Hengyi Xiao

Lysosomal dysfunction is a hallmark of cellular senescence, yet the mechanisms governing lysosomal protein trafficking remain incompletely understood. Here, we show that CD-M6PR, a principal receptor for lysosomal enzyme transport, is markedly reduced in senescent fibroblasts and in aged mice and humans, and that its loss correlates with the severity of autolysosomal impairment. Mechanistically, the reduction of CD-M6PR in senescent cells mainly stems from the accelerated proteasome-mediated degradation. Utilizing structural predictions and experimental validation, we identified the E3 ubiquitin ligase ZNRF2 as a critical mediator of CD-M6PR’s rapid degradation in senescent cells, facilitated by ZNRF2's elevated expression in these cells. We further link stress-induced mTORC1 activation to increased ZNRF2 expression, which in turn reduces CD-M6PR protein levels, impairs lysosomal enzyme trafficking, and compromises autolysosomal function, thereby exacerbating cellular senescence. Collectively, these data define a previously unrecognized mTORC1–ZNRF2–CD-M6PR axis and reveal a novel mechanism by which aberrant mTORC1 signaling promotes lysosomal dysfunction and senescence, with potential implications for therapeutic targeting of age-related pathologies. Graphical abstract The alternative text for this image may have been generated using AI.

Background: Gastric cancer is one of the most lethal malignancies in the world, but effective therapeutic options for patients with this disease remain limited. Claudin-18.2 (CLDN18.2) has emerged as a promising therapeutic target, yet the functional role of CLDN18.2 and the mechanisms of CLDN18.2-directed immunotherapy remain poorly understood. This study aims to. Methods: The antitumor efficacy and immunological mechanisms of the CLDN18.2-CD3 bispecific antibody IBI389 were evaluated through two preclinical models: a human peripheral blood mononuclear cell (PBMC)-reconstituted AGS xenograft and a B-hCD3EDG murine KPC pancreatic cancer model. Stable CLDN18.2-overexpressing cell lines were established for in vitro functional assays. Tumor growth inhibition was assessed through volume and weight measurements. Immune modulation was analyzed via flow cytometry, multiplex immunofluorescence, cytokine profiling, and histopathology. Human gastric cancer tissue microarrays were further used to validate spatial findings. Results: CLDN18.2 overexpression enhanced the proliferation and migration of gastric and pancreatic cancer cells in vitro. In vivo, IBI389 significantly suppressed tumor growth, with the greatest efficacy achieved when combined with programmed death-1 (PD-1) blockade. Mechanistically, IBI389 increased the abundance of tumor-infiltrating CD8⁺ T cells; reshaped the cytokine milieu toward an antitumor profile characterized by elevated interleukin (IL)-2, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels with concomitant reductions in IL-4, IL-10, and IL-17A; and reduced the spatial distance between CLDN18.2⁺ tumor cells and CD3⁺ T cells. These spatial changes were consistent with observations of human gastric cancer tissues. Histopathological analysis of the liver, kidney, and spleen identified no overt drug-related toxicity. Conclusions: In this study, we demonstrated that IBI389 effectively redirects T cells to CLDN18.2-expressing tumors, suppresses tumor growth, and synergizes with PD-1 blockade and has a favorable safety profile. By virtue of its ability to enhance immune infiltration, remodel cytokine responses, and reduce tumor-immune spatial separation, IBI389 may have considerable potential as a novel therapeutic strategy for CLDN18.2-positive gastric cancer and related malignancies.

The catabolism of glutamine is essential for living organisms, so that its first step, driven by glutaminase 1 (GLS1), generally referred to as glutaminolysis, plays important roles in physiological metabolism. However, the status and impact of glutaminolysis in pathological contexts such as aging and age-related diseases remain elusive. In this study, through metabolomics analysis and different aging models, we verified the hyperactivation status of glutaminolysis in senescent cells and aged Drosophila and mice, which we term “hyperglutaminolysis”. We further confirmed the aging-promoting role of this hyperglutaminolysis by addition and removal intervention experiments. Intriguingly, a novel signaling axis connecting to senescence-associated persistent mTORC1 activation was found. This pathway begins with glutaminase-catalyzed production of ammonium and glutamate, which drives arginine biosynthesis and is subsequently sensed by CASTOR1, leading to persistent mTORC1 activation. The regulatory roles of two key enzymes within this cascade, GLS1 and argininosuccinate lyase (ASL), were specifically investigated and verified by cellular and in vivo experiments, including those using stress-promoted and naturally aged animals, combined with GLS1 and ASL knockdown, and multiple rounds of metabolite analysis. In conclusion, our work positions dysregulated glutaminolysis as a key driver of aging and delineates a previously unrecognized molecular cascade that directly links glutaminolysis, arginine biosynthesis, and mTORC1 activation. These findings significantly expand our understanding of the relationship between glutamine catabolism and aging and are valuable for identifying novel intervention targets aimed at mitigating aging-related processes.

