Immunometabolism in the Aging Heart

Abstract

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.

Nonstandard Abbreviations and Acronyms

AS

aortic stenosis

CANTOS

Canakinumab Anti‐inflammatory Thrombosis Outcome Study

CoQ10

coenzyme Q10

ECM

extracellular matrix

EMBRACE

Evaluation of Myocardial Effects of MTP‐131 for Reducing Reperfusion Injury in Patients With Acute Coronary Events

HSC

hematopoietic tem cell

IMICA

Interleukin‐6 Inhibition for Modulating Inflammation After Cardiac Arrest

MMP

matrix metalloproteinase

MMPOWER

Safety, Tolerability, and Efficacy of MTP‐131 for the Treatment of Mitochondrial Myopathy

NOX

nicotinamide adenine dinucleotide phosphate oxidase

OXPHOS

oxidative phosphorylation

PANDA

Protective Effect of CoQ10 Against Negative Inflammatory Response and Organ Dysfunction in Cardiovascular Surgery

ROS

reactive oxygen species

TGF‐β

transforming growth factor‐β

Tregs

regulatory T cells

The term immunometabolism centers around the interplay between the disciplines of immunology and cellular metabolism. Although immunometabolism was described as an emerging frontier in 2011 by Mathis and Shoelson, ¹ the foundation of the interaction goes back to the early 1900s. It is based on the preclinical and clinical observations that indicated the influence of systemic metabolism on the activation, function, and differentiation of the immune responses and vice versa. The scope of immunometabolism relies on the role of metabolic intermediates and regulators of pathways including glycolysis, oxidative phosphorylation (OXPHOS), amino acid and fatty acid metabolism, that is, ATP, nicotinamide adenine dinucleotide, and reactive oxygen species (ROS), that interact with immune signaling and function. ² , ³ , ⁴ In the context of aging, endogenous alterations in metabolic pathways lead to a consequential impact on the immune system, a concept known as “inflammaging,” wherein chronic low‐grade inflammation due to biological aging and multiple comorbidities has metabolic implications. ⁵ , ⁶

The US population is rapidly aging, and the number of individuals aged ≥65 years will double between 2010 and 2030. ⁷ Coinciding with an aging population, US cancer incidence rates in these individuals are predicted to increase by 67% in the same time frame. ⁸ Among the ≈15.5 million cancer survivors in the United States in 2022, 67% of cancer survivors were aged ≥65 years. ⁹

As cancer survival rates improve, there is an increasing need to address chronic adverse sequelae affecting the quality of life of cancer survivors. Cardiotoxicity is defined as the occurrence of cardiac electrophysiology dysfunction or muscle damage encompassing numerous heterogeneous side effects including arrhythmias, changes in blood pressure, myocardial ischemia, thrombosis, and impairment in systolic or diastolic function. ¹⁰ As a well‐recognized side effect of cancer therapy, cardiotoxicity affects the structural, functional, and molecular aspects of the heart. The risk of cardiotoxicity due to conventional cancer therapies increases exponentially in older populations due to endogenous physiological and cellular changes including endothelial dysfunction, structural changes, mitochondrial dysfunction, immunosenescence, and inflammation as well as associated comorbidities. ¹¹ Immunometabolic changes have been shown to negatively impact cardiac aging by contributing to pathologies including arrhythmias, heart failure, and atherosclerosis. ¹² , ¹³ Targeting the metabolic pathways that regulate the remodeling of the aging heart thus presents a favorable avenue that can be strategically exploited to design therapeutic interventions that modulate the immune responses in various pathologies like cancer and chronic normal tissue damage due to cancer therapies. This review will focus on the various aspects of immunometabolism in the context of aging and its cardiac implications. Furthermore, it will provide recent insights into preclinical and therapeutic interventions currently utilized in immunometabolism.

Structural and Functional Landscape of the Aging Heart

Biological aging encompasses a progressive decline in the structural and functional aspects of cellular living systems and organs. A global decline in the aging heart often manifests as reduced diastolic function, increased left ventricular (LV) hypertrophy, atrial fibrillation, and increased susceptibility to infections due to immune dysfunction. While some of these changes are related to pathology or disease, many arise naturally as part of the endogenous aging process. These aging‐induced structural, functional, and molecular changes in the heart tissues can predispose older individuals to cancer therapy–induced normal tissue complications (Figure 1). This predisposition has been proposed to occur through aging‐related increases in mitochondrial dysfunction and DNA damage, ¹⁴ cellular senescence, ¹⁵ and endothelial dysfunction. ¹⁶ These immunometabolic alterations not only contribute to cardiac functional decline but also drive structural changes that compound diastolic dysfunction, leading to heart failure.

Figure 1. Landscape of the aging heart.

Various facets of cardiac aging include structural, functional, inflammaging, apoptosis/necrosis, epigenetic modification, and metabolic changes. CAVD indicates calcified aortic valve disease; FFA, free fatty acid; LV, left ventricular; OXPHOS, oxidative phosphorylation; and ROS, reactive oxygen species.

