Inflammation in Aging: Cause, Effect, or

Both?
Published on June 25, 2012

Author: Nancy S Jenny

Specialty: Epidemiology, Biochemistry
Institution: Department of Pathology, University of Vermont College of Medicine
Address: Burlington, Vermont, 05405, United States

Abstract: Aging is a progressive degenerative process tightly integrated with inflammation. Cause
and effect are not clear. A number of theories have been developed that attempt to define the role of
chronic inflammation in aging: redox stress, mitochondrial damage, immunosenescence,
endocrinosenescence, epigenetic modifications, and age-related diseases. However, no single
theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all
are intertwined with inflammatory responses. Human immunodeficiency virus (HIV)-infected patients
undergo a premature aging phenomenon which may provide clues to better elucidate the nature of
inflammation in aging. Environmental and lifestyle effectors of inflammation may also contribute to
modulation of both inflammation and age-related dysfunction.

Introduction
What causes aging? Aging itself is not a disease (Hayflick, 2000). Instead, aging results from the
accumulation over time of detrimental changes at the molecular and cellular levels, and ultimately at
the level of tissues and organs, resulting in disease and increased risk of morbidity and mortality
(Singh and Newman, 2011). Evolutionarily, strong immune and inflammatory responses allowed
early humans to survive to reproductive age. However, these same response mechanisms lead to a
variety of deleterious consequences now that humans routinely survive to older age (Neese and
Williams, 1998). In a highly convoluted process, organs lose functionality and/or structural integrity
both deriving from and leading to age-related diseases like atherosclerosis, dementia, and cancer.
While the etiology of the aging process is not fully understood (Singh and Newman, 2011),
inflammation clearly plays a major role, inextricably linking inflammation and aging (Chung et al.,
2009).
It is not clear, however, whether inflammation causes age-related processes, results from these
processes or both. This review will cover current theories about the nature of chronic
inflammation associated with aging, the causes and effects of inflammation with a focus on the
highly intertwined nature of aging and inflammation and potential interventions to moderate the
effects of inflammation in aging.
Inflammation
Subsequent to trauma or infection, the inflammatory response is initiated at a local, cellular level. A
number of cellular mediators such as macrophages and monocytes are activated. These cells
release cytokines like tumor necrosis factor- and interleukin-6 which act as molecular mediators
and are responsible for the progression of the response to a systemic level encompassing multiple
organs. The inflammatory cascade is designed to destroy microbial pathogens, initiate tissue repair
processes, and promote a return to physiological homeostasis (Gabay and Kushner, 1999). At an
acute level, this process is marked by easily discernible heat, swelling, redness, and pain. However,
in terms of aging and age-related diseases, the inflammation response is a chronic, low level,

