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TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 121, 2010

PRESIDENT’S 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 inthe 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 find-

ings inferred that at some early stage(s) of many diseases, commonpathophysiologic 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 19

th

century,environmental causes of disease became increasingly apparent. A ma-

jor focus was on infectious diseases and their enablement by unsani-

tary 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 ulti-

Correspondence 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:

[email protected]

Potential Conflicts of Interest: None disclosed.

1



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 inefficiency 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 pro-

cessing 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 avail-

ability 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 Statesin 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 theearly 1900s with the chemical defining of food components and micro-

nutrients including vitamins. Population studies from the 1940s pro-

vided 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). Car-

diovascular 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 dur-ing the war years, but rebounded afterwards. Thus, decrease in avail-

2 R. WAYNE ALEXANDER



able food, and perhaps most importantly saturated animal fats, was

associated with decreased risk of cardiovascular disease. The mecha-

nisms 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 gaininsights into causes. Two major initiatives were particularly transfor-

mative. 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 exami-

nation and lifestyle interviews, which changed the face of cardiovas-

cular 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 indi-

vidual 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 Framing-

ham, Ancel Keys and colleagues in the late 1950s launched a popula-

tion-based cohort study in multiple countries with varying ecological

characteristics (3). The Seven Countries Study compared cardiovascu-

lar death rates among the United States, Greece (Crete), Finland, The

Netherlands, Japan, Italy and Yugoslavia in 13,000 men of ages 40 to59 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 (3–5). At 15 years, mor-

tality 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 sim-ilar 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 popu-

lation in the overall cohort (6). This inverse relationship betweenserum cholesterol and CHD mortality within a regional cohort per-

3 VEGETABLES AND EXERCISE



sisted after 25 years of follow-up even after adjusting for age, smoking

and blood pressure (7). Strikingly, CHD mortality rate varied approx-

imately 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 ad-

justed CHD mortality rate for a similar cholesterol level of about 200mg/dL in Northern Europe is about 300–400% greater than that in

Southern Europe. The role of the observed dietary variations in differ-

ences 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. Impor-

tantly 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 5–9 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 amodest use of monounsaturated fats, chiefly from olive oil (3). A broad

variety of protective, defensive chemicals help create synergistic ef-

fects 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 asdiscussed 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 in-

teractions among many cultural and environmental influences, dietaryfactors play an important role, as noted. The French have a low




coronary artery event rate, even though they enjoy a robust culinary

tradition of rich food that is hardly Mediterranean and is high insaturated fat. The apparent inconsistency is known as the “French

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).




Paradox.” In fact, France is hardly a Mediterranean country. The

appellation “Mediterranean” has been equated with a region’s 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,” how-

ever, between the French diet and the Mediterranean diet may be more

apparent than real. For example, in both France and countries moredefinitively 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 hydro-

genated 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 epide-

miology on cardiovascular disease was driven by the high prevalence

rates of the first 60 years of the 20th

century. The Lyon Heart Study in1994 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 cardio-

vascular 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 anal-

ysis provided evidence, but not firm proof, that the additional effectsinclude prevention of cancers (12).




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, athero-sclerosis has been recognized widely as an inflammatory disease only

in the past 20 years, and hypertension has been associated with im-

muno-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 phe-

notypes and secrete cytokines and chemokines that are active both

locally and systemically (16). Similarly, chronic inflammation is rec-

ognized as an antecedent of malignant transformation in certain cir-

cumstances (17). Indeed, one is hard pressed to identify human dis-

eases 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 inflam-

mation, 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 colonos-

copy 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 syn-

drome and a history of smoking, both of which are associated withsystemic inflammation (21).

Inflammation and Reactive Oxygen Species

Reactive oxygen species (ROS) were identified decades ago as chem-

ically 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 weregenerally toxic agents associated with cell death rather than being the




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 sig-

naling at all involved activation of an inflammatory mechanism. En-

dothelial cell vascular cell adhesion molecule-1 (VCAM-1) recruits

mononuclear cells into the arterial wall in animal models of athero-

sclerosis (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 demon-

strated 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 spec-

trum 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 ar-

thritis and osteoporosis. Thus, multiple clinical phenotypes share com-

mon mechanisms of molecular pathogenesis.

TABLE 1

Conditions Associated with Increased Reactive Oxygen Species

• Aging • Amyotrophic lateral sclerosis• Alzheimer’s disease• Adult respiratory distress syndrome• Asthma• Atherosclerosis• Cancer• Cataracts• Congestive heart failure• Cystic fibrosis• Diabetes• Hypertension• Macular degeneration• Metabolic syndrome• Obesity• Osteoporosis• Parkinson’s disease• Rheumatoid arthritis

• Ulcerative colitisEtc.