Morphological and structural changes in cardiac tissues include myocardial fibrosis, characterized by increased collagen deposition leading to increased myocardial stiffness and reduced conformity, which impairs diastolic function and contributes to heart failure. ¹⁷ , ¹⁸ Age‐associated cardiac hypertrophy is characterized by shifts in the immune cell subsets, particularly in the proinflammatory M1 macrophage subset in the ischemic heart tissue that consequently contributes to a chronic inflammatory state exacerbating cardiac dysfunction. ¹⁹ Age‐associated extracellular matrix (ECM), myocardial remodeling, and cardiac hypertrophy are structural hallmarks that serve as a segway for immunometabolism and are associated with increased collagen deposition and increased degradation capacity of the ECM because of increased expression of matrix metalloproteinases (MMPs) in cardiac fibroblasts, vascular smooth muscle cells, and leukocytes. ²⁰ , ²¹ Several studies have indicated that ECM controls and guides the movement and positioning of immune cells. For example, T cells prefer sites containing thin ECM fibers compared with densely cross‐linked collagen matrices. ²² Studies have also shown that MMP‐9 triggers the activation of cytokines and chemokines, including interleukin‐1β, interleukin‐6, interleukin‐8, tumor necrosis factor‐α (TNF‐α), and transforming growth factor‐β (TGF‐β) by cleaving their inactive precursors into active forms or by binding to specific receptors, thereby regulating the fibrotic and inflammatory cascade during cardiac remodeling. ²³ , ²⁴ , ²⁵ , ²⁶ For example, MMP‐9 cleaves pro–interleukin‐1β to activate the inflammatory cytokine interleukin‐1β, enhancing the inflammatory response. ²⁷ , ²⁸ , ²⁹ Likewise, MMP‐9–mediated cleavage has been shown to activate TGF‐β, contributing to increased collagen synthesis and tissue remodeling. ³⁰ , ³¹ In addition to the ECM components, tissue remodeling also influences cellular responses in cardiac tissues.

Progressive cardiomyocyte hypertrophy is another hallmark of cardiac aging, resulting in the enlargement of myocytes as a response to the loss of myocytes and increased functional demands, reducing the compensatory capacity of the heart tissue. ³² ANP (atrial natriuretic peptide) and BNP (brain‐type natriuretic peptide) have been identified as markers of aging‐associated hypertrophy. ³³ , ³⁴ In addition to cardiomyocyte enlargement, increased LV thickness without any changes in LV mass due to aging can reduce the internal dimension and volume of diastole, altering the filling capacity. ³⁵ Valvular degeneration, often indicated by calcification of the heart valves, especially the aortic valve, can lead to aortic stenosis (AS) and impaired valve function. ³⁶ The Tromsø study demonstrated that the prevalence of AS increases with aging, with the average values being 0.2% (50–59 years), 1.3% (60–69 years), 3.9% (70–79 years) and 9.8% (80–89 years). ³⁷ Calcified aortic valve disease due to aging is a bidirectional inflammation‐associated disease characterized by ossified aortic valves containing macrophages, T lymphocytes, and foam cells. ³⁷ , ³⁸ Calcified aortic valve disease progression thus contributes to the overall cardiac health affecting the valve structure and the functional capacity of the heart.

The age‐associated cardiac functional landscape presents with decreased contractility impairing systolic function and β‐adrenergic desensitization, thereby diminishing the heart's ability to increase heart rate and contractility during stress and exercise. ³⁹ Furthermore, studies have shown that impaired relaxation due to increased myocardial stiffness and calcium handling dysregulation in cardiomyocytes from older individuals has been associated with diastolic dysfunction. ⁴⁰ , ⁴¹ Electrophysiological conduction abnormalities as a result of aging have been associated with a degenerated sinoatrial and atrioventricular node, and conduction pathways can lead to arrhythmias with an increased risk for bradycardia and atrial fibrillation. ⁴² , ⁴³ , ⁴⁴ The pathophysiology of arrhythmias is associated with apoptosis of cardiac myocytes that contribute to progressive pump failure thereby exacerbating cardiac dysfunction. Additionally, studies have shown arrhythmogenicity of fibro‐fatty infiltrations wherein the size and percentage of adipose infiltrates influenced wave propagation and the onset of arrhythmias. ⁴⁵

Increased levels of apoptosis and necrosis, concomitant with the limited regenerative capacity of cardiomyocytes due to aging, leads to a decrease in the number of functional cardiac cells. ⁴⁶ , ⁴⁷ Furthermore, microRNAs have also recently emerged as a regulator of physiological pathways, including aging of the cardiovascular system. ⁴⁸ Age‐associated increased expression of microRNA 34a and decreased level of microRNA 146a has been observed in endothelial cells that induce apoptosis and reduce oxidative stress via downregulation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 expression, a catalytic subunit of NOX. ⁴⁹ , ⁵⁰ , ⁵¹ Increased steady‐state levels of reactive oxygen species (ROS) due to 1‐ and 2‐electron reductions of molecular oxygen in the mitochondrial electron transport chain can contribute to higher levels of mitochondrial oxidative damage to DNA and proteins of OXPHOS, causing a decline in ATP production. ⁵²