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subclinical process mediated by the same effectors, but differing significantly in degree (Tracy,
2003).
Inflammation as a function of age has been well characterized in numerous epidemiologic studies.
Levels of inflammatory mediators typically increase with age even in the absence of acute infection
or other physiologic stress (Singh and Newman, 2011). While levels are still in the sub-acute range,
this chronic inflammation underlies many aging-related conditions (Chung et al., 2009). However, a
key question remains. Is inflammation a cause of the aging process or an effect?
Mechanisms of Inflammation in Aging
Multiple complex inter-related mechanisms contribute to age-related inflammation. The redox stress
hypothesis of aging is based on age-related alterations in cellular redox balance (Sohal and Orr,
2012) accompanied by age-related dysregulation of the immune system (immunosenescence)
(Chung et al., 2009). Other processes such as endocrinosenescence and declining levels of sex
hormones also likely contribute to elevated inflammation in older age (Singh and Newman, 2011). In
addition, a number of diseases, especially age-related diseases such as atherosclerosis and
dementia, have strong inflammatory components (Tracy, 2003).
Redox stress
Endogenous reactive oxygen species (ROS) are hypothesized to play a key role in molecular,
cellular, and structural damage over time (Sohal and Orr, 2012). Under normal physiological
conditions, reactive oxygen species like hydrogen peroxide (H2O2) have vital roles in signal
transduction cascades and function to reversibly oxidize/reduce protein cysteine thiol groups as
molecular on/off switches. However, age-associated increases in reactive oxygen species lead to
over-oxidation and irreversible changes in protein structure and function (Sohal and Orr, 2012). The
biological process to remove these accumulated damaged proteins stimulates inflammatory
responses leading to a chronic inflammatory state (Cannizzo et al., 2011).
Mitochondrial damage
Mitochondria, the primary sites for chemical energy (ATP) production, are essential for normal cell
function and maintenance of redox homeostasis as well as regulating programmed cell
death (Marzetti et al., 2010). Mitochondria are the main source for reactive oxygen species and,
therefore, are key components in redox stress. The mitochondrial free radical theory of aging is
based on oxidative damage to mitochondrial DNA (mtDNA) due to overproduction of reactive oxygen
species. This damage results in dysregulation of cell and organ function leading to the overall
system decline recognized as aging (Marzetti et al., 2010). mtDNA mutations have been reported to
accumulate with age (Bua et al., 2006); the ensuing loss of energy production likely underlies
sarcopenia (age-related muscle loss) (Marzetti et al., 2010). Other tissues affected by age-related
mtDNA mutations include ovary, testis, and adrenal organs with noted loss of function with age
(Wei and Lee, 2002). In addition, apoptosis, or programmed cell death, is a highly regulated process
that leads to cell death without stimulation of the inflammation response and damage to surrounding
tissue. With age, mismanagement of apoptosis due to mitochondrial dysfunction results in increased
inflammation and tissue injury (Green et al., 2011).
Immunosenescence
Oxidative stress and energy dysregulation are also hypothesized to play a key role in
immunosenescence, the gradual decline of the immune system with age. Immunosenescence
results from the accumulation of molecular and cellular defects due to oxidative damage and thymic
involution, the age-related reduction in thymus size and activity, and hyperstimulation of both the
innate and adaptive immune systems. The net result of these processes is increased susceptibility to
diseases and increased morbidity and mortality due to infections and other age-associated diseases
(Singh and Newman, 2011).