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, recep-

tor and non-receptor tyrosine kinases, G-proteins and inflammatory

chemical mediators such as advanced glycation end products and oxi-

dized LDL, activate one or more members of the NOX family. The

ubiquitous and sentinel roles of NOXs in physiology and pathophysi-

ology are illustrated by a clinically relevant example. Both angiotensin

II (AngII), acting through the AngII type 1 receptor (AT1R) and prod-

ucts of the HMG CoA reductase pathway involved in cholesterol syn-

thesis impact the activity NOX in vascular cells (27). AngII activates

NOX directly and isoprenoids formed in the cholesterol synthesis path-

way 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 toinhibit inflammatory and growth pathways. Blockade of activation of the angio-

tensin II Type 1 receptor (AT1R) by angiotensin converting enzyme inhibitors (ACEI) or

by AT1R blockers (ARB) inhibits AngII generated reactive oxygen species (ROS) result-

ing 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 inflammationas a common causal mechanism.




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 vaso-

protective effects at least in part by inhibiting NOX-dependent, ROS-

mediated inflammation. Both classes of drugs are being tested for

efficacy in multiple other disease states supporting the general prin-

ciple that shared oxidative inflammatory mechanisms are involved in

a broad spectrum of clinical phenotypes. These model constructs in-

form 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 ca-

loric 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 neo-

vascularization and induces NOX expression and enhanced oxidative

stress from ROS production. Most importantly, visceral adiposity is

associated with systemic inflammation and oxidative stress (15). (Fig-

ure 4). Secretion of protective adipokines and cytokines, such as adi-

poncetin and IL10, decrease as inflammatory adipokines and cytokines

decrease. These systemic inflammatory/oxidative stresses have ad-

verse effects on multiple organs. A potential general contributor to the

multi-system dysfunction seen in abdominal obesity/metabolic syn-

drome 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 functionsof the endothelium and particularly in the nutritive micro-vasculature




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 thebroad 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 particu-

larly red wine, long has been associated with health and protection,

specifically against cardiovascular disease, although the evidence hasuntil recently been somewhat anecdotal. The search for chemicals

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 mono-

cyte 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;454:463–9.

Modified 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 longev-

ity, 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, themammalian 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 co-

activator 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 ox-idative stress, abnormal glucose metabolism and mitochondrial dys-

FIG. 4. Linking obesity to cardiovascular disease. Abdominal obesity is associ-

ated with insulin resistance, oxidative stress and increased levels of different (adipo)cy-

tokines and inflammatory markers, all of which ultimately lead to endothelial dysfunc-

tion. (Modified from Van Gaal LF, et al. Nature 2006;444:875–80. With permission).




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.

FIG. 5. Panel A: Resveratrol improves health and survival of mice on a high-

calorie 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).




XENOHORMESIS

Plant derived substances provide a broad range of beneficial effectsto 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 poly-phenols thus provides protective benefit to animals. The conservation

FIG. 6. In Vino Veritas. Mechanism of Action of Resveratrol. Resveratrol Stimulates

the Sirt1-PGC-1 Pathway. Resveratrol improves insulin sensitivity in mice by stimu-

lating mitochondrial function via the Sirt1-PGC-1 pathway. Under basal conditionsPGC-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 in-

creases 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;127:1091–93.

With permission).




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 interac-

tion between various polyphenols and protective cell-signaling net-

works is illustrated in Figure 7 (37). The power of nature’s polyphar-macy 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 Mediterra-

nean diet were individually and additively associated with decrease inall 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 path-

ways 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;3:387–91.With permission).




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-inflam-

matory, 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 inflam-

matory 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 Medi-

terranean-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 at-

tributed 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 all-cause 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 life-

style choices. These observations inform important opportunities to

intervene in disease processes in the early, premorbid stages whensuccess will likely be not only greater but also less expensive than are




FIG. 8. Inflammation and Chronic Diseases. Inactivity and obesity trigger per-

sistent, 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. Inflam-

matory 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;454:463–9. 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.

REFERENCES1. Blackburn H, SFJ. Cross-cultural Comparisons of Cardiovascular Diseases: A Brief

History. 2004.

2. Dawber TR, The Framingham Study: The Epidemiology of Atherosclerotic Disease.

1980.

3. Keys A, et al. The seven countries study: 2,289 deaths in 15 years. Preventive

Medicine 1984;13(2):141–54.

4. Menotti A, et al. Forty-year coronary mortality trends and changes in major risk

factors in the first 10 years of follow-up in the seven countries study. European

Journal of Epidemiology 2007;22(11):747–54.

5. Menotti A, et al. Twenty-five-year coronary mortality trends in the seven countries

study using the accelerated failure time model. European Journal of Epidemiology2003;18(2):113–22.

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 severalbenefits. Consequently, a reduction in systemic inflammation is observed in individuals

who exercise, particularly in those who engage in chronic exercise. By contrast, inactiv-

ity, 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;454:463–9. With permission).




6. Seven Countries Study special supplement. Circulation 1970;41(4S1):20–39.

7. Verschuren WMM, et al. Serum total cholesterol and long-term coronary heart

disease mortality in different cultures: twenty-five-year follow-up of the Seven Coun-

tries Study. JAMA 1995;274(2):131–6.

