Cuntai Zhang

Time‐restricted feeding (TRF) restricts food intake to daily windows, yet its efficacy against vascular aging and underlying mechanisms remain unclear. Here, we demonstrate that TRF attenuates angiotension II ‐induced accelerated vascular aging by reshaping gut microbiota, stabilizing microbial diversity, and elevating the Firmicutes/Bacteroidetes ratio. TRF preserved intestinal barrier integrity, upregulated tight junction proteins (Occludin, ZO‐1, MUC2), reduced serum lipopolysaccharide, and suppressed systemic inflammation. These benefits translated into alleviated hypertension, aortic stiffness (reflected by pulse wave velocity), and pathological cardiac remodeling. Fecal microbiota transplantation recapitulated these effects, whereas antibiotic‐induced microbiota depletion abolished TRF protection; importantly, exogenous acetate supplementation fully restored the phenotypes, establishing acetic acid as the critical downstream mediator. Mechanistically, acetic acid bound to GPR43, inhibited HDAC3, increased H4K8ac acetylation, blocked NLRP3‐mediated pyroptosis, and reduced senescence markers (p53, p21, p16) in human umbilical vein endothelial cells, aorta, and heart. 16S rRNA sequencing and short ‐ chain fatty acids metabolomic profiling further identified Limosilactobacillus as the primary acetic acid‐producing bacterium enriched by TRF. Together, we uncover a Limosilactobacillus ‐acetic acid‐GPR43/HDAC3/H4K8ac/NLRP3 axis, offering mechanistic insights into TRF as a non‐pharmacological strategy against age‐related cardiovascular diseases.

Aging is accompanied by progressive immune remodeling and functional decline across multiple organs. However, the role of neutrophils and their heterogeneous states in these processes remains incompletely understood. Here we integrated single‐cell RNA sequencing datasets from multiple organs of young and aged mice to characterize aging‐associated neutrophil remodeling. We identified organ‐dependent changes in neutrophil abundance and state composition, together with neutrophil subsets enriched for inflammatory, oxidative stress, complement, and IL‐6‐related transcriptional programs. In vitro, exposure to conditioned media from neutrophils isolated from aged mice or IL‐6‐stimulated neutrophil‐like cells increased inflammatory and senescence‐associated responses in vascular smooth muscle and hepatocyte‐derived cells. Bone marrow single‐cell analysis further revealed aging‐associated shifts in progenitor composition and transcriptional states, including an old‐enriched HPC11 population characterized by enhanced myeloid priming. Silico perturbation analysis nominated FGF didate regulators of HPC subtype‐specific transcriptional programs. Together, our study provides a multi‐organ single‐cell resource for defining neutrophil remodeling during aging and highlights candidate neutrophil states and potential signaling axes associated with age‐related inflammatory tissue environments.

DNA damage is considered one of the major contributors to aging. DHCR24, a multifunctional enzyme located within the endoplasmic reticulum (ER), is closely related to DNA damage. Our previous study showed that DHCR24 could delay vascular endothelial cells (ECs) senescence. The relationship between DHCR24 and DNA damage during ECs senescence requires further investigation. Here, we demonstrate that aging activates ATM‐mediated DNA damage response (DDR) in human umbilical vein endothelial cells (HUVECs) and mouse pulmonary microvascular endothelial cells (PMVECs), and DHCR24 expression is downregulated. Knocking down DHCR24 in young HUVECs induces the activation of ATM‐mediated DDR, which has been confirmed in PMVECs of DHCR24 endothelial‐specific knockout mice. Consistently, RNAseq indicated that DHCR24 was essential for cell cycle regulation. Further investigations revealed that both replicatively senescent HUVECs and young HUVECs with DHCR24 knockout exhibited ER stress and mitochondrial dysfunction, which might be attributable to calcium overload resulting from DHCR24 deficiency. In this pathological process, the DHCR24‐deficiency‐induced upregulation of ENKUR markedly exacerbates calcium overload. Conversely, ENKUR knockdown not only alleviates the ER stress and mitochondrial dysfunction caused by DHCR24 inhibition, but also suppresses the ATM‐mediated DDR. Moreover, DHCR24 overexpression reduces the elevated ENKUR levels and simultaneously mitigates DOX‐induced calcium overload in HUVECs. Collectively, these findings identify DHCR24‐ENKUR‐dependent Ca ²⁺ signaling as a mechanism linking ER‐mitochondrial homeostasis to endothelial DNA damage and senescence. Accordingly, restoring DHCR24 function or regulating calcium signal transduction through this pathway may hold therapeutic potential for delaying vascular ECs senescence and preventing age‐related diseases.

