TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL.

121, 2010

PRESIDENTS ADDRESS: COMMON MECHANISMS OF MULTIPLE DISEASES: WHY VEGETABLES AND EXERCISE ARE GOOD FOR YOU
R. WAYNE ALEXANDER, M.D., Ph.D.
ATLANTA, GEORGIA

INTRODUCTION Lifestyle Choices as the Fundamental Platform for Health A good diet and exercise have been recognized to promote health for hundreds and perhaps thousands of years. Epidemiologic studies in the mid 1900s focused initially on cardiovascular disease. Diets high in saturated animal fats resulted in higher cardiovascular mortality rates than did diets that were based on monounsaturated fats such as olive oil, fish and a variety of fruits and vegetables. Similarly, regular exercise gave protection from cardiac events relative to those with sedentary life styles. Dietary studies with and without concomitant assessment of exercise recently revealed salutary benefits of both exercise and diet on a broad range of clinical phenotypes. These findings inferred that at some early stage(s) of many diseases, common pathophysiologic mechanisms were at work. Insights into underlying cellular mechanisms are leading to a transformation in the way we view chronic diseases. BACKGROUND Impact of Diet on Health and Disease As modern medicine and public health evolved in the 19th century, environmental causes of disease became increasingly apparent. A major focus was on infectious diseases and their enablement by unsanitary conditions, resulting from polluted and/or stagnant water, lack of sewage systems and increasing concentrations of people in developing cities. Among the major advances of the 20th century were the use of public hygienic measures, quarantine of infected patients, and ultiCorrespondence and reprint requests: R. Wayne Alexander, M.D., Ph.D., Department of Medicine, 1364 Clifton Road, Suite H-153, Atlanta, GA 30322, Tel: 404-727-1749, E-mail: ralexan@emory.edu Potential Conflicts of Interest: None disclosed.

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mately, vaccines and antibiotics, all of which improved control of infectious diseases in medically advanced societies. The cotemporaneous industrialization of western society extended to agriculture, resulting in an abundance of relatively inexpensive food. The associated increase in wealth led to increased consumption of meat from animals fattened on industrialized farms. The general increase in efficiency of food production resulted from deliberate public policy in the United States, as well as business innovation and creativity. Giant commercial agricultural operations in the United States quickly drove out of business less efficient small farmers, traditional sources of food for nearby residents. As with other industrial products, food came to be mass-produced and distributed through nationwide transportation networks. This development logically led to new methods of food processing to prolong shelf life and prevent spoilage. New kinds of chemical concoctions were developed by food chemists and engineers that provided caloric content, appealed to at least most human palates, were visually consistent with something edible and spoiled slowly (if at all). These processed food products became known, mostly derisively, as junk food or to zealots as just junk, because many are engineered to be essentially devoid of essential micronutrients. The wide availability of food of high caloric density and saturated fat content, but with low nutritional value, proved an unanticipated environmental hazard. Cardiovascular death rates began rising in the United States in the 1920s (even without the benefit of modern junk food) and continued well into the 1950s, at which point they were at record levels. Studies Linking Diet to Cardiovascular Disease: The Development of Cardiovascular Epidemiology Appreciation of the fundamental role of good food as the equivalent of medicine in maintaining health dates at least from the time of Hippocrates. The scientific study of nutrition began in earnest in the early 1900s with the chemical defining of food components and micronutrients including vitamins. Population studies from the 1940s provided insights into the role of food availability on cardiovascular death rates during the social disruption of World War II in Scandinavian countries (Sweden, Finland and Norway), in comparison with the United States, where food supply was relatively unaffected (1). Cardiovascular death rates during the war increased without interruption in the United States, almost doubling between 1925 and 1947. In contrast, the death rates in Scandinavia decreased substantially during the war years, but rebounded afterwards. Thus, decrease in avail-

