Air Pollution in Diseases of Aging

Chapter 3

Air Pollution in Diseases of Aging Chapter Outline 3.1 Overview 3.2 Arterial Thickening and Atheroma Formation 3.2.1 Cigarette Smoke 3.2.2 Ambient Air Pollution 3.2.3 Biomass Smoke 3.3 The Brain

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3.3.1 Cigarette Smoke 99 3.3.2 Ambient Air Pollution 103 3.3.3 Biomass Smoke 110 3.4 Interactions of Ambient Air Pollution and Cigarette Smoke 111 3.5 Conclusions 114 References 114

85 86 90 92 97

3.1 OVERVIEW The larger landscape of exposomics now opens up the reality that most diseases of aging are accelerated by airborne pollutants. Chapter 1 showed the global picture of mortality links to ambient air pollution (AAP), cigarette smoke (CS), and biomass burning in household air pollution (HAP). The toxicants and their sources described in Chapter 2 share organic components and elements derived from the combustion of dead animals, plants, and microorganisms, melded with industrial effluents and natural dust from deserts and deforestation. Our next challenge is to understand how inhalation of these diverse materials accelerates diseases of aging and shortens life span. Preceding clinical-grade dysfunctions from AAP and CS are inflammatory and metabolic dysfunctions, which are risk factors for many diseases of aging. Recent findings on AAP and CS for major chronic diseases of aging are summarized in Table 3.1 for humans and rodent models. AAP and CS promote the same diseases of aging throughout the body, lung to artery to brain. These convergent outcomes in human populations and in rodent models give a basis for considering that AAP and CS contain shared gerogens. Although AAP, CS, and HAP are usually studied separately, we must also consider their interactions. Synergies with greater than additivity of effect are shown for AAP and CS in a few epidemiological studies but have not been neglected in experimental models. While HAP from burning wood and dung globally adds 4 million additional premature deaths (WHO, 2016; Gordon et al., 2014), it is less documented in rodent models. Pursuit of these questions takes us beyond the industrial The Role of Global Air Pollution in Aging and Disease. https://doi.org/10.1016/B978-0-12-813102-2.00003-0 Copyright © 2018 Elsevier Inc. All rights reserved.

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84  The Role of Global Air Pollution in Aging and Disease

TABLE 3.1  Ambient Air Pollution (AAP) and Cigarette Smoke (CS) in Chronic Diseases of Aging AAP

CS

Carotid

Aguilera et al. (2016), Liu et al. (2015)

Hansen et al. (2016), Huang et al. (2016)

Coronary

Hartiala et al. (2016), Kaufman et al. (2016)

Benziger et al. (2016), Nicoll et al. (2016)

Hamra et al. (2014), Cui et al. (2015)

Doll et al. (2004), Chen et al. (2015c)

Insulin sensitivity, adult

Wolf et al. (2016), Thiering et al. (2016)

Weak or no association

Body mass index, children

McConnell et al. (2015)

McConnell et al. (2015)

Chen et al. (2015a), Casanova et al. (2016)

Karama et al. (2015), Prom-Wormley et al. (2016)

AAP–CS Interactions

A. Human Atherosclerosis

Cancer Lung

Burnett et al. (2014), Turner et al. (2014)

Metabolism

Kim et al. (2014), McConnell et al. (2015)

Neurodegeneration Gray matter atrophy Myelin atrophy Cognitive decline

Ailshire and Crimmins (2014)

Ailshire and Crimmins (2014)

Cacciottolo et al. (2017) Alzheimer disease

Cacciottolo et al. (in prep), Oudin et al. (2016), Jung et al. (2015)

Barnes and Yaffe (2011), Durazzo et al. (2014), Deochand et al. (2016)

Stroke

Scheers et al. (2015), Wang et al. (2014)

O’Donnell et al. (2011)

Air Pollution in Diseases of Aging Chapter | 3  85

TABLE 3.1  Ambient Air Pollution (AAP) and Cigarette Smoke (CS) in Chronic Diseases of Aging—cont’d AAP

CS

Chen et al. (2013b), Li et al. (2013a,b), Rao et al. (2014)

Lietz et al. (2013), Lo Sasso et al. (2016)

Liu et al. (2014)

Thatcher et al. (2014)

Neurite atrophy

Woodward et al. (2017a), Fonken et al. (2011)

Torres et al. (2015)

Alzheimer disease

Cacciottolo et al. (2017)

Moreno-Gonzalez et al. (2013)

Stroke

Liu et al. (2016)

Cao et al. (2013), Yang et al. (2008)

AAP–CS Interactions

B. Rodents Atherosclerosis, aorta

No reports

Metabolism Insulin sensitivity Neurodegeneration

world into remote parts of Bolivia and Ghana where ischemic disease is rare. Traditional farmers from these countries have high levels of inflammation from chronic infections, but very low exposure to fossil fuels and tobacco. Could there be critical differences between inflammation driven by pathogenic infections versus sterile inflammogens from the combustion of fossil fuels and tobacco?

3.2 ARTERIAL THICKENING AND ATHEROMA FORMATION Although heart attacks and strokes mostly afflict our later years, the onset of arterial degeneration begins early in life. For more than a century, pathologists noticed that arteries of the stillborn usually had fatty streaks suggestive of early stages of atheromas (Hirsch, 1941; Leistikow and Bolande, 1999). A well-defined postmortem series showed that lipids accumulated progressively on artery surfaces from ages 3 to 80 years (D’Armiento et al., 2001) (Fig. 3.1A). The lipid accumulation was linear with advancing age in the aorta and carotid from childhood into later ages. More alarming was the exponential accumulation of lipids in the basilar and middle cerebral arteries that feed the brain (not shown). The other two arrows represent alternate trajectories of arterial aging, accelerated by exposure to air pollutants or CS, and possibly retarded by exercise, diet, and drugs as well as reduced exposure.

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FIGURE 3.1  Arterial aging interacts with the environment. (A) Lipids on the surface of the abdominal aorta, measured by histochemistry as the intimal area covered by the general lipid dye Oil Red O; individual postmortem specimens. The upward dotted arrow represents increased atherosclerosis exposure to ambient air pollution (AAP) (AirPoll) or cigarette smoke (CigSmoke). The lower dotted arrow represents slowed atherosclerosis from drugs, exercise, or diet, or lower exposure to AAP. (B) CIMT, carotid intimal thickening per year by smoking status: nonS, nonsmoker; formerS, former smoker; activeS, active smoker. Ultrasound data from The Atherosclerosis Risk in Communities (ARIC) Study, a population-based sample of 10,914 adults aged 45–64 years at entry from urban and rural regions of four sites in Maryland, Mississippi, Minnesota, and North Carolina; 1987–89, with 3-year follow-up. ((A) Redrawn from Finch (2007a), based on lipid data of D’Armiento et al. (2001). (B) Redrawn from Howard et al. (1998).)

During the same ages, the thickening arteries become less elastic, contributing to increasing blood pressure with aging. On top of all this is the formation of atheromas. These slowly growing bumps are aggregations of macrophages and other immune-inflammatory cells on the inner walls of arteries. Cardiologists recognize multiple stages of atherosclerosis by the size and cell composition of the atheromas that form on the inner surfaces of our arteries (Stary et al., 1994). Later stages tend to break up and throw off blood clots that can block blood flow downstream. End-stage atheromas are typically calcified (detected by CT scans) and are strong risk indictors or predictors of ischemic events (Budoff et al., 2013). The next section shows that cigarette exposure accelerates arterial wall thickening; air pollution follows.

3.2.1 Cigarette Smoke The carotid artery thickness is a common measure of arterial aging, as assessed by ultrasound. The CIMT represents the thickness of the carotid wall intima plus media, its two main layers. Despite its value as a marker of atherosclerosis, CIMT does not predict ischemic events (Lorenz et al., 2012; Naqvi and Lee, 2014). As a strong example of CIMT responses to CS, the longitudinal ARIC Study of accelerated aging showed that active smokers had twofold greater CIMT than never-smokers at middle age (Howard et al., 1998) (Fig 3.1B).

Air Pollution in Diseases of Aging Chapter | 3  87

Former smokers had CIMT that was intermediate between nonsmokers and active smokers, in parallel with their mortality (Section 1.2; Fig. 1.2). The dose–response to CS has been defined as pack-years of smoking per increment of CIMT (Ambrose and Barua, 2004; Hisamatsu et al., 2016; McEvoy et al., 2015). As expected, by-stander exposure to secondhand smoke (SHS) increased the CIMT, as seen in the community-based Bogalusa Heart Study in Mississippi (Chen et al., 2015b) and in a large clinical panel of type 2 diabetics (Jiang et al., 2015). Jiang et al. (2015) emphasize the need to protect diabetic patients from CS, which I argue should be generally considered in clinical trials (Chapter 5). Systemic inflammation and oxidative stress are hypothesized to mediate the atherosclerotic effects of CS (Ambrose and Barua, 2004; Siasos et al., 2014). In the definitive Multi-Ethnic Study of Atherosclerosis (MESA), blood levels of C-reactive protein (CRP), IL-6, and fibrinogen are elevated in smokers in proportion to cigarettes per day (Al Rifai et al., 2017; McEvoy et al., 2015). Former smokers sow improvement in proportion to the years of cessation (Section 5.3.3). Because CS inhibits immune defenses to infections (Section 2.4), individual inflammatory profiles can vary widely. We await assays for the vast array of blood proteins at the same resolution now available for RNA sequences by cloning technology. The available multiplex immunoassays catch but a glimpse of the multithousands of blood peptides. Genetic variants are under discussion. The ApoE4 genotype is important as a risk factor for ischemic heart disease (IHD) and elevated cholesterol (Sing and Davignon, 1985; Mahley, 2016). The ApoE gene encodes the major lipoprotein apolipoprotein E, which transports lipids in blood and brain (Box 3.1). Carriers of the ApoE4 allele, which increases the risk of cardiovascular disease (CVD), showed further risk of CS (Holmes et al., 2014). However, this metaanalysis of 10,000 CVD cases in 100,000 individuals did not show CVD risk benefits to former smokers by ApoE allele status. ApoE4 carriers may be more vulnerable to interactions with air pollution and dementia risk (Section 3.3.2). Genetic variants in CRP that are identified with differences of inflammatory response showed some impact on risk of ischemic stroke in a sample of Chinese smokers (Wu et al., 2017). Expecting many more studies! Epigenetic effects of airborne toxins are recognized in modifications of DNA methylation (DNAme). In the CHARGE Study (Cohorts for Heart and Aging Research), with 15,907 subjects, more than a thousand genes had different DNAme in white blood cells (WBCs) between smokers and nonsmokers (Joehanes et al., 2016). Hundreds of genes with smoking-enriched DNAme were associated with disease risk variants for heart, lung, inflammation, and cancer. Moreover, DNAme differences were also associated in the same individuals with altered mRNA levels. Genes of interest include AHRR (aryl hydrocarbon repressor), a tumor suppressor gene, which regulates detoxification of foreign chemicals that may also influence vulnerability to air pollution. Former

