Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways.

Aging leads to a progressive decline in cardiac function, increasing the risk of heart failure with preserved ejection fraction (HFpEF). This study elucidates the impact of α-Klotho, an anti-aging hormone, on cardiac diastolic dysfunction and explore its downstream mechanisms. Aged wild-type and heterozygous Klotho-deficient mice received daily injection of soluble α-Klotho (sKL) for 10 weeks, followed by a comprehensive assessment of heart function by echocardiography, intracardiac pressure catheter, exercise tolerance, and cardiac pathology. Our findings show that klotho deficiency accentuated cardiac hypertrophy, diastolic dysfunction, and exercise intolerance, while sKL treatment ameliorates these abnormalities and improves cardiac capillary densities. Downstream of klotho, we focused on the Sirtuin1 (Sirt1) signaling pathway to elucidate the potential underlying mechanism by which Klotho improves diastolic function. We found that decreased Klotho levels were linked with Sirt1 deficiency, whereas sKL treatment restored Sirt1 expression in aged hearts and mitigated the DNA damage response pathway activation. Through tandem mass tag proteomics and unbiased acetylomics analysis, we identified 220 significantly hyperacetylated lysine sites in critical cardiac proteins of aged hearts. We found that sKL supplementation attenuated age-dependent DNA damage and cardiac diastolic dysfunction. In contrast, Klotho deficiency significantly increased hyperacetylation of several crucial cardiac contractile proteins, potentially impairing ventricular relaxation and diastolic function, thus predisposing to HFpEF. These results suggest the potential benefit of sKL supplementation as a promising therapeutic strategy for combating HFpEF in aging.

Dysfunctional mitochondria elicit bioenergetic decline in the aged heart.

Aging represents a complex biological progression affecting the entire body, marked by a gradual decline in tissue function, rendering organs more susceptible to stress and diseases. The human heart holds significant importance in this context, as its aging process poses life-threatening risks. It entails macroscopic morphological shifts and biochemical changes that collectively contribute to diminished cardiac function. Among the numerous pivotal factors in aging, mitochondria play a critical role, intersecting with various molecular pathways and housing several aging-related agents. In this comprehensive review, we provide an updated overview of the functional role of mitochondria in cardiac aging.

Exploratory bibliometric analysis and text mining to reveal research trends in cardiac aging.

Objectives: We conducted a text mining analysis of 40 years of literature on cardiac aging from PubMed to investigate the current understanding on cardiac aging and its mechanisms. This study aimed to embody what most researchers consider cardiac aging to be. Methods: We used multiple text mining and machine learning tools to extract important information from a large amount of text. Results: Analysis revealed that the terms most frequently associated with cardiac aging include "diastolic," "hypertrophy," "fibrosis," "apoptosis," "mitochondrial," "oxidative," and "autophagy." These terms suggest that cardiac aging is characterized by mitochondrial dysfunction, oxidative stress, and impairment of autophagy, especially mitophagy. We also revealed an increase in the frequency of occurrence of "autophagy" in recent years, suggesting that research on autophagy has made a breakthrough in the field of cardiac aging. Additionally, the frequency of occurrence of "mitophagy" has increased significantly since 2019, suggesting that mitophagy is an important factor in cardiac aging. Conclusions: Cardiac aging is a complex process that involves mitochondrial dysfunction, oxidative stress, and impairment of autophagy, especially mitophagy. Further research is warranted to elucidate the mechanisms of cardiac aging and develop strategies to mitigate its detrimental effects.

Enhanced Cardiomyocyte NLRP3 Inflammasome-Mediated Pyroptosis Promotes d-Galactose-Induced Cardiac Aging.

