Jul 2026· Cardiovascular Drugs and Therapy· 0 citations· 78 references
Medicine
TL;DR
This review integrates current insights into the complex interplay among metabolic stress, mitochondrial injury, and cellular senescence in Diabetic cardiomyopathy and highlights promising directions for mechanism-based interventions aimed at combating diabetic cardiac remodeling.
Cardiac fibrosis, a major pathological hallmark of aging that leads to heart failure, is characterized by excessive collagen deposition. Our knowledge of what sustains collagen synthesis in the aging heart is still very preliminary. Here, we uncover a central role for chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, in this process. We demonstrate that CMA is suppressed in the aging heart, which promotes collagen overproduction in fibroblasts, whereas enhancing CMA activity ameliorates fibrosis and diastolic dysfunction. Mechanistically, we identify SHMT2 (serine hydroxymethyltransferase 2) as a CMA substrate whose accumulation with aging drives collagen synthesis by increasing glycine availability. Integrative omics revealed a systemic downregulation of the ketone body β-hydroxybutyrate (BHB) in aged mice. BHB supplementation - via a cyclic ketogenic diet - restored CMA, attenuated fibrosis, and improved cardiac function. This recovery was mediated through BHB-induced activation of the HCAR2 receptor and subsequent phosphorylation of HSPA8/HSC70, which systemically reactivates the CMA machinery. Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging.
Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by progressively increased pulmonary vascular resistance and right heart failure. Its pathogenesis involves multiple factors, including genetic predisposition, inflammation, oxidative stress, and imbalances between cell proliferation and apoptosis. Recent studies indicate that autophagy has a context-dependent dual role in PAH. Flux-competent autophagy may be protective by clearing damaged mitochondria, limiting excessive inflammation, and maintaining metabolic homeostasis, whereas excessive autophagy initiation or impaired autophagosome-lysosome degradation may promote metabolic dysfunction, inflammatory signaling, abnormal vascular cell phenotypes, and pulmonary vascular remodeling. This focused narrative review summarizes the molecular mechanisms and key signaling pathways linking autophagy to PAH, with emphasis on PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis. It also evaluates potential therapeutic strategies targeting key nodes of autophagy, such as AMPK activators and mTOR inhibitors, along with their clinical research progress. Finally, this review provides an outlook on future research directions, emphasizing the need to further elucidate the dynamic regulatory mechanisms and cell-type specificity of autophagy in order to advance the clinical translation of autophagy-targeted precision therapies for PAH.
Miao Li, Li-Mei Piao· Journal of Cardiovascular De...· 0 citations
Cardiac ageing is a major biological substrate underlying the increasing burden of age-associated cardiovascular disease. It is characterized by structural and functional remodeling, mitochondrial dysfunction, chronic low-grade inflammation, genomic instability, defective proteostatic control, and impaired regenerative capacity. Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), particularly the cardiac-predominant CaMKIIδ isoform, has emerged as a central stress-responsive signaling node linking Ca²⁺ mishandling, redox imbalance, inflammatory activation, impaired autophagic flux, mitochondrial injury, and maladaptive transcriptional remodeling in the ageing myocardium. Under physiological conditions, CaMKII activation is transient and Ca²⁺/calmodulin dependent. In the ageing heart, sustained oxidation, O-GlcNAcylation, and autophosphorylation prolong kinase activity and amplify pathological signaling. Evidence from aged rodent models, pressure-overload and ischemia-reperfusion models, diabetic cardiomyopathy models, and human failing cardiomyocytes supports a contributory role for CaMKII in multiple age-related cardiovascular disorders. Experimental inhibition of CaMKII has been shown to attenuate pathological remodeling and improve stress maladaptation in preclinical settings. This review integrates current evidence on the role of CaMKII across major hallmarks of cardiac ageing and proposes a conceptual framework in which CaMKII connects molecular stress signaling to age-related cardiac disease phenotypes. Current evidence remains limited by the predominance of animal and cell-based studies, limited direct evidence from older human myocardium without overt cardiovascular disease, incomplete definition of splice-variant-specific actions, and lack of late-stage clinical validation. Selective targeting of pathological CaMKII signaling may therefore warrant further investigation as a strategy for attenuating cardiac ageing and its related disease burden.
