Heart Age Research Articles

AMPK, a key molecule regulating aging-related myocardial ischemia-reperfusion injury.

Aging leads to the threat of more diseases to the biological anatomical structure and the decline of disease resistance, increasing the incidence and mortality of myocardial ischemia-reperfusion injury (MI/RI). Moreover, MI/RI promotes damage to an aging heart. Notably, 5'-adenosine monophosphate-activated protein kinase (AMPK) regulates cellular energy metabolism, stress response, and protein metabolism, participates in aging-related signaling pathways, and plays an essential role in ischemia-reperfusion (I/R) injury diseases. This study aims to introduce the aging theory, summarize the interaction between aging and MI/RI, and describe the crosstalk of AMPK in aging and MI/RI. We show how AMPK can offer protective effects against age-related stressors, lifestyle factors such as alcohol consumption and smoking, and hypertension. We also review some of the clinical prospects for the development of interventions that harness the effect of AMPK to treat MI/RI and other age-related cardiovascular diseases.

Prevalence and Spectrum of Iron Deficiency in Heart Failure Patients in a Tertiary Cardiac Centre in Nepal

Background: Iron deficiency (ID) is a major heart failure comorbidity associated with increased mortality, worse symptoms and a poorer quality of life, irrespective of anaemia. In Nepal, limited data are available to permit an estimation of the spectrum and prevalence of ID associated with heart failure, which the present study aimed to find. Methods: A single-centre, cross-sectional, observational study was conducted at a tertiary care hospital in Kathmandu, Nepal. Patients meeting validated clinical criteria of heart failure were included and assessed for their iron status. Absolute ID was defined as serum ferritin <100 μg/l and functional ID was defined as normal ferritin (100–300 μg/l), with low transferrin saturation <20%. Data were analysed using SPSS (version 23). A logistic regression model was used to calculate the OR, with p-values <0.05 and 95% CIs. Results: A total of 400 patients were studied. Anaemia was present in 244. ID was present in 314 (78.5%) patients, out of which absolute deficiency was present in 181 (57.6%) and functional deficiency was present in 133 (42.4%) patients. ID with anaemia was present in 222 patients. Female sex (OR 1.93; 95% CI [1.18–3.18]), New York Heart Association class III/IV (OR 2.46; 95% CI [1.48–4.07]), age >65 years (OR 1.97; 95% CI [1.21–3.21]) and anaemia (OR 7.01; 95% CI [4.08–12.06]) were significantly associated with ID. ID without anaemia was present in 29% of patients. Conclusion: The present study showed a high prevalence of ID in heart failure patients, which was significantly associated with older age, female sex and higher New York Heart Association class. It also showed that a significant number of patients who were non-anaemic had ID. Therefore, iron profiling and treatment should be a part of the routine assessment of patients with heart failure.

Marker associations of chronic heart failure severity and cognitive dysfunction in elderly patients

Introduction. Next to neurodegenerative disorders, cardiovascular diseases are now the most common cause of cognitive impairment. The combination of factors such as older age and chronic heart failure is a corner-stone of a greater risk for developing vascular cognitive impairment.Aim. To study the relationship between the parameters of the left ventricular ejection fraction and the concentration of NT-proBNP with the results of neuropsychological testing in patients with chronic heart failure in old age.Materials and methods. The study included 200 elderly patients with CHF II–III FC. The neuropsychological examination included tests: tracking, Schulte tables, verbal associations, the Montreal Cognitive Function Assessment Scale (МоСА test). Laboratory tests included determination of the concentration of NT-proBNP in serum.Results. During neuropsychological testing, reduced indicators were obtained: during the MOS test in patients with left ventricular ejection fraction (LVEF) values < 40% and ≥ 40% and < 50% and with a concentration of NT-proBNP 7230 [3325; 8830] pg/ml; in the Schulte test, an increase in execution time was noted in patients with LVEF values < 40% and ≥ 40% and < 50% and with a concentration of NT-proBNP 2900 [700; 7500] pg/ml; in the tracking test – an increase in time in part A in patients with LVEF values < 40% and ≥ 40% and < 50% and with a concentration of NT-proBNP 5385 [2125; 8675] pg/ml and part B in patients with LVEF values < 40% and ≥ 40% and < 50% and with a concentration of NT-proBNP 6947 [3325; 9310] pg/ml, in the verbal association test – in patients with LVEF values < 40% and ≥ 40% and < 50% and with a concentration of NT-proBNP 2090 [608; 7126] pg/ml. Correlation analysis showed the presence of a significant relationship between LVEF indicators, the concentration of NT-proBNP and the results of neuropsychological testing (p < 0.001), while, according to the Rea&Parker classification, the connection was assessed as relatively strong and medium strength.Conclusion. The cognitive impairments identified in this study in elderly patients with chronic heart failure were characterized by a decrease in concentration, memory, executive functions and the overall integrative index of cognitive functions. These disorders were significantly associated with a decrease in the left ventricular ejection fraction and a high concentration of NT-proBNP.