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able food, and perhaps most importantly saturated animal fats, was associated with decreased risk of cardiovascular disease. The mechanisms were unknown. The dramatic increase of cardiovascular death rates in the United States and in certain western European countries by the late 1940s stimulated the development of epidemiologic studies to attempt to gain insights into causes. Two major initiatives were particularly transformative. The Framingham Heart Study (2), launched in 1948, is an ongoing cohort study in which the investigators sought to identify the then-unknown risk factors for development of cardiovascular disease (CVD). More than 5,000 men and women took part in medical examination and lifestyle interviews, which changed the face of cardiovascular research and ultimately, therapy. Specific risk factors such as smoking, high serum cholesterol levels, family history of heart disease and hypertension contributed to the overall predicted risk for an individual and led to the so-called risk factor paradigm that is a central element of contemporary preventive cardiology. In contrast to the approach of studying individuals as in Framingham, Ancel Keys and colleagues in the late 1950s launched a population-based cohort study in multiple countries with varying ecological characteristics (3). The Seven Countries Study compared cardiovascular death rates among the United States, Greece (Crete), Finland, The Netherlands, Japan, Italy and Yugoslavia in 13,000 men of ages 40 to 59 years. Coronary heart disease mortality rates, blood cholesterol levels, blood pressure, activity and smoking and dietary habits were assessed basally and at 10, 15 and 25 years (35). At 15 years, mortality rates related directly to saturated fat intake and were inversely related to monounsaturated fatty acid consumption (3). The coronary death rates varied strikingly among countries (regions). Within a region CHD death rates were driven by serum cholesterol levels, smoking and blood pressure. Crete had the lowest and Finland had the highest rates. Coronary heart disease death rates in Finns were similar to those in the United States. The diets in both countries were characteristically high in saturated animal fat. In contrast, the Cretan diet was low in animal fats and rich in monounsaturated fatty acids, such as those found in olive oil, which is the common cooking oil in the region. The Seven Countries Study famously demonstrated that coronary heart disease (CHD) mortality related directly and linearly with the initial median concentration of serum cholesterol of the subject population in the overall cohort (6). This inverse relationship between serum cholesterol and CHD mortality within a regional cohort per-

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sisted after 25 years of follow-up even after adjusting for age, smoking and blood pressure (7). Strikingly, CHD mortality rate varied approximately 3-fold among cohorts in, for example, Northern Europe and the United States in comparison to Southern Europe and Japan (Figure 1). Cholesterol levels do not explain fully these differences since the adjusted CHD mortality rate for a similar cholesterol level of about 200 mg/dL in Northern Europe is about 300 400% greater than that in Southern Europe. The role of the observed dietary variations in differences in CHD death rates in the regions of the Seven Countries Study became a rich subject of speculation and investigation. Although this or other population cohort studies do not provide mechanistic insights into disease pathogenesis, inferential conclusions were drawn. Importantly and accurately, the Cretan diet was imbued with a healthy, protective aura. It was the basis of what is generally known as the Mediterranean diet. The Mediterranean Diet The foods that are included in the Mediterranean diet vary by country, based on geography. They generally include: generous amounts of vegetables and fruits of various colors (ideally 59 servings daily); carbohydrates from whole grain sources, including breads and other cereals; potatoes, beans, nuts and seeds; modest amounts of lean meat, oily fish (for omega-3 fatty acids) and low-fat dairy foods; and a modest use of monounsaturated fats, chiefly from olive oil (3). A broad variety of protective, defensive chemicals help create synergistic effects within the diet. It is these health promoting properties that frequently accompany meals in the Mediterranean region. Subsequent analysis of the data from the Seven Countries Study showed that current smoking and intake of saturated fat and of the polyphenolic flavonoids accounted for the great majority of the between cohort difference in CHD mortality rate (8). The flavonoids are polyphenols that are found widely in plant foods and many are antioxidants as discussed subsequently. Flavonoids/polyphenols have been suggested to protect from CHD and are several-fold higher in diets in Southern Europe and Japan than in Northern Europe and the United States (8). The French appeared to be an exception to the rule that having high saturated fat content in the diet is associated with a high coronary artery disease event rate. A recent report found that deaths from ischemic coronary heart disease were lowest in France, among all European countries (9). Although mortality rates involve complex interactions among many cultural and environmental influences, dietary factors play an important role, as noted. The French have a low

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FIG. 1. Relationship of serum cholesterol at entry examination and an average of up to 3 measurements in 10 years, with CHD death risk among middle aged men in 7 countries during 40 years of follow-up. (Modified from Eur J Cardiovasc Prev Rehabil 2009;15:719 25. With permission).

coronary artery event rate, even though they enjoy a robust culinary tradition of rich food that is hardly Mediterranean and is high in saturated fat. The apparent inconsistency is known as the French

