The journal of cardiovascular aging最新文献

Myocardial infarction (MI), commonly known as a heart attack, results from the rupture of atherosclerotic plaques in coronary arteries, which triggers a series of pathological events including cardiomyocyte death, thrombus formation, and systemic inflammation. These pathological events lead to significant structural and functional changes in the heart, potentially precipitating heart failure. The ramifications of MI extend beyond cardiac dysfunction and impact cerebral health. Accordingly, this review examines the cerebral implications of MI, focusing on how systemic inflammation and reduced cardiac output post-MI affect cerebral blood flow (CBF) and brain function. MI-induced changes in cardiac output can lead to cerebral hypoperfusion, while neuroinflammation and increased blood-brain barrier (BBB) permeability contribute to cognitive decline and neuronal damage, with potential links to Alzheimer's disease (AD). Furthermore, the review explores the role of estrogen in modulating cardiovascular and cerebral health, particularly in post-menopausal women who exhibit distinct cardiovascular risk profiles. Estrogen protects the heart by regulating local renin-angiotensin-aldosterone systems (RAAS) and has significant impacts on brain function. Declining estrogen levels during menopause exacerbate neuroinflammation and cognitive deficits, highlighting the importance of estrogen in maintaining cerebrovascular function. Experimental studies on estrogen replacement therapies, including 17β-estradiol and selective estrogen receptor modulators (SERMs), show potential in mitigating these detrimental effects, enhancing neurogenesis, and improving cognitive outcomes. Estrogen therapy is crucial in preventing cognitive decline and reducing amyloid plaque formation in Alzheimer's models. This review underscores the potential benefits of estrogen therapy in promoting brain recovery post-MI and improving functional outcomes.

Aging is a primary driver of atrial remodeling and dysfunction, and contributes to the increasing prevalence of atrial myopathy in the aging population. Atrial myopathy, characterized by structural, functional, and electrophysiological abnormalities of the atria, is a key pathological process underlying adverse cardiovascular outcomes such as atrial fibrillation (AF), heart failure with preserved ejection fraction (HFpEF), and ischemic stroke. Although these outcomes are often treated as distinct clinical entities, emerging evidence suggests that they may represent symptomatic manifestations of an underlying atrial disease process. Aging promotes atrial myopathy through multiple mechanisms, including inflammation, extracellular matrix remodeling, electrophysiological alterations, cellular senescence, epigenetic modifications, and non-coding RNA regulation. These changes collectively lead to atrial fibrosis, impaired mechanical function, conduction abnormalities, and a prothrombotic state. Despite its clinical significance, atrial myopathy remains an underrecognized entity, with current management strategies primarily focusing on treating its downstream complications rather than the underlying disease. Advances in imaging techniques, biomarker discovery, and molecular research have the potential to improve the early detection and risk stratification of atrial myopathy, paving the way for novel therapeutic strategies. In this review, we discuss the structural, mechanical, electrophysiological, and metabolic changes that occur in the aging atrium, explore the cellular and molecular mechanisms that drive these changes, and highlight recent advances in diagnostic and therapeutic approaches. By shifting the focus from managing AF and HFpEF to targeting the underlying atrial myopathy, we can unlock new avenues for prevention and treatment, ultimately improving cardiovascular health in the aging population.

Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with advancing age being the primary, nonmodifiable risk factor. Vascular dysfunction, namely arterial stiffening and endothelial dysfunction, is the key antecedent to the development of clinical CVD with aging. Fundamental aging macro-mechanistic processes that drive vascular aging include excess oxidative stress, chronic inflammation, and declines in the vasodilatory molecule nitric oxide. An important hallmark of aging that contributes to the vascular aging processes is cellular senescence - a stress response characterized by cell cycle arrest and accompanied by the production and secretion of proinflammatory molecules (i.e., the senescence-associated secretory phenotype [SASP]). Excess senescent cells and the SASP have deleterious effects on vascular function and in states of CVD, making it a putative therapeutic target for improving vascular function and preventing or reversing CVD. This review will focus on the role of cellular senescence in age-related vascular dysfunction and CVD. We will examine established and emerging mechanisms underlying cellular senescence-induced vascular dysfunction. We will then discuss groups with impaired vascular function and high cellular senescence burden and examine strategies to reduce or remove excess senescent cells and the SASP in the groups who are likely to benefit most from these therapies. Finally, we will highlight the systemic effects of vascular senescent cell suppression on other tissues and organs, given the integrative role of the vasculature in physiology. Together, this review will underscore the imperative role of cellular senescence in vascular dysfunction and the need for a deeper understanding of the translational use of cellular senescence and SASP targeting therapies in groups with high senescent cell burden.

Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known.

Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging.

Methods and results: We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7, were significantly induced, with a substantial induction of Clpp and Clpx. However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1), but significant induction of Dnaja2, a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2, suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels.

Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.

Age is a major risk factor for heart failure, but one that has been historically viewed as non-modifiable. Emerging evidence suggests that the biology of aging is malleable, and can potentially be intervened upon to treat age-associated chronic diseases, such as heart failure. While aging biology represents a new frontier for therapeutic target discovery in heart failure, the challenges of translating Geroscience research to the clinic are multifold. In this review, we propose a strategy that prioritizes initial target discovery in human biology. We review the rationale for starting with human omics, which has generated important insights into the shared (patho)biology of human aging and heart failure. We then discuss how this knowledge can be leveraged to identify the mechanisms of aging biology most relevant to heart failure. Lastly, we provide examples of how this human-first Geroscience approach, when paired with rigorous functional assessments in preclinical models, is leading to early-stage clinical development of gerotherapeutic approaches for heart failure.

The age-related decline in diastolic function can result in heart failure with a preserved ejection fraction (HFpEF) and atrial fibrillation (AF), which are comorbid conditions that are increasingly prevalent and have a high socioeconomic burden. In humans, diastolic dysfunction results from structural and functional changes that increasingly impede diastolic filling after midlife. Comorbidities and pathomechanisms that lead to additional increases in cardiac filling pressures accelerate the age-related deterioration in diastolic function. It is, therefore, that targeting the accelerators of diastolic dysfunction holds the most promise in reducing the risk for HFpEF and AF.

Atrial fibrillation (AF) is the most common sustained arrhythmia, with a particularly high prevalence in the elderly. As the global aging population rapidly expands, it is increasingly important to examine how alterations to the aging heart contribute to an increased AF susceptibility. This work critically reviews the key molecular mechanisms that may underpin the complex association between aging and AF. Moreover, we identify emerging novel opportunities for therapeutic intervention that may be able to prevent and/or improve the current treatment paradigms for age-related AF. This review contributes to a holistic understanding of the intricate relationship between aging and AF.

This review discusses the pathophysiological changes associated with cardiac aging and the potential therapeutic role of the anti-aging protein Klotho. It highlights key contributors to heart failure, such as arterial stiffening, myocardial fibrosis, and impaired cardiac relaxation, all of which lead to the declining function of the aging heart. This review also explores the regulation of Klotho expression, its various forms, and its impact on cardiac health, emphasizing its protective roles against oxidative stress, inflammation, and cardiac remodeling. Klotho's potential as a therapeutic target for mitigating cardiac aging and improving cardiovascular health in the elderly is a central theme, making it a promising candidate for future interventions aimed at enhancing cardiac function and longevity.

Introduction: Angiotensin II (AngII) affects cardiovascular health, mediating impacts through AngII type 1 (AT1R) and type 2 (AT2R) receptors. The present study investigated sex and aging-related differences in microvascular AngII receptor function in mice and humans.

Methods: Mesenteric resistance arteries (MRA) were isolated from 3-, 12-, and 18-month-old female and male C57/Bl6 mice. Wire myography was used to measure vasoconstriction to AngII and vasodilation to an AT2R agonist (compound 21, C21). Seven healthy adults (3 premenopausal women and 4 age-matched men) were recruited to participate in a study measuring cutaneous microvascular vasoconstriction to AngII in the presence and absence of 10 μM PD123319, an AT2R antagonist.

Results: In murine MRA, AngII-induced constriction increases by 18 months in females and by 12 months in males. AT2R-mediated vasodilation was reduced with age in females only, which corresponds with a female-specific decrease in mesenteric AT2R mRNA expression. AT2R inhibition enhances AngII-induced constriction in young female, but not male, mice. Clinical data support that premenopausal women have attenuated AngII constriction vs. men, which is abrogated by AT2R inhibition. AT2R expression is greater in primary aortic smooth muscle cells, but not endothelial cells, from young women compared with men.

Conclusions: These data demonstrate enhanced microvascular AT2R function in young female mice and young women. There is a female-specific loss of AT2R function with age in mice, concomitant with declining AT2R expression. These findings implicate AT2R as a sex-specific target for microvascular dysfunction and aging-associated cardiovascular disease.