Oxidative stress, aging, metabolism, SIRT1, and the gut microbiota: the neurocardiac basis of cognitive loss

Abstract

Cardiovascular disease and cognitive loss have a neurocardiac basis. Poor vascular perfusion can impair cognitive function in both Alzheimer’s disease and multiple sclerosis. However, a treatment gap exists because current approaches do not adequately address the shared underlying cellular mechanisms responsible for cognitive dysfunction in these conditions. Current treatments for cognitive impairment in diseases such as cardiovascular disease, Alzheimer’s disease, multiple sclerosis, and diabetes often fail to fully address the shared underlying cellular mechanisms. Consequently, the prevailing precision treatment strategy, which focuses on managing symptoms and preventing disease progression, is insufficient. This highlights the urgent need for innovative approaches capable of targeting these common cellular pathways across these diverse conditions. Novel investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E and glucagon-like peptide-1 receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), mitochondrial dynamics, and the gut microbiome offer the potential to address the risk factors and clinical treatments for cardiovascular disease and cognitive loss. These pathways are exquisitely dependent upon one another and require in-depth knowledge of the modulatory cellular mechanisms for effective translation to clinical care.

Introduction

With recent improvements in healthcare across the globe, which include improved public health policies, greater access to acute and chronic healthcare, and early disease detection and treatment,1,2,3,4,5,6,7,8,9,10,11,12,13,14 lifespan has increased worldwide to the extent that by the year 2030, almost 20% of individuals will be over the age of 60 years, and by the year 2050, more than 425 million individuals will be over the age of 80 years.7,15,16,17,18 As a result of the global rise in aging and lifespan, a parallel increase in non-communicable diseases (NCDs) has occurred, with 40 million people annually succumbing to NCDs as a result of leading causes of death from cardiovascular disease19,20,21 and Alzheimer’s disease (AD).22,23,24,25,26 Interestingly, there is a neurocardiac relationship between cardiovascular disease and cognitive loss in patients with AD, as well as other memory-associated disorders, such as multiple sclerosis (MS). The neurocardiac relationship is the close network of system and cellular pathways that connect and influence the cardiovascular system and the nervous system. Disorders of the cardiovascular system that include angina, congestive heart failure, myocardial infarction, microvascular injury, endothelial cell injury, platelet dysfunction, and susceptibility to viral infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) have been associated with the development of memory loss, intellectual disability, and behavioral health illnesses.27,28,29,30,31,32,33,34,35 In AD, poor perfusion from an impaired cardiac system can cause hypoperfusion to the brain, but the underlying cellular pathways need to be investigated to identify pathological targets and treatment regimens that ultimately lead to AD, which can involve amyloid and tau deposition, loss of metabolic function, and inflammatory cell microglial activity. In a similar respect to MS, cardiac rhythm irregularities and loss of cerebral perfusion can affect cognitive and motor function, but the underlying cellular mechanisms require future clinical care given that these mechanisms are similar to those of AD and lead to amyloid and tau deposition in the brain to foster cognitive and motor loss and impair oligodendrocyte maturation to lead to demyelination.36,37,38 These cardiovascular disease and cognitive loss disorders are associated with cellular metabolic dysfunction with diabetes mellitus (DM), which can lead to heart failure, decreased cerebral blood flow, insulin resistance, glucose intolerance, perivascular pathway impairment, blood–brain barrier failure, and inflammation.39,40,41,42,43,44,45,46

Several new clinical therapies and care pathways for cardiovascular disease, AD, and DM are emerging. This neurocardiac and metabolic axis encompasses the functional network that connects the cardiovascular system, the nervous system, and metabolic homeostasis, which ultimately can impact cognitive function. Cardiovascular disease risk can be reduced through the management of blood pressure elevation, serum cholesterol reduction, improved nutrition, regular exercise, minimal use or elimination of tobacco and alcohol consumption, a reduction in exposure to environmental toxins, and appropriate weight control. Additional care pathways for cardiac disease, such as those for endothelial dysfunction and atherosclerosis, offer early disease detection.47,48 With respect to patients with cognitive loss with conditions such as AD and MS, treatments rely upon lifestyle changes such as cognitive exercises, physical exercise, cholinesterase inhibitors, monitoring with wearable biosensors, new immunotherapies designed to clear brain amyloid-β (Aβ) deposition, and disease-modifying therapies for MS to reduce relapses in patients who are relapsing–remitting of the disease. DM care includes nutritional care, weight management, regular physical exercise, and pharmaceutical agents to control hyperglycemia and hypoglycemia. However, these current therapies for cardiovascular disease, AD, and DM are targeted for symptomatic relief and cannot prevent the eventual progression of the underlying disease process. Furthermore, these therapies are not without potential complications and can involve brain microhemorrhages, brain volume loss, and the comorbidity of off-target disabilities that result in cardiac and neuronal cell injury and organ atrophy.34,49,50,51,52,53 With these challenges, innovative studies that consider oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E (APOE) and glucagon-like peptide-1 (GLP-1) receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome provide exciting prospects to address the shared underlying mechanisms for cardiovascular disease and cognitive loss that form the critical neurocardiac foundation for the development of vital treatment strategies for these disorders. This review aimed to identify the shared cellular pathways linking cardiovascular disease, cognitive loss, and diabetes mellitus, thereby bridging the treatment gap beyond symptomatic care toward mechanism-based strategies.