Ting Li, Yuan Chen, Bei Xu et al.· Artery Research· 0 citations
Cellular senescence contributes to the pathology of diabetic kidney disease (DKD). Besides, mitochondrial dysfunction and cellular senescence are closely associated pathological processes that may influence one another during kidney injury progression. Dapagliflozin has demonstrated its renal protective benefits independent of the glucose-lowering effects, yet whether it acts via modulating cellular senescence is poorly understood. The design of our study is to explore the potential renal protective mechanism of dapagliflozin, focusing on cellular senescence and mitochondrial function. The streptozotocin-induced diabetic mice and high glucose-treated human renal tubular epithelial (HK-2) cells were used to achieve the purpose. We also employed Compound C and Sirt3 knockdown by small interfering RNA transfection to examine dapagliflozin's effect on AMPK/Sirt3 signalling pathway in HK-2 cell experiments. Dapagliflozin reduced the expression of renal senescence markers in both in vivo and in vitro experiments. Concurrently, dapagliflozin improved mitochondrial function, with evidence in mitochondrial membrane potential restoration, mitochondrial dynamics, and mitochondrial reactive oxygen species reduction, and lowered the levels of senescence-associated secretory phenotypes. Mechanistically, AMPK phosphorylation and Sirt3 expression level were attenuated by AMPK inhibitor compound C, which consequently attenuated dapagliflozin-mediated protective effects. Knockdown of Sirt3 in HK-2 cells substantially reduced dapagliflozin's improvements on mitochondrial function and its protective effects against cellular senescence, thereby reversing its alleviation of kidney function. Dapagliflozin treatment attenuated renal cellular senescence and improved mitochondrial function in DKD. Our findings support the involvement of AMPK/Sirt3 signaling in these renoprotective effects, as evidenced by the attenuation of dapagliflozin-mediated protection following AMPK inhibition and knockdown of Sirt3.
Xin Tong, Bin Wang, Fen-Fei Gao et al.· Biochemical Pharmacology· 0 citations
In general, epigenetic regulation provides a new conceptual framework for understanding TEC dysfunction in DKD and provides a potential direction for the development of precision therapeutic strategies.
Hanxue Li, Meng-Meng Ma, Qiuyue Ren et al.· International Urology and Ne...· 0 citations
Highlights What are the main findings? Metabolic stress promotes senescence across hematopoietic stem cells and circulating immune-cell populations through interconnected oxidative, mitochondrial, DNA-damage, nutrient-sensing, autophagic, epigenetic, and inflammatory pathways. Senescent blood cells amplify inflammaging and immune dysfunction, providing a mechanistic link between metabolic syndrome, clonal hematopoiesis, and cardiometabolic disease. What are the implications of the main findings? Composite blood-cell senescence signatures may complement conventional cardiometabolic risk assessment and treatment monitoring but require analytical standardization and prospective clinical validation. Senolytic, senomorphic, and inflammation-modulating strategies are promising, although longitudinal and interventional human studies are needed to establish causality, efficacy, and safety. Abstract Metabolic syndrome (MetS) is a complex metabolic disorder characterized by central obesity, insulin resistance, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to an increased risk of type 2 diabetes mellitus, cardiovascular disease, and premature mortality. Emerging evidence suggests that cellular senescence plays a central role in the pathophysiology of MetS by linking metabolic stress to chronic inflammation, immune dysfunction, as well as cell and tissue damage. Although senescence has traditionally been studied in tissue-resident cells, growing attention has focused on the role of blood-cell senescence in the initiation and progression of metabolic disease. This review summarizes current knowledge regarding the molecular and cellular mechanisms driving senescence in hematopoietic stem cells and circulating blood-cells (BCs) and how these mechanisms affect specific blood-cell populations leading to altered immune function, impaired tissue homeostasis, and persistent inflammatory activation. The link between clonal hematopoiesis to immunosenescence and cardiometabolic disease is also highlighted, providing additional insight into the complex interactions between hematopoietic aging and metabolic dysfunction.
K. Gioti, Maria Trapali, Irene Belouka et al.· Cells· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