A small molecule macrophage migration inhibitory factor agonist ameliorates age-related myocardial intolerance to ischemia-reperfusion insults via metabolic regulation

Macrophage migration inhibitory factor (MIF) is an innate cytokine that regulates both inflammatory and homeostatic responses. MIF is expressed by cardiomyocytes, where it exerts a protective action against ischemia-reperfusion (I/R) injury by activating AMP-activated protein kinase (AMPK). This effect is attenuated in the senescent heart due to an intrinsic, age-related reduction in MIF expression. We hypothesized that treating the aged heart with the small molecule MIF agonist (MIF20) can reinforce protective MIF signaling in cardiomyocytes, leading to a beneficial effect against I/R stress. The administration of MIF20 at the onset of reperfusion was found to not only decrease myocardial infarct size but also preserves systolic function in the aged heart. Protection from I/R injury was reduced in mice with cardiomyocyte-specific Mif deletion, consistent with the mechanism of action of MIF20 to allosterically increase MIF affinity for its cognate receptor CD74. We further found MIF20 to contribute to the maintenance of mitochondrial fitness and to preserve the contractile properties of aged cardiomyocytes under hypoxia/reoxygenation. MIF20 augments protective metabolic responses by reducing the NADH/NAD ratio, leading to a decrease in the accumulation of reactive oxygen species (ROS) in the aged myocardium under I/R stress. We also identify alterations in the expression levels of the downstream effectors PDK4 and LCAD, which participate in the remodeling of the cardiac metabolic profile. Data from this study demonstrates that pharmacologic augmentation of MIF signaling provides beneficial homeostatic actions on senescent myocardium under I/R stress.

Contribution of Left Ventricular Diastolic Dysfunction to Survival and Breathlessness in Systemic Sclerosis-Associated Interstitial Lung Disease.

To explore the effect of left ventricular (LV) diastolic dysfunction (LVDD) in systemic sclerosis (SSc)-associated interstitial lung disease (ILD), and to investigate SSc-specific associations and clinical correlates of LVDD. There were 102 Australian Scleroderma Cohort Study participants with definite SSc and radiographic ILD included. Diastolic function was classified as normal, indeterminate, or abnormal according to 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of LV diastolic function. Associations between clinical features and patient- and physician-reported dyspnea were evaluated using logistic regression. Survival analyses were performed using Kaplan-Meier survival estimates and Cox regression modeling. LVDD was identified in 26% of participants, whereas 19% had indeterminate and 55% had normal diastolic function. Those with ILD and LVDD had increased mortality (hazard ratio 2.4, 95% CI 1.0-5.7; P = 0.05). After adjusting for age and sex, those with ILD and LVDD were more likely to have severe dyspnea on the Borg Dyspnoea Scale (odds ratio [OR] 2.6, 95% CI 1.0-6.6; P = 0.05) and numerically more likely to record World Health Organization Function Class II or higher dyspnea (OR 4.2, 95% CI 0.9-20.0; P = 0.08). Older age (95% CI 1.0-6.4; P = 0.05), hypertension (OR 5.0, 95% CI 1.8-13.8; P < 0.01), and ischemic heart disease (OR 4.8, 95% CI 1.5-15.7; P < 0.01) were all associated with LVDD, as was proximal muscle atrophy (OR 5.0, 95% CI 1.9-13.6; P < 0.01) and multimorbidity (Charlson Comorbidity Index scores ≥ 4, OR 3.0, 95% CI 1.1-8.7; P = 0.04). LVDD in SSc-ILD is more strongly associated with traditional LVDD risk factors than SSc-specific factors. LVDD is associated with worse dyspnea and survival in those with SSc-ILD.

