Aging and Disease最新文献

Aging involves chronic organ degeneration, characterized by a continued decline in cellular regenerative ability and excessive buildup of extracellular matrix (ECM), leading to organ fibrosis. Fibrosis is now widely recognized as a key sign of organ failure, which has inspired new anti-aging strategies through antifibrosis treatments. In cancer, excessive ECM around and within tumors, known as desmoplasia, helps support tumor growth and malignancy. Age-related chronic inflammation and impaired tissue regeneration lead to a range of cell changes, which favor the development of fibroblast-like types, promote unchecked ECM buildup, and increased tissue stiffness. Notably, many mechanisms of aging closely overlap with those behind fibrotic progression. Understanding the critical cell groups, especially cancer-associated fibroblasts, could open promising options for anti-fibrotic and cancer treatments. The integration of progress in molecular medicine, traditional herbal therapies, and new technologies provides a powerful path for drug discovery and therapy development. In this review, we outline the main cell types and molecular pathways involved in organ aging and fibrosis. We also highlight the recent advances in anti-fibrotic Traditional Chinese Medicine (TCM) and gene and cell therapies in cancer and anti-aging research. Lastly, we examine the role of new technologies, including nanomedicine and organoid models, in the development and testing of drugs for anti-fibrotic therapies.

As the global population ages, the number of people living with dementia is projected to increase significantly. Estimations indicate that over 150 million people worldwide will be living with dementia by 2050, with Alzheimer's disease being the most common cause. Elderly people are also at greater risk of undergoing surgery, either elective or emergency, escalating the associated likelihood leading to cognitive decline, especially if accumulative. However, the relationship between surgery and dementia development remains controversial. The cause seems to lie in the heterogeneous preoperative state of subjects participating in research studies. Interpreting and comparing the results of these studies could be an arduous task due to variables such as medication, follow-up time, type of surgery and anesthesia, duration and invasiveness of the surgical intervention, differential neuroinflammatory response, the patient metabolic/biochemical status or if there are comorbidities. Considering the complexity of this type of studies, the present review summarizes the most important factors/biomarkers that could provide useful information for pre- and post-operative medical decision making in relation to the development of dementia. Emphasis will be placed on the relationship between temperature, Tau phosphorylation, whose plasma detection as an early diagnostic factor is gaining great relevance, and other neurodegenerative biomarker interplay. The prolonged maintenance of key biomarkers in blood could be detrimental and, therefore, a more comprehensive individualized hospital study may improve the prevention of postoperative complications.

Aging has emerged as a critical focus in understanding human diseases. Among many factors in aging, immunosenescence stands out as a significant focus. Immunosenescence is the process of physiological and functional deterioration of the immune system, which consists of organs, cells, immune components and regulatory networks. In hematologic diseases, immunosenescence could affect the bone marrow (BM) microenvironment, resulting in reduced function of hematopoietic stem and progenitor cells, and interfering with normal hematopoiesis. However, how the nature and function of immune cells change during immunosenescence and the effects have not yet been summarized and explored. Therefore, this review reveals the dual role of immunosenescence in increased disease risk and reduced therapeutic efficacy by providing an overview of the characteristics of immunosenescence, the interaction with the mechanisms of development of hematologic diseases, and the impact of immunosenescence on the function of individual immune cells during the diseases. It includes separate descriptions of various immune cells (innate and adaptive immune response cells) involved in immunosenescence, which covers changes in their cell numbers, subpopulations, receptors, cytokine levels, and other aspects. Additionally, it provides an in-depth analysis of how these changes influence the progression of hematologic diseases (both neoplastic and non-neoplastic hematological diseases). Additionally, we explore the impact of senescence on therapeutic strategies and propose treatment programs for elderly patients. With this review, we endeavor to further disclose the mystery of how immunosenescence impacts the onset and progression of hematologic disorders, aiming to offer a scientific footing for devising novel therapeutic approaches for elderly patients and to enhance their prognosis.

