Cellular senescence—an aging hallmark in chronic obstructive pulmonary disease pathogenesis

Chronic obstructive pulmonary disease (COPD),¹ a representative aging-related pulmonary disorder, is mainly caused by cigarette smoke (CS) exposure. Age is one of the most important risk factors for COPD development, and increased cellular senescence in tissues and organs is a component of aging. CS exposure can induce cellular senescence, as characterized by irreversible growth arrest and aberrant cytokine secretion of the senescence-associated secretory phenotype; thus, accumulation of senescent cells is widely implicated in COPD pathogenesis. CS-induced oxidative modifications to cellular components may be causally linked to accelerated cellular senescence, especially during accumulation of damaged macromolecules. Autophagy is a conserved mechanism whereby cytoplasmic components are sent for lysosomal degradation to maintain proteostasis. Autophagy diminishes with age, and loss of proteostasis is one of the hallmarks of aging. We have reported the involvement of insufficient autophagy in regulating CS-induced cellular senescence with respect to COPD pathogenesis. However, the role of autophagy in COPD pathogenesis can vary based on levels of cell stress and type of selective autophagy because excessive activation of autophagy can be responsible for inducing regulated cell death. Senotherapies targeting cellular senescence may be effective COPD treatments. Autophagy activation could be a promising sonotherapeutic approach, but the optimal modality of autophagy activation should be examined in future studies.     

Biological Versus Chronological Aging: JACC Focus Seminar

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations.     

Ischemic Heart Disease and Vascular Risk Factors Are Associated With Accelerated Brain Aging

BackgroundIschemic heart disease (IHD) has been linked with poor brain outcomes. The brain magnetic resonance imaging–derived difference between predicted brain age and actual chronological age (brain-age delta in years, positive for accelerated brain aging) may serve as an effective means of communicating brain health to patients to promote healthier lifestyles.ObjectivesThe authors investigated the impact of prevalent IHD on brain aging, potential underlying mechanisms, and its relationship with dementia risk, vascular risk factors, cardiovascular structure, and function.MethodsBrain age was estimated in subjects with prevalent IHD (n = 1,341) using a Bayesian ridge regression model with 25 structural (volumetric) brain magnetic resonance imaging features and built using UK Biobank participants with no prevalent IHD (n = 35,237).ResultsPrevalent IHD was linked to significantly accelerated brain aging (P < 0.001) that was not fully mediated by microvascular injury. Brain aging (positive brain-age delta) was associated with increased risk of dementia (OR: 1.13 [95% CI: 1.04-1.22]; P = 0.002), vascular risk factors (such as diabetes), and high adiposity. In the absence of IHD, brain aging was also associated with cardiovascular structural and functional changes typically observed in aging hearts. However, such alterations were not linked with risk of dementia.ConclusionsPrevalent IHD and coexisting vascular risk factors are associated with accelerated brain aging and risk of dementia. Positive brain-age delta representing accelerated brain aging may serve as an effective communication tool to show the impact of modifiable risk factors and disease supporting preventative strategies.     

Cardiovascular Aging and Longevity: JACC State-of-the-Art Review

Cardiovascular aging and longevity are interrelated through many pathophysiological mechanisms. Many factors that promote atherosclerotic cardiovascular disease are also implicated in the aging process and vice versa. Indeed, cardiometabolic disorders such as hyperglycemia, insulin resistance, dyslipidemia, and arterial hypertension share common pathophysiological mechanisms with aging and longevity. Moreover, genetic modulators of longevity have a significant impact on cardiovascular aging. The current knowledge of genetic, molecular, and biochemical pathways of aging may serve as a substrate to introduce interventions that might delay cardiovascular aging, thus approaching the goal of longevity. In the present review, the authors describe pathophysiological links between cardiovascular aging and longevity and translate these mechanisms into clinical data by reporting genetic, dietary, and environmental characteristics from long-living populations.     