Dysregulation of the renin‐angiotensin‐aldosterone system (RAAS) constitutes a pivotal factor in the onset and progression of various geriatric diseases, including cardiovascular diseases, diabetes, and chronic kidney disease (CKD), all closely linked to adverse cardiorenal outcomes in older patients. Excessive activation of the mineralocorticoid receptor (MR) drives inflammation, fibrosis, and oxidative stress across tissues and organs, representing a fundamental mechanism underlying systemic metabolic disorders, diabetes, cardiovascular diseases, and kidney pathologies. Emerging clinical evidence indicates that the non‐steroidal mineralocorticoid receptor antagonist (ns‐MRA) finerenone can block MR with high selectivity, significantly reducing cardiorenal event risks in older patients and thereby enhancing overall health status. This offers a novel therapeutic avenue for the long‐term management of older patients burdened with multiple chronic comorbidities.

Background: Prehypertension is more likely to develop into hypertension in individuals with adiposity. We aimed to explore how adiposity influences prehypertension through gut microbiota. Methods: Kaplan–Meier and Cox proportional hazard regression models were employed to evaluate the association between prehypertension and adiposity in 649 individuals. Among them, 197 consented to provide fecal samples and were divided, along with 184 additional participants, into healthy controls (HC), individuals with adiposity and normal tension (Ad-NT), and those with prehypertension (Ad-pHT) based on body mass index (BMI) and blood pressure. Shotgun metagenomic sequencing was performed on fecal samples, followed by taxonomic and functional annotations using MetaPhlAn and HUMAnN. Linear discriminant analysis effect size (LEfSe) was used to analyze differences in microbial species and metabolic pathways across groups. Partial Spearman rank correlation analysis was used to assess microbial interactions, and the relationships among metabolic pathways, species, BMI, and blood pressure. Results: Elevated BMI independently predicted the risk of prehypertension (adjusted HR = 1.072, 95% CI: 1.002–1.147). We observed the depletion of Blautia wexlerae and Parabacteroides distasonis in populations with Ad-pHT. A multiclass logistic regression model distinguished individuals with Ad-pHT from HC and those with adiposity and normal tension (Ad-NT) (AUC = 0.704). Microbiota-microbiota interactions gradually become complex from HC to Ad-NT to Ad-pHT groups. Blautia wexlerae and Parabacteroides distasonis were associated with pathways involved in carbohydrate degradation (PWY-8004), fermentation (ANAEROFRUCAT-PWY), biosynthesis of secondary metabolites (PWY-6270), amino acid (ARGININE-SYN4-PWY), quinol and quinone (PWY-7992), and nucleoside and nucleotide (PWY-6700). Conclusion: Shifts in Blautia wexlerae and Parabacteroides distasonis , as well as their relationships with pathways (energy metabolism and amino acid biosynthesis), were observed in adiposity-related prehypertension. Blautia wexlerae and Parabacteroides distasonis might represent promising candidates for next-generation probiotics targeting weight management and blood pressure reduction, which require validation in clinical studies.

Arterial stiffness is a hallmark of vascular aging and a major risk factor for cardiovascular disease. While immune aging—typically characterized by reduced T cell receptor (TCR) diversity and CD8 ⁺ memory expansion—contributes to this process, growing evidence suggests that peripheral immune dysregulation may impair vascular function through mechanisms distinct from classical immunosenescence. To investigate this, we profiled peripheral TCRβ repertoires from 563 adults without clinically overt cardiovascular disease and assessed their association with pulse wave velocity (PWV), a gold‐standard marker of arterial stiffness. Surprisingly, individuals with elevated PWV exhibited a paradoxical increase in TCR diversity, driven by broad remodeling of numerous low‐frequency CD4 ⁺ clonotypes that preferentially mapped to a naive‐like/early‐differentiation CD4 ⁺ compartment. Single‐cell transcriptomic analyses further indicated chronic activation, proliferative restraint, and dysfunctional immune states in these PWV‐associated CD4 ⁺ T cells. Furthermore, a machine learning model trained on these PWV‐associated repertoire features accurately identified individuals with high PWV (AUC = 0.817), suggesting potential utility in subclinical vascular risk stratification. These findings define a distinct, CD4 ⁺ T cell–driven immune remodeling process—termed “vascular immune remodeling”—that is dissociable from classical immunosenescence and may contribute to arterial stiffening, uncovering an unexpected immune trajectory in early vascular aging and offering new avenues for immune‐based vascular risk assessment and intervention.

