Aging is a multifactorial process involving a gradual decline in cellular and tissue functions, making it a major risk factor for aging-related degenerative diseases. In this study, we utilized the senescence-accelerated mouse prone 8 mice model, which mimics pathological characteristics of Alzheimer's disease, fatty liver disease, and cardiac fibrosis, to construct a heterochronic parabiosis model and systematically investigate the rejuvenating effects of heterochronic parabiosis on the brain, liver, and heart. Our findings revealed that heterochronic parabiosis promotes synaptic plasticity and neuronal communication, restores hepatocyte metabolic functions, and reduces chronic inflammation and fibrosis in the heart. Notably, heterochronic parabiosis significantly downregulates the expression of age-related disease risk genes. In addition, endothelial cells, as cell types directly exposed to the circulatory environment, demonstrated the highest sensitivity to heterochronic parabiosis across three organs, and exhibited significantly reduced inflammation after intervention, suggesting that they may play an early and central role in the rejuvenation process. Overall, our study increases the understanding of the molecular and cellular mechanisms of aging and its related diseases, highlights the multiorgan and multitarget potential of heterochronic parabiosis in delaying aging and mitigating aging-related diseases, and provides new therapeutic targets for achieving healthy aging.
Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. Human blastoids can be generated in large numbers, making them well-suited for high-throughput screening. However, automated methods for evaluating and characterizing blastoid morphology are lacking. We developed a deep-learning model-deepBlastoid-for automated classification of live human blastoids using only brightfield images. The model processes 273.6 images per second with an average accuracy of 87%, which is further improved to 97% by integrating a Confidence Rate metric. deepBlastoid outperformed human experts in throughput while matching accuracy in blastoid classification. We demonstrated the utility of the model in two use cases:(i) systematic assessment of the effect of lysophosphatidic acid (LPA) on blastoid formation and (ii) evaluating the impact of dimethyl sulfoxide (DMSO) on blastoid formation. The evaluation results of deepBlastoid using over 10,000 images were consistent with the known drug effects and showed subtle but significant effects that might have been overlooked in manual assessments. The publicly available deepBlastoid model enables researchers to train customized models based on their imaging and protocols, providing an efficient, automated tool for blastoid classification with broad applications in research, drug screening, and in-vitro-fertilization applications.
Ovarian function is increasingly recognized as a systemic process influenced by cross-organ communication, yet knowledge regarding the underlying mechanisms remains fragmented. In addition to the ovary, multiple organs, including the hypothalamus, adipose tissue, gut, liver, thyroid, adrenal gland, and heart, converge to regulate ovarian function. These interactions span endocrine signals (e.g. insulin hormones), immune mediators (e.g. cytokines), and metabolic cues (e.g. adipokines), collectively impacting folliculogenesis, steroidogenesis, and ovulation. Importantly, these interactions suggest novel therapeutic targets to mitigate ovarian dysfunction. However, causal relationships and organ-specific contributions require further mechanistic exploration. This synthesis underscores the necessity of a multisystem perspective in both the research and clinical management of ovarian disorders.
Reactive oxygen species (ROS) involve in oocyte postovulatory aging, yet the mechanism of ROS accumulation is not fully understood. We explored iron metabolic status and its relationship with ROS in mouse oocytes during postovulatory aging in vivo. We found that heme oxygenase 1 (HO-1) expression was increased in oviduct and iron metabolism was disordered in oocytes with time post-ovulation. The aging oocytes were manifested with high iron content and disturbed expressions of iron metabolic proteins, including ferritin heavy chain (FHC), mitochondrial ferritin (FtMT), divalent metal transporter 1 (DMT1), ferroportin1 (FPN1), iron regulatory protein 2 (IRP2) and transferrin receptor 1 (TFR1), along with increased cytosolic free Fe2+, lipid peroxidation, DNA damage, mitochondrial and lysosomal abnormality, and defects in spindle and chromosome alignment. These in vivo aging cells contained stable glutathione peroxidase 4 (GPX4) and 4-hydroxynonenal (4-HNE), unexpectedly, but had more iron and degenerative changes than their in vitro counterparts. The intraperitoneal deferoxamine (DFO) could alleviate all these changes and improve the fertilization competence and preimplantation development. Similarly, the HO-1 inhibitor Zinc Protoporphyrin (ZnPP) also could do this. Together, the iron homeostasis disturbance participates in ROS accumulation and degenerative changes in postovulatory aging oocytes, which can be alleviated by iron chelating.
Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising approach for hematological malignancies, yet its efficacy in solid tumors is hindered by limited persistence. To address this, immune checkpoint inhibitors (ICIs) and cytokines have been explored as potential solutions. In this study, we developed a novel monoclonal antibody (mAb), m8A8, which exhibits high specificity for human PD-1 and effectively disrupts its ligand interactions. Furthermore, we engineered CAR-T cells to express human IL-7, resulting in enhanced anti-tumor efficacy in xenograft models. Additionally, the human-mouse chimeric antibody C8A8, derived from m8A8, was found to significantly amplify the anti-tumor activity of IL-7-engineered CAR-T cells. Our findings provide compelling evidence and a robust rationale for the synergistic integration of ICIs, cytokines, and CAR-T cell therapy in the treatment of solid tumors.