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BOX 3.1  ApoE Alleles in Brain Aging and Dementia The ApoE gene encodes the major lipoprotein apolipoprotein E, which transports lipids in blood and brain. Human populations have three protein isoforms encoded by the genes ApoE2,3,4. Their different binding affinity for blood lipids and for their receptors affects blood cholesterol levels (Sing and Davignon, 1985; Mahley, 2016). Globally, ApoE3 is the most common allele (55%–90%), followed by ApoE4 (5%–35%) and ApoE2 (<10%). Populations differ widely in allele frequencies along regional gradients: E4 ranges greater than fivefold across Western Europe and is higher in Mediterranean districts (Singh et al., 2006). Regional variations are found in all climate zones. In some populations, ApoE4 carriers have shorter life spans than E3, confirmed in several populations (Brooks-Wilson, 2013; Christensen et al., 2006). ApoE alleles also influence the risk of Alzheimer disease (AD) and cardiovascular disease: ApoE2 < ApoE3 < ApoE4, with stronger E4 associations for AD in women (Finch and Shams, 2016). ApoE4 is considered semidominant: while 50% of AD patients carry E4, 30% do not develop AD. ApoE alleles influence brain development: E4 children have thinner entorhinal cortex (Shaw et al., 2007) and other cerebral regions (Austad and Finch, 2016; Knickmeyer et al., 2014). As young adults, health ApoE4 carriers have accelerated brain atrophy (O’Dwyer et al., 2012) and abnormal cerebral metabolism (Filippini et al., 2008; Reiman et al., 2005). The greater vulnerability of ApoE women to dementia from exposure to PM2.5 (Section 3.3.2) leads me to ask: do E4 carriers have greater neurodevelopmental vulnerability to environmental pollutants? The entorhinal cortex as a seat of AD spread merits attention for developmental impact of air pollution and cigarettes.

smokers retained DNAme differences from never-smokers in a subset of these genes, including AHRR. Of particular interest are associations with TNFα and with the AhR pathway, which detoxifies the polyaromatic hydrocarbons (PAHs) found in all three smokes. Mouse models also show proatherosclerotic effects of CS. Most studies have focused on CS effects on the lung and airways, and arteries and brains have only recently been included. This apparent neglect may arise from the fact that normal inbred mice do not develop atherosclerosis or ischemic disease, even on fatty diets at the oldest ages. However, with very high levels of blood cholesterol >500 mg/dL obtained by gene-knockouts (“-ko”) that impair blood lipid transport, the ApoE-ko and LDLR-ko mice develop fatty plaques in the aortic arch. Remarkably, even a high-fat diet that drives plasma cholesterol over 1000 mg/dL does not cause cardiovascular or other ischemic diseases in ApoE-ko mice. The protocols for mouse exposure to air pollutants and tobacco are outlined in Box 3.2. ApoE-ko mice exposed to SHS for 3 months had 50% larger atheromas (Lietz et al., 2013). Three months after SHS exposure ended, their plaques had shrunk by 30%. Although still larger than atheromas of the nonexposed

Air Pollution in Diseases of Aging Chapter | 3  89

BOX 3.2  Rodent Exposure Protocols for Ambient Air Pollution (AAP) and Cigarette Smoke (CS) Ambient air Pollution l  Concentrated air particles (CAPs) are obtained from ambient traffic-related air pollution (TRAP-PM) by the Harvard University Concentrated Ambient Particle System (HUCAPS) for direct exposure of rodents (Gupta et al., 2004). HUCAPS yields CAPs fractioned by size, as used by the Rochester University group (Section 4.4; Allen et al., 2013). l  Alternatively, TRAP-PM of different size classes are collected by the Versatile Aerosol Concentrator Enrichment System (VACES) on filters, resuspended by sonication, and reaerosolized for exposure of defined time and dose. The suspension can also be assayed with cells in vitro. VACES was developed by our USC collaborator Constantinos Sioutas (Kim et al., 2001) to collect PM of specified size cumulatively and continuously for extended times, days to months. These time-averaged samples have much less variation than ambient PM, which fluctuates seasonally and diurnally, e.g., PM2.5 varies diurnally by up to twofold in Los Angeles (Hasheminassab et al., 2014). We designated this subfraction of PM0.2 as nPM (nanoparticulate material) in distinction from total PM0.2, because the process of water elution from the filter depletes the water-insoluble organic carbon (WIOC) and black carbon (Morgan et al., 2011). Batches of nPM collected 4 years ago gave the same dose responses for TNFα release by glial cells (Cheng et al., 2016). l  Orally administered TRAP is also neurotoxic (Ejaz et al., 2014; McCallister et al., 2008, Section 4.4). This route is a model for ingested TRAP, swallowed after mucociliary transport of PM from the upper respiratory tract (Section 2.7). l  Diesel exhaust particles (DEPs) collected from a diesel engine are available from the EPA and from Sigma–Aldrich. The Duke University group delivers DEPs directly to lungs in suspension by “oropharyngeal aspiration” (Bolton et al., 2013, Section 4.3). l  Wood smoke particles can be administered intra-tracheally (Danielsen et al., 2010). Cigarette Smoke l  Secondhand smoke for mouse exposure is generated by commercially available “cigarette smoking machines” or by peristaltic pumps, and yields blood cotinine levels comparable to human smokers (Moreno-Gonzalez et al., 2013). l  Standardized cigarettes and other tobacco products are available from the University of Kentucky Center for Tobacco Reference Products (CTRP). l  Cigarette tar (CS condensate) is available from Sigma–Aldrich or can be collected from CS bubbled through water.

controls, this observation importantly shows potential atheroma reversibility. Similarly, lipids in blood and the aortic wall changed in parallel to CS exposure, with increased cholesterol and phospholipids that slowly normalized after smoke exposure. The lipidomic analysis showed similarities of the ApoE-ko mouse aortic lipid content to human atheromas (Boue et al., 2012).

90  The Role of Global Air Pollution in Aging and Disease

CS also induced hepatic oxidative stress pathways involving iron (Lo Sasso et al., 2016). Notably, these studies came from the Philip Morris International Research Lab. Their findings that CS accelerates atheroma formation are in striking contrast with the tobacco industry propaganda on the benefits of smoking. One must ask, does the tobacco industry seek drugs to reduce the atherogenicity of CS?

3.2.2 Ambient Air Pollution Many ongoing studies assess the vascular disease costs of air pollution from fossil fuels. Most convincing to me is the recent report on coronary artery calcification (CAC) from the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) (Kaufman et al., 2016). This 10-year longitudinal study of middleage to elderly examined nearly 6000 individuals twice or more for CAC from six urban areas with extensive variations in PM2.5 and nitrogen oxides (NOx). During the decade 2000–10, CAC increased in all individuals, but in proportion to local PM2.5 and total NOx (Fig. 3.2). By my calculation, a PM2.5 difference of 5 μg/m3 contributed about 15% of CAC increment per year (see Fig. 3.1 legend). NOx had similar associations with CAC; the lack of association with black carbon was attributed to shorter-term data. The PM2.5 effect on CAC progression was stronger for ages above 65 years and hypertension, suggesting synergies with these two major risk factors for ischemic events. These findings generally agree with the global associations of PM2.5 with mortality (Fig. 1.4). As noted above, CAC is a major clinical risk indicator for ischemic heart disease (Budoff et al., 2013).

(A)

(B)

Air pollutant

15

(5 μg/m ) Agatston units per year

PM

20

NO (40 ppb)

NO (10 ppb)

10 5 California Illinois Minnesota Maryland New York North Carolina

0 –5

Black carbon* (0·5 μg/m )

–4

–2

0

2

4

6

Agatston units per year

8

10

12

14

16

Long-term average PM

18

20

(μg/m )

FIGURE 3.2  Coronary artery calcium (CAC) increase per year by ambient air pollution.  CAC was accelerated by 4% in proportion to levels of PM2.5 and NOX in Baltimore, Chicago, Los Angeles, NYC, St Paul, Winston–Salem; 6795 participants, 45–84 years; 62 ± 10 years. CAC measured by Agatston units per year (AU/year). With baseline average increase of 24 AU/year, a PM2.5 difference of 5 μg/m3 contributed 4 AU, or about 15% per year. (Copied with permission from Kaufman et al. (2016).)