Vascular aging, characterized by progressive structural and functional deterioration of the vasculature, serves as a critical pathophysiological nexus between chronological aging and cardiovascular disease (CVD). This study establishes a quantitative vascular age model to decode individualized vascular senescence patterns, thereby enabling early identification of accelerated aging phenotypes for targeted intervention. We collected physical examination records from 2009 to 2019 and a total of 8578 participants aged 20–70 years were enrolled in this study. We constructed sex‐specific basic vascular age models based on healthy individuals by Klemera‐Doubal method and calculated the normalized cardiovascular age acceleration (NCAA, η ) as an estimate of vascular aging status. The association between η and CVD risk were evaluated across subgroups. Furthermore, we developed expanded models by incorporating traditional CVD risk factors that were significantly associated with η index. Male with lower values of η , which meant relatively higher vascular aging velocity, had a higher risk of CVD adjusted by chronological age (HR = 1.21, 95% CI = 1.01–1.45). In subgroup analysis, η index exhibited age‐ and sex‐specific associations with traditional CVD risk factors. After adding body mass index, fasting blood glucose, and triglycerides significantly related to η in male, the CVD prediction by expand η were improved in age‐adjusted model (HR = 1.25, 95% CI = 1.04–1.50). The vascular age model emerges as a robust composite biomarker for CVD risk stratification. Our findings establish an evidence‐based framework for precision prevention, prioritizing high‐risk phenotypes for early intervention to mitigate CVD burden.

Vascular aging is a significant factor in cardiovascular and cerebrovascular diseases and serves as a predictor of all-cause mortality. Although disturbances in lipid metabolism are known risk factors, their links with standardized stages of vascular aging have not been thoroughly assessed in the Chinese population. This multicenter study analyzed the distribution of vascular aging stages in the China Standardized Vascular Aging Management Centers (VMCs). It investigated the relationships between lipid-adiposity-related indices and the progression of vascular aging. A total of 668 participants who underwent examinations at multiple VMCs between June 2023 and February 2025 were included. Baseline data were collected from standardized questionnaires, anthropometric measurements, and laboratory tests. The participants were classified into stage 1 (normal vessels), stage 2 (vascular injury), and stage 3 (vascular aging-related diseases). Multiple linear and logistic regression models were used to assess associations between lipid-adiposity-related indices and brachial-ankle pulse wave velocity (baPWV) or vascular aging stages. Restricted cubic spline analyses were used to examine potential nonlinear relationships. After controlling for demographic factors, lifestyle behaviors, comorbidities, and medication use, most lipid-adiposity-related indices showed significant positive associations with baPWV. The bilateral baPWV measurements exhibited high consistency. According to the multivariable models, waist circumference (WC), A Body Shape Index (ABSI), waist-to-hip ratio (WHR), waist-height ratio (WHtR), triglyceride (TG), atherogenic index of plasma (AIP), and lipid accumulation product (LAP) were significantly linked to vascular aging stages, with several anthropometric indices (WC, ABSI, WHR, WHtR) increasing progressively across stages. No notable nonlinear relationships were observed. Standardized lipid-adiposity-related indices, especially WC, ABSI, WHR, and WHtR, were independently linked to baPWV and vascular aging stages.

Pyroptosis is a lytic and highly inflammatory type of programmed cell death that is mediated primarily by members of the gasdermin (GSDM) protein family. Upon activation by inflammatory stimuli or danger signals, GSDMs are cleaved to release N‑terminal fragments that oligomerize and form pores in the plasma membrane. This disrupts cellular integrity, resulting in osmotic lysis and the release of potent proinflammatory cytokines, such as interleukin (IL)‑1β and IL‑18. The progression of an aortic aneurysm (AA) is driven by complex pathophysiological processes, with the loss of vascular smooth muscle cells and sustained vascular inflammation being central to disease pathogenesis. Emerging evidence indicates that pyroptosis markedly contributes to AA development by amplifying inflammatory activation and promoting cellular disintegration within the aortic wall. Further preclinical evidence has demonstrated that pharmacological inhibition of key pyroptosis signaling pathways effectively attenuates AA formation in murine models, underscoring its promising therapeutic potential. The present review summarizes the molecular mechanisms of pyroptosis, highlights its pathophysiological role in AAs and discusses novel therapeutic strategies targeting pyroptosis for the treatment of AAs.