Surface Lin28A expression consistent with cellular stress parallels indicators of senescence.
Cardiovascular research
AIMS:Declining cellular functional capacity resulting from stress or ageing is a primary contributor to impairment of myocardial performance. Molecular pathway regulation of biological processes in cardiac interstitial cells (CICs) is pivotal in stress and ageing responses. Altered localization of the RNA-binding protein Lin28A has been reported in response to environmental stress, but the role of Lin28A in response to stress in CICs has not been explored. Surface Lin28A redistribution is indicative of stress response in CIC associated with ageing and senescence. METHODS AND RESULTS:Localization of Lin28A was assessed by multiple experimental analyses and treatment conditions and correlated to oxidative stress, senescence, and ploidy in adult murine CICs. Surface Lin28A expression is present on 5% of fresh CICs and maintained through Passage 2, increasing to 21% in hyperoxic conditions but lowered to 14% in physiologic normoxia. Surface Lin28A is coincident with elevated senescence marker p16 and beta-galactosidase (β-gal) expression in CICs expanded in hyperoxia, and also increases with polyploidization and binucleation of CICs regardless of oxygen culture. Transcriptional profiling of CICs using single-cell RNA-Seq reveals up-regulation of pathways associated with oxidative stress in CICs exhibiting surface Lin28A. Induction of surface Lin28A by oxidative stress is blunted by treatment of cells with the antioxidant Trolox in a dose-dependent manner, with 300 μM Trolox exposure maintaining characteristics of freshly isolated CICs possessing low expression of surface Lin28A and β-gal with predominantly diploid content. CONCLUSION:Surface Lin28A is a marker of environmental oxidative stress in CICs and antioxidant treatment antagonizes this phenotype. The biological significance of Lin28 surface expression and consequences for myocardial responses may provide important insights regarding mitigation of cardiac stress and ageing.
10.1093/cvr/cvac122
Longitudinal aortic strain, ventriculo-arterial coupling and fatty acid oxidation: novel insights into human cardiovascular aging.
GeroScience
Aging-induced aortic stiffness has been associated with altered fatty acid metabolism. We studied aortic stiffness using cardiac magnetic resonance (CMR)-assessed ventriculo-arterial coupling (VAC) and novel aortic (AO) global longitudinal strain (GLS) combined with targeted metabolomic profiling. Among community older adults without cardiovascular disease, VAC was calculated as aortic pulse wave velocity (PWV), a marker of arterial stiffness, divided by left ventricular (LV) GLS. AOGLS was the maximum absolute strain measured by tracking the phasic distance between brachiocephalic artery origin and aortic annulus. In 194 subjects (71 ± 8.6 years; 88 women), AOGLS (mean 5.6 ± 2.1%) was associated with PWV (R = -0.3644, p < 0.0001), LVGLS (R = 0.2756, p = 0.0001) and VAC (R = -0.3742, p <0.0001). Stiff aorta denoted by low AOGLS <4.26% (25 percentile) was associated with age (OR 1.13, 95% CI 1.04-1.24, p = 0.007), body mass index (OR 1.12, 95% CI 1.01-1.25, p = 0.03), heart rate (OR 1.04, 95% CI 1.01-1.06, p = 0.011) and metabolites of medium-chain fatty acid oxidation: C8 (OR 1.005, p = 0.026), C10 (OR 1.003, p = 0.036), C12 (OR 1.013, p = 0.028), C12:2-OH/C10:2-DC (OR 1.084, p = 0.032) and C16-OH (OR 0.82, p = 0.006). VAC was associated with changes in long-chain hydroxyl and dicarboxyl carnitines. Multivariable models that included acyl-carnitine metabolites, but not amino acids, significantly increased the discrimination over clinical risk factors for prediction of AOGLS (AUC [area-under-curve] 0.73 to 0.81, p = 0.037) and VAC (AUC 0.78 to 0.87, p = 0.0044). Low AO GLS and high VAC were associated with altered medium-chain and long-chain fatty acid oxidation, respectively, which may identify early metabolic perturbations in aging-associated aortic stiffening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.
10.1007/s11357-024-01127-x
Cardiomyocyte ageing and cardioprotection: consensus document from the ESC working groups cell biology of the heart and myocardial function.