Age‐associated epigenetic dysregulation also affects the transcription of genes involved in cardiac function. ⁵³ Methylation at 5‐cytosine (5‐methylcytosine) is a key epigenetic modification associated with the onset of pathology. ⁵³ Interestingly, DNA methylome profiling in failing cardiomyocytes of mice returned to a fetal methylation pattern implicating that failing cardiomyocytes may undergo cellular reprogramming that affects their function, regenerative potential, and stress response resembling the plasticity seen in fetal cardiomyocytes. ⁵⁴ This epigenetic reprogramming presents avenues for therapeutic interventions that promote a stable methylation pattern that potentially enhances overall cardiac function and promotes better outcomes in heart failure patients. Dysregulated DNA hydroxymethylation patterns including alterations in 5‐hydroxymethylcytosine could lead to maladaptive repair programs promoting cardiac fibrosis hypertrophy and apoptosis, all of which directly affect cardiac function. ⁵⁵ Other posttranslational modifications including linker and core histone modifications are also involved in cardiovascular aging and pathologies. For example, H3K27ac, which functions as an active promoter and enhancer, has been implicated as a promoter of age‐related genes in murine models. ⁵⁶ Other histone modifications of posttranslational modifications on histone H3 including H3K79me2, ⁵⁷ H3K9me2, ⁵⁸ and H4K20me3 ⁵⁹ have also been associated with pathological cardiac hypertrophy and aging. Although increased ROS promotes autophagy, repression of autophagy is observed in cardiac aging, possibly due to the exhaustion of the autophagic machinery due to the persistent and progressive increase in ROS with age. ⁶⁰

Cardiac aging is often associated with changes in the metabolic landscape including bioenergetics and metabolism whereby aging hearts demonstrate decreased oxidation of fatty acids with accumulation of free fatty acids and lipid droplets in heart tissue and increased glucose utilization a common feature in hypertrophic or dilated cardiomyopathy associated with cardiac aging. ⁶¹ , ⁶² This observation has been exploited using dietary interventions, including long‐term calorie restriction, and has been shown to significantly alleviate age‐associated mitochondrial dysfunction and offer cardiac protection. ⁶³ Transcriptional profile data of genes coding for the mitochondrial proteins from the ventricles of young (6 months) and old (24 months) mice showed a 95% downregulation of mitochondrial electron transport chain genes. ⁶⁴ Interestingly, the transcriptional downregulation of the mitochondrial electron transport chain genes in the ventricles of old mice contribute to increased metabolic stress that potentially imbalances the pro‐ and anti‐inflammatory responses associated with age‐associated heart disease.

Morphological and functional manifestations in the aging heart thus contribute to a deterioration in cardiac performance. An insight into the crosstalk between immunometabolism and these age‐related changes can prove crucial for developing effective therapeutic strategies aimed at alleviating the risks of chronic implications, particularly in older patients.

Metabolism in the Aging Heart

Age‐related cardiac degeneration due to impairments in structural, metabolic, and functional flexibilities contributes to an overall decline in cardiac efficiency, leading to the development of various cardiac pathologies (Figure 2). Endogenous aging is often associated with a progressive decline in mitochondrial efficiency due to aberrant mitochondrial function, increased ROS production, decreased ATP production, and metabolic reprogramming, all of which can cause changes in immune cell metabolism. ⁶² , ⁶⁵ Decreased oxidative capacity of the mitochondria, concomitant with increased oxidative damage, results in damage to essential macromolecules, including DNA, mitochondrial DNA, lipids, and proteins. ⁶⁶ , ⁶⁷ Cardiac output and myocardial efficiency serve as an index for the cardiac ATP supply. ⁶⁵ Perturbations in ATP production can lead to impairment in the contractile function of cardiomyocytes lowering the cardiac efficiency. Studies in a murine model of metabolic heart disease suggested that impairments in ATP production contribute to diastolic dysfunction. ⁶⁸ Age‐related impairments in ATP production and increased oxidative damage can thus result in metabolic and functional inflexibility in cardiomyocytes, impairing contractility and increasing susceptibility to cardiac pathologies. Modulation of mitochondrial metabolism and ATP generation may offer therapeutic avenues to mitigate diastolic dysfunction and improve overall cardiac health in older patients.

Figure 2. Structural, metabolic, and functional impairments in the aging heart.

Mitochondrial dysfunction manifests collectively as impairments in mitophagy, mitochondrial dynamics, and bioenergetics (ATP production) concomitantly with increased ROS levels, contributing to oxidative damage. Thus, the redox imbalance causes alterations in substrate utilization, including decreased fatty acid oxidation, increased glucose metabolism, and insulin resistance leading to metabolic inflexibility, lipid accumulation, and inflammation. Increased mitochondrial ROS also causes cardiac lipid accumulation^109,110 leading to cardiomyopathy in the aging heart. ROS indicates reactive oxygen species.

Age‐associated increased production of superoxide from the mitochondrial OXPHOS and other cellular sources contributes to oxidative damage that exacerbates mitochondrial electron transport chain dysfunction, creating a vicious cycle of oxidative stress.³⁵ OXPHOS is fueled by fatty acid β‐oxidation by providing reducing equivalents, namely, nicotinamide adenine dinucleotide and reduced flavin adenine dinucleotide that enter OXPHOS through complexes I and III. ⁶⁹ Aging leads to decreased fatty acid β‐oxidation in the mitochondrial matrix of cardiomyocytes, resulting in the generation of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, bolstering glucose metabolism and an increased production of cytokines including TNF‐α, interleukin‐1β, and interleukin‐6 creating a state of metabolic/substrate inflexibility. ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ Decreased fatty acid β‐oxidation along with increased glycolysis in cardiomyocytes, is a hallmark of metabolic remodeling that occurs in cardiac hypertrophy. ⁷⁶ Additionally, increased levels of glycolysis and glucose metabolism at the expense of fatty acid β‐oxidation and increased insulin secretion have been shown to correlate with immune activation. ⁷⁷ Age‐associated increase in the generation of mitochondrial ROS also contributes to increased cardiac lipid accumulation, leading to cardiomyopathy associated with the downregulation of peroxisome proliferator‐activated receptor that regulates cardiac fatty acid metabolism. ⁷⁸ , ⁷⁹ Peroxisome proliferator‐activated receptor is ubiquitous in almost every immune cell type and is considered anti‐inflammatory with increased expression associated with low levels of proinflammatory cytokines including TNF, interleukin‐1, and interleukin‐6. ⁸⁰