Impact of nurse-led interprofessional work in older patients with heart failure and multimorbidity: A retrospective cohort study

BackgroundThe number of patients with multimorbidity has increased due to the aging of the global population. Although the World Health Organization has indicated that multimorbidity will be a major medical problem in the future, the appropriate interventions for patients with multimorbidity are currently unknown. This study aimed to investigate whether nurse-led interprofessional work is associated with improved prognosis in heart failure patients with multimorbidity aged ≥65 years who were admitted in an acute care hospital. MethodsPatients who were admitted to the cardiovascular medicine ward of an acute care hospital in Osaka, Japan, and underwent nurse-led interprofessional work from April 1, 2017 to March 31, 2020, and from April 1, 2014 to March 31, 2016, were included in this retrospective cohort study. The patients were matched by age, sex, and New York Heart Association classification. The nurse-led interprofessional work was based on a three-step model that incorporates recommendations from international guidelines for multimorbidity. The primary outcome was all-cause mortality. ResultsThe mean age of the participants was 80 years, and 62 % were men. The nurse-led interprofessional work group showed a significant difference in all-cause mortality compared with the usual care group (hazard ratio, 0.45; 95 % confidence interval [CI], 0.29–0.69; P < 0.001). Compared with the usual care group, the nurse-led interprofessional work group exhibited a 7 % difference in mortality rate at 1-year post-discharge (P < 0.001). ConclusionsNurse-led interprofessional work may reduce the all-cause mortality in older patients with heart failure and multimorbidity.

Identification of Reduced mTOR T1262 Phosphorylation as a Novel Mechanism and Therapeutic Target of Apoptosis in Senescent Cardiomyocytes: Aging and Cardiomyocyte Apoptosis.

The mechanisms through which aging increases heart injury remain partially understood. Protein phosphorylation plays a critical regulatory role in cell survival and death. Using an unbiased phosphoproteomics approach, we aimed to identify the proteins whose phosphorylation could be causatively related to aging-related cardiomyocyte apoptosis and elucidate the underlying mechanisms. Comparative phosphoproteomics was conducted on cardiac tissues obtained from young (8 weeks) and aged (24 months) mice. Our findings revealed that the Mammalian Target of Rapamycin phosphorylation at T1262 (mTORT1262) was reduced in the aging heart. Immunohistochemical and Western blot analyses confirmed these findings in aging myocardia and D-galactose-induced senescent AC16 cardiomyocytes. In hypoxia/reoxygenation cardiomyocytes, mTORT1262 phosphorylation deficiency (mTORT1262A, lentivirus-mediated transfection) inhibited AKT1, suppressed NF-κB, activated FOXO1/3a signaling, and ultimately exacerbated apoptosis. Conversely, mTORT1262 pseudophosphorylation (mTORT1262E) exhibited opposite effects. Through bioinformatics and CO-IP, purinergic receptor P2X4 (P2X4R) was found to be the possible receptor responsible for mTORT1262 phosphorylation. Knockdown of P2X4R increased apoptosis, whereas its overexpression decreased it. In senescent cardiomyocytes, P2X4R expression and mTORT1262 and AKT1S473 phosphorylation were reduced, NF-κB signaling was suppressed, and FOXO1/3a signaling was activated. We demonstrated that P2X4R downregulation and the subsequent reduction of mTORT1262 phosphorylation is a novel mechanism contributing to cardiomyocyte apoptosis in aging hearts. The P2X4R-mTOR-AKT1 signaling pathway represents a potential therapeutic target against accelerated cardiac injury in aging.

Analysis of the correlations between the extracranial internal carotid artery and extracranial vertebral artery and mild cognitive impairment.

Vascular tortuosity is a prevalent morphological change that frequently occurs in arteries across different parts of the body. To analyze the relationship between the tortuosities of the extracranial internal carotid artery (EICA) and extracranial vertebral artery (EVA) with mild cognitive impairment. The tortuosity index (TI), vascular deviation degree, tortuosity degree, and angle number of the EICA and EVA were retrospectively analyzed and calculated in 160 patients who underwent computed tomography angiography (CTA) in this study's department, and the Montreal cognitive assessment was adopted to evaluate the cognitive function of the patients. The differences in age, gender, arterial hypertension (AH), and diabetes mellitus (DM) between the normal group and the mild cognitive impairment group were statistically significant (p< 0.01). The TI was negatively correlated with the score of cognitive function. The tortuosities of the EICA and EVA were correlated with mild cognitive impairment (p< 0.05). The reduction in visual-spatial ability was correlated with the right EICA tortuosity, and the reduction in memory was correlated with the EVA tortuosity. Age, gender, HP, DM, and coronary heart disease (CHD) were potential risk factors for carotid tortuosity (p< 0.05). There was a significant correlation observed between the TIs of both the EICA and EVA and the presence of mild cognitive impairment. Advanced age, female, HP, DM, and CHD were independent risk factors for EICA and EVA tortuosities.

