Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures.

Introduction

The global population is experiencing a significant increase in the number and proportion of individuals aged 60 years and older. According to the World Health Organization (WHO), the number of people over 60 years old reached 1 billion in 2019 and is projected to surpass 2.1 billion by 2050 [ 1 ]. This demographic shift is accompanied by a rising prevalence of age-related non-communicable diseases (NCDs) in aging societies, particularly in the Western world. These NCDs include cardiovascular and cerebrovascular diseases (such as heart failure, myocardial infarction, stroke, vascular cognitive impairment), cancers, chronic respiratory diseases (like chronic obstructive pulmonary disease), chronic kidney disease, type-2 diabetes mellitus, musculoskeletal diseases, and neurodegenerative diseases. The impact of these chronic age-related NCDs on the quality of life for affected individuals spans several decades and carries substantial socioeconomic implications for Western societies. Deterioration of cognitive health associated with age-related NCDs is especially important in that regard.

In the USA, over 90% of older individuals have at least one chronic NCD, with approximately three-quarters experiencing two or more [ 2 ]. The economic burden associated with age-related chronic diseases has been estimated at a staggering $47 trillion for the period from 2010 to 2030 [ 3 ]. The financial strain imposed by the costly care required for older individuals with age-related NCDs affects pension systems and healthcare systems alike. Recognizing the magnitude of this problem, the World Health Organization emphasizes the importance of focusing on prevention of age-related NCDs and the promotion of healthy aging [ 4 , 5 ].

In recent years, advances in geroscience have led to a paradigm shift in our understanding of the pathogenesis of chronic age-related NCDs [ 6 , 7 ]. It is now recognized that all age-associated diseases share common underlying cellular and molecular mechanisms of aging. These mechanisms include increased oxidative stress, cellular mitochondrial and energetic dysfunction, impaired cellular stress resilience, genetic instability and DNA damage, induction of cell senescence, heightened state of inflammation, epigenetic dysregulation, altered proteostasis, disruption of intercellular communication (including endocrine changes), stem cell dysfunction, and dysregulation of energy sensing pathways [ 6 , 8 – 10 ] (Fig. 1 ). These pathways are genetically determined, but environmental and lifestyle factors play a critical role in modulating the rate of cellular and organismal aging, thereby defining the trajectories of age-related functional decline (Fig. 1 ). It is now emerging that environmental and lifestyle risk factors can exacerbate fundamental cellular and molecular aging processes, promoting accelerated aging phenotypes and the premature development of chronic age-related NCDs (Fig. 1 ). Fig. 1 Conceptual model illustrating the contribution of environmental drivers to unhealthy aging, characterized by accelerated aging processes, increased biological age, and the development and progression of various age-associated diseases. Environmental toxicants (depicted in orange) play a key role in promoting age-related cardiovascular, cerebrovascular, and brain pathologies, as well as the pathogenesis of age-associated diseases in other organ systems. These toxicants exacerbate fundamental molecular and cellular aging processes (depicted as roots), which serve as the underlying mechanisms. The consequences of accelerated vascular aging induced by toxicants give rise to the genesis of micro- and macrovascular pathologies, including atherosclerotic vascular diseases, cerebral small vessel disease, and Alzheimer’s disease. Furthermore, many of these toxicants have the ability to cross the blood–brain barrier, leading to neurotoxic effects, neuroinflammation, and neuronal dysfunction, promoting the genesis of neurodegenerative diseases and cognitive decline. Clinical disciplines, biogerontology, and environmental toxicology, along with public health research, traditionally focus on specific age-related diseases (depicted as leaves), mechanisms of aging (depicted as roots), and environmental risk factors, respectively. Geroscience, as an integrative scientific field, considers the interaction between all these levels, facilitating a comprehensive understanding of the complex relationship between environmental factors and unhealthy aging

The role of the environment in controlling human aging is increasingly being explored within an exposomic framework [ 11 ]. The exposome, as originally proposed by Dr. Wild in 2005 [ 12 ], encompasses all environmental exposures from conception that influence health outcomes. It encompasses internal factors (e.g., physical activity, microbiome, metabolism), general external factors (e.g., education, social status, climate, urban–rural environment), and specific external factors (environmental pollutants and chemical contaminants, lifestyle factors, occupation). It is worth noting that in our developed world, the majority of the population is exposed to approximately 80,000 to 100,000 artificially produced substances in their daily lives. In heavily polluted work environments, this number can reach up to 200,000 substances. The estimated number of “manmade” xenobiotic compounds currently stands at 10 million, highlighting the extensive exposure to synthetic chemicals in our modern society. These environmental toxicants have the potential to disrupt physiological processes and promote the pathogenesis of NCDs. Understanding the impact of this vast array of chemical exposures on aging and age-related diseases is critical for public health. Studies employing environmental epidemiology approaches, including geographical data linkages, have confirmed the significant contribution of exposure to environmental pollutants, including particulate matter in air pollution and occupational exposures, to the shared exposome, influencing longevity, geographic clustering, and the development of various age-related chronic NCDs such as neurodegenerative diseases, cardiovascular diseases, and cancer [ 11 , 13 – 23 ].

Notably, exposure to environmental toxicants has been shown to associate with molecular hallmarks of aging [ 24 – 31 ]. In this review, we delve into the pathophysiological roles of environmental toxicants in modulating the fundamental cellular and molecular mechanisms of aging. Specifically, we examine their contributions to the pathogenesis of age-related NCDs, with a particular focus on cardiovascular, cerebrovascular and brain pathologies (Fig. 1 ). The selection of exposure factors considered in this review is based on an extensive literature search, encompassing a wide range of environmental toxicants, including ambient particulate matter, pesticides, heavy metals, and organic solvents, which have been previously identified as significant contributors to aging disorders in both the cardiovascular system and the brain. By exploring the interconnectedness between potential mechanisms of cardiovascular, cerebrovascular, and brain aging and the pathways affected by environmental factors, we gain insights into the complex relationships between environmental toxicants and unhealthy aging processes. Additionally, we explore the interaction between these cellular and molecular aging processes and disease-specific pathways. By examining the intricate relationships between environmental toxicants and cardiovascular, cerebrovascular, and brain aging, we can identify potential targets for public health interventions aimed at promoting healthy aging. By implementing preventive measures and interventions to mitigate the detrimental effects of environmental toxicants, we can strive to improve the overall well-being of the aging population. Our comprehensive review aims to provide valuable insights into the multifaceted role of environmental drivers in aging and guide future research efforts and public health strategies for healthy aging.

Exacerbation of chronic age-related diseases by environmental toxicants

From a geroscience perspective, certain “risk factors” contribute to the pathogenesis of NCDs by exacerbating cellular and molecular mechanisms of aging (Fig. 1 ). Among these factors, environmental toxicants have been found to have significant detrimental effects on biological aging processes [ 20 , 23 , 24 , 26 – 35 ]. Research indicates that environmental toxicants play a critical role in the development of NCDs, with the World Health Organization (WHO) estimating that 24% (13.7 million) of all global deaths per year are linked to environmental factors [ 36 ]. Within this number, 8.5 million deaths are attributed to NCDs, and the top three causes related to the environment are ischemic heart disease, chronic respiratory diseases, and cancer. In the following sections, we will briefly discuss the interaction between environmental toxicants, aging processes, and the genesis of organ-specific NCDs.

Cardiovascular diseases

Vascular aging contributes to the age-dependent rise in a broad range of macrovascular and microvascular pathologies, including hypertension, atherosclerotic diseases (such as ischemic heart disease, peripheral artery disease, and stroke), aortic aneurysms, heart failure, cerebral small vessel disease, and age-related microvascular pathologies affecting other organs (such as glomerulosclerosis, microvascular rarefaction, and retinal pathologies) [ 8 , 37 , 38 ]. Aging alone confers a significantly higher risk for these diseases compared to “conventional” risk factors like lipid levels, smoking, diabetes mellitus, and sedentary lifestyle [ 8 , 37 ].

The cellular and molecular mechanisms of aging that contribute to the pathogenesis of age-related cardiovascular diseases have been the subject of recent reviews [ 8 , 37 , 39 ]. Increased oxidative stress plays a significant role in vascular aging [ 8 , 37 , 40 – 51 ]. The elevated production of reactive oxygen species (ROS) leads to endothelial dysfunction by inactivating endothelium-derived nitric oxide (NO) and producing peroxynitrite (ONOO-) [ 8 , 37 , 52 ]. Consequently, it results in age-related reduction in endothelium-dependent dilation [ 53 , 54 ], enhanced vasoconstriction, and dysregulation of tissue perfusion [ 8 , 37 ]. The lack of NO and increased oxidative stress also promotes vascular inflammation and the development of a proatherogenic vascular phenotype in aging [ 8 , 37 , 50 ]. Increased oxidative stress can activate matrix metalloproteinases, which disrupt the structural integrity of aged arteries, potentially contributing to large artery stiffening and the pathogenesis of aortic aneurysms and cerebral microhemorrhages [ 37 , 44 , 49 , 55 – 59 ]. Oxidative stress is also associated with DNA damage and DNA damage–induced cellular senescence, which are additional mechanisms of aging contributing to vascular pathologies [ 37 , 60 , 61 ].

Mitochondrial alterations, including mitochondrial ROS production, impaired mitochondrial biogenesis, impaired cellular energy production, and mitochondrial DNA damage, further exacerbate vascular aging processes [ 8 , 37 , 39 , 62 – 69 ]. Additionally, the release of several proinflammatory molecules increases with aging, leading to macrovascular and microvascular pathologies such as atherogenesis, aneurysm formation, and microvascular dysfunction [ 37 ].

The role of Nrf2, which coordinates an adaptive antioxidant response, has also been emphasized in recent studies [ 70 – 80 ]. Aging causes Nrf2 dysfunction in the vasculature, impairing the oxidative stress resilience of aged cells and contributing to age-related vascular pathologies induced by pro-oxidative, DNA damaging stimuli [ 75 – 77 ]. Aging also impacts the proteostasis system of the vasculature by impairing chaperones, the ubiquitin–proteasome system, and the lysosome-autophagy system [ 8 , 37 ]. Furthermore, endothelial senescence contributes to endothelial dysfunction in aging and pathophysiological conditions associated with accelerated vascular aging [ 8 , 37 , 46 , 73 , 81 – 83 ]. Epigenetic alterations, such as changes in DNA methylation patterns or miRNA dysregulation, also contribute to impairment of angiogenic processes, vascular inflammation, or atherogenesis [ 8 , 37 ].

The heart and vascular system are highly vulnerable to various environmental agents. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated that long-term exposure to ambient fine particulate matter (PM2.5) contributed to 2.9 million deaths globally each year, with nearly 50% of these deaths attributable to ischemic heart disease and stroke [ 84 ]. Even at concentrations below current regulatory standards in the USA and European Union, long-term exposure to PM10 and PM2.5 within metropolitan areas is associated with the progression of coronary calcification, indicating accelerated atherosclerosis [ 85 ]. Air pollution has been identified as a risk factor for ischemic heart disease [ 86 ] and stroke [ 87 , 88 ]. Ambient air pollution and household air pollution from cooking with polluting fuels are estimated to cause 13 and 17% of cardiovascular diseases, respectively [ 89 – 91 ]. Acrolein, a highly reactive unsaturated aldehyde, is generated during the burning of diesel fuels, gasoline, woods, plastics, cigarette smoking, and frying of food with fats. The Environmental Protection Agency classifies acrolein as a high-priority air and water toxicant. Strong evidence suggests that acrolein can cause damage to cardiac myocytes and endothelial cells, promoting endothelial dysfunction, vascular disease, and heart failure [ 92 – 95 ].

Smoking and exposure to secondhand smoke play significant roles in the pathogenesis of cardiovascular diseases [ 96 , 97 ]. Cigarette smoke contains numerous harmful substances, including carbon monoxide, nicotine, and a range of toxic chemicals and particulate matter. Smoking is a well-established risk factor for cardiovascular diseases, particularly ischemic heart disease, peripheral artery disease, stroke and vascular cognitive impairment [ 96 , 97 ]. The detrimental effects of smoking on the cardiovascular system arise from multiple mechanisms [ 98 – 109 ]. Firstly, smoking promotes the development of atherosclerosis by damaging the endothelial lining of blood vessels, increasing inflammation, and accelerating the formation of fatty deposits within the arterial walls [ 96 , 97 ]. Secondly, smoking leads to increased oxidative stress and endothelial dysfunction, impairing the production and bioavailability of NO and promoting nitrative stress [ 96 , 97 , 103 , 110 , 111 ]. Increased oxidative stress also contributes to lipid oxidation, induces expression of adhesion molecules of the endothelium and activates macrophages and platelets [ 96 , 97 , 110 , 111 ]. Macrophages engulf oxidized lipids, leading to the formation of foam cells within the aortic wall. Subsequent foam cell death triggers the release of these lipids, promoting the development of lipid-rich aortic plaques [ 96 ]. Furthermore, cigarette smoke leads to an increased expression and activity of matrix metalloproteinases (MMPs), as well as to decreased expression of MMP inhibitors causing alterations of vascular extracellular matrix and tissue remodeling that play a significant role not just in atherogenesis but in the formation of aneurysms as well [ 96 ]. Moreover, smoking promotes platelet aggregation and blood clot formation, increasing the risk of thrombotic events. Additionally, smoking causes an unfavorable lipid profile, with lower levels of beneficial high-density lipoprotein (HDL) cholesterol and elevated levels of harmful low-density lipoprotein (LDL) cholesterol. Furthermore, smoking induces systemic inflammation and adversely affects the balance of various pro-inflammatory and anti-inflammatory molecules, contributing to the progression of cardiovascular diseases [ 98 , 102 , 103 , 112 – 114 ]. Results from the Cardiovascular Health Study suggest that smoking-induced inflammation promotes cardiomyocyte injury exacerbating heart failure [ 115 ]. Secondhand smoke, which is the involuntary inhalation of smoke emitted by smokers, also poses a significant risk to cardiovascular health. Exposure to secondhand smoke has been associated with an increased risk of developing cardiovascular diseases, similar to active smoking. The toxic components in secondhand smoke can lead to endothelial dysfunction, inflammation, and increased oxidative stress in non-smokers, thereby contributing to the pathogenesis of cardiovascular diseases. Overall, the avoidance of smoking and secondhand smoke exposure is crucial for preventing and reducing the burden of cardiovascular diseases.

Water pollution is a significant environmental concern that can have adverse effects on cardiovascular health. Various pollutants and contaminants found in water sources can increase the risk of cardiovascular diseases [ 116 ]. For example, arsenic in drinking water has been identified as a potential risk factor for cardiovascular diseases [ 117 ]. Prolonged exposure to elevated levels of arsenic in drinking water has been associated with an increased incidence of hypertension, atherosclerosis, and cardiovascular mortality [ 117 ]. Similarly, exposure to lead and cadmium, often found in contaminated water sources, has been linked to an elevated risk of developing cardiovascular diseases [ 118 – 126 ]. Other pollutants present in water pollution that can pose harm to the cardiovascular system include mercury. Mercury is a toxic heavy metal that can contaminate water sources, primarily through industrial processes and the burning of fossil fuels. Chronic exposure to mercury has been associated with an increased risk of cardiovascular diseases, including hypertension, coronary artery disease, and myocardial infarction [ 127 – 134 ]. Water pollution may also contain various organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), pesticides, and industrial chemicals. These substances have been linked to adverse cardiovascular effects, including endothelial dysfunction, oxidative stress, inflammation, and disruption of cardiac function [ 135 – 137 ]. Water treatment processes often involve the use of chlorine and other disinfectants to eliminate microbial contaminants. However, the reaction between chlorine and organic matter in water can lead to the formation of disinfection by-products (DBPs), such as trihalomethanes (THMs) and haloacetic acids (HAAs) [ 138 – 140 ]. Long-term exposure to elevated levels of DBPs in drinking water has been associated with an increased risk of cardiovascular diseases, particularly in relation to heart disease and adverse cardiac remodeling [ 138 – 140 ]. Microplastics are tiny plastic particles that have become a pervasive environmental pollutant, including in water sources. While the direct impact of microplastics on cardiovascular health is still being studied, emerging evidence suggests that microplastic exposure may contribute to oxidative stress, inflammation, and endothelial dysfunction, all of which can increase the risk of cardiovascular diseases [ 141 – 147 ]. The specific health effects of water pollution may vary depending on the concentration and duration of exposure. To safeguard cardiovascular health, ensuring access to clean and uncontaminated water sources is crucial, along with implementing effective water treatment and pollution control measures.

The pollutants mentioned, ranging from PM2.5 and cigarette smoke to microplastics, can exacerbate biological mechanisms of aging through various interconnected pathways. Firstly, these pollutants contribute to increased oxidative stress within cells of the cardiovascular system and other organs [ 148 – 158 ]. They generate excessive reactive oxygen species (ROS), overwhelming the body’s antioxidant defense mechanisms and leading to oxidative damage to cellular structures, including DNA, proteins, and lipids. This oxidative stress contributes to the acceleration of aging processes, as well as the development of age-related diseases.

Secondly, exposure to these pollutants can induce increased DNA damage and cellular senescence [ 159 – 163 ]. DNA damage can occur due to direct interaction with the genetic material or through the generation of ROS. Persistent exposure to pollutants can lead to accumulation of DNA damage, impairing the cell’s ability to repair and maintain genomic integrity. In turn, this initiates cellular senescence, a state of irreversible growth arrest characterized by significant phenotypic alterations, including the emergence of the pro-inflammatory senescence-associated secretory phenotype (SASP). This senescence-driven inflammatory milieu contributes to tissue dysfunction and accelerates the aging process.

Furthermore, pollutants have been shown to impact stem cell function [ 164 – 174 ]. Pesticides, tobacco smoke, and heavy metals have been identified as disruptors of stem cell homeostasis, leading to impaired regenerative capacity and tissue repair. This disruption can further contribute to accelerated aging and compromised organ function.

Inflammation is another critical mechanism affected by these pollutants [ 10 , 155 , 175 – 186 ]. Chronic exposure to pollutants can trigger a sustained inflammatory response within the cardiovascular system and other organs as well. Inflammatory molecules are released, leading to the activation of immune cells and the production of pro-inflammatory mediators. This chronic state of inflammation contributes to tissue damage, promotes aging-related pathologies, and increases the risk of age-related diseases.

Additionally, pollutants can disrupt mitochondrial function, leading to mitochondrial dysfunction [ 24 , 26 , 27 , 30 ]. These toxic substances interfere with mitochondrial processes, such as energy production and oxidative phosphorylation. As a consequence, mitochondrial dysfunction occurs, leading to decreased energy availability, increased oxidative stress, and compromised cellular function.