Human cerebral organoids (hCOs), generated in vitro from induced pluripotent stem cells (iPSCs) or human embryonic stem cells (hESCs), exhibit cellular compositions similar to those of specific human brain regions. These organoids simulate early stages of brain development and can serve as in vitro disease models, providing a unique platform for studying neurodevelopmental processes and investigating underlying disease mechanisms. This review systematically summarizes research progress on cellular characteristics and neural electrophysiology in hCO-based models of neurodevelopmental disorders, neurodegenerative diseases, psychiatric disorders, epilepsy, viral infections, and traumatic brain injuries. These studies have elucidated the mechanisms underlying neuroelectrophysiological dysfunction in related diseases and facilitated innovative therapeutic explorations. Current limitations include prolonged culture durations and high costs, insufficient standardization that compromises reproducibility, the absence of neurovascular units that restrict pathological fidelity, immature laminar architectures that hinder complex circuit modeling, and electrophysiological bottlenecks in network-level analysis. Future efforts should focus on optimizing hCO culture protocols, innovating electrophysiological detection technologies, and promoting their clinical translation.

In chronic obstructive pulmonary disease, the senescence of type II alveolar epithelial cells is a key driver of disease progression, severely impacting lung function and structure. Lactate accumulation, a common feature of chronic hypoxic conditions such as COPD, is increasingly recognized for its role in modulating cellular functions via epigenetic mechanisms. This study aimed to investigate the specific effects of lactate-induced histone lactylation on AEC2 senescence and its contribution to COPD progression. Our experiments revealed a significant increase in histone lactylation levels in COPD models, with site-specific screening identifying histone H4 lysine 12 lactylation as a predominant modification. Using the Cleavage Under Targets and Tagmentation technique (CUT&Tag) sequencing, we demonstrated that H4K12la modulates the CD38-nicotinamide adenine dinucleotide (NAD⁺) signaling pathway, thereby promoting AEC2 senescence and exacerbating COPD progression. Further in vitro and in vivo analyses confirmed that elevated H4K12la expression was associated with increased CD38 levels and decreased NAD⁺ concentrations. To interrogate this pathway, we employed the p300/CBP inhibitor A485, which specifically inhibits H4K12la levels. This intervention significantly improved AEC2 senescence and reduced COPD-related pathology. Subsequently, we explored additional therapeutic strategies using the CD38 inhibitor 78c and the NAD⁺ precursor β - nicotinamide mononucleotide (NMN), both of which effectively reduced senescence markers and further ameliorated COPD symptoms. These findings highlight the critical role of lactate-induced histone lactylation, specifically H4K12la, in COPD pathogenesis. Targeting the H4K12la-CD38-NAD⁺ axis, with strategies such as p300/CBP inhibition, offers promising therapeutic avenues for managing the disease.

In our recent research on AIDS Elite controllers, we demonstrated that the HLA-B*57:01 allele is part of an extensive MHC haplotype associated with impaired MICA/MICB function. Considering the pivotal role of natural killer (NK) cells and innate immunity in fighting cancer and infectious diseases, we investigated whether this allele could also influence human longevity. To this end, we performed a multinational European study including 2,597 centenarians and 9,973 controls. We found that HLA-B*57:01 was consistently less frequent in the European centenarian cohorts compared with the corresponding controls (OR ≈ 0.68, p &;lt 0.0005). These findings provide the first in vivo genetic evidence that innate immunity and NK cell function are key components of human longevity.

Fibrotic diseases are characterized by high incidence and mortality rates, posing substantial challenges to global public health due to their considerable disease burden. Mitochondrial damage is a common feature in all fibrotic diseases. Mitochondria do not function in isolation; rather, they are often influenced by stress signals from adjacent organelles. Mitochondria and the endoplasmic reticulum are frequently studied as a subfunctional unit. Mitochondria-associated endoplasmic reticulum membranes (MAM) serve as physical connectors between mitochondria and the endoplasmic reticulum. MAM plays a pivotal role in multiple pathological and physiological processes, including lipid metabolism, inflammation, mitochondrial function, cell death, and cellular senescence. These pathological processes are also implicated in the progression of fibrotic diseases. In this review, we examine the relationship between MAM and key pathological mechanisms in fibrotic diseases, such as cell death, cellular senescence, and inflammation. We further explore the potential of MAM as diagnostic biomarkers and therapeutic targets for fibrotic diseases, thereby offering novel research directions and treatment strategies aimed at improving outcomes for patients with fibrotic diseases.