Revascularisation of type 2 diabetics with coronary artery disease: Insights and therapeutic targeting of O-GlcNAcylation

AimCoronary artery bypass graft (CABG) using autologous saphenous vein continues to be a gold standard procedure to restore the supply of oxygen-rich blood to the heart muscles in coronary artery disease (CAD) patients with or without type 2 diabetes mellitus (T2DM). However, CAD patients with T2DM are at higher risk of graft failure. While failure rates have been reduced through improvements in procedure-related factors, much less is known about the molecular and cellular mechanisms by which T2DM initiates vein graft failure. This review gives novel insights into these cellular and molecular mechanisms and identifies potential therapeutic targets for development of new medicines to improve vein graft patency.Data synthesisOne important cellular process that has been implicated in the pathogenesis of T2DM is protein O-GlcNAcylation, a dynamic, reversible post-translational modification of serine and threonine residues on target proteins that is controlled by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Protein O-GlcNAcylation impacts a range of cellular processes, including trafficking, metabolism, inflammation and cytoskeletal organisation. Altered O-GlcNAcylation homeostasis have, therefore, been linked to a range of human pathologies with a metabolic component, including T2DM.ConclusionWe propose that protein O-GlcNAcylation alters vascular smooth muscle and endothelial cell function through modification of specific protein targets which contribute to the vascular re-modelling responsible for saphenous vein graft failure in T2DM.     

The Alzheimer’s Disease Amyloid-Beta Hypothesis in Cardiovascular Aging and Disease: JACC Focus Seminar

Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer’s disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aβ) peptides may function as a link among aging, CVD, and AD. Aging-related vascular and cardiac deposition of Αβ induces tissue inflammation and organ dysfunction, both important components of the Alzheimer’s disease amyloid hypothesis. In this review, the authors describe the determinants of Aβ metabolism, summarize the effects of Aβ on atherothrombosis and cardiac dysfunction, discuss the clinical value of Αβ1-40 in CVD prognosis and patient risk stratification, and present the therapeutic interventions that may alter Aβ metabolism in humans.     

Trajectories of Age-Related Arterial Stiffness in Chinese Men and Women

BackgroundArterial stiffening is central in the vascular aging process. Traditionally, vascular research has focused on atherosclerotic vascular disease, whereas arterial stiffness has not attracted similar attention.ObjectiveSThe purpose of this study was to assess lifetime trajectories of arterial stiffening in Chinese populations facing a high burden of cardiovascular disease, with a particular focus on age–sex interactions and potential determinants.MethodsThis large-scale observational study comprised 2 independent cross-sectional population samples and 1 prospective cohort totaling 80,415 healthy subjects with brachial-ankle pulse wave velocity (baPWV) measurements available. Associations with potential risk conditions were analyzed using linear regression, linear random intercepts mixed models, and L1-regularized linear models.ResultsThe dynamics of age-dependent arterial stiffening differed in sexes, with stiffer vessel observed in men from adolescence to age 58 years and in women thereafter. The steeper increase in baPWV in women after menopause is partly explained by the fact that vascular risk factors are more strongly associated with arterial stiffness in women than in men. Age and systolic blood pressures were the strongest determinants of baPWV, whereas other vascular and metabolic risk factors, except low-density lipoprotein cholesterol, showed consistent associations of moderate strength.ConclusionsThe significant age–sex interaction in arterial stiffening provides an important clue of explanation for the heightened cardiovascular disease risk in postmenopausal women. Detailed knowledge on lifetime trajectories of arterial stiffening, and its potential risk factors is a prerequisite for the development of new prevention strategies counteracting vascular aging.     

Delirium After TAVR: Crosspassing the Limit of Resilience

Patients who undergo transcatheter aortic valve replacement often are frail and elderly. Delirium is a frequently observed complication, associated with impaired recovery, prolonged hospital stay, and mortality. In different hospital settings, interventions that reduced the incidence of delirium resulted in improved clinical outcome and reduced costs. In that context, prevention, early recognition, and timely interventions could be the next step toward better outcomes of transcatheter aortic valve replacement. This review is focused on awareness and recognition of delirium, including predisposing “vulnerability” factors (such as cognitive impairment and carotid artery disease) and “trigger” factors (such as anesthesia, hemodynamic imbalance, and complications). For prevention and treatment, clinicians should focus on sleep hygiene, orientation, pain management, and early mobilization. In case of delirium, a thorough search and treatment of trigger factors is warranted. Future studies should focus on risk assessment, preventive and therapeutic interventions, and their potential benefit in terms of costs and clinical outcomes.     