In addition to OXPHOS and cellular energy production, the selective degradation of dysfunctional mitochondria occurs through mitophagy, which aids in mitochondrial quality control. ⁸¹ Accumulation of damaged mitochondria due to impairments in mitophagy can contribute to age‐related implications including neurodegeneration, cancer, diabetes, and inflammation disorders. ⁸² Age‐associated decreased levels of Parkin and PTEN‐induced kinase 1, regulators of mitophagy can lead to accumulation of dysfunctional mitochondria, increasing oxidative stress levels thereby contributing to impaired cardiac contractility, myocardial stiffness, and development of fibrosis. ⁸³ , ⁸⁴ Studies have shown that age‐associated impairments in mitophagy can also lead to inflammation. For example, impaired mitophagy can result in cytosolic leakage of mitochondrial DNA that can activate the cyclic GMP‐AMP synthase–stimulator of interferon genes pathway of macrophage inflammatory response. ⁸⁵ Furthermore, age‐associated impaired mitophagy results in dysfunctional mitochondria, activating the NOD‐like receptor protein 3 inflammasome, augmenting the inflammatory response, and contributing to systemic inflammation. ⁸⁶

The overall metabolic shift in the aging heart coupled with the functional decline of mitochondrial oxidative metabolism thus contributes to oxidative stress, lipid accumulation, and inflammation driving toward the pathology of cardiomyopathy and impaired cardiac function. The cardiac milieu in the aging heart is thus a collective dysregulation of various pivotal aspects of metabolism that are highly interlinked and can be attributed causatively to age‐associated cardiac pathologies.

Immune Landscape and the Aging Heart

Cardiac aging is driven by degenerative structural, functional, and metabolic changes that result in a visceral increased inflammatory status due to impairments in the various aspects of the innate immune response caused by endogenous aging and exposure to stress. The accurate functional crosstalk between metabolism and the immune landscape during aging is thus deemed crucial for maintaining cardiac homeostasis to prevent the exacerbated development of age‐associated cardiac implications.

Chronic low‐grade inflammation, coined as “inflammaging” is an evolutionary perspective on the concept of “immunosenescence” that centers around the idea that aging is associated with increased infiltration of immune cells as a result of provoked antigenic load and stress (physical, chemical, and biological), which exacerbates tissue damage and overall fibrosis. ⁶ The adaptive immune response is capable of retaining specific memory related to stress as we age; activated T cells following stress will shrink and retain a subset of memory T cells that are prone to senescence with age and thus produce increased amounts of proinflammatory cytokines, mediators, and chemokines. ⁸⁷ , ⁸⁸ , ⁸⁹

Systemic and tissue‐specific (cardiac) low‐grade inflammation, commonly referred to as “inflammaging” is often associated with physiological changes such as aging and obesity and closely resembles immunosenescence. ⁹⁰ It is typically characterized by high levels of proinflammatory markers, TGF‐β, TNF‐α, and C‐reactive protein. ⁶ , ⁹¹ The levels of several immune mediators were found to be increased with age including interferon‐γ, interleukin‐2, interleukin‐6, and interleukin‐8. ⁹² , ⁹³ Increased levels of proinflammatory markers and cytokines cause a persistent inflammatory environment with changes in subsets of the myeloid cell population. This in conjunction with impaired repair, fibroblast activation, and altered mechanical properties, consequently leads to an overall functional decline and contributes to the development of myocardial fibrosis. ⁹⁴ , ⁹⁵