8. Hertog MGL, et al. Flavonoid intake and long-term risk of coronary heart disease

and cancer in the Seven Countries Study. Arch Intern Med 1995;155(4):381–6.

9. Muller-Nordhorn J, et al. An update on regional variation in cardiovascular mortal-ity within Europe. Eur Heart J 2008:ehm604.

10. Kagan A, et al. Epidemiologic studies of coronary heart disease and stroke in Japa-

nese men living in Japan, Hawaii and California: demographic, physical, dietary and

biochemical characteristics. Journal of Chronic Diseases 1974;27(7– 8):345– 64.

11. de Lorgeril M, et al. Mediterranean alpha-linolenic acid-rich diet in secondary pre-

vention of coronary heart disease. The Lancet 1994;343(8911):1454 –9.

12. de Lorgeril M, et al. Mediterranean dietary pattern in a randomized trial: pro-

longed survival and possible reduced cancer rate. Arch Intern Med 1998;158(11):

1181–7.

13. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation2002;105:1135– 43.

14. Guzik TJ, et al. Role of the T cell in the genesis of angiotensin II induced hyperten-

sion and vascular dysfunction. J Exp Med 2007;204(10):2449–60.

15. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardio-

vascular disease. Nature 2006;444(7121):875– 80.

16. Semple RK, Chatterjee VKK, O’Rahilly S. PPARI’ and human metabolic disease. The

Journal of Clinical Investigation 2006;116(3):581–9.

17. Mantovani A, et al. Cancer-related inflammation. Nature 2008;454(7203):436 – 44.

18. Berk BC, Weintraub WS, Alexander RW, Elevaton of C-reactive protein in “active”

coronary artery disease. Am J Cardiol 1990;65:168–72.

19. Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein inrisk assessment. 2004.

20. Nakajima T, et al. De novo expression of killer immunoglobulin-like receptors and

signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary

syndromes. Circ Res 2003;93(2):106–13.

21. Handschin C, Spiegelman BM. The role of exercise and PGC1 in inflammation and

chronic disease. Nature 2008;454(7203):463–9.

22. Alexander RW, Hypertension and the pathogenesis of atherosclerosis. Oxidative

stress and the mediation of arterial inflammatory response: a new perspective.

Hypertension 1995;25:155–61.

23. Gimbrone MA, Jr, Bevilacqua MP, Cybulsky MI. Endothelial-dependent mecha-

nisms of leukocyte adhesion in inflammation and atherosclerosis. Ann NY Acad Sci1990;598:77–85.

24. Marui N, et al. Vascular cell-adhesion molecule-1 (VCAM-1) gene-transcription and

expression are regulated through an antioxidant-sensitive mechanism in human

vascular endothelial cells. J Clin Invest 1993;92(4):1866 –74.

25. Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress.

J Biol Chem 1997;272:20313–6.

26. Zafari A, et al. Arachidonic acid metabolites mediate angiotensin II-induced hyper-

trophy by stimulation of NADH/NADPH oxidase activity in cultured vascular

smooth muscle cells. FASEB J 1996;10:A1013.

27. Griendling KK, et al. Angiotensin II stimulates NADH and NADPH oxidase activity

in cultured vascular smooth muscle cells. Circ Res 1994;74:1141–8.28. HOPE Investigators. Effects of an angiotensin-converting-enzyme inhibitor,




ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Pre-

vention Evaluation Study Investigators. N Engl J Med 2000;342:145–53.

29. Reaven GM. Banting lecture 1988: role of insulin resistance in human disease.

Nutrition 1997;13(1):64.

30. Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sciences

2009;84(21–22):705–12.

31. Huang PL. eNOS, metabolic syndrome and cardiovascular disease. TRENDS inEndocrinology & Metabolism 2009;20(6):295–302.

32. Jaen. International conference on the healthy effect of virgin olive oil. European

Journal of Clinical Investigation 2005;35(7):421– 4.

33. Arita M, et al. Stereochemical assignment, antiinflammatory properties, and recep-

tor for the omega-3 lipid mediator resolvin E1. J Exp Med 2005;201(5):713–22.

34. Koo S-H, Montminy M. In vino veritas: a tale of two Sirt1s? Cell 2006;127(6):1091–3.

35. Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie

diet. Nature 2006;444(7117):337–42.

36. Lagouge M, et al. Resveratrol improves mitochondrial function and protects against

metabolic disease by activating SIRT1 and PGC-1. Cell 2006;127(6):1109–22.

37. Howitz KT, Sinclair DA. Xenohormesis: Sensing the chemical cues of other species.

Cell 2008;133(3):387–91.

38. Yates LB, et al. Exceptional longevity in men: modifiable factors associated with

survival and function to age 90 years. Arch Intern Med 2008;168(3):284–90.

39. Knoops KTB, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in

elderly European men and women: The HALE Project. JAMA 2004;1292(12):1433–9.

40. Tjonna AE, et al. Aerobic interval training versus continuous moderate exercise as

a treatment for the metabolic syndrome: a pilot study. Circulation 2008;118(4):346–

54.


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