The heart-brain crosstalk in age related cardiovascular and neurodegenerative diseases

Abstract

Aging is a major risk factor for both cardiovascular and neurodegenerative diseases. The bidirectional communication between the heart and brain, commonly referred to as heart-brain crosstalk, is increasingly disrupted with age. In this review, we summarize current evidence linking cardiovascular and neurodegenerative disorders, particularly in the context of aging. We also discuss the underlying mechanisms responsible for the heart-brain crosstalk, including blood-brain barrier breakdown, vascular dysfunction, nervous system alterations, inflammation, and endocrine dysregulation, which may explain the frequent co-occurrence of dysfunction in both organs during aging. Understanding these interconnections provides critical insights into the pathophysiology of age-related diseases and highlights potential therapeutic targets to preserve both heart and brain health in the aging population.

Introduction

Cardiovascular and neurodegenerative diseases are among the leading causes of morbidity and mortality in the aging population. In the United States, approximately 75% of individuals aged 60–79 years and over 89% of those aged 80 and above are affected by cardiovascular diseases (CVDs), including hypertension, coronary heart disease, and stroke [1]. In 2016, stroke caused 5.5 million deaths and accounted for 116.4 million disability adjusted life years (DALYs) lost globally [2]. After an ischemic stroke, approximately 70% of patients are dead or disabled, and these numbers are expected to increase in the future [3, 4]. Simultaneously, the prevalence of neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), increases with age. It is estimated that one in ten individuals aged 65 and older has AD, with prevalence rising significantly in more advanced age groups [5]. Gender-based studies suggest that women may be more susceptible to the effects of aging. For instance, heart failure with preserved ejection fraction (HFpEF) is more common in women, even in the absence of coronary artery disease (CAD) or atrial fibrillation. While women demonstrate better overall survival than men, they experience more pronounced symptoms, greater congestion, and reduced quality of life [6, 7]. In addition, studies consistently show that women have a higher risk of developing AD than men [8].

Aging is a major risk factor for both cardiovascular and neurodegenerative diseases, not only due to the accumulation of traditional risk factors such as hypertension, diabetes, and atherosclerosis, but also because of intrinsic biological changes during aging. These changes include endothelial and arterial alterations, increased myocardial thickness, breakdown of the blood-brain barrier, and impaired neurovascular coupling [9, 10]. Despite advances in the management of neurological and cardiovascular disorders, their systemic impact often extends beyond the primary organs, with the cardiovascular system playing a significant role in overall morbidity and mortality [11]. The intricate, bidirectional communication between the heart and brain, commonly referred to as heart-brain crosstalk, becomes increasingly critical with aging. This interaction is primarily mediated by the autonomic nervous system, immune signals, and endocrine pathways, enabling the two organs to work in harmony under normal conditions [11]. However, aging disrupts this communication. Autonomic dysfunction, vascular changes, and oxidative stress contribute to impaired heart-brain crosstalk, thereby increasing the risk of both cardiovascular and neurodegenerative diseases [12, 13].

This review summarizes the latest studies on heart-brain interactions in age-related cardiovascular and neurodegenerative diseases. We also discuss the underlying mechanisms responsible for such heart-brain crosstalk. This review addresses the increasingly recognized yet underexplored concept of brain-heart crosstalk in term of aging, emphasizing how dysfunction in one system can significantly influence the other and how aging modifies these influences.

Evidence for heart-brain interactions in age-related cardiovascular and neurodegenerative diseases (Table 1)

Table 1.