Air Pollution in Diseases of Aging Chapter | 3  91

However, unlike CAC, CIMT did not covary with PM2.5 or NOx. This is an unexpected divergence from many studies linking CIMT to PM2.5. I am impressed by three examples. In Los Angeles County, a longitudinal study showed twofold greater rate of CIMT increase for residence within 100 m of a highway (Künzli et al., 2010). A cross-sectional analysis of four Northern Europe communities showed CIMT increase by 0.72% per 5 μg PM2.5/m3 (Perez et al., 2015). In 10 regions of China, the CIMT increased slightly faster than in Great Britain during a 10-year follow-up (Clarke et al., 2017), consistent with the higher levels of PM2.5 and cigarette smoking in China. Taken together, the evidence shows exacerbation of CIMT by AAP. Mouse models ApoE-ko or LDLR-ko on high-fat diets show definitive acceleration of atherosclerosis by particles from urban air. Three modes of PM0.2 exposure gave similar augmentation of atherogenesis: directly inhaled ambient urban air or concentrated air particles; or intratracheal diesel exhaust particles (DEPs) (Box 3.1). All three approaches consistently enlarged the aortic plaques: Beijing PM2.5 (Chen et al., 2013b; Li et al., 2013a, 2015b), Los Angeles PM0.2 (Li et al., 2013a,b), and diesel PM0.2 (Campen et al., 2010b; Miller et al., 2013). The Los Angeles and Beijing studies both showed elevations of blood IL-6 and TNFα by urban air PM. Links to the TLR4 inflammatory pathway (Section 2.3; Fig. 2.9) are shown by TLR4-ko mice, which did not have increase of blood TNFα or activation of NADPH oxidase in monocytes (p47phox) (Kampfrath et al., 2011). CD36, a scavenger receptor that mediates oxidized LDL uptake, is also involved in air pollution atherogenesis (Rao et al., 2014). After PM2.5 exposure of LDLR-ko mice, oxidized cholesterol (7-ketocholesterol) was sevenfold higher in aortic plaques and twofold higher in blood. Monocytes from PM2.5 exposed mice had twofold higher CD36. An elegant experiment defined the role of CD36 by bone marrow transplant of CD36-ko cells, which blocked atherogenic response of LDLR-ko mice to PM2.5 exposure. In cultured aortic endothelial cells, diesel exhaust PM0.2 caused oxidative stress, with threefold higher carbonyl content and the induction of heme oxygenase-1 (HO-1); the HO-1 induction was blocked by inhibitors of JNK and by N-acetyl cysteine, an antioxidant (Li R et al., 2009). The rapid induction of JNK phosphorylation within 5 min suggests its upstream role in HO-1 induction. The transcription factor NF-kB was also induced by diesel nPM obtained in a driving mode, but not from idling (Li et al., 2010). This finding shows the complexity of engine exhausts, which may differ by engine activity, as well as engine type. As a potential drug intervention, the Hsiai–Sioutas collaboration is exploring an apolipoprotein A-1 mimetic peptide, D-4F, which can attenuate hypercholesterolemia and atheromas of ApoE-ko and LDLR-ko mice (Sherman et al., 2010). ApoA-1 is a major component of the HDL, which is considered antiatherogenic. D-4F effectively attenuated the proatherogenic effects of PM0.2 (Li et al., 2013a). Moreover, D-4F blocked plasma inflammatory responses of

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TNFα and SAA, as well as attenuated the increase of oxidized metabolites of arachidonic acid, which mediate atherogenesis and reduce the atrophy of intestinal villi (Li et al., 2015). Together these studies show convergent prooxidant activities of several types of PM in AAP-accelerated atherogenesis, with roles of CD36, TLR4, and NF-kB. Together, these early studies pave the path to mechanisms shared by many organs in the body-wide impact of air pollution and CS.

3.2.3 Biomass Smoke Four million deaths per year are attributed to HAP from biomass fuels, about as many premature deaths as from outdoor air pollution (Section 1.2). Lung dysfunction has received the most attention in the disease burden of HAP, particularly respiratory infections (Gordon et al., 2014) and cancer (Bruce et al., 2015). The relative neglect of HAP for heart and vascular conditions was highlighted by Burroughs Peña and Rollins (2017). The trends expected from PM2.5 of industrialized countries are suggested in several studies. In high-altitude Peru, the CRONICAS Cohort Study compared the CIMT of middle-aged adults in households with 10-fold differences in indoor PM2.5, 250 μg/m3 versus < 25 μg/m3 (Painschab et al., 2013). The excess PM2.5 households that burned biomass (wood) had 50% more atherosclerotic plaques, 10% thicker CIMT, and higher mean systolic pressure by 9 mm Hg; cardiovascular events were not noted. In Northeastern Iran, the Golestan Cohort Study showed 1.14-fold higher risk for IHD for rural households burning high-­pollution fuels (50,045 individuals of 40–75 years; no measurements of PM2.5) (Mitter et al., 2016). More systematic studies are needed, following the MESA Air model. The lung microbiome is just now being studied in HAP-caused lung dysfunction. An exploratory study of 44 healthy adults from Malawi showed those living in homes with high versus low PM levels had several-fold more pathogenic bacteria in bronchial lavages (Streptococcus, twofold; Neisseria, fivefold) (Rylance et al., 2016). The household smoke exposure was also represented in carbon particles within bronchial alveolar macrophages. I anticipate an expanding lung biome literature because of the high mortality associated with HAP and potential interactions of cigarette smoking and HAP with the lung biome. Because wood smoke induces nitric oxide (NO%) in the airways (Stockfelt et al., 2012), one might expect robust systemic inflammatory responses. However, several lines of evidence consistently show a modest impact of wood smoke. Rural Peruvian households with elevated PM2.5 from wood smoke had slightly elevated endothelial inflammatory markers (10% higher soluble ICAM-1 and VCAM-1) (Caravedo et al., 2016), but no elevations of blood CRP or SAA (Painschab et al., 2013). Firefighter’s occupational exposure to smoke from controlled burning also shows modest responses. Those experiencing 10 “burn days” with smoke density PM2.5 of 248 ± 60 μg/m3 had modest elevations of urinary 8-oxo-dG (DNA damage marker), but no change in malondialdehyde (lipid peroxidation) (Adetona et al., 2013). All firefighters had two- to fourfold

Air Pollution in Diseases of Aging Chapter | 3  93

increases of urinary polycyclic aromatic hydrocarbons, specifically oxidized PAHs (Adetona et al., 2017), but only those with two or fewer years of firefighting had increased 8-oxo-dG. The lack of response by the more experienced may represent their adaptation to smoke toxins, as well as to emotional and physical stresses of firefighting. The chemistry of smoke from landmass fires is less known than for domestic wood smoke (Section 2.6; Table 2.5). The just published first analysis of aerial samples of wildfire smoke had high levels of oxidized organic aerosols; numerous low-molecular-weight hydrocarbons and halocarbons were assayed, but PAH was not included (Liu et al., 2017). Two well-controlled studies of smoke exposure also concluded that domestic wood smoke has limited inflammatory impact on healthy adults during shortterm exposure. In the “Viking House Study,” young Danes exposed themselves to 7 days of very continually high levels of indoor wood smoke to simulate living in a Viking house: with PM2.5 of 700–3600 μg/m3, NO2 of 140–154 μg/m3, and CO of 10.7–15.3 ppm (Jensen et al., 2014). Contrary to their expectations, these huge levels of indoor pollutants did not elevate blood IL-6 or other inflammatory markers. Moreover, WBC DNA did not show damage by the comet assay, which is sensitive to in vivo damage from silica nPM (Pfuhler et al., 2017). A more modest exposure to wood smoke did not alter blood IL-6 or fibrinogen but did decrease urinary F2-isoprostane, a marker of lipid peroxidation (two sessions of 3 h, a week apart, reaching PM2.5 of 395 μg/m3) (Stockfelt et al., 2012). No lung distress or persistent coughing was reported in either study. Their lack of blood inflammatory responses to heavy indoor smoke may be telling us that healthy young adults cannot be compared with the impoverished in developing countries who also suffer from chronic respiratory infections and marginal diets. Animal experimental studies of wood smoke also show modest responses. An extensive multipollutant study at the Lovelace Research Institute in Albuquerque NM (NERC) compared responses of rodents to hardwood smoke (WS), diesel engine (DE), and gasoline engine (GE) exhaust, and a mixture that modeled downwind coal combustion emissions (CE) (Mauderly et al., 2014). Inbred rats and mice of both sexes were exposed to PM at levels over a wide range with overlap at lower levels of PM/m3. The effects were also modest. After exposure for 6 months, animals appeared healthy, with no loss of body weight or gross pathology at necropsy. Lower production of oxidants by lung macrophages was among the few responses shared by these different “smokes.” Wood smoke stimulated the largest lung cell change in reduced glutathione (GSSG), while only diesel PM inhibited bacterial clearance. In ApoE-ko mice, arterial markers of remodeling (HO-1, MMP-9, TBARS) responded more weakly to 7 or 50 days of exposure to wood smoke than to diesel exhaust, both at 320 μg/m3 (Campen et al., 2010a; Seilkop et al., 2012). Similarly, another group showed that DEPs caused more oxidative damage to rat lung and liver DNA than wood smoke particles (Danielsen et al., 2010). Again, these findings

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BOX 3.3  The Tsimane, a Preindustrial Life History Led by anthropologists Hillard Kaplan and Michael Gurven, the Tsimane Health and Life History Project has studied the Tsimane Amerindians of lowland Bolivia since 2002. These 16,000 indigenous farmer-foragers live under preindustrial conditions with chronic loads of parasites: protozoan and nematode parasites are detected in >75% of adults at any time, with an average of 1.6 species (Vasunilashorn et al., 2010; Martin et al., 2013). Malaria and HIV are absent, but tubercular lesions are nearly universal (lung CT images, Kaplan et al., 2017). Because of limited access to modern medicine and unhygienic living practices, people of all ages suffer frequent acute illnesses of the gastrointenstinal and respiratory tracts (Martin et al., 2013; Tanner and Rosinger, 2015; Kaplan et al., 2017). Blood cells reflect these pathogens: in a 2009 sample of 400 adults, the total white blood cell (WBC) count averaged 10,400, threefold over clinical norms for the United States; eosinophils were 20% of total WBC versus <5% for the United States (Vasunilashorn et al., 2010). Blood cholesterol is very low by US standards: total cholesterol, 3.9 ± 0.8; LDL-C, 2.4 ± 0.7; and HDL-C, 1.0 ± 0.7 (nmol/L). Their body mass index averages 24 ± 3.5 and obesity is rare (Kaplan et al., 2017). Blood pressure remains low throughout life (Fig. 3.3B). A pilot genetic survey did not show unusual distributions of ApoE4, or of SNP variants of CRP and IL-6 (Vasunilashorn et al., 2011). Detailed genetic data are forthcoming. The anthropology team includes regular Bolivian physicians for yearly medical checkups and emergency treatment. They also arrange transport and entry to regional hospitals and help Tsimane navigate the Bolivian medical system. Because of improving health, their life expectancy at birth has increased from 45 years in mid-20th century to 53 years since 1990 (Gurven et al., 2007); about 40% died before 60 years. These demographics are close to preindustrial Sweden, where most mortality was also caused by infections (Finch and Crimmins, 2004; Gurven et al., 2007; also Fig 5.10A). With the continual heat and humidity, most homes are not enclosed, and indoor smoke was not prominent during my 2-day visit in July 2014. Tsimane are occasionally exposed to fossil fuel exhaust from few outboard motors on dugout canoes and from visits to the nearest town of San Borja, which has dense motor traffic. Cigarette smoking is limited and secondhand smoke is negligible. The 28% of adults who self-identified as smokers reported 10 cigarettes/month, which is equivalent to 0.5 pack-years over the life span (Kaplan et al., 2017). The Tsimane give an unusual opportunity to study effects of biomass and household air pollution smoke with minor, if any, input from the other main global airborne pollutants. Plans are under way to characterize the airborne particles and gases in Tsimane villages, fields, and households.

