Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that develops in several clinical settings. Despite its complex pathogenesis, evidence indicates a central role for fibrosis in the progression of left ventricular diastolic dysfunction (LVDD). Through exploratory research into adipokines derived from brown adipose tissue (BAT), we identified a secreted-type profibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), whose expression increased in BAT with aging. PCPE-1 promotes the cleavage of procollagens and is a critical initiator of fibrillogenesis. This molecule was increased in the plasma of aged mice. In addition to aging, obesity led to an increase in PCPE-1 expression in the LV of mice. Both systemic and BAT-specific PCPE-1 depletion ameliorated LV fibrosis and LVDD in the obese HFpEF model. Our data also showed that age-associated LVDD was ameliorated in the systemic PCPE-1-KO mouse fed with a normal chow diet. Conversely, the overexpression of PCPE-1 expression in BAT was shown to lead to aggravation of LV fibrosis and LVDD. Mechanistically, we found ROS/DNA damage/c-Fos/c-Jun signaling resulted in an increased production of PCPE-1 in brown adipocytes. These results indicate PCPE-1 may represent a druggable target for aging- and obesity-related HFpEF.

Cardiac aging reflects a convergence of intrinsic molecular damage and maladaptive stress responses that progressively erode myocardial resilience. Accumulating genomic instability, telomere dysfunction, chromatin remodeling, and metabolic dysregulation activate innate immune signaling and cellular senescence across cardiomyocytes, endothelial cells, fibroblasts, and immune cells. At the tissue level, these processes manifest as microvascular rarefaction, fibrosis, hypertrophy, neurovascular uncoupling, and impaired adaptive capacity, creating a substrate that overlaps extensively with cardiomyopathy, heart failure, and atrial fibrillation (AF). Importantly, senescence in the heart is not monolithic. Emerging multi-omics and spatial analyses reveal context-dependent senescence programs, including transient, injury-associated states that support angiogenesis and repair, alongside chronic senescent phenotypes that propagate inflammation and remodeling through the senescence-associated secretory phenotype (SASP). These observations indicate that senescence is not uniformly deleterious but rather comprises functionally heterogeneous responses within the aging myocardium. Non-cell autonomous interactions-spanning cardiomyocyte-fibroblast crosstalk, immune niche signaling, endothelial cell-neuronal axis, and systemic organ-to-heart communication-further amplify or constrain these trajectories. Advances in biomarker discovery, imaging, and circulating epigenetic signatures now enable biological aging of the heart to be quantified beyond chronological aging, although many circulating biomarkers are not cardiac-specific and may also reflect systemic inflammation, fibrosis, frailty, or generalized biological aging. In parallel, preclinical studies demonstrate that senolytic, senomorphic, metabolic, and nutrient-sensing-targeted interventions can partially restore cardiac homeostasis. Together, these insights suggest that cellular senescence may represent a key mechanism and a potentially targetable process in cardiac aging, with important implications for the prevention and treatment of age-related cardiovascular disease.

Introduction Cardiac hypertrophy is a major precursor of heart failure and is closely associated with mitochondrial dysfunction. Although andrographolide has demonstrated cardioprotective properties, its effects on mitochondrial quality control (MQC) during hypertensive cardiac remodelling remain unclear. This study investigated whether andrographolide attenuates salt-sensitive cardiac hypertrophy by modulating MQC and apoptosis-associated signalling in a uninephrectomy-deoxycorticosterone acetate-salt (UNX-DOCA-salt) rat model. Material and methods Male Sprague-Dawley rats subjected to the UNX-DOCA-salt model were treated with andrographolide or spironolactone. Cardiac hypertrophy was assessed by cardiac weight, cardiac weight-to-body weight ratio, and cardiomyocyte cross-sectional area. Mitochondrial function was evaluated by succinate dehydrogenase activity, mitochondrial calcium concentration, and mitochondrial DNA copy number, while the expression of hypertrophy-, MQC-, and apoptosis-related genes was quantified by RT-qPCR. Partial least squares regression (PLS-R), correlation analysis, molecular docking, and MM/GB(PB)SA were performed to identify and computationally validate key molecular determinants. Results UNX-DOCA-salt induced marked cardiac hypertrophy, mitochondrial dysfunction, and upregulation of DRP1, PINK1, PGC-1α, TFAM, p53, and BNP. Among the tested doses, andrographolide at 30 mg/kg body weight more consistently restored structural, mitochondrial, and molecular alterations than 60 mg/kg body weight. Multivariate analysis identified DRP1 as the principal molecular determinant associated with hypertrophic remodeling, whereas molecular docking and MM/GB(PB)SA demonstrated energetically favorable interactions of andrographolide within the DRP1 GTPase-binding region. Discussion These findings suggest that andrographolide attenuates salt-sensitive cardiac hypertrophy, at least in part, through modulation of mitochondrial homeostasis. DRP1-mediated mitochondrial dynamics may represent a promising therapeutic target underlying the cardioprotective effects of andrographolide in hypertensive cardiac remodeling.

