Periodontology 2000, Vol. 64, 2014, 7–19 © 2013 John Wiley & Sons A/S.
Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Modifiable risk factors in
periodontitis: at the intersection
of aging and disease
M A R K A. R E Y N O L D S
Chronic diseases are the primary cause of disability and
death worldwide (101). Approximately 50% of adults in
the USA have one or more chronic conditions (165),
paralleling the prevalence of periodontitis (48). Cardio-
vascular diseases (heart disease and stroke), cancer,
chronic obstructive pulmonary disease and type 2
diabetes are among the most prominent chronic
diseases (12). These chronic conditions are linked by
common and preventable biological risk factors (such
as high blood pressure, high blood cholesterol and
overweight) and behavioral risk factors (such as an
unhealthy diet, physical inactivity and tobacco use).
Moreover, age-related diseases often occur in combina-
tion with other chronic conditions, particularly among
the elderly, strongly implicating common underlying
risk factors (57). The presence of multiple chronic con-
ditions, or comorbidities, is one of the most important
predictors of increased health costs, hospitalization
and adverse health-related outcomes, including mor-
tality (31, 130, 150, 152, 160, 173). Rheumatoid arthritis,
for example, is associated with a 1.5-fold increase in
mortality associated with cardiovascular disease (7),
when compared with the general population. Among
patients with diabetes, the comorbidity of depression is
associated with increased utilization of health-care ser-
vices and increased mortality (75). Such evidence high-
lights the significant impact of modifiable risk factors
on health as well as the resulting burden of multiple
chronic conditions on health-related outcomes.
Multiple genes acting together and in response to the
environment appear to underlie susceptibility to many
chronic, noncommunicable, diseases. Health-care pro-
viders and programs targeting modifiable risk factors,
such as smoking and obesity, therefore have the poten-
tial to significantly improve the risk profiles for common
diseases and also life expectancy. In a retrospective
cohort study of 9,949 patients who had undergone gas-
tric bypass surgery for obesity, Adams et al. (1) found a
PERIODONTOLOGY 2000
40% reduction in mortality of these patients during a
7.1-year follow up when compared with control subjects
matched for age, sex and body mass index at baseline.
Cause-specific mortality in the surgery group decreased
by 56% for coronary artery disease, by 92% for diabetes
and by 60% for cancer (1). Other investigators have
reported similar health benefits following bariatric sur-
gery in obese individuals (143).
This volume of Periodontology 2000 examines the role
of modifiable risk factors in periodontitis and other
chronic inflammatory diseases. Current evidence is pre-
sented on the complex role of oral bacterial communi-
ties and viral infection, particularly cytomegalovirus, in
the etiology and pathogenesis of periodontitis. Suscepti-
bility to periodontitis and other inflammatory diseases
appears to change in response to complex interactions
of genetic, environmental and stochastic factors
throughout the lifespan. Many modifiable risk factors,
such as depression and cigarette smoking, contribute to
increases in systemic markers of inflammation and
modify gene regulation through a variety of biologic
mechanisms (e.g. epigenetic modifications). Therefore,
periodontitis and other inflammatory diseases share
many common modifiable risk factors, such as tobacco
smoking, psychological stress and depression, alcohol
consumption, obesity, diabetes, metabolic syndrome
and osteoporosis. Evidence is reviewed on the potential
roles of diet, nutrition and anti-inflammatory drugs in
reducing the risk for chronic disease. An understanding
of modifiable risk factors is essential for clinical practice.
Burden of chronic diseases
In the USA, chronic diseases account for 7 out of 10
deaths each year (81). Recent estimates indicate that
nearly 25% of adults have multiple chronic conditions
(165). Cardiovascular disease (heart disease and
7
Reynolds
stroke) and cancer are responsible for more deaths
annually (over 50%) than any other major causes of
death (120). In 2010, health care and related expenses
for cardiovascular disease were over $500 billion (87);
direct medical costs associated with cancer were esti-
mated at $124.6 billion (94). Direct health-care costs
resulting from chronic diseases comprise about 75%
of health-care expenditures, and, among older adults,
chronic diseases account for almost 95% of expenses
for health care (66).