are consistent with the modest cell inflammatory responses to biomass smoke (Section 2.6.1). Looking further into the smoky world of the Tsimane (Box 3.3), we find a remarkable surprise that heart attacks and CVD are rare, even at advanced ages (Kaplan et al., 2017). The apparent low levels of ischemic disease in Tsimane

Air Pollution in Diseases of Aging Chapter | 3  95

seemed contrary to findings of arterial calcium by CT imaging in ancient mummies by the Horus team, led by Greg Thomas and Randy Thompson (Thompson et al., 2013). Your author, as a member of both teams, convened their collaboration on CT imaging of heart and brain. We already knew that Tsimane have remarkably low blood total cholesterol, with low LDL-C, but also low HDL-C (Fig 3.3B; Box 3.2). Because of elevated inflammatory markers and low HDL-C, current clinical thinking would anticipate extensive atherosclerosis (Ridker, 2016). We were amazed to find very low levels of coronary artery calcium (CAC) (Fig. 3.3C). By the age of 80 years, only 8% had reached CAC scores of 100 versus >50% in the United States in the MESA Study. Although CAC scores increased slowly from 40 to 80+ years of age, this progression of CAC was 25 years slower in the Tsimane than in North America (Kaplan et al., 2017)—a stark opposition to current expectations from clinical grade elevations of CRP and low HDL. We anticipate further genetic information on vascular risk genes will extend the preliminary finding that Tsimane 3:1 ratio of ApoE3: ApoE4 is within global norms (Vasunilashorn et al., 2011). While blood CRP had weak association with the presence or absence of CAC, other inflammatory markers varied inversely with CAC (IL-5, erythrocyte sedimentation rate, neutrophil count). Similarly, rural Ghanaian villagers with a high infectious load had little ischemic disease (Koopman et al., 2012). These findings on indigenous people living in preindustrial conditions diverge from the well-documented associations of CRP elevations with risk of cardiovascular disease. Their rate of brain aging, assessed by gray matter atrophy, may also be much slower (Fig. 3.3D) (Irimia et al., in prep.), discussed in Section 3.3. This evidence for negligible ischemic disease in two rural populations with high levels of infections has many important implications for clinical practice and for thinking about the vascular impact of air pollution. While elevated CRP and low HDL-C may still be useful for high-risk patients (Ridker, 2016), I suggest that we need to rethink our assumptions about inflammation in arterial degeneration and other diseases of aging. For starters, consider the difference in the physiology of pathogen-driven inflammation versus inflammation driven by sterile inflammogens, such as fossil fuel air pollutants. Pathogen-driven inflammation is metabolically costly because fever and tissue repair require glucose and nutrients, e.g., for each 1°C of fever, human basal metabolism is increased by 10%–15% (Roe and Kinney, 1965). Throughout life, a load of chronic infections burns excess blood lipids and glucose for immune defenses. The Horus team cardiologists conclude that the low LDL-C may be the main explanation for the slower atherosclerosis in Tsimane. To this, I would add that some parasites specifically consume cholesterol (reviewed in Vasunilashorn et al., 2010). For example, HDL-C varied inversely with levels of infection by three species of parasitic worms in the Shipibo, another indigenous Amazonian group (Wiedermann et al., 1991). Thus, as public hygiene and medical progress eliminated infections, our metabolism shifted to elevate blood lipids and glucose that are now recognized as proatherogenic.

96  The Role of Global Air Pollution in Aging and Disease

FIGURE 3.3  Tsimane: slow aging of heart and brain during high levels of blood inflammatory markers and low blood cholesterol.  (A) Plasma C-reactive protein (CRP); (B) total plasma cholesterol; (C) coronary artery calcium (CAC) in Agatston units (AU); and (D) brain gray matter atrophy with aging in cerebral cortex: preliminary analysis of Tsimane 391 individual brain CT images (Andrei Irimia et al., in prep); Tsimane CT data are compared with MRI data from industrialized Countries, normal elderly controls (211 subjects, weighted average of three longitudinal studies), ADNI (Alzheimer Disease Neuroimaging Network, United States), London, and Oslo (Anderson et al., 2012; Fjell et al., 2013; Nygaard et al., 2015). Rate of gray matter decline: Tsimane, −0.15% per year (CI, 0.02%–0.29%); industrialized countries, −0.5% per year (CI, 0.49–0.51). ((A) Redrawn from Gurven et al. (2008). (B) Redrawn from Gurven et al. (2009). (C) Redrawn from Kaplan et al. (2017).)

In healthier environments, lower pathogen exposure does not eliminate chronic lung infections, which often accompany domestic smoke, CS, and elevated ambient PM2.5. Thus, even sterile inflammogens can trigger increased infections. In the near future, we hope to characterize the AAP and HAP in the Tsimane.

Air Pollution in Diseases of Aging Chapter | 3  97

3.3 THE BRAIN Lucretius, the Roman philosopher, presciently noted that charcoal smokes readily penetrated the brain “Carborundum…quam facile in cerebrum” (Section 1.5). Two millennia later, we know that inflammatory processes are accelerated by AAP and CS, from lungs to arteries to brain. There is a remarkable convergence of inflammatory processes shared by atherosclerotic plaques and the senile plaques of aging brains (Akiyama et al., 2000; Finch, 2009; McGeer et al., 2016). Each of these arterial and brain lesions slowly accumulate macrophagelike inflammatory cells with extracellular deposits of inflammatory cytokines, various amyloids, and oxidized proteins and lipids (Table 3.2). Atheromas, also known as arterial plaques, have characteristic “foam cells” that are macrophages with ingested lipids. Senile plaques of the brain also have macrophage-like cells, the microglia, that mingle among the extracellular fibrils of aggregated Aβ40 and Aβ42 peptides (these numbers give the peptide length in numbers of amino acids) (Box 3.4). Atheromas also contain the Aβ40 peptide, attributable to blood platelets, which may mediate iNOS induction in the foam cells (De Meyer et al., 2002; Kokjohn et al., 2011; Jans et al., 2006).

TABLE 3.2  Shared Inflammatory Processes in Atheromas and Brain Senile Plaques Atheroma

Senile Plaque

Macrophage (CD68)

+++ (foam cells)

++ (microglia)

T-helper cells (Th-1)

++

0

Mast cells (CD117)

++

++

Amyloid β-peptide (Aβ) of 40–42 amino acids

+ Aβ40 (platelet)

+++ Aβ40, 42

Serum amyloid P

++

++

C-reactive protein

++

+

Complement: C3, C5b-9, clusterin (apoJ)

+

+

Cytokines: IL-1, IL-6, TNFα

++

++

Cells

Proteins

My lab was among several in the early days of molecular AD research that unexpectedly found increased mRNA of innate immune inflammatory genes in AD. We provided the first evidence that neurons synthesize several complement proteins that also occur in atherosclerotic plaques (Johnson et al., 1992; Pasinetti et al., 1992; Finch, 2007b). We also discovered that clusterin (ApoJ) altered Aβ aggregation to form the toxic Aβ oligomers, which have become a major therapeutic target (Oda et al., 1995; Klein et al., 2001). Updated from Finch (2005): mast cells (Harcha et al., 2015; Maslinska et al., 2007); clusterin in arteries Aragonès et al. (2016).

BOX 3.4  The Amyloid β Peptide All vertebrates produce a version of the Aβ peptide recognized as an early link in the causal chain of Alzheimer disease (AD) neurodegeneration. The Aβ peptide of 42 amino acids has the same sequence in most vertebrate species, humans to fish. Even senescent Pacific salmon develop brain amyloid deposits (Maldonado et al., 2002), while aging lab rodents do not (Sullivan et al., 2008; Finch and Shams, 2016). The rodent Aβ peptide differs from most others in three amino acids (R5G, H13R, Y19P) that lower its toxicity and aggregation into amyloid fibrils (De Strooper et al., 1995; Boyd-Kimball et al., 2005). In rodents and humans, Aβ peptides are made by the same enzymes that cleave the amyloid precursor protein, sAPPβ (Fig. 3.6). The sAPPα and sAPPβ of rodents and humans have roles in normal synapse functions and plasticity (Hick et al., 2015; Weyer et al., 2014). Rodents are nature’s gift to experimenters: not only that they do not develop amyloid plaques during aging unless given human transgenes, but they also lack atherosclerosis (Finch and Shams, 2016). The slow loss of synapses and gradual increase of glial inflammatory activity in aging lab rodents (Teter and Finch, 2004; Finch, 2009) reveals a basic pattern of brain aging that is independent of the amyloid deposits and cerebrovascular disease that are normative in human aging. We have no idea why rodents evolved a different Aβ peptide sequence. Surprising to many neurobiologists, Aβ has antibiotic activities (Soscia et al., 2010). The formation of Aβ protofibrils may entrap microbial pathogens (Kumar et al., 2016). This positive activity gives a reason for its evolutionary persistence across 500 million years of vertebrate evolution as an example of antagonistic pleiotropy, in which a gene product may be advantageous in earlier life history stages but adverse at later ages when older individuals contribute less to reproductive success. Amyloid production is another critical redox-sensitive brain response observed in brains of Alzheimer transgenic mice in response to both urban AirPoll and CS (Section 3.3). The mechanisms include altered enzymatic cleavage of the amyloid precursor protein (APP), with increased APPβ from which the Aβ is derived (Cacciottolo et al., 2017). Even in wild-type mice with the endogenous APP gene, chronic nanoparticulate matter (nPM) exposure increased levels of the sAPPβ. As discussed in Section 2.3, short-term exposure of mice to nickel nanoparticles increased brain Aβ peptides (Kim et al., 2012), possibly relevant to a role of metals in AD (Bondy 2010; Bush and Tanzi, 2002; Roberts et al., 2012. We further defined these amyloidogenic mechanisms at the cell level. In cell cultures of neurons carrying familial AD genes, traffic-derived PM0.2 increased Aβ with dose effects (Cacciottolo et al., 2017). The Aβ increase by nPM was blocked by the N-acetyl cysteine, a reactive oxygen species inhibitor and antioxidant, consistent with nPM-induced oxidative stress in mice (Cacciottolo et al., in prep). Moreover, the cell outer membranes where APP is processed enzymatically to the Aβ peptide are altered by cell exposure to nPM with “lipid raft reorganization.” Similarly, silica nPM induced Aβ production in association with oxidative stress in cultured neurons (N2a cells) (Yang et al., 2014). Lipid raft changes are also induced by silica nPM in blood macrophages (Premasekharan et al., 2011). The activities of APP extend beyond the brain. Adipose cells make APP and release the Aβ peptide into the venous blood (Lee et al., 2008, 2009). APP expression increases with obesity in correlation with glucose dysregulation. A role of metabolic dysregulation in Alzheimer’s and accelerated brain aging is joined by other systemic inflammatory influences (Verdile et al., 2015; Willette et al., 2015). So much to discover!