Recent clinical studies for heart-brain interactions

Author	Journal	Main clinical finding
Çalik, A.N. et al. [17]	Clin Interv Aging	AD is associated with left ventricular diastolic dysfunction (decreased mitral e velocity (52.3 ± 9.1 cm/s), increased LA AP-diameter (42.1 ± 2.4 mm), increased atrial conduction time through the mitral valve (67.1 ± 6.3 mm), increased aortic stiffness (11.8 ± 5.7 mm), decreased diastolic blood pressure and aortic diameter (34.1 ± 3.9 mm).
Johansen, M. C. et al. [18]	Stroke	Left ventricular diameter is associated with deposition of Aβ (β-amyloid) (1 cm increase in diameter is associated with double the odds for Aβ (OR: 2.04).
Olesen, K. K. W. et al. [15]	European journal of preventive cardiology	CAD alone and together with diabetes increased the risk for all-cause dementia: CAD alone (HR: 1.11); CAD & diabetes (HR: 1.37), and AD dementia (HR: 1.41).
Zheng, F. et al. [16]	JACC. Heart failure	Patients with HF had a higher risk for all-cause dementia (HR:1.18), AD (HR:1.64), and VD (HR: 1.27) with earlier age of onset of HF correlating to higher HR (age < 65 years, HR: 1.67).
Park, J.H. et al. [21]	Circulation	Parkinson’s disease increases the risk of MI (HR: 1.43), ischemic stroke (HR: 1.42), CHF (HR: 1.65), and all-cause mortality (HR: 2.7).
Xu, K. et al. [22]	J Clin Neurosci	Hypertension (OR: 1.04), and CAD (OR: 1.19) were related to ALS. HF increased the progression rate of ALS (OR: 6.33).
Ke, L. et al. [23]	Lipids Health Dis	PD was associated with an adjusted HR of 1.82 for cardiovascular death and 1.84 for all-cause mortality.
Corraini, P. et al. [24]	Stroke	The risk of dementia among stroke survivors was 11.5% with the HR for dementia being 1.72 after ischemic stroke.
Montellano, F.A. et al. [26]	BMC Neurol	37% of patients after ischemic stroke had elevated troponin T, which was independently associated with older age (OR: 1.05), systolic dysfunction (OR: 2.79), diastolic dysfunction (OR: 2.29), atrial fibrillation (OR: 2.30), and increased levels of C-reactive protein (OR: 1.48).
Waziry, R. et al. [25]	Neurology	Individuals with AD had a 42% increased risk of hemorrhagic stroke (RR: 1.42), while the risk of ischemic stroke was also higher (RR: 1.15).
Bunch, T. J. et al. [28]	Heart Rhythm	Atrial fibrillation is significantly associated with AD (HR: 1.38).
Qiu C. et al. [29]	JAMA internal medicine	Dementia and AD risk was increased in patients with HF (HR:1.80).
Shore, S. et al. [30]	Circulation: Heart Failure	HF is associated with decrease in cognitive and executive function, and change in memory (-1.1 points).
Xie, b. et al. [31]	Brain and behavior	Carotid atherosclerosis is prevalent in AD (OR: 1.46).
Park, J. H. et al. [21]	Circulation	PD increases the risk of MI (HR:1.43), ischemic stroke (HR: 1.42), congestive heart failure (HR: 1.65), and all-cause mortality (HR: 2.7).
Brodtmann, A. et al. [32]	Frontiers in neurology	Individuals who had ischemic stroke showed significantly greater total brain volume loss compared to stroke-free controls (adjusted mean difference 7.88).
Debette, S. et al. [33]	Congestive heart failure	Cognitive impairment was found in 31% patients who were presented with decompensate heart failure.
Zhou J. et al. [34]	Journal of Alzheimer’s Disease	A meta-analysis comprising 9 studies found increased risk for AD after stroke (effect size = 1.59).
Dhana. et al. [35]	JAMA Network	Better cardiovascular health scores were significantly associated with lower levels of neurodegenerative biomarkers such as neurofilament light chain and total tau.

OR: odds ratio; LA: left atrium; AP: anteroposterior; PP: pulse pressure; CAD: coronary artery disease; HR: hazards ratio; RR: relative risk; AD: Alzheimer’s disease; VD: vascular dementia; MI: myocardial infarction; CHF: congestive heart failure; ALS: amyotrophic lateral sclerosis; PD: Parkinson’s disease

Clinical and animal studies have shown a strong association between age-related cardiovascular and neurodegenerative diseases. Zhang F et al. found a higher risk of angina pectoris in patients genetically predisposed to AD in a large genome-wide association study [14]. Similarly, CAD and heart failure (HF) increase the risk of all-cause dementia, including vascular dementia and AD, with earlier onset of CVDs having a stronger correlation with cognitive impairment [15, 16]. Moreover, evidence suggests that individuals with AD exhibit greater diastolic dysfunction, prolonged atrial conduction times, and increased arterial stiffness when compared to age- and sex-matched controls [17]. Patients with increased end-diastolic left ventricular diameter show deposition of Aβ (β-amyloid), a pathological marker for AD, in brain tissue [18]. Another clinical study also identified cardiac abnormalities and diastolic dysfunction in AD patients [19]. Consistent with these clinical observations, it has been reported that APPSWE/PS1Tg mice (an AD mouse model) exhibited cardiac remodeling characterized by increased fibrosis, cardiac hypertrophy, and diastolic dysfunction [20]. In addition, other neurodegenerative disorders, such as PD and amyotrophic lateral sclerosis (ALS), demonstrate increased risks of cardiovascular disorders, including ischemic stroke, MI, HF, and all-cause mortality [21–23]. Stroke is an important risk factor for dementia and AD, and individuals with AD may have an increased risk of hemorrhagic stroke [24, 25]. Moreover, studies support potential heart-brain crosstalk in age-related cardiovascular diseases. For example, cardiac complications of ischemic stroke, including atrial fibrillation (23.6%), systolic dysfunction (10.4%), coronary artery disease (17.1%), and diastolic dysfunction (24.5%), have been reported [26]. There is also evidence showing cardiac diastolic dysfunction in post-stroke mice [27]. Taken together, these studies highlight the close and complex connection between the heart and brain, especially in aging populations. This growing body of evidence indicates the importance of further exploring this bidirectional relationship to better understand shared mechanisms, reduce complications, enhance quality of life, and potentially slow disease progression in older adults.

Potential molecular mechanisms involved in heart-brain crosstalk during aging

The heart-to-brain axis refers to the communication from the heart to the brain, encompassing several feedback mechanisms that originate from the heart and influence the physiological and cognitive states and functions of the brain. Conversely, the brain-to-heart axis represents a complex neurocardiac network through which the central nervous system exerts regulatory control over cardiac structure and function. Dysregulation within this axis, whether due to structural, functional, or inflammatory insults, can precipitate a spectrum of cardiovascular disturbances, ranging from myocardial dysfunction to autonomic failure. Here, we discuss the potential contributions of several molecular mechanisms along the heart-to-brain and brain-to-heart axes in age-related cardiovascular and neurodegenerative diseases.

Age-related decline in blood-brain barrier function (Fig. 1)

Fig. 1.