The majority of noncommunicable diseases are
attributable to preventable behavioral, metabolic and
environmental risk factors (6). Estimates from the
National Health and Nutrition Examination Survey
(2009–2010) indicate that nearly 50% of adults have
one or more risk factors for cardiovascular disease in
the USA (101). The risk of heart disease and stroke
closely parallel the cumulative burden of risk factors
(15, 88–90). Estimates suggest that nearly 50% of all
cancers are attributable to infection and chronic
inflammation (68, 129, 165) or to excess body weight
and a sedentary lifestyle (21, 99). Many of these com-
mon, preventable risk factors appear to modify the
development of periodontitis.
The National Health and Nutrition Examination
Survey (2009–2010) revealed that over 47% of the
population, representing 64.7 million adults, has peri-
odontitis. For adults ≥65 years of age, 64% exhibited
either moderate or severe periodontitis (48). Epidemi-
ologic and experimental data strongly indicate that
cigarette smoking (158) and diabetes mellitus (114)
are major risk factors for periodontitis. Increases in
the prevalence of overweight and obesity forecast
rises in the prevalence of diabetes mellitus (120).
Obesity and concomitant comorbidities, including
diabetes mellitus and periodontitis, are associated
with a state of low-grade inflammation (121). Evi-
dence supports the presence of bidirectional relation-
ships among obesity, diabetes mellitus, and other
chronic conditions, including periodontal diseases
(154). The treatment of periodontal disease has been
associated with improved glycemic control in patients
with type 2 diabetes (83, 141). In a recent 3-year longi-
tudinal study, the average number of hospitalizations
and physician visits, as well as overall medical expen-
ditures, were shown to be significantly lower for dia-
betic patients with periodontitis who received
periodontal therapy compared with those with peri-
odontitis who failed to undergo appropriate peri-
odontal care (71). Such evidence underscores the
potential clinical significance of periodontitis as a co-
morbid disease in health-related outcomes.
8
Aging: inflammation and disease
Aging is associated with declines in mental and physi-
cal health as well as with increases in the risk of
chronic disease, including atherosclerosis, cancer,
diabetes and periodontitis (33, 48, 59, 142). Aging is
also associated with elevations in systemic markers of
inflammation (142). Human longevity and healthy
aging show moderate heritability, with estimates
ranging from 20 to 50% (164). Multiple genes proba-
bly mediate the aging process through different bio-
logical processes and environmental interactions (45,
164). Although the genetic, molecular and cellular
events that underlie aging are not fully understood
(142), inflammation is widely considered as a central
component (32, 33).
The free-radical theory of aging provides a robust,
mechanistic model of aging and age-related disease
(63). Oxidative stress was initially conceptualized as
the cellular and molecular consequence of reactive
oxygen species, or free radicals, exceeding normal
metabolic antioxidant defense mechanisms (61).
Reactive nitrogen species, which also serve normal
physiologic functions, are regulated within the same
or similar homeostatic defense mechanisms (171).
The free-radical theory of aging postulates that the
accumulation of free radicals contributes to cellular
damage and the development of pathologic disorders.
Inflammation is one of the manifestations of oxida-
tive stress.
Chronic inflammation is associated with the pro-
duction of free radicals, which can result in oxidative
damage to DNA and to other cellular components
(67), resulting in loss of function and cell death (34).
Neutrophils and macrophages produce reactive oxy-
gen and nitrogen species, such as superoxide and
nitric oxide, in response to phagocytosis and ligands
of pattern recognition receptors (27, 29, 30, 50, 92).
Free radicals appear to play an important role in the
tissue destruction associated with chronic inflamma-
tion, including periodontal diseases (27).
The prevalence and severity of periodontitis
increases with age – older adults are more likely to
have moderate or severe periodontitis compared with
younger adults (48). The number of chronic condi-
tions (multimorbidity) observed in adults also
increases with age (128), consistent with a possible
link between inflammation and age-related diseases.
The levels of inflammatory mediators generally exhibit
an age-related increase, even in the absence of acute
infection or other sources of physiologic stress (142).