Air Pollution in Diseases of Aging Chapter | 3  99

Table 3.2 also shows mast cells, found in atheromas and in senile plaques of humans and rodent models. Besides key roles in allergic reactions, mast cells mediate the infiltration of blood monocytes into atheromas (Smith et al., 2012). Although we lack data on brain mast cell responses to AAP or smoking, the lung’s mast cells are activated by CS (Li H et al., 2015), diesel exhaust (Ghio et al., 2012), and wood smoke (Muala et al., 2015). Mast cells may prove broadly important for aging interactions with the three smokes. Although AD is a neuron-centered disease, AD is deeply associated with cerebrovascular aging (Finch and Shams, 2016; Montagne et al., 2015). Moreover, hypertension, obesity, and other CVD risk factors also predict AD. For coronary artery calcium (CAC), and for all ApoE genotypes, incident dementia risk was increased by 25% per standard deviation increase in the CAC score (Fujiyoshi et al., 2017; Lu, 2017). These and many other findings show association between subclinical cardiovascular disease and incident dementia. Meanwhile, strong epidemiological and experimental evidence links AD risk to both cigarette smoking and urban air pollution.

3.3.1 Cigarette Smoke More than 10% of AD cases are attributable to direct effects of cigarette smoking, more specifically in the United States 11% and worldwide 14% (Barnes and Yaffe, 2011). There is broad consensus that CS promotes neurodegeneration as well as cerebrovascular damage (Durazzo et al., 2014). Not surprisingly, some tobacco industry–supported researchers still argue that smoking benefits AD (Cataldo et al., 2010). The continued decline of smoking in the United States and other high-income countries could be among the contributors to the recent declines in age-specific risk of AD (Langa et al., 2017). For example, in the US Health and Retirement Survey (HRS), dementia prevalence decreased by 25% from 2000 to 2012. SHS interactions with dementia–atherosclerosis were also shown in the Cardiovascular Health Cognition Study (Barnes and Yaffe, 2011). This careful analysis examined 1000 lifetime nonsmokers from four communities, enrolled at the age of 65 years or older from 1989. Dementia was threefold higher for those with >25% carotid stenosis and >25 years of SHS exposure versus <15 years SHS and <25% stenosis. The dementias included Alzheimer (64%), vascular (28%), and mixed dementia (7%). The interactions of CS and AAP for CIMT and cardiovascular disease suggest convergent effects for dementias. A Chinese study strongly associated SHS with dementia across five provinces that included urban and rural population samples (Chen et al., 2013a,b). Postmortem studies also show the neurotoxicity of smoking. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) showed more amyloid and atrophy in smokers (Durazzo et al., 2014). Moreover, ApoE4 increased brain amyloid deposits of smokers (Durazzo et al., 2016) (Table 3.3). While ApoE4 is considered the major genetic risk factor for AD (Box 3.4), its further aggravation

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TABLE 3.3  Cigarette Smoke, ApoE4, and Brain Amyloid in Normal Elderly Amyloid +, Non-ApoE4 (%) Nonsmoker Smoker

Amyloid +, ApoE4 (%)

0

85

13

94

ADNI: 261 Ss; averages of all groups: age, 75 years, MMSE, 28. Amyloid in cerebral cortex by florbetapir PET, scored as present or absent (+or −) (Durazzo et al., 2016). Women had excess amyloid, consistent with their greater AD risk.

by smoking is the first gene–environment (G×E) interaction shown for AD. Because ApoE4 also causes cortical thinning during prenatal and postnatal development (Box 3.2), we must consider potential G×E effects from maternal smoking and air pollution, inside and out (Chapter 4). Looking in more detail by MRI, another ADNI study showed dose dependence of thinning of four cortical regions in proportion to pack-years of smoking (Cho et al., 2016). The symmetric thinning of different cerebral cortex subregions is important because it suggests a minimal contribution from strokes, which are typically on one side. White matter damage in “healthy” smokers was also shown by MRI in two independent studies (Paul et al., 2008; Zhang et al., 2011). Consistent with cortical atrophy, middle-aged smokers had 23%–33% lower cerebral blood perfusion than nonsmokers in frontal cortex subregions, also proportionate to lifetime pack-years (Durazzo et al., 2015) and worse cognitive performance independent of ApoE alleles (Durazzo et al., 2016). At two decades younger than the ADNI patients, middle-aged men from the Vietnam Era Twin Study of Aging (VETSA) had modest atrophy of cortical and subcortical regions in proportion to pack-years (Prom-Wormley et al., 2016). In a smaller sample of middle-aged men and women, the smokers had greater white matter changes (fractional anisotropy) (Paul et al., 2008). Smokers’ brains are not healthy! A broader picture is sketched in Fig. 3.4. I suggest that CS interacts with basic inflammatory processes of brain aging by accelerating cortical synapse loss, which is well defined in normal populations by the age of 40 years in parallel to the slowing of cognitive speed (Fig. 3.4A). Concurrently during healthy middle age, brain levels of the amyloid peptide (Aβ40-42) begin to increase, followed by increased aggregates of Aβ (Fig. 3.4B). I anticipate that CS, direct or passive, will synergize with airborne particulate matter from fossil fuels and biomass of AAP and HAP to accelerate cognitive decline of normal aging and increase AD risk. In rodent models discussed below, particles from CS and air pollution stimulate Aβ peptide production. Arterial aging warrants inclusion because it is accelerated by air pollution and CS. Fig. 3.4 sketches this cross-talk and potential synergies with more than additive effect. Because cerebrovascular degeneration can cause dementia

Air Pollution in Diseases of Aging Chapter | 3  101

FIGURE 3.4  Brain aging and Alzheimer disease (AD) (CEF, original figure).  (A) Decline of synapse density during normative human brain aging, from maturity into old age (Finch, 2009). The synapse loss trend of 0.5%–1% per year is based on postmortem data from my lab in human striatum by Severson et al., (1982) and extended to cerebral cortex by Masliah et al., (1993). The speed of cognitive processing also declines by 0.5%–1.0% per year after the age of 30 years (McArdle et al., 2002; McArdle, 2009; Park et al., 2002). The AD trajectory is shown as accelerated decline. The downward thick arrow represents accelerated decline and increased AD risk from ambient air pollution (AAP) and cigarette smoke (CS, direct and passive). (B) The onset of molecular pathology is detected in the cognitively normal during middle age. This schema represents data from two studies. Postmortem analysis of 20 brains for temporal cortex sAβ (soluble Aβ42, formic acid extract) indicated an exponential increase, 30–70 years (Fukumoto et al., 2004). A PET study of 980 individuals from the Mayo Clinic showed approximately parallel curves for increasing fAβ (fibrillar amyloid) and NFTs (neurofibrillary tangles, 50–89 years) (Jack et al., 2014). These curves approximate the findings from each report; the formic acid extract of postmortem brains probably includes some fAβ.

independent of “pure” AD (Finch and Shams, 2016), I use “dementia” to represent aggregate effects. SHS is included as a likely contributor to dementia, by accelerating arterial degeneration and/or amyloid deposition. Besides cerebral ischemic events, vascular pathology of aging includes blood–brain barrier leakage, which begins in healthy middle age (Montagne et al., 2015), and small vessel disease, which is associated with cerebral microhemorrhages (“microbleeds”), which both have ApoE4 bias (Finch and Shams, 2016). Rodent models confirm these associations of CS and AD, suggesting mechanisms shared with CS and AAP. Wild-type rodents do not develop age-related amyloid deposits because of amino acid differences from human Aβ (Box 3.3). Because aging wild-type rodents also are free of ischemic arterial disease as noted earlier, they allow us to study the impact of air pollutants without vascular complications. The enzyme pathways for processing the amyloid precursor protein (APP) are shared in humans and rodents (Fig. 3.6; Box 3.4).

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FIGURE 3.5  Potential interactions of air pollution and cigarette smoke in vascular disease and dementia (CEF, original figure).

FIGURE 3.6  Amyloid precursor protein (APP) and its processing to Aβ peptides.