Age-related blood-brain barrier dysfunction and its role in cardiovascular and neurodegenerative diseases. Aging reduces the expression of protective molecules, including sirtuin-1, connexin-43, and occludin, while increasing oxidative and inflammatory stress and disrupting the BBB. This disruption allows entrance of harmful substances into the brain and impairs nutrient transport, raising the risk of neurodegenerative diseases (NDDs). In turn, NDDs can worsen cardiovascular diseases (CVDs) via autonomic nervous system (ANS) dysfunction, creating a cycle of brain-heart deterioration. TNF: tumor necrosis factor; ROS: reactive oxygen species; BBB: blood brain barrier; BECs: brain endothelial cells; NO: nitrogen oxide; HRV: heart rate variability

The blood-brain barrier (BBB) is a continuous network of non-fenestrated vessels that tightly regulate the exchange of nutrients and other molecules between the brain and the circulation. It maintains the brain’s homeostasis and protects it from internal and external dangers [36]. The BBB is mainly composed of brain endothelial cells (BECs), astrocytic endfeet, pericytes, and the basal lamina [37]. BECs possess specialized characteristics that limit the uncontrolled movement of substances from the bloodstream into the brain, while selectively allowing nutrients and hormones to pass through [38]. Besides acting as a barrier and transport system, they also help the brain communicate with the rest of the body and keep the immune system in check inside the brain [39]. Astrocytic endfeet are specialized, finger-like extensions of astrocytes that surround and wrap around blood vessels. These structures play vital roles in the regulation of BBB integrity and cerebral blood flow [40]. Pericytes, which are mural cells located along capillaries, actively contribute to BBB function and cerebral perfusion [41]. The basal lamina is a highly organized structure composed of extracellular matrix proteins, including laminin, collagen IV, nidogen, and perlecan [37] .

Aging is associated with progressive disruption of BBB integrity, characterized by increased paracellular and transcellular permeability, loss of tight junction proteins (e.g., claudin-5 and occludin), dysfunction of pericytes and astrocytic endfeet [42, 43]. Aging-related BBB dysfunction is driven by several molecular mechanisms, including endothelial cell senescence, oxidative stress, and inflammatory responses [44, 45]. Age-related vascular dysfunction and systemic inflammation are often linked to cardiovascular diseases, which can further compromise BBB permeability, allowing the entrance of pro-inflammatory cytokines and oxidative stress markers into the brain, thereby contributing to neuronal injury [46]. A decline in sirtuin-1 (SIRT1) expression in BECs disrupts tight junction integrity by downregulating claudin-5 and occludin, thereby exacerbating BBB breakdown [46]. Similarly, aging reduces BECs expression of connexin 43 (CX43), which plays a non-canonical role in maintaining BBB integrity. Mechanistically, CX43 suppresses poly ADP-ribose polymerase 1 (PARP1), a major NAD⁺ consumer. Loss of CX43 leads to PARP1 overactivation, NAD⁺ depletion, mitochondrial dysfunction, and ultimately BBB leakage. Notably, pharmacological inhibition of PARP1 or restoration of NAD⁺ levels rescues BBB integrity, highlighting the CX43-PARP1-NAD⁺ axis as a promising therapeutic target in vascular aging [47]. In addition, Atg7, an essential autophagy-related gene, plays a critical role in maintaining BBB structure. Endothelial-specific deletion of Atg7 disrupts fibronectin-mediated pericyte-BECs association, leading to pericyte detachment and increased BBB permeability [48]. Senescent endothelial cells are characterized by irreversible growth arrest, increased oxidative stress, and reduced production of nitric oxide (NO) , a critical signaling molecule that regulates vascular tone. These cells also secrete pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP) [49]. These inflammatory mediators, such as tumor necrosis factor (TNF), can enter systemic circulation and upregulate endothelial inflammatory receptors, including intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. This cascade leads to endothelial dysfunction, a central pathological mechanism in the development of hypertension, atherosclerosis, and coronary artery disease [49, 50]. Moreover, the heart-brain axis relies on an intact BBB to mediate neurohormonal signaling, including the transport of key molecules essential for neuronal function and cerebrovascular health (e.g. insulin, leptin, and neurotrophic factors) [51]. In aging, disruptions in these signaling pathways can lead to cerebrovascular stiffening, impaired neuronal repair, and increased vulnerability to ischemic injury [44]. BBB dysfunction can impair the brain’s ability to regulate sympathetic nervous system (SNS) activity, leading to increased blood pressure variability and a heightened risk of hypertension and cardiac arrhythmias [50]. A compromised BBB also permits the accumulation of neurotoxic substances within the brain, contributing to the development of cerebral small vessel disease (CSVD). CSVD is strongly associated with an increased risk of ischemic stroke, which can exacerbate cardiovascular complications [52].

Preserving the integrity of the BBB is essential for maintaining cognitive function and mitigating cardiovascular complications, especially during aging. Therapeutic strategies aimed at enhancing endothelial function, reducing systemic inflammation, and supporting neurovascular health, are of growing interest. Among these, sirtuin modulators, especially SIRT1 and SIRT3 activators, have shown promise in promoting endothelial stability, mitochondrial function, and BBB maintenance [53]. Additionally, the functions of stem cell-derived extracellular vesicles, NLRP3 inflammasome inhibitors, and hydrogen-rich water in BBB integrity are being explored currently [44, 45]. Collectively, these emerging strategies highlight the therapeutic potential of targeting BBB dysfunction to slow the progression of both neurodegenerative and cardiovascular diseases.