The accumulation of senescent cells drives age-related diseases, and their removal (senolysis) has been reported to ameliorate pathological aging phenotypes. Here, we identified Rhodiola rosea extract (Rosea) as a senolytic agent through screening of edible natural products. In mice, Rosea eliminated irradiation-induced senescent cells and reduced the burden of senescent cells in adipose tissue during obesity, as well as in adipose tissue, skin, and skeletal muscle during aging. These effects were accompanied by improvements in metabolic abnormalities, physical function, skin abnormalities, and behavioral impairments. We further identified oligomers of epigallocatechin (EGC) and epigallocatechin gallate (EGCG), specifically EGC-EGCG and EGCG-EGCG, as the senolytic components. EGC-EGCG targeted vulnerabilities in calcium dynamics between the endoplasmic reticulum and mitochondria in senescent cells, thereby inducing paraptosis-like cell death. These findings suggest that Rosea, containing EGC-EGCG and EGCG-EGCG, represents a natural senolytic candidate capable of delaying, mitigating, or preventing the progression of age-related pathologies.

Ischemic cardiomyopathy (ICM) is characterized by impaired myocardial function resulting from reduced coronary blood flow, resulting in heart failure. Emerging evidence from proteomic studies indicates that ischemic preconditioning confers cardioprotection against ICM through the regulation of mitochondrial proteins. Proteomic analyses have identified phosphorylation in mitochondrial proteins, including malate dehydrogenase 2 (MDH2), as mediators of cardioprotective mechanisms. However, the mechanism by which MDH2 phosphorylation contributes to cardioprotection in cardiovascular diseases remains poorly understood. This study investigates the role of MDH2 phosphorylation, particularly at S246, in regulating cardiac function. Analysis of patients with dilated cardiomyopathy indicated no significant change in MDH2 expression, similar to a trend observed in ischemic patient data. Considering that a previous proteomic analysis of ischemic preconditioned rat hearts indicated phosphorylation at S246, we analyzed the functional role of this phosphorylation by introducing S246A phosphomutation. S246A phosphomutation significantly decreased MDH2 activity, accompanied by an increased accumulation of acetate and lactate as demonstrated by metabolomics. S246A phosphomutation also lowers mitochondrial membrane potential and ATP production. Under hypoxia/reoxygenation (H/R) conditions, S246A phosphomutation downregulates mitochondrial biogenesis and fusion proteins such as PGC1α and OPA1. Overall, these findings suggest that MDH2 phosphorylation at S246 is important in protecting against H/R injury through mitochondrial function regulation and activation of metabolic pathways. This discovery establishes a potential therapeutic strategy and a clear direction for drug development to specifically address conditions such as ICM.

Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence-assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.