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Thymic involution results in significantly reduced levels of nave T cells at older ages. While the
adaptive immune response to previously seen antigens dependent on memory T cells remains
functional, although in a reduced capacity, the ability to respond to new infectious agents, requiring
nave T cells, is severely impaired. Poor immune function, combined with continued exposure to
antigens, results in chronic activation of macrophages and other pro-inflammatory cells and
contributes to chronic low level inflammation common in older age (Franceschi et al., 2000). In
addition, senescent cells demonstrate significant increases in production and secretion of many pro-
inflammatory cytokines. Chronic inflammation, therefore, not only results from, but also drives
immunosenescence (Freund et al., 2010).
Endocrinosenescence
In addition to immunosenescence, the endocrine system also experiences age-related declines in
function (endocrinosenescence) most notably affecting sex steroid production (Singh and Newman,
2011). Levels of growth hormone and dehydroepiandrosterone (DHEA) and its primary circulating
form dehydroepiandrosterone sulfate (DHEAS) decrease with age as well (Migeon et al., 1957).
However, cortisol production is increased due to over-stimulation of the hypothalamic-pituitary-
adrenal (HPA) axis (Luz et al., 2003).
Chronic over-stimulation of the hypothalamic-pituitary-adrenal axis leads to immune dysregulation
and contributes to immunosenescence (Bauer et al., 2009). Decreased levels of DHEA and growth
hormone also likely play a role in immunosenescence. Both DHEA and growth hormone enhance the
proliferation and activity of cellular mediators of immunity and DHEA reduces inflammatory cytokine
production (Traish et al., 2011). Reduction in levels of these hormones and increasing levels of
cortisol with age would therefore lead to increased inflammation (Buford and Willoughby, 2008;
Traish et al., 2011).
Sex hormones also modulate the production of inflammatory cytokines. Studies indicate that
interleukin-6 gene transcription and secretion are inhibited by both estrogen and androgen (Keller et
al., 1996; Pottratz et al., 1994). Many studies show an increase in interleukin-6 and other pro-
inflammatory cytokines in women subsequent to menopause (Singh and Newman, 2011). Similar
inverse relationships have been reported for testosterone levels and inflammatory markers in older
men (Maggio et al., 2006). As levels of these steroid hormones decrease with age, levels of
inflammatory cytokines are increased contributing to chronic inflammation, cellular senescence, and
other age-related diseases (Singh and Newman, 2011).
Telomere attrition and cellular senescence
Telomeres, tandem repeats of DNA sequence TTAGGG and associated proteins forming protective
caps at the end of chromosomes, are thought to be markers of biological aging and the cellular
senescence which contributes to immunosenescence and endocrinosenescence (Blackburn, 2001).
Cellular, or replicative, senescence, occurs with loss of telomeric DNA. Telomeric DNA is lost during
each replication cycle and with repetitive cycles over the life course, eventually reaches a critically
short length which no longer supports replication. Telomere attrition results from aging (repeated
cellular divisions), stress, infection, and chronic diseases (Effros, 2011). If shortened telomeric DNA
is not repaired by the enzyme telomerase, cells with critically short telomere length become
senescent.
Telomere length is directly impacted by both immune and endocrine functions (Andrews et al., 2010;
Kaszubowska, 2008) as telomerase activity is upregulated by estrogen (Lin et al., 2011) and
inhibited by cortisol (Choi et al., 2008). As part of the aging process, levels of estrogen are
decreased and cortisol increased leading to down-regulation of telomerase activity and cellular
senescence further fueling both immunosenescence and endocrinosenescence.
Cellular senescence is theorized to limit carcinogenesis by stopping replication in cells carrying
mutations and chromosomal damage (Olovnikov, 1996). While beneficial in this aspect, senescent