In summary, environmental pollutants exacerbate biological mechanisms of aging through increased oxidative stress, increased DNA damage and cellular senescence, stem cell dysfunction, inflammation, mitochondrial dysfunction, and other interconnected pathways. Pollutants can also alter epigenetic mechanisms of aging [ 187 ]. Understanding these mechanisms is crucial for developing strategies to mitigate the detrimental effects of pollutants and promote healthy aging.

Environmental drivers of unhealthy cerebrovascular and brain aging

Alzheimer’s disease and Parkinson’s disease are the two most prevalent age-related neurodegenerative diseases affecting the central nervous system. These conditions have a profound impact on cognitive function, motor control, and overall quality of life, particularly in the elderly population. As individuals age, the incidence of both Alzheimer’s and Parkinson’s diseases increases, highlighting the significant burden these conditions pose on global health [ 188 – 190 ]. The pathogenesis of Alzheimer’s and Parkinson’s diseases involves a complex interplay of genetic, environmental, and lifestyle factors. While the exact causes of these diseases remain to be fully elucidated, several mechanisms have been proposed to contribute to their development and progression. In the case of Alzheimer’s disease, important hallmarks are microvascular pathologies (amyloid angiopathy, microhemorrhages, blood–brain barrier disruption) [ 191 – 201 ] and accumulation of amyloid-beta plaques and tau tangles in the brain. These abnormal protein aggregates disrupt normal neuronal communication and function, leading to cognitive decline. Importantly, hypertension has been found to exacerbate several manifestations of Alzheimer’s disease [ 55 , 202 – 205 ]. Aging itself plays a crucial role in the development of Alzheimer’s disease by contributing to increased oxidative stress [ 148 , 206 , 207 ], impaired mitochondrial function [ 25 ], DNA damage [ 208 – 211 ], and inflammation [ 212 ]. These aging-related processes can have significant implications for the cerebral microcirculation, leading to the emergence of microvascular pathologies and promoting the formation and accumulation of amyloid-beta and tau pathology, the hallmark features of Alzheimer’s disease. Additionally, genetic factors, such as mutations in genes like amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2), can further increase the risk of developing Alzheimer’s disease.

Parkinson’s disease, on the other hand, is characterized by the degeneration of dopaminergic neurons in the substantia nigra region of the brain. This neuronal loss leads to motor symptoms such as tremors, rigidity, and bradykinesia. Aging is a significant risk factor for Parkinson’s disease, as the brain undergoes age-related changes that contribute to the vulnerability of dopaminergic neurons. These changes include mitochondrial dysfunction, impaired protein handling and clearance mechanisms, oxidative stress, and inflammation. Additionally, genetic factors, such as mutations in the alpha-synuclein (SNCA) gene and genes involved in mitochondrial function, can increase the susceptibility to Parkinson’s disease.

Cognitive impairment caused by macrovascular (atherosclerosis) and microvascular pathologies (vascular cognitive impairment or VCI) is the second most common form of age-related cognitive decline [ 213 – 217 ]. Microvascular pathologies also play a central role in the pathogenesis of Alzheimer’s disease [ 55 , 191 , 193 , 194 , 198 , 218 , 219 ]. Age-related changes in the microvasculature [ 220 – 225 ], including alterations in endothelial function [ 59 , 226 , 227 ], blood–brain barrier integrity [ 199 , 200 , 228 ], and cerebral blood flow regulation, contribute to cognitive impairment and the development of neurodegenerative diseases.

Environmental toxicants can adversely affect cerebrovascular and brain health. Common sources of environmental pollutants linked to neurotoxic manifestations include pesticides, solvents, industrial waste, automobile exhaust, cigarette smoke and burning of terrestrial waste. Growing epidemiological and experimental evidence suggests that exposure to environmental toxicants, such as pesticides [ 229 ], heavy metals (e.g., lead) and organic solvents (e.g., trichloroethylene, n-hexane, and others) [ 230 , 231 ], exerts neurotoxic effects and may increase the risk of developing Alzheimer’s and Parkinson’s diseases [ 25 ]. These toxicants may damage the cerebral microvasculature and also can cross the blood–brain barrier, leading to cytotoxic effects, neuroinflammation, and consequential neuronal dysfunction and injury. Ambient outdoor air pollution has also been implicated in the exacerbation of the pathogenesis of both Parkinson’s and Alzheimer’s diseases [ 148 , 208 , 232 – 242 ]. Longitudinal cohort studies have shown associations between increased levels of PM2.5 (fine particulate matter) and a higher hazard of hospital admission for Parkinson’s disease and Alzheimer’s disease and related dementias [ 243 ]. Neurovascular damage and cerebromicrovascular dysfunction are increasingly recognized as important contributors to cognitive decline and neurodegeneration [ 59 , 199 – 201 , 244 – 246 ]. Cells of the neurovascular unit, including cerebromicrovascular endothelial cells, pericytes, astrocytes, and perivascular microglia, are sensitive to the harmful effects of environmental toxicants [ 29 , 247 , 248 ].

The cellular and molecular mechanisms underlying the impact of environmental toxicants on neurodegeneration and neurovascular injury can involve mitochondrial dysfunction [ 25 – 31 ], which impairs cellular energy production, metabolism, alters intracellular signaling, promotes increased free radical production, and apoptosis. Environmental toxicants can also exacerbate oxidative stress [ 208 ], which is causally linked to microglia activation and neuroinflammation [ 10 ], cellular senescence [ 249 , 250 ], and protein aggregation, ultimately leading to neuronal damage and death. It is likely that air pollution contributes to neuronal injury, oxidative stress, neuroinflammation, and cerebromicrovascular impairment, thereby exacerbating the pathogenesis of neurodegenerative diseases [ 148 , 208 , 235 , 237 , 241 , 242 ]. The complex interplay between environmental toxicants and the underlying cellular and molecular mechanisms highlights the importance of understanding and mitigating the impact of these environmental drivers to promote brain health and reduce the burden of cerebrovascular and neurodegenerative disorders.

Pulmonary diseases

Aging has a significant impact on the incidence and development of pulmonary diseases, particularly chronic obstructive pulmonary disease (COPD [ 251 – 254 ]) and other respiratory disorders. In 2019, there were 212.3 million prevalent cases of COPD reported globally, resulting in 3.3 million deaths and accounting for 74.4 million DALYs (disability-adjusted life years) [ 255 ]. The prevalence and death rate of COPD show an increasing tendency with age, peaking in the oldest age group (≥ 95 years) [ 255 ]. Studies have revealed that the prevalence of COPD is two to three times higher in individuals over the age of 60 years compared to younger age groups [ 256 ]. Furthermore, there are striking similarities between the mechanisms of lung aging and COPD, including cell senescence, shortened telomeres, inflammation, and oxidative stress, suggesting that accelerated aging processes may be involved in the pathogenesis of COPD [ 256 – 259 ].

Ambient particulate matter, a major component of outdoor air pollution, is considered a significant risk factor for respiratory disorders such as COPD. While tobacco smoking was traditionally seen as the primary cause of COPD, it is now recognized that air pollution, including fine particulate matter, plays a substantial role in the development and progression of the disease. According to the World Health Organization (WHO), 18% of premature deaths related to outdoor air pollution are attributed to COPD, making it the most prevalent chronic respiratory disorder [ 260 ]. Additionally, 25% of deaths from chronic COPD can be attributed to exposure to household air pollution, primarily in low- and middle-income countries. Certain occupational environments, such as coal and hard-rock mining, construction work, and various manufacturing industries (e.g., concrete, plastics, textiles, rubber, leather, and food products), pose a high risk for COPD [ 261 – 263 ].

The cellular and molecular mechanisms underlying the impact of air pollution and other environmental toxicants on the genesis of pulmonary diseases involve several interconnected pathways. These include increased oxidative stress, DNA damage, cellular senescence, inflammation, and mitochondrial dysfunction. Exposure to air pollution and environmental toxicants leads to an imbalance between the production and neutralization of ROS, resulting in increased oxidative stress. This oxidative stress contributes to cellular injury, DNA damage and induction of senescence, inflammation, and the activation of signaling pathways involved in the pathogenesis of pulmonary diseases. Chronic inflammation, triggered by environmental toxicants, can perpetuate tissue damage and contribute to the progression of pulmonary diseases. Additionally, mitochondrial dysfunction, caused by exposure to pollutants, disrupts cellular energy production and metabolism, further compromising lung function.

Malignant diseases

The etiology of cancer is multifaceted, influenced by a wide range of factors, and varies depending on the specific type of cancer. Many cancers are considered quintessential diseases of aging (e.g., colorectal cancer, multiple myeloma [ 264 ]), as their incidence increases exponentially with age, and mechanisms associated with aging contribute to their pathogenesis [ 265 , 266 ]. In animal models, interventions and genetic manipulations that delay aging and extend lifespan, such as caloric restriction, have been shown to exert significant anti-cancer effects [ 267 – 274 ]. Conversely, interventions and genetic manipulations that accelerate aging and shorten lifespan promote tumorigenesis and cancer progression [ 275 – 277 ].

Numerous environmental factors have been causally linked to the genesis of various cancer types. Outdoor air pollution, for example, has been identified as a cause of lung cancer occurrence [ 278 , 279 ] and is increasingly being associated with other types of cancer, including bladder cancer and breast cancer [ 280 ]. Indoor air pollution resulting from the burning of solid fuels has been associated with oral, cervical, and esophageal cancer [ 279 ].

Workplace or home exposure to a wide range of chemicals has also been causally linked to the development of diverse types of cancer. Asbestos, silica, diesel exhaust, uranium, arsenic, beryllium, cadmium, silica, vinyl chloride, nickel compounds, chromium compounds, coal products, mustard gas, and chloromethyl ethers are significant risk factors for lung cancer [ 281 – 291 ]. Exposure to vinyl chloride increases the risk of liver cancer [ 292 – 295 ], while limited evidence suggests an increased risk with exposure to arsenic [ 296 ] and trichloroethylene [ 297 , 298 ].

The International Agency for Research on Cancer (IARC) classifies asbestos as a cause of ovarian cancer, as well as other cancers [ 299 ]. Long-term workplace exposure to polycyclic aromatic hydrocarbons (PAH) and already banned chemicals like arylamines is linked to bladder cancer [ 300 , 301 ]. Chemicals used in the rubber production industry, coal and tin mining and metal processing increase the risk of gastric cancer, and exposure to asbestos and inorganic lead compounds has limited evidence linking them to gastric cancer [ 302 – 304 ]. Occupational exposure to trichloroethylene, organochlorine and organophosphate pesticides increases the risk of non-Hodgkin’s lymphoma [ 305 – 308 ]. Importantly, women’s hairdresser and textile occupations increase non-Hodgkin’s lymphoma risk [ 308 ].

Laryngeal cancer risk is elevated with exposure to coal dust, paint fumes, diesel fumes, formaldehyde, nickel, isopropyl alcohol, and asbestos [ 309 – 316 ]. Furthermore, there are other environmental toxicants known to cause cancer that should be considered. Glyphosate, a commonly used herbicide, has raised concerns and is being investigated for its potential carcinogenic effects [ 317 – 321 ]. Benzene, a chemical found in gasoline, industrial solvents, and tobacco smoke, is a known carcinogen associated with various cancers, including leukemia and multiple myeloma [ 322 – 329 ]. Ionizing radiation, such as in-house exposure to radon, is a risk factor for lung cancer and possibly ovarian cancer [ 330 ]. Exposure to ultraviolet (UV) radiation is a major risk factor for most melanomas [ 331 ].

The cellular and molecular mechanisms of aging that are exacerbated by the aforementioned environmental factors and exposures contribute to tumorigenesis. These mechanisms include increased production of ROS, DNA damage, genetic instability, and various other pathways associated with aging. The interplay between these aging mechanisms and the effects of environmental toxicants contributes to the initiation and progression of malignant diseases. Importantly, there is evidence that the inflammatory milieu maintained by senescent cells contribute to the development of metastases [ 332 – 336 ]. Understanding the impact of environmental toxicants on accelerated aging and cancer development is crucial for implementing preventive measures, promoting environmental regulations, and reducing the burden of cancer in aging populations. Continued research and vigilance are needed to identify and mitigate the risks associated with exposure to environmental toxicants and their role in cancer incidence.

Diseases of the musculoskeletal system

Aging of the musculoskeletal system plays a significant role in the pathogenesis of common diseases that have a negative impact on the quality of life, such as osteoporosis, sarcopenia, rheumatoid arthritis, and osteoarthritis [ 337 ]. Osteoporosis, characterized by a dysregulation of osteoclast and osteoblast function, is influenced by age-related mechanisms including the accumulation of senescent cells, heightened inflammation, mitochondrial dysfunction, and dysregulated autophagy [ 338 – 341 ]. Mechanisms underlying the pathogenesis of osteoporosis involve endocrine changes, dysfunction of myo-satellite cells, increased inflammation, elevated reactive oxygen species production, macromolecular damage, and dysregulation of proteostasis, cellular energetics, and mitochondrial function [ 342 – 357 ]. Sarcopenia, the gradual decline in muscle mass and strength, contributes to frailty and increases the risk of falls and life-threatening bone fractures in older adults, particularly when combined with osteoporosis. The mechanisms underlying sarcopenia involve impaired muscle protein synthesis, dysregulation of anabolic and catabolic signaling pathways, mitochondrial dysfunction, increased oxidative stress, and altered muscle stem cell function, all contributing to the progressive loss of muscle mass and strength with advancing age. Rheumatoid arthritis, a chronic autoimmune disease affecting the joints, also exhibits an increased incidence with age. The aging of the immune system, known as immunosenescence, and subsequent dysregulation of inflammatory processes are implicated in the pathogenesis of rheumatoid arthritis [ 358 ].

There are several environmental toxicants that have been linked to the development of musculoskeletal diseases.

Accumulating evidence suggests that both outdoor and indoor air pollution have detrimental effects on musculoskeletal aging. Two comprehensive studies, involving over 9 million individuals aged 65 years and older over an 8-year period, have demonstrated an association between poor air quality and longitudinal bone loss. Individuals living in areas with higher concentrations of PM2.5 particles were found to have a greater risk of osteoporotic fractures [ 359 ]. Furthermore, emerging evidence suggests a potential link between ambient air pollution and arthritis [ 360 , 361 ]. Household air pollution exposure may also play a significant role in the development of arthritis, particularly in low- and middle-income countries [ 362 ]. Understanding the effects of air pollution on musculoskeletal aging is of great importance for public health. Mitigating exposure to poor air quality and implementing measures to improve air pollution levels may help prevent or reduce the burden of musculoskeletal diseases associated with aging. Further research is needed to elucidate the underlying mechanisms linking air pollution and musculoskeletal disorders, as well as to explore potential interventions and strategies for promoting healthy musculoskeletal aging in an increasingly polluted environment.

Exposure to lead, commonly found in old paint, contaminated water, and certain occupational settings, has been associated with various musculoskeletal disorders [ 363 – 365 ]. Lead exposure can impair bone health, leading to decreased bone mineral density, increased fracture risk, and disturbances in bone remodeling. Certain organophosphate pesticides used in agricultural practices have been implicated in musculoskeletal disorders [ 366 ]. Prolonged exposure to these pesticides has been associated with decreased grip strength, muscle weakness, and altered neuromuscular function. Cadmium is a toxic metal present in certain industrial processes, batteries, and cigarette smoke. Prolonged exposure to cadmium has been linked to adverse effects on bone health, including decreased bone mineral density, osteoporosis, and an increased risk of fractures [ 367 ]. Polychlorinated biphenyls (PCBs) are persistent organic pollutants that were widely used in electrical equipment and industrial applications. Exposure to PCBs has been associated with adverse effects on the musculoskeletal system [ 368 – 370 ].

Certain toxicants have been associated with an increased risk or exacerbation of arthritis. For example, occupational exposure to crystalline silica, commonly found in industries such as mining, construction, and manufacturing, has been linked to an increased risk of developing rheumatoid arthritis [ 371 – 375 ]. It is also possible that prolonged exposure to benzene, a chemical commonly found in industrial settings and certain products such as gasoline, and to vinyl chloride, commonly found in the plastics industry, may also increase the developing of autoimmune diseases, such as arthritis [ 376 , 377 ].

The mechanisms by which environmental toxicants exacerbate musculoskeletal diseases are complex and involve multiple pathways, including impaired satellite cell function, dysregulation of hormonal signaling, mitochondrial dysfunction, disruption of intracellular signaling pathways involved in muscle protein turnover induction of oxidative stress and inflammation.

Perspectives

In conclusion, the impact of environmental factors on unhealthy cardiovascular, cerebrovascular, and brain aging cannot be overstated. The integration of geroscience, environmental health sciences, and toxicology is crucial in bridging gaps and enhancing our understanding of the relationship between environmental drivers and aging processes. This multidisciplinary approach promotes collaborative efforts and enables a comprehensive assessment of the complex interplay between environmental factors and aging outcomes.

The exposomic framework has emerged as a powerful tool in advancing our understanding of the associations between environmental factors and healthy aging. By capturing the totality of environmental exposures throughout an individual’s life, the exposomic approach provides a holistic perspective on the cumulative effects of these exposures on aging processes. While capturing exposures over a lifetime poses challenges and requires resources, leveraging historical data sources such as retrospective surveys or longitudinal cohorts offers a practical avenue for conducting research in this area. By harnessing existing data, researchers can gain valuable insights into the long-term impact of environmental exposures on aging and identify potential strategies for promoting healthy aging in the population.

Biomarkers of biological age have emerged as valuable tools for assessing the effects of environmental toxicants on aging. These biomarkers provide objective measures of an individual’s physiological state and reflect the cumulative impact of genetic, lifestyle, and environmental factors on the aging process. Telomere length, epigenetic modifications, DNA damage markers, inflammation markers, oxidative stress markers, and mitochondrial function indicators are among the commonly used biomarkers of biological age. Assessing the effects of environmental toxicants on aging through biomarkers allows for a comprehensive understanding of the underlying mechanisms and helps identify individuals at higher risk of accelerated aging or age-related diseases.

Emerging methodologies for determining biological age, such as epigenetic clocks, proteomic clocks, and lipidomic clocks, have brought new insights to the field of aging research [ 378 – 383 ]. Epigenetic clocks utilize DNA methylation patterns to predict biological age, while proteomic clocks assess changes in protein levels and modifications associated with aging. By integrating these clocks with physiological measurements, researchers can obtain a more comprehensive understanding of an individual’s biological age and the factors influencing the rate of aging. These methodologies hold great potential for advancing our understanding of healthy aging, identifying individuals at higher risk of age-related diseases, and developing targeted interventions to promote healthier and more vibrant aging.