Data Sources

Data sources were selected on the basis of a literature search using the PubMed, Scopus, Web of Science, and ScienceDirect databases from January 2021 through March 2026. The search terms included “cardiovascular disease,” “dementia,” “neurodegenerative,” “Alzheimer’s disease,” “cardiac,” “gut microbiota,” “aging,” “metabolism,” “diabetes mellitus,” “programmed cell death,” “oxidative stress,” “sirtuin,” and “mitochondria” with Boolean operators (AND, OR) to focus the search strategy. Peer-reviewed original research and review papers, including the citations in the review papers, were included, while non-peer reviewed works, duplicate studies, unrelated studies, and abstracts or meeting presentations with incomplete information were excluded.

Lifespan Extension, Aging, and Non-communicable Diseases

Throughout the global community, lifespan has been increasing in both developed and developing countries.54,55,56 One factor that has contributed to an increased lifespan is the decrease in overdoses of drug use and the decline in deaths from viral infections with SARS-CoV-2 and COVID-19.33,57,58,59 Other factors include the availability of educational programs to promote healthy nutrition and cardiovascular training, greater access to local and tertiary healthcare centers, improved public healthcare policies that target disease prevention, a reduction in environmental toxins, and enhanced sanitation, and the development of sophisticated diagnostics for early disease detection and nutritional analysis.1,2,3,4,5,6,7,8 In developed nations, the number of individuals who are older than 65 years has increased by more than 100% over the past 50 years. Furthermore, in developing nations, the population of individuals over the age of 65 years is expected to increase by 10%. By the year 2030, at least 17% of individuals worldwide will be over the age of 60 years, and by the year 2050, approximately 80% of the elderly population will reside in low- and middle-income countries as the aging of the population rapidly increases.49,56,60 During the next 20 years, the number of individuals aged over 60 years will increase from 1.4 billion people to 2.1 billion people, with the expected lifespan reaching 80 years of age for most individuals. At this point, the number of individuals over the age of 80 years is expected to exceed 425 million people.7,15,16,17,18

With the global increase in lifespan and aging, there has been a corresponding rise in NCDs. Although NCDs are chronic disorders that are linked to aging, nearly 20 million deaths related to NCDs can occur before the age of 70 years. Approximately 75% of deaths related to NCDs occur in low- and middle-income countries, and over 40 million people die annually from NCDs. More than 30% of individuals less than 60 years of age will suffer from NCDs in low- and middle-income countries, while only 10% of individuals in high-income countries will succumb to NCDs.55,61 Poor nutrition, a lack of physical activity, tobacco and alcohol use, air pollution exposure, hypertension, obesity, metabolic disorders such as DM, and elevated serum lipid levels with high cholesterol levels all contribute to the risk of developing NCDs. NCDs include cardiovascular diseases that involve myocardial infarction and stroke; dementia, which includes AD; cancer; musculoskeletal disease, which involves osteoarthritis; trauma; reproductive disorders; pulmonary disease; metabolic disorders with DM; and mental health disorders, which can include suicide and renal disease.61,62,63,64,65,66,67,68,69 As a result of increased aging of the population with increasing lifespan, the neurocardiac axis is affected by increased cardiac failure, vascular disease, valvular dysfunction, increased arrhythmias, atherosclerosis, hypertension, and elevated oxidative stress.20,21,39,70,71,72,73,74 Similarly, the nervous system can undergo atrophy of the brain, degeneration of myelin, increased levels of neuronal intracellular toxins, impairments in motor and sensory function, and cognitive dysfunction.54,72,75,76,77,78,79,80,81,82 Loss of metabolic homeostasis is an important component of the aging of the neurocardiac axis and leads to insulin resistance, inflammation, body weight changes, cellular senescence, and mitochondrial dysfunction.39,47,66,68,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97

Cardiovascular Disease, Oxidative Stress, Cell Senescence, and Programmed Cell Death

In regard to NCDs, cardiovascular disorders are the leading cause of death for men and women, with over 20 million deaths annually, approximately one-third of the deaths that occur throughout the world.9,98,99,100 Almost 90% of these deaths are the result of myocardial infarction and stroke, with 75% of these deaths occurring in low- and middle-income countries.101 With respect to individuals under the age of 70 years, approximately 40% of deaths from NCDs are a result of cardiovascular disease, and compared with women, men can succumb to cardiovascular disease earlier, which occurs at the age of 35 years.102 In the US alone, it is reported that one person succumbs to cardiovascular disease every 33 seconds. Similar to the risk factors for NCDs, cardiovascular disease risk factors include a lack of nutritional care, a lack of physical activity, tobacco and alcohol use, air pollution exposure, hypertension, obesity, metabolic disease, such as DM, increased serum lipids with cholesterol, and infection.43,103,104,105,106,107,108,109,110 Financial costs for cardiovascular care are a significant challenge for all nations. In the US, direct medical costs for cardiovascular care exceed 420 billion US dollars, with average direct medical costs per patient equal to almost 19,000 US dollars. Projected costs for cardiovascular care by the year 2034 are expected to exceed 1.45 trillion US dollars.111,112

Oxidative stress and the generation of reactive oxygen species (ROS) are significant components of cardiovascular disease and aging.113,114,115,116,117,118 ROS include free radical species such as nitric oxide, singlet oxygen, hydrogen peroxide, superoxide free radicals, and peroxynitrite.49,66,119,120,121 At the cellular level, antioxidant systems that involve superoxide dismutase, vitamins C, K, E, B, and D, glutathione peroxidase, and catalase serve to block the detrimental effects of ROS.11,87,122,123,124,125,126,127,128 If cellular antioxidant systems become incapable of reducing oxidative stress during disease onset in the cardiovascular system, then multiple disorders can result, including cardiomyopathy, stem cell loss, atherosclerosis, cardiomyocyte cell loss, programmed cell death, and inflammation.41,93,113,114,115,116,129,130,131,132,133,134,135 During cardiovascular events such as myocardial infarction, oxidative stress can lead to cell death, endothelial cell loss, cardiomyocyte death, cellular energy depletion with mitochondrial stress, and programmed cell death through autophagy, ferroptosis, and pyroptosis.116,129,131,136,137 Notably, pathways associated with oxidative stress that lead to cell death are complex and dependent upon the induction of closely linked cellular mechanisms. For example, oxidative stress injury can be tissue- and sex-specific, reliant upon cellular energy pathways with the coenzyme β-nicotinamide adenine dinucleotide (NAD⁺), linked to inflammatory cell activity that affects immune homeostasis, and requires restorative treatments targeted to maintain redox energy balance.18,138,139,140,141