Subclinical vascular disease in patients with diabetes is associated with insulin resistance

Patients with diabetes experience increased cardiovascular risk that is not fully explained by deficient glycemic control or traditional cardiovascular risk factors such as smoking and hypercholesterolemia. Asymptomatic patients with diabetes show structural and functional vascular damage that includes impaired vasodilation, arterial stiffness, increased intima-media thickness and calcification of the arterial wall. Subclinical vascular injury associated with diabetes predicts subsequent manifestations of cardiovascular disease, such as ischemic heart disease, peripheral artery disease and stroke. Noninvasive detection of subclinical vascular disease is commonly used to estimate cardiovascular risk associated to diabetes. Longitudinal studies in normotensive subjects show that arterial stiffness at baseline is associated with a greater risk for future hypertension independently of established risk factors. In patients with type 2 diabetes, vascular disease begins to develop during the latent phase of insulin resistance, long before the clinical diagnosis of diabetes. In contrast, patients with type 1 diabetes do not manifest vascular injury when they are first diagnosed due to insulin deficiency, as they lack the preceding period of insulin resistance. These findings suggest that insulin resistance plays an important role in the development of early vascular disease associated with diabetes. Cross-sectional and prospective studies confirm that insulin resistance is associated with subclinical vascular injury in patients with diabetes, independently of standard cardiovascular risk factors. Asymptomatic vascular disease associated with diabetes begins to occur early in life having been documented in children and adolescents. Insulin resistance should be considered a therapeutic target in order to prevent the vascular complications associated with diabetes.     

Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel

Cognitive impairment associated with aging has emerged as one of the major public health challenges of our time. Although Alzheimer’s disease is the leading cause of clinically diagnosed dementia in Western countries, cognitive impairment of vascular etiology is the second most common cause and may be the predominant one in East Asia. Furthermore, alterations of the large and small cerebral vasculature, including those affecting the microcirculation of the subcortical white matter, are key contributors to the clinical expression of cognitive dysfunction caused by other pathologies, including Alzheimer’s disease. This scientific expert panel provides a critical appraisal of the epidemiology, pathobiology, neuropathology, and neuroimaging of vascular cognitive impairment and dementia, and of current diagnostic and therapeutic approaches. Unresolved issues are also examined to shed light on new basic and clinical research avenues that may lead to mitigating one of the most devastating human conditions.     

Primary and Secondary Prevention of Ischemic Stroke and Cerebral Hemorrhage: JACC Focus Seminar

Stroke is a leading cause of permanent disability. Therefore, primary prevention of first stroke and secondary prevention of recurrent stroke are a high priority. Primary prevention of ischemic stroke includes lifestyle modification and diet, treatment of risk factors including hypertension, diabetes mellitus and lipid disorders, antiplatelet therapy for high vascular risk patients, and anticoagulation in atrial fibrillation. Secondary prevention of ischemic stroke includes additional carotid surgery or stenting in selected symptomatic patients, closure of patent foramen ovale after cryptogenic stroke, treatment of insulin resistance, and best medical treatment of intracranial stenosis. The most important preventive strategies in the primary and secondary prevention of cerebral hemorrhage include the treatment of hypertension, reduction in alcohol intake, and occlusion of the left atrial appendage in patients with atrial fibrillation and permanent contraindications for oral anticoagulation.     

Glycogen storage disease type I patients with hyperlipidemia have no signs of early vascular dysfunction and premature atherosclerosis