Integrating the analysis of biological age and biomarkers of aging with epidemiological and toxicological studies allows for a more comprehensive assessment of the relationship between environmental toxicants and aging. This multidimensional approach provides valuable data for developing strategies to mitigate the adverse effects of toxicants, promoting healthier aging, and informing public health policies aimed at reducing exposure to harmful environmental factors. Longitudinal studies tracking changes in biomarker profiles and the subjects’ biological age in response to environmental exposures can provide valuable information on the impact of toxicants over time. Additionally, biomarker assessments can aid in evaluating the effectiveness of interventions or preventive measures aimed at mitigating the detrimental effects of toxicants on aging.

A geroscience approach to environmental health sciences will further identify potential new areas of interdisciplinary research. Environmental toxicants can exacerbate mitochondrial DNA damage and mutagenesis, accelerating mitochondrial aging and promoting dysfunction, cellular energetic dysfunction, apoptosis signaling, and increased production of mitochondria-derived free radicals [ 384 ]. Future epidemiological studies should aim to characterize in detail the impacts of environmental chemical exposures on mitochondrial DNA mutagenesis, linking it to the genesis of accelerated aging phenotypes and the incidence of age-related non-communicable diseases.

Furthermore, intersecting area-level indicators with trends in biological aging and the incidence of age-related diseases in a population opens new horizons in epidemiology. By employing this approach, longitudinal studies can lead to a deeper understanding of the role of the exposome in modulating biological aging processes and its contribution to health inequalities in aging. Identifying the role of environmental toxicants in accelerated aging and the increased prevalence of cognitive impairment, dementia, and other age-related diseases in vulnerable populations will advance opportunities for intervention and prevention.

In summary, by advancing our knowledge of the environmental drivers of unhealthy aging and employing an integrative approach, we can develop effective strategies to promote healthier aging, mitigate the detrimental effects of environmental toxicants, and improve the overall well-being of the aging population.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Tamas Pandics, David Major and Vince Fazekas-Pongor have equal contributions.

Funding

Open access funding provided by Semmelweis University. Drs. Anna Csiszar and Zoltan Ungvari were supported by the National Institute on Aging (RF1AG072295, R01AG055395, R01AG068295; R01AG070915, R03AG070479), the National Institute of Neurological Disorders and Stroke (R01NS100782), the National Cancer Institute (R01CA255840), the Presbyterian Health Foundation, the Reynolds Foundation, the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (P20GM125528). Project no. TKP2021-NKTA-47 has been implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NKTA funding scheme. Funding for the project through the National Cardiovascular Laboratory Program (RRF-2.3.1–21-2022–00003) was provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund. Project no. 135784 has also been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the K_20 funding scheme. This work was also supported by grants from the European University for Well-Being (EUniWell) program (grant agreement number: 101004093/ EUniWell/EAC-A02-2019 / EAC-A02-2019–1). Prof. Dr. Zoltan Benyo was supported by grants from the Ministry of Innovation and Technology of Hungary from the NRDI Fund (2020–1.1.6-JÖVŐ-2021–00010, RRF-2.1.2–21-2022–00010, and TKP2021-EGA-25). The authors acknowledge the scientific contributions of Gen. Artúr Görgei [ 385 ]. The views expressed are those of the author and not necessarily those of the NIH or of the other funding agencies. The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. The 3.5 version of ChatGPT, developed by OpenAI, proved to be a useful tool in refining the writing and enhancing the clarity of the work.

Declarations

Competing interests

Dr. Stefano Tarantini, Dr. Andriy Yabluchanskiy, Dr. Shannon Conley, Dr. Anna Csiszar, Dr. Zoltan Benyo and Dr. Roza Adany serve as Associate Editors for GeroScience. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience.

References

1. WHO Data Platform. https://platform.who.int/data/maternal-newborn-child-adolescent-ageing/indicator-explorer-new/mca/number-of-persons-aged-over-60-years-or-over-(thousands ). Accessed 05/01/2023.

2. National Council on Aging. Chronic inequities: measuring disease cost burden among older adults in the U.S. A health and retirement study analysis. https://ncoa.org/article/get-the-facts-on-healthy-aging . Accessed 05/01/2023.

3. Chen S Kuhn M Prettner K Bloom DE The macroeconomic burden of noncommunicable diseases in the United States: estimates and projections PLoS One 2018 13 e0206702 10.1371/journal.pone.0206702 30383802 PMC6211719

4. WHO’s work on the UN Decade of Healthy Ageing (2021–2030). https://www.who.int/initiatives/decade-of-healthy-ageing (accessed on 03/15/2023).

5. World Health Organization Decade of healthy ageing: baseline report 2020 Summary. Geneva World Health Organization

6. Kennedy BK Berger SL Brunet A Campisi J Cuervo AM Epel ES Franceschi C Lithgow GJ Morimoto RI Pessin JE Rando TA Richardson A Schadt EE Wyss-Coray T Sierra F Geroscience: linking aging to chronic disease Cell 2014 159 709 713 10.1016/j.cell.2014.10.039 25417146 PMC4852871

7. Sierra F Kohanski R Geroscience and the trans-NIH Geroscience Interest Group GSIG Geroscience 2017 39 1 5 10.1007/s11357-016-9954-6 28299635 PMC5352582

8. Ungvari Z Tarantini S Sorond F Merkely B Csiszar A Mechanisms of vascular aging, a geroscience perspective: JACC Focus Seminar J Am Coll Cardiol 2020 75 931 941 10.1016/j.jacc.2019.11.061 32130929 PMC8559983

9. Lopez-Otin C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging Cell 2013 153 1194 1217 10.1016/j.cell.2013.05.039 23746838 PMC3836174

10. Furman D Campisi J Verdin E Carrera-Bastos P Targ S Franceschi C Ferrucci L Gilroy DW Fasano A Miller GW Miller AH Mantovani A Weyand CM Barzilai N Goronzy JJ Rando TA Effros RB Lucia A Kleinstreuer N Slavich GM Chronic inflammation in the etiology of disease across the life span Nat Med 2019 25 1822 1832 10.1038/s41591-019-0675-0 31806905 PMC7147972

11. Misra BB The chemical exposome of human aging Front Genet 2020 11 574936 10.3389/fgene.2020.574936 33329714 PMC7732411

12. Wild CP Complementing the genome with an “exposome”: the outstanding challenge of environmental exposure measurement in molecular epidemiology Cancer Epidemiol Biomarkers Prev 2005 14 1847 1850 10.1158/1055-9965.EPI-05-0456 16103423

13. Dunn AR O’Connell KMS Kaczorowski CC Gene-by-environment interactions in Alzheimer’s disease and Parkinson’s disease Neurosci Biobehav Rev 2019 103 73 80 10.1016/j.neubiorev.2019.06.018 31207254 PMC6700747

14. Finch CE Kulminski AM The Alzheimer’s disease exposome Alzheimers Dement 2019 15 1123 1132 10.1016/j.jalz.2019.06.3914 31519494 PMC6788638

15. Huang SY Yang YX Chen SD Li HQ Zhang XQ Kuo K Tan L Feng L Dong Q Zhang C Yu JT Investigating causal relationships between exposome and human longevity: a Mendelian randomization analysis BMC Med 2021 19 150 10.1186/s12916-021-02030-4 34281550 PMC8290559

16. Herceg Z Ghantous A Wild CP Sklias A Casati L Duthie SJ Fry R Issa JP Kellermayer R Koturbash I Kondo Y Lepeule J Lima SCS Marsit CJ Rakyan V Saffery R Taylor JA Teschendorff AE Ushijima T Vineis P Walker CL Waterland RA Wiemels J Ambatipudi S Degli Esposti D Hernandez-Vargas H Roadmap for investigating epigenome deregulation and environmental origins of cancer Int J Cancer 2018 142 874 882 10.1002/ijc.31014 28836271 PMC6027626

17. Vineis P, Chadeau-Hyam M, Gmuender H, Gulliver J, Herceg Z, Kleinjans J, Kogevinas M, Kyrtopoulos S, Nieuwenhuijsen M, Phillips DH, Probst-Hensch N, Scalbert A, Vermeulen R, Wild CP and Consortium EX The exposome in practice: design of the EXPOsOMICS project Int J Hyg Environ Health 2017 220 142 151 10.1016/j.ijheh.2016.08.001 27576363 PMC6192011

18. Agusti A Melen E DeMeo DL Breyer-Kohansal R Faner R Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene-environment interactions across the lifespan Lancet Respir Med 2022 10 512 524 10.1016/S2213-2600(21)00555-5 35427533 PMC11428195

19. Finch CE Haghani A Gene-environment interactions and stochastic variations in the gero-exposome J Gerontol A Biol Sci Med Sci 2021 76 1740 1747 10.1093/gerona/glab045 33580247 PMC8436990

20. Kalia V Belsky DW Baccarelli AA Miller GW An exposomic framework to uncover environmental drivers of aging Exposome 2022 2 osac002 10.1093/exposome/osac002 35295547 PMC8917275

21. Lan Y Wu S Impacts of environmental insults on cardiovascular aging Curr Environ Health Rep 2022 9 11 28 10.1007/s40572-022-00335-x 35103958

22. Letellier N Gutierrez LA Pilorget C Artaud F Descatha A Ozguler A Goldberg M Zins M Elbaz A Berr C Association between occupational exposure to formaldehyde and cognitive impairment Neurology 2022 98 e633 e640 10.1212/WNL.0000000000013146 34937783

23. Malecki KMC Andersen JK Geller AM Harry GJ Jackson CL James KA Miller GW Ottinger MA Integrating environment and aging research: opportunities for synergy and acceleration Front Aging Neurosci 2022 14 824921 10.3389/fnagi.2022.824921 35264945 PMC8901047

24. Boovarahan SR Kurian GA Mitochondrial dysfunction: a key player in the pathogenesis of cardiovascular diseases linked to air pollution Rev Environ Health 2018 33 111 122 10.1515/reveh-2017-0025 29346115

25. Agnihotri A Aruoma OI Alzheimer’s disease and Parkinson’s disease: a nutritional toxicology perspective of the impact of oxidative stress, mitochondrial dysfunction, nutrigenomics and environmental chemicals J Am Coll Nutr 2020 39 16 27 10.1080/07315724.2019.1683379 31829802

26. Blajszczak C Bonini MG Mitochondria targeting by environmental stressors: implications for redox cellular signaling Toxicology 2017 391 84 89 10.1016/j.tox.2017.07.013 28750850 PMC5939563

27. Caito SW Aschner M Mitochondrial redox dysfunction and environmental exposures Antioxid Redox Signal 2015 23 578 595 10.1089/ars.2015.6289 25826672 PMC4544749

28. Helley MP Pinnell J Sportelli C Tieu K Mitochondria: a common target for genetic mutations and environmental toxicants in Parkinson’s disease Front Genet 2017 8 177 10.3389/fgene.2017.00177 29204154 PMC5698285

29. McCann MS Fernandez HR Flowers SA Maguire-Zeiss KA Polychlorinated biphenyls induce oxidative stress and metabolic responses in astrocytes Neurotoxicology 2021 86 59 68 10.1016/j.neuro.2021.07.001 34265337 PMC8440398

30. Meyer JN Leung MC Rooney JP Sendoel A Hengartner MO Kisby GE Bess AS Mitochondria as a target of environmental toxicants Toxicol Sci 2013 134 1 17 10.1093/toxsci/kft102 23629515 PMC3693132

31. Zhou Z Goodrich JM Strakovsky RS Mitochondrial epigenetics and environmental health: making a case for endocrine disrupting chemicals Toxicol Sci 2020 178 16 25 10.1093/toxsci/kfaa129 32777053 PMC7818895

32. Brahadeeswaran S Lateef M Calivarathan L An insight into the molecular mechanism of mitochondrial toxicant-induced neuronal apoptosis in Parkinson’s disease Curr Mol Med. 2023 23 63 75 10.2174/1566524022666220203163631 35125081

33. Duarte-Hospital C Tete A Brial F Benoit L Koual M Tomkiewicz C Kim MJ Blanc EB Coumoul X Bortoli S Mitochondrial dysfunction as a hallmark of environmental injury Cells. 2022 11 110 10.3390/cells11010110 PMC8750015 35011671

34. Kunovac A Hathaway QA Pinti MV Taylor AD Hollander JM Cardiovascular adaptations to particle inhalation exposure: molecular mechanisms of the toxicology Am J Physiol Heart Circ Physiol 2020 319 H282 H305 10.1152/ajpheart.00026.2020 32559138 PMC7473925

35. Lopert P Patel M Mitochondrial mechanisms of redox cycling agents implicated in Parkinson’s disease J Neural Transm (Vienna) 2016 123 113 123 10.1007/s00702-015-1386-4 25749885 PMC5049695

36. World Health Organization: The Global Health Observatory; Public healthand environment. https://www.who.int/data/gho/data/themes/public-health-and-environment (accessed on 05/29/2023).

37. Ungvari Z Tarantini S Donato AJ Galvan V Csiszar A Mechanisms of vascular aging Circ Res 2018 123 849 867 10.1161/CIRCRESAHA.118.311378 30355080 PMC6248882

38. Fang X Crumpler RF Thomas KN Mazique JN Roman RJ Fan F Contribution of cerebral microvascular mechanisms to age-related cognitive impairment and dementia Physiol Int. 2022 109 20 30 10.1556/2060.2022.00020 PMC10710737 35238800

39. Dai DF Rabinovitch PS Ungvari Z Mitochondria and cardiovascular aging Circ Res 2012 110 1109 1124 10.1161/CIRCRESAHA.111.246140 22499901 PMC3867977

40. Kiss T Balasubramanian P Valcarcel-Ares MN Tarantini S Yabluchanskiy A Csipo T Lipecz A Reglodi D Zhang XA Bari F Farkas E Csiszar A Ungvari Z Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment Geroscience 2019 41 619 630 10.1007/s11357-019-00074-2 31144244 PMC6885080

41. Springo Z Tarantini S Toth P Tucsek Z Koller A Sonntag WE Csiszar A Ungvari Z Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries J Gerontol A Biol Sci Med Sci 2015 70 1355 1359 10.1093/gerona/glu244 25631392 PMC4612385

42. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Fulop GA, Hertelendy P, Gautam T, Farkas E, Perz A, Rabinovitch PS, Sonntag WE, Csiszar A, Ungvari Z. Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell. 2018;17:e12731. 10.1111/acel.12731 PMC5847870 29405550

43. Tarantini S Yabluchanskiy A Csipo T Fulop G Kiss T Balasubramanian P DelFavero J Ahire C Ungvari A Nyul-Toth A Farkas E Benyo Z Toth A Csiszar A Ungvari Z Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging Geroscience 2019 41 533 542 10.1007/s11357-019-00101-2 31679124 PMC6885075

44. Toth P Tarantini S Springo Z Tucsek Z Gautam T Giles CB Wren JD Koller A Sonntag WE Csiszar A Ungvari Z Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection Aging Cell 2015 14 400 408 10.1111/acel.12315 25677910 PMC4406669

45. Tucsek Z Toth P Sosnowsk D Gautam T Mitschelen M Koller A Szalai G Sonntag WE Ungvari Z and Csiszar A Obesity in aging exacerbates blood brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease J Gerontol A Biol Sci Med Sci 2014 69 1212 1226 10.1093/gerona/glt177 24269929 PMC4172034

46. Ungvari Z Buffenstein R Austad SN Podlutsky A Kaley G Csiszar A Oxidative stress in vascular senescence: lessons from successfully aging species Front Biosci 2008 13 5056 5070 10.2741/3064 18508570

47. Ungvari Z Orosz Z Labinskyy N Rivera A Xiangmin Z Smith K Csiszar A Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries Am J Physiol Heart Circ Physiol 2007 293 H37 47 10.1152/ajpheart.01346.2006 17416599

48. Ungvari Z Parrado-Fernandez C Csiszar A de Cabo R Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging Circ Res 2008 102 519 528 10.1161/CIRCRESAHA.107.168369 18340017 PMC2424221

49. Ungvari Z Tarantini S Kirkpatrick AC Csiszar A Prodan CI Cerebral microhemorrhages: mechanisms, consequences, and prevention Am J Physiol Heart Circ Physiol 2017 312 H1128 H1143 10.1152/ajpheart.00780.2016 28314762 PMC5495931

50. Ungvari ZI Orosz Z Labinskyy N Rivera A Xiangmin Z Smith KE Csiszar A Increased mitochondrial H2O2 production promotes endothelial NF-kB activation in aged rat arteries Am J Physiol Heart Circ Physiol 2007 293 H37 47 10.1152/ajpheart.01346.2006 17416599

51. Wiedenhoeft T Tarantini S Nyul-Toth A Yabluchanskiy A Csipo T Balasubramanian P Lipecz A Kiss T Csiszar A Csiszar A Ungvari Z Fusogenic liposomes effectively deliver resveratrol to the cerebral microcirculation and improve endothelium-dependent neurovascular coupling responses in aged mice Geroscience 2019 41 711 725 10.1007/s11357-019-00102-1 31654270 PMC6925096

52. Csiszar A Ungvari Z Edwards JG Kaminski PM Wolin MS Koller A Kaley G Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function Circ Res 2002 90 1159 1166 10.1161/01.RES.0000020401.61826.EA 12065318

53. Tarantini S Nyul-Toth A Yabluchanskiy A Csipo T Mukli P Balasubramanian P Ungvari A Toth P Benyo Z Sonntag WE Ungvari Z Csiszar A Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype Geroscience 2021 43 2387 2394 10.1007/s11357-021-00405-2 34383203 PMC8599783

54. Kiss T Tarantini S Csipo T Balasubramanian P Nyul-Toth A Yabluchanskiy A Wren JD Garman L Huffman DM Csiszar A Ungvari Z Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood Geroscience 2020 42 727 748 10.1007/s11357-020-00180-6 32172434 PMC7205954

55. Csiszar A Tarantini S Fulop GA Kiss T Valcarcel-Ares MN Galvan V Ungvari Z Yabluchanskiy A Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease Geroscience. 2017 39 359 372 10.1007/s11357-017-9991-9 28853030 PMC5636770

56. Miller LR Tarantini S Nyul-Toth A Johnston MP Martin T Bullen EC Bickel MA Sonntag WE Yabluchanskiy A Csiszar A Ungvari ZI Elliott MH Conley SM Increased susceptibility to cerebral microhemorrhages is associated with imaging signs of microvascular degeneration in the retina in an insulin-like growth factor 1 deficient mouse model of accelerated aging Front Aging Neurosci 2022 14 788296 10.3389/fnagi.2022.788296 35356301 PMC8959924

57. Nyul-Toth A Tarantini S Kiss T Toth P Galvan V Tarantini A Yabluchanskiy A Csiszar A Ungvari Z Increases in hypertension-induced cerebral microhemorrhages exacerbate gait dysfunction in a mouse model of Alzheimer’s disease Geroscience. 2020 42 1685 1698 10.1007/s11357-020-00256-3 32844283 PMC7732885