With the onset of oxidative stress, processes involving progressive aging occur and initiate cellular senescence.142,143,144,145,146,147 Cellular senescence is involved chronic inflammation, mitochondrial dysfunction, autophagy impairment, cardiomyocyte apoptotic cell death, gut microbiota changes, cellular metabolic disturbances, energy loss, fibrosis, downregulation of gene transcription, and altered lipid metabolism.56,89,113,133,143,145,148,149,150,151,152,153,154,155,156 The onset of cellular senescence is mediated by dysfunction in telomere (TL) processing.7,39,142 TLs are complexes of DNA that control the replication and survival of cells through the protection of genomic DNA.39,112,147,148,157 TLs exist on chromosome ends and contain more than 2000 repetitions of non-coding double-stranded DNA, are finalized at the ends with guanine-rich single-stranded DNA, and have the sequence “TTAGGG.” As components of the TL group, the protein complexes shelterin, telosome, and CTC1-STN1-TEN1 control TL activity and stability.158 With the oversight of the effects of TLs on cell replication, telomerase protein functions to limit the loss of base pairs in TLs and becomes active during cell division, which can result in the loss of 25–200 bp during this process. Telomerase adds tandem repeat RNA templates for the maintenance of TL length. However, as time progresses, TLs lose function, which can involve telomerase impairment, with TLs having less than 500 bp in length, cell senescence progresses in the absence of cellular replication, and the induction of oxidative stress is promoted by energy impairment and mitochondrial dysfunction.23,131,137,159,160,161,162,163,164,165,166,167,168

Closely linked to the pathways involved in cellular senescence and oxidative stress is the induction of programmed cell death, which includes apoptosis, ferroptosis, pyroptosis, and autophagy. Apoptosis can lead to cell death through an initial juncture that requires membrane phosphatidylserine (PS) residue externalization. Once this process occurs, inflammatory cells, such as microglia, seek injured cells with PS externalization to remove these cells.169,170,171,172,173 As the initial presentation of apoptotic cell death, this particular phase of PS externalization is reversible as a potential point of treatment through the blockade of PS externalization and prevention of microglial phagocytosis to rescue injured cells destined for apoptotic cell death.174,175,176,177 In the process of cell survival, microglia can play variable roles, such as during AD, to remove Aβ deposits,178,179,180,181,182 but they can also promote oxidative stress.138,183,184,185 Triggering receptor expressed on myeloid cells 2, which can promote microglial cell survival, can also reduce inflammation and oxidative stress in environments that otherwise lead to cell death.7,186,187 Following the juncture with membrane PS externalization, a second stage of apoptotic cell death proceeds that is irreversible with mitochondrial membrane depolarization, release of cytochrome c, activation of caspase pathways, and DNA degradation.114,164,188,189,190 During oxidative stress, apoptosis can lead to cardiomyocyte death in the ischemic myocardium,191 the death of cardiac tissue during diabetic cardiomyopathy,114,117 the loss of cardiac cells during exposure to environmental toxins,115 the absence of cardiac cell regeneration during metabolic dysfunction,192 the promotion of cardiac aging during ROS exposure,167 and myocardial susceptibility during ischemia–reperfusion injury.

Ferroptosis results in programmed cell death through mechanisms that result in excessive cellular iron storage with the loss of glutathione homeostasis. In the absence of the ability of cells to protect themselves through glutathione-based systems, lipid peroxidation results in cell death.49,193,194,195,196,197 Ischemia–reperfusion injury can lead to cell death through ferroptosis,198 and ferroptosis also promotes decreased cell survival during myocardial infarction.116 During cardiotoxicity with doxorubicin, ferroptosis results in cardiomyocyte cell death as well.199

In regard to pyroptosis, programmed cell death is overseen by the inflammasome, also termed the pyroptosome, which modulates inflammation.116,166,200,201 The inflammasome family of nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors (NLRs) contains NLRP1, NLRP3, NLRP6, and NLRC4 as members and activates inflammasomes. NLRs ultimately activate caspase 1, caspase 4, and caspase 5 through pattern recognition receptors that respond to damage-associated molecular patterns (DAMPs) and through pathogen-associated molecular patterns (PAMPs). Gasdermin proteins, activated by caspase 1, generate membrane pores through their N-terminal domains following cleavage from the C-terminal domains, fostering DAMP molecules such as DNA and adenosine triphosphate (ATP) to pass through the open cell membrane. As a result, activation of the canonical NLRP3 inflammasome occurs, cytokines such as interleukin-1 family members are released, and caspase 4 and caspase 5 activate noncanonical inflammasomes with lipopolysaccharide proteins during infectious processes in gram-negative bacteria.179,186,202,203,204 Pyroptosis is activated during oxidative stress, which can occur with myocardial infarction and result in cardiac cell death.116 In cardiomyopathy with DM, the expression of gasdermin is increased by NLRP3, and the induction of pyroptosis subsequently results in cardiomyocyte injury200,205 in conjunction with insulin resistance and glucose intolerance.92,156,206