BACKGROUND: Cardiac aging represents an independent risk factor for aging-associated cardiovascular diseases. Although evidence suggests an association between NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome formation and numerous cardiovascular diseases, its role in cardiac aging remains largely unclear. METHODS AND RESULTS: The longevity of mice with wild-type and NLRP3 knockout (NLRP3-/-) genotypes was assessed, with or without d-galactose treatment. Cardiac function was evaluated using echocardiography, and cardiac histopathology was examined through hematoxylin and eosin and Masson's trichrome staining. Senescence-associated ß-galactosidase (SA-ß-gal) staining was employed to detect cardiac aging. Western blotting was used to assess aging-related proteins (p53, p21) and pyroptosis-related proteins. Additionally, dihydroethidium staining, lactate dehydrogenase release, and interleukin-1ß ELISA assays were performed, along with measurements of total superoxide dismutase and malondialdehyde levels. In vitro, H9c2 cells were exposed to d-galactose for 24 hours in the absence or presence of N-acetyl-l-cysteine (reactive oxygen species inhibitor), BAY-117082 (nuclear factor κ-light-chain enhancer of activated B cells inhibitor), MCC950 (NLRP3 inhibitor), and VX-765 (Caspase-1 inhibitor). Immunofluorescence staining was employed to detect p53, gasdermin D, and apoptosis-associated speck-like protein proteins. Intracellular reactive oxygen species levels were assessed using fluorescence microscopy and flow cytometry. Senescence-associated ß-galactosidase staining and Western blotting were also employed in vitro for the same purpose. The results showed that NLRP3 upregulation was implicated in aging and cardiovascular diseases. Inhibition of NLRP3 extended life span, mitigated the aging phenotype, improved cardiac function and blood pressure, ameliorated lipid metabolism abnormalities, inhibited pyroptosis in cardiomyocytes, and ultimately alleviated cardiac aging. In vitro, the inhibition of reactive oxygen species, nuclear factor κ-light-chain enhancer of activated B cells, NLRP3, or caspase-1 attenuated NLRP3 inflammasome-mediated pyroptosis. CONCLUSIONS: The reactive oxygen species/nuclear factor κ-light-chain enhancer of activated B cells/NLRP3 signaling pathway loop contributes to d-galactose-treated cardiomyocyte senescence and cardiac aging.

Cardiac aging: from hallmarks to therapeutic opportunities.

Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of aging on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac aging and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological aging. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of aging populations worldwide.

Dental pulp stem cells ameliorate D-galactose-induced cardiac ageing in rats.

Background: Ageing is a key risk factor for cardiovascular disease and is linked to several alterations in cardiac structure and function, including left ventricular hypertrophy and increased cardiomyocyte volume, as well as a decline in the number of cardiomyocytes and ventricular dysfunction, emphasizing the pathological impacts of cardiomyocyte ageing. Dental pulp stem cells (DPSCs) are promising as a cellular therapeutic source due to their minimally invasive surgical approach and remarkable proliferative ability. Aim: This study is the first to investigate the outcomes of the systemic transplantation of DPSCs in a D-galactose (D-gal)-induced rat model of cardiac ageing. Methods. Thirty 9-week-old Sprague-Dawley male rats were randomly assigned into three groups: control, ageing (D-gal), and transplanted groups (D-gal + DPSCs). D-gal (300 mg/kg/day) was administered intraperitoneally daily for 8 weeks. The rats in the transplantation group were intravenously injected with DPSCs at a dose of 1 × 106 once every 2 weeks. Results: The transplanted cells migrated to the heart, differentiated into cardiomyocytes, improved cardiac function, upregulated Sirt1 expression, exerted antioxidative effects, modulated connexin-43 expression, attenuated cardiac histopathological alterations, and had anti-senescent and anti-apoptotic effects. Conclusion: Our results reveal the beneficial effects of DPSC transplantation in a cardiac ageing rat model, suggesting their potential as a viable cell therapy for ageing hearts.

New Insights into IGF-1 Signaling in the Heart.

Insulin-like growth factor-1 (IGF-1) signaling has multiple physiological roles in cellular growth, metabolism, and aging. Myocardial hypertrophy, cell death, senescence, fibrosis, and electrical remodeling are hallmarks of various heart diseases and contribute to the progression of heart failure. This review highlights the critical role of IGF-1 and its cognate receptor in cardiac hypertrophy, aging, and remodeling.

Combined Endurance and Resistance Exercise Mitigates Age-Associated Cardiac Dysfunction.

Aging is associated with a decline in cardiac function. Exercise has been shown to effectively reduce the risks of cardiovascular diseases. Here whether a combination of endurance and resistance exercises can improve cardiac function in aged mice during late life is investigated. Through transcriptome analysis, several signaling pathways activated in the hearts of 22-month-old mice after combined exercise, including cardiac muscle contraction, mitophagy, and longevity regulation are identified. Combined exercise training mitigated age-associated pathological cardiac hypertrophy, reduced oxidative stress, cardiac senescence, and enhanced cardiac function. Upstream stimulatory factor 2 (Usf2) is upregulated in the aged mouse hearts with combined exercise compared to sedentary mice. In the human cardiomyocytes senescent model, overexpression of Usf2 led to anti-senescence effects, while knockdown of Usf2 exacerbated cellular senescence. The results suggest that a combination of endurance and resistance exercises, such as swimming and resistance running, can mitigate age-related pathological cardiac remodeling and cardiac dysfunction in late life. These cardioprotective effects are likely due to the activation of Usf2 and its anti-senescence effect. Therefore, Usf2 can potentially be a novel therapeutic target for mitigating age-related cardiac dysfunction.