58. Tarantini S Valcarcel-Ares NM Yabluchanskiy A Springo Z Fulop GA Ashpole N Gautam T Giles CB Wren JD Sonntag WE Csiszar A Ungvari Z Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype Aging Cell 2017 16 469 479 10.1111/acel.12583 28295976 PMC5418199

59. Toth P Tarantini S Csiszar A Ungvari Z Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging Am J Physiol Heart Circ Physiol 2017 312 H1 H20 10.1152/ajpheart.00581.2016 27793855 PMC5283909

60. Bloom SI Tucker JR Lim J Thomas TG Stoddard GJ Lesniewski LA Donato AJ Aging results in DNA damage and telomere dysfunction that is greater in endothelial versus vascular smooth muscle cells and is exacerbated in atheroprone regions Geroscience 2022 44 2741 2755 10.1007/s11357-022-00681-6 36350415 PMC9768045

61. Tarantini S Balasubramanian P Delfavero J Csipo T Yabluchanskiy A Kiss T Nyul-Toth A Mukli P Toth P Ahire C Ungvari A Benyo Z Csiszar A Ungvari Z Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice Geroscience 2021 43 2427 2440 10.1007/s11357-021-00440-z 34427858 PMC8599595

62. Csiszar A Labinskyy N Orosz Z Ungvari Z Altered mitochondrial energy metabolism may play a role in vascular aging Med Hypotheses 2006 67 904 908 10.1016/j.mehy.2006.03.037 16750895

63. Das A Huang GX Bonkowski MS Longchamp A Li C Schultz MB Kim LJ Osborne B Joshi S Lu Y Trevino-Villarreal JH Kang MJ Hung TT Lee B Williams EO Igarashi M Mitchell JR Wu LE Turner N Arany Z Guarente L Sinclair DA Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging Cell 2018 173 74–89 e20 10.1016/j.cell.2018.02.008 PMC5884172 29570999

64. Kiss T Tarantini S Csipo T Balasubramanian P Nyul-Toth A Yabluchanskiy A Wren JD Garman L Huffman DM Csiszar A Ungvari Z Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood Geroscience 2020 42 727 748 10.1007/s11357-020-00180-6 32172434 PMC7205954

65. Marzetti E Csiszar A Dutta D Balagopal G Calvani R Leeuwenburgh C Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics Am J Physiol Heart Circ Physiol. 2013 305 H459 476 10.1152/ajpheart.00936.2012 23748424 PMC3891249

66. Ungvari ZI Labinskyy N Gupte SA Chander PN Edwards JG Csiszar A Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats Am J Physiol Heart Circ Physiol 2008 294 H2121 H2128 10.1152/ajpheart.00012.2008 18326800

67. Wenzel P Schuhmacher S Kienhofer J Muller J Hortmann M Oelze M Schulz E Treiber N Kawamoto T Scharffetter-Kochanek K Munzel T Burkle A Bachschmid MM Daiber A Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction Cardiovasc Res 2008 80 280 289 10.1093/cvr/cvn182 18596060 PMC3937602

68. Zinovkin RA Romaschenko VP Galkin II Zakharova VV Pletjushkina OY Chernyak BV Popova EN Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium Aging (Albany NY) 2014 6 661 674 10.18632/aging.100685 25239871 PMC4169860

69. Csiszar A Yabluchanskiy A Ungvari A Ungvari Z Tarantini S Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice Geroscience 2019 41 609 617 10.1007/s11357-019-00111-0 31643012 PMC6885076

70. Bailey-Downs LC Mitschelen M Sosnowska D Toth P Pinto JT Ballabh P Valcarcel-Ares MN Farley J Koller A Henthorn JC Bass C Sonntag WE Ungvari Z Csiszar A Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging J Gerontol A Biol Sci Med Sci 2012 67 313 329 10.1093/gerona/glr164 22021391 PMC3309870

71. Csiszar A Gautam T Sosnowska D Tarantini S Banki E Tucsek Z Toth P Losonczy G Koller A Reglodi D Giles CB Wren JD Sonntag WE Ungvari Z Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats Am J Physiol Heart Circ Physiol 2014 307 H292 306 10.1152/ajpheart.00307.2014 24906921 PMC4121647

72. Csiszar A Sosnowska D Wang M Lakatta EG Sonntag WE Ungvari Z Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment J Gerontol A Biol Sci Med Sci 2012 67 811 820 10.1093/gerona/glr228 22219513 PMC3536544

73. Fulop GA Kiss T Tarantini S Balasubramanian P Yabluchanskiy A Farkas E Bari F Ungvari Z Csiszar A Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation Geroscience 2018 40 513 521 10.1007/s11357-018-0047-6 30470983 PMC6294722

74. Tarantini S Valcarcel-Ares MN Yabluchanskiy A Tucsek Z Hertelendy P Kiss T Gautam T Zhang XA Sonntag WE de Cabo R Farkas E Elliott ME Kinter MT Deak F Ungvari Z Csiszar A Nrf2 deficiency exacerbates obesity-induced oxidative stress, neurovascular dysfunction, blood brain barrier disruption, neuroinflammation, amyloidogenic gene expression and cognitive decline in mice, mimicking the aging phenotype J Gerontol A Biol Sci Med Sci. 2018 73 853 863 10.1093/gerona/glx177 29905772 PMC6001893

75. Ungvari Z Bailey-Downs L Gautam T Sosnowska D Wang M Monticone RE Telljohann R Pinto JT de Cabo R Sonntag WE Lakatta E Csiszar A Age-associated vascular oxidative stress, Nrf2 dysfunction and NF-kB activation in the non-human primate Macaca mulatta J Gerontol A Biol Sci Med Sci 2011 66 866 75 10.1093/gerona/glr092 21622983 PMC3148762

76. Ungvari Z Bailey-Downs L Sosnowska D Gautam T Koncz P Losonczy G Ballabh P de Cabo R Sonntag WE Csiszar A Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2-mediated antioxidant response Am J Physiol Heart Circ Physiol 2011 301 H363 72 10.1152/ajpheart.01134.2010 21602469 PMC3154665

77. Ungvari Z Tarantini S Nyul-Toth A Kiss T Yabluchanskiy A Csipo T Balasubramanian P Lipecz A Benyo Z Csiszar A Nrf2 dysfunction and impaired cellular resilience to oxidative stressors in the aged vasculature: from increased cellular senescence to the pathogenesis of age-related vascular diseases Geroscience 2019 41 727 738 10.1007/s11357-019-00107-w 31655958 PMC6925097

78. Ungvari ZI Bailey-Downs L Gautam T Jimenez R Losonczy G Zhang C Ballabh P Recchia FA Wilkerson DC Sonntag WE Pearson KJ de Cabo R Csiszar A Adaptive induction of NF-E2-Related Factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia Am J Physiol Heart Circ Physiol 2011 300 H1133 H1140 10.1152/ajpheart.00402.2010 21217061 PMC3075025

79. Valcarcel-Ares MN Gautam T Warrington JP Bailey-Downs L Sosnowska D de Cabo R Losonczy G Sonntag WE Ungvari Z Csiszar A Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging J Gerontol A Biol Sci Med Sci 2012 67 821 9 10.1093/gerona/glr229 22219515 PMC3403863

80. Valcarcel-Ares MN Gautam T Warrington JP Bailey-Downs L Sosnowska D de Cabo R Losonczy G Sonntag WE Ungvari Z Csiszar A Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging J Gerontol A Biol Sci Med Sci 2012 67 821 829 10.1093/gerona/glr229 22219515 PMC3403863

81. Kiss T Nyul-Toth A Balasubramanian P Tarantini S Ahire C DelFavero J Yabluchanskiy A Csipo T Farkas E Wiley G Garman L Csiszar A Ungvari Z Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain Geroscience 2020 42 429 444 10.1007/s11357-020-00177-1 32236824 PMC7205992

82. Kiss T Nyul-Toth A DelFavero J Balasubramanian P Tarantini S Faakye J Gulej R Ahire C Ungvari A Yabluchanskiy A Wiley G Garman L Ungvari Z Csiszar A Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain Geroscience 2022 44 661 681 10.1007/s11357-022-00521-7 35098444 PMC9135953

83. Tarantini S Balasubramanian P Delfavero J Csipo T Yabluchanskiy A Kiss T Nyul-Toth A Mukli P Toth P Ahire C Ungvari A Benyo Z Csiszar A Ungvari Z Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice Geroscience 2021 43 2427 2440 10.1007/s11357-021-00440-z 34427858 PMC8599595

84. GBD Risk Factors Collaborators Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019 Lancet 2020 396 1223 1249 10.1016/S0140-6736(20)30752-2 33069327 PMC7566194

85. Kaufman JD Adar SD Barr RG Budoff M Burke GL Curl CL Daviglus ML Roux AVD Gassett AJ Jacobs DR Kronmal R Larson TV Navas-Acien A Olives C Sampson PD Sheppard L Siscovick DS Stein JH Szpiro AA Watson KE Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study The Lancet 2016 388 696 704 10.1016/S0140-6736(16)00378-0 PMC5019949 27233746

86. Hayes RB Lim C Zhang Y Cromar K Shao Y Reynolds HR Silverman DT Jones RR Park Y Jerrett M Ahn J Thurston GD PM2.5 air pollution and cause-specific cardiovascular disease mortality Int J Epidemiol 2020 49 25 35 10.1093/ije/dyz114 31289812 PMC7124502

87. Scheers H Jacobs L Casas L Nemery B Nawrot TS Long-term exposure to particulate matter air pollution is a risk factor for stroke Stroke 2015 46 3058 3066 10.1161/STROKEAHA.115.009913 26463695

88. Boehme AK Esenwa C Elkind MS Stroke risk factors, genetics, and prevention Circ Res 2017 120 472 495 10.1161/CIRCRESAHA.116.308398 28154098 PMC5321635

89. Baumgartner J Clark ML Studies of household air pollution and subclinical indicators of cardiovascular disease fill important knowledge gaps J Clin Hypertens (Greenwich) 2016 18 481 10.1111/jch.12720 26490173 PMC8031973

90. Kanagasabai T Xie W Yan L Zhao L Carter E Guo D Daskalopoulou SS Chan Q Elliott P Ezzati M Yang X Xie G Kelly F Wu Y Baumgartner J Household air pollution and blood pressure, vascular damage, and subclinical indicators of cardiovascular disease in older Chinese adults Am J Hypertens 2022 35 121 131 10.1093/ajh/hpab141 34505873 PMC8807175

91. Noubiap JJ Essouma M Bigna JJ Targeting household air pollution for curbing the cardiovascular disease burden: a health priority in sub-Saharan Africa J Clin Hypertens (Greenwich) 2015 17 825 829 10.1111/jch.12610 26140428 PMC8031568

92. Henning RJ Johnson GT Coyle JP Harbison RD Acrolein can cause cardiovascular disease: a review Cardiovasc Toxicol 2017 17 227 236 10.1007/s12012-016-9396-5 28084565

93. Crowley LN Le BL Cicalo C Brown J Li Y Kim YJ Lee JH Pan JH Lennon SL Han BK Kim JK Acrolein, An environmental toxicant and its applications to in vivo and in vitro atherosclerosis models: an update Environ Toxicol Pharmacol 2022 93 103890 10.1016/j.etap.2022.103890 35613694

94. Klein LW. Pathophysiologic mechanisms of tobacco smoke producing atherosclerosis. Curr Cardiol Rev. 2022;18:e110422203389. 10.2174/1573403X18666220411113112 PMC9893148 35410615

95. Zirak MR Mehri S Karimani A Zeinali M Hayes AW Karimi G Mechanisms behind the atherothrombotic effects of acrolein, a review Food Chem Toxicol 2019 129 38 53 10.1016/j.fct.2019.04.034 31009736

96. Messner B Bernhard D Smoking and cardiovascular disease Arterioscler Thromb Vasc Biol 2014 34 509 515 10.1161/ATVBAHA.113.300156 24554606

97. Csordas A Bernhard D The biology behind the atherothrombotic effects of cigarette smoke Nat Rev Cardiol 2013 10 219 230 10.1038/nrcardio.2013.8 23380975

98. Churg A Wang RD Tai H Wang X Xie C Dai J Shapiro SD Wright JL Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release Am J Respir Crit Care Med 2003 167 1083 1089 10.1164/rccm.200212-1396OC 12522030

99. Jaimes EA DeMaster EG Tian RX Raij L Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation Arterioscler Thromb Vasc Biol 2004 24 1031 1036 10.1161/01.ATV.0000127083.88549.58 15059808

100. Kalra VK Ying Y Deemer K Natarajan R Nadler JL Coates TD Mechanism of cigarette smoke condensate induced adhesion of human monocytes to cultured endothelial cells J Cell Physiol 1994 160 154 162 10.1002/jcp.1041600118 7517402

101. Nagy J Demaster EG Wittmann I Shultz P Raij L Induction of endothelial cell injury by cigarette smoke Endothelium 1997 5 251 263 10.3109/10623329709052590 9588817

102. Nordskog BK Blixt AD Morgan WT Fields WR Hellmann GM Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate Cardiovasc Toxicol 2003 3 101 117 10.1385/CT:3:2:101 14501029

103. Orosz Z Csiszar A Labinskyy N Smith K Kaminski PM Ferdinandy P Wolin MS Rivera A Ungvari Z Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation Am J Physiol Lung Cell Mol Physiol 2007 292 H130 H139 10.1152/ajpheart.00599.2006 17213480

104. Ota Y Kugiyama K Sugiyama S Ohgushi M Matsumura T Doi H Ogata N Oka H Yasue H Impairment of endothelium-dependent relaxation of rabbit aortas by cigarette smoke extract–role of free radicals and attenuation by captopril Atherosclerosis 1997 131 195 202 10.1016/S0021-9150(97)06106-6 9199272

105. Raij L DeMaster EG Jaimes EA Cigarette smoke-induced endothelium dysfunction: role of superoxide anion J Hypertens 2001 19 891 897 10.1097/00004872-200105000-00009 11393672

106. Shen Y Rattan V Sultana C Kalra VK Cigarette smoke condensate-induced adhesion molecule expression and transendothelial migration of monocytes Am J Physiol 1996 270 H1624 H1633 8928867 10.1152/ajpheart.1996.270.5.H1624

107. Tithof PK Elgayyar M Cho Y Guan W Fisher AB Peters-Golden M Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2-dependent mechanism Faseb J 2002 16 1463 1464 10.1096/fj.02-0092fje 12205049

108. Wang H Ye Y Zhu M Cho C Increased interleukin-8 expression by cigarette smoke extract in endothelial cells Environ Toxicol Pharmacol 2000 9 19 23 10.1016/S1382-6689(00)00056-9 11137464

109. Wang J Wilcken DE Wang XL Cigarette smoke activates caspase-3 to induce apoptosis of human umbilical venous endothelial cells Mol Genet Metab 2001 72 82 88 10.1006/mgme.2000.3115 11161833

110. Csiszar A Podlutsky A Wolin MS Losonczy G Pacher P Ungvari Z Oxidative stress and accelerated vascular aging: implications for cigarette smoking Front Biosci 2009 14 3128 3144 10.2741/3440 PMC2756477 19273262

111. Csiszar A Labinskyy N Podlutsky A Kaminski PM Wolin MS Zhang C Mukhopadhyay P Pacher P Hu F de Cabo R Ballabh P Ungvari Z Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations Am J Physiol Heart Circ Physiol 2008 294 H2721 H2735 10.1152/ajpheart.00235.2008 18424637 PMC2551743

112. Anto RJ Mukhopadhyay A Shishodia S Gairola CG Aggarwal BB Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2 Carcinogenesis 2002 23 1511 1518 10.1093/carcin/23.9.1511 12189195

113. Yang SR Chida AS Bauter MR Shafiq N Seweryniak K Maggirwar SB Kilty I Rahman I Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages Am J Physiol Lung Cell Mol Physiol 2006 291 L46 57 10.1152/ajplung.00241.2005 16473865

114. Yang SR Wright J Bauter M Seweryniak K Kode A Rahman I Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging Am J Physiol Lung Cell Mol Physiol 2007 292 L567 L576 10.1152/ajplung.00308.2006 17041012

115. Gottdiener JS Buzkova P Kahn PA DeFilippi C Shah S Barasch E Kizer JR Psaty B Gardin JM Relation of cigarette smoking and heart failure in adults ≥65 years of age (from the Cardiovascular Health Study) Am J Cardiol 2022 168 90 98 10.1016/j.amjcard.2021.12.021 35045935 PMC8930705

116. Moon K Guallar E Navas-Acien A Arsenic exposure and cardiovascular disease: an updated systematic review Curr Atheroscler Rep 2012 14 542 555 10.1007/s11883-012-0280-x 22968315 PMC3483370

117. Xu L Mondal D Polya DA Positive association of cardiovascular disease (CVD) with chronic exposure to drinking water arsenic (As) at concentrations below the WHO provisional guideline value: a systematic review and meta-analysis Int J Environ Res Public Health. 2020 17 2536 10.3390/ijerph17072536 32272785 PMC7178156

118. Basha DC Basha SS Reddy GR Lead-induced cardiac and hematological alterations in aging Wistar male rats: alleviating effects of nutrient metal mixture Biogerontology 2012 13 359 368 10.1007/s10522-012-9380-9 22534743

119. Bjorklund G Dadar M Chirumbolo S Aaseth J High content of lead is associated with the softness of drinking water and raised cardiovascular morbidity: a review Biol Trace Elem Res 2018 186 384 394 10.1007/s12011-018-1336-8 29656350

120. Moore MR Meredith PA Goldberg A Carr KE Toner PG Lawrie TD Cardiac effects of lead in drinking water of rats Clin Sci Mol Med 1975 49 337 341 1192693 10.1042/cs0490337

121. Revis NW Zinsmeister AR Bull R Atherosclerosis and hypertension induction by lead and cadmium ions: an effect prevented by calcium ion Proc Natl Acad Sci U S A 1981 78 6494 6498 10.1073/pnas.78.10.6494 6947240 PMC349066

122. Roncal C Mu W Reungjui S Kim KM Henderson GN Ouyang X Nakagawa T Johnson RJ Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease Am J Physiol Renal Physiol 2007 293 F1391 F1396 10.1152/ajprenal.00216.2007 17715263

123. Ryan PB Huet N MacIntosh DL Longitudinal investigation of exposure to arsenic, cadmium, and lead in drinking water Environ Health Perspect 2000 108 731 735 10.1289/ehp.00108731 10964793 PMC1638277

124. Shen XF Huang P Fox DA Lin Y Zhao ZH Wang W Wang JY Liu XQ Chen JY Luo WJ Adult lead exposure increases blood-retinal permeability: a risk factor for retinal vascular disease Neurotoxicology 2016 57 145 152 10.1016/j.neuro.2016.09.013 27663850