Autophagy is also a critical pathway for programmed cell death in the cardiovascular system.114,116,130,199,207,208 In the process of autophagy, cytoplasmic organelles and additional subunits are engulfed and recycled for future use.176,177,208,209 Three subtypes of autophagy are involved: macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy is the most common subtype in which autophagosomes are used to merge organelles and cytoplasmic proteins into lysosomes for degradation and recycling. Microautophagy relies upon the invagination of lysosomal membranes to recycle organelles, whereas chaperone-mediated autophagy directly transfers “protein chaperones” to lysosomes for degradation.145,210,211 Autophagy induction can be critical for maintaining metabolic homeostasis in cardiac muscle, since loss of autophagy leads to high-fat diet-induced glucose intolerance, inability to limit oxidative stress during exercise, and reduced muscle endurance.212 During DM, the activation of autophagy can protect against cardiac apoptosis and increase cardiac function and tissue structure.213 During chronic hypoxia, the activation of autophagy pathways can limit apoptotic myocardial cell death.214 During periods of sustained cold stress, autophagy can protect against pressure overload and assist with myocardial contractile capacity.215 Autophagy activation is also protective during DM and the loss of cellular glucose homeostasis. Activation of autophagy can reduce diabetic retinopathy,216 limit insulin resistance, which can involve growth factors, such as erythropoietin (EPO),217,218,219 protect cardiac cells during DM under conditions of ischemia–reperfusion, control oxidative stress and lipotoxicity, and protect cells during DM-induced cell ischemia through the maintenance of inflammatory cell mitochondrial autophagy activity.220

However, autophagy induction is not consistently beneficial and can lead to cell injury during periods of autophagic flux and excessive activation of autophagy.207,221 Increased autophagy activity may lead to decreased muscle mass,222 promote oxidative stress pathways that lead to cell injury,223,224 disrupt circadian rhythm,225,226,227 promote diabetic retinopathy,221 and induce cardiomyocyte cell death during ischemia–reperfusion injury.228,229 In cases when the modulation of autophagy is essential to protect cell survival, pathways associated with the mechanistic target of rapamycin (mTOR) can complement autophagy pathways that would otherwise lead to injury, since mTOR is an inverse regulator of autophagy. For example, mTOR activation can stabilize atherosclerotic lesions with autophagy inhibition,230 can promote growth factor protection, such as with EPO, during oxidative stress for vascular cells,173,231,232,233,234 and can be necessary for TL stabilization.235

Interdependence between Cardiovascular Disorders, Alzheimer’s Disease, and Cellular Metabolism

Cardiovascular disease has a bidirectional relationship with the nervous system and is associated with cognitive loss and AD.70,107,236,237,238 Approximately 11% of the population suffers from the sporadic form of AD, which is expected to increase in the US alone from 7 million people to 30 million people by the year 2050.23,24,25,26,239 In contrast to the sporadic form of AD, which usually affects individuals older than 65 years, familial AD affects approximately 200 families globally before 55 years of age, with amyloid precursor protein (APP) gene mutations on chromosomes 1, 14, and 21.82,178,184,227,240,241 MS, which has an increased risk for cardiovascular disease,242 is also similar to AD with the loss of cognition, such that memory loss can be progressive with word finding difficulties and object naming impairments.32,34,243,244,245,246

Vascular artery disease of the cardiac system is associated with increased dementia and memory loss,247 as well as depression.248 In fact, disturbances in behavior can be a precursor or comorbid disease with cardiovascular disease and cognitive loss in AD and MS patients.27,28,29,30,31,32,33,34,35 Almost 25% of individuals with cardiovascular disease, such as angina, congestive heart failure, and myocardial infarction, suffer from depression.248 Increased mental health conditions occur in people with developmental and intellectual disability,249 and depression is associated with the initial stages of cognitive loss.250 Depression and anxiety can trigger inflammation that promotes long-term disability in patients with AD or MS.30,31,34,251,252 With respect to pathways involved in aging and cell senescence, patients with dilated cardiomyopathy and progressive memory loss have decreased TL length and cell senescence progression.39,157 In addition, other factors can solidify the link between cardiovascular disease and dementia with AD, such as platelet dysfunction (Figure 1). A high-density population of platelets can promote Aβ formation, which leads to AD253 and results in oxidative stress with impairment of platelet mitochondria.254 The increased presence of atherosclerosis can affect regions of the brain involved in memory, such as the hippocampus,93,255,256 and endothelial dysfunction can lead to neuronal cell injury, altered mitochondrial bioenergetics, and decreased Aβ clearance from the brain.257 Microvascular injury in the cardiovascular system and the brain can also result in inflammatory cell injury and facilitate infections such as SARS-CoV-2 and COVID-19.258,259,260

Figure 1.

The neurocardiac basis for cardiovascular disease and cognitive loss.

Cardiovascular disease and cognitive loss with Alzheimer’s disease (AD) and multiple sclerosis (MS) have a neurocardiac basis that are tied to cellular metabolic pathways that can involve diabetes mellitus (DM). With progressive aging and increased lifespan, non-communicable diseases that involve cardiovascular diseases and metabolic disorders lead to clinical disabilities with heart failure, vascular disease, platelet dysfunction, reduced cerebral blood flow, glymphatic (perivascular) pathway impairment, glucose intolerance, and susceptibility to viral infections with severe acute respiratory syndrome (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) that are directly tied to the loss of cognition, intellectual disability, and behavior health illnesses. Given that therapies for cardiovascular disease, cognitive loss, and co-morbidities with DM are principally symptomatic in nature, innovative avenues that examine the shared underlying pathways of oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E (APOE) and glucagon-like peptide-1 (GLP-1) receptor agonism, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are warranted to offer new opportunities to address the shared neurocardiac basis for the onset and progression of cardiovascular and cognitive loss disorders. Created with Microsoft PowerPoint Software (version 16.103.1).