Brown adipose tissue (BAT) is essential for thermoregulation and energy metabolism, converting fatty acids into thermal energy in response to cold exposure and dietary intake, thereby contributing to both cold-induced thermogenesis and diet-induced thermogenesis (DIT). Our previous research suggests that boysenberry anthocyanins (BoyACs) may activate BAT under cold conditions, and we hypothesized that BoyACs could also influence DIT through the activation of BAT. This pilot randomized, double-blind crossover trial aimed to evaluate the effects of daily intake of BoyACs on DIT in healthy adults (registration number: UMIN000047413). Twenty-two participants consumed either a boysenberry juice (BoyJ) beverage containing 61.0 mg of BoyACs or a placebo beverage daily for four weeks, with a four-week washout period separating the two interventions. Three participants withdrew during the trial, resulting in data from 19 participants being analyzed. Results showed no significant changes in DIT, defined as increase in postprandial energy expenditure, or skin temperature of BAT regions. However, a significant increase in postprandial fat oxidation was observed. No significant differences were observed in other outcomes. These results suggest that BoyJ intake does not significantly affect postprandial energy expenditure but may influence substrate utilization to promote fat oxidation. Further studies focusing on substrate utilization, particularly fat oxidation, as the primary outcome are necessary to confirm these results and fully understand the implications of BoyJ intake on energy metabolism.

Insulin Resistance (IR) is a complication that frequently occurs in obesity. The inflammation-mediated senescence in White Adipose Tissue (WAT) is important in obesity-induced IR. Centella asiatica (CA) is a potential medicinal plant with anti-aging and anti-obesity properties. Here, we explored the effect of CA on obesity-mediated IR in mice fed with a High Fat-High Fructose (HFHF) diet and treated simultaneously with CA at 150 mg/kgBW (CA150) or 300 mg/kgBW (CA300). The total body mass and visceral WAT weight in both CA groups decreased in comparison with HFHF group alone. We demonstrated that HFHF-diet mice treated with CA300 improved insulin sensitivity and enhanced Irs-1 activation in WAT. CA300, but not CA150, prevented the senescence phenotype in WAT, represented by decreased Senescence-associated beta-galactosidase (SA-β-Gal) activity and diminished Cdkn2a and Cdkn1a expression levels at mRNA level. Mechanistically, CA300 prevented the enhancement of Il6 and Il1b mRNA expression levels and macrophage activity in the immunostaining analysis of WAT. In vitro, RAW264.7 cells stimulated with high glucose and low dose of Lipopolysaccharides (LPS) also confirmed that CA 200 μg/ml alleviated the expression levels of M1 markers such as Ccl2, Il6, Il1b, and Tnf at mRNA level. Our data indicated that CA has therapeutic potential for obesity-mediated IR by suppressing proinflammatory M1 macrophages and preventing inflammation-induced senescence in WAT.

Evidence indicates a role of cellular senescence and systemic insulin resistance (hyperinsulinemia) in the pathogenesis of age-related cardiovascular-metabolic disorders, including heart failure, atherosclerotic diseases, obesity, and diabetes. "Metabolic remodeling" is one of the keywords for aging research, and studies with brown adipose tissue have shown that maintaining the homeostasis of this organ is crucial to suppressing the progression of pathologies in obesity and heart failure. The mechanisms contributing to the synchronization of aging (sync-aging) are mysterious and interesting. "Senometabolite" or "senoprotein" are defined as circulating molecules that have causal roles in sync-aging, which requires the establishment of new concepts: age-related fibrotic disorders (A-FiDs), and senometabolite-related disorders (SRDs). Globally, researchers are active in comprehensive and conclusive studies targeting age-related circulating molecules. Recently, the senolytic approach opened a new avenue for aging research. Senolysis, mediated through a genetic/pharmacologic/vaccination approach, reversed aging and pathologies in age-related diseases. Suppression of prosenescent molecules (senocules) and senolysis, the specific depletion of senescent cells, will become next-generation therapies for cardiovascular diseases.

center dot This study investigated how cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex that selectively degrades ion channels, targets cardiac transient receptor potential channel 1 (TRPC1). center dot Physiologically, CRBN ablation upregulated TRPC1 expression. center dot Mechanistically, the CRBN Lon domain directly interacts with the C- and N-terminals of TRPC1. center dot Increasing CRBN levels enhanced TRPC1 ubiquitination and proteasomal degradation. center dot TRPC1 overexpression in HEK293-CRBN KO cells enhanced TRPC1 current density and Ca2+ transients. center dot Pathologically, cardiac TRPC1 expression in CRBN-deficient mice was increased during ex vivo ischemic/reperfusion. center dot Targeting the CRBN-TRPC1 axis may serve as a novel therapeutic approach to address cardiac disease.

Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.

AbstractBrown adipose tissue (BAT) plays an important role in energy metabolism because it uses fatty acids for thermogenesis during cold exposure. Preclinical studies found that boysenberry anthocyanins (BoyACs) activate BAT. Therefore, the aim of this preliminary study was to evaluate how BoyAC intake affects BAT in humans. We performed an open-label single-arm nonrandomized study in healthy volunteers. Before and after 4 weeks of daily consumption of 100 ml boysenberry juice (BoyJ) containing 61 mg of BoyACs, participants were assessed at 24 °C and then after 1 h of mild cold exposure (18 °C). An infrared thermography camera was used to measure skin surface temperatures in the supraclavicular BAT region (Tscv) and the non-BAT region of the upper chest (Tch). Energy metabolism was measured by indirect calorimetry. For each endpoint, we calculated Δ as the difference between values before and after cold exposure and compared the values before and after BoyJ intake. 10 volunteers participated (age: 36.1 ± 4.1, body mass index (BMI): 20.9 ± 0.6). After BoyJ intake, ΔTscv-ch was significantly higher (p = 0.029), but Δ energy expenditure, Δ fat oxidation, and Δ carbohydrate oxidation were not significantly different. We found a significant positive correlation between BMI and Δfat oxidation with BoyJ intake. The results indicate that 4 weeks of BoyJ intake activates cold-induced thermogenesis in the scv-BAT but does not have a significant effect on energy metabolism. BoyJ intake may increase fat oxidation during cold exposure in individuals with higher BMI.Trial registry number: UMIN000043476, 05/03/2021.

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells. Katsuumi, Shimizu, Suda et al. report that SGLT2 inhibition reduces the senescence burden and alleviates aging traits in mice. The authors demonstrate an indirect mechanism of senescent cell removal, through enhancing immunosurveillance.

BACKGROUND: Chronic exposure of high glucose (HG) in endothelial cell induces senescence which may contribute to the development and progression of age-related diseases including insulin resistance. Andrographis paniculata improves insulin resistance in recent in vitro and in vivo studies. Anti-inflammatory and antioxidant properties of A. paniculata may be the new therapeutic approach to inhibiting premature senescence. However, the senolytic effect of A. paniculata on endothelial cells has not been investigated comprehensively. This study was conducted to evaluate the effect of A. paniculata extract on HG-induced endothelial cell senescence and the underlying mechanisms. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with 33 mM HG and 7.5 μg/mL A. paniculata extract for 48 hours. The expressions of p16, p21, interleukin (IL)-6, IL-8, insulin receptor substrate (IRS)-1, mammalian target of rapamycin, and sirtuin 1 (SIRT1) were measured by performing real-time quantitative polymerase chain reaction (RT-qPCR). The senescence-associated-β-galactosidase (SA-β-gal) staining was performed to observe the positive-stained senescent cells, while the cell surface expression of IL-1α was examined with flow cytometry method. RESULTS: A. paniculata extract reversed senescence in HUVECs under HG conditions by reducing mRNA expressions of p16 and p21, the number of SA-β-gal-positive-stained cells, and the expression of IL-1α on cell surface, which decreased the activation of IL-6 and IL-8. In addition, A. paniculata extract decreased the mRNA expression of mTOR and increased the mRNA expressions of IRS-1 as well as SIRT1. CONCLUSION: A. paniculata extract ameliorated senescence and improved insulin sensitivity by regulating the mTOR, SIRT1, and IRS-1 mRNA expressions on HG-treated HUVECs. KEYWORDS: Andrographis paniculata, endothelial cell, senescence, high glucose, nutrient-sensing pathways