Metabolic-inflammatory syndrome represents a major global health challenge, closely linked to diabetes, cardiovascular disease, obesity, and non-alcoholic fatty liver disease. The core of these disorders involves remodeling of metabolic pathways under nutritional stress and the ensuing chronic inflammatory vicious cycle. This review systematically examines the mechanisms by which metabolic reprogramming drives metabolic-inflammatory syndrome, revealing the significant role of the gut microbiota in this process. Furthermore, it evaluates current metabolic-inflammatory syndrome early-warning systems and proposes innovative therapeutic strategies precisely targeting the metabolic-immune axis, establishing a foundation for enhancing early detection and clinical intervention.

Aging constitutes a complex biological phenomenon that is shaped and modulated by a wide range of genetic, metabolic, and environmental factors. A key characteristic of aging is the progressive shortening of telomeres, a process worsened by both physical and mental stressors. This shortening is interdependent with oxidative imbalance, persistent low-level inflammation, mitochondrial decline, and defective DNA repair mechanisms, factors that collectively drive age-associated disorders. Our review highlights the role of telomeres in the aging process. It examines the therapeutic potential of varied natural compounds, including flavonoids, carotenoids, peptides, polysaccharides, essential oils, and postbiotics in modulating these age-associated pathways. Experimental findings suggest that such compounds may safeguard telomeres, diminish oxidative injury, stabilize inflammatory signaling, and support mitochondrial bioenergetics. The convergence of findings from molecular, cellular, and in vivo studies supports the notion that integrating such compounds into both therapeutic and preventive dietary strategies may not only contribute to prolonged lifespan but also significantly enhance healthspan, the portion of life spent in good physical and cognitive health. However, the complex nature of aging pathways means that these promising insights also emphasize the importance of multidisciplinary research, which is indispensable for validating efficacy in clinical settings and exploring synergistic effects. Thorough human studies evaluating dosage, bioavailability, long-term safety, and population-specific effects are necessary to translate encouraging in vitro and animal findings into safe and effective interventions. The integrated examination of telomere biology and six classes of natural compounds along three main mechanistic axes-mitochondrial function, inflammatory modulation, and telomere maintenance-with a focus on translational relevance, is what makes this review novel. The dynamic relationship between telomere biology and naturally derived bioactive substances offers an interesting direction for low-risk interventions aimed at promoting healthy aging and reducing the global burden of age-related diseases.

Obesity is associated with low-grade inflammation and microgliosis, contributing to brain dysfunction and cognitive decline. Sphingosine-1-phosphate (S1P) and its generating enzymes sphingosine kinase 1/2 (SphK1/2) have been implicated in metabolic and inflammatory regulation. Plasma S1P levels are elevated in obese mice and humans, and genetic ablation of SphK2 in mice protects from age- and diet-induced weight gain. As SphK2 is the predominant isoform in the brain, the present study examined whether pharmacological SphK2 inhibition mitigates obesity-associated microgliosis. Male C57BL/6J mice were fed either a high-fat diet (HFD; 60% fat) or control diet (CD; 10% fat) for 9 weeks. After 7 weeks, mice received the SphK2 inhibitor ABC294640 (SphK2i; 5 mg/kg, s.c.) or vehicle every other day for two weeks. Brain tissue was analyzed for microglial morphology (classification of ramified, intermediate, and amoeboid phenotypes, as well as branch length and endpoints), profiling of pro-inflammatory cytokines and S1P pathway components, and S1P concentrations. SphK2 inhibition attenuated HFD-induced microgliosis in cortex and dentate gyrus, with partial restoration of microglial arborization and branch length in cortex, in the absence of pro-inflammatory cytokine expression alterations. S1P pathway responses showed regional specificity, including elevated cortical S1P levels after HFD feeding accompanied by reduced S1P receptor 1 (S1PR1) expression, whereas hippocampal S1P levels and S1PR1 expression remained unchanged. SphK2 was undetectable in cortical microglia, while hippocampal microglia were SphK2-positive. Despite regional specificities of HFD-induced S1P/S1PR1 alterations, pharmacological SphK2 inhibition reduced microglial activation across regions, highlighting its potential relevance for obesity-associated neuroinflammation in a brain region-specific manner.