125. Silva MA de Oliveira TF Almenara CC Broseghini-Filho GB Vassallo DV Padilha AS Silveira EA Exposure to a low lead concentration impairs contractile machinery in rat cardiac muscle Biol Trace Elem Res 2015 167 280 287 10.1007/s12011-015-0300-0 25795172

126. Wu S Liu H Zhao H Wang X Chen J Xia D Xiao C Cheng J Zhao Z He Y Environmental lead exposure aggravates the progression of Alzheimer’s disease in mice by targeting on blood brain barrier Toxicol Lett 2020 319 138 147 10.1016/j.toxlet.2019.11.009 31730887

127. Brake J Thaxton P Hester PY Mercury induced cardiovascular abnormalities in the chicken Arch Environ Contam Toxicol 1977 6 269 277 10.1007/BF02097768 901007

128. Wildemann TM Siciliano SD Weber LP The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio Toxicology 2016 339 1 8 10.1016/j.tox.2015.11.004 26612503

129. Wildemann TM Weber LP Siciliano SD Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats J Appl Toxicol 2015 35 918 926 10.1002/jat.3092 25523840

130. Downer MK Martinez-Gonzalez MA Gea A Stampfer M Warnberg J Ruiz-Canela M Salas-Salvado J Corella D Ros E Fito M Estruch R Aros F Fiol M Lapetra J Serra-Majem L Bullo M Sorli JV Munoz MA Garcia-Rodriguez A Gutierrez-Bedmar M Gomez-Gracia E Investigators PS Mercury exposure and risk of cardiovascular disease: a nested case-control study in the PREDIMED (PREvention with MEDiterranean Diet) study BMC Cardiovasc Disord 2017 17 9 10.1186/s12872-016-0435-8 28056794 PMC5216562

131. Houston MC Role of mercury toxicity in hypertension, cardiovascular disease, and stroke J Clin Hypertens (Greenwich) 2011 13 621 627 10.1111/j.1751-7176.2011.00489.x 21806773 PMC8108748

132. Hu XF Lowe M Chan HM Mercury exposure, cardiovascular disease, and mortality: a systematic review and dose-response meta-analysis Environ Res 2021 193 110538 10.1016/j.envres.2020.110538 33285155

133. Larsen TJ Jorgensen ME Larsen CVL Dahl-Petersen IK Ronn PF Bjerregaard P Byberg S Whole blood mercury and the risk of cardiovascular disease among the Greenlandic population Environ Res 2018 164 310 315 10.1016/j.envres.2018.03.003 29554622

134. Mozaffarian D Shi P Morris JS Spiegelman D Grandjean P Siscovick DS Willett WC Rimm EB Mercury exposure and risk of cardiovascular disease in two U.S. cohorts N Engl J Med 2011 364 1116 25 10.1056/NEJMoa1006876 21428767 PMC3082949

135. Alhamdow A Lindh C Albin M Gustavsson P Tinnerberg H Broberg K Early markers of cardiovascular disease are associated with occupational exposure to polycyclic aromatic hydrocarbons Sci Rep 2017 7 9426 10.1038/s41598-017-09956-x 28842704 PMC5573323

136. Clark JD 3rd Serdar B Lee DJ Arheart K Wilkinson JD Fleming LE Exposure to polycyclic aromatic hydrocarbons and serum inflammatory markers of cardiovascular disease Environ Res 2012 117 132 137 10.1016/j.envres.2012.04.012 22626472 PMC3444300

137. Rojas GA Saavedra N Saavedra K Hevia M Morales C Lanas F Salazar LA Polycyclic aromatic hydrocarbons (PAHs) exposure triggers inflammation and endothelial dysfunction in BALB/c mice: a pilot study Toxics. 2022 10 497 10.3390/toxics10090497 36136462 PMC9504903

138. Chaves RS Guerreiro CS Cardoso VV Benoliel MJ Santos MM Hazard and mode of action of disinfection by-products (DBPs) in water for human consumption: evidences and research priorities Comp Biochem Physiol C Toxicol Pharmacol 2019 223 53 61 10.1016/j.cbpc.2019.05.015 31136853

139. Kali S Khan M Ghaffar MS Rasheed S Waseem A Iqbal MM Bilal Khan Niazi M Zafar MI Occurrence, influencing factors, toxicity, regulations, and abatement approaches for disinfection by-products in chlorinated drinking water: a comprehensive review Environ Pollut 2021 281 116950 10.1016/j.envpol.2021.116950 33819670

140. Srivastav AL Patel N Chaudhary VK Disinfection by-products in drinking water: occurrence, toxicity and abatement Environ Pollut 2020 267 115474 10.1016/j.envpol.2020.115474 32889516

141. Chen YC Chen KF Andrew Lin KY Su HP Wu DN Lin CH Evaluation of toxicity of polystyrene microplastics under realistic exposure levels in human vascular endothelial EA.hy926 cells Chemosphere 2023 313 137582 10.1016/j.chemosphere.2022.137582 36529175

142. Li Z Zhu S Liu Q Wei J Jin Y Wang X Zhang L Polystyrene microplastics cause cardiac fibrosis by activating Wnt/beta-catenin signaling pathway and promoting cardiomyocyte apoptosis in rats Environ Pollut 2020 265 115025 10.1016/j.envpol.2020.115025 32806417

143. Persiani E Cecchettini A Ceccherini E Gisone I Morales MA Vozzi F Microplastics: a matter of the heart (and vascular system) Biomedicines. 2023 11 264 10.3390/biomedicines11020264 36830801 PMC9953450

144. Wang F Zhang Q Cui J Bao B Deng X Liu L Guo MY Polystyrene microplastics induce endoplasmic reticulum stress, apoptosis and inflammation by disrupting the gut microbiota in carp intestines Environ Pollut 2023 323 121233 10.1016/j.envpol.2023.121233 36804561

145. Watts GF Chan DC Microplastics, cardiometabolic risk, genetics and Alzheimer’s disease Curr Opin Endocrinol Diabetes Obes 2022 29 85 86 10.1097/MED.0000000000000718 35197423

146. Wu D Feng Y Wang R Jiang J Guan Q Yang X Wei H Xia Y Luo Y Pigment microparticles and microplastics found in human thrombi based on Raman spectral evidence J Adv Res. 2023 9 141 150 10.1016/j.jare.2022.09.004 PMC10334115 36116710

147. Yuan Z Nag R Cummins E Human health concerns regarding microplastics in the aquatic environment - from marine to food systems Sci Total Environ 2022 823 153730 10.1016/j.scitotenv.2022.153730 35143789

148. Moulton PV Yang W Air pollution, oxidative stress, and Alzheimer’s disease J Environ Public Health 2012 2012 472751 10.1155/2012/472751 22523504 PMC3317180

149. Niemann B Rohrbach S Miller MR Newby DE Fuster V Kovacic JC Oxidative stress and cardiovascular risk: obesity, diabetes, smoking, and pollution: part 3 of a 3-part series J Am Coll Cardiol 2017 70 230 251 10.1016/j.jacc.2017.05.043 28683970 PMC5568826

150. Sorensen M Daneshvar B Hansen M Dragsted LO Hertel O Knudsen L Loft S Personal PM2.5 exposure and markers of oxidative stress in blood Environ Health Perspect 2003 111 161 6 10.1289/ehp.111-1241344 12573899 PMC1241344

151. Wilson SJ Miller MR Newby DE Effects of diesel exhaust on cardiovascular function and oxidative stress Antioxid Redox Signal 2018 28 819 836 10.1089/ars.2017.7174 28540736

152. Daiber A Munzel T Special issue "Impact of environmental pollution and stress on redox signaling and oxidative stress pathways" Redox Biol 2020 37 101621 10.1016/j.redox.2020.101621 32863186 PMC7767751

153. Angeli JK Cruz Pereira CA de Oliveira FT Stefanon I Padilha AS Vassallo DV Cadmium exposure induces vascular injury due to endothelial oxidative stress: the role of local angiotensin II and COX-2 Free Radic Biol Med 2013 65 838 848 10.1016/j.freeradbiomed.2013.08.167 23973752

154. Daiber A Kuntic M Hahad O Delogu LG Rohrbach S Di Lisa F Schulz R Munzel T Effects of air pollution particles (ultrafine and fine particulate matter) on mitochondrial function and oxidative stress - Implications for cardiovascular and neurodegenerative diseases Arch Biochem Biophys 2020 696 108662 10.1016/j.abb.2020.108662 33159890

155. Ehsanifar M Montazeri Z Taheri MA Rafati M Behjati M Karimian M Hippocampal inflammation and oxidative stress following exposure to diesel exhaust nanoparticles in male and female mice Neurochem Int 2021 145 104989 10.1016/j.neuint.2021.104989 33582162

156. Fiorito G Vlaanderen J Polidoro S Gulliver J Galassi C Ranzi A Krogh V Grioni S Agnoli C Sacerdote C Panico S Tsai MY Probst-Hensch N Hoek G Herceg Z Vermeulen R Ghantous A Vineis P Naccarati A dagger EXc Oxidative stress and inflammation mediate the effect of air pollution on cardio- and cerebrovascular disease: a prospective study in nonsmokers Environ Mol Mutagen 2018 59 234 246 10.1002/em.22153 29114965

157. Gangwar RS Bevan GH Palanivel R Das L Rajagopalan S Oxidative stress pathways of air pollution mediated toxicity: Recent insights Redox Biol 2020 34 101545 10.1016/j.redox.2020.101545 32505541 PMC7327965

158. Guan L Geng X Stone C Cosky EEP Ji Y Du H Zhang K Sun Q Ding Y PM(2.5) exposure induces systemic inflammation and oxidative stress in an intracranial atherosclerosis rat model Environ Toxicol 2019 34 530 538 10.1002/tox.22707 30672636

159. Buchner N Ale-Agha N Jakob S Sydlik U Kunze K Unfried K Altschmied J Haendeler J Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes Exp Gerontol 2013 48 8 16 10.1016/j.exger.2012.03.017 22507566

160. Shiwakoti S Ko JY Gong D Dhakal B Lee JH Adhikari R Gwak Y Park SH Jun Choi I Schini-Kerth VB Kang KW Oak MH Effects of polystyrene nanoplastics on endothelium senescence and its underlying mechanism Environ Int 2022 164 107248 10.1016/j.envint.2022.107248 35461096

161. Soundararajan A Prabu P Mohan V Gibert Y Balasubramanyam M Novel insights of elevated systemic levels of bisphenol-A (BPA) linked to poor glycemic control, accelerated cellular senescence and insulin resistance in patients with type 2 diabetes Mol Cell Biochem 2019 458 171 183 10.1007/s11010-019-03540-9 31004310

162. Yu F Ye K Hu Y Li J An Y Qu D Exposure to polycyclic aromatic hydrocarbons derived from vehicle exhaust gas induces premature senescence in mouse lung fibroblast cells Mol Med Rep 2019 19 4326 4334 30942392 10.3892/mmr.2019.10086 PMC6471379

163. Dhakal B Shiwakoti S Park EY Kang KW Schini-Kerth VB Park SH Ji HY Park JS Ko JY Oak MH SGLT2 inhibition ameliorates nano plastics-induced premature endothelial senescence and dysfunction Sci Rep 2023 13 6256 10.1038/s41598-023-33086-2 37069192 PMC10110533

164. Hodjat M Rezvanfar MA Abdollahi M A systematic review on the role of environmental toxicants in stem cells aging Food Chem Toxicol 2015 86 298 308 10.1016/j.fct.2015.11.002 26582272

165. Chandy M Obal D Wu JC Elucidating effects of environmental exposure using human-induced pluripotent stem cell disease modeling EMBO Mol Med 2022 14 e13260 10.15252/emmm.202013260 36285490 PMC9641419

166. Hua T Kiran S Li Y Sang QA Microplastics exposure affects neural development of human pluripotent stem cell-derived cortical spheroids J Hazard Mater 2022 435 128884 10.1016/j.jhazmat.2022.128884 35483261

167. Lai KP Li JW Chan TF Chen A Lee CYL Yeung WSB Wong CKC Transcriptomic and methylomic analysis reveal the toxicological effect of 2,3,7,8-Tetrachlorodibenzodioxin on human embryonic stem cell Chemosphere 2018 206 663 673 10.1016/j.chemosphere.2018.05.058 29778942

168. Liu D Liu NY Chen LT Shao Y Shi XM Zhu DY Perfluorooctane sulfonate induced toxicity in embryonic stem cell-derived cardiomyocytes via inhibiting autophagy-lysosome pathway Toxicol In Vitro 2020 69 104988 10.1016/j.tiv.2020.104988 32861759

169. Liu S Yang R Yin N Wang YL Faiola F Environmental and human relevant PFOS and PFOA doses alter human mesenchymal stem cell self-renewal, adipogenesis and osteogenesis Ecotoxicol Environ Saf 2019 169 564 572 10.1016/j.ecoenv.2018.11.064 30476818

170. Ngalame NNO Luz AL Makia N Tokar EJ Arsenic alters exosome quantity and cargo to mediate stem cell recruitment into a cancer stem cell-like phenotype Toxicol Sci 2018 165 40 49 10.1093/toxsci/kfy176 30169766 PMC6111788

171. Nunes HC Tavares SC Garcia HV Cucielo MS Dos Santos SAA Aal MCE de Golim MA Justulin LA Jr Ribeiro AO Deffune E Scarano WR Delella FK Bisphenol A and 2,3,7,8-tetrachlorodibenzo-p-dioxin at non-cytotoxic doses alter the differentiation potential and cell function of rat adipose-stem cells Environ Toxicol 2022 37 2314 2323 10.1002/tox.23598 35661558

172. Praveena SM Teh SW Rajendran RK Kannan N Lin CC Abdullah R Kumar S Recent updates on phthalate exposure and human health: a special focus on liver toxicity and stem cell regeneration Environ Sci Pollut Res Int 2018 25 11333 11342 10.1007/s11356-018-1652-8 29546515

173. Shen J Wang X Zhou D Li T Tang L Gong T Su J Liang P Modelling cadmium-induced cardiotoxicity using human pluripotent stem cell-derived cardiomyocytes J Cell Mol Med 2018 22 4221 4235 10.1111/jcmm.13702 29993192 PMC6111808

174. Yang Y He S Qi Z Chai X Zhao Q Hu B Li G Yu Y Proliferation toxicity and mechanism of novel mixed bromine/chlorine transformation products of tetrabromobisphenol A on human embryonic stem cell J Hazard Mater 2023 449 131050 10.1016/j.jhazmat.2023.131050 36821903

175. Azzouz M Xu Y Barregard L Fagerberg B Zoller B Molnar P Oudin A Spanne M Engstrom G Stockfelt L Air pollution and biomarkers of cardiovascular disease and inflammation in the Malmo Diet and Cancer cohort Environ Health 2022 21 39 10.1186/s12940-022-00851-1 35413834 PMC9004064

176. Choi MS Jeon H Yoo SM Lee MS Activation of the complement system on human endothelial cells by urban particulate matter triggers inflammation-related protein production Int J Mol Sci. 2021 22 3336 10.3390/ijms22073336 33805189 PMC8038114

177. Daiber A Kroller-Schon S Oelze M Hahad O Li H Schulz R Steven S Munzel T Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases Redox Biol 2020 34 101506 10.1016/j.redox.2020.101506 32371009 PMC7327966

178. Hahad O Lelieveld J Birklein F Lieb K Daiber A Munzel T Ambient air pollution increases the risk of cerebrovascular and neuropsychiatric disorders through induction of inflammation and oxidative stress Int J Mol Sci. 2020 21 4306 10.3390/ijms21124306 32560306 PMC7352229

179. Han B Xu J Zhang Y Li P Li K Zhang N Han J Gao S Wang X Geng C Yang W Zhang L Bai Z Associations of exposure to fine particulate matter mass and constituents with systemic inflammation: a cross-sectional study of urban older adults in China Environ Sci Technol 2022 56 7244 7255 10.1021/acs.est.1c04488 35148063

180. Hernandez M Harrington A Ma Y Galdanes K Halzack B Zhong M Vaughan J Sebasco E Gordon T Lippmann M Chen LC World Trade Center Dust induces airway inflammation while promoting aortic endothelial dysfunction Toxicol Appl Pharmacol 2020 400 115041 10.1016/j.taap.2020.115041 32428593 PMC7370403

181. Oikonomou E Lazaros G Mystakidi VC Papaioannou N Theofilis P Vogiatzi G Chasikidis C Fountoulakis P Papakostantinou MA Assimakopoulos MN Barmparesos N Tasios P Kaski JC Tousoulis D The association of air pollutants exposure with subclinical inflammation and carotid atherosclerosis Int J Cardiol 2021 342 108 114 10.1016/j.ijcard.2021.07.056 34339768

182. Orysiak J Mlynarczyk M Piec R Jakubiak A Lifestyle and environmental factors may induce airway and systemic inflammation in firefighters Environ Sci Pollut Res Int 2022 29 73741 73768 10.1007/s11356-022-22479-x 36094704 PMC9465149

183. Osborne MT Abohashem S Naddaf N Abbasi T Zureigat H Mezue K Ghoneem A Dar T Cardeiro AJ Mehta NN Rajagopalan S Fayad ZA Tawakol A The combined effect of air and transportation noise pollution on atherosclerotic inflammation and risk of cardiovascular disease events J Nucl Cardiol 2023 30 665 679 10.1007/s12350-022-03003-7 35915324 PMC9889575

184. Wang T Chen X Li H Chen W Xu Y Yao Y Zhang H Han Y Zhang L Que C Gong J Qiu X Zhu T Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: roles of lipid peroxidation and systemic inflammation Part Fibre Toxicol 2022 19 65 10.1186/s12989-022-00503-9 36280873 PMC9590143

185. Wu X Cao X Lintelmann J Peters A Koenig W Zimmermann R Schneider A Wolf K and group KO-S Assessment of the association of exposure to polycyclic aromatic hydrocarbons, oxidative stress, and inflammation: a cross-sectional study in Augsburg, Germany Int J Hyg Environ Health 2022 244 113993 10.1016/j.ijheh.2022.113993 35777219

186. Xu Z Wang W Liu Q Li Z Lei L Ren L Deng F Guo X Wu S Association between gaseous air pollutants and biomarkers of systemic inflammation: a systematic review and meta-analysis Environ Pollut 2022 292 118336 10.1016/j.envpol.2021.118336 34634403

187. Newby DE Mannucci PM Tell GS Baccarelli AA Brook RD Donaldson K Forastiere F Franchini M Franco OH Graham I Hoek G Hoffmann B Hoylaerts MF Kunzli N Mills N Pekkanen J Peters A Piepoli MF Rajagopalan S Storey RF Esc Working Group on Thrombosis EAfCP, Rehabilitation and Association ESCHF Expert position paper on air pollution and cardiovascular disease Eur Heart J 2015 36 83 93b 10.1093/eurheartj/ehu458 25492627 PMC6279152

