with Alzheimer's or Parkinson's disease compared to age-matched, neurologically normal controls. Furthermore, pS65-Ub levels have been used to identify disease risk and potential resilience factors in cells and in human brain. However, it remains unknown whether pS65-Ub measured in biofluids may also be suitable as a clinical biomarker. Here, we used a validated sandwich ELISA based on the Mesoscale discovery platform to assess pS65-Ub levels in over 1500 plasma samples from different cohorts across a spectrum of mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. We further analyzed almost 150 CSF samples from two independent case-control series with Parkinson's disease to determine whether pS65-Ub levels are associated with disease status and other clinical parameters. While pS65-Ub levels are significantly changed with disease compared to controls in certain samples, current measurements in plasma are not sufficiently discriminatory to serve as a robust diagnostic marker. However, in CSF, pS65-Ub levels were decreased in patients with Parkinson's disease compared to controls, and there was better discrimination between these groups. Our data indicate that pS65-Ub shows promise as a biomarker in CSF but will require further replication in larger cohorts and possibly in combination with additional other measures.

The aging process is accompanied by a gradual decline in tissue function, in part due to chronic low-grade inflammation that contributes to cardiovascular, neurodegenerative, and metabolic disease development. In the endocrine pancreas, Langerhans islets exhibit age-related structural and functional changes, including immune cell infiltration and fibrotic remodeling, as we recently demonstrated. Macrophages, as key immune mediators in both diabetic and aged islets, play a central role in Toll-like receptor 4 (TLR4) signaling, a pathway activated by bacterial lipopolysaccharides and known to exacerbate inflammation and tissue damage in multiple organs. We therefore hypothesize that TLR4 signaling contributes to the inflammatory changes during islet aging. To investigate this, two complementary mouse studies were performed. Aged C57BL/6J mice were treated with the TLR4 inhibitor TAK-242 for four months, which reduced insulitis, macrophage infiltration, and fibrosis, while preserving insulin secretion. In contrast, mice with a lifelong myeloid-specific deletion of TLR4 showed altered islet cell composition in young age, potentially leading to dysregulated insulin secretion, and signs of insulin resistance in aging, despite unchanged islet inflammation. These results indicate that TLR4 inhibition attenuates inflammatory islet remodeling in aging, whereas lifelong loss of myeloid TLR4 signaling seems to disrupt immune-endocrine interactions and impairs insulin secretion. Thus, TLR4-driven immune activation emerges as a mechanism linking inflammation to pancreatic islet aging.

Malocclusion is a dental disorder that has often been overlooked in physiological studies. It is defined as any malrelationship of dental arches with or without aberration in the teeth developmental disorder, which alters functions like mastication, swallowing, speech, etc. Mounting evidence implies that malocclusion might be associated with adjacent and remote organ dysfunction, albeit the underlying mechanisms are obscure. However, to date, no review has unified the framework correlating malocclusion with oral (mastication, speech) and distant organ pathologies such as ocular, auditory, nasal, cerebral, respiratory, musculoskeletal, cardiovascular, blood-related, renal, and sexual physiologies. Therefore, this perspective provides the first integrated framework correlating malocclusion with multiorgan pathology and outlines a prioritized research agenda to investigate the causality. We have also documented the prevalence of malocclusion types in children as well as adolescents, which has been revealed in Africans, followed by Europeans, Americans, and Asians. Specifically, the impact of occlusal disharmony on brain activity could be attributed to rich neurological connections between the stomatognathic system (jaw, teeth, muscles, joints) and brain regions involved in sensory, autonomic, and emotional regulation. Consequently, chronic orofacial pain and dysfunction related to malocclusion can activate limbic and cortical pathways modulating systemic inflammatory responses and immune regulation, potentially influencing other organ systems through neuroimmune crosstalk and neurobiological circuits. Malocclusion-associated dysfunction might alter neural inputs affecting broader systemic control, thereby impacting bone metabolism, vascular tone, and inflammation. Taken together, we presented our perspective on emerging data implying the possible malocclusion-associated pathological complications. A detailed understanding of these intricate associations between malocclusion and multi-organ system pathologies will offer a new direction for comprehensive intervention strategies to reduce significant mortality and morbidity, resulting in improved quality of life.

Cerebral small vessel disease (CSVD), which is linked to age and vascular risk factors, is a prominent cause of vascular cognitive impairment and an important contributor to stroke incidence. The therapeutic management of vascular risk factors has failed to reduce the incidence of CSVD, and a trend toward an increasing prevalence of CSVD forms accompanied by neurodegeneration has been observed. These changes, driven primarily by aging and other poorly understood risk factors, coupled with the lack of pathogenetic therapy and specific biomarkers for disease progression, underscore the need for further molecular genetic research into CSVD. Advances in MRI-based CSVD diagnosis have enhanced the translational potential of such studies. The use of high-throughput technologies, such as next-generation sequencing (NGS) and tandem mass spectrometry (MS/MS), combined with meta-analytical approaches that integrate data from large, multi-ethnic cohorts, has enabled the identification of the first reproducible genetic determinants underlying various CSVD MRI markers, as well as their cell-type-specific expression patterns and roles in molecular processes. However, the identification of candidate therapeutic targets remains challenging, largely due to a lack of standardized experimental design for population-based studies. This review highlights key findings from large-scale population-based and multi-omics genetic research that hold promise for significant advancements in CSVD treatment.