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Experimental Gerontology xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Experimental Gerontology
journal homepage: www.elsevier.com/locate/expgero

Review

Aging, inflammation and the environment



Arsun Bektasa,1, Shepherd H. Schurmanb,1, Ranjan Senc, Luigi Ferruccia,
a
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
b
Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
c
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The aging process is driven by interrelated mechanisms that lead to the emergence of characteristic phenotypes
Aging that include changes in body composition, energy production and utilization imbalance, homeostatic dysregu-
Inflammation lation, and neurodegeneration and loss of neuroplasticity. Mainstream theories of aging all recognize that the
Environment aging phenotypes result from an imbalance between stressors and stress buffering mechanisms and a resultant
Inflammaging
loss of compensatory reserve leading to accumulation of unrepaired damage. This in turn results in increased
Longitudinal studies
disease susceptibility, reduced functional reserve, reduced healing capacity and stress resistance, unstable health
and finally failure to thrive. The resultant physical and cognitive decline that culminates with the frailty syn-
drome is a tipping point of healthspan and implies a high risk of system decompensation and death. Preserving
physical and cognitive function is the main focus of geriatric and gerontological research, but it is important to
recognize that accomplishing this goal requires a profound understanding of the molecular, cellular and phy-
siological mechanisms that ultimately determine functional changes. In this context, the proinflammatory state
of aging plays a major role. Longitudinal studies have shown that with aging most individuals tend to develop a
chronic low-grade proinflammatory state, and that such a state is a strong risk factor for multimorbidity, physical
and cognitive disability, frailty and death. A number of environmental factors may play an important role in
modifying the proinflammatory state. We explore processes and mechanisms of aging that affect human biology
and the possible links of inflammation and the environment to aging, especially those related to metabolism. We
point out that longitudinal studies with a life course approach are needed to gain further mechanistic insight on
the processes that lead to functional decline with aging, and the role played in this process by inflammation and
environmental challenges.

1. Introduction associated with the severity of multimorbidity and with future risk of
severe multimorbidity. Based on these studies, it has been suggested
Aging is the strongest risk factor for most chronic diseases. The that the proinflammatory state of aging may be a proxy biomarker of
number of coexistent chronic diseases, usually defined a as multi- the pace of aging. Despite the strong epidemiological evidence that high
morbidity, increase with aging and this observation has been con- levels of proinflammatory markers in older people are associated with
sistently confirmed in large population studies (Marengoni et al., 2011; risk of developing most of the diseases typical of aging as well as
Vetrano et al., 2017; Yancik et al., 2007). There is some evidence that multiple chronic diseases (Fabbri et al., 2015; Stepanova et al., 2015),
the accumulation of multiple chronic disease in some older individuals why older people tend to have a proinflammatory state as well as the
deviates from the distribution expected based on the compound prob- specific mechanisms that connect inflammation with chronic diseases
ability of having each single disease, even when diseases not patho- remain unclear. Progress in this field is essential if we want to target
physiologically correlated are considered. This has been interpreted as inflammation in interventions that promote healthy and successful
suggesting that some individuals experience “accelerated” aging and aging.
that multimorbidity severity can be thought as a proxy measure of the We propose that more insight can be gathered by studying the
“force of aging”. There have been many attempts to identify char- confluence between inflammation and the environment and their ef-
acteristics associated with multimorbidity progression. Overall, central fects on aging and healthspan. Once comorbidities arise, these inter-
obesity and inflammation have consistently been found to be strongly actions appear to lead to decreased longevity and physical and


Corresponding author at: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
E-mail address: ferruccilu@mail.nih.gov (L. Ferrucci).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.exger.2017.12.015
Received 28 October 2017; Received in revised form 17 December 2017; Accepted 19 December 2017
0531-5565/ Published by Elsevier Inc.