Characterizing Age-related Changes in Intact Mitochondrial Proteoforms in Murine Hearts using Quantitative Top-Down Proteomics.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational protein modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying all protein sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging. METHODS: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified. RESULTS: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N-terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. CONCLUSION: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart.

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.

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.

Parishin treatment alleviates cardiac aging in naturally aged mice.

Background: Cardiac aging progressively decreases physiological function and drives chronic/degenerative aging-related heart diseases. Therefore, it is crucial to postpone the aging process of heart and create products that combat aging. Aims & methods: The objective of this study is to examine the effects of parishin, a phenolic glucoside isolated from traditional Chinese medicine Gastrodia elata, on anti-aging and its underlying mechanism. To assess the senescent biomarkers, cardiac function, cardiac weight/body weight ratio, cardiac transcriptomic changes, and cardiac histopathological features, heart tissue samples were obtained from young mice (12 weeks), aged mice (19 months) treated with parishin, and aged mice that were not treated. Results: Parishin treatment improved cardiac function, ameliorated aging-induced cardiac injury, hypertrophy, and fibrosis, decreased cardiac senescence biomarkers p16Ink4a, p21Cip1, and IL-6, and increased the "longevity factor" SIRT1 expression in heart tissue. Furthermore, the transcriptomic analysis demonstrated that parishin treatment alleviated the cardiac aging-related Gja1 downregulation and Cyp2e1, Ccna2, Cdca3, and Fgf12 upregulation in the heart tissues. The correlation analysis suggested a strong connection between the anti-aging effect of parishin and its regulation of gut microbiota and metabolism in the aged intestine. Conclusion: The present study demonstrates the protective role and underlying mechanism of parishin against cardiac aging in naturally aged mice.

Circulating Total Extracellular Vesicles Cargo Are Associated with Age-Related Oxidative Stress and Susceptibility to Cardiovascular Diseases: Exploratory Results from Microarray Data.

Aging is a risk factor for many non-communicable diseases such as cardiovascular and neurodegenerative diseases. Extracellular vesicles and particles (EVP) carry microRNAs that may play a role in age-related diseases and may induce oxidative stress. We hypothesized that aging could impact EVP miRNA and impair redox homeostasis, contributing to chronic age-related diseases. Our aims were to investigate the microRNA profiles of circulating total EVPs from aged and young adult animals and to evaluate the pro- and antioxidant machinery in circulating total EVPs. Plasma from 3- and 21-month-old male Wistar rats were collected, and total EVPs were isolated. MicroRNA isolation and microarray expression analysis were performed on EVPs to determine the predicted regulation of targeted mRNAs. Thirty-one mature microRNAs in circulating EVPs were impacted by age and were predicted to target molecules in canonical pathways directly related to cardiovascular diseases and oxidative status. Circulating total EVPs from aged rats had significantly higher NADPH oxidase levels and myeloperoxidase activity, whereas catalase activity was significantly reduced in EVPs from aged animals. Our data shows that circulating total EVP cargo-specifically microRNAs and oxidative enzymes-are involved in redox imbalance in the aging process and can potentially drive cardiovascular aging and, consequently, cardiac disease.

Extracellular Vesicles and Cardiac Aging.

Global population aging is a major challenge to health and socioeconomic policies. The prevalence of diseases progressively increases with aging, with cardiovascular disease being the major cause of mortality among elderly people. The allostatic overload imposed by the accumulation of cardiac senescent cells has been suggested to play a pivotal role in the aging-related deterioration of cardiovascular function. Senescent cells exhibit intrinsic disorders and release a senescence-associated secretory phenotype (SASP). Most of these SASP compounds and damaged molecules are released from senescent cells by extracellular vesicles (EVs). Once secreted, these EVs can be readily incorporated by recipient neighboring cells and elicit cellular damage or otherwise can promote extracellular matrix remodeling. This has been associated with the development of cardiac dysfunction, fibrosis, and vascular calcification, among others. The molecular signature of these EVs is highly variable and might provide important information for the development of aging-related biomarkers. Conversely, EVs released by the stem and progenitor cells can exert a rejuvenating effect, raising the possibility of future anti-aging therapies.