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Paradox. In fact, France is hardly a Mediterranean country. The appellation Mediterranean has been equated with a regions climate and its ability to sustain the growth of olive trees. Only a sliver of the country along the coast meets that definition. The differences, however, between the French diet and the Mediterranean diet may be more apparent than real. For example, in both France and countries more definitively identified as being Mediterranean vegetables and fruit are served commonly and frequently are grown in local gardens. Fish may be served several times a week, food generally is not highly processed, and essential protective nutrients are preserved. Drinking wine with meals is the cultural norm. Meals are leisurely events and associated with congeniality. There is no definitive explanation for the relatively low rate of cardiovascular deaths in France. The answer likely resides in the combination of elements enumerated above that are features of the traditional Mediterranean diet and/or in the fact that saturated fats in the French diet were more likely to come from natural sources such as dairy products rather than processed hydrogenated cooking fats. The Japanese historically also had a very low prevalence of coronary artery disease (10). Their diet content was low in saturated animal fats and high in multiple varieties of vegetables as well as fish. Thus, the weight of evidence informs a pivotal role in promoting cardiovascular health for dietary elements that are still incompletely defined or mechanistically understood. MEDITERRANEAN DIET AND NON-CARDIOVASCULAR DISEASES Cancer Mediterranean-style diets rich in fruits and vegetables have been associated with good health for centuries. The focus of modern epidemiology on cardiovascular disease was driven by the high prevalence rates of the first 60 years of the 20th century. The Lyon Heart Study in 1994 provided evidence in post-myocardial infarction patients that the beneficial effects of a Mediterranean diet supplemented with the plant omega-3 fatty acid and alpha-linolenic acid decreased not only cardiovascular mortality, but also cause mortality when compared with patients who also received standard therapy but were instructed in a prudent, American Heart Association Step I diet (11). These results inferred that the Mediterranean diet was favorably affecting diseases in addition to those of the cardiovascular system. A subsequent analysis provided evidence, but not firm proof, that the additional effects include prevention of cancers (12).

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Medical science and practice have had an organ- or system-based orientation for much of modern history. We may specialize in, for example, coronary heart disease or hypertension generally under the usually unarticulated presumption that the clinical phenotype of each is mechanistically unique. Common, shared mechanisms, however, have become apparent only relatively recently. To illustrate, atherosclerosis has been recognized widely as an inflammatory disease only in the past 20 years, and hypertension has been associated with immuno-inflammatory mechanisms in the past decade (13, 14). Type 2 diabetes mellitus with insulin resistance and beta cell exhaustion results from, at least in part, abdominal obesity and the systemic inflammatory state induced by infiltration of mononuclear cells into visceral fat (15). Macrophages and T-cells assume inflammatory phenotypes and secrete cytokines and chemokines that are active both locally and systemically (16). Similarly, chronic inflammation is recognized as an antecedent of malignant transformation in certain circumstances (17). Indeed, one is hard pressed to identify human diseases not obviously associated with inflammation at some stage. We are moving beyond the concept of diseases and the associated inflammation as being purely local. Coronary artery disease (CAD) is a case in point. C-reactive protein (CRP), a marker of systemic inflammation, is increased in the acute coronary syndrome (ACS) (18). ACS is associated with an active atherosclerotic lesion with exacerbation of inflammation, plaque rupture and promotion of clot formation and/or unstable angina or infarction (19). ACS is associated with multiple indicators of systemic inflammation in addition to CRP, including activation of circulating T-cells (20). Interestingly, ACS was associated with increased frequency of advanced colon malignancy when colonoscopy was performed by study protocol six weeks after the cardiac episode. The association between the presence of advanced colonic lesions and CAD was enhanced in persons with the metabolic syndrome and a history of smoking, both of which are associated with systemic inflammation (21). Inflammation and Reactive Oxygen Species Reactive oxygen species (ROS) were identified decades ago as chemically reactive oxygen-containing entities that are formed upon the gain or loss of an electron. These reactive species were formerly known as free radicals. The more general term ROS recognizes that not all oxidizing agents are free radicals, for example, hydrogen peroxide. The conventional wisdom until about 20 years ago was that ROS were generally toxic agents associated with cell death rather than being the