Ruiz-Meana Marisol,Bou-Teen Diana,Ferdinandy Péter,Gyongyosi Mariann,Pesce Maurizio,Perrino Cinzia,Schulz Rainer,Sluijter Joost P G,Tocchetti Carlo G,Thum Thomas,Madonna Rosalinda
Cardiovascular research
Advanced age is a major predisposing risk factor for the incidence of coronary syndromes and comorbid conditions which impact the heart response to cardioprotective interventions. Advanced age also significantly increases the risk of developing post-ischaemic adverse remodelling and heart failure after ischaemia/reperfusion (IR) injury. Some of the signalling pathways become defective or attenuated during ageing, whereas others with well-known detrimental consequences, such as glycoxidation or proinflammatory pathways, are exacerbated. The causative mechanisms responsible for all these changes are yet to be elucidated and are a matter of active research. Here, we review the current knowledge about the pathophysiology of cardiac ageing that eventually impacts on the increased susceptibility of cells to IR injury and can affect the efficiency of cardioprotective strategies.
10.1093/cvr/cvaa132
Senescent cardiac fibroblasts: A key role in cardiac fibrosis.
Biochimica et biophysica acta. Molecular basis of disease
Cardiac fibroblasts are a cell population that controls the homeostasis of the extracellular matrix and orchestrates a damage response to maintain cardiac architecture and performance. Due to these functions, fibroblasts play a central role in cardiac fibrosis development, and there are large differences in matrix protein secretion profiles between fibroblasts from aged versus young animals. Senescence is a multifactorial and complex process that has been associated with inflammatory and fibrotic responses. After damage, transient cellular senescence is usually beneficial, as these cells promote tissue repair. However, the persistent presence of senescent cells within a tissue is linked with fibrosis development and organ dysfunction, leading to aging-related diseases such as cardiovascular pathologies. In the heart, early cardiac fibroblast senescence after myocardial infarction seems to be protective to avoid excessive fibrosis; however, in non-infarcted models of cardiac fibrosis, cardiac fibroblast senescence has been shown to be deleterious. Today, two new classes of drugs, termed senolytics and senostatics, which eliminate senescent cells or modify senescence-associated secretory phenotype, respectively, arise as novel therapeutical strategies to treat aging-related pathologies. However, further studies will be needed to evaluate the extent of the utility of senotherapeutic drugs in cardiac diseases, in which pathological context and temporality of the intervention must be considered.
10.1016/j.bbadis.2023.166642
D-galactose-induced cardiac ageing: A review of model establishment and potential interventions.
Journal of cellular and molecular medicine
Cardiovascular disease (CVD) is highly prevalent in an ageing society. The increased incidence and mortality rates of CVD are global issues endangering human health. There is an urgent requirement for understanding the aetiology and pathogenesis of CVD and developing possible interventions for preventing CVD in ageing hearts. It is necessary to select appropriate models and treatment methods. The D-galactose-induced cardiac ageing model possesses the advantages of low mortality, short time and low cost and has been increasingly used in the study of cardiovascular diseases in recent years. Therefore, understanding the latest progress in D-galactose-induced cardiac ageing is valuable. This review highlights the recent progress and potential therapeutic interventions used in D-galactose-induced cardiac ageing in recent years by providing a comprehensive summary of D-galactose-induced cardiac ageing in vivo and in vitro. This review may serve as reference literature for future research on age-related heart diseases.
10.1111/jcmm.17580
Rejuvenation of the Aging Heart: Molecular Determinants and Applications.
The Canadian journal of cardiology
In Canada and worldwide, the elderly population (ie, individuals > 65 years of age) is increasing disproportionately relative to the total population. This is expected to have a substantial impact on the health care system, as increased aged is associated with a greater incidence of chronic noncommunicable diseases. Within the elderly population, cardiovascular disease is a leading cause of death, therefore developing therapies that can prevent or slow disease progression in this group is highly desirable. Historically, aging research has focused on the development of anti-aging therapies that are implemented early in life and slow the age-dependent decline in cell and organ function. However, accumulating evidence supports that late-in-life therapies can also benefit the aged cardiovascular system by limiting age-dependent functional decline. Moreover, recent studies have demonstrated that rejuvenation (ie, reverting cellular function to that of a younger phenotype) of the already aged cardiovascular system is possible, opening new avenues to develop therapies for older individuals. In this review, we first provide an overview of the functional changes that occur in the cardiomyocyte with aging and how this contributes to the age-dependent decline in heart function. We then discuss the various anti-aging and rejuvenation strategies that have been pursued to improve the function of the aged cardiomyocyte, with a focus on therapies implemented late in life. These strategies include 1) established systemic approaches (caloric restriction, exercise), 2) pharmacologic approaches (mTOR, AMPK, SIRT1, and autophagy-targeting molecules), and 3) emerging rejuvenation approaches (partial reprogramming, parabiosis/modulation of circulating factors, targeting endogenous stem cell populations, and senotherapeutics). Collectively, these studies demonstrate the exciting potential and limitations of current rejuvenation strategies and highlight future areas of investigation that will contribute to the development of rejuvenation therapies for the aged heart.
10.1016/j.cjca.2024.03.004
Environmental and genetic predictors of human cardiovascular ageing.