Time‐restricted feeding (TRF) is a distinct regimen of intermittent fasting advocated for health improving. Although nighttime TRF (NRF) in rodents is analogous to daytime TRF (DRF) in humans and has health benefits, the effects of DRF on rodent's health remain uncertain. The adverse health effects of DRF in rodents are primarily attributed to its implementation‐induced temporal shift in the expression of circadian rhythm‐related genes. However, studies also demonstrate the health–beneficial effect of restricted feeding itself on metabolic homeostasis, particularly in periphery tissues. Moreover, the direct effects of DRF on aging progression in rodents are underexplored, highlighting a gap in current research. To explore the overall health effects of long‐term DRF in rodents, especially its influence on aging progression, we investigated the impact of long‐term DRF on mice under a progeric aging condition. Results showed that both 4‐h and 8‐h DRF regimens exerted positive effects on aging retardation; these effects were manifested as improved physical and memory capacities, enhanced liver and kidney functions, and reduced oxidative damage and inflammatory response. These DRF regimens also lowered the manifestation of aging‐related markers in peripheral tissues, with decreased SA‐β‐gal staining and p16 expression. Mechanistically, DRF regimens, especially DRF8, upregulated AMPK signaling and downregulated mTORC1 signaling. Interestingly, the health benefits of DRF are similar to those of metformin intervention. In conclusion, our study demonstrates for the first time that DRF effectively counteracts oxidative stress‐induced aging progression in mice, supporting the viewpoint that TRF as a promising strategy for preventing aging and aging‐related disorders.

The side population (SP) cells are identified through Hoechst 33342 staining and analyzed using flow cytometry (FCM). The Hoechst SP method is utilized ... Jove

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro‐proliferative factor and a pro‐aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.

Senescence‐associated microRNAs (SA‐miRNAs) are important molecules for aging regulation. While many aging‐promoting SA‐miRNAs have been identified, confirmed aging‐suppressive SA‐miRNAs are rare, that impeded our full understanding on aging regulation. In this study, we verified that miR‐708 expression is decreased in senescent cells and aged tissues and revealed that miR‐708 overexpression can alleviate cellular senescence and aging performance. About the molecular cascade carrying the aging suppressive action of miR‐708, we unraveled that miR‐708 directly targets the 3′UTR of the disabled 2 ( Dab2 ) gene and inhibits the expression of DAB2. Interestingly, miR‐708‐caused DAB2 downregulation blocks the aberrant mammalian target of rapamycin complex 1 (mTORC1) activation, a driving metabolic event for senescence progression, and restores the impaired autophagy, a downstream event of aberrant mTORC1 activation. We also found that AMP‐activated protein kinase (AMPK) activation can upregulate miR‐708 via the elevation of DICER expression, and miR‐708 inhibitor is able to blunt the antiaging effect of AMPK. In summary, this study characterized miR‐708 as an aging‐suppressive SA‐miRNA for the first time and uncovered a new signaling cascade, in which miR‐708 links the DAB2/mTOR axis and AMPK/DICER axis together. These findings not only demonstrate the potential role of miR‐708 in aging regulation, but also expand the signaling network connecting AMPK and mTORC1.

With the increase of aging population and prevalence of obesity, the incidence of cardiovascular disease (CVD) and cancer has also presented an increasing tendency. These two different diseases, which share some common risk factors. Relevant studies in the field of reversing Cardio-Oncology have shown that the phenotype of CVD has a significant adverse effect on tumor prognosis, which is mainly manifested by a positive correlation between CVD and malignant progression of concomitant tumors. This distal crosstalk and the link between different diseases makes us aware of the importance of diagnosis, prediction, management and personalized treatment of systemic diseases. The circulatory system bridges the interaction between CVD and cancer, which suggests that we need to fully consider the systemic and holistic characteristics of these two diseases in the process of clinical treatment. The circulating exosome-miRNAs has been intrinsically associated with CVD -related regulation, which has become one of the focuses on clinical and basic research (as biomarker). The changes in the expression profiles of cardiovascular disease-associated miRNAs (Cardio-miRNAs) may adversely affect concomitant tumors. In this article, we sorted and screened CVD and tumor-related miRNA data based on literature, then summarized their commonalities and characteristics (several important pathways), and further discussed the conclusions of Cardio-Oncology related experimental studies. We take a holistic approach to considering CVD as a risk factor for tumor malignancy, which provides an in-depth analysis of the various regulatory mechanisms or pathways involved in the dual attribute miRNAs (Cardio-/Onco-miRNAs). These mechanisms will be key to revealing the systemic effects of CVD on tumors and highlight the holistic nature of different diseases. Therefore, the Cardio-miRNAs should be given great attention from researchers in the field of CVD and tumors, which might become new targets for tumor treatment. Meanwhile, based on the principles of precision medicine (such as the predictive preventive personalized medicine, 3PM) and reverse Cardio-oncology to better improve individual outcomes, we should consider developing personalized medicine and systemic therapy for cancer from the perspective of protecting cardiovascular function.