Age-related coronary vessels dysfunction

As individuals age, the coronary vasculature, a network of small blood vessels supplying oxygen and nutrients to the heart muscle, undergoes structural and functional changes that not only impair cardiac performance but also influence brain health. Aging is associated with endothelial dysfunction, increased arterial stiffness, and microvascular rarefaction in the coronary arteries, all of which contribute to reduced myocardial perfusion and diminished cardiac efficiency [54]. These alterations can lead to decreased cardiac output, which in turn compromises cerebral perfusion, particularly in brain regions vulnerable to hypoxia. Chronic reduction in cerebral blood flow (CBF), the volume of blood passing through a given amount of brain tissue per unit time, is known to accelerate neurodegeneration and cognitive decline, especially in individuals with HF or CAD [55]. Moreover, shared microvascular pathology has been observed in both the heart and brain, suggesting a common pathophysiological basis involving oxidative stress, inflammation, and impaired NO signaling [56]. El-Rabadi et al. demonstrated that aging reduced the density of nerve fibers in the coronary microvasculature, potentially affecting cardiac rhythm & stress responses and altering neural signals transmitted to the brain [57]. In addition, chronic low-grade inflammation and oxidative stress contribute to atherosclerotic plaque formation, further impairing coronary circulation and increasing the risks of MI and stroke [58].

Age-related coronary vascular dysfunction also disrupts autonomic regulation, contributing to hypertension and arrhythmias, which further compromise cerebral perfusion and brain health. In summary, age-associated changes in the coronary vasculature play a critical role in the deterioration of heart-brain communication. These changes not only impair myocardial function but also contribute to cerebral hypoperfusion, cognitive decline, and increased susceptibility to neurovascular and neurodegenerative diseases.

Impairment of neurovascular coupling in aging

Neurovascular coupling (NVC) is a fundamental physiological process that links neuronal activity to local changes in cerebral blood flow, ensuring that active brain regions receive adequate oxygen and nutrients. This tightly regulated mechanism involves a complex interplay among neurons, astrocytes, and vascular cells, mediated by signaling molecules such as NO, potassium ions, and arachidonic acid derivatives [59]. Aging significantly impairs NVC through multiple interrelated mechanisms (Fig. 2). One major factor is endothelial dysfunction, where increased oxidative stress and inflammation reduce the bioavailability of NO, a critical vasodilator, thereby weakening vascular responses to neuronal activity. Additionally, aging alters astrocyte signaling and pericyte contractility, disrupting the precise regulation of capillary blood flow. Mitochondrial dysfunction further compromises the energy metabolism of vascular and glial cells, exacerbating the decline in NVC efficiency. Structural changes, such as capillary rarefaction and vessel stiffening, also limit the brain’s ability to dynamically adjust blood flow, contributing to cognitive decline and increased vulnerability to neurodegenerative diseases (NDDs) [60]. CVDs exacerbate the impairment of NVC in aging, accelerating cognitive decline and increasing the risk of neurodegeneration. Conditions such as hypertension, HF, and atherosclerosis disrupt this finely tuned regulation by inducing endothelial dysfunction, reducing NO bioavailability, and promoting oxidative stress and inflammation [61, 62]. While interpericyte tunneling nanotubes (IP-TNTs) have been shown to play a critical role in coordinating pericyte responses during NVC [63], their role in aging remains unexplored. Given the known age-related decline in pericyte function and calcium signaling, it is plausible that IP-TNT integrity or signaling efficiency may deteriorate with age, contributing to impaired NVC.

Fig. 2.

Neurovascular coupling impairment in aging. Aging impairs neurovascular coupling through autonomic nervous system (ANS) dysfunction, reduced baroreceptor and chemoreceptor sensitivity, and structural changes in the blood-brain barrier (BBB). These alterations disrupt cerebral blood flow regulation, leading to chronic hypoxia, oxidative stress, and hypertension. These factors drive both cardiovascular and neurodegenerative diseases in a self-reinforcing cycle. ANS: autonomic nervous system; BECs; brain endothelial cells; ROS: reactive oxygen species; NO: nitrogen oxide; BP: blood pressure; CVDs: cardiovascular diseases; NDDs: neurodegenerative diseases

A recent population-based study from the Chicago Health and Aging Project (CHAP) demonstrated that better cardiovascular health is associated with lower serum levels of neurofilament light chain and total tau, both of which are established markers of neuronal injury and neurodegenerative disease. These findings suggest that maintaining cardiovascular health may help preserve neurovascular integrity and reduce the burden of neurodegeneration in aging populations [64]. Similarly, nicotinamide mononucleotide (NMN), a precursor to NAD⁺, has been shown to reverse age-related declines in endothelial NO production, reduce oxidative stress, and enhance vasodilatory responses to neuronal activity. These improvements in NVC were accompanied by enhanced cognitive performance in behavioral tests, suggesting that NMN may counteract age-related cognitive decline by preserving vascular and neurovascular health [65].