Nature communications
Cardiovascular ageing is a process that begins early in life and leads to a progressive change in structure and decline in function due to accumulated damage across diverse cell types, tissues and organs contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence and end-organ damage, however the genetic architecture of cardiovascular ageing is not known. Here we use machine learning approaches to quantify cardiovascular age from image-derived traits of vascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing is found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated by cardiometabolic risk factors and we also identify prescribed medications that are potential modifiers of ageing. Through large-scale modelling of ageing across multiple traits our results reveal insights into the mechanisms driving premature cardiovascular ageing and reveal potential molecular targets to attenuate age-related processes.
10.1038/s41467-023-40566-6
The impact of aging on cardiac repair and regeneration.
The Journal of biological chemistry
In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is rare. This is unfortunate as aging induces many changes in the heart. The first part of this review covers the main technologies being pursued in the cardiac regeneration field and how they are impacted by the aging processes. The second part of the review covers the significant amount of aging-related research that could be used to aid cardiac regeneration. Finally, a perspective is provided to suggest how cardiac regenerative technologies can be improved by addressing aging-related effects.
10.1016/j.jbc.2024.107682
Immunometabolism in the Aging Heart.
Journal of the American Heart Association
Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.
10.1161/JAHA.124.039216
Impact of gut microbiota on cardiac aging.
Archives of gerontology and geriatrics
Recent research has suggested imbalances in gut microbiota composition as contributors to cardiac aging. An individual's physical condition, along with lifestyle-associated factors, including diet and medication, are significant determinants of gut microbiota composition. This review discusses evidence of bidirectional associations between aging and gut microbiota, identifying gut microbiota-derived metabolites as potential regulators of cardiac aging. It summarizes the effects of gut microbiota on cardiac aging diseases, including cardiac hypertrophy and fibrosis, heart failure, and atrial fibrillation. Furthermore, this review discusses the potential anti-aging effects of modifying gut microbiota composition through dietary and pharmacological interventions. Lastly, it underscores critical knowledge gaps and outlines future research directions. Given the current limited understanding of the direct relationship between gut microbiota and cardiac aging, there is an urgent need for preclinical and clinical investigations into the mechanistic interactions between gut microbiota and cardiac aging. Such endeavors hold promise for shedding light on the pathophysiology of cardiac aging and uncovering new therapeutic targets for cardiac aging diseases.
10.1016/j.archger.2024.105639
Non-coding RNAs and Cardiac Aging.
Zhao Cuimei,Li Guoping,Li Jin
Advances in experimental medicine and biology
Aging is an important risk factor for cardiovascular diseases. Aging increasing the morbidity and mortality in cardiovascular disease patients. With the society is aging rapidly in the world, medical burden of aging-related cardiovascular diseases increasing drastically. Hence, it is urgent to explore the underlying mechanism and treatment of cardiac aging. Noncoding RNAs (ncRNAs, including microRNAs, long noncoding RNAs and circular RNAs) have been reported to be involved in many pathological processes, including cell proliferation, cell death differentiation, hypertrophy and aging in wide variety of cells and tissues. In this chapter, we will summarize the physiology and molecular mechanisms of cardiac aging. Then, the recent research advances of ncRNAs in cardiac aging will be provided. The lessons learned from ncRNAs and cardiac aging studies would bring new insights into the regulatory mechanisms ncRNAs as well as treatment of aging-related cardiovascular diseases.
10.1007/978-981-15-1671-9_14
Targeting Age-Related Pathways in Heart Failure.
Li Haobo,Hastings Margaret H,Rhee James,Trager Lena E,Roh Jason D,Rosenzweig Anthony
Circulation research
During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.
10.1161/CIRCRESAHA.119.315889
Cardiac Pacemaker Activity and Aging.
Annual review of physiology
A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which results from electrical remodeling of individual pacemaker cells along with structural remodeling and a blunted β-adrenergic response. In this review, we summarize current evidence about the tissue, cellular, and molecular mechanisms that underlie the reduction in pacemaker activity with age and highlight key areas for future work.
10.1146/annurev-physiol-021119-034453
Senescence mechanisms and targets in the heart.
Cardiovascular research
Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence, the senescent state can also be induced by oxidative stress, metabolic dysfunction, and epigenetic regulation, among other stressors. It is critical that we understand the molecular pathways that lead to cellular senescence and the consequences of cellular senescence in order to develop new therapeutic approaches to treat CVD. In this review, we discuss molecular mechanisms of cellular senescence, explore how cellular senescence of different cardiac cell types (including cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, and valve interstitial cells) can lead to CVD, and highlight potential therapeutic approaches that target molecular mechanisms of cellular senescence to prevent or treat CVD.
10.1093/cvr/cvab161