Metabolic disease that involves DM is a critical cellular mechanism that closely links cardiovascular disease to dementia and AD. DM leads to 2 million annual deaths, with half of those deaths occurring in individuals younger than 70 years.226,261 Many other individuals lack a proper diagnosis and are believed to have prediabetes, with elevated fasting glucose levels and hemoglobin A1c levels.49,166,262 Risk factors for DM include lower education level and socioeconomic status; high blood pressure; elevated serum cholesterol; high alcohol and tobacco consumption; SARS-CoV-2 infection; limited physical activity; and obesity.33,50,58,261,263,264,265 In relation to obesity, multiple disorders of metabolism affect both cardiac and cognitive function, including poor cerebral blood flow, oxidative stress, glucose intolerance, insulin resistance, inflammation, impaired stem cell survival, infection susceptibility to COVID-19, and mitochondrial dysfunction.91,118,121,266,267,268,269,270,271,272,273

During DM, disorders of the cardiovascular system that involve loss of cardiac mitochondrial homeostasis, increased oxidative stress, heightened cardiac inflammation, dyslipidemia, cardiomyocyte apoptosis, impaired cardiac function, and ischemia–reperfusion susceptibility can be multiple factors that foster impaired cognition and AD.39,40,41,42,43,44,45,274 Both vascular and nervous system components are affected during DM, with systemic autonomic dysfunction resulting in memory loss in AD, vascular dementia, and Parkinson’s disease.275,276,277 Obesity during DM can affect endothelial cell function and increase the permeability of the blood–brain barrier, leading to dementia on a vascular basis.278,279 The perivascular system is also an important pathway that can be affected by DM and cardiac heart failure with reduced arterial pulse pressure. The perivascular system is a perivascular network of cerebrospinal fluid in the brain that eliminates metabolic waste and toxins such as Aβ, tau, and α-synuclein.158,280,281,282 This system can fail during periods of sleep loss and sleep fragmentation involving circadian rhythm impairment, resulting in cardiovascular dysfunction, inflammation, and cognitive loss with long-COVID-19 infection, also known as long-haul COVID-19, chronic COVID-19, or post-acute COVID-19.57,58,109,110,166,283,284,285,286,287 During DM, perivascular system function may be significantly impaired, which can add to prior dysfunction from cardiac insufficiency.158,288 With cardiac impairment during DM, the loss of metabolic homeostasis can also result in Aβ and tau deposition, increased Aβ and tau toxicity with insulin resistance, and the activation of programmed cell death pathways with autophagy.33,96,289,290,291,292 As demonstrated by elevated serum levels of neurofilament light chain, which can be used as an early diagnostic marker of brain cell death, long-term injury to the cortex of the brain can lead to the development of DM.6,293,294

DM can also lead to a decrease in the expression of growth factors, such as EPO, that can impair both cardiac and neurological function. EPO in the cardiovascular system is necessary to prevent cardiac fibrosis and microvessel disease,295 promotes positive ionotropic effects,296 limits hypoxic cardiac cell death,297,298 and stimulates coronary collateral development.299 In the nervous system, EPO can limit inflammatory cell responses,300 improve verbal memory and reduce behavior disorders,301 protect endothelial cells,117,173,302,303 reduce injury from ischemic environments,304,305 and assist with nerve myelination.306 EPO also functions as a modulatory regulator of autophagy, since EPO can rely upon mTOR pathways117,182,307,308 and decrease the activity of autophagy to promote cell survival.309

With respect to cellular metabolism pathways, APOE is a critical component that plays a significant role in cardiovascular disorders and neurodegenerative diseases, including AD. APOE is necessary for metabolism to oversee lipid function and the transport of phospholipids, triglycerides, and cholesterol.33,58,166,310,311,312,313 Peripherally, APOE is produced by liver cells, but in the nervous system, astrocytes produce APOE to transfer cholesterol to neurons through receptors of APOE.83,139 In the cardiovascular system, the ε4 allele of the APOE (APOE-ε4) gene can be an important risk factor for heart disease and early-onset cardiovascular dysfunction, whereas APOE-ε2 can be related to elevated triglyceride levels, and APOE-ε3 is not thought to lead to increased risk for cardiac disease.314 In the nervous system, individuals with two APOE-ε4 alleles (homozygous ε4/ε4) have a 20-fold greater risk of developing AD by the age of 85 years.166,257,310 APOE-ε4 carrier status, which includes homozygotes and heterozygotes, can also result in accelerated age-related cognitive loss after the age of 70 years.315 In individuals with MS, APOE-ε4 may lead to cognitive impairment, yielding a clinically relevant slower response to stimuli316, and the APOE-ε3/ε3 genotype may increase the risk for optic neuritis in males.317 APOE-ε4 can also promote viral antigen infection with SARS-CoV-2 and COVID-19, resulting in cognitive loss, microhemorrhages, depression, and long-COVID in AD and MS patients.34,58,108,318,319 However, APOE-ε2 alleles have been associated with decreased Aβ aggregation and the prevention of apoptotic PS membrane exposure.320

