Aging is a gradual and irreversible natural process. With aging, the body experiences a functional decline, and the effects amplify the vulnerability to a range of age-related diseases, including neurodegenerative, cardiovascular, and metabolic diseases. Within the aging process, the morphology and function of mitochondria and the endoplasmic reticulum (ER) undergo alterations, particularly in the structure connecting these organelles known as mitochondria-associated membranes (MAMs). MAMs serve as vital intracellular signaling hubs, facilitating communication between the ER and mitochondria when regulating various cellular events, including calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis. The formation of MAMs is partly dependent on the interaction between the vesicle-associated membrane protein-associated protein-B (VAPB) and protein tyrosine phosphatase-interacting protein-51 (PTPIP51). Accumulating evidence has begun to elucidate the pivotal role of the VAPB-PTPIP51 tether in the initiation and progression of age-related diseases. In this study, we delineate the intricate structure and multifunctional role of the VAPB-PTPIP51 tether and discuss its profound implications in aging-associated diseases. Moreover, we provide a comprehensive overview of potential therapeutic interventions and pharmacological agents targeting the VAPB-PTPIP51-mediated MAMs, thereby offering a glimmer of hope in mitigating aging processes and treating age-related disorders.

Conventional methods, such as open and arthroscopy-assisted surgery, still encounter challenges in terms of tool flexibility when addressing knee diseases in patients. Robotics has enhanced the precision and efficiency of numerous surgical procedures. However, there is still a lack of minimally invasive surgical tools capable of flexibly resecting knee lesions. Here, we present a flexible fiberbot that integrates steerable midinfrared laser ablation and active navigation functions. The fiberbot features an internal multicore structure for midinfrared laser delivery and an external magnetic elastomer, allowing precise control under an applied magnetic field. The fiberbot was demonstrated to perform precise navigation and steering in a constrained spherical model and an isolated pig knee joint. Moreover, the fiberbot was further demonstrated in steerable laser ablation for leg bones of rats in vivo. Given its compact design, safer actuation, and quicker manipulation, our fiberbot is expected to pave a promising avenue for future knee surgery.

Aging, an inevitable aspect of human existence, serves as one of the predominant risk factors for vascular diseases. Delving into the mystery of vascular disease's pathophysiology, the profound involvement of programmed cell death (PCD) has been extensively demonstrated. PCD is a fundamental biological process that plays a crucial role in both normal physiology and pathology, including a recently discovered form, ferroptosis. Ferroptosis is characterized by its reliance on iron and lipid peroxidation, and its significant involvement in vascular disease pathophysiology has been increasingly acknowledged. This phenomenon not only offers a promising therapeutic target but also deepens our understanding of the complex relationship between ferroptosis and age-related vascular diseases. Consequently, this article aims to thoroughly review the mechanisms that enable the effective control and inhibition of ferroptosis. It focuses on genetic and pharmacological interventions, with the goal of developing innovative therapeutic strategies to combat age-related vascular diseases.

Vascular calcification (VC) increases with age and markedly exacerbates the risk of cardiovascular morbidity and mortality. However, effective pharmaceutical interventions are lacking and the molecular mechanisms linking aging to VC remain elusive. This study explored the role of nuclear factor erythroid 2-related factor 2 (NRF2) in age-associated VC, specifically focusing on vascular smooth muscle cell (VSMC) senescence. Using a chronologically aging mouse model, we noted a significant decline in the expression of NRF2 in the aged mice aortas, coinciding with increased VC. Administering NRF2 activators effectively reduced calcification. By establishing adenine-and vitamin D-induced VC models in VSMC-specific Nrf2 knockout (Nrf2^SMCKO) mice, there was an increase in VC with increased VSMC senescence. Aortic rings and primary VSMCs from Nrf2^SMCKO mice also showed increased VC under high-phosphate conditions. Furthermore, Nrf2 overexpression inhibited VSMC calcification with decreased VSMC senescence and an osteogenic phenotype, whereas Nrf2 silencing aggravated calcification. Transcriptome RNA-seq analysis of the aortas from Nrf2^SMCKO and control mice revealed that inhibitor of DNA binding 2 (Id2) is a core downstream gene of NRF2. Id2 overexpression alleviated NRF2 knockdown-induced VC and VSMC senescence, while silencing Id2 negated the protective effects of NRF2. Moreover, results of a dual luciferase reporter assay indicated that NRF2 promotes the transcriptional activity of the Id2 gene promoter region. This study emphasizes the critical role of age-related NRF2 dysfunction in the nexus between VSMC senescence and VC. The NRF2-ID2 axis in VSMCs has been proposed as a promising therapeutic target for reducing VC and mitigating age-related cardiovascular diseases.