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normal, second messenger mediators of cell signaling that they are now recognized to be (22). One of the first demonstrations that ROS mediate normal cell signaling at all involved activation of an inflammatory mechanism. Endothelial cell vascular cell adhesion molecule-1 (VCAM-1) recruits mononuclear cells into the arterial wall in animal models of atherosclerosis (23). Antioxidants inhibited cytokine-induced expression of VCAM-1, but not other adhesion molecules, in cultured endothelial cells (24). ROS became recognized as a major mediator of signaling pathways in inflammation generally. A recent PubMed search limited to review articles in the last 3 years using the search term ROS and inflammation generated 409 hits. A prescient paper in 1997 demonstrated that multiple tissue specimens representing a broad spectrum of human diseases contained chemical footprints (carbonyl groups) of oxidative stress (25). A table in that paper informed the broad spectrum of diseases posited at the time to involve excessive generation of ROS. An updated but necessarily abridged version is shown in Table 1. ROS have been implicated in the pathogenesis of illnesses of vastly different phenotypes, such as neurodegenerative diseases, diabetes mellitus, cardiomyopathy, depression, atherosclerosis, rheumatoid arthritis and osteoporosis. Thus, multiple clinical phenotypes share common mechanisms of molecular pathogenesis.

TABLE 1 Conditions Associated with Increased Reactive Oxygen Species Aging Amyotrophic lateral sclerosis Alzheimers disease Adult respiratory distress syndrome Asthma Atherosclerosis Cancer Cataracts Congestive heart failure Cystic fibrosis Diabetes Hypertension Macular degeneration Metabolic syndrome Obesity Osteoporosis Parkinsons disease Rheumatoid arthritis Ulcerative colitis Etc.

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NADPH Oxidases: Generators of ROS and Therapeutic Targets Although there are multiple sources of ROS that are important in disease pathogenesis, the NADPH oxidases (NOXs) have been studied most widely (26). Multiple hormones, physical forces, cytokines, receptor and non-receptor tyrosine kinases, G-proteins and inflammatory chemical mediators such as advanced glycation end products and oxidized LDL, activate one or more members of the NOX family. The ubiquitous and sentinel roles of NOXs in physiology and pathophysiology are illustrated by a clinically relevant example. Both angiotensin II (AngII), acting through the AngII type 1 receptor (AT1R) and products of the HMG CoA reductase pathway involved in cholesterol synthesis impact the activity NOX in vascular cells (27). AngII activates NOX directly and isoprenoids formed in the cholesterol synthesis pathway enable its activation indirectly through lipid modification driving translocation to the cell membrane of the GTPase RAC1. RAC1 is a key component of the NOX enzyme complex that generates ROS. These mechanisms are illustrated in Figure 2. Clinically, in patients with coronary artery disease, inhibition of AngII formation by angiotensin

FIG. 2. ACE inhibitors, ARB and Statins act effectively as antioxidants to inhibit inflammatory and growth pathways. Blockade of activation of the angiotensin II Type 1 receptor (AT1R) by angiotensin converting enzyme inhibitors (ACEI) or by AT1R blockers (ARB) inhibits AngII generated reactive oxygen species (ROS) resulting from the inhibition of NOX. These anti-oxidation effects decrease local and systemic inflammation. Statins also inhibit NOX but by a different pathway. The small GTPase RAC is a critical component of the NOX complex but must be recruited to the cell membrane to complete the activation of the oxidase. The translocation to the cell membrane of RAC requires its modification by geranyl-geranyl pyrophosphate (GG-PP) that enables formation of the active NOX holoenzyme. GG-PP formation is inhibited by statins. Both statins and AngII blockers are therapeutically effective individually and synergistically in multiple disease phenotypes that share ROS-mediated inflammation as a common causal mechanism.