Kiosk 7R-TA-09 - Evaluation of T1 Mapping in the Aging Heart

Kiosk 7R-TA-09 - Evaluation of T1 Mapping in the Aging Heart

The Role of Biomarkers in Predicting Cognitive Impairment in Elderly Patients with Heart Failure.

This study explores the impact of sST2, Growth Differentiation Factor 15 (GDF-15), and clinical factors on cognitive dysfunction in elderly patients with heart failure with reduced ejection fraction (HFrEF). A cohort of 101 chronic stable HFrEF patients aged over 65 years old participated in the study. Cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) test and the Mini Mental State Examination (MMSE). Levels of sST2, GDF-15, and N-terminal pro b-type natriuretic peptide (NT-proBNP) were also measured. Notably higher levels of NT-proBNP and GDF-15 were observed in the group with cognitive dysfunction, whereas sST2 levels were similar between the groups. The cognitive dysfunction group consisted of older patients. A higher proportion of patients with normal cognitive function had received influenza vaccinations. Furthermore, GDF-15 levels inversely correlated with MMSE score. Right ventricular diameter was negatively correlated, while hemoglobin levels were positively correlated with both MoCA and MMSE scores. Logistic regression analysis identified increased GDF-15 levels, older age, and advanced New York Heart Association (NYHA) classes as predictors of higher cognitive dysfunction risk, whereas influenza vaccination was linked to a reduced risk of cognitive dysfunction. Cognitive dysfunction in elderly patients with heart failure may be influenced by factors such as age, right ventricular enlargement, anemia, NYHA functional class, and levels of GDF-15 and NT-proBNP.

Risk of Atrial Fibrillation and Adverse Outcomes in Patients With Cardiac Implantable Electronic Devices.

Comprehensive epidemiological data are lacking on the incident atrial fibrillation (AF) in patients with cardiac implantable electronic devices (CIEDs). This study aimed to examine the incidence, risk factors, and AF-related adverse outcomes of patients with CIEDs. This was an observational cohort study that analyzed patients without prevalent AF who underwent CIED implantation in 2009-2018 using a Korean nationwide claims database. The subjects were divided into three groups by CIED type and indication: pacemaker (n=21,438), implantable cardioverter defibrillator (ICD)/cardiac resynchronization therapy (CRT) with heart failure (HF) (n=3,450), and ICD for secondary prevention without HF (n=2,146). The incidence of AF, AF-associated predictors, and adverse outcomes were evaluated. During follow-up, the incidence of AF was 4.3, 7.3, and 5.1 per 100 person-years in the pacemaker, ICD/CRT with HF, and ICD without HF cohorts, respectively. Across the three cohorts, older age and valvular heart disease were commonly associated with incident AF. Incident AF was consistently associated with an increased risk of ischemic stroke (3.8-11.4-fold), admission for HF (2.6-10.5-fold), hospitalization for any cause (2.4-2.7-fold), all-cause death (4.1-5.0-fold), and composite outcomes (3.4-5.7-fold). Oral anticoagulation rates were suboptimal in patients with incident AF (pacemaker, 51.3%; ICD/CRT with HF, 51.7%; and ICD without HF, 33.8%, respectively). A substantial proportion of patients implanted CIED developed newly diagnosed AF. Incident AF was associated with a higher risk of adverse events. The importance of awareness, early detection, and appropriate management of AF in patients with CIED should be emphasized.