Several lines of evidence indicate that interleukin-6

is a central mediator of systemic inflammation, regu-
lating the body temperature set point and the acute-
phase response (54). Circulating interleukin-6 is
detectable within 1 h after surgery or accidental
injury (18), and higher levels of interleukin-6 are cor-
related to poorer outcome (146). Elevations in inter-
leukin-6 and in other serum markers of
inflammation have been associated with increased
mortality in community-dwelling elderly adults
(123). Therefore, biomarkers of systemic inflamma-
tion may provide important insight into aging and
into the onset, progression and therapeutic out-
comes of age-related diseases and conditions. Recent
advances in our understanding of the etiology and
pathogenesis of periodontitis have helped to identify
biologic pathways underlying the effects of modifi-
able risk factors on susceptibility to periodontitis and
other common chronic diseases.
Periodontitis: etiology and
pathogenesis
Bacterial biofilms constitute the major etiologic factor
underlying the initiation of periodontal inflammation
and, presumably, the progression of periodontitis.
Biofilms are normally complex and appear to provide
individual cells with many ecological advantages,
including environmental protection, nutrients, meta-
bolic cooperation and the acquisition of new genetic
traits (43, 65). The specific role of individual bacterial
pathogens in contributing to the susceptibility to
periodontitis remains unclear; however, recent stud-
ies reveal a high level of communication and micro-
bial interaction that direct the maturation of a
distinct community structure. This community struc-
ture is often characterized by a shift in biofilm com-
position in disease (38). There is growing evidence
that certain low-abundance microbial pathogens
induce inflammatory disease by transforming a nor-
mally benign microbiota into a dysbiotic one (60).
Porphyromonas gingivalis is widely thought to
represent a keystone pathogen and may provide
the basis for developing treatment for periodontitis
(38). P. gingivalis is postulated to subvert comple-
ment and impair host defense, leading to over-
growth of oral commensal bacteria. The latter
overgrowth presumably induces a complement-
dependent inflammation, tissue destruction and
nutrient-rich inflammatory exudate to support further
bacterial growth (60). Interestingly, heterogeneous
structural isoforms of P. gingivalis lipopolysaccharide
differentially interact with toll-like receptors 2 and 4,
Modifiable risk factors in periodontal disease
eliciting activation of different downstream signal-
transduction cascades. Thus, P. gingivalis possesses
the capacity to differentially modulate the immune–
inflammatory response (64, 80, 126, 173). Therefore,
having an understanding of the composition and
development of oral bacterial communities is critical
for developing novel treatment strategies.
The oral bacterial microbiome includes over 700
different phylotypes, with approximately 400 species
found in subgingival plaque (111, 112). Despite this
bacterial diversity, nearly half of the phylotypes can
be present at any one time in any one individual
(108). Palmer (108) provides an in-depth review of
factors impacting the composition and development
of oral bacterial communities, which undergo
changes in structure during the onset and progres-
sion of periodontal disease. This author critically
reviews factors, such as bacterial adherence, cell–cell
binding and interorganismal interactions, which are
thought to contribute to alterations in the local envi-
ronment and the initiation and progression of dis-
ease. New strategies for the prevention and control of
periodontal diseases will emerge from a better under-
standing of the microbial factors responsible for path-
ogenicity.
Clinical and experimental evidence shows that
viruses can directly affect the homeostasis of micro-
bial populations as well as modulate the host
response to bacterial biofilms. Phages are known to
significantly affect microbial community composition
in many ecological niches, including the gut (148).
Phages appear to play a crucial role in the evolution,
diversity and abundance of bacteria in ecosystems (8,
148, 149). Recent culture-independent studies of the
microbial and viral communities in cystic fibrosis air-
way infections suggest that complex ecological, evolu-
tionary and temporal pressures shape these
communities (36). Conrad et al. (36) hypothesize the
existence of two major functional communities – a
transient viral and microbial population that induces
a strong innate immune response, and a microenvi-
ronment conducive to the establishment of a slower-
growing, and inherently antibiotic-resistant, commu-
nity.