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converting enzyme inhibitors and inhibition of HMG CoA reductase by statins reduce additively recurrent coronary events (28). Inhibition of NOX-generated ROS through both mechanisms very likely contributes to the anti-atherosclerotic, vascular protective effects observed. Thus, a drug class developed as anti-hypertensives and a lipid-lowering drug class developed to prevent atherosclerosis both appear to have vasoprotective effects at least in part by inhibiting NOX-dependent, ROSmediated inflammation. Both classes of drugs are being tested for efficacy in multiple other disease states supporting the general principle that shared oxidative inflammatory mechanisms are involved in a broad spectrum of clinical phenotypes. These model constructs inform the general disease prevention mechanisms of healthy diets and exercise discussed subsequently. Obesity and the Metabolic Syndrome: Prototype of Oxidative Stress/ Inflammation in the Pathogenesis of Multiple Clinical Phenotypes Gerald Reaven of Stanford first called attention to the clustering of abdominal obesity, hypertension and insulin resistance associated with Type 2 diabetes (29). The debate of whether or not the metabolic syndrome is, indeed, a syndrome is ongoing but is probably an issue of semantics and of little consequence. The most important issue is that the study of the pathogenesis and clinical sequelae of abdominal obesity has contributed enormously to the understanding of the role of systemic inflammation/oxidative stress broadly in human disease (30). Abdominal obesity, which is commonly associated with excessive caloric intake, is an inflammatory disease (15). The adipocytes of the new visceral fat hypertrophy and mononuclear cells infiltrate the adipose tissue (Figure 3). The resulting inflammatory milieu stimulates neovascularization and induces NOX expression and enhanced oxidative stress from ROS production. Most importantly, visceral adiposity is associated with systemic inflammation and oxidative stress (15). (Figure 4). Secretion of protective adipokines and cytokines, such as adiponcetin and IL10, decrease as inflammatory adipokines and cytokines decrease. These systemic inflammatory/oxidative stresses have adverse effects on multiple organs. A potential general contributor to the multi-system dysfunction seen in abdominal obesity/metabolic syndrome is a generalized dysfunction of the endothelium. Endothelial dysfunction is a consequence of excessive production of ROS and the resultant degradation of nitric oxide (31). Compromise of the integrity of the vasodilator, antiithrombogenic and anti-inflammatory functions of the endothelium and particularly in the nutritive micro-vasculature

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FIG. 3. Both abdominal (visceral) fat and insulin resistance may contribute to cardiovascular disease in obesity. Visceral fat, in particular, contributes to endothelial dysfunction through the direct effect of adipokines, mainly adiponectin and TNF-, which are secreted by fat tissue after macrophage recruitment (through monocyte chemoattractant protein-1, MCP-1). Indirect effects of TNF- and IL-6 might influence inflammation (CRP) and endothelial dysfunction. Insulin resistance induced by cytokines (IL-6, TNF- and adiponectin) NEFA and retinol-binding protein 4 (RBP-4) may induce oxidative stress and subsequent endothelial dysfunction (PAI-1 and ICAM-1). Fat accumulation, insulin resistance, liver-induced inflammation and dyslipidaemic features may all lead to the premature atherosclerotic process. (Nature 2008;454:4639. Modified with permission).

could contribute to dysfunction of any organ system. This concept could inform the interrelationships of many of the diseases shown in Table 1. The generalized protective effects of the Mediterranean diet are generally thought to be related to the anti-inflammatory effects of the constituent components taken together. The protective effects of the broad array of polyphenols/flavonoids and other chemical entities found in plant foods have been mentioned. Many of these compounds may function chemically and directly as anti-oxidants, although that activity may not be the sole or even major reason for their salutary effects on health. Similarly, monounsaturated fatty acids, such as olive oil, are anti-inflammatory (32). The omega-3 fatty acids found in fish have novel anti-inflammatory effects (33). Finally, wine, and particularly red wine, long has been associated with health and protection, specifically against cardiovascular disease, although the evidence has until recently been somewhat anecdotal. The search for chemicals

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FIG. 4. Linking obesity to cardiovascular disease. Abdominal obesity is associated with insulin resistance, oxidative stress and increased levels of different (adipo)cytokines and inflammatory markers, all of which ultimately lead to endothelial dysfunction. (Modified from Van Gaal LF, et al. Nature 2006;444:875 80. With permission).