New electrocardiographic parameters and risk of atrial arrhythmias in INOCA patients

Aims: Ischemia with no obstructive arteries (INOCA) is a clinical condition in which symptoms and signs of coronary artery disease are present, but coronary angiography does not show severe vessel narrowing. Atrial fibrillation (AF) is a common arrhythmia in cardiology practice, with an increasing prevalence with age and concomitant heart disease. P-wave dispersion (PWD) is an electrocardiographic (ECG) parameter defined as the difference between the maximum and minimum P-wave duration. There is an increasing number of studies showing an association between PWD and cardiovascular events. In this study, we aimed to evaluate the risk of AF in INOCA patients by detecting PWD, a new ECG parameter. Methods: The study included 51 INOCA patients and 36 healthy subjects as a control group. The groups were compared in terms of demographic characteristics, laboratory findings, echocardiography, and ECG findings. The difference between the longest P wave (Pmax) and the shortest P wave (Pmin) was considered as PWD (PWD=Pmax-Pmin). Results: When the patient group was compared with the control group, no difference was detected in terms of demographic characteristics or laboratory findings. When compared with the control group, Pmax duration and Pd values were significantly longer in the patient group compared to the control group (Pmax durations 112.7±7.09 ms and 98.1±5.5 ms, respectively, p&lt;0.001; Pd durations 43.0±9.4 ms and 31.4±12.4 ms, respectively, p&lt;0.001). On the other hand, Pmin durations did not differ significantly between the groups (p&gt;0.05). Conclusion: We observed that PWD was higher in INOCA patients compared to controls, and our results suggest that INOCA patients are at risk for AF.

Loss of cardiac mitochondrial complex I persulfidation impairs NAD+ homeostasis in aging

Protein persulfidation is a significant post-translational modification that involves addition of a sulfur atom to the cysteine thiol group and is facilitated by sulfide species. Persulfidation targets reactive cysteine residues within proteins, influencing their structure and/or function across various biological systems. This modification is evolutionarily conserved and plays a crucial role in preventing irreversible cysteine overoxidation, a process that becomes prominent with aging. While, persulfidation decreases with age, its levels in the aged heart and the functional implications of such a reduction in cardiac metabolism remain unknown. Here we interrogated the cardiac persulfydome in wild-type adult mice and age-matched mice lacking the two sulfide generating enzymes, namely cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST). Our findings revealed that cardiac persulfidated proteins in wild type hearts are less abundant compared to those in other organs, with a primary involvement in mitochondrial metabolic processes. We further focused on one specific target, NDUFB7, which undergoes persulfidation by both CSE and 3MST derived sulfide species. In particular, persulfidation of cysteines C80 and C90 in NDUFB7 protects the protein from overoxidation and maintains the complex I activity in cardiomyocytes. As the heart ages, the levels of CSE and 3MST in cardiomyocytes decline, leading to reduced NDUFB7 persulfidation and increased cardiac NADH/NAD+ ratio. Collectively, our data provide compelling evidence for a direct link between cardiac persulfidation and mitochondrial complex I activity, which is compromised in aging.

Underlying factors that may affect the treatment of Platelet-rich plasma in chronic wounds

Platelet-rich plasma (PRP) has gained widespread usage in the treatment of various chronic wounds due to its ease of preparation and high safety profile. But not every treatment can achieve satisfactory results. The quality of PRP is based on individual biological characteristics. Autologous PRP technology is greatly affected by the patient himself. Individual responses to PRP treatment are different and will produce different therapeutic effects. Especially in patients with uncontrollable factors such as aging, diabetes, and coronary heart disease, the use of antiplatelet drugs may potentially reduce the quality of autologous platelet-rich plasma (PRP). When treating related diseases, it is important to consider the impact of factors such as age, gender, and the specific disease. Currently, many researchers are focusing on the development of allogeneic PRP technology to avoid the inconvenience of collecting autologous blood and reduce potential negative effects that may exist in the patient's disease itself. In this review, we explore the factors generally recognized in current research which influence the efficacy of PRP.

Remodeling of the Cardiac Extracellular Matrix Proteome During Chronological and Pathological Aging