Baroreceptors and chemoreceptors

Baroreceptors are pressure-sensitive nerve endings located throughout the cardiovascular system, including the aorta, carotid arteries, and heart. These receptors communicate with the nucleus tractus solitarius in the brainstem to regulate vascular tone, heart rate, cardiac contractility, and preload, thereby maintaining cardiovascular homeostasis. This regulation is mediated through neurohormonal pathways, including the renin-angiotensin-aldosterone system (RAAS) and vasopressin signaling [66, 67]. In cardiovascular diseases such as MI and HF, baroreceptor sensitivity is often impaired, leading to sympathetic overactivity and worsened clinical outcomes [67]. Notably, reduced baroreceptor sensitivity is an independent predictor of cardiovascular mortality following MI [68]. Similarly, neurological disorders, such as epilepsy, traumatic brain injury, and stroke, can impair baroreceptor function and autonomic reflexes, further exacerbating cardiovascular risk [69]. Chemoreceptors, located centrally in the brain and peripherally in the carotid and aortic bodies, detect changes in blood pH and gas concentrations (CO₂ and O₂). These receptors are integral to the heart-brain axis, modulating respiratory and cardiovascular responses to metabolic demands [70]. High chemosensitivity induced sympathetic outflow and impairment of baroreceptors have been identified in cardiovascular disorders. Ablation of chemoreceptors improves cardiac remodeling and attenuates the deterioration of left ventricular ejection fraction [71].

Aging significantly impacts the function of these receptors. In the carotid bodies, glomus cells undergo age-related degeneration, characterized by increased oxidative stress, reduced mitochondrial and secretory vesicle content, and accumulation of lipofuscin, a marker of cellular aging [72]. Concurrently, baroreceptor function declines with age, contributing to increased blood pressure, vascular stiffness, and reduced adaptability to hemodynamic changes. This decline in baroreceptor sensitivity is believed to underlie the age-related increase in sympathetic nervous system activity, which contributes to the development of hypertension and other cardiovascular diseases in older adults [66, 73]. Together, these age-related changes in sensory receptor function disrupt autonomic regulation and impair heart-brain communication, increasing the risks of both cardiovascular and neurological complications.

Autonomic nervous system

Cardiac activity is initiated by the sinoatrial (SA) node located in the right atrium, and is modulated by the autonomic nervous system (ANS) through the release of norepinephrine, epinephrine, and acetylcholine. Higher centers in the brain and spinal cord regulate the ANS, which comprises the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). The SNS originates from the spinal cord and mediates the “fight or flight” response, while the PNS promotes relaxation and recovery. These systems work in concert to maintain cardiovascular homeostasis [74]. The extrinsic cardiac ANS includes sympathetic and parasympathetic fibers, while the intrinsic system consists of 700 to 1500 ganglia and neurons distributed across the epicardial surface of the heart [75]. This intrinsic network communicates with the extrinsic system via a complex arrangement of afferent, interneuronal, and efferent pathways [76].

Following MI, the ANS undergoes significant remodeling, characterized by increased sympathetic outflow and parasympathetic dysfunction, which lower the threshold for ventricular fibrillation and other arrhythmias [76]. In the infarct border zone, nerve sprouting leads to hyperinnervation, creating a substrate for arrhythmogenesis [77]. In addition, apoptotic and inflammatory pathways are activated in the thoracic dorsal root ganglia, with increased expression of immunomodulatory neuropeptides such as CXCL10 and KHLH18 [78, 79]. Neuronal hypertrophy has also been observed in the left stellate ganglion in both animal models and human patients with chronic MI and cardiomyopathies [80]. Interestingly, studies have reported plasticity in neuronal identity, with some showing a shift from adrenergic to cholinergic phenotypes and others reporting the opposite, highlighting the dynamic nature of autonomic remodeling [79].

Heart rate variability (HRV) after an ischemic event serves as the predictor for ischemic stroke and cardiovascular events [81]. HRV, an autonomic system function marker, decreases with age. pNN50, a measure of HRV, declines rapidly after the age of 60 [82]. Low HRV is directly associated with increased mortality post-MI [83], and is linked to a two-fold increase in MI risk among individuals with low to intermediate cardiovascular risk but no known CAD [84]. Impaired HRV also elevates the risk of ischemic stroke [85]. Aging further contributes to autonomic dysfunction through declining catecholamine receptor sensitivity, as demonstrated in both human and animal studies [86, 87]. Similarly, muscarinic receptor activity diminishes with age, reducing parasympathetic responsiveness [88]. The combination of increased sympathetic tone, reduced parasympathetic activity, and diminished receptor sensitivity predisposes older individuals to both cardiovascular and cerebrovascular complications. Following either MI or ischemic stroke, this autonomic imbalance is further exacerbated, potentially leading to dysfunction in other organ systems. Notably, individuals with AD and dementia with Lewy bodies (DLB) also exhibit reduced HRV, likely reflecting broader autonomic dysfunction associated with neurodegeneration [89, 90].

Insular cortex: a central hub for neurocardiac control

Multiple brain regions, including the forebrain, limbic system, thalamus, and brainstem, are involved in the regulation of the ANS and maintenance of neuro-cardiac homeostasis [91, 92]. Among these, the insular cortex plays a central role in cardiovascular control. Damage to this region can result in significant autonomic disturbances, including abnormal blood pressure regulation, myocardial ischemia, and cardiac arrhythmias. Notably, the right insular cortex is predominantly associated with sympathetic nervous system control, while the left insular cortex is more involved in parasympathetic regulation [93, 94]. Clinical studies have shown that right hemisphere strokes often lead to parasympathetic dominance, reflected by increased heart rate variability (HRV) and elevated parasympathetic indices such as the root mean square of successive differences (RMSSD) [95]. Conversely, sympathetic hyperactivity, indicated by reduced RMSSD/pNN50 values and overall HRV, is associated with a higher risk of cardiac arrhythmias [94]. These findings underscore the importance of assessing autonomic function in stroke patients to identify those at elevated risk for cardiovascular complications.