Cigarette smoke (CS), secondhand smoke (SHS), and ambient air pollution (AAP) accelerate vascular disease, while AAP and CS accelerate risks of dementia. Because cerebrovascular degeneration can cause dementia independent of “pure” AD, the term dementia can represent their aggregate effects. SHS is included as a likely contributor to dementia. The Aβ peptides of rodents and humans are produced within cells by the same enzymes in both species. The initial APP peptide of 770 amino acids is cleaved by enzyme complexes (“secretases”) that determine two pathways of its metabolism, one of which produces the neurotoxic Aβ peptide: The α-secretase pathway yields the sAPPα peptide, which is a normal synapse protein in rodents and humans (Box 3.4). The β-secretase pathway yields sAPPβ and the C99 peptide, then it is cleaved by γ-secretase to Aβ. The increased ratio of sAPPβ to sAPPα (sAPPβ:α) (Fig. 3.9C) indicates increased Aβ production. Transgenic mice carrying familial AD mutations (APP/PS1) were exposed to CS for 4 weeks at two concentrations that model direct inhalation (“high dose”) and SHS (“low dose”) (Moreno-Gonzalez et al., 2013). The high dose of CS increased brain amyloid by 50% (total amyloid and the numbers of plaques) with increased tau-phosphorylation, an indicator of neurofibrillary degeneration. The low dose of CS caused intermediate responses. CS exposure increased glial inflammatory changes with reactive glia (microglial Iba1, astrocyte glial fibrillary acidic protein [GFAP]) paralleling the increase of brain amyloid. Rats (wild type) exposed to CS also showed twofold increases of increased sAPPβ and tau-phosphorylation (Ho et al., 2012). These proamyloidogenic effects of CS anticipate similar impact of urban air pollution in mice, described below.

Air Pollution in Diseases of Aging Chapter | 3  103

During aging and AD, the white matter (myelinated) pathways that mediate high-speed transmission between brain regions are also damaged, synergizing with circuit dysfunctions from loss of neurons. Consistent with white matter damage in human smokers, wild-type mice (A/J) showed extensive damage to myelin from 2 months of exposure to CS, with increased 4-HNE and carbonyl content, with loss of myelin phospholipids and sphingolipids (sulfatides) (Nunez et al., 2016; Yu et al., 2016). These biochemical changes were accompanied by altered expression of myelin genes: decreased mRNA for myelin basic protein (MBP) and possible compensatory increased mRNA for the “oligodendrocyte transcription factor 1” (Oligo1) (Yu et al., 2016). CS exposure also decreased phosphorylation of IGF-1R and IRS-1 of the insulin-like growth factor (IGF) signaling (Deochand et al., 2016). I anticipate that these brain changes interact with systemic effects of CS, as indicated below for AAP. The chemical components of CS are being studied for neurotoxic effects. The nicotine-specific nitrosamine ketone (NNK) (Section 2.4) caused 35% shrinkage of myelinated fibers in the frontal lobes of rats within 8 weeks (PappPeka et al., 2016). Because NNK is a powerful carcinogen, NNK and other nicotine-derived carcinogens may be neurotoxic, directly or indirectly. Nicotine itself increased APP protein by 40% in cultured neurons (SH-SY5Y cells); this robust response was shown as mediated by nicotinic cholinergic receptors (blocked by mecamylamine, an antagonist of nAch receptors). Similarly, nicotine given orally to wild-type C57BL/6 mice induced APP mRNA by 30% in the hippocampus (Gutala et al., 2006), a brain region vulnerable to AD. In contrast to these findings are neuroprotective benefits of nicotine. Oral nicotine decreased amyloid deposits in AD transgenic mice (Hellstrom-Lindahl et al., 2004), while α-bungarotoxin (cholinergic α7 receptor antagonist) blocked Aβ neurotoxicity in cultured neurons (Jin et al., 2015). Both nicotinic and muscarinic ACh drugs are used in AD cognitive treatment, with modest benefits to some patients, but without arresting or reversing the underlying neurodegeneration (Lombardo and Maskos, 2015). The larger conclusion remains clear: CS increases AD risk.

3.3.2 Ambient Air Pollution Lilian Calderón-Garcidueñas has shown potential associations of air pollution with accelerated brain aging and neurodegeneration in numerous reports from Mexico City, where PM2.5 often exceeds 150 μg/m3 (Calderón-Garcidueñas et al., 2008, 2012, 2016). Based on postmortem studies, brains of cognitive normal young to middle-aged adults had hyperphosphorylated tau and diffuse amyloid deposits with greater prevalence in Mexico City than less polluted cities. Recent epidemiological evidence extends these neurodegenerative associations of small samples. In studies from Los Angeles, the Mexican “Sister City,” my USC colleagues identified cognitive deficits of healthy older men and women with specific

104  The Role of Global Air Pollution in Aging and Disease

pollutant associations adjusted for age (Gatto et al., 2014). Verbal learning decreased in proportion to elevated PM2.5 above EPA standards, by 30% excess; NO2 >20 ppb with deficits of logical memory; ozone >49 ppb, with deficits of executive function. These 5698 Ss were screened to exclude cardiovascular disease, diabetes, and hypertension. Cognitive impairments for ozone and PM2.5 were confirmed in two US-wide studies. The National Health and Nutrition Surveys (NHANES) showed 4 years greater loss per 10 ppb increase in ozone (3.5 years for symbol–digit substitution test [SDST]; 5.3 years for serial–digit learning test [SDLT]) (Chen and Schwartz, 2009). The Health Retirement Study (HRS) showed residence in elevated PM2.5 zones accelerated cognitive decline by 1.7–2.8 years (Ailshire and Crimmins, 2014). Current smokers had worse cognition at relatively lower PM2.5. In these community-based studies, 30%–50% resided above EPA standards. No clear sex differences were reported. Besides accelerating cognitive aging, dementia risk is definitively increased by AAP (Table 3.4). This summary is based on the excellent review of Killin et al. (2016) and on two large community-based studies of dementia, which were published within a few weeks of each other in winter 2017 (Chen et al., 2017; Cacciottolo et al., 2017). The “dementia” category of these studies represents cerebrovascular and other dementias, but the majority of cases are AD. The most comprehensive population-based study of dementia and trafficrelated air pollution (TRAP) is from Canada, representing all adult residents

TABLE 3.4  Environmental Factors in Dementia Review of Killin et al. (2016)

Main Citations

Ozone

Medium

Killin et al. (2016), Jung et al. (2015), Wu et al. (2015)

Nitrogen oxides

Strong

Killin et al. (2016), Chang et al. (2014), Oudin et al. (2016)

PM2.5

Strong

Killin et al. (2016), Cacciottolo et al. (2017), Chen et al. (2017)

Diesel exhaust

No

Killin et al. (2016)

Pesticides

Mixed

Killin et al. (2016)

Aluminum

Mixed, PAQUID strong

Killin et al. (2016), Rondeau et al. (2009)

Trace Cu, Fe Mb, Ni, U, Zn

Mixed

Killin et al. (2016)

The possible associations of pesticides and metals with dementia require further confirmation.

Air Pollution in Diseases of Aging Chapter | 3  105

of the province of Ontario, totaling 6.5 million by Hong Chen of Chen et al. (2017). Please note that this Chen is different from Jiu-Chiuan Chen of Chen and Schwartz (2009), which was the first epidemiological study to show neurobehavioral deficits from AAP. JC Chen is also senior author with me in Cacciottolo et al. (2017). The TRAP-associated dementia showed a steep gradient by proximity to a major roadway (Fig. 3.5). As discussed in Section 2.1, TRAP includes particles generated from petroleum combustion, as well as from particles from brake and tire wear, and local industries. The PM2.5 includes the ultrafine PM0.2u, which are typically more reactive than PM10-0.2u. Both PM2.5u and NO2 had positive associations with incident dementia. The population attributable fraction (PAF) of dementia was 7%–11%. In contrast to dementia, the incidence of multiple sclerosis or Parkinson disease was not associated with TRAP. This study is the first to evaluate these three major degenerative conditions for association with TRAP with notable specificity for dementia (Fig. 3.7). Dementia in US women of the WHIMS cohort also showed strong associations with PM2.5 (Cacciottolo et al., 2017). The senior author Jiu-Chiuan Chen designed and carried out the analysis of WHIMS cognitive data, which was published together with experimental data from my lab. The WHIMS cohort (Womens Health Initiative Memory Study; a subgroup of the WHI) is a long-term study of hormone treatments that may reduce risks of dementia. Women were reassessed at least twice for cognition during 8 years or more of follow-up. Their exposure to excess air pollution was based on residential location. According to EPA guidelines for PM2.5 of >12 μg/m3, about 30% of

FIGURE 3.7  Dementia risk and residence near roadways with heavy traffic. Risk of dementia by distance of individual residences from roadways with heavy automotive traffic in the province of Ontario, Canada. Two cohorts were analyzed: ages 20–50 years, for multiple sclerosis (4.4 million) and ages 55–85 years for dementia and Parkinson disease; combined total of 6.5 million. Adjusted for smoking, physical activity, body mass index, and education; baseline age, 66.8 ± 8.2 years (range 20–85 at entry in 2010). About 50% resided within 200 m of a busy roadway. (Redrawn from Chen et al. (2017).)