Mitral Valve Repair in Advanced Age Groups: Does Cardiac Age Differ from Chronological Age?

OBJECTIVE: Advanced age is a risk factor in cardiac surgery contributing significantly to a worse outcome. The reasons are frailty and multimorbidity. In this study, we asked: Is there an aging of the heart which differs from chronological age? METHODS: Propensity score matching was performed between 115 seniors ≥ 80 years and 345 juniors < 80 years. After the patients were found to be comparable in terms of cardiac and noncardiac disease and risk profiles, they were further analyzed for cardiac parameters. In addition, the seniors and juniors were compared in terms of cardiac health and postoperative outcome. Furthermore, the patients were subdivided into several age groups (<60 years, 60-69 years, 70-79 years, and >80 years) and compared regarding outcome. RESULTS: The seniors demonstrated significantly lower tricuspid annular plane systolic excursion (TAPSE), significantly more frequent diastolic dysfunction, significantly higher plasma levels of NT-proBNP, and significantly larger left ventricular end-diastolic and end-systolic diameters and left atrial diameters (p < 0.001, respectively). Furthermore, in-hospital mortality and most postoperative complications were significantly higher in seniors compared with juniors. While old cardiac healthy patients showed better outcome than old cardiac aged patients, the outcome from young cardiac aged patients was better than old cardiac aged patients. The outcome and survival deteriorated with increasing life decades. CONCLUSIONS: The elderly suffer significantly more from cardiac deterioration, i.e., cardiac aging, and show higher multimorbidity. Mortality risk is significantly higher and they suffer more often from a complicated postoperative course compared to younger patients. Further approaches to prevention and treatment of cardiac aging are needed to address the needs of an aging society.

The mTOR signaling pathway in cardiac aging.

The mammalian target of rapamycin (mTOR) is one of the most important signaling pathways that regulate nutrient sensing, cell growth, metabolism, and aging. The mTOR pathway, particularly mTOR complex 1 (mTORC1), has been shown to control aging, lifespan, and healthspan through the regulation of protein synthesis, autophagy, mitochondrial function, and metabolic health. The mTOR pathway also plays critical roles in the heart, from cardiac development, growth and maturation, and maintenance of cardiac homeostasis. Hyperactivation of mTORC1 signaling is well documented in aging and many age-related pathologies, including age-related cardiac dysfunction and heart failure. Suppression of mTORC1 by calorie restriction or rapamycin not only extends lifespan but also restores youthful phenotypes in the heart. In this article, we review model organisms of cardiac aging and highlight recent advances in the impact of the mTORC1 pathway on organismal and cardiac aging, particularly in Drosophila and mice. We focus on the downstream signaling pathways S6 kinase and 4EBP1, which regulates protein synthesis, as well as ULK1 and its related pathway that regulates autophagy. The interaction with mTOR complex 2 (mTORC2) and its potential role in cardiac aging are also discussed.

WGCNA and molecular docking identify hub genes for cardiac aging.

Background: Cardiac aging and ageing-related cardiovascular diseases remain increase medical and social burden. Discovering the molecular mechanisms associated with cardiac aging is expected to provide new perspectives for delaying aging and related disease treatment. Methods: The samples in GEO database were divided into older group and younger group based on age. Age-associated differentially expressed genes (DEGs) were identified by limma package. Gene modules significantly associated with age were mined using weighted gene co-expression network analysis (WGCNA). Protein-protein interaction networks (PPI) networks were developed using genes within modules, and topological analysis on the networks was performed to identify hub genes in cardiac aging. Pearson correlation was used to analyze the association among hub genes and immune and immune-related pathways. Molecular docking of hub genes and the anti-aging drug Sirolimus was performed to explore the potential role of hub genes in treating cardiac aging. Results: We found a generally negative correlation between age and immunity, with a significant negative correlation between age and b_cell_receptor_signaling_pathway, fc_gamma_r_mediated_phagocytosis, chemokine signaling pathway, t-cell receptor signaling pathway, toll_like_receptor_signaling_pathway, and jak_stat_signaling_pathway, respectively. Finally, 10 cardiac aging-related hub genes including LCP2, PTPRC, RAC2, CD48, CD68, CCR2, CCL2, IL10, CCL5 and IGF1 were identified. 10-hub genes were closely associated with age and immune-related pathways. There was a strong binding interaction between Sirolimus-CCR2. CCR2 may be a key target for Sirolimus in the treatment of cardiac aging. Conclusion: The 10 hub genes may be potential therapeutic targets for cardiac aging, and our study provided new ideas for the treatment of cardiac aging.