Daniele O et al. reported that approximately 75% of stroke patients exhibited new-onset ECG abnormalities, with cardiac arrhythmias accounting for nearly 29% of these cases. These arrhythmias were particularly common in ischemic strokes affecting the right hemisphere, where the incidence (26.8%) was almost double that seen with left-sided lesions (14.3%) [96]. These findings highlight the complexity of brain-heart interactions and suggest that outcomes may depend on the location, extent, and timing of the cerebral lesion.

The insular cortex also undergoes significant age-related changes, including cortical thinning [97, 98], accumulation of pathological proteins, and altered functional connectivity [99]. These changes have been implicated in the pathogenesis of NDDs [100]. However, there is currently a lack of literature directly examining how age-related alterations in the insular cortex influence stroke outcomes or cardiovascular disorders. Thus, it represents an important area for future research, particularly in the context of aging and the heart-brain axis.

Neuroinflammation

Transient middle cerebral artery occlusion (MCAO) induces localized neuroinflammation marked by microglial activation. Upon activation, microglia undergo morphological changes from a ramified to an amoeboid morphology and upregulate inflammatory mediators, including interferon-stimulated genes (ISGs) and chemokines [101]. MCAO is also associated with cardiac dysfunction, evidenced by reduced left ventricular ejection fraction and increased mitochondrial translocator protein (TSPO) activity in both the brain and heart. The severity of cardiac impairment correlates with stroke severity, and suppression of microglial activation reduces TSPO signal and preserves cardiac function [102]. The ISGs are also elevated in aged microglia, suggesting a link between aging and heightened neuroinflammatory responses [103]. Functionally, microglia can exert both neuroprotective and detrimental effects depending on their cytokine profile. For example, galectin-3 inhibition impairs microglial function and worsens ischemic stroke outcomes [104]. Similarly, tumor necrosis factor-alpha (TNF-α) levels rise in the brain following myocardial infarction (MI), with increased expression of the pro-inflammatory TNF receptor 1 (TNFR1) and reduced levels of the protective TNF receptor 2 (TNFR2) [105]. These responses are attenuated by vagotomy or epicardial phenol application, indicating that intact sympathetic and parasympathetic pathways are essential for neuroinflammatory signaling following MI [106].

Another key player in neuroinflammation is the perivascular macrophage (PVM). PVMs contribute to phagocytosis, antigen presentation, and BBB maintenance. They are increasingly recognized for their roles in cerebrovascular diseases, brain aging, and neuroinflammation [107]. Following MI, PVMs upregulate cyclooxygenase-2 (COX-2) and increase prostaglandin E2, promoting sympathetic activity-effects that are abolished by PVM depletion [108]. In AD, PVMs interact with microglia to drive synaptic phagocytosis via SPP1 signaling [109]. Two subsets of PVMs have been identified: MHCII-expressing PVMs, which recruit leukocytes and increase with age, and LYVE1-expressing PVMs, which support cerebrospinal fluid circulation but decline in aged brains [110]. These cellular mechanisms collectively contribute to increased sympathetic nerve activity, potentially setting the stage for myocardial abnormalities. In patients with MI, TNF-α converting enzyme (TACE) is upregulated in cardiovascular brain regions, such as the hypothalamic paraventricular nucleus (PVN), leading to elevated TNF-α levels and enhanced sympathetic excitation [111]. Neurons and astrocytes in these regions express TACE, and its inhibition reduces neuroinflammation and improves cardiac function [112]. Additionally, stromal cell-derived factor 1 (SDF-1) and MAPK signaling pathways (p44/42 MAPK, JNK, and p38 MAPK) are implicated in sympathetic overactivity post-MI. SDF-1 expression in the PVN is driven by TNF-α and angiotensin II, and its activation of MAPK pathways increases blood pressure, heart rate, and renal sympathetic nerve activity. Inhibition of these pathways improves hemodynamic parameters and cardiac outcomes [113, 114].

Age-related dysregulation of hypothalamic pituitary adrenal (HPA) axis

The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the physiological response to stress. It involves a complex interaction between the hypothalamus, pituitary gland, and adrenal glands, which collectively regulate the release of cortisol, a key stress hormone [115]. With aging, the HPA axis exhibits impaired feedback control, leading to elevated and dysregulated cortisol levels. This chronic elevation results in prolonged tissue exposure to cortisol, contributing to systemic inflammation, vascular dysfunction, and cognitive decline [116]. Furthermore, a decline in both type I and type II glucocorticoid receptors in the hippocampus leads to reduced inhibition of the hypothalamic PVN, decreasing the negative feedback control of the HPA axis in aged rodents [117]. Chronic HPA axis activation, often triggered by prolonged psychological or physiological stress, leads to sustained cortisol elevation, which increases blood pressure, heart rate, and oxidative stress, thereby promoting hypertension and other cardiovascular diseases [118]. In parallel, elevated cortisol levels are associated with hippocampal atrophy, memory impairment, and an increased risk of neurodegenerative diseases [118].