Age‐associated pathologies are often associated with changes in the different subsets of myeloid cell populations and immunosenescence. Macrophages represent the primary source of MMPs and tissue inhibitors of metalloproteinases and, along with myofibroblasts, have been shown to play a crucial role in the secretion of ECM components and their remodeling. ⁹⁴ , ⁹⁶ Macrophages are phagocytic cells with high plasticity and can change their functional phenotypic states from proinflammatory, antitumorigenic to anti‐inflammatory, protumorigenic, or wound healing macrophages in response to stress within the tissue microenvironment including infections, tissue injury, and cancer. ⁹⁷ , ⁹⁸ Activated to a proinflammatory phenotype (M1) in the early stages of the inflammation process, macrophages secrete proinflammatory cytokines and chemokines, including TNF‐α, interleukin‐6, interleukin‐12, and chemokine (C‐X‐C motif) ligands (CXCL9 and CXCL10) that subsequently recruit helper cluster of differentiation (CD) 4+ T cells and effector CD8+ T cells. ⁹⁷ , ⁹⁹ , ¹⁰⁰ Additionally, M1 macrophages release factors responsible for fibroblast activation, stimulating the production of ECMs, leading to excessive collagen deposition and fibrosis, increased stiffness, and diastolic dysfunction. ¹⁰¹ Aging has been associated with increased polarization of macrophages to the M1 phenotype resulting in an endogenously heightened inflammatory state. ⁹⁷ Moreover, age‐associated decline in the regenerative capacity of the heart along with the inflammatory input from the M1 macrophages can impede repair mechanisms leading to poor recovery in older patients. ⁹⁷ In contrast, reparative macrophages polarize to a fibrotic/wound healing (M2) phenotype following phagocytosis of apoptotic neutrophils characterized by decreased expression of interleukin‐6 and TNF‐α and an increase in TGF‐β, galectin‐3, and interleukin‐10. ¹⁰² , ¹⁰³ , ¹⁰⁴ While M2 macrophages are typically associated with repair and anti‐inflammatory responses, excessive activation can lead to the overproduction of ECM, increased production of profibrotic factors, and fibrosis. ¹⁰⁵ Interestingly, increased expression of anti‐inflammatory macrophages was observed in the lung ¹⁰⁶ and muscle ¹⁰⁷ of C57BL/6J mice with aging. Age‐related ROS accumulation resulting from altered mitochondrial metabolism leads to the accumulation of monocyte‐derived C‐C chemokine receptor type 2⁺ macrophages to replace cardiac resident macrophages and induced vascular endothelial cells to express high levels of vascular cell adhesion molecule 1, which furthers the monocyte infiltration into cardiac tissues contributing to inflammation and tissue damage. ¹⁰⁸ , ¹⁰⁹ Following infiltration into the cardiac tissues, the recruited monocytes can differentiate into macrophages, releasing inflammatory mediators, thereby contributing to tissue damage and remodeling under pathologies like myocardial infarction. ¹⁰⁸ Furthermore, increased accumulation of cardiac‐specific macrophages can induce the secretion of MMP9 that supports the progression of macrophages to the inflammatory phenotype (M1), which contributes to a chronic inflammation state in the aging heart, thereby activating collagen accumulation to promote interstitial fibrosis. ¹¹⁰ , ¹¹¹

T‐cell dysregulation impacts the aging heart due to profound changes induced due to immunosenescence. Studies have shown a progressive decrease in the population of naïve T cells and an increased population of memory and effector T cells. ⁶ , ¹¹² , ¹¹³ , ¹¹⁴ The skewing of T‐cell subsets to a memory phenotype occurs concurrently with the downregulation of costimulatory factors, including CD27 and CD28, which are aspects of human T‐cell senescence and increase the susceptibility to aging‐related pathologies like cardiovascular complications and cancer. ¹¹⁵ CD27 and CD28 provide a costimulatory signal and promote the assembly of the T‐cell complex to amplify the T‐cell receptor signals and support T‐cell expansion. ¹¹⁶ CD28 has been shown to promote cell cycle entry and activity as well as promote the survival of activated T cells through the upregulation of the anti‐apoptotic regulator of the Bcl‐2 family, Bcl‐xL. ¹¹⁷ Age‐related decrease in helper T cell populations has been linked to reduced myocardial inflammation and preserved cardiac function relative to age‐matched controls. ¹¹⁸ Furthermore, a unique population of memory CD4+ T cells referred to as senescence‐associated T cells expressing programmed cell death 1, CD153, a TNF family protein, and osteopontin have been identified to increase progressively in aging mice. ¹¹⁹ , ¹²⁰ Senescence‐associated T cells classically express programmed cell death 1, CD153, and osteopontin, which are markers attributed to immunosenescense and chronic low‐grade inflammation. ¹²¹ Osteopontin is involved in the regulation of cardiac fibrosis, with elevated levels of osteopontin observed in both the myocardium and the plasma of patients with both dilated and hypertrophic cardiomyopathy, as a result of fibroblast activation. ¹²² Recently, a growing body of research has identified a subpopulation of age‐associated granzyme K–expressing CD8+ T cells that are distinct from T‐effector memory cells that express markers of tissue homing and exhaustion ¹²³ and are suggested to be an intermediate memory‐like preterminally differentiated population of nonnaïve cells. ¹²⁴ These clonally expanded memory CD8+ T cells have been shown to accumulate in atherosclerotic plaques and are identified as proatherogenic in aged mice. ¹²⁵ Additionally, the age‐associated decline in telomere length and the consequent DNA damage during replicative senescence is driven by the homeostatic proliferation of T cells wherein T cells divide in the absence of a cognate antigen to reconstitute the lymphoid populations. ¹²⁶ , ¹²⁷ , ¹²⁸ In the aging heart, dysregulation of T cells can present in several ways: (1) as senescent CD4+ T cells leading to inflammation and age‐related cardiac dysfunction, ¹²¹ (2) changes in the makeup of cardiac‐resident leukocyte population with age, ³⁵ (3) secretion of proinflammatory cytokines that promote vascular pathology and increase the risk of cardiovascular disease, ¹²⁹ and (4) a decline in the rate of thymic T cells with age. ¹³⁰ Inflammaging has been shown to tip the scales toward memory T cells over the naïve cell population with CD4+ T cells polarizing toward a T‐helper 17 phenotype, consequently leading to the production of proinflammatory cytokines (interleukin‐17 and interferon‐γ), a concept often associated with atherosclerotic plaques within arteries, promoting the progression of the disease. ¹³¹ , ¹³² , ¹³³ This T‐helper 17 phenotype is often induced by a metabolic switch, resulting in the upregulation of glycolysis, facilitating sustained inflammation. Thus, the implications of aging‐associated immune senescence depend not only on the balance between the different T‐cell subsets and their functional decline but also influence the overall immune response including the activity/frequency of other immune cells like neutrophils.