Abdominal aortic aneurysm (AAA), a vascular degenerative disease, is a potentially life-threatening condition characterised by the loss of vascular smooth muscle cells (VSMCs), degradation of extracellular matrix (ECM), inflammation, and oxidative stress. Despite the severity of AAA, effective drugs for treatment are scarce. At low doses, terazosin (TZ) exerts antiapoptotic and anti-inflammatory effects in several diseases, but its potential to protect against AAA remains unexplored. Herein, we investigated the effects of TZ in two AAA animal models: Angiotensin II (Ang II) infusion in Apoe^-/- mice and calcium chloride application in C57BL/6J mice. Mice were orally administered with TZ (100 or 1000 μg/kg/day). The in vivo results indicated that low-dose TZ alleviated AAA formation in both models. Low-dose TZ significantly reduced aortic pulse wave velocity without exerting an apparent antihypertensive effect in the Ang II-induced AAA model. Paternally expressed gene 3 (Peg3) was identified via RNA sequencing as a novel TZ target. PEG3 expression was significantly elevated in both mouse and human AAA tissues. TZ suppressed PEG3 expression and reduced the abundance of matrix metalloproteinases (MMP2/MMP9) in the tunica media. Functional experiments and molecular analyses revealed that TZ (10 nM) treatment and Peg3 knockdown effectively prevented Ang II-induced VSMC senescence and apoptosis in vitro. Thus, Peg3, a novel target of TZ, mediates inflammation-induced VSMC apoptosis and senescence. Low-dose TZ downregulates Peg3 expression to attenuate AAA formation and ECM degradation, suggesting a promising therapeutic strategy for AAA.

(1) Background: Despite the evidence that ferroptosis is involved in myocardial ischemia-reperfusion (MIR), the critical regulator of ferroptosis in MIR remains unclear. (2) Methods: We included three GEO datasets and a set of ferroptosis-related genes with 259 genes. Following the identification of the differentially expressed ferroptosis-related genes (DEFRGs) and hub genes, we performed the functional annotation, protein–protein interaction network, and immune infiltration analysis. The GSE168610 dataset, a cell model, and an animal model were then used to verify key genes. (3) Results: We identified 17 DEFRGs and 9 hub genes in the MIR samples compared to the control. Heme oxygenase 1 (Hmox1), activating transcription factor 3 (Atf3), epidermal growth factor receptor (Egfr), and X-box binding protein 1 (Xbp1) were significantly upregulated in response to ischemic and hypoxic stimuli. In contrast, glutathione peroxidase 4 (Gpx4) and vascular endothelial growth factor A (Vegfa) were consistently decreased in either the oxygen and glucose deprivation/reoxygenation cell or the MIR mouse model. (4) Conclusions: This study emphasized the relevance of ferroptosis in MIR. It has been successfully demonstrated that nine ferroptosis-related genes (Hmox1, Atf3, Egfr, Gpx4, Cd44, Vegfa, asparagine synthetase (Asns), Xbp1, and bromodomain containing 4 (Brd4)) are involved in the process. Additional studies are needed to explore potential therapeutic targets for MIR.