Beyond the adrenal cortex, the adrenal medulla also plays a critical role in heart-brain communication. Following neurological injury, excessive release of epinephrine and norepinephrine from both neurons and the adrenal medulla leads to catecholamine surges in the bloodstream. This results in calcium overload, cardiomyocyte death, microvascular dysfunction, arrhythmias, and cardiac dysfunction [119, 120]. This phenomenon, known as the catecholamine excess hypothesis, underlies neurogenic stress cardiomyopathy-a condition characterized by transient left ventricular dysfunction in the absence of coronary artery obstruction. It accounts for 2–3% of patients presenting with acute coronary syndrome and is most commonly observed in women over the age of 50, who represent over 90% of cases [121]. Prolonged catecholamine exposure, particularly during chronic midlife stress, has also been implicated in neuronal degeneration and is strongly associated with the development of neurodegenerative disorders [122]. Although the precise mechanisms remain unclear, it is proposed that monoamine oxidase (MAO) mediated metabolism of catecholamines produces hydrogen peroxide, contributing to mitochondrial damage and subsequent neuronal degeneration. Similarly, MAO activity in the heart has been associated with oxidative stress–induced fibrosis, impaired myocardial relaxation, and the progression of HF [123].

In summary, the HPA axis is a pivotal regulator of the stress response, and its dysregulation with aging has profound implications for both cardiovascular and cognitive health (Fig. 3). Impaired feedback mechanisms lead to sustained cortisol elevation, promoting hypertension, oxidative stress, and neurodegeneration. Additionally, catecholamine surges from the adrenal medulla following neurological insults highlight the bidirectional communication between the brain and heart. Understanding these interconnections provides critical insights into the pathophysiology of age-related diseases and identifies potential targets for therapeutic intervention aimed at preserving heart and brain health in the aging population.

Fig. 3.

Mechanisms linking HPA axis dysfunction to age-associated cardiovascular and neurodegenerative diseases. Chronic stress, injury, and biological aging disrupt the HPA axis, leading to elevated secretion of cortisol and catecholamines from adrenal cortex and medulla, respectively. This dysregulation is partly driven by reduced glucocorticoid receptor (GR) expression in the hypothalamus and weakened negative feedback control. Persistently high cortisol levels contribute to disease pathology by promoting amyloid-β (Aβ) accumulation, increasing reactive oxygen species (ROS), and impairing cardiovascular regulation. Simultaneously, excessive catecholamine release induces calcium overload and oxidative stress, triggering apoptosis, myocardial fibrosis, impaired cardiac relaxation, and neuronal damage. Together, these hormonal imbalances accelerate the onset and progression of both cardiovascular and neurodegenerative diseases. HPA: hypothalamic-pituitary-adrenal axis; BP: blood pressure; NE: norepinephrine; Ep: epinephrine; HTN: hypertension; HF: heart failure; HR: heart rate; MAO: monoamine oxidase; AD: Alzheimer’s Disease

Reactive oxygen species

Reactive oxygen species (ROS) are highly reactive molecules containing oxygen, including free radicals such as superoxide and hydroxyl radical, as well as non-radical species like hydrogen peroxide. In aging and pathological conditions, elevated levels of ROS in the cardiovascular system not only damage cardiac tissue but also impair cerebral vascular and parenchymal function, which establishes a mechanistic link between cardiac and neurological dysfunction. Ungvari et al. demonstrated that aged mice exhibited increased vascular superoxide production, resulting in impaired endothelium dependent dilation in both carotid and cerebral vessels. Administration of the superoxide scavenger TEMPOL restored normal vascular responses, underscoring the systemic impact of cardiovascular oxidative stress [124]. Similar findings were reported by Zhang et al. in the basilar arteries of aged mice [125].

Oxidative stress reduces the bioavailability of NO, while ROS scavenging restores NO signaling [126]. MI further exacerbates systemic oxidative stress, extending its effects to the brain and contributing to cognitive decline through ROS mediated mechanisms. In murine models of myocardial ischemia/reperfusion, elevated levels of hydrogen peroxide and malondialdehyde were detected in the hippocampus, correlating with increased gliosis, reduced neurogenesis, and impaired memory performance two months post-MI [127, 128]. In addition to oxidative damage, MI induces significant endoplasmic reticulum (ER) stress and protein aggregation in both cardiac and neural tissues. These aggregates resemble those observed in AD, suggesting shared neurodegenerative mechanisms. ER stress and ROS are tightly interconnected, forming a vicious cycle. ROS disrupt redox homeostasis and trigger ER stress, while ER overload activates ROS-generating systems, such as NADPH oxidase and mitochondria. Furthermore, ROS-induced calcium release from the ER amplifies mitochondrial ROS production, intensifying proteotoxicity and cellular dysfunction [129, 130]. This calcium dysregulation is mediated by ROS-induced inhibition of sarco/endoplasmic reticulum Ca²⁺-ATPase activity, along with increased activity of phospholipase A2 and protein kinase C [131]. Elevated intracellular calcium activates phospholipases, proteinases, and endonucleases, leading to lipid peroxidation, cytoskeletal degradation, DNA fragmentation, and ultimately, cell death and apoptosis [132, 133]. Importantly, therapeutic interventions, such as mesenchymal stem cell-derived exosomes and the SERCA activator CDN1163, have demonstrated efficacy in attenuating ER stress and protein aggregation, offering promising strategies to mitigate MI-induced systemic proteotoxicity and heart-brain dysfunction [129]. Human studies corroborate these findings, showing that ischemia-reperfusion injury and post-MI or post-stroke remodeling are accompanied by significant oxidative stress, which exacerbates tissue damage and impairs recovery [134, 135]. Despite these insights, clinical translation remains limited. Therefore, well-designed clinical trials are urgently needed to validate ROS-targeted therapies and improve long-term cardiovascular and neurological outcomes in MI patients.