Impaired extracellular matrix (ECM) remodeling is a hallmark of many chronic inflammatory disorders that can lead to cellular dysfunction, aging, and disease progression. The ECM of the aged heart and its effects on cardiac cells during chronological and pathological aging are poorly understood across species. For this purpose, we first used mass spectrometry-based proteomics to quantitatively characterize age-related remodeling of the left ventricle (LV) of mice and humans during chronological and pathological (Hutchinson-Gilford progeria syndrome (HGPS)) aging. Of the approximately 300 ECM and ECM-associated proteins quantified (named as Matrisome), we identified 13 proteins that were increased during aging, including lactadherin (MFGE8), collagen VI α6 (COL6A6), vitronectin (VTN) and immunoglobulin heavy constant mu (IGHM), whereas fibulin-5 (FBLN5) was decreased in most of the data sets analyzed. We show that lactadherin accumulates with age in large cardiac blood vessels and when immobilized, triggers phosphorylation of several phosphosites of GSK3B, MAPK isoforms 1, 3, and 14, and MTOR kinases in aortic endothelial cells (ECs). In addition, immobilized lactadherin increased the expression of pro-inflammatory markers associated with an aging phenotype. These results extend our knowledge of the LV proteome remodeling induced by chronological and pathological aging in different species (mouse and human). The lactadherin-triggered changes in the proteome and phosphoproteome of ECs suggest a straight link between ECM component remodeling and the aging process of ECs, which may provide an additional layer to prevent cardiac aging.

Importance of Exercise in Mitigating Age-Related Cardiac Apoptosis

Aging causes a progressive decline in heart function. Loss of cardiomyocytes through programmed cell death or apoptosis is a critical factor contributing to this age-related damage. As we age, the heart undergoes structural changes, such as loss of cardiomyocytes, cardiomyocyte hypertrophy, and increased connective tissue with changes in heart geometry. It is widely known that mitochondria are vital sites of apoptosis. Mitochondrial-mediated apoptotic pathways are important regulators of apoptosis with aging. Mitochondrial dysfunction and oxidative stress also contribute to the cardiac remodeling and apoptosis associated with the aging process. On the other hand, exercise can improve heart function and reduce the risk of heart disease. Recent studies suggest that aging increases apoptotic signaling in the left ventricle. However, chronic exercise reduces this mitochondrial-mediated apoptotic signaling pathway in the aging heart. This review will describe the impacts of aging and exercise on cardiac apoptosis, highlighting the importance of exercise in reducing age-related cardiac apoptosis.

Age-Induced Accumulation of Succinate Promotes Cardiac Fibrogenesis.

Age-related cardiac fibrosis is a risk factor for heart failure and a marker for heart aging. However, the mechanisms underlying age-related cardiac fibrosis remain unclear. Ischemia and hypoxia are inevitable events in the aging process, which are direct causes of mitochondrial dysfunction and metabolic alterations. In this study, we identified metabolic changes and determined the mechanisms by which succinate (a tricarboxylic acid cycle intermediate) accumulation promotes fibroblast activation and apoptosis resistance in the aging heart. We also assessed its significance in relation to cardiac fibrosis and diastolic dysfunction. We first investigated how aging promotes persistent cardiac fibrosis. Following this, the metabolic alterations of the aging heart were identified by untargeted metabolomics, and the succinate level was verified via quantitative analysis. Furthermore, the correlations between succinate and fibrosis or diastolic dysfunction in older mice/people were assessed. We also described the role of succinate and its receptor SUCNR1/GPR91 in establishing a fibrosis network during diastolic dysfunction with age using SUCNR1-/- mouse model and an AAV9-based approach. We further identified the specific mechanisms involved in PKM2 dimerization, which regulate fibroblast activation and apoptosis resistance. We demonstrated that aging promotes fibrogenesis and diastolic dysfunction, which are linked to fibroblast activation and apoptosis resistance in the heart. Succinate levels were correlated with diastolic dysfunction and cardiac fibrosis in older mice and people. Functionally, succinate promoted fibroblast activation and apoptosis resistance, which aggravate cardiac fibrosis formation in both young and old mice. This was attributed to the ability of succinate to stimulate PKM2 dimerization via succinate receptor SUCNR1. Furthermore, dimeric PKM2 translocated to the nucleus and mitochondria, where it promoted fibroblast activation and apoptosis resistance, respectively. Accumulated PKM2 in the nucleus interacted with HIF-1α, increasing the DNA binding of HIF-1α and the expression of fibrogenic genes, resulting in fibroblast activation. In the mitochondria, accumulated PKM2 phosphorylated VDAC1 at T93 and increased VDAC1 degradation by promoting SYVN1-based E3 ligase binding to VDAC1, which is associated with increased apoptosis resistance and fibrosis persistence. We found that targeting succinate accumulation by metformin can inhibit fibroblast activation and apoptosis resistance in mice, which is a potential strategy to control age-related cardiac fibrosis and diastolic dysfunction. Our findings indicate that targeting metabolic dysregulation has significant implications for the treatment of age-related cardiac fibrosis and diastolic dysfunction. We further demonstrate a novel mechanism by which succinate induces fibroblast activation and apoptosis resistance by promoting PKM2 dimerization. Hence, inhibiting succinate generation or blocking its downstream effects is potentially a promising new strategy for slowing the heart aging.