Current evidence strongly implicates viruses, partic-
ularly cytomegalovirus and other herpesviruses, in the
pathogenesis of periodontitis (144, 145). Herpesvirus-
es subvert the innate and adaptive antiviral defense
mechanisms, thereby establishing a lifelong latent
infection. Contreras et al. (37) examine the mecha-
nisms of pathogenesis of human cytomegalovirus as
well as the immune response against cytomegalovi-
rus infection. These authors suggest that immune
9
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responses to cytomegalovirus can play an important
role in controlling or aggravating periodontitis.
Cytomegalovirus, for example, infects periodontal
macrophages and T-cells and elicits the release of
interleukin-1b and tumor necrosis factor-a. These
inflammatory cytokines play an important role in
the host defense against the virus; however, these
cytokines also contribute to local inflammation and
risk for periodontal breakdown and attachment loss.
Cytomegalovirus infection also alters the normal
activity of fibroblasts, which exhibit diminished col-
lagen production and increased release of metallo-
proteinases (37). The presence of combined viral–
bacterial infections may help explain certain clinical
features of periodontal disease, such as isolated
periodontal destruction, as well as the role of peri-
odontal disease as a risk factor for systemic diseases
(37).
Genetic risk factors underlie, in part, individual dif-
ferences in susceptibility to periodontitis (77), includ-
ing the host immune and inflammatory responses,
which can lead to alterations in the subgingival
microenvironment, favoring the emergence of peri-
odontal pathogens (10). Moreover, this complex host
defense is responsive to behavioral, biological and
environmental factors, such as obesity and smoking.
Cekici et al. (26) examine the complex immune and
inflammatory cascades initiated by oral bacterial bio-
films. These investigators conclude that a dysregula-
tion of inflammatory and immune pathways is
responsible for the transition to chronic inflamma-
tion. The conversion of acute to chronic inflamma-
tion is marked in neutrophils by a ‘class switch’ of
eicosanoid pathways, as evidenced by the up-regula-
tion of 15-lipoxygenase (85, 161). Of particular impor-
tance is the understanding that active inflammation,
coupled with a failure of mucosal innate defense sys-
tems, is necessary for persistence of periodontal
pathogens and a shift to chronicity of infection (26).
Cekici et al. (26) underscore the clinical implications
of evidence that the resolution of inflammation is reg-
ulated as an active process, particularly with respect
to potential therapeutic targets for the control of peri-
odontitis and other chronic diseases.
Susceptibility: setting the stage
Susceptibility to periodontitis varies widely among
adults (55), with the initiation and progression of
most forms of periodontitis representing a complex
interaction among genetic, behavioral, metabolic
and environmental factors (153). In a recent review,
10
Genco & Borgnakke (55) critically evaluated the evi-
dence of risk factors for periodontal disease within
the following categories: (i) gender, smoking and
alcohol, (ii) diabetes, (iii) obesity and metabolic syn-
drome, (iv) osteoporosis, dietary calcium and vita-
min D, (v) stress, and (vi) genetic factors. Men
exhibit greater susceptibility to periodontitis than
do women (48, 134), consistent with findings in a
nonhuman primate model (118). Strong evidence
exists for sexual dimorphisms in immune function,
involving both innate and acquired immunity (23).
Injury and infection have been associated with
higher levels of inflammatory cytokines in men than
in women, paralleling sex-specific differences in
periodontitis (135). Differential gene regulation, par-
ticularly in sex steroid-responsive genes, and sexual
dimorphisms in immune defense may contribute to
a sexual dimorphism in susceptibility to perio-
dontitis (135).
As with other chronic diseases, multiple gene–
gene and gene–environment interactions are
involved in the biological response to microbial bio-
films and injury. Allelic variants at multiple gene
loci probably influence susceptibility to periodonti-
tis (153). Evidence that genetic factors modify
susceptibility to periodontitis is stronger for aggres-
sive periodontitis than for chronic periodontitis
(55). Nevertheless, the genetic basis of aggressive
and chronic periodontitis remains poorly under-
stood. Selected polymorphisms may contribute to
individual differences in susceptibility to multiple
inflammatory conditions, including periodontitis
(53). Schaefer et al. (127), for example, have shown
that three of the genetic variant single-nucleotide
polymorphisms found in coronary heart dis-
ease are also associated with aggressive perio-
dontitis.