Limitations and perspectives

There is growing body of evidence linking cardiovascular and neurodegenerative disorders, particularly within the context of aging. It emphasizes shared pathological processes, such as nervous system alterations, inflammation, vascular dysfunction, and endocrine dysregulation, which may explain the frequent co-occurrence of dysfunction in both the heart and the brain (Fig. 4). Understanding this bidirectional crosstalk is key to developing more integrated strategies for predicting, preventing, and managing age-related diseases. Recognizing aging as a systemic process that simultaneously affects multiple organ systems is essential. Such approaches support the development of holistic treatment paradigms that address systemic health rather than isolated organ-specific conditions. Despite promising insights, the complexity of heart-brain interactions presents significant challenges. Although clinical associations between CVDs and neurodegenerative disorders are well-documented, establishing causality remains difficult due to the multifactorial nature of both conditions and the influence of confounding factors, such as lifestyle, medication use, and genetic predisposition. Furthermore, much of the existing evidence is based on short-term observational studies or animal models, which may not fully capture the complexity of human aging or account for individual variability. Future research should aim to elucidate the causal mechanisms through which dysfunction in one organ contributes to impairment in another. For instance, human brain and heart organoids can be generated in vitro and connected using microfluidic systems or co-culture platforms to investigate inter-organ communication. Brain organoids derived from AD patients or patients with other neurodegenerative diseases could be used to explore how neurodegenerative changes influence cardiac function. Additionally, aging-related systemic factors, such as inflammatory cytokines and metabolites, can be introduced into this co-culture system or in vitro BBB model to study their effects and underlying mechanisms. Long-term cohort studies may be employed to elucidate causal links between heart-brain dysfunctions. In addition, given that aged women are at a higher risk of developing HFpEF and AD, there is an urgent need for gender or sex specific research to identify the underlying mechanisms of heart-brain crosstalk. Addressing these limitations is essential for advancing our understanding and improving the management of age-related diseases.

Fig. 4.

Potential molecular mechanisms involved in heart-brain crosstalk during aging. Baroreceptor and chemoreceptor impairment, autonomic nervous system (ANS) dysfunction, neuroinflammation, BBB disruption, dysfunction of coronary vasculature and HPA axis may be involved in the heart-brain crosstalk in age-related cardiovascular diseases and neurodegenerative diseases. PVMs: perivascular macrophages; TNF-α: tumor necrosis factor α; TNFα-R: tumor necrosis factor α receptor; COX-2: Cyclooxygenase-2; HRV: heart rate variability; Sym: sympathetic activity; Para: parasympathetic activity; BBB: Blood brain barrier; ECs; endothelial cells, NO : nitric oxide, HPA axis: Hypothalamic-Pituitary-Adrenal axis; NE: norepinephrine; Ep: epinephrine; NDDs: neurodegenerative diseases; AD: Alzheimer’s Disease; PD: Parkinson’s disease; CVDs: cardiovascular diseases; MI: myocardial infarction; HF: heart failure

Conclusion

The increasing prevalence of cardiovascular and neurodegenerative diseases in aging population reflects not only the accumulation of traditional risk factors but also shared pathophysiological mechanisms between the brain and the heart. BBB dysfunction impairs neurovascular coupling, while chronic inflammation and elevated levels of ROS are central contributors to the progression of both diseases. Targeting these interconnected pathways presents promising opportunities for therapeutic interventions. Therapeutic strategies aiming to restore BBB integrity by targeting senescent ECs, including sirtuin modulators, SASP inhibitors, and senolytics, may offer significant benefits. Additionally, NLRP3 inflammasome inhibitors represent a novel class of therapeutics with potential applications across inflammatory, cardiovascular, and neurodegenerative conditions. Notable candidates currently under investigation include RRx-001 and NT-0796 [136]. Therefore, advancing research into these inter-organ connections may facilitate the development of integrative treatment strategies that transcend traditional organ-specific approaches, ultimately improving clinical outcomes and reducing the burden on healthcare systems.

Abbreviations

CVDs

Cardiovascular diseases

NDDs

Neurodegenerative diseases

DALYs

Disability-adjusted life years

HFpEF

Heart failure with preserved ejection fraction

ALS

Amyotrophic lateral sclerosis

SNS

Sympathetic nervous system

PNS

Parasympathetic nervous system

CAD

Coronary artery disease

RMSSD

Root mean square of successive differences

MCAO

Middle cerebral artery occlusion

PVMs

Perivascular macrophages

TNF-α

Tumor necrosis factorα

TNFα-R

Tumor necrosis factor α receptor

ACTH

Adrenocorticotropic hormone

LYVE1

Lymphatic vessel endothelial hyaluronan receptor 1

CSF

Cerebrospinal fluid

COX-2

Cyclooxygenase-2

HRV

Heart rate variability

BBB

Blood brain barrier

BECs

Brain endothelial cells

NO

Nitric oxide

HPA axis

Hypothalamic-Pituitary-Adrenal axis

NE

Norepinephrine

AD

Alzheimer’s Disease

PD

Parkinson’s disease

MI

Myocardial infarction

HF

Heart failure

OR

Odds ratio

LA

Left atrium

AP

Anteroposterior

PP

Pulse pressure

HR

Hazards ratio

RR

Relative risk

GR

Glucocorticoid receptor

SASP

Senescence-associated secretory phenotype

Author contributions

MAF drafted the manuscript. YY, SMT and WX reviewed and edited the manuscript. All authors have read and approved the final manuscript.

Funding

This work was supported by the National Institutes of Health (AG070145) to W. Xuan and Saunders Endowment and Corridor Undergraduate Research Funding to SMT.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.