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cells may, however, accelerate other disease pathways including some cancers (Rodier and
Campisi, 2011). Senescent cells are not quiescent but rather have significantly altered phenotypes
and activities including increased production of inflammatory cytokines, which likely contributes to
the chronic inflammation associated with aging (Freund et al., 2010; Rodier and Campisi, 2011).
Evidence for this association is found in a number of epidemiologic studies of associations of
telomere length and inflammation and disease. Telomere attrition has been linked to increased
inflammation (ODonovan et al., 2011) and cardiovascular disease risk and death (Fitzpatrick et al.,
2007; 2011) in cohorts of older men and women. Patients with Alzheimers disease were also found
to have shorter telomeres than similarly aged healthy subjects (Hochstrasser et al., 2012).
Epigenetic modifications
Epigenetic modifications are modifications to phenotypes or gene expression resulting from changes
other than changes in the underlying DNA sequence. These changes may be retained by the cell
throughout its lifespan and, for germline cells, may be passed to future generations (Birney et al.,
2007). DNA methylation is one of the most well characterized epigenetic changes (Rodriguez-
Rodero et al., 2010).
DNA methylation is essential for normal development and survival (Munoz-Najar and Sedivy, 2011).
During aging, however, the DNA methylation pattern can change resulting in a global decrease in
methylation with hypermethylation of some promoter regions, most notably promoters of several
tumor repressor genes (Munoz-Najar and Sedivy, 2011). Histone modifications lead to both gene
activation and suppression (Munoz-Najar and Sedivy, 2011). Histone modifications and changes in
DNA methylation near telomeric regions correlate with telomere attrition and cellular senescence
(Gonzalo et al., 2006). In addition, these epigenetic changes are associated not only with activation
of inflammatory genes (Medzhitov and Horng, 2009), but also with cancer, dementia,
atherosclerosis, and a number of other diseases (Munoz-Najar and Sedivy, 2011; Urdinguio et al.,
2009).
Inflammatory diseases
Many diseases common in older adults have clear inflammatory components. Similar to cellular
senescence, it is likely that inflammation both reflects the development and progression of disease
and promotes disease evolution itself (Tracy, 2003). Many studies of the association of disease and
inflammation have focused on C-reactive protein (CRP), used clinically as a biomarker, or circulating
plasma marker, of inflammation. CRP is an acute phase protein produced in the liver; its levels are
upregulated by pro-inflammatory cytokines like interleukin-6. CRP activates the complement
cascade and functions in innate immunity. As such, CRP is a marker of the general systemic
response to insult through inflammation. For acute illnesses such as sepsis, CRP levels can reach
10,000 mg/L; however, in terms of chronic inflammation, levels of interest are in the 1-10 mg/L range
(high sensitivity CRP) (Tracy, 2003). CRP levels in this range, reflecting low level chronic
inflammation, directly correlate with the presence and extent of metabolic syndrome, diabetes,
subclinical and clinical cardiovascular disease, dementia, macular degeneration, chronic obstructive
pulmonary disease, renal disease, osteoporosis, sarcopenia, and cancer (Tracy, 2003). Based on
these and many other studies, a consensus panel set the following cardiovascular disease risk
categories based on plasma CRP level: low risk, CRP<1 mg/L; intermediate risk, 1-3 mg/L; and high
risk, >3 mg/L (Pearson et al., 2003).
In a highly entangled web, CRP serves as a biomarker of disease presence, and CRP and cytokines
such as interleukin-6 that upregulate CRP also feed the inflammatory response, driving disease
initiation and progression. CRP, through activation of the classic complement system and
unregulated stimulation of the innate immune response, leads to tissue destruction and organ
dysfunction, potentiating aging-related diseases (Chung et al., 2009).

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In addition to endogenous agents like inflammatory cytokines and CRP, other factors such
as obesity and smoking contribute to both disease and inflammation. Inflammation and obesity are
highly interrelated; obesity is associated with diabetes and cardiovascular disease as well as a
growing number of other diseases with inflammatory components including dementia and cancer
(Knight, 2011). Adipocytes, especially those in visceral adipose tissue, are metabolically active and
synthesize and release a number of pro-inflammatory molecules (Chung et al., 2009; Manabe,
2011). Inflammation may also drive obesity. Adipose tissue secretes adipokines, proteins with
endocrine, paracrine, and autocrine properties, which mediate whole body energy balance and
storage (Chung et al., 2009; ORourke, 2009).
A well-characterized example of the inflammatory damage process underlying many age-related
diseases is atherosclerotic lesion development and growth. Injury or damage to the vascular
endothelium through deposition of excess plasma LDL cholesterol, hypertension (mechanical sheer
stress injury), free radicals from cigarette smoke, or a number of other stimuli leads to altered
endothelial cell activity (Ross, 1999). Under normal conditions, endothelial cells are actively anti-
thrombotic and anti-inflammatory, promote vasodilation and maintain tight, impermeable cell
junctions. When activated or perturbed by a stimulus, endothelial cells undergo a number of
phenotypic and morphologic changes and express receptors for inflammatory cells, cellular junctions
become permeable, the endothelium becomes procoagulant, and endothelial cells promote
vasoconstriction and initiate production and secretion of inflammatory cytokines and growth factors
(Ross, 1999). If the injury stimulus continues, the resulting chronic inflammation leads to increased
migration of macrophages and lymphocytes to the area. These cells release inflammatory cytokines
causing additional damage to the endothelium accompanied by formation of fibrotic tissue,
thickening of vessel walls, and vascular dysfunction (Ross, 1999). Similar responses to chronic
inflammatory stimuli in other cell systems result in diabetes, kidney disease, dementia, and cancer
(Manabe, 2011). In combination, even small losses of function in individual organs create overall
homeostatic imbalance and global dysfunction.
Frailty
While frailty is considered to be a syndrome of contemporaneous conditions (weakness, immobility,
and poor tolerance of physiologic or psychologic stress) (Fried et al., 2001) and not a disease itself,
it clearly illustrates the importance of inflammation in aging and the interlinked nature of the multiple
mechanisms involved in aging. Frailty results from the accumulation of functional declines in multiple
systems that decrease overall physiologic reserve leading to weight loss, especially loss of muscle,
reduced strength and endurance, and overall poor physical function (Fried et al., 2001). A number of
inflammatory cytokines are associated with the individual components of frailty in older adults:
weight loss, decline in muscle function, and reduced overall physical function (Reuben et al., 2002;
Zoico and Roubenoff, 2002). A greater burden of inflammatory diseases, likely reflecting a higher
degree of overall inflammation, is associated with increased risk of frailty (Chang et al., 2012).
However, the association of frailty with inflammation persists even in the absence of other common
diseases of aging (Walston et al., 2002).
As demonstrated by the frailty syndrome, multiple processes, both endogenous and environmental,
contribute to inflammation over the life course. Inflammation, in turn, also plays a role in facilitating
decline in physiologic reserve and function and initiation and progression of a variety of diseases.
The cumulative effects of this complex interplay form the basis of aging. As there is no cure for
aging, a key question, then, is how to modulate the effects of inflammation on aging and to age
successfully.