Metabolic disease that links the pathologies of cardiovascular disorders and AD may also center on GLP-1 receptor agonism (Figure 1). Currently approved US Food and Drug Administration treatments for obesity and glucose homeostasis, such as the GLP-1 receptor agonists semaglutide, tirzepatide, and liraglutide, may have potential applications throughout the body, such as in cardiovascular and neurological systems.23,118,321,322 As G protein-coupled receptors, GLP-1 receptors reside across membranes with an extracellular N-terminus and an intracellular C-terminus and have 7α-helical transmembrane domains. GLP-1 receptors are expressed in pancreatic β-cells, neurons, cardiomyocytes, gastrointestinal cells, renal cells, immune cells, hepatic cells, and cells of the musculoskeletal system.23,322,323,324,325,326 GLP-1 receptor agonism can promote glucose homeostasis, improve insulin receptor function, limit oxidative stress, and prevent mitochondrial dysfunction.51,323,324,327,328,329 The maintenance of glucose homeostasis through GLP-1 receptor agonism may be overseen through the activity of transient receptor potential cation channel subfamily V member 2 (TRPV2) channels.326 In this family of channels, the TRPV1 receptor family is a vital contributor to controlling cell survival, cellular metabolism, inflammation, and oxidative stress.330,331,332,333 In the cardiovascular system, GLP-1 receptor activation can protect cardiomyocytes and vascular tissue against oxidative stress in patients with DM329 and prevent cell injury during doxorubicin exposure.118 Similarly, to provide cellular protection in the nervous system, GLP-1 receptor agonism increases neuronal cell survival during experimental models of encephalopathy with DM,327 improves cell glucose transport and reduces brain insulin resistance,51 functions as a neurotransmitter to improve cognition,51 and contributes to altered cellular metabolism in AD,324 and it reduces mortality with brain metastasis during DM.334

GLP-1 receptor agonism can promote mTOR pathway activation to protect pancreatic β-cells against cholesterol-mediated apoptotic cell death and glucose toxicity.328,335 mTOR with GLP-1 receptor agonism is also essential for protection during cognitive loss and depression, which can occur with the loss of metabolic homeostasis.336 GLP-1 receptor activation also requires mTOR activity and autophagy modulation to promote neuronal survival in models of Huntington’s disease and encephalopathy with DM.327,337 However, under some circumstances, GLP-1 receptor activation requires the induction of autophagy with mTOR inhibition to induce retinopathy during DM216 and during cellular protection in osteoarthritis.338 The modulation of autophagic flux is vital for the use of GLP-1 receptors in both cardiac and cognitive loss disorders and may be related to the emerging “off-target” clinical effects of GLP-1 receptor agonists, which include anterior ischemic optic neuropathy, acute pancreatitis, depression, alopecia, nausea, vomiting, and diarrhea.339,340,341,342

Influence of SIRT1, Mitochondrial Dynamics, and the Gut Microbiota

Given the role cellular metabolism plays in cardiovascular disease and AD, the SIRT1 pathway is a critical mechanism that links cardiovascular disease with neurodegeneration.39,43,62,114,115,134,167,343,344,345,346,347 Seven mammalian homologs of Sir2, including SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7, oversee aging processes, cell development and proliferation, oxidative stress, cellular senescence, cellular metabolism, and post-translational protein modifications.39,348,349,350,351,352,353,354,355,356,357,358,359 In regard to SIRT1, this enzyme is a histone deacetylase that oversees the transcription of DNA through acetyl group transfer from ε-N-acetyl lysine amino acids to DNA histones and is present in the liver, heart, brain, skeletal muscle, spleen, pancreas, and adipose tissue.116,132,287,360,361,362,363 NAD⁺ is a substrate for SIRT1.18,123,226,362,364,365,366 SIRT1 controls nicotinamide phosphoribosyl-transferase, which is necessary for NAD⁺ production. NAD⁺ is crucial for blocking vascular disease and dementia and maintaining mitochondrial function.90,292,365,367 Fluctuations in pools of cellular NAD⁺ can occur with aging and changes in circadian clock gene expression.7,143,149,368

Interestingly, the agent nicotinamide, the amide form of vitamin B3 (niacin), is a precursor for NAD⁺ and functions to reduce oxidative stress, increase cell survival during apoptosis, maintain mitochondrial membrane potential, reduce inflammation, and control insulin resistance.11,122,369,370,371,372,373,374 SIRT1 and nicotinamide are dependent upon one another through NAD⁺.107,165,258,347,375 Nicotinamide can be produced by SIRT1, promoting the transfer of the acetyl residue of the histone acetyllysine residue to the ADP-ribose moiety of NAD⁺. Cellular protection with nicotinamide can occur in a narrow concentration range, since high levels can limit SIRT1 protection by binding nicotinamide to sirtuins through NAD⁺ in the sirtuin C pocket and noncompetitively inhibiting SIRT1.376 As a feedback mechanism, SIRT1 activation through nicotinamide phosphoribosyl-transferase increases NAD⁺ levels and decreases nicotinamide levels such that they become insufficient to block SIRT1 activity.377 Increased physical activity can facilitate this process.368 In this feedback pathway, nicotinamide can also limit SIRT1 activity through the interception of an ADP-ribosyl-enzyme-acetyl peptide intermediate with the regeneration of NAD⁺,378 which may be necessary at times to restore acetylation levels, mitigate mitochondrial impairment, and limit autophagy.362,379