188. Akushevich I Yashkin A Kovtun M Kravchenko J Arbeev K Yashin AI Forecasting prevalence and mortality of Alzheimer’s disease using the partitioning models Exp Gerontol 2023 174 112133 10.1016/j.exger.2023.112133 36842469 PMC10103071

189. Gillis C Montenigro P Nejati M Maserejian N Estimating prevalence of early Alzheimer’s disease in the United States, accounting for racial and ethnic diversity Alzheimers Dement 2023 19 1841 1848 10.1002/alz.12822 36322470

190. Yang L Wan W Yu C Xuan C Zheng P Yan J Associations between PM(2.5) exposure and Alzheimer’s disease prevalence Among elderly in eastern China Environ Health 2022 21 119 10.1186/s12940-022-00937-w 36447194 PMC9706836

191. Castillo-Carranza DL Nilson AN Van Skike CE Jahrling JB Patel K Garach P Gerson JE Sengupta U Abisambra J Nelson P Troncoso J Ungvari Z Galvan V Kayed R Cerebral microvascular accumulation of Tau oligomers in Alzheimer’s disease and related Tauopathies Aging Dis 2017 8 257 266 10.14336/AD.2017.0112 28580182 PMC5440106

192. Cheung CY Ong YT Ikram MK Ong SY Li X Hilal S Catindig JA Venketasubramanian N Yap P Seow D Chen CP Wong TY Microvascular network alterations in the retina of patients with Alzheimer’s disease Alzheimers Dement 2014 10 135 142 10.1016/j.jalz.2013.06.009 24439169

193. Clark LR Berman SE Rivera-Rivera LA Hoscheidt SM Darst BF Engelman CD Rowley HA Carlsson CM Asthana S Turski P Wieben O Johnson SC Macrovascular and microvascular cerebral blood flow in adults at risk for Alzheimer’s disease Alzheimers Dement (Amst) 2017 7 48 55 10.1016/j.dadm.2017.01.002 28239641 PMC5318539

194. Farkas E Luiten PG Cerebral microvascular pathology in aging and Alzheimer’s disease Prog Neurobiol 2001 64 575 611 10.1016/S0301-0082(00)00068-X 11311463

195. Merlini M Wanner D Nitsch RM Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer’s disease-related microvascular cerebral amyloid angiopathy Acta Neuropathol 2016 131 737 752 10.1007/s00401-016-1560-2 26988843 PMC4835519

196. Moody DM Brown WR Challa VR Ghazi-Birry HS Reboussin DM Cerebral microvascular alterations in aging, leukoaraiosis, and Alzheimer’s disease Ann N Y Acad Sci 1997 826 103 116 10.1111/j.1749-6632.1997.tb48464.x 9329684

197. Steinman J Sun HS Feng ZP Microvascular alterations in Alzheimer’s disease Front Cell Neurosci 2020 14 618986 10.3389/fncel.2020.618986 33536876 PMC7849053

198. Zipser BD Johanson CE Gonzalez L Berzin TM Tavares R Hulette CM Vitek MP Hovanesian V Stopa EG Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease Neurobiol Aging 2007 28 977 986 10.1016/j.neurobiolaging.2006.05.016 16782234

199. Sweeney MD Kisler K Montagne A Toga AW Zlokovic BV The role of brain vasculature in neurodegenerative disorders Nat Neurosci 2018 21 1318 1331 10.1038/s41593-018-0234-x 30250261 PMC6198802

200. Sweeney MD Sagare AP Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders Nat Rev Neurol 2018 14 133 150 10.1038/nrneurol.2017.188 29377008 PMC5829048

201. Sweeney MD Zhao Z Montagne A Nelson AR Zlokovic BV Blood-brain barrier: from physiology to disease and back Physiol Rev 2019 99 21 78 10.1152/physrev.00050.2017 30280653 PMC6335099

202. Israeli-Korn SD Masarwa M Schechtman E Abuful A Strugatsky R Avni S Farrer LA Friedland RP Inzelberg R Hypertension increases the probability of Alzheimer’s disease and of mild cognitive impairment in an Arab community in northern Israel Neuroepidemiology 2010 34 99 105 10.1159/000264828 20016220 PMC2855875

203. Javanshiri K Waldo ML Friberg N Sjovall F Wickerstrom K Haglund M Englund E Atherosclerosis, hypertension, and diabetes in Alzheimer’s disease, vascular dementia, and mixed dementia: prevalence and presentation J Alzheimers Dis 2018 65 1247 1258 10.3233/JAD-180644 30149459

204. Nazarian A Arbeev KG Yashkin AP Kulminski AM Genetic heterogeneity of Alzheimer’s disease in subjects with and without hypertension Geroscience 2019 41 137 154 10.1007/s11357-019-00071-5 31055733 PMC6544706

205. Skoog I Gustafson D Update on hypertension and Alzheimer’s disease Neurol Res 2006 28 605 611 10.1179/016164106X130506 16945211

206. Cheignon C Tomas M Bonnefont-Rousselot D Faller P Hureau C Collin F Oxidative stress and the amyloid beta peptide in Alzheimer’s disease Redox Biol 2018 14 450 464 10.1016/j.redox.2017.10.014 29080524 PMC5680523

207. Ionescu-Tucker A Cotman CW Emerging roles of oxidative stress in brain aging and Alzheimer’s disease Neurobiol Aging 2021 107 86 95 10.1016/j.neurobiolaging.2021.07.014 34416493

208. Calderon-Garciduenas L Herrera-Soto A Jury N Maher BA Gonzalez-Maciel A Reynoso-Robles R Ruiz-Rudolph P van Zundert B Varela-Nallar L Reduced repressive epigenetic marks, increased DNA damage and Alzheimer’s disease hallmarks in the brain of humans and mice exposed to particulate urban air pollution Environ Res 2020 183 109226 10.1016/j.envres.2020.109226 32045727

209. Pao PC Patnaik D Watson LA Gao F Pan L Wang J Adaikkan C Penney J Cam HP Huang WC Pantano L Lee A Nott A Phan TX Gjoneska E Elmsaouri S Haggarty SJ Tsai LH HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease Nat Commun 2020 11 2484 10.1038/s41467-020-16361-y 32424276 PMC7235043

210. Welty S Thathiah A Levine AS DNA damage increases secreted Abeta40 and Abeta42 in neuronal progenitor cells: relevance to Alzheimer’s disease J Alzheimers Dis 2022 88 177 190 10.3233/JAD-220030 35570488 PMC9277680

211. Wong GC Chow KH DNA damage response-associated cell cycle re-entry and neuronal senescence in brain aging and Alzheimer’s disease J Alzheimers Dis. 2023 94 S429 S451 10.3233/JAD-220203 35848025 PMC10473156

212. Heneka MT Carson MJ El Khoury J Landreth GE Brosseron F Feinstein DL Jacobs AH Wyss-Coray T Vitorica J Ransohoff RM Herrup K Frautschy SA Finsen B Brown GC Verkhratsky A Yamanaka K Koistinaho J Latz E Halle A Petzold GC Town T Morgan D Shinohara ML Perry VH Holmes C Bazan NG Brooks DJ Hunot S Joseph B Deigendesch N Garaschuk O Boddeke E Dinarello CA Breitner JC Cole GM Golenbock DT Kummer MP Neuroinflammation in Alzheimer’s disease Lancet Neurol 2015 14 388 405 10.1016/S1474-4422(15)70016-5 25792098 PMC5909703

213. Dichgans M Leys D Vascular cognitive impairment Circ Res 2017 120 573 591 10.1161/CIRCRESAHA.116.308426 28154105

214. Girouard H Munter LM The many faces of vascular cognitive impairment J Neurochem 2018 144 509 512 10.1111/jnc.14287 29430652

215. Gorelick PB Bowler JV Advances in vascular cognitive impairment Stroke 2010 41 e93 e98 10.1161/STROKEAHA.109.569921 20075354

216. Gorelick PB Counts SE Nyenhuis D Vascular cognitive impairment and dementia Biochim Biophys Acta 2016 1862 860 868 10.1016/j.bbadis.2015.12.015 26704177 PMC5232167

217. Iadecola C Duering M Hachinski V Joutel A Pendlebury ST Schneider JA Dichgans M Vascular cognitive impairment and dementia: JACC scientific expert panel J Am Coll Cardiol 2019 73 3326 3344 10.1016/j.jacc.2019.04.034 31248555 PMC6719789

218. Costanza A Xekardaki A Kovari E Gold G Bouras C Giannakopoulos P Microvascular burden and Alzheimer-type lesions across the age spectrum J Alzheimers Dis 2012 32 643 652 10.3233/JAD-2012-120835 22842869

219. Gold G Giannakopoulos P Herrmann FR Bouras C Kovari E Identification of Alzheimer and vascular lesion thresholds for mixed dementia Brain 2007 130 2830 2836 10.1093/brain/awm228 17878206

220. van Dinther M Schram MT Jansen JFA Backes WH Houben A Berendschot T Schalkwijk CG Stehouwer CDA van Oostenbrugge RJ Staals J Extracerebral microvascular dysfunction is related to brain MRI markers of cerebral small vessel disease: The Maastricht Study Geroscience 2022 44 147 157 10.1007/s11357-021-00493-0 34816376 PMC8811003

221. Nyul-Toth A Fulop GA Tarantini S Kiss T Ahire C Faakye JA Ungvari A Toth P Toth A Csiszar A Ungvari Z Cerebral venous congestion exacerbates cerebral microhemorrhages in mice Geroscience 2022 44 805 816 10.1007/s11357-021-00504-0 34989944 PMC9135950

222. Bagi Z Kroenke CD Fopiano KA Tian Y Filosa JA Sherman LS Larson EB Keene CD Degener O’Brien K Adeniyi PA Back SA Association of cerebral microvascular dysfunction and white matter injury in Alzheimer’s disease Geroscience 2022 44 1 14 10.1007/s11357-022-00585-5 35612774 PMC9617002

223. Szczesniak D Rymaszewska J Zimny A Sasiadek M Poltyn-Zaradna K Smith EE Zatonska K Zatonski T Rangarajan S Yusuf S Szuba A Cerebral small vessel disease and other influential factors of cognitive impairment in the middle-aged: a long-term observational cohort PURE-MIND study in Poland Geroscience 2021 43 279 295 10.1007/s11357-020-00271-4 33074422 PMC8050144

224. Kerkhofs D Wong SM Zhang E Uiterwijk R Hoff EI Jansen JFA Staals J Backes WH van Oostenbrugge RJ Blood-brain barrier leakage at baseline and cognitive decline in cerebral small vessel disease: a 2-year follow-up study Geroscience 2021 43 1643 1652 10.1007/s11357-021-00399-x 34160780 PMC8492799

225. Fan F Roman RJ Reversal of cerebral hypoperfusion: a novel therapeutic target for the treatment of AD/ADRD? Geroscience 2021 43 1065 1067 10.1007/s11357-021-00357-7 33772733 PMC8110616

226. Toth L Czigler A Hegedus E Komaromy H Amrein K Czeiter E Yabluchanskiy A Koller A Orsi G Perlaki G Schwarcz A Buki A Ungvari Z Toth PJ Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults Geroscience 2022 44 2771 2783 10.1007/s11357-022-00623-2 35869380 PMC9768079

227. Ahire C, Nyul-Toth A, DelFavero J, Gulej R, Faakye JA, Tarantini S, Kiss T, Kuan-Celarier A, Balasubramanian P, Ungvari A, Tarantini A, Nagaraja R, Yan F, Tang Q, Mukli P, Csipo T, Yabluchanskiy A, Campisi J, Ungvari Z, Csiszar A. Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)-induced chemobrain. Aging Cell. 2023:e13832. 10.1111/acel.13832 PMC10352561 37243381

228. Nyul-Toth A Tarantini S DelFavero J Yan F Balasubramanian P Yabluchanskiy A Ahire C Kiss T Csipo T Lipecz A Farkas AE Wilhelm I Krizbai IA Tang Q Csiszar A Ungvari Z Demonstration of age-related blood-brain barrier disruption and cerebromicrovascular rarefaction in mice by longitudinal intravital two-photon microscopy and optical coherence tomography Am J Physiol Heart Circ Physiol 2021 320 H1370 H1392 10.1152/ajpheart.00709.2020 33543687 PMC8260380

229. Weiss B Vulnerability to pesticide neurotoxicity is a lifetime issue Neurotoxicology 2000 21 67 73 10794386

230. Kukull WA Larson EB Bowen JD McCormick WC Teri L Pfanschmidt ML Thompson JD O’Meara ES Brenner DE van Belle G Solvent exposure as a risk factor for Alzheimer’s disease: a case-control study Am J Epidemiol 2015 141 1059 71 10.1093/oxfordjournals.aje.a117370 7771442

231. Santibanez M Bolumar F Garcia AM Occupational risk factors in Alzheimer’s disease: a review assessing the quality of published epidemiological studies Occup Environ Med 2007 64 723 732 10.1136/oem.2006.028209 17525096 PMC2078415

232. Alemany S Crous-Bou M Vilor-Tejedor N Mila-Aloma M Suarez-Calvet M Salvado G Cirach M Arenaza-Urquijo EM Sanchez-Benavides G Grau-Rivera O Minguillon C Fauria K Kollmorgen G Domingo Gispert J Gascon M Nieuwenhuijsen M Zetterberg H Blennow K Sunyer J Luis Molinuevo J study A Associations between air pollution and biomarkers of Alzheimer’s disease in cognitively unimpaired individuals Environ Int 2021 157 106864 10.1016/j.envint.2021.106864 34537521

233. Astrom DO Adolfsson R Segersson D Forsberg B Oudin A Local contrasts in concentration of ambient particulate air pollution (PM2.5) and incidence of Alzheimer’s disease and dementia: results from the Betula cohort in Northern Sweden J Alzheimers Dis 2021 81 83 85 10.3233/JAD-201538 33749652 PMC8203233

234. Attademo L Bernardini F Air pollution as risk factor for mental disorders: in search for a possible link with Alzheimer’s disease and schizophrenia J Alzheimers Dis 2020 76 825 830 10.3233/JAD-200289 32568207

235. Calderon-Garciduenas L Reynoso-Robles R Vargas-Martinez J Gomez-Maqueo-Chew A Perez-Guille B Mukherjee PS Torres-Jardon R Perry G Gonzalez-Maciel A Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer’s disease Environ Res 2016 146 404 417 10.1016/j.envres.2015.12.031 26829765

236. Calderon-Garciduenas L Torres-Jardon R Franco-Lira M Kulesza R Gonzalez-Maciel A Reynoso-Robles R Brito-Aguilar R Garcia-Arreola B Revueltas-Ficachi P Barrera-Velazquez JA Garcia-Alonso G Garcia-Rojas E Mukherjee PS Delgado-Chavez R Environmental nanoparticles, SARS-CoV-2 brain involvement, and potential acceleration of Alzheimer’s and Parkinson’s diseases in young urbanites exposed to air pollution J Alzheimers Dis 2020 78 479 503 10.3233/JAD-200891 32955466

237. Fu P Yung KKL Air pollution and Alzheimer’s disease: a systematic review and meta-analysis J Alzheimers Dis 2020 77 701 714 10.3233/JAD-200483 32741830

238. He F Tang J Zhang T Lin J Li F Gu X Chen A Nevill A Chen R Impact of air pollution exposure on the risk of Alzheimer’s disease in China: a community-based cohort study Environ Res 2022 205 112318 10.1016/j.envres.2021.112318 34742710

239. Kim SH Knight EM Saunders EL Cuevas AK Popovech M Chen LC Gandy S Rapid doubling of Alzheimer’s amyloid-beta40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution F1000Res 2012 1 70 10.12688/f1000research.1-70.v1 24358824 PMC3782349

240. Lin FC Chen CY Lin CW Wu MT Chen HY Huang P Air pollution is associated with cognitive deterioration of Alzheimer’s disease Gerontology 2022 68 53 61 10.1159/000515162 33882496

241. Patten KT Valenzuela AE Wallis C Berg EL Silverman JL Bein KJ Wexler AS Lein PJ The effects of chronic exposure to ambient traffic-related air pollution on Alzheimer’s disease phenotypes in wildtype and genetically predisposed male and female rats Environ Health Perspect 2021 129 57005 10.1289/EHP8905 33971107 PMC8110309

242. Power MC Growing evidence links air pollution exposure to risk of Alzheimer’s disease and related dementia Brain 2020 143 8 10 10.1093/brain/awz396 31886492 PMC8127070

243. Shi L Wu X Danesh Yazdi M Braun D Abu Awad Y Wei Y Liu P Di Q Wang Y Schwartz J Dominici F Kioumourtzoglou M-A Zanobetti A Long-term effects of PM2·5 on neurological disorders in the American Medicare population: a longitudinal cohort study Lancet Planet Health 2020 4 e557 e565 10.1016/S2542-5196(20)30227-8 33091388 PMC7720425

244. Zlokovic BV Gottesman RF Bernstein KE Seshadri S McKee A Snyder H Greenberg SM Yaffe K Schaffer CB Yuan C Hughes TM Daemen MJ Williamson JD Gonzalez HM Schneider J Wellington CL Katusic ZS Stoeckel L Koenig JI Corriveau RA Fine L Galis ZS Reis J Wright JD Chen J Vascular contributions to cognitive impairment and dementia (VCID): a report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop Alzheimers Dement. 2020 16 1714 1733 10.1002/alz.12157 33030307

245. Kisler K Nelson AR Montagne A Zlokovic BV Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease Nat Rev Neurosci 2017 18 419 434 10.1038/nrn.2017.48 28515434 PMC5759779

246. Tarantini S Tran CHT Gordon GR Ungvari Z Csiszar A Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline Exp Gerontol 2017 94 52 58 10.1016/j.exger.2016.11.004 27845201 PMC5429210

247. Iqubal A Ahmed M Ahmad S Sahoo CR Iqubal MK Haque SE Environmental neurotoxic pollutants: review Environ Sci Pollut Res Int 2020 27 41175 41198 10.1007/s11356-020-10539-z 32820440

248. McCann MS Maguire-Zeiss KA Environmental toxicants in the brain: a review of astrocytic metabolic dysfunction Environ Toxicol Pharmacol 2021 84 103608 10.1016/j.etap.2021.103608 33556584

249. Bondy SC Anthropogenic pollutants may increase the incidence of neurodegenerative disease in an aging population Toxicology 2016 341–343 41 46 10.1016/j.tox.2016.01.007 26812399

250. Wan C Liu J Nie X Zhao J Zhou S Duan Z Tang C Liang L Xu G 2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD) induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms PLoS One 2014 9 e89811 10.1371/journal.pone.0089811 24587053 PMC3933666