106  The Role of Global Air Pollution in Aging and Disease

(B) Hazard ratio (95% Cl)

Hazard ratio (95% Cl)

(A) 3

2

1

0

15 cognitive decline all cause dementia 10

5

0 all APOE

e3/e3

e3/e4

e4/e4

FIGURE 3.8  Risk of dementia and accelerated cognitive decline in WHIMS cohort.  Longitudinal assessment in the Womens Health Initiative Memory Study (WHIMS); 4504 women from 48 states who were initially cognitively normal at the age of 65–79 years. The PM2.5 was based on data from U.S. EPA Air Quality System (AQS) to calculate a 3-year moving average PM2.5 up through 2010. (A) Main effect. (B) Stratified by ApoE alleles. (Regraphed from Cacciottolo et al. (2017).)

the WHIMS cohort was exposed to high PM2.5. The main effects increased the risk of all-cause dementia by 92% and of accelerated cognitive declines by 81% (Fig. 3.8A). For all US women, this risk is equivalent to about 20% of Alzheimer cases (calculated as the “population attributable fraction”). Possible hormone–PM2.5 interactions, or the role of CS have not been studied. These findings with longitudinal follow-up are more powerful than crosssectional dementia associations that did not have baseline data on cognition (Table 3.4). MRI studies of WHIMS show deficits of gray matter (neurons and synaptic fields) and white matter (myelinated pathways) from PM2.5 excess that are equivalent to 1–2 years of accelerated aging (Chen et al., 2015a; Casanova et al., 2016). Ongoing imaging studies may define longitudinal trends. Most recently, the ApoE4 carriers in the WHIMS cohort had higher risks of accelerated cognitive aging and dementia, up to threefold above non-E4 carriers (Fig. 3.8B). The non-E4 carriers were mostly ApoE3, which is the majority allele in all human populations (Box 3.1). This is the first documentation that ApoE4, the major risk factor for AD, interacts with AAP in adults as a risk factor for both accelerated cognitive aging and dementia. Nonetheless, ApoE3 carriers have increased risk of accelerated cognitive decline and dementia risk during aging with elevated PM2.5. These findings confirm other indications of ApoE4 associations with pollution. In a cross-sectional study of older German women, ApoE4 carriers had greater deficits in figure copying accuracy, a measure of constructional praxis, in association with PM2.5, but not with NOx (Schikowski et al., 2015). The accelerated neurodegeneration in ApoE4 carriers (Box 3.1) anticipates that longitudinal imaging studies will show air pollution accelerated loss of brain gray and white matter. Postmortem brains from Mexico City indicate greater accumulations of diffuse amyloid in ApoE4 carriers (Calderón-Garcidueñas et al., 2012). However, this study of children and adolescents did not include

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ApoE4 carriers from a less polluted city. Diffuse amyloid deposits would be unlikely at these young ages from less polluted cities. Is cognitive aging much faster in many cities where PM is >100 μg/m3? Indoor air pollution is being studied by the Mexican Health and Aging Study (MHAS). Wood or coal is used in about 16% of homes nationwide, with more than 50% use in rural indigenous areas. Older adults exposed to these fuels had lower cognitive scores for attention, immediate recall, orientation, and verbal fluency (Saenz et al., 2017). While high PM2.5 and accelerated cognitive decline show consistent associations in large samples, US neighborhoods show marked differences in sensitivity to PM2.5 (Fig 1.3) (Ailshire et al., 2017). Underlying factors may include household CS and exposure to air pollution during commuting and in the workplace. Rodents exposed to TRAP also show increased Aβ peptide production and fibrillary amyloid deposition as a mechanism in the AAP–dementia associations. Our model was mice carrying human familial dominant AD transgenes (FAD) and human ApoE alleles (E3FAD and E4FAD genotype); females were used to model the WHIMS cohort. Exposure to PM0.2 from TRAP increased brain fibrillar amyloid and Aβ oligomers (Cacciottolo et al., 2017) (Fig. 3.9A). The increases of fibrillary amyloid were greater in E4FAD mice than E3FAD mice, consistent with the ApoE4 excess in WHIMS. These findings extend the initial report of Michele Block (Levesque et al., 2011) that exposure of male wild-type rats (F344) to diesel exhaust increased the brain levels of soluble Aβ, in proportion to PM density. As noted in Box 3.4, wild-type rodents do not develop deposits of amyloid fibrils during aging.

FIGURE 3.9  Air pollution PM0.2 stimulates brain Aβ amyloid production.  (A) Mice transgenic for human ApoE and familial Alzheimer genes (EFAD) were exposed to 11 weeks of PM0.2 from traffic-related air pollution (Box 3.1). In female E4FAD cerebral cortex, deposits of fibrillar amyloid (Thioflavin S histochemistry) and levels of Aβ oligomers were elevated (Box 3.4). (B) Mouse neuronal N2a cells carrying the human AD gene APPswe were exposed to 5 μg/mL PM0.2 for 24 h in culture. The increased ratio of sAPPα to sAPPβ (sAPPα:β) paralleled the increase of Aβ42 (see Fig. 3.6). (Redrawn from Cacciottolo et al. (2017).)

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To further explore mechanisms, we developed a cell culture model. The N2a undifferentiated neurons respond to low levels of PM0.2 with increased proamyloidogenic APP processing, which yielded more sAPPβ and Aβ42 peptide (Fig. 3.9B). The APP processing takes place on specialized membrane domains (“lipid rafts”) that are disrupted by PM0.2 (Box 3.5). Many of these responses are also induced in cultured glia by suspended ultrafine PM (Woodward et al., 2017b; Davis et al., 2013; Morgan et al., 2011) (Section 2.5; Fig. 2.9). The shared pathways with LPS (endotoxin) include TLR4, a major defense system to microbial infections. Because the Aβ peptide has antimicrobial activity (Box 3.4), its induction by air pollution may be considered as a basic immune system response. The part of immunity activated by air pollution is the “innate immune system,” an evolutionarily ancient “911” emergency response to invading infections. Moreover, many of the TRAP-induced brain inflammatory responses arise during normal aging in lab rodents without specific exposure to air pollution (Finch, 2009). Normal human cerebral cortex also shows progressive age-related astrocyte hypertrophy (increased astrocyte cell size) (Hansen et al., 1987). This marker of astrocyte activation increased smoothly (linearly) from age 25 to 98 years and was concurrent with a progressive decline of synapse numbers (Masliah et al., 1993). While these 25 specimens were carefully screened to BOX 3.5  Ultrafine Particulate Matter (PM0.2) and Disease Associations Most epidemiological studies have only considered PM2.5, because data for ultrafine PM (PM0.2) were insufficient. The first large-scale analysis of both ultrafine PM and PM2.5 for source apportionment was based on the California Teachers Study. This multiethnic cohort of 100,000 of older women (57 ± 4 years) has been followed since 1995 and continues to yield major environmental findings on cancer risks. Most recently, eight sites across California tested for mortality associated with PM2.5 and PM0.2 mass and composition of 50 airborne components, at 4-km resolution during 2001–07 (Ostro et al., 2015). This innovative study assessed both PM2.5 and PM0.2, the sources of primary particles, tobacco smoke exposure, and medications for vascular conditions. For PM2.5, mortality from ischemic heart disease (IHD) was associated with hazard ratio (HR) increments of 10 μg PM2.5/m3: nitrate (HR  =  1.28), anthropogenic secondary organic aerosols (“SOA_ant”) (HR = 1.23), and PM2.5 mass (HR = 1.18). Nitrate is associated with organic toxic compounds, particularly from diesel NOx. For PM0.2, the IHD associations were similar: SOA-ant (HR = 1.25) and PM0.2 mass (HR = 1.10). For both PM2.5 and PM0.2, Cu, Fe, and other metals had lower HR. For sources of primary particles, on- and off-road diesel and gasoline had similar HR = 1.12–1.14, while high sulfur fuels and smoke from meat cooking had HR of 1.08. Surprisingly, pulmonary disease mortality was not associated with any traffic-related air pollution component or source, despite causing nearly as many deaths as IHD (929 vs. 1085). The authors laudably noted that the high correlations of levels between the 50 components may obscure their independent toxicity.

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eliminate AD or other major neuropathology, we do not know their exposure to AAP. Because my lab, like most other academic labs, resides in an urban setting with baseline PM2.5 close to, or above, the US EPA guideline of 12.5 μg/m3, we do not know how much “normal aging” in our rodent models is due to AAP. Some role of AAP may be expected because of the strong correlations of PM2.5 with cognitive deficits in normal aging humans in the WHIMS cohort (Fig. 3.6) and in other national samples discussed above. Mouse models also show cognitive deficits. Exposure of male wild-type C57BL/6J mice for 10 months to TRAP PM2.5 caused deficits in spatial learning and loss of synapses (dendritic spines) in the CA1 region of the hippocampus (Fonken et al., 2011). Moreover, we showed that exposure to ultrafine PM from TRAP for only 10 weeks caused CA1 neuronal atrophy in wild-type and EFAD mice (Fig. 3.10B) (Cacciottolo et al., 2017). Importantly, the dentate gyrus (DG) of the hippocampus did not show neuronal atrophy in either study (Fonken et al., 2011; Cacciottolo et al., 2017). This selective CA1 neuron vulnerability to TRAP in mice nicely models human AD and stroke, wherein the CA1 neurons are more vulnerable than dentate gyrus neurons (West et al., 2004; Serrano-Pozo et al., 2011). Additional deficits in the CA1 white matter subfield (stratum radiatum) include 30% decrease

FIGURE 3.10  Air pollution–induced neuron atrophy and inflammation in mouse brain. Mice (“wild-type” C57BL/6 males) were exposed to PM0.2 for 10 weeks (black bars) versus filtered air (open bars). (A) Neurons in the hippocampus were stained by silver nitrate: CA1 and CA2/3 represent Cajal-layer neurons; DG represents dentate gyrus. (B) Neurite density of CA1 versus DG neurites without change in DG. (C) Glutamate receptors, GluR1 subtype. (D) Hippocampus TNFα protein by Western blots. (E) Hippocampus microglial density (Iba1) immunohistochemistry. (From author’s lab Cacciottolo et al. (2017) and Morgan et al. (2011).)

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of myelin basic protein and 30% increased microglial activity, a measure of inflammation (Woodward et al., 2017a). In wild-type C57BL/6J and EFAD mice, we also find decreased levels of the hippocampal GluR1 (Cacciottolo et al., 2017; Morgan et al., 2011), a glutamate receptor subunit that mediates declarative memory. Future studies with humans and animals may identify how air pollution interacts with the progression of neurodegeneration along the AD-characteristic pathways defined in postmortem brains by the eminent neuropathologist, Heiko Braak. Neurofibrillary tangles (tauopathy) appear first in the “locus coeruleus,” a tiny cluster of noradrenergic neurons in the brain stem. The tauopathy spreads forward into the frontal lobes and thence from the entorhinal cortex to the hippocampus and subcortical regions (Braak et al., 2011). These changes may include a separate “primary age-related tauopathy” (“PART”), which includes the entorhinal cortex and hippocampus, but may be distinct from AD (Duyckaerts et al., 2015). Remarkably, the cerebellum, which also receives locus coeruleus projections, has negligible neurodegeneration, even in advanced AD. Live brain imaging of humans aged 50–89 years confirms the spread of neurodegeneration into subcortical structures (Jack et al., 2014) and may be able to detect brain region targets of air pollution. Our mouse studies show broad inflammatory responses from cerebellum to forebrain (Cheng et al., 2016) that extend beyond the regional and pathway specificity of AD. A working hypothesis is that myelinated pathways are damaged by inflammatory changes from air pollution, as observed in mice (Woodward et al., 2017a), noted above, and interact with baseline AD neurodegeneration.