An interferon gamma response signature links myocardial aging and immunosenescence.

AIMS: Aging entails profound immunological transformations that can impact myocardial homeostasis and predispose to heart failure. However, preclinical research in the immune-cardiology field is mostly conducted in young healthy animals, which potentially weakens its translational relevance. Herein, we sought to investigate how the aging T-cell compartment associates with changes in myocardial cell biology in aged mice. METHODS AND RESULTS: We phenotyped the antigen-experienced effector/memory T cells purified from heart-draining lymph nodes of 2-, 6-, 12-, and 18-month-old C57BL/6J mice using single-cell RNA/T cell receptor sequencing. Simultaneously, we profiled all non-cardiomyocyte cell subsets purified from 2- to 18-month-old hearts and integrated our data with publicly available cardiomyocyte single-cell sequencing datasets. Some of these findings were confirmed at the protein level by flow cytometry. With aging, the heart-draining lymph node and myocardial T cells underwent clonal expansion and exhibited an up-regulated pro-inflammatory transcription signature, marked by an increased interferon-γ (IFN-γ) production. In parallel, all major myocardial cell populations showed increased IFN-γ responsive signature with aging. In the aged cardiomyocytes, a stronger IFN-γ response signature was paralleled by the dampening of expression levels of transcripts related to most metabolic pathways, especially oxidative phosphorylation. Likewise, induced pluripotent stem cells-derived cardiomyocytes exposed to chronic, low grade IFN-γ treatment showed a similar inhibition of metabolic activity. CONCLUSIONS: By investigating the paired age-related alterations in the T cells found in the heart and its draining lymph nodes, we provide evidence for increased myocardial IFN-γ signaling with age, which is associated with inflammatory and metabolic shifts typically seen in heart failure.

Age-related increases in cardiac excitability, refractoriness and impulse conduction favor arrhythmogenesis in male rats.

The effects of excitability, refractoriness, and impulse conduction have been independently related to enhanced arrhythmias in the aged myocardium in experimental and clinical studies. However, their combined arrhythmic effects in the elderly are not yet completely understood. Hence, the aim of the present work is to relate relevant cardiac electrophysiological parameters to enhanced arrhythmia vulnerability in the in vivo senescent heart. We used multiple-lead epicardial potential mapping in control (9-month-old) and aged (24-month-old) rat hearts. Cardiac excitability and refractoriness were evaluated at numerous epicardial test sites by means of the strength-duration curve and effective refractory period, respectively. During sinus rhythm, durations of electrogram intervals and waves were prolonged in the senescent heart, compared with control, demonstrating a latency in tissue activation and recovery. During ventricular pacing, cardiac excitability, effective refractory period, and dispersion of refractoriness increased in the aged animal. This scenario was accompanied by impairment of impulse propagation. Moreover, both spontaneous and induced arrhythmias were increased in senescent cardiac tissue. Histopathological evaluation of aged heart specimens revealed connective tissue deposition and perinuclear myocytolysis in the atria, while scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium. This work suggests that enhanced arrhythmogenesis in the elderly is a multifactorial process due to the joint increase in excitability and dispersion of refractoriness in association with enhanced conduction inhomogeneity. The knowledge of these electrophysiological changes will possibly contribute to improved prevention of the age-associated increase in cardiac arrhythmias.

Mitochondrial proton leak in cardiac aging.

Age-associated diseases are becoming progressively more prevalent, reflecting the increased lifespan of the world's population. However, the fundamental mechanisms of physiologic aging are poorly understood, and in particular, the molecular pathways that mediate cardiac aging and its associated dysfunction are unclear. Here, we focus on certain ion flux abnormalities of the mitochondria that may contribute to cardiac aging and age-related heart failure. Using oxidative phosphorylation, mitochondria pump protons from the matrix to the intermembrane space to generate a proton gradient across the inner membrane. The protons are returned to the matrix by the ATPase complex within the membrane to generate ATP. However, a portion of protons leak back to the matrix and do not drive ATP production, and this event is called proton leak or uncoupling. Accumulating evidence suggests that mitochondrial proton leak is increased in the cardiac myocytes of aged hearts. In this mini-review, we discuss the measurement methods and major sites of mitochondrial proton leak with an emphasis on the adenine nucleotide transporter 1 (ANT1), and explore the possibility of inhibiting augmented mitochondrial proton leak as a therapeutic intervention to mitigate cardiac aging.