251. Fazekas-Pongor V Fekete M Balazs P Arva D Penzes M Tarantini S Urban R Varga JT Health-related quality of life of COPD patients aged over 40 years Physiol Int. 2021 108 261 273 10.1556/2060.2021.00017 34166221

252. Fekete M, Fazekas-Pongor V, Balazs P, Tarantini S, Szollosi G, Pako J, Nemeth AN, Varga JT. Effect of malnutrition and body composition on the quality of life of COPD patients. Physiol Int. 2021. 10.1556/2060.2021.00170 34224400

253. Fekete M, Szollosi G, Tarantini S, Lehoczki A, Nemeth AN, Bodola C, Varga L, Varga JT. Metabolic syndrome in patients with COPD: causes and pathophysiological consequences. Physiol Int. 2022. 10.1556/2060.2022.00164 35238797

254. Peterfi A, Meszaros A, Szarvas Z, Penzes M, Fekete M, Feher A, Lehoczki A, Csipo T, Fazekas-Pongor V. Comorbidities and increased mortality of COVID-19 among the elderly: a systematic review. Physiol Int. 2022. 10.1556/2060.2022.00206 35575986

255. Safiri S Carson-Chahhoud K Noori M Nejadghaderi SA Sullman MJM Ahmadian Heris J Ansarin K Mansournia MA Collins GS Kolahi AA Kaufman JS Burden of chronic obstructive pulmonary disease and its attributable risk factors in 204 countries and territories, 1990–2019: results from the Global Burden of Disease Study 2019 BMJ 2022 378 e069679 10.1136/bmj-2021-069679 35896191 PMC9326843

256. MacNee W Is chronic obstructive pulmonary disease an accelerated aging disease? Ann Am Thorac Soc 2016 13 S429 S437 10.1513/AnnalsATS.201602-124AW 28005421

257. Meiners S Eickelberg O Konigshoff M Hallmarks of the ageing lung Eur Respir J 2015 45 807 827 10.1183/09031936.00186914 25657021

258. Brandsma CA, de Vries M, Costa R, Woldhuis RR, Konigshoff M, Timens W. Lung ageing and COPD: is there a role for ageing in abnormal tissue repair? Eur Respir Rev. 2017;26. 10.1183/16000617.0073-2017 PMC9488745 29212834

259. Mercado N Ito K Barnes PJ Accelerated ageing of the lung in COPD: new concepts Thorax 2015 70 482 489 10.1136/thoraxjnl-2014-206084 25739910

260. World Health Organization: ambient (outdoor) air pollution. https://www.who.int/news-room/fact-sheets/detail/ambient-(outdoor)-air-quality-and-health (accessed on 05/29/2023)

261. Wen CP Gao W PM(2.5): an important cause for chronic obstructive pulmonary disease? Lancet Planet Health 2018 2 e105 e106 10.1016/S2542-5196(18)30025-1 29615221

262. Schraufnagel DE Balmes JR Cowl CT De Matteis S Jung SH Mortimer K Perez-Padilla R Rice MB Riojas-Rodriguez H Sood A Thurston GD To T Vanker A Wuebbles DJ Air pollution and noncommunicable diseases: a review by the Forum of International Respiratory Societies’ Environmental Committee, Part 2: Air Pollution and Organ Systems Chest 2019 155 417 426 10.1016/j.chest.2018.10.041 30419237 PMC6904854

263. GBD Chronic Respiratory Disease Collaborators Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet Respir Med 2020 8 585 596 10.1016/S2213-2600(20)30105-3 32526187 PMC7284317

264. Urban VS Cegledi A Mikala G Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment Geroscience 2023 45 727 746 10.1007/s11357-022-00698-x 36508077 PMC9742673

265. Schmidlin K Spoerri A Egger M Zwahlen M Stuck A Clough-Gorr KM Swiss NC Cancer, a disease of aging (part 1) - trends in older adult cancer mortality in Switzerland 1991–2008 Swiss Med Wkly 2012 142 w13637 22893506 10.4414/smw.2012.13637

266. Schmidlin K Spoerri A Egger M Zwahlen M Stuck A Clough-Gorr KM Swiss NC Cancer, a disease of aging (part 2) - risk factors for older adult cancer mortality in Switzerland 1991–2008 Swiss Med Wkly 2012 142 w13607 22893456 10.4414/smw.2012.13607

267. Colman RJ Anderson RM Johnson SC Kastman EK Kosmatka KJ Beasley TM Allison DB Cruzen C Simmons HA Kemnitz JW Weindruch R Caloric restriction delays disease onset and mortality in rhesus monkeys Science 2009 325 201 204 10.1126/science.1173635 19590001 PMC2812811

268. Garcia AM Busuttil RA Calder RB Dolle ME Diaz V McMahan CA Bartke A Nelson J Reddick R Vijg J Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues Mech Ageing Dev 2008 129 528 533 10.1016/j.mad.2008.04.013 18565572 PMC2581895

269. Heydari AR Unnikrishnan A Lucente LV Richardson A Caloric restriction and genomic stability Nucleic Acids Res 2007 35 7485 7496 10.1093/nar/gkm860 17942423 PMC2190719

270. Kritchevsky D Caloric restriction and experimental mammary carcinogenesis Breast Cancer Res Treat 1997 46 161 167 10.1023/A:1005960410225 9478271

271. Michels KB Ekbom A Caloric restriction and incidence of breast cancer JAMA 2004 291 1226 1230 10.1001/jama.291.10.1226 15010444

272. Weindruch R Effect of caloric restriction on age-associated cancers Exp Gerontol 1992 27 575 581 10.1016/0531-5565(92)90012-O 1426090

273. Anisimov VN Mutant and genetically modified mice as models for studying the relationship between aging and carcinogenesis Mech Ageing Dev 2001 122 1221 1255 10.1016/S0047-6374(01)00262-7 11438116

274. Sun LY, Fang Y, Patki A, Koopman JJ, Allison DB, Hill CM, Masternak MM, Darcy J, Wang J, McFadden S, Bartke A. Longevity is impacted by growth hormone action during early postnatal period. Elife. 2017;6. 10.7554/eLife.24059 PMC5515575 28675141

275. Morales-Valencia J David G The contribution of physiological and accelerated aging to cancer progression through senescence-induced inflammation Front Oncol 2021 11 747822 10.3389/fonc.2021.747822 34621683 PMC8490756

276. Takeda T Matsushita T Kurozumi M Takemura K Higuchi K Hosokawa M Pathobiology of the senescence-accelerated mouse (SAM) Exp Gerontol 1997 32 117 127 10.1016/S0531-5565(96)00068-X 9088909

277. Zhang Y Unnikrishnan A Deepa SS Liu Y Li Y Ikeno Y Sosnowska D Van Remmen H Richardson A A new role for oxidative stress in aging: the accelerated aging phenotype in Sod1(-/)(-) mice is correlated to increased cellular senescence Redox Biol 2017 11 30 37 10.1016/j.redox.2016.10.014 27846439 PMC5109248

278. Raaschou-Nielsen O Andersen ZJ Beelen R Samoli E Stafoggia M Weinmayr G Hoffmann B Fischer P Nieuwenhuijsen MJ Brunekreef B Xun WW Katsouyanni K Dimakopoulou K Sommar J Forsberg B Modig L Oudin A Oftedal B Schwarze PE Nafstad P De Faire U Pedersen NL Ostenson CG Fratiglioni L Penell J Korek M Pershagen G Eriksen KT Sorensen M Tjonneland A Ellermann T Eeftens M Peeters PH Meliefste K Wang M Bueno-de-Mesquita B Key TJ de Hoogh K Concin H Nagel G Vilier A Grioni S Krogh V Tsai MY Ricceri F Sacerdote C Galassi C Migliore E Ranzi A Cesaroni G Badaloni C Forastiere F Tamayo I Amiano P Dorronsoro M Trichopoulou A Bamia C Vineis P Hoek G Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE) Lancet Oncol 2013 14 813 822 10.1016/S1470-2045(13)70279-1 23849838

279. Straif K Cohen A Samet J Air pollution and cancer 2013 IV. series. Geneva International Agency for Research on Cancer

280. Tagliabue G Borgini A Tittarelli A van Donkelaar A Martin RV Bertoldi M Fabiano S Maghini A Codazzi T Scaburri A Favia I Cau A Barigelletti G Tessandori R Contiero P Atmospheric fine particulate matter and breast cancer mortality: a population-based cohort study BMJ Open 2016 6 e012580 10.1136/bmjopen-2016-012580 28076275 PMC5129133

281. Barta JA, Powell CA and Wisnivesky JP. Global epidemiology of lung cancer. Ann Glob Health. 2019;85. 10.5334/aogh.2419 PMC6724220 30741509

282. Cheng ES, Egger S, Hughes S, Weber M, Steinberg J, Rahman B, Worth H, Ruano-Ravina A, Rawstorne P, Yu XQ. Systematic review and meta-analysis of residential radon and lung cancer in never-smokers. Eur Respir Rev. 2021;30. 10.1183/16000617.0230-2020 PMC9488946 33536262

283. Ciabattini M Rizzello E Lucaroni F Palombi L Boffetta P Systematic review and meta-analysis of recent high-quality studies on exposure to particulate matter and risk of lung cancer Environ Res 2021 196 110440 10.1016/j.envres.2020.110440 33181136

284. Corrales L Rosell R Cardona AF Martin C Zatarain-Barron ZL Arrieta O Lung cancer in never smokers: the role of different risk factors other than tobacco smoking Crit Rev Oncol Hematol 2020 148 102895 10.1016/j.critrevonc.2020.102895 32062313

285. Honaryar MK Lunn RM Luce D Ahrens W Mannetje TA Hansen J Bouaoun L Loomis D Byrnes G Vilahur N Stayner L Guha N Welding fumes and lung cancer: a meta-analysis of case-control and cohort studies Occup Environ Med 2019 76 422 431 10.1136/oemed-2018-105447 30948521

286. Li J Ran J Chen LC Costa M Huang Y Chen X Tian L Bituminous coal combustion and Xuan Wei Lung cancer: a review of the epidemiology, intervention, carcinogens, and carcinogenesis Arch Toxicol 2019 93 573 583 10.1007/s00204-019-02392-y 30649585

287. Rodriguez-Martinez A Torres-Duran M Barros-Dios JM Ruano-Ravina A Residential radon and small cell lung cancer A Syst Rev Cancer Lett 2018 426 57 62 10.1016/j.canlet.2018.04.003 29654890

288. Shankar A Dubey A Saini D Singh M Prasad CP Roy S Bharati SJ Rinki M Singh N Seth T Khanna M Sethi N Kumar S Sirohi B Mohan A Guleria R Rath GK Environmental and occupational determinants of lung cancer Transl Lung Cancer Res 2019 8 S31 S49 10.21037/tlcr.2019.03.05 31211104 PMC6546634

289. Soza-Ried C Bustamante E Caglevic C Rolfo C Sirera R Marsiglia H Oncogenic role of arsenic exposure in lung cancer: a forgotten risk factor Crit Rev Oncol Hematol 2019 139 128 133 10.1016/j.critrevonc.2019.01.012 30878179

290. Stepanek L, Sevcikova J, Horakova D, Patel MS, Durdakova R. Public health burden of secondhand smoking: case reports of lung cancer and a literature review. Int J Environ Res Public Health. 2022;19. 10.3390/ijerph192013152 PMC9603183 36293731

291. Wang N Mengersen K Kimlin M Zhou M Tong S Fang L Wang B Hu W Lung cancer and particulate pollution: a critical review of spatial and temporal analysis evidence Environ Res 2018 164 585 596 10.1016/j.envres.2018.03.034 29626820

292. Du CL Wang JD Increased morbidity odds ratio of primary liver cancer and cirrhosis of the liver among vinyl chloride monomer workers Occup Environ Med 1998 55 528 532 10.1136/oem.55.8.528 9849539 PMC1757621

293. Lewis R Rempala G Dell LD Mundt KA Vinyl chloride and liver and brain cancer at a polymer production plant in Louisville Kentucky J Occup Environ Med 2003 45 533 537 10.1097/01.jom.0000058348.05741.1d 12762078

294. Mundt KA Dell LD Crawford L Gallagher AE Quantitative estimated exposure to vinyl chloride and risk of angiosarcoma of the liver and hepatocellular cancer in the US industry-wide vinyl chloride cohort: mortality update through 2013 Occup Environ Med 2017 74 709 716 10.1136/oemed-2016-104051 28490663 PMC5629943

295. Towle KM Benson SM Egnot NS Marsh GM An ecological evaluation of vinyl chloride exposure and liver cancer incidence and mortality in Texas J Clin Transl Hepatol 2021 9 99 105 33604260 10.14218/JCTH.2020.00073 PMC7868703

296. Wang W Cheng S Zhang D Association of inorganic arsenic exposure with liver cancer mortality: a meta-analysis Environ Res 2014 135 120 125 10.1016/j.envres.2014.08.034 25262084

297. Alexander DD Kelsh MA Mink PJ Mandel JH Basu R Weingart M A meta-analysis of occupational trichloroethylene exposure and liver cancer Int Arch Occup Environ Health 2007 81 127 143 10.1007/s00420-007-0201-4 17492303

298. Vlaanderen J Straif K Pukkala E Kauppinen T Kyyronen P Martinsen JI Kjaerheim K Tryggvadottir L Hansen J Sparen P Weiderpass E Occupational exposure to trichloroethylene and perchloroethylene and the risk of lymphoma, liver, and kidney cancer in four Nordic countries Occup Environ Med 2013 70 393 401 10.1136/oemed-2012-101188 23447073

299. Camargo MC Stayner LT Straif K Reina M Al-Alem U Demers PA Landrigan PJ Occupational exposure to asbestos and ovarian cancer: a meta-analysis Environ Health Perspect 2011 119 1211 1217 10.1289/ehp.1003283 21642044 PMC3230399

300. Burstyn I Kromhout H Johansen C Langard S Kauppinen T Shaham J Ferro G Boffetta P Bladder cancer incidence and exposure to polycyclic aromatic hydrocarbons among asphalt pavers Occup Environ Med 2007 64 520 526 10.1136/oem.2006.029801 17332134 PMC2078500

301. Clavel J Mandereau L Limasset JC Hemon D Cordier S Occupational exposure to polycyclic aromatic hydrocarbons and the risk of bladder cancer: a French case-control study Int J Epidemiol 1994 23 1145 1153 10.1093/ije/23.6.1145 7721515

302. Raj A Mayberry JF Podas T Occupation and gastric cancer Postgrad Med J 2003 79 252 258 10.1136/pmj.79.931.252 12782770 PMC1742699

303. Eguchi H Wada K Prieto-Merino D Smith DR Lung, gastric and colorectal cancer mortality by occupation and industry among working-aged men in Japan Sci Rep 2017 7 43204 10.1038/srep43204 28230191 PMC5322319

304. Yoshinaga Y Tanaka H Wada K Ikeda S Gastric cancer mortality rates by occupation and industry among male and female workers aged 25–64 years in Japan Ind Health 2020 58 554 564 10.2486/indhealth.2020-0136 32981909 PMC7708745

305. Boffetta P de Vocht F Occupation and the risk of non-Hodgkin lymphoma Cancer Epidemiol Biomarkers Prev 2007 16 369 372 10.1158/1055-9965.EPI-06-1055 17372232

306. Cano MI Pollan M Non-Hodgkin’s lymphomas and occupation in Sweden Int Arch Occup Environ Health 2001 74 443 449 10.1007/s004200100248 11563608

307. Schenk M Purdue MP Colt JS Hartge P Blair A Stewart P Cerhan JR De Roos AJ Cozen W Severson RK Occupation/industry and risk of non-Hodgkin’s lymphoma in the United States Occup Environ Med 2009 66 23 31 10.1136/oem.2007.036723 18805886 PMC3051169

308. Mannetje TA De Roos AJ Boffetta P Vermeulen R Benke G Fritschi L Brennan P Foretova L Maynadie M Becker N Nieters A Staines A Campagna M Chiu B Clavel J de Sanjose S Hartge P Holly EA Bracci P Linet MS Monnereau A Orsi L Purdue MP Rothman N Lan Q Kane E Costantini AS Miligi L Spinelli JJ Zheng T Cocco P Kricker A Occupation and risk of non-Hodgkin lymphoma and its subtypes: a pooled analysis from the InterLymph Consortium Environ Health Perspect 2016 124 396 405 10.1289/ehp.1409294 26340796 PMC4829988

309. Baan R Grosse Y Straif K Secretan B El Ghissassi F Bouvard V Benbrahim-Tallaa L Guha N Freeman C Galichet L Cogliano V Group WHOIAfRoCMW A review of human carcinogens–Part F: chemical agents and related occupations Lancet Oncol 2009 10 1143 4 10.1016/S1470-2045(09)70358-4 19998521

310. Barul C Carton M Radoi L Menvielle G Pilorget C Bara S Stucker I Luce D group Is Occupational exposure to petroleum-based and oxygenated solvents and hypopharyngeal and laryngeal cancer in France: the ICARE study BMC Cancer 2018 18 388 10.1186/s12885-018-4324-7 29621977 PMC5887173

311. Becher H Ramroth H Ahrens W Risch A Schmezer P Dietz A Occupation, exposure to polycyclic aromatic hydrocarbons and laryngeal cancer risk Int J Cancer 2005 116 451 457 10.1002/ijc.21049 15810012

312. Dietz A Ramroth H Urban T Ahrens W Becher H Exposure to cement dust, related occupational groups and laryngeal cancer risk: results of a population based case-control study Int J Cancer 2004 108 907 911 10.1002/ijc.11658 14712496

313. Hall AL Kromhout H Schuz J Peters S Portengen L Vermeulen R Agudo A Ahrens W Boffetta P Brennan P Canova C Conway DI Curado MP Daudt AW Fernandez L Hashibe M Healy CM Holcatova I Kjaerheim K Koifman R Lagiou P Luce D Macfarlane GJ Menezes A Menvielle G Polesel J Ramroth H Richiardi L Stucker I Thomson P Vilensky M Wunsch-Filho V Yuan-Chin AL Znaor A Straif K Olsson A Laryngeal cancer risks in workers exposed to lung carcinogens: exposure-effect analyses using a quantitative job exposure matrix Epidemiology 2020 31 145 154 10.1097/EDE.0000000000001120 31577634

314. Peng WJ Mi J Jiang YH Asbestos exposure and laryngeal cancer mortality Laryngoscope 2016 126 1169 1174 10.1002/lary.25693 26418833

315. Ramroth H Dietz A Ahrens W Becher H Occupational wood dust exposure and the risk of laryngeal cancer: a population based case-control study in Germany Am J Ind Med 2008 51 648 655 10.1002/ajim.20605 18626911