Potential Intervention Strategies

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In order to understand how to delay or prevent age-related declines in function, it is important to
distinguish between successful or healthy aging and pathologic aging. Some individuals survive to
older age with relatively intact health and physical and cognitive function (exceptional survival)
(Newman et al., 2011). However, there is significant heterogeneity in rates of physical and cognitive
declines among individuals (Guralnik and Kritchevsky, 2010). Genes and gene-environment
interactions likely play a key role in successful aging (Iannitti and Palmieri, 2011). However, even in
the absence of infection or trauma, inflammatory stimuli are inescapable, although certain
environmental and lifestyle factors may be avoidable. Therapeutic interventions may also modulate
the effects of inflammation and age-related disease. For example, several potential anti-
inflammatory interventions have been proposed. In addition, epidemiologic studies have examined
the use of biomarker panels to better assess and monitor inflammation status as a means to target
interventions.
Environmental factors
Cigarette smoke is a well known cause of morbidity and mortality (Sopori, 2002; Vardavas and
Panagiotakos, 2009). Smoke exposure directly stimulates immune and inflammatory responses. In
addition, chronic airway inflammation leads to tissue injury and remodeling and thus chronic
inflammation (Sopori, 2002). In support of this, markers of oxidative stress (Mandraffino et al., 2010)
and inflammatory proteins (Levitzky et al., 2008) are higher and telomere length lower (Babizhayev
and Yegorov, 2011) in smokers compared to never smokers. Similar results are seen for exposure to
second hand smoke (Hamer et al., 2010).
As is cigarette smoke, particulate air pollution is a major environmental factor contributing to
inflammation, morbidity, and mortality (Brook et al., 2010). Higher levels of air pollution are
associated with increased incidence of cardiovascular and other diseases (Brook et al., 2010; Gill et
al., 2011). Inflammation likely mediates this increased risk. Even short-term exposure to particulate
air pollution is associated with increased levels of inflammatory proteins. Some studies also link air
pollution exposure to increased oxidative stress and epigenetic changes as well (Brook et al., 2010).
Lifestyle factors
Regular physical activity and healthy diet are associated with decreased risk of many diseases and
increased likelihood of successful aging. Physical activity is associated with increased lifespan,
lower risk of functional and cognitive impairment, and lower levels of inflammatory markers in older
adults (Simpson and Guy, 2010). Exercise has also been reported to favorably impact immune
function (Simpson and Guy, 2010).
Although anti-oxidant dietary supplements have shown equivocal effects in modulating inflammation
and disease (Yoshihara et al., 2010), overall diet is strongly linked to levels of inflammation and
disease risk (Willett, 2008). Western diet (low intake of fruits, vegetables, and fiber and high intake of
processed grains and saturated fat, particularly red meat), especially combined with a sedentary
lifestyle, is associated with elevated CRP (Koenig et al., 1999) and higher risk of chronic disease
(Odermatt, 2011) compared to a healthy or Mediterranean style diet. Conversely, the Mediterranean
diet (high intake of fruits, vegetables, whole grains, fish, and olive oil and low intake of red meat) is
associated with lower levels of inflammation and decreased risk of cardiovascular disease,
dementia, and some cancers compared to the Western type diet (Carter et al., 2010; Pauwels, 2011;
Solfrizzi et al., 2011). Poor diet may also accelerate telomere attrition (Shiels et al., 2011) and
epigenetic alterations in DNA (Niculescu and Lupu, 2011).
Caloric restriction, long-term dietary intervention where caloric intake is reduced but levels of
essential nutrients are maintained, has been successful in extending the average and maximum
lifespan of a number of species (Anderson and Weindruch, 2012). In rodents, limiting total calories
results in increases in lifespan of as much as 50% compared to animals allowed free choice feeding
(Li et al., 2011). Evidence for a similar effect in humans can be found in the population of Okinawa,