Sex steroids in aging and disease
Sex-specific genetic architecture clearly influences
multiple human attributes, including the preva-
lence, course and severity of many common dis-
eases (106). Moreover, the overall genetic
contribution, or heritability, of many common dis-
ease-associated quantitative phenotypes differs
between men and women (74, 132). Sex-specific
linkages have been found for psychiatric traits, such
as autism, and for immune-mediated disorders,
such as inflammatory bowel disease and osteoar-
thritis. There is increasing evidence to support the
notion that sex can actually be considered an

environmental factor which can modify both pene-
trance and expressivity of traits, such as obesity,
blood pressure and lipid levels, as well as suscepti-
bility to disease (167). Sex-specific temporal
differences in gene regulation, particularly in aging,
have profound influences on disease susceptibility
(13).
Sex steroids are fundamental to skeletal develop-
ment, bone homeostasis and immune function. Sex-
ual dimorphisms in immune function are well
documented in humans. In general, women generate
more robust and potentially protective humoral and
cell-mediated immune responses, whereas men fre-
quently mount a more aggressive and potentially
damaging inflammatory immune response to micro-
bial stimuli (95), perhaps offering insight into sex dif-
ferences in risk for periodontitis (48, 134). Sexual
dimorphisms in cortical bone size and strength
appear to be determined by independent and tempo-
ral-specific actions of sex steroids and insulin-like
growth factor (24). Although men generally reach a
higher peak bone mass, greater bone size and stron-
ger skeletal strength than women, the long bones
exhibit comparable bone densities (172). Sex steroids
play an essential role in the maintenance of bone
health throughout life – estrogens and androgens
appear to be necessary for normal skeletal health in
both men and women (35). Estrogen deficiency is a
major pathogenetic factor in the bone loss associated
with the menopause and postmenopausal osteoporo-
sis. Pronounced sexual dimorphisms emerge in the
microarchitecture of the aging skeleton, which appear
to impact remodeling and osteocyte lacunar density
in bone (51, 163).
Shiau et al. (136) critically examine sex steroids in
relation to aging, immune function and risk for peri-
odontitis. These authors highlight the pleiotropic
effects of sex-steroid hormones on tissues and organs,
which occur throughout the lifespan, as well as the
clinical significance of such alterations on risk for
common age-related diseases. Reductions in estro-
gen, for example, represent a major risk factor for
osteoporosis and other chronic conditions in women,
which may help to explain the association between
osteoporosis and alveolar bone loss (136).
Epigenetics: turning up the heat
A growing body of literature now implicates epige-
netic processes in chronic diseases. Epigenetics
refers to environment–gene interactions that influ-
Modifiable risk factors in periodontal disease
ence the regulation of gene expression, occurring
independently of DNA sequence and mediated prin-
cipally through changes in DNA methylation and
chromatin structure (159). Epigenetic changes
include an array of molecular modifications, which
are potentially reversible and heritable. The most
extensively studied molecular modifications are
DNA methylation, which occurs at the carbon-5
position of cytosine in CpG dinucleotides, and post-
translational histone modifications of chromatin
(72). Therefore, environmental exposures have the
potential to alter gene expression and modify
susceptibility to disease through changes in the epi-
genome. Studies in mice provide strong evidence of
an effect of prenatal environmental exposures on
postnatal phenotypes. For example, maternal die-
tary supplementation of mice with methyl-donors,
such as folic acid, results in a shift in coat color
from yellow to brown (pseudoagouti) in the off-
spring. This shift in color is directly linked to the
extent of DNA methylation. Moreover, maternal
dietary supplementation with genistein (a phytoes-
trogen) induces hypermethylation that persists into
adulthood, decreasing ectopic Agouti expression
and protecting offspring from obesity in adulthood
(47).