316. Shangina O Brennan P Szeszenia-Dabrowska N Mates D Fabianova E Fletcher T Tmannetje A Boffetta P Zaridze D Occupational exposure and laryngeal and hypopharyngeal cancer risk in central and eastern Europe Am J Epidemiol 2006 164 367 75 10.1093/aje/kwj208 16801374

317. Andreotti G Koutros S Hofmann JN Sandler DP Lubin JH Lynch CF Lerro CC De Roos AJ Parks CG Alavanja MC Silverman DT Beane Freeman LE Glyphosate use and cancer incidence in the agricultural health study J Natl Cancer Inst 2018 110 509 516 10.1093/jnci/djx233 29136183 PMC6279255

318. Davoren MJ Schiestl RH Glyphosate-based herbicides and cancer risk: a post-IARC decision review of potential mechanisms, policy and avenues of research Carcinogenesis 2018 39 1207 1215 10.1093/carcin/bgy105 30060078 PMC7530464

319. Franke AA Li X Shvetsov YB Lai JF Pilot study on the urinary excretion of the glyphosate metabolite aminomethylphosphonic acid and breast cancer risk: the Multiethnic Cohort study Environ Pollut 2021 277 116848 10.1016/j.envpol.2021.116848 33714786 PMC8044054

320. Marino M Mele E Viggiano A Nori SL Meccariello R Santoro A Pleiotropic outcomes of glyphosate exposure: from organ damage to effects on inflammation, cancer, reproduction and development Int J Mol Sci. 2021 22 12606 10.3390/ijms222212606 34830483 PMC8618927

321. Ward EM Glyphosate use and cancer incidence in the agricultural health study: an epidemiologic perspective J Natl Cancer Inst 2018 110 446 447 10.1093/jnci/djx247 29155945

322. Chaiklieng S Suggaravetsiri P Autrup H Risk assessment on benzene exposure among gasoline station workers Int J Environ Res Public Health. 2019 16 2545 10.3390/ijerph16142545 31315313 PMC6678808

323. Costantini AS Benvenuti A Vineis P Kriebel D Tumino R Ramazzotti V Rodella S Stagnaro E Crosignani P Amadori D Mirabelli D Sommani L Belletti I Troschel L Romeo L Miceli G Tozzi GA Mendico I Maltoni SA Miligi L Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: evidence from the Italian Multicenter Case-control study Am J Ind Med 2008 51 803 811 10.1002/ajim.20592 18651579

324. Infante PF Benzene exposure and multiple myeloma: a detailed meta-analysis of benzene cohort studies Ann N Y Acad Sci 2006 1076 90 109 10.1196/annals.1371.081 17119195

325. Kawasaki S Takizawa H Takami K Desaki M Okazaki H Kasama T Kobayashi K Yamamoto K Nakahara K Tanaka M Sagai M Ohtoshi T Benzene-extracted components are important for the major activity of diesel exhaust particles: effect on interleukin-8 gene expression in human bronchial epithelial cells Am J Respir Cell Mol Biol 2001 24 419 426 10.1165/ajrcmb.24.4.4085 11306435

326. Maltoni C Ciliberti A Cotti G Conti B Belpoggi F Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology Environ Health Perspect 1989 82 109 124 10.1289/ehp.8982109 2792037 PMC1568122

327. Savitz DA Andrews KW Risk of myelogenous leukaemia and multiple myeloma in workers exposed to benzene Occup Environ Med 1996 53 357 358 8673185 PMC1128481

328. Sonoda T Nagata Y Mori M Ishida T Imai K Meta-analysis of multiple myeloma and benzene exposure J Epidemiol 2001 11 249 254 10.2188/jea.11.249 11769942 PMC11798636

329. Teitelbaum DT Brautbar N Benzene and multiple myeloma: appraisal of the scientific evidence Blood 2000 95 2995 2997 10.1182/blood.V95.9.2995.009k40c_2995_2997 10841614

330. Gaskin J Coyle D Whyte J Krewksi D Global estimate of lung cancer mortality attributable to residential radon Environ Health Perspect 2018 126 057009 10.1289/EHP2503 29856911 PMC6072010

331. Rivers JK Is there more than one road to melanoma? The Lancet 2004 363 728 730 10.1016/S0140-6736(04)15649-3 15005091

332. Campisi J Aging, cellular senescence, and cancer Annu Rev Physiol 2013 75 685 705 10.1146/annurev-physiol-030212-183653 23140366 PMC4166529

333. Campisi J d’Adda di Fagagna F Cellular senescence: when bad things happen to good cells Nat Rev Mol Cell Biol 2007 8 729 40 10.1038/nrm2233 17667954

334. Demaria M O’Leary MN Chang J Shao L Liu S Alimirah F Koenig K Le C Mitin N Deal AM Alston S Academia EC Kilmarx S Valdovinos A Wang B de Bruin A Kennedy BK Melov S Zhou D Sharpless NE Muss H Campisi J Cellular senescence promotes adverse effects of chemotherapy and cancer relapse Cancer Discov 2017 7 165 176 10.1158/2159-8290.CD-16-0241 27979832 PMC5296251

335. Krtolica A Parrinello S Lockett S Desprez PY Campisi J Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging Proc Natl Acad Sci USA 2001 98 12072 12077 10.1073/pnas.211053698 11593017 PMC59769

336. Lecot P Alimirah F Desprez PY Campisi J Wiley C Context-dependent effects of cellular senescence in cancer development Br J Cancer 2016 114 1180 1184 10.1038/bjc.2016.115 27140310 PMC4891501

337. Vincent HK Raiser SN Vincent KR The aging musculoskeletal system and obesity-related considerations with exercise Ageing Res Rev 2012 11 361 373 10.1016/j.arr.2012.03.002 22440321 PMC3356456

338. Guo Y Yang TL Liu YZ Shen H Lei SF Yu N Chen J Xu T Cheng Y Tian Q Yu P Deng HW Mitochondria-wide association study of common variants in osteoporosis Ann Hum Genet 2011 75 569 574 10.1111/j.1469-1809.2011.00663.x 21762117 PMC3155639

339. Foger-Samwald U Kerschan-Schindl K Butylina M Pietschmann P Age related osteoporosis: targeting cellular senescence Int J Mol Sci. 2022 23 2701 10.3390/ijms23052701 35269841 PMC8910503

340. Guo Y Jia X Cui Y Song Y Wang S Geng Y Li R Gao W Fu D Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis Redox Biol 2021 41 101915 10.1016/j.redox.2021.101915 33662874 PMC7930642

341. Pignolo RJ Law SF Chandra A Bone aging, cellular senescence, and osteoporosis JBMR Plus 2021 5 e10488 10.1002/jbm4.10488 33869998 PMC8046105

342. Coen PM Musci RV Hinkley JM Miller BF Mitochondria as a target for mitigating sarcopenia Front Physiol 2018 9 1883 10.3389/fphys.2018.01883 30687111 PMC6335344

343. Daussin FN Boulanger E Lancel S From mitochondria to sarcopenia: role of inflammaging and RAGE-ligand axis implication Exp Gerontol 2021 146 111247 10.1016/j.exger.2021.111247 33484891

344. Del Campo A Contreras-Hernandez I Castro-Sepulveda M Campos CA Figueroa R Tevy MF Eisner V Casas M Jaimovich E Muscle function decline and mitochondria changes in middle age precede sarcopenia in mice Aging (Albany NY) 2018 10 34 55 10.18632/aging.101358 29302020 PMC5811241

345. Sataranatarajan K Pharaoh G Brown JL Ranjit R Piekarz KM Street K Wren JD Georgescu C Kinter C Kinter M Freeman WM Richardson A Van Remmen H Molecular changes in transcription and metabolic pathways underlying muscle atrophy in the CuZnSOD null mouse model of sarcopenia Geroscience 2020 42 1101 1118 10.1007/s11357-020-00189-x 32394347 PMC7394980

346. Lagerwaard B Nieuwenhuizen AG de Boer VCJ Keijer J In vivo assessment of mitochondrial capacity using NIRS in locomotor muscles of young and elderly males with similar physical activity levels Geroscience 2020 42 299 310 10.1007/s11357-019-00145-4 31858399 PMC7031190

347. Siegel MP Kruse SE Percival JM Goh J White CC Hopkins HC Kavanagh TJ Szeto HH Rabinovitch PS Marcinek DJ Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice Aging Cell 2013 12 763 771 10.1111/acel.12102 23692570 PMC3772966

348. Reznick RM Zong H Li J Morino K Moore IK Yu HJ Liu ZX Dong J Mustard KJ Hawley SA Befroy D Pypaert M Hardie DG Young LH Shulman GI Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis Cell Metab 2007 5 151 156 10.1016/j.cmet.2007.01.008 17276357 PMC1885964

349. Romanick MA Rakoczy SG Brown-Borg HM Long-lived Ames dwarf mouse exhibits increased antioxidant defense in skeletal muscle Mech Ageing Dev 2004 125 269 281 10.1016/j.mad.2004.02.001 15063102

350. Schriner SE Linford NJ Martin GM Treuting P Ogburn CE Emond M Coskun PE Ladiges W Wolf N Van Remmen H Wallace DC Rabinovitch PS Extension of murine life span by overexpression of catalase targeted to mitochondria Science 2005 308 1909 1911 10.1126/science.1106653 15879174

351. Schwarze SR Lee CM Chung SS Roecker EB Weindruch R Aiken JM High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys Mech Ageing Dev 1995 83 91 101 10.1016/0047-6374(95)01611-3 8569289

352. Trounce I Byrne E Marzuki S Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing Lancet 1989 1 637 639 10.1016/S0140-6736(89)92143-0 2564459

353. Ubaida-Mohien C, Lyashkov A, Gonzalez-Freire M, Tharakan R, Shardell M, Moaddel R, Semba RD, Chia CW, Gorospe M, Sen R, Ferrucci L. Discovery proteomics in aging human skeletal muscle finds change in spliceosome, immunity, proteostasis and mitochondria. Elife. 2019;8:e49874. 10.7554/eLife.49874 PMC6810669 31642809

354. Yeo D Kang C Ji LL Aging alters acetylation status in skeletal and cardiac muscles Geroscience 2020 42 963 976 10.1007/s11357-020-00171-7 32300965 PMC7286993

355. Zhang H Ryu D Wu Y Gariani K Wang X Luan P D’Amico D Ropelle ER Lutolf MP Aebersold R Schoonjans K Menzies KJ Auwerx J NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice Science 2016 352 1436 1443 10.1126/science.aaf2693 27127236

356. Zhang Y Ikeno Y Qi W Chaudhuri A Li Y Bokov A Thorpe SR Baynes JW Epstein C Richardson A Van Remmen H Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity J Gerontol A Biol Sci Med Sci 2009 64 1212 1220 10.1093/gerona/glp132 19776219 PMC2781787

357. Wiedmer P Jung T Castro JP Pomatto LCD Sun PY Davies KJA Grune T Sarcopenia - molecular mechanisms and open questions Ageing Res Rev 2021 65 101200 10.1016/j.arr.2020.101200 33130247

358. Chalan P van den Berg A Kroesen BJ Brouwer L Boots A Rheumatoid arthritis, immunosenescence and the hallmarks of aging Curr Aging Sci 2015 8 131 146 10.2174/1874609808666150727110744 26212057 PMC5388800

359. Prada D Zhong J Colicino E Zanobetti A Schwartz J Dagincourt N Fang SC Kloog I Zmuda JM Holick M Herrera LA Hou L Dominici F Bartali B Baccarelli AA Association of air particulate pollution with bone loss over time and bone fracture risk: analysis of data from two independent studies Lancet Planet Health 2017 1 e337 e347 10.1016/S2542-5196(17)30136-5 29527596 PMC5841468

360. Berenbaum F Wallace IJ Lieberman DE Felson DT Modern-day environmental factors in the pathogenesis of osteoarthritis Nat Rev Rheumatol 2018 14 674 681 10.1038/s41584-018-0073-x 30209413

361. Shin J, Lee J, Lee J, Ha E-H. Association between exposure to ambient air pollution and rheumatoid arthritis in adults. International Journal of Environmental Research and Public Health. 2019;16.

362. Yamamoto SS Yacyshyn E Jhangri GS Chopra A Parmar D Jones CA Household air pollution and arthritis in low-and middle-income countries: cross-sectional evidence from the World Health Organization’s study on Global Ageing and Adult Health PLoS One 2019 14 e0226738 10.1371/journal.pone.0226738 31881058 PMC6934325

363. Ravibabu K Bagepally BS Barman T Association of musculoskeletal disorders and inflammation markers in workers exposed to lead (Pb) from Pb-battery manufacturing plant Indian J Occup Environ Med 2019 23 68 72 10.4103/ijoem.IJOEM_192_18 31619878 PMC6783524

364. Manocha A Srivastava LM Bhargava S Lead as a risk factor for osteoporosis in post-menopausal women Indian J Clin Biochem 2017 32 261 265 10.1007/s12291-016-0610-9 28811684 PMC5539005

365. Sun Y Sun D Zhou Z Zhu G Zhang H Chang X Lei L Jin T Osteoporosis in a Chinese population due to occupational exposure to lead Am J Ind Med 2008 51 436 442 10.1002/ajim.20567 18381596

366. Kirkhorn SR Schenker MB Current health effects of agricultural work: respiratory disease, cancer, reproductive effects, musculoskeletal injuries, and pesticide-related illnesses J Agric Saf Health 2002 8 199 214 10.13031/2013.8432 12046806

367. Ciosek Z Kot K Rotter I Iron, zinc, copper, cadmium, mercury, and bone tissue Int J Environ Res Public Health. 2023 20 2197 10.3390/ijerph20032197 36767564 PMC9915283

368. Anderson HA Lilis R Selikoff IJ Rosenman KD Valciukas JA Freedman S Unanticipated prevalence of symptoms among dairy farmers in Michigan and Wisconsin Environ Health Perspect 1978 23 217 226 10.1289/ehp.7823217 209979 PMC1637438

369. Broding HC Schettgen T Hillert A Angerer J Goen T Drexler H Subjective complaints in persons under chronic low-dose exposure to lower polychlorinated biphenyls (PCBs) Int J Hyg Environ Health 2008 211 648 657 10.1016/j.ijheh.2008.02.001 18396099

370. Guo YL Lin CJ Yao WJ Ryan JJ Hsu CC Musculoskeletal changes in children prenatally exposed to polychlorinated biphenyls and related compounds (Yu-Cheng children) J Toxicol Environ Health 1994 41 83 93 10.1080/15287399409531828 8277528

371. Boudigaard SH Schlunssen V Vestergaard JM Sondergaard K Toren K Peters S Kromhout H Kolstad HA Occupational exposure to respirable crystalline silica and risk of autoimmune rheumatic diseases: a nationwide cohort study Int J Epidemiol 2021 50 1213 1226 10.1093/ije/dyaa287 33462590 PMC8407872

372. Cavalin C Lescoat A Sigaux J Macchi O Ballerie A Catinon M Vincent M Semerano L Boissier MC Rosental PA Crystalline silica exposure in patients with rheumatoid arthritis and systemic sclerosis: a nationwide cross-sectional survey Rheumatology (Oxford). 2023 62 2707 2715 10.1093/rheumatology/keac675 36458909

373. Min YS Kim MG Ahn YS Rheumatoid arthritis in silica-exposed workers Int J Environ Res Public Health. 2021 18 12776 10.3390/ijerph182312776 34886499 PMC8657481

374. Morotti A Sollaku I Franceschini F Cavazzana I Fredi M Sala E De Palma G Systematic review and meta-analysis on the association of occupational exposure to free crystalline silica and rheumatoid arthritis Clin Rev Allergy Immunol 2022 62 333 345 10.1007/s12016-021-08846-5 33651342 PMC8994741

375. Wrangel O Graff P Bryngelsson IL Fornander L Wiebert P Vihlborg P Silica dust exposure increases risk for rheumatoid arthritis: a Swedish National Registry Case-Control Study J Occup Environ Med 2021 63 951 955 10.1097/JOM.0000000000002281 34091575 PMC8562940

376. Veraldi A Costantini AS Bolejack V Miligi L Vineis P van Loveren H Immunotoxic effects of chemicals: a matrix for occupational and environmental epidemiological studies Am J Ind Med 2006 49 1046 1055 10.1002/ajim.20364 17036363

377. Biton J Saidenberg-Kermanac’h N Decker P Boissier MC Semerano L Sigaux J The exposome in rheumatoid arthritis Joint Bone Spine 2022 89 105455 10.1016/j.jbspin.2022.105455 35964886

378. Jokai M Torma F McGreevy KM Koltai E Bori Z Babszki G Bakonyi P Gombos Z Gyorgy B Aczel D Toth L Osvath P Fridvalszky M Teglas T Posa A Kujach S Olek R Kawamura T Seki Y Suzuki K Tanisawa K Goto S Kerepesi C Boldogh I Ba X Davies KJA Horvath S Radak Z DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation Geroscience. 2023 10.1007/s11357-023-00826-1 37209203 PMC10643800

379. Oblak L, van der Zaag J, Higgins-Chen AT, Levine ME, Boks MP. A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration. Ageing Res Rev. 2021;69:101348. 10.1016/j.arr.2021.101348 33930583

380. Grodstein F Lemos B Yu L Klein HU Iatrou A Buchman AS Shireby GL Mill J Schneider JA De Jager PL Bennett DA The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes Neurobiol Dis 2021 157 105428 10.1016/j.nbd.2021.105428 34153464 PMC8373772

381. Horvath S Raj K DNA methylation-based biomarkers and the epigenetic clock theory of ageing Nat Rev Genet 2018 19 371 384 10.1038/s41576-018-0004-3 29643443

382. Marioni RE Shah S McRae AF Ritchie SJ Muniz-Terrera G Harris SE Gibson J Redmond P Cox SR Pattie A Corley J Taylor A Murphy L Starr JM Horvath S Visscher PM Wray NR Deary IJ The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936 Int J Epidemiol 2015 44 1388 1396 10.1093/ije/dyu277 25617346 PMC4588858

383. Subedi P Palma-Gudiel H Fiehn O Best LG Lee ET Howard BV Zhao J Lipidomics profiling of biological aging in American Indians: the Strong Heart Family Study Geroscience 2023 45 359 369 10.1007/s11357-022-00638-9 35953607 PMC9886745

384. Leuthner TC Meyer JN Mitochondrial DNA mutagenesis: feature of and biomarker for environmental exposures and aging Curr Environ Health Rep 2021 8 294 308 10.1007/s40572-021-00329-1 34761353 PMC8826492

385. Görgey A. Über die festen, flüchtigen, fetten Säueren des Cocusnussöles Sitzungsberichte der mathematisch-naturwissenschaftlichen Classe der k Akademie der Wissenschaften in Wien Vienna: Akademie der Wissenschaften in Wien.;1848(3): 208—227.