Neutrophils respond to stress or injury by migrating to injured tissue sites to phagocytose pathogens, producing ROS that alleviates the sterile inflammation, which typically occurs in the absence of infection to aid in the clearance of damaged tissue debris. ¹³⁴ The differentiation of hematopoietic stem cells (HSCs) into mature neutrophils also known as granulopoiesis, is the de novo production of neutrophils in the hematopoietic cords of the bone marrow. ¹³⁵ , ¹³⁶ The stemness of HSCs decreases as a function of age toward a fate of myeloid lineage due to inflammation, dysfunctional mitochondrial metabolism, replicative stress, and reduced telomere length. ¹³⁷ Accumulation of gene mutations, particularly in stem cells, increases the proliferative potential of mutant HSCs, predisposing tissues to hematopoietic malignancies and cardiovascular disease. Sano et al demonstrated that Tet‐2 deficiency in HSCs exacerbates cardiac dysfunction in a murine heart failure model, primarily through the activation of interleukin‐1β–NOD‐like receptor protein 3 inflammasome signaling. ¹³⁸ Although aged HSCs shift toward a myeloid lineage, studies suggest that this may have minimal effect on neutrophil populations in healthy individuals. ¹³⁹ , ¹⁴⁰ However, murine studies consistently show an age‐associated increase in neutrophils within lymphoid organs. ¹³⁹ , ¹⁴¹ , ¹⁴² An age‐associated increase in CD16^high/CD62L^low immunosuppressive neutrophils was observed in conjunction with a low phagocytic index and reduced ROS production that increases the susceptibility to infections in older patients. ¹⁴³ Interestingly, age‐associated impairment in the myocardium correlates with a shift in the cardiac‐specific leukocytes and an increased population of neutrophils and monocytes. ¹¹⁸ These studies are suggestive of the concept that inflammaging in the heart renders mice susceptible to cardiac dysfunction.

Over the past few decades, substantial evidence has indicated immunosenescence as a risk factor for cardiovascular disease with an impact on myocardial physiology and function, thereby affecting the susceptibility to cardiovascular pathologies. ⁹¹ , ¹¹⁸ , ¹⁴⁴ With the significance of different subsets of leukocyte populations, including neutrophils, T cells, B cells, and macrophages/monocytes in cardiac repair and remodeling, the global landscape of immune response can thus impact the development and progression of cardiovascular diseases.

Clinical Interventions in the Aging Heart Pathologies

Modulation of immune tolerance by suppressing age‐associated inflammation to augment cardiac remodeling and metabolism has gained research precedence in the field of aging research. The age‐associated functional and metabolic decline in cardiac tissues has warranted the need for easily implementable, nontoxic therapeutic interventions that bolster the endogenous cardiovascular regenerative and reparative capacity. Several metabolic pathways and their metabolites have emerged as promising avenues to target immunometabolism in aging heart tissues, including mitochondria‐targeted biologics, anti‐inflammatory therapies, metabolic modulators, and lifestyle interventions.

With the detrimental role of oxidative stress and mitochondrial impairment in age‐associated cardiac functional decline and the associated pathologies, there is a rising interest in using conventional antioxidant therapies to mitigate the endogenous effects of aging on cardiac function. Some commonly used nonspecific antioxidants include NOX inhibitors and N‐acetylcysteine. Studies using pharmacological NOX inhibitors, apocynin, and VAS2870 have demonstrated improved β‐adrenergic stimulated contractility and intracellular calcium handling in aged rat hearts. ¹⁴⁵ Additionally, treatment with GLX481304, a pharmacological inhibitor of Nox 2 and 4, has been shown to inhibit ROS production in isolated mouse cardiomyocytes and improve contractility and function following ischemia–reperfusion injury in mice via direct effects on the cardiomyocytes by inhibiting a ROS‐induced modification of the contractile system. ¹⁴⁶ Moreover, NOX4 has been shown to regulate cardiac intermediatory metabolism via H₂O₂‐specific signaling. ¹⁴⁷ , ¹⁴⁸ Although different isoforms of NOXs have been favorably used to modulate ROS and thereby modify the redox environment, the functional diversity of NOX enzymes in the cardiovascular system has prevented using specific NOX inhibitors to alleviate age‐associated cardiac pathologies. N‐acetylcysteine is known for its antioxidant and anti‐inflammatory properties and acts by upregulating the rate of glutathione synthesis, suppressing nuclear factor κ B, and decreasing the production of proinflammatory cytokines, i.e., interleukin‐1, interleukin‐6, and TNF. ¹⁴⁹ Several studies have focused on the clinical implications of N‐acetylcysteine, which include protection against coronary artery disease, myocardial infarction, atrial fibrillation, and cardiomyopathy. ¹⁵⁰ , ¹⁵¹ , ¹⁵²