Genetic and epigenetic traits associated with sys-
temic exposures, such as smoking, appear to influ-
ence the inflammatory and metabolic states of the
periodontal tissues in response to injury or infection.
Barros & Offenbacher (9) review the advances in epi-
genetics, focusing on the role of DNA methylation in
the pathogenesis of periodontal disease and the
potential of epigenetic therapy. Virus and bacterial
infections can establish several types of epigenetic
modifications (37). Barros & Offenbacher (9) provide
data showing multiple methylated CpG islands in
chronically inflamed gingival tissue, consistent with
an epigenetic modification of fields. Therefore, epige-
netic modifications may contribute to the establish-
ment and progress of periodontal diseases. The
authors also highlight the significance of the epige-
netic field effect, whereby DNA methylation poten-
tially increases the risk of the region for subsequent
malignant transformation. Epigenetic field effects
may help to provide a biologic basis for the observed
associations between periodontal disease and oral
precancerous lesions and tumors (155). Evidence of
epigenetic modification supports the concept that
chronic infection and inflammation can affect gene-
specific epigenetic reprogramming in periodontal
tissues.
11
Reynolds
Smoking, alcohol and periodontal
inflammation
Tobacco use is the leading preventable cause of pre-
mature death of adults in the USA (162). Cigarette
smoke contains a complex chemical mixture of com-
bustion compounds that can induce DNA damage,
inflammation and oxidative stress (151). The risk and
severity of many adverse health outcomes, such as
cardiovascular and pulmonary diseases, are directly
related to the duration and level of exposure to
tobacco smoke. Several major classes of chemicals in
tobacco smoke are toxic and carcinogenic (151).
Tobacco smoking produces a chronic inflammatory
state and decreased insulin sensitivity, which can
accelerate microvascular disease (69).
Tobacco smoking is widely considered as the most
important environmental risk factor for periodontitis
(14, 109, 124, 147). Data from the 2009–2010 National
Health and Nutrition Examination Survey cycle
revealed a prevalence of periodontitis of 64.2%
among current smokers, compared with 39.8%
among nonsmokers (48). Johannsen et al. (73) exam-
ine cigarette smoking as a causal and preventable risk
factor for periodontitis. These authors conclude that
tobacco smoking modifies both the local and the sys-
temic host response. This modified response is char-
acterized by a stronger inflammatory reaction, with
increased levels of inflammatory cytokines, reactive
oxygen species, collagenase and serine proteases. Jo-
hannsen et al. (73) also highlight parallels in the neg-
ative effect of tobacco smoking on other chronic
conditions, including rheumatic arthritis, multiple
sclerosis, cardiovascular disease and inflammatory
bowel disease. These authors found only limited evi-
dence to support the hypothesis that tobacco smok-
ing has a detrimental influence on the subgingival
microbiota (73).
Tobacco smokers are at heightened risk of hazard-
ous alcohol drinking and alcohol-related diagnoses
(98). Alcohol abuse adversely affects the risk for infec-
tious diseases (115), such as tuberculosis (91) and
pneumonia (125). The overall impact of alcohol con-
sumption on infectious diseases appears to be sub-
stantial (116, 117), attributable largely to the adverse
effects of alcohol on the immune system (116, 122).
The effect of alcohol appears greatest for persons
consuming more than 40 g of pure alcohol per day
(91, 125). There is limited evidence indicating that
alcohol consumption may be associated with
increased severity of clinical attachment loss (5, 17,
70, 79, 82, 113, 133, 137, 156, 157).
12
Stress and depression: a state of
inflammation
Major depression is a severe widespread psychiatric
disorder, ranking fifth among the leading causes of
global disease (96). Laboratory and clinical studies
provide compelling evidence that psychological stress
plays a causal role in the etiology of major depression
(11). Chronic stress and depression have a negative
effect on the immune system and increase the risk of
atherosclerotic cardiovascular disease, diabetes and
other systemic conditions (58). The World Health
Organization World Health Survey of 245,404 partici-
pants from 60 countries found that, compared with
the chronic diseases angina, arthritis, asthma and
diabetes, depression produced the greatest decre-
ment in health (103). Chronic stress and depression
also affect the course and the outcome of many of
these conditions (97, 110, 170).