3.3.3 Biomass Smoke More complexities lie ahead in the tangled role of inflammation in brain aging and AD. The Tsimane are exposed to smoke from cooking fires on a daily basis. While respiratory infections are very common, aging of arteries and brains is very slow. By comparison with North America, the older Tsimane have much slower progression of CAC (Fig. 3.2C) and brain gray matter atrophy (Irimia et al., in prep.) (Fig. 3.3D). This emerging evidence suggests that their rate per year of gray matter atrophy with aging is at least 50% slower than in three MRI studies from industrialized countries. Ongoing studies of Tsimane cognition at later ages may define the extent of AD-like cognitive decline. The Tsimane’s slower brain atrophy and arterial calcification are broadly consistent with the lower risk of AD in individuals without ischemic disease or hypertension in industrialized countries (Gorelick et al., 2011; Gottesman et al., 2017). Their slow brain and arterial aging despite high systemic inflammation (Fig. 3.3A) challenges the broad hypothesis that systemic inflammation drives age-related neurodegeneration and AD. As noted above, the Tsimane have minimal exposure to fossil fuel exhaust and CS, but considerable exposure to wood smoke (Box 3.3 and book cover). Because wood smoke apparently does not

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induce major inflammatory responses, their systemic inflammation is largely driven by pathogenic infections. I propose that we must consider a basic difference between inflammation that is driven by pathogenic infections and that is driven by sterile inflammogens (sterile vs. pathogen-driven inflammation). The Tsimane have chronic pathogen-driven inflammation from their lifelong burden of parasites and tuberculosis, to which is added frequent acute infections of gut and lung. Their perpetual load of infections draws energy for fever and nutrients for tissue repair. Additionally, the Tsimane have relentless physical demands of farming and hunting under arduous jungle conditions. A measure of these metabolic costs is their low blood glucose (HbA1c) and low blood cholesterol. In contrast, residents in developed countries have minimal infections, modest physical workloads, and richer diets. The trends for elevated blood glucose and cholesterol represent our energy excess. In developed economies with low infections, systemic inflammation is driven by sterile inflammogens from air pollution, CS, and fat deposits, which harbor macrophages and release inflammatory cytokines, e.g., venous IL-6 is higher than arterial blood input in human fat depots, a difference that obesity magnifies by 10-fold or more (Madani et al., 2009). We do not know how much of the AD in industrialized countries is attributable to sterile inflammogen–driven inflammation.

3.4 INTERACTIONS OF AMBIENT AIR POLLUTION AND CIGARETTE SMOKE Up to now, most of the studies I reviewed have considered AAP and CS separately. But they interact! An instructive example is lung cancer, which the British Doctors Study allowed could also be caused by other factors besides CS (Box 1.1). Global evidence is unequivocal for nonsmokers linking lung cancer to AAP, with risk increases of 8% per 10 μg/m3 of PM2.5 (Pope et al., 2009). In 2013, the International Agency for Research on Cancer has classified outdoor air pollution as carcinogenic. Besides cigarettes, household smoke from solid fuels is associated with chronic pulmonary and cardiac mortality, globally adding 4 million additional premature deaths (WHO, 2016). Three combustion sources: AAP, CS, and household fuels were evaluated by Burnett et al. (2014) in an innovative analysis of PM2.5. The “integrative dose–response model” with exponential components was developed for IHD, cerebrovascular disease (stroke), lung cancer (LC), and chronic obstructive pulmonary disease (COPD). Two dose–response patterns for relative risk (RR) by the PM2.5 exposure emerged (Fig. 3.11A and B), a plateau versus continued linear increase. The risk of IHD (Fig. 3.11A) and stroke (not shown) reached maximum risks of 2–3 after initial linear increases; the upper range of PM2.5 μg/m3 represents CS. In contrast, the risks for LC (Fig. 3.11B) and COPD (not shown) continued to increase in the upper exposure range, with

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FIGURE 3.11  Associations of ischemic heart disease (IHD) and lung cancer with total PM2.5 exposure from air pollution, cigarette smoke, and household fuels. Relative risk (RR) for IHD (Panel A) and lung cancer (LC) (Panel B) versus exposure to total PM2.5 from ambient air pollution, cigarette smoke (primary and secondary), and household fuels (coal and biomass). Calculated from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010, representing 187 countries (Lim et al., 2012). The best-fit model curve was redrawn by CEF from Burnett et al. (2014).

lung cancer approaching 50-fold. The model gave “reasonable predictions over the range of risk” for the higher ambient PM2.5 in highly polluted Asian cities. The lower range of PM2.5 still showed positive risks below 5 μg/m3, confirming findings for Canadian cardiovascular mortality (Crouse et al., 2012) and for the recent Medicare analysis (Di et al., 2017) (Section 1.3.1) (Fig. 3.11). These calculations assume the same toxicity by weight in PM2.5 from all sources (Burnett et al., 2014; Pope et al., 2011). By their calculation, each cigarette would deliver the equivalent of the daily intake of ambient PM2.5 at 667 μg/m3. While the assumed intake of 18 m3 of air volume by an adult is reasonable, the PM2.5 density required per cigarette equivalent warrants further inquiry. Henry Forman and I suggest another calculation based on the gap between the initial nicotine content and the resulting blood levels (Box 2.7) (Forman and Finch, 2018). Based on the clearance rates (pharmacokinetics) of blood nicotine, about 10% of the nicotine per cigarette reaches the circulation (Benowitz and Jacob, 1984). We suggest that 10% also approximates the delivery of soluble cigarette toxin associated with the PM2.5. This conclusion may still be consistent with careful studies that lungs retain the majority (60%–90%) of particles inhaled by smokers (Baker and Dixon, 2006). However, few of these studies considered the solubility of potential toxins. For example, in air pollution analysis, many components are classified as water insoluble, e.g., metals and organic carbon (Saffari et al., 2013). These adjustments of delivered PM2.5 would introduce a leftward shift by about 10-fold for values above 10,000, but would not alter the main conclusion that the IHD risk reaches a plateau, while lung cancer increases linearly

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at higher levels of PM2.5 exposure. The role of ultrafine PM (PM0.2) is unclear (Box 3.5). The analysis also assumed that household biomass PM2.5 had equivalent toxicity, which may be an overestimate (Section 3.2.3). Synergies are emerging for interactions of the three smokes with combined effects on disease risks that are superadditive. While Burnett et al. (2014) reasonably assumed additive effects of PM2.5, superadditive synergies of AAP and CS in lung cancer were shown by Turner et al. (2014). Based on a cohort of 1.2 million from the Cancer Prevention Study II, smokers had 2.2-fold more mortality than expected for simple additive effects of PM2.5 and smoking. They concluded “Potential biological mechanisms for greater-than-additive effect remain unclear.” I fully agree with this gap of understanding. No experimental studies have combined CS and fossil fuels in animal and cell models for lung cancer. Children’s obesity also showed synergies of AAP with SHS in the Southern California Children’s Health Study. For ages 10–18 years, the body mass index (BMI) was higher in those exposed to SHS, with further increases for residing near heavy traffic (Fig. 3.12) (McConnell et al., 2015). The combined effect by the age of 18 years was 3 BMI units above those with low PM2.5 and with no SHS exposure. Maternal smoking during pregnancy also increased BMI at 18 years. As observed for lung cancer, the effects synergized, yielding 30% higher BMI than expected from simple additivity. Possible mechanisms include the obesogenic effects of PAHs, which inhibit catecholamine-induced lipolysis and which are present in the smokes of fossil fuels and cigarettes (Section 2.8). Synergies of PAH exposure with CS in obesity (Fig. 4.2) are discussed in the next chapter. Consistent with these findings on childhood obesity, increased insulin resistance had strong association with PM2.5 and NOx in German adolescents (Thiering et al., 2016) and adults (Wolf et al., 2016). AAP is now recognized as

FIGURE 3.12  The body mass index (BMI) of children aged years who were exposed to secondhand smoke (SHS) and near roadway air pollution (NRP). From longitudinal annual measurements of 3318 children aged 10–18 years in the Southern California Children’s Health Study. These effects showed dose responses with the number of household smokers. (Redrawn from McConnell et al. (2015).)

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an endocrine disruptor for insulin resistance (Holmes et al., 2016). Blood insulin levels increased by 14.5% per 8 μg/m3 increase in PM2.5 in a sample of 3000 (Panni et al., 2016). The effects were greater in individuals with prediabetes than in nondiabetics. These findings suggest that air pollution increases risks for type 2 diabetes mellitus, particularly in prediabetics. Will PM2.5 also synergize with CS for insulin resistance and diabetes? Lastly, I return to genetics. DNAme sites in a huge sample of lung cancers (adenocarcinomas) from Asian smokers and nonsmokers showed eight mutations (SNPs) differing by smoking status (Seow et al., 2017). Two of these were shared with Europeans. These regional differences are relevant because Asian lung cancers have more mutations in the EGFR gene (epidermal growth factor receptor). Could these DNAme mutation sites also be sensitive to AAP? A genome-wide DNAme study showed 12 methylation sites that correlated with PM2.5 exposure in samples from the Normative Aging Study (US-wide) and KORA (Augsburg Germany) (Panni et al., 2016). Two of the four genes with altered DNAme can be placed on AAP or CS response pathways: NSMAF is linked to the 55-kD tumor necrosis factor receptor, while MSGN1 regulates chemokine responses related to AhR: CCL5 (RANTES) and CXCL8 (IL-8). Ongoing human genome projects may show other environmentally sensitive gene targets for lung cancer and conditions associated with the three smokes.

3.5 CONCLUSIONS Airborne toxins from AAP and CS act as gerogens to promote many diseases of aging, from lung to arteries to brain. l  Airborne toxins from AAP and CS synergize with superadditive effects on lung cancer risk and on childhood obesity. l Biomass smoke toxicity is strongly associated with risk of lung infections, but less defined for other chronic diseases. l  Epigenetic modifications by methylation of DNA and histone proteins show some shared responses to AAP and CS with possible life-long and transgenerational influences. l

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