involved in the protective effects of red wine (and by extension plants generally) has led to important, landmark scientific discoveries. IN VINO VERITAS In wine there is truth is a phrase that originally referred to the tendency of one to become loose-tongued after drinking wine and reveal things that would otherwise be kept confidentially. It entered the scientific literature in a commentary concerning the enhanced understanding of the mechanisms by which resveratrol, a polyphenol found in relatively high concentrations in red wine, improves longevity, metabolic function and exercise performance in mice made obese by the feeding of a high fat diet (34 36). (Figure 5). Resveratrol was found to have a high affinity activating interaction with Sirt 1, the mammalian homologue of Sir, a histone deacetylase that was first identified as a longevity gene in worms. Sirt 1 has multiple functions. In the present context, its role as a deacetylator and activator of the peroxisome proliferator-activated receptor co-activator (PGC-1) is the most important (34). (Figure 6) PGC-1 is a transcriptional coactivator for multiple genes that modulate in a salutatory fashion glucose and fatty acid metabolism, ROS-metabolizing enzymes, such as superoxide dismutase and catalase, mitochondrial biogenesis and angiogenesis. Inactivation of PGC-1 is associated with enhanced oxidative stress, abnormal glucose metabolism and mitochondrial dys-

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FIG. 5. Panel A: Resveratrol improves health and survival of mice on a highcalorie diet. Kaplan-Meier survival curves. Hazard ratio for HCR is 0.69 (2 5.39, P 0.020) versus HC, and 1.03 (2 0.022, P 0.88) versus SD. The hazard ratio for HC versus SD is 1.43 (2 5.75, P 0.016). Panel B: Time to fall from an accelerating rotarod was measured every 3 months for all survivors from a pre-designated subset of each group; n 15 (SD), 6 (HC) and 9 (HCR). Asterisk, P 0.05 versus HC; hash, P 0.05 versus SD. Error bars indicate s.e.m. (Modified with permission from Nature 2006;444:337 42).

function. Given its broad protective effects, it is not surprising that PGC-1 recently also was identified as a longevity gene. Thus, the activation of these powerful protective pathways by resveratrol is likely a prototype for even broader protective effects of multiple plant polyphenols and other chemicals in mediating the beneficial effects of Mediterranean-style diets.

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FIG. 6. In Vino Veritas. Mechanism of Action of Resveratrol. Resveratrol Stimulates the Sirt1-PGC-1 Pathway. Resveratrol improves insulin sensitivity in mice by stimulating mitochondrial function via the Sirt1-PGC-1 pathway. Under basal conditions PGC-1 is heavily acetylated and inactivated by GCN5. Elevations in cellular NAD during fasting and in response to exercise trigger the Sirt1-mediated deacetylation of PGC-1. Deacetylated PGC-1 stimulates genes for oxidative phosphorylation in part by functioning as a coactivator for nuclear respiratory factor-1 (NRF-1). Resveratrol increases Sirt1 activation under high-fat diet conditions by increasing the affinity of Sirt1 for NAD and for acetylated PGC-1. (Kos S, Montminy M. Cell 2006;127:109193. With permission).

XENOHORMESIS Plant derived substances provide a broad range of beneficial effects to human health, and some, such as salicylic acid, have been in use for centuries. Many current top selling drugs were derived from plant products. For example, resveratrol itself in mammals affects more than 20 receptors and enzymes (37). The high affinity interaction with many of these binding partners suggests that the interactions are not random events but represent an ancient and beneficial interaction between plant stress response molecules, such as resveratrol, and animals that also respond to stress in the environment. Ingesting environmentally stressed plants with enhanced concentrations of polyphenols thus provides protective benefit to animals. The conservation

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by mammals of a myriad of high affinity binding sites for multiple plant stress-response molecules that are generally protective suggests that selection rather than coincidence is at work (37). This general theory is called xenohormesis by Sinclair. The scope of the interaction between various polyphenols and protective cell-signaling networks is illustrated in Figure 7 (37). The power of natures polypharmacy may be a primary underpinning of the striking benefits of Mediterranean-style diets in promoting human health. INTERACTION OF EXERCISE AND DIET Exercise increases longevity (38). Also, in an observational cohort study of an elderly European population aged 60 90 followed for ten years, regular exercise, moderate alcohol intake and the Mediterranean diet were individually and additively associated with decrease in all cause, cancer, and cardiovascular mortalities (39). The probable

FIG. 7. Direct Modulation of Key Mammalian Enzymes by Plant Metabolites. A surprising number of plant molecules in our diet interact with key regulators of mammalian physiology to provide health benefits. Shown are 3 examples: resveratrol found in numerous plants and concentrated in red wine; curcumin from turmeric; and epigallocatechin-3-gallate (EGCG) in green tea. These compounds modulate key pathways that control inflammation, the energy status of cells, and cellular stress responses in a way that is predicted to increase health and survival of the organism. Such observations raise the question, are these biochemical interactions merely a remnant of what existed in the common ancestor of plants and animals, or is selection maintaining interactions between the molecules of plants and animals? Some interactions activate signaling pathways (arrows) whereas others inhibit them (bars). Solid arrows or bars indicate instances where there is some evidence of a direct interaction of the plant metabolite with a mammalian protein. (Horwitz KT, Sinclair DA. Cell 133;3:38791. With permission).