In the cardiovascular system, SIRT1 oversees multiple cardiac disease entities, including hypertension, atherosclerosis, cardiac failure, and myocardial function (Figure 1).43,112,113,380 Patients with inflammatory dilated cardiac myopathy have increased inflammatory markers, especially in women, when compared with men, but lack vital elevations in SIRT1 activity, suggesting a failure for sufficient SIRT1 activity to offer cytoprotective pathways for these patients.39 In experimental models of DM cardiomyopathy and cardiac hypertrophy, SIRT1 activation is necessary to reduce oxidative stress, block apoptosis, and maintain mitochondrial function.114,120,134 In models of cardiotoxicity and aging, SIRT1 can promote cellular proliferation, limit programmed cell death, reduce inflammation, and diminish oxidative stress.70,115,118,167 During periods of lipotoxicity and the loss of metabolic homeostasis, SIRT1 can restore physiological cellular metabolism through increased physical activity.44,78,381 Increased expression of SIRT1 can reduce cellular senescence, improve cardiac performance, promote stem cell viability, and limit endothelial cell dysfunction during myocardial infarction.43,78,382,383,384 SIRT1 activation through heightened NAD⁺ can reduce cardiac injury, limit inflammation, and promote metabolic homeostasis.385,386,387,388 Growth factors, such as EPO, also rely upon SIRT1 activation to maintain cellular function, such as during exposure to toxic agents and oxidative stress.218,233,389,390

Considering its role in cognitive loss and metabolic dysfunction, SIRT1 is associated with DM and can function as a regulatory protein for glucose homeostasis and obesity in several clinical populations.391,392,393 SIRT1 can reduce oxidative stress, restore glucose homeostasis and insulin levels, and improve cellular survival in experimental models of DM.40,89,114,216,268,394 In models of cognitive loss and AD, SIRT1 can mitigate Aβ toxicity and preserve cellular survival.343,344,395 SIRT1 activation can decrease oxidative stress in the brain, block apoptosis, improve spatial memory, and increase synaptic density.345,346,347,396,397 SIRT1 can promote neuronal stem cell differentiation, oversee the microglial inflammatory response, maintain astrocyte survival, and prevent blood–brain barrier disruption.373,398,399,400,401 Through the activation of SIRT1, the memory function of hippocampal neurons is maintained, synaptic function is preserved, and the clearance of tau and Aβ is promoted in models of AD.361,402,403,404,405,406 A lack of SIRT1 activity may lead to inflammation, delays in wound healing, and neurodegeneration with decreased lifespan.407,408,409

During cardiovascular disease and dementia, mitochondrial dynamics also play a significant role in the onset and progression of these disorders through pathways that involve cellular metabolism. In patients with DM, mitochondrial dysfunction can be associated with impaired energy expenditure, loss of cardiac contractility, renal impairments, ferroptosis activation, apoptotic cell death, oxidative stress, insulin resistance, circadian rhythm disorders, altered lipid metabolism, endothelial cell loss, and pancreatic β-cell loss.49,114,156,261,267,410,411,412,413,414,415 Mitochondrial integrity is necessary for redox cellular signaling, which is involved in physiological metabolic consumption.163,416 Loss of mitochondrial function results in caspase activation, endoplasmic reticulum stress, microvascular disease, programmed cell death, and mitoptosis.25,77,131,158,164,165,346,351,417,418,419,420

SIRT1 significantly affects the maintenance of mitochondrial dynamics during cardiovascular and memory loss disorders.62,362,380,421 During cardiac aging, SIRT1 maintains mitochondrial integrity to block inflammation and oxidative stress in cardiac tissue.70,167 During oxidative stress, SIRT1 can modulate autophagy and mitochondrial function in embryonic stem cells,422 reduce severe cardiac dysfunction through SIRT1 activity and the maintenance of mitochondrial integrity,44,384 and protect coronary artery endothelial cells from mitochondrial oxidative stress.423 In experimental models of AD, SIRT1 can block Aβ cell toxicity, preserve mitochondrial membrane potential, reduce the generation of ROS,343 and prevent apoptotic cell death.346,424 In the absence of SIRT1 and the loss of mitochondrial integrity, Aβ toxicity, memory loss, and programmed cell death of microglia, neurons, and astrocytes can occur.404,425,426 Intact cognition also appears to be reliant upon GLP-1 activation with SIRT1 and mitochondrial preservation, which can protect both cardiac and neurological function.118,337

In addition to cellular metabolism pathways, SIRT1, and mitochondrial dynamics, one of the important complex ecosystems of the body that can link cardiovascular disease and AD is the gut microbiota (Figure 1).414,427,428,429,430 Approximately 100 billion bacteria form the gut microbiota, and this system functions as an endocrine organ since beneficial organisms can generate short-chain fatty acids and synthesize vitamins such as vitamin B for the host to consume throughout the body.155,239,431,432 The gut microbiota is connected to protective pathways for both the cardiovascular system and the nervous system that involve SIRT1 activity. Experimental studies that clarify Aβ and tau aggregates for the treatment of AD rely upon SIRT1 activation and the gut microbiota to regulate indole metabolites, such as 3-indollepropionic acid, which may be neuroprotective.30,361 Investigations have shown that altering the gut microbiota to promote SIRT1 activation and suppress inflammatory cytokines leads to improved memory and blocks degeneration of the hippocampus in models of AD.403 Increased SIRT1 expression can also protect the vascular endothelium, improve cardiovascular function, and block inflammation during high-fat diets through the prevention of detrimental effects on the gut microbiota that normally impair vascular endothelial function.433,434 Recent investigations have employed directed changes in the gut microbiota, such as to reduce the abundance of Bacteroidota and Firmicutes species, that offer beneficial effects in AD models with aging and assist with cardiovascular disorders to improve memory, prevent hippocampal neuronal cell loss, and promote cardiac function.427,430,435,436,437,438 Other studies of the gut microbiota in individuals with DM also point to increasing species, such as Lactobacillus, with mTOR activation, which can increase the levels of short-chain fatty acids to reduce inflammation, block insulin resistance, and improve metabolic homeostasis to improve cardiovascular and neurological systems.92,155,432,439