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Japan who reportedly eat fewer calories than the mainland Japanese population and have a larger
proportion of centenarians (Anderson and Weindruch, 2012). Caloric restriction has also been
reported to postpone development of age-related diseases in non-human primates as well as
humans (Cruzen and Colman, 2009; Holloszy and Fontana, 2007). Several studies, such as the
Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE)
Study (Rickman et al., 2011) are currently underway looking at the effects of caloric restriction in
humans. Regardless of the outcome of these studies, sensible diet, combined with physical activity,
is still an important formula to maintain health (Anderson and Weindruch, 2012).
Stress may also play an important role in mediating inflammation. Stress is induced by a variety of
factors including caregiving and socioeconomic status. Lower socioeconomic status (based on
education, income, and wealth) and pessimism are associated with higher levels of inflammation
markers (Hajat et al., 2010; Nazmi et al., 2010; Roy et al., 2010). In addition, psychosocial stress
may also lead to accelerated telomere attrition; telomere length was found to be reduced in those
with lower socioeconomic status (Shiels et al., 2011). Caregiver stress is associated with increased
levels of inflammation markers and increased risk of frailty and cardiovascular disease (von Kanel et
al., 2006). Life stress overall is associated with accelerated telomere loss which likely contributes to
the association between stress and age-related disease (Epel et al., 2004).
Hormone replacement therapy
Replacement of hormones that undergo age-related decreases in levels (estrogen, androgens,
DHEA, growth hormone) has been investigated for potential age-mediating effects. While some
hormone replacement trials have shown limited benefits, negative side effects of replacement,
including increased risk of cancers, have been reported (Tosato et al., 2007). There are no current
recommendations for replacement therapy although studies continue to explore risks and benefits
especially in terms of individualized care (Schwartz and Holtorf, 2011; Schwartz et al., 2011).
Anti-inflammatory mediators
In addition to cardiovascular disease prevention through reduction of plasma LDL
cholesterol, statins are under study as anti-inflammatory agents. The Justification for the Use of
Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial
examined the potential for cardiovascular disease prevention in apparently healthy adults aimed not
at reducing LDL cholesterol levels, but targeted at decreasing CRP (Ridker et al., 2008). Trial data
suggested that in this group of adults with LDL cholesterol levels below the threshold for lipid-
lowering therapy (130 mg/dL) but with elevated CRP (2 mg/L intermediate to high risk),
rosuvastatin treatment may be beneficial both in terms of cardiovascular disease prevention and
reduction in non-cardiovascular mortality due to anti-inflammatory effects (Ridker et al., 2008).
However, there are no current recommendations for statin treatment based only on elevated CRP
(Kones, 2010).
Other therapies aimed at reducing inflammation include direct inflammatory cytokine antagonists and
depletion of pro-inflammatory lymphocyte populations. A number of these drugs are in clinical trials
aimed at prevention of chronic inflammatory diseases (Little et al., 2011).
HIV and premature aging
Model systems are important to study aging phenomena. However, it is difficult to follow human
subjects across the entire life course. Human immunodeficiency virus (HIV) may provide a novel
population for aging research. While antiretroviral therapy has led to the ability to control HIV in
almost all patients, long-term treated patients have an expected life span that is significantly shorter
than that of non-infected persons (Deeks, 2011). The increased risk of morbidity and mortality is
primarily due to non-HIV complications like atherosclerosis, frailty, and dementia diseases
common in older adults leading to the hypothesis that HIV-infected patients undergo accelerated
or premature aging (Deeks, 2011; Desai and Landay, 2010). This may result from early