Aging-induced mitochondrial dysfunction: two distinct populations of mitochondria versus a combined population.

Mitochondrial function in aged hearts is impaired, and studies of isolated mitochondria are commonly used to assess their function. The two populations of cardiac mitochondria, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), are affected by aging. However, the yield of these mitochondria, particularly SSM, is limited in the mouse heart because of the smaller heart size. To address this issue, the authors developed a method to isolate a mixed population (MIX) of SSM and IFM mitochondria from a single mouse heart. The aim of the study was to compare the mitochondrial function between SSM, IFM, and the MIX population from young and aged mouse hearts. The MIX population had a higher yield of total protein and citrate synthase activity from both young and aged hearts compared with the individual yields of SSM or IFM. Oxidative phosphorylation (OXPHOS) decreased in aged SSM and IFM compared with young SSM and IFM, as well as in the MIX population isolated from aged hearts compared with young hearts, when using complex I or IV substrates. Furthermore, aging barely affected the sensitivity to mitochondrial permeability transition pore (MPTP) opening in SSM, whereas the sensitivity was increased in IFM isolated from aged hearts and in the MIX population from aged hearts compared with the corresponding populations isolated from young hearts. These results suggest that mitochondrial dysfunction exists in aged hearts and the isolation of a MIX population of mitochondria from the mouse heart is a potential approach to studying mitochondrial function in the mouse heart.NEW & NOTEWORTHY We developed two methods to isolate mitochondria from a single mouse heart. We compared mitochondrial function in young and aged mice using mitochondria isolated with different methods. Both methods can be successfully used to isolate cardiac mitochondria from single mouse hearts. Our results provide the flexibility to isolate mitochondria from a single mouse heart based on the purpose of the study.

Age-related structural and functional changes of the intracardiac nervous system

BackgroundAlthough aging is known to be associated with an increased incidence of both atrial and ventricular arrhythmias, there is limited knowledge about how Schwann cells (SC) and the intracardiac nervous system (iCNS) remodel with age. Here we investigate the differences in cardiac SC, parasympathetic nerve fibers, and muscarinic acetylcholine receptor M2 (M2R) expression in young and old mice. Additionally, we examine age-related changes in cardiac responses to sympathomimetic and parasympathomimetic drugs. Methods and resultsLower SC density, lower SC proliferation and fewer parasympathetic nerve fibers were observed in cardiac and, as a control sciatic nerves from old (20–24 months) compared to young mice (2–3 months). In old mice, chondroitin sulfate proteoglycan 4 (CSPG4) was increased in sciatic but not cardiac nerves. Expression of M2R was lower in ventricular myocardium and ventricular conduction system from old mice compared to young mice, while no significant difference was seen in M2R expression in sino-atrial or atrio-ventricular node pacemaker tissue. Heart rate was slower and PQ intervals were longer in Langendorff-perfused hearts from old mice. Ventricular tachycardia and fibrillation were more frequently observed in response to carbachol administration in hearts from old mice versus those from young mice. ConclusionsOn the background of reduced presence of SC and parasympathetic nerve fibers, and of lower M2R expression in ventricular cardiomyocytes and conduction system of aged hearts, the propensity of ventricular arrhythmogenesis upon parasympathomimetic drug application is increased. Whether this is caused by an increase in heterogeneity of iCNS structure and function remains to be elucidated.

MiR-203 improves cardiac dysfunction by targeting PARP1-NAD+ axis in aging murine.

Heart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA-203 (miR-203) as a senescence-associated microRNA that regulates NAD+ homeostasis. We found that the blood miR-203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR-203 (TgN (miR-203)) showed resistance to aging-induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR-203 significantly prevented D-gal-induced cardiomyocyte senescence and mitochondrial damage, while miR-203 knockdown aggravated these effects. Mechanistically, miR-203 inhibited PARP1 expression by targeting its 3'UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR-203 as a genetic tool for anti-heart aging by restoring NAD+ function in cardiomyocytes.