Mitochondrially targeted antioxidants that specifically reduce mitochondrial ROS have also been clinically used to target the implications on the aging heart. Mitoquinone, a ubiquinol antioxidant with high bioavailability, attached to a triphenylphosphonium moiety, enables it to cross cell membranes and accumulate in the mitochondrial matrix to reduce mitochondrial ROS and improve mitochondrial function. ¹⁵³ , ¹⁵⁴ Preclinical models have shown that treatment with 200‐μM mitoquinone in drinking water for up to 7 weeks decreased MitoSOX oxidation in bone marrow–derived neutrophils in both male and female mice along with reduced neutrophil ROS and neutrophil extracellular traps formation. ¹⁵⁵ A clinical trial in 2018 showed that mitoquinone was well tolerated in healthy older adults and led to a 42% increase in brachial artery flow‐mediated dilation following treatment with 20 mg/day mitoquinone for 6 weeks, along with alleviation in mitochondrial ROS‐related suppression of endothelial function and lower aortic stiffness (Mitochondrial‐Targeted Antioxidant Supplementation for Improving Age‐Related Vascular Dysfunction in Humans, NCT04851288). ¹⁵⁶ Furthermore, the plasma levels of oxidized low‐density lipoprotein were also found to be lower in the mitoquinone‐treated groups relative to placebo, indicating that targeting mitochondria ROS may be of significance in treating age‐associated vascular dysfunction. ¹⁵⁶ Furthermore, in a double‐blinded, randomized clinical trial, mitoquinone and endurance training, individually and in combination, effectively enhanced cardiovascular health by reducing inflammation and increasing antioxidant defense. ¹⁵⁷ The study suggested that the combination of mitoquinone and endurance training significantly decreased systolic blood pressure, improved cardiac function indices including LV mass and LV end‐systolic diameter, and reduced interleukin‐6 levels via modulation of microRNA‐222. ¹⁵⁷ Additionally, an ongoing clinical trial at the University of Connecticut is assessing the effects of mitoquinone supplementation on vasodilation, mobility, and cognitive performance in frail older adults (The Mito‐Frail Trial: Effects of MitoQ on Vasodilation, Mobility and Cognitive Performance in Frail Older Adults, NCT06027554).

Another mitochondria‐targeted synthetic tetrapeptide, elamipretide, also known as bendavia, has emerged as a mitochondria‐specific therapeutic that has been shown to restore mitochondrial bioenergetics by targeting cardiolipin and accumulating in the inner mitochondrial membrane. ¹⁵⁸ , ¹⁵⁹ , ¹⁶⁰ , ¹⁶¹ Elamipretide has been shown to reduce the generation of mitochondrial ROS and optimize ATP synthesis and mitochondrial electron transport thereby preventing cardiac pathologies. ¹⁵⁸ , ¹⁵⁹ , ¹⁶⁰ , ¹⁶¹ Additionally, elamipretide has also been in several clinical trials for acute and chronic cardiac events (EMBRACE [Evaluation of Myocardial Effects of MTP‐131 for Reducing Reperfusion Injury in Patients With Acute Coronary Events], NCT01572909; A Study to Evaluate the Effects of 4 Weeks Treatment With Subcutaneous Elamipretide on Left Ventricular Function in Subjects With Stable Heart Failure With Preserved Ejection Fraction, NCT02814097; Effect of Elamipretide on Left Ventricular Function in Subjects With Stable Heart Failure With Reduced Ejection Fraction, NCT02788747; A Phase 2 Study to Evaluate the Cardiac and Renal Effects of Short Term Treatment With Elamipretide in Patients Hospitalized With Congestion Due to Heart Failure, NCT02914665; A Study Investigating the Safety, Tolerability, and Pharmacokinetics of MTP‐131 in Subjects With Congestive Heart Failure, NCT02388464) and mitochondrial disorders (MMPOWER [Safety, Tolerability, and Efficacy of MTP‐131 for the Treatment of Mitochondrial Myopathy], NCT02367014). The highly lipophilic quinone, coenzyme Q10 (CoQ10), or ubiquinone, is a potent antioxidant that has been shown to facilitate mitochondrial‐associated ATP production. ¹⁶² In addition to serving as an electron carrier in the mitochondria, the anti‐inflammatory role of CoQ10 is attributed to its ability to repress inflammatory gene expression, thereby improving immune function. Preclinical data demonstrate a pathophysiological role for CoQ10 in heart failure and other cardiovascular events with improved outcomes following CoQ10 supplementation. ¹⁶³ CoQ10 has been in clinical trials for >30 years as an intervention for cardiovascular diseases, including heart failure (PANDA [Protective Effect of CoQ10 Against Negative Inflammatory Response and Organ Dysfunction in Cardiovascular Surgery], NCT04444349) and coronary artery disease (Coenzyme Q10 in Relation of the Lipid Peroxidation, Antioxidant Enzyme Activities in Coronary Artery Disease Patients, NCT01163500).