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immunosenescence in HIV-infected patients (Desai and Landay, 2010). Many of the degenerative
changes in immunity seen with aging are common in HIV-infected patients who are either untreated
or fail to fully respond to treatment (Desai and Landay, 2010). Similarly, chronic inflammation is
strongly linked to morbidity and mortality in HIV-infected persons as it is in older adults (Deeks,
2011). Many of the therapies aimed at reducing loss of function in aging are being examined in the
HIV patient population (Harding et al., 2011). Further exploration of premature aging associated with
HIV may lead to additional interventions that would benefit both HIV-infected patients and older
adults.
Biomarker panels for assessing inflammation status
In order to be effective, potential therapies need to be appropriately targeted. Development of better
strategies for assessing inflammation status or inflammation burden is one means to achieve this
goal. Chronic inflammation is typically measured by the individual serum levels of pro-inflammatory
mediators like interleukin-6 and acute phase proteins like CRP. While levels increase with age,
healthy aging, defined as aging without overt disease and loss of physical or cognitive function, is
associated with smaller increases in inflammation factors over time and a lower inflammation status
(Freund et al., 2010). Using a panel of multiple biomarkers representing different facets of
inflammation (i.e., immune system activation, adipocyte-secreted products, and markers of specific
cellular perturbation such as vascular endothelial cell activation) may improve risk prediction by
better defining the subtle differences in inflammation status between those are aging in a healthy
manner versus those who are not (Jenny et al., 2007; Kizer et al., 2011; Reuben et al., 2002).
Conclusions
The importance of studying aging and age-related loss of function is clear. Adults aged 70 years and
over are the fastest growing segment of the U.S. population (Manton and Vaupel, 1995). However,
aging is not a simple linear process where cumulative insults lead to chronic inflammation which in
turn leads to protein, cell, and organ dysregulation and the structural and functional changes that
accompany aging. While there are a number of theories as to why aging occurs, they are not
mutually exclusive and no single theory explains all aspects of aging. Instead, multiple processes
form a labyrinth network where loss of function in one system, whether from environmental insults
and/or natural programmed phenomena, impacts all other systems, leading to and derived from
inflammatory responses, and resulting in what is defined as aging.

While there does not appear to be a cure for the complex process of aging, it should be possible to
facilitate successful aging, namely, aging without significant loss of cognitive or physical function and
relatively free of disease. There are lifestyle factors and potential interventions that can slow specific
processes primarily through reduction or prevention of chronic inflammation and therefore forestall
aging itself. Studies such as the Lifestyle Interventions and Independence for Elders Study
(Fielding et al., 2011) currently underway will help elucidate pathways for better preservation of
function and exceptional aging.
Disclosure
The author reports no conflicts of interest.

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