Warren et al. (166) review the literature on the role
of chronic stress and depression in periodontal dis-
ease. The authors conclude that available evidence
supports the hypothesis that stress and depression
can modify the host defense and the progression of
periodontal infections in patients susceptible to peri-
odontitis. This conclusion is also consistent with clin-
ical and experimental evidence that stress and
depression delay wound healing (16, 76). Although
stress and depression are often associated with
changes in health-related behaviors, such as oral
hygiene, smoking and diet, these changes do not fully
account for the differences observed in wound heal-
ing or disease (166).
Obesity, diabetes mellitus and
metabolic syndrome
Data from the National Health and Nutrition Survey
(2009–2010) indicated that 35.7% of adults are obese
(with a body mass index of ≥30), and that adults
≥60 years of age are more likely to be obese than
younger adults (107). For this same period, 8.3% of
the population was affected with diabetes, and a dis-
proportionately higher percentage of adults ≥65 years
of age (26.9%) was found to have diabetes (25).
Obesity, diabetes and metabolic syndrome contrib-
ute to both inflammation and chronic disease (49,
78). Metabolic syndrome refers to a constellation of
disturbances including central obesity, dyslipidemia,
hyperglycemia or diabetes, and hypertension. A cen-
tral feature of the metabolic syndrome is insulin resis-

tance, which significantly increases the risk for devel-
oping diabetes (138). Obesity and the metabolic syn-
drome are associated with elevations in mortality,
mainly attributable to cardiovascular disease (22, 52).
Adipocytes are metabolically active and synthesize
and release a number of proinflammatory molecules
(32, 93). Recent research has identified specific
molecular mediators linking inflammation and insu-
lin resistance in obesity (105). Insulin has been shown
to exert anti-inflammatory effects, in part, through
the suppression of several proinflammatory tran-
scription factors, such as nuclear factor-kappa B and
activator protein-1 (4, 40, 41).
In a recent review, Linden et al. (86) concluded that
the evidence supports an association between obesity
and periodontal disease. Studies have also supported
an association between metabolic syndrome and
periodontitis (39, 104); however, the risk of type 2 dia-
betes may confound the association of metabolic syn-
drome with periodontitis (86).
Bullon et al. (19) critically evaluate the evidence for
the biologic basis underlying the inter-relationships
among obesity, diabetes mellitus, atherosclerosis and
chronic periodontitis. The authors conclude that
these chronic conditions share oxidative stress and
mitochondrial dysfunction as common intracellular
features (19). Bullon et al. (19) highlight common
inflammatory cascades and events, particularly mito-
chondrial dysfunction, which appear to underlie
obesity, diabetes, atherosclerosis and periodontitis.
Nutrients and disease risk
Nutrigenomics is the field of nutrition science exam-
ining the interaction of diet, genome and disease (2).
Individual differences in response to dietary factors,
particularly in relation to cardiovascular parameters,
are well documented in the literature (84, 102). Lefe-
vre et al. (84), for example, found that reductions in
low-density lipoprotein cholesterol in response to a
dietary intervention were inversely related to pre-
treatment fasting insulin concentrations. High con-
sumption of mono- and disaccharides, as well as
total fat, increases the risk of developing inflamma-
tory bowel disease (20, 56). Dietary regimes may
modify disease symptoms, in part, through their
actions on the gut microbiota (56). There is growing
evidence that diets characterized by high ratios of
omega-6 to omega-3 fatty acids may have important
adverse physiological consequences, because omega-
6 acids promote inflammation (139, 140). Therefore,
reductions in this ratio would be expected to contrib-
Modifiable risk factors in periodontal disease
ute to an inflammatory environment (168). Anti-
inflammatory diets have been recommended to help
control inflammation secondary to obesity and
diabetes (131).
Dang et al. (42) review the evidence for a direct link
between periodontal disease and nutrition. Numer-
ous nutritional genetic studies provide proof of prin-
ciple that diet can modify the risk for chronic
diseases, such as cardiovascular disease and cancer.