Background and aimsGlycogen storage disease type I (GSD I) is associated with hyperlipidemia, a known risk factor for premature atherosclerosis. Few studies have addressed endothelial dysfunction in patients with GSD I, and these studies yielded controversial results.Methods and resultsWe investigated vascular dysfunction in a cohort of 32 patients with GSD I (26 GSD Ia, 6 GSD Ib, mean age 20.7 (4.8–47.5) years) compared to 32 age-, gender-, and BMI-matched healthy controls using non-invasive techniques such as quantification of carotid intima media thickness, retinal vessel analysis and 24 h-blood pressure measurements. In addition, early biomarkers of inflammatory and oxidative endothelial stress were assessed in blood. Although GSD I patients had a clearly proatherogenic lipid profile, increased oxidative stress, higher levels of high sensitivity C-reactive protein and increased lipoprotein associated phospholipase A2 activity, functional and structural parameters including carotid intima media thickness and retinal vessel diameters did not indicate premature atherosclerosis in this patient cohort. Blood pressure values and pulse wave velocity were comparable in patients and healthy controls, while central blood pressure and augmentation index were higher in GSD patients.ConclusionOur data suggest that GSD I is not associated with early vascular dysfunction up to the age of at least 20 years. Further studies are needed to elucidate the possibly protective mechanisms that prevent early atherosclerosis is GSD I. Longer follow-up studies are required to assess the long-term risk of vascular disease with increased oxidative stress being present in GSD I patients.     

Cardiovascular Risk in Patients With Psoriasis: JACC Review Topic of the Week

Psoriasis is a chronic inflammatory skin disease that affects 2% to 3% of the U.S. population. The immune response in psoriasis includes enhanced activation of T cells and myeloid cells, platelet activation, and up-regulation of interferons, tumor necrosis factor-α, and interleukins (ILs) IL-23, IL-17, and IL-6, which are linked to vascular inflammation and atherosclerosis development. Patients with psoriasis are up to 50% more likely to develop cardiovascular disease (CV) disease, and this CV risk increases with skin severity. Major society guidelines now advocate incorporating a psoriasis diagnosis into CV risk prediction and prevention strategies. Although registry data suggest treatment targeting psoriasis skin disease reduces vascular inflammation and coronary plaque burden, and may reduce CV risk, randomized placebo-controlled trials are inconclusive to date. Further studies are required to define traditional CV risk factor goals, the optimal role of lipid-lowering and antiplatelet therapy, and targeted psoriasis therapies on CV risk.     

Role of intracellular zinc in molecular and cellular function in allergic inflammatory diseases

Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems.In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions.In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases.     

Growth differentiation factor 11: A proangiogenic drug as a potential antiaging regulating molecule

Organs and tissues are subjected to numerous alterations during aging, as a result of complex biochemical changes. Aging is certainly associated with the accumulation of “antiaging” and “proaging” factors in the systemic circulation. The effects of young blood on rejuvenation of regenerative capacity suggest the existence of multiple “proyouthful” factors, such as growth differentiation factor 11 (GDF11), in the young blood of animals. GDF11 is a member of the transforming growth factor beta (TGFβ) superfamily of cytokines, and appears to be a critical rejuvenation factor in aging organs. In the context of aging, GDF11 promotes vascular and neural plasticity of the central nervous system. Parabiosis, the surgical linking of circulations between old and young mice, was employed to identify GDF11 as an antihypertrophic factor that appears to rejuvenate the aging murine heart. Current theories suggest that GDF11 in young blood has beneficial effects on cognitive and cardiovascular functions and wound healing. The cellular mechanisms of GDF11 in cardiovascular, neurological, skin and skeletal muscle diseases are not clearly defined, but evidence indicates that it may function as a proneurogenic and proangiogenic drug. GDF11 binds and activates specific receptor complexes, which transmit signals by two procedures: the TGFβ-Smad pathway and the bone morphogenic protein (BMP)-Smad pathway. GDF11 is perhaps only the first in a series of circulating molecules that will be found to influence the aging of different tissues, and it may be a potential candidate for therapeutic intervention against angiogenesis-related disorders.     

Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review

Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality worldwide. Although conventionally managed as separate disease processes, recent research has lent insight into compelling commonalities between CVD and cancer, including shared mechanisms for disease development and progression. In this review, the authors discuss several pathophysiological processes common to both CVD and cancer, such as inflammation, resistance to cell death, cellular proliferation, neurohormonal stress, angiogenesis, and genomic instability, in an effort to understand common mechanisms of both disease states. In particular, the authors highlight key circulating and genomic biomarkers associated with each of these processes, as well as their associations with risk and prognosis in both cancer and CVD. The purpose of this state-of-the-art review is to further our understanding of the potential mechanisms underlying cancer and CVD by contextualizing pathways and biomarkers common to both diseases.     