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linkage among the diet and wine and the Sirt1/PGC1- transcriptional control pathways has been discussed. As noted in Figure 6, exercise also stimulates this axis. More specifically, exercise activates both the activity and expression of PGC1- in human skeletal muscle (40). Handschin and Spiegelman have recently put forth in Nature a general hypothesis about the centrality of PGC1- in inflammation and chronic diseases generally, including most of those listed in Table 1 (21). The central notion is that the sedentary state is fundamentally pro-inflammatory, because of high systemic levels of inflammatory mediators secreted by adipose tissue and non exercising muscle (Figure 8). As shown in Figure 9, chronic exercise activates transcription of the same protective anti-inflammatory genes that resveratrol and probably other polyphenols in the Mediterranean diet do. They posited that there are quantitative threshold levels of systemic cytokines that, when chronically present, induce disease in multiple other organs. Specific clinical phenotypes thus would result from systemic inflammatory effects and organ specific susceptibilities. Thus, this threshold in a given tissue is more likely to be reached in individuals who are both obese and sedentary. This hypothesis is consistent with the data and polemics presented in this paper. In the present context, a Mediterranean-style diet and exercise would decrease the likelihood that the inflammatory threshold for the development of organ pathology would be reached. CONCLUSION Many if not most human diseases are caused by oxidative stress and associated inflammation. As much as two thirds of the mortality attributed to chronic diseases is related to the lifestyle factors of tobacco smoking, lack of exercise and poor diet (39). Regular exercise, eating a Mediterranean-style diet, moderate alcohol intake and abstaining from smoking promote longevity and reduce cardiovascular and allcause mortality, including that from cancer. These lifestyle attributes are anti-inflammatory, and to an important extent, act by modulating the transcriptional pathways controlling oxidative response genes, carbohydrate and fatty acid metabolism, and mitochondrial biogenesis. At least three of the transcription mediators involved are longevity genes. The manifestation of clinical phenotypes of chronic disease is likely a late stage of sustained systemic inflammation related to lifestyle choices. These observations inform important opportunities to intervene in disease processes in the early, premorbid stages when success will likely be not only greater but also less expensive than are

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FIG. 8. Inflammation and Chronic Diseases. Inactivity and obesity trigger persistent, low-grade systemic inflammation. Moreover, inflammation in certain tissues is linked to the development of many chronic diseases. Examples of such tissues and the consequences of inflammation are shown. Inflammatory cytokines released from adipose tissue are linked to the development of insulin resistance and type 2 diabetes. Inflammatory responses by immune cells and glial cells are associated with atherosclerosis and neurodegenerative diseases, respectively. The systemic and local production of cytokines contributes to the aetiology of certain cancers. (Nature 2008;454:4639. With permission).

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FIG. 9. Effect of PGC1 on chronic systemic inflammation. Physical activity determines the amount of PGC1 in skeletal muscle: the more activity, the more PGC1. PGC1 , in turn, controls the adaptation of muscle fibers to exercise and confers several benefits. Consequently, a reduction in systemic inflammation is observed in individuals who exercise, particularly in those who engage in chronic exercise. By contrast, inactivity, and thus small amounts of PGC1 in skeletal muscle, results in a chronic systemic inflammatory state, which has serious pathological consequences. This inactivity-driven systemic inflammation is further exacerbated by obesity (not shown). FOXO3, forkhead box O3; ROS, reactive oxygen species. (Nature 2008;454:4639. With permission).

our current practices. Current insights into molecular mechanisms may also foreshadow the development of new preventive drugs and/or non pharmaceutical supplements. ACKNOWLEDGEMENTS
I thank my wife Janie for introducing me to the wonders of nutrition and for her support, guidance, wisdom and tolerance during the development of this project. I also thank Sarah Banick for her excellent editorial support in development of the manuscript and to Kate Harris for her helpful suggestions.

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