Several anti‐inflammatory therapies have also been employed to maintain homeostasis in the endogenous inflammation‐prone environment of the aging heart. For example, increased levels of interleukin‐6 in older patients have demonstrated an increased risk for cardiovascular death by 69%, thereby increasing the risk of “all‐cause” death. ¹⁶⁴ Cytokine inhibitors that target proinflammatory cytokines like interleukin‐6 can aid in decreasing age‐associated chronic inflammation in the heart. More specifically, tocilizumab, an antagonist for the interleukin‐6 receptor, has shown potential in dampening systemic inflammation, thereby improving age‐associated cardiac outcomes to mitigate organ injury in patients. ¹⁶⁵ In a clinical trial for modulation of systemic inflammatory response after out‐of‐hospital cardiac arrest, treatment with tocilizumab was shown to profoundly decrease the levels of C‐reactive protein (−84%) and leukocytes (−34%) (IMICA [Interleukin‐6 Inhibition for Modulating Inflammation After Cardiac Arrest], NCT03863015). ¹⁶⁵ Increased circulating levels of TNF have been associated with increased prevalence of atherosclerosis in older patients. ¹⁶⁶ As such, TNF antagonists that have the potential to reduce inflammation have been investigated for their potential benefits in age‐associated cardiovascular pathologies, including rheumatoid arthritis, and atherosclerosis, and have been associated with a decreased risk of myocardial infarction ¹⁶⁷ and acute coronary syndrome. ¹⁶⁸ Upregulation in macrophage‐associated inflammatory cytokines, including TNF, interleukin‐1β, and interleukin‐6, has been seen in rheumatoid arthritis, with interleukin‐6 as a crucial factor in plaque destabilization and atherothrombosis. ¹⁶⁹ Etanercept (Enbrel) is a soluble, TNF receptor–IgG1 fusion protein that binds and inhibits TNF, thereby preventing TNF‐mediated inflammatory responses. Etanercept has been approved by the Food and Drug Administration for rheumatoid arthritis. ¹⁷⁰ Although the pathological role of TNF has been assessed using population‐based studies in cardiac pathologies with elevated serum levels of the proinflammatory cytokine, the complex nature of cytokine‐based therapies presents with disease‐associated benefits and side effects. As such, anti‐TNF therapies have been criticized for their poor cardiac clinical outcomes including increased deaths, increasing hospitalizations, and worsening congestive heart failure. ¹⁷¹ , ¹⁷² The CANTOS (Canakinumab Anti‐inflammatory Thrombosis Outcome Study, NCT01327846) trial demonstrated that inhibition of interleukin‐1β (a highly pleiotropic, proinflammatory cytokine) in patients with previous myocardial infarction and a high C‐reactive protein lowered the rate of recurrent cardiovascular events compared with placebo. ¹⁷³ Notably, interleukin‐1β inhibition has been shown to reduce the T‐helper 17/regulatory T cell (Treg) imbalance and promote the differentiation of naïve CD4+ T cells into T‐helper 17 cells. ¹⁷⁴ Additionally, anakinra (kineret), interleukin‐1 receptor antagonist, has been employed to treat a wide spectrum of cardiovascular diseases. ¹⁷⁵ , ¹⁷⁶ Other immunomodulatory therapies include infliximab, a TNF inhibitor that has been shown to enhance Treg function by increasing their proliferation and capacity to suppress proinflammatory cytokine production. ¹⁷⁷ It needs to be noted that although effective in modulating the proinflammatory response, cytokine‐targeting therapies have been shown to increase the risk of infection particularly due to immune suppression. In CANTOS, canakinumab was associated with increased rates of neutropenia, cellulitis, pseudomembranous colitis, fatal infection, or sepsis, limiting its use in nonautoimmune conditions including atherosclerosis. ¹⁷³ Additionally, the TNF inhibitor infliximab significantly increases the risk of developing bacterial infections due to its immunosuppressive effects as well as latent tuberculosis infections due to the risk of reactivation of latent tuberculosis. ¹⁷⁸ The efficacy of repurposed therapeutic drugs thus needs to be evaluated to outweigh the risk of adverse side effects in cardiovascular and metabolic disease conditions.

Therapies that modulate specific immune cell subsets have also been employed to alleviate the cardiac inflammatory phenotype. Tregs are the immunosuppressive subset of CD4+ T cells that alternate between glycolysis and OXPHOS for proliferation. ¹⁷⁹ Tregs play a key role in the modulation of the inflammatory cascade and maintain immune homeostasis. ¹⁷⁹ Characterized by the expression of CD4, CD25, and the transcription factor forkhead box P3, Tregs are derived from the thymus or peripheral naïve T cells. ¹⁸⁰ Tregs secrete anti‐inflammatory cytokines including interleukin‐10 and TGF‐β that aid in immune activation and mitigate tissue damage. ¹⁸⁰ Naïve T cells undergo differentiation into 4 different subsets including T‐helper T cells, T‐helper 2 cells, T‐helper 17 cells, and Tregs. ¹⁸⁰ , ¹⁸¹ Among these, T‐helper 17 has emerged as a marker in the context of cardiovascular diseases. T‐helper 17 cells generate increased levels of the proinflammatory cytokine interleukin‐17 in patients with acute coronary syndrome ¹⁸² and heart failure. ¹⁸⁰ , ¹⁸³ Increased T‐helper 17 cells relative to Tregs create a functional imbalance in the T‐helper 17/Treg ratio thereby promoting an inflammatory phenotype and disease progression. Recent studies have shown that elderly patients with atrial fibrillation enhance the Treg population in the spleen and blood upon oral administration of Bacteroides fragilis, an anaerobic, gram‐negative bacterium commonly found in the microbiota of the human colon. ¹⁸⁴ Ex vivo expansion or adoptive transfer therapies of Tregs have emerged in recent years as a clinical approach in cardiovascular pathologies. The global burden of an aging population and the increasing number of “cancer survivors” populace is associated with an enhanced risk of cardiovascular diseases due to endogenous aging implications or as a chronic impression of cancer therapies. Although the field of immunometabolic interventions has been of much research interest, there is still a lack of rigorous clinical evidence/data from randomized trials that tests the effects of targeted immune interventions on metabolism and vice versa. In terms of improving aging heart pathologies, targeting immunometabolic pathways and their modulation has been effective in alleviating chronic inflammatory changes and metabolic impairments that are characteristic of the aging heart to enhance cardiac function and repair, reduce the incidence of age‐related cardiovascular diseases, and ultimately improve the quality of life in the elderly population.

Sources of Funding

This work was supported by National Institutes of Health grants UO1 AI184289 and R21 CA270742‐01.

Disclosures

None.