Lifestyle behaviors and cardiovascular risk profiles among parous women by gestational diabetes status, 2007–2018

Background and aimsWomen with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20–44 by history of GDM.Methods and resultsUsing data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history.ConclusionAmong parous U.S. women ages 20–44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.     

Predicting Long-Term Absence of Coronary Artery Calcium in Metabolic Syndrome and Diabetes: The MESA Study

ObjectivesThe purpose of this study was to identify predictors of healthy arterial aging (long-term coronary artery calcification [CAC] of 0) among individuals with metabolic syndrome (MetS) or type 2 diabetes (T2D), which may improve primary prevention strategies.BackgroundIndividuals with MetS or T2D have a heterogeneously increased risk of atherosclerotic cardiovascular disease and not all have a high-intermediate risk.MethodsWe included 574 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with MetS or T2D who had CAC=0 at baseline and a repeat CAC scan 10 years later. Multivariable logistic regression assessed the association of traditional and novel atherosclerotic cardiovascular disease risk factors and the MetS severity score (based on the 5 MetS criteria) with healthy arterial aging.ResultsThe mean age of participants was 58.9 years, 67% were women, 422 participants had MetS, and 152 had T2D. The proportion with long-term CAC=0 was similar for MetS (42%) and T2D (44%). A younger age was the only individual low/normal traditional risk factor associated with an increased likelihood of long-term CAC=0 (odds ratio [OR]: 1.50; 95% confidence interval [CI]: 1.22 to 1.85 per 10-years younger). The strongest associations of nontraditional risk factors were observed for an absence of thoracic calcification (OR: 2.42; 95% CI: 1.24 to 4.72), absence of carotid plaque (OR: 1.81; 95% CI: 1.25 to 2.61), and among persons with a high sensitivity troponin <3 ng/ml (OR: 1.55; 95% CI: 1.01 to 2.38). In addition, persons with the lowest quartile MetS severity score had a substantially higher odds of healthy long-term CAC=0 (OR: 2.71; 95% CI: 1.27 to 5.76).ConclusionSMore than 40% of adults with MetS or T2D and baseline CAC=0 had long-term absence of CAC, which was most strongly associated with an absence of extracoronary atherosclerosis and a low MetS score. An optimal overall cardiovascular profile appears to be more important than an ideal value of any individual risk factor to maintain healthy arterial aging.     

Long Working Hours and Risk of Recurrent Coronary Events

BackgroundEvidence from prospective studies has suggested that long working hours are associated with incident coronary heart disease (CHD) events. However, no previous study has examined whether long working hours are associated with an increased risk of recurrent CHD events among patients returning to work after a first myocardial infarction (MI).ObjectivesThe purpose of this study was to examine the effect of long working hours on the risk of recurrent CHD events.MethodsThis is a prospective cohort study of 967 men and women age 35 to 59 years who returned to work after a first MI. Patients were recruited from 30 hospitals across the province of Quebec, Canada. The mean follow-up duration was 5.9 years. Long working hours were assessed on average 6 weeks after their return to work. Incident CHD events (fatal or nonfatal MI and unstable angina) occurring during follow-up were determined using patients’ medical files. Hazard ratios were estimated using Cox proportional hazard regression models. Splines and fractional polynomial regressions were used for flexible exposure and time modeling.ResultsRecurrent CHD events occurred among 205 patients. Participants working long hours (≥55 h/week) had a higher risk of recurrent CHD events after controlling for sociodemographics, lifestyle-related risk factors, clinical risk factors, work environment factors, and personality factors (hazard ratio vs. 35 to 40 h/week: 1.67; 95% confidence interval: 1.10 to 2.53). These results showed a linear risk increase after 40 h/week and a stronger effect after the first 4 years of follow-up and when long working hours are combined with job strain.ConclusionsAmong patients returning to work after a first MI, longer working hours per week is associated with an increased risk of recurrent CHD events. Secondary prevention interventions aiming to reduce the number of working hours among these patients may lower the risk of CHD recurrence.