Limitations

Examinations of the neurocardiac basis related to cardiovascular disease and cognitive loss that investigate biological gas pathways are considered innovative and represent a developing line of investigations. As a result, there exist limitations and challenges to be recognized. First, the role of biological gas pathways related to oxidative stress and the presence of ROS is not simplistic in nature and is tied to multiple cellular pathways that can influence clinical outcomes. The generation of ROS can lead to cell injury in tissue- and cell-specific regions that is overseen by multiple factors that can include whether inflammatory cell activation is beneficial or detrimental, whether cellular energy pathways are maintained at physiological levels, and whether protective pathways that can include SIRT1 are sufficiently effective during redox energy balance that can be sex specific. Second, our knowledge of metabolic pathways is under continual growth and requires further clarification. For example, APOE-ε4 gene is a significant risk factor for cardiac disease, early-onset cardiovascular dysfunction, accelerated age-related cognitive loss, and viral infection with SARS-CoV-2 and COVID-19, leading to brain microhemorrhages and mental disability. However, other subtypes of APOE can affect specific tissues and systems of the body, with APOE-ε2 related to elevated triglyceride levels in the cardiovascular system, decreased brain Aβ aggregation and a reduction in apoptotic membrane PS exposure in the nervous system, and APOE-ε3 is either not detrimental to cardiac disease or potentially affects only males with optic neuritis in the nervous system. Third, the shared pathways bridging cardiovascular disease with cognitive loss are at early developmental stages for clinical and diagnostic use. Therefore, additional studies will be critical for clinical translation to human care from the present in vitro and in vivo animal models. Future clinical trials will be necessary to help determine whether specific subsets of cardiovascular disease, such as individuals with atherosclerosis or heart failure, share underlying pathways that can also be targeted for either early- or late-stage cognitive loss and AD. Even current clinical studies require further development with new trials that consider patient comorbidities that can affect clinical outcomes, as evidenced by work with new diagnostic methods, such as neurofilament light chains, that can detect early brain neuronal cell death in patients with cognitive loss but may be valid only in a limited subset of patients. These limitations elucidate the necessary path forward to translate into clinical care the shared underlying pathways for neurocardiac care.

Conclusion and Future Perspectives

In both developed and developing nations, lifespan is significantly increasing, with the number of individuals over the age of 65 doubling during the prior 50 years, and over the next two decades, it is expected that more than 2 billion people will reach a lifespan of 80 years old. With the increase in lifespan there has been a corresponding rise in NCDs. Cardiovascular disease representes the leading cause of death annually, and a significant portion of the global population is suffering from cognitive loss and AD. Interestingly, cardiovascular disease and cognitive loss with AD form a neurocardiac axis by sharing underlying cellular mechanisms that can lead to the onset and progression of these disorders. Approximately one-quarter of individuals with cardiovascular disease that involves angina, congestive heart failure, and myocardial infarction suffer from changes in cognition because of platelet dysfunction, atherosclerosis, endothelial disease, metabolic disease with DM, perivascular pathway failure, and microvascular injury. These disorders lead to the progression of cognitive loss and AD with decreased brain Aβ and tau clearance and susceptibility to long-COVID. Metabolic pathways tied to APOE also play a significant role in cardiovascular disease and AD with APOE-ε4 carrier status, resulting in early-onset cardiovascular dysfunction, accelerated age-related cognitive loss, and memory loss with viral infection of SARS-CoV-2 and long-COVID-19. Given that current therapies for cardiovascular disease, cognitive loss with AD, and comorbidities with DM are primarily symptomatic in nature, innovative strategies that examine the shared underlying cellular mechanisms of these disorders are highly warranted for the development of future clinical care. Investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with APOE and GLP-1 receptor agonism, SIRT1, mitochondrial dynamics, and the gut microbiome can offer new and invaluable insights into effective strategies that can address risk factors and clinical treatments for cardiovascular disease and AD (Figure 1). Notably, these pathways have intimate and complex relationships that necessitate thoughtful approaches. For instance, although autophagy induction may at times suppress oxidative stress and enhance cell survival in the cardiovascular and neurological systems, pathways such as those involving mTOR can become essential, particularly during aging via TL-related processes and through directed modulation of the gut microbiota, to regulate and oversee dysfunctional autophagic flux that might otherwise block the desired clinical outcomes of agents such as GLP-1 receptor agonists and growth factors like EPO.

Facts

1. Cardiovascular disease, Alzheimer’s disease, and multiple sclerosis share a neurocardiac basis linked by cellular metabolism and diabetes, indicating the presence of common pathological pathways.

2. Current care remains symptomatic and prevention focused, and interventions targeting shared pathways such as oxidative stress, senescence, and autophagy are lacking.

3. Apolipoprotein E (APOE), glucagon-like peptide-1 (GLP-1) agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are key modulators of the neurocardiac axis and are highly interdependent.

4. Understanding the interactions among ferroptosis, pyroptosis, and apoptosis under comorbid conditions is essential for clinical translation.

Open Questions

1. Is oxidative stress a primary driver or a consequence of autophagy dysregulation that links cardiac dysfunction to cognitive decline?

2. Are GLP-1 receptor agonists neuroprotective independent of glycemic control, and what is the optimal timing and disease stage?

3. Which microbial metabolites influence mitochondrial dynamics and senescence, and can microbiome targeting improve both cardiac and cognitive outcomes?

4. Is combined inhibition of ferroptosis and pyroptosis superior to single-pathway blockade, and how can strategies for different comorbidity profiles be chosen?

5. How can APOE genotypes and individual metabolic states guide personalized therapies that simultaneously reduce cardiovascular risk and neurodegeneration?

Funding Statement

Funding: This work was supported by the American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, NS053956, and NIH ARRA.

Data availability statement:

Not available.