These authors report that a large number of studies
have found no significant association between
selected nutrients and markers of periodontal disease
status; however, they note that most studies failed to
consider potentially important interactions between
genotype and diet (42). Dang et al. (42) highlight the
importance of interactions between genotype and
diet in determining the risk of the most common
complex diseases, including periodontitis.
Modulating the inflammatory
cascade: diet and medications
Given the central role of inflammation in aging and in
many age-related diseases, including periodontitis,
considerable effort has focused on strategies to mod-
ulate inflammatory cascades and thereby reduce
chronic inflammation. Diet and systemic medications
appear to offer great potential in modulating inflam-
mation.
Overall diet is strongly linked to levels of inflamma-
tion and disease risk (20, 169). Strong clinical and lab-
oratory evidence links multiple inflammatory
pathways to high caloric intake, particularly diets
high in refined carbohydrates (28). Dietary caloric
restriction has been found to reduce systemic mark-
ers of inflammation and may attenuate the effects of
chronic inflammatory conditions. Caloric restriction
has been shown to improve serum lipid and glucose
profiles, to lower blood pressure and to increase insu-
lin sensitivity (119). Long-term caloric restriction was
also shown to lower the risk for naturally occurring
periodontal disease and the production of inflamma-
tory mediators in male rhesus monkeys when com-
pared with ad-libitum fed controls, but not in female
monkeys (118).
Dawson et al. (44) examine the biologic basis under-
lying the effect of dietary polyunsaturated fatty acids
on inflammation as well as current evidence on the
therapeutic efficacy of dietary interventions in control-
ling inflammatory conditions. These authors review
the three major types of dietary omega-3 fatty acids
used by the body: a-linolenic acid; eicosapentaenoic
13
Reynolds
acid; and docosahexaenoic acid. Dietary consumption
of eicosapentaenoic acid and docosahexaenoic acid
is thought to be most clinically important because
these omega-3 acids serve as important precursors
for lipid-derived modulators of cell signaling, gene
expression and inflammatory processes. Oxidation
products of eicosapentaenoic acid and docosahexae-
noic acid include resolvins, which exhibit potent
anti-inflammatory activity (46). A recent systematic
review of 23 studies examining the effect of omega-3
polyunsaturated fatty acids in patients with rheuma-
toid arthritis revealed a relatively consistent, but
modest, benefit on joint swelling, pain and use of
nonsteroidal anti-inflammatory drugs (100). Dawson
et al. (44) provide an in-depth review of the preclini-
cal and clinical evidence on the therapeutic efficacy
of polyunsaturated fatty acids in the treatment of
rheumatoid arthritis, inflammatory bowel disease
and other chronic inflammatory conditions, includ-
ing periodontitis.
Several categories of medication modulate the
inflammatory cascade, including corticosteroids, cy-
clooxygenase inhibitors, immunosuppressants, anti-
cytokines and statins. Alani & Seymour (3) examine
the modes of action and relative effects of common
systemic medications on periodontal tissues. These
authors address the status of current research and
conclude that the selective cyclooxygenase-2 inhibi-
tors appear to offer most promise in terms of adjunc-
tive benefit in the treatment of periodontal diseases
(3). A recent systematic review concluded that anti-
tumor necrosis-alpha agents reduce local production
of inflammatory cytokines and periodontal inflam-
mation in rheumatoid arthritis patients with peri-
odontitis (62). Systemic medications may have a
greater role in the management of periodontitis in
patients with comorbidity.
Conclusions
Chronic inflammation is a prominent feature of aging
and of age-related diseases. Periodontitis and other
common chronic inflammatory diseases share a rela-
tively small set of common modifiable risk factors,
which can contribute to increases in systemic mar-
kers of inflammation and modify gene regulation
through a variety of biologic mechanisms. Interven-
tions that target modifiable risk factors have the
potential to improve risk profiles for periodontitis as
well as for other chronic diseases. An understanding
of modifiable risk factors is essential for clinical
practice.
14
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