Please cite this article as: Bektas, A., Experimental Gerontology (2017), https://doi.org/10.1016/j.exger.2017.12.015
A. Bektas et al. Experimental Gerontology xxx (xxxx) xxx–xxx

cognitive decline. Here, we explore processes and mechanisms of aging measured by a walking test (Ferrucci and Studenski, 2012). The amount
that affect human biology and possible links of inflammation and the of energy used at rest, the resting metabolic rate, decreases with age in
environment to aging, especially related to metabolism. We propose large part because of a loss of lean body mass but will decline less in
that these mechanisms are best explored in the context of longitudinal those with multiple chronic conditions (Ferrucci et al., 2010; Ruggiero
studies. and Ferrucci, 2006). Hence, sick older individuals will use most of their
available energy in the performance of essential activities of daily living
2. Systemic effects of aging (Ferrucci et al., 2010), and when the energy “produceable” becomes
even lower, they may no longer be able to maintain autonomy even for
The systemic consequences of aging on the development of the simple, self-care activities. As mentioned above, resting metabolic rate
aging phenotypes can be roughly summarized into four major domains progressively declines with aging, and such a decline is explained in
that include dimensions that change in all animals, from worms to part, but not fully, by the age-related decline of lean body mass. The
humans (Fig. 1): 1) changes in body composition; 2) imbalance between decline occurs even in persons who remain very healthy in late life and
energy availability and demand; 3) dysregulated signaling networks has been confirmed in individuals who experience extreme longevity,
that maintain homeostasis; and 4) neurodegeneration with impaired such as centenarians (Pereira da Silva et al., 2016).
neuroplasticity.
2.3. Homeostatic dysregulation
2.1. Changes in body composition
In all living organisms, a status of homeostatic equilibrium in spite
Changes in body composition with age are among the most apparent of continuous challenges is maintained through a complex signaling
and unavoidable effects of aging. Overall, weight increases until late system that includes hormones, inflammatory mediators, and anti-
middle age and will decline in men between the ages 65 and 70 and oxidants; all of which are affected by aging. Hormones such as testos-
slightly later in women (Ferrucci et al., 2010). Lean body mass, on the terone (Harman et al., 2001), growth hormone, insulin growth factor I,
other hand, decreases steadily after the third decade (Ferrucci et al., 25(OH) vitamin D, aldosterone, and melatonin decline character-
2010), while fat mass increases in middle age and then declines fol- istically with age in both men and women; while cholecystokinin,
lowing the trajectory of weight change (Ferrucci and Studenski, 2012). cortisol, prolactin, norepinephrine and insulin go up with age (Ferrucci
Visceral fat, which is responsible for much of obesity-related pathology and Studenski, 2012). A mild proinflammatory state, discussed below,
and is an independent risk factor for coronary artery disease, stroke and develops in most aging individuals reflected in high levels of proin-
death (Folsom et al., 1993), continues to accumulate and is reflected in flammatory markers such as interleukin 6 (IL-6) and c-reactive protein
waist circumference increasing throughout life (Ferrucci and Studenski, (CRP) (Ferrucci et al., 2005). Oxidative stress damage also increases
2012). Higher total body fat mass and lower total lean mass, in parti- with aging because of the increase in production of reactive oxygen
cular, are predictive of a faster decline in muscle quality (strength-to- species (ROS) and perhaps because of a decrease in the concentration
mass ratio) with age (Fabbri et al., 2017). The loss of muscle quality and effectiveness of antioxidant buffers (Ferrucci and Studenski, 2012).
that at least in part is due to the accumulation of intramyocellular lipids These hormones, inflammatory biomarkers, and antioxidants are part of
can lead to morbidity and mortality through both metabolic dysregu- complex signaling networks that control homeostasis and individual
lation and mobility limitations, falls and fractures (Ferrucci et al., biomarker levels could reflect adaptation within homeostatic feedback
2014). It is evident that all organs experience some change in tissue loops rather than be a reflection of causative factors. Also important in
composition through life and these age-related changes are directly the homeostatic regulation of metabolism are micronutrients such as
connected to subclinical and clinical pathology, including neurode- vitamins like vitamin D, minerals such as magnesium and selenium, and
generation (Camandola and Mattson, 2017), physical frailty, increase in antioxidants such vitamins D and E. Reduced amounts of micro-
fibroconnective tissue build-up in muscle, and demineralization and nutrients have been implicated with accelerated aging and increased
loss of strength of bone (Ferrucci et al., 2014). risk of disease (Ferrucci and Studenski, 2012). Interestingly, except for
vitamin D, supplementation has not been clearly associated with better
2.2. Energy production and utilization imbalance health.

The balance between energy availability and energy demand is 2.4. Neurodegeneration and neuroplasticity
tightly regulated; the phosphate release from ATP provides cells with
the energy necessary for many essential biological functions and its The number of neurons decline throughout life as neurons in gen-
continuous resynthesis maintains the ATP concentration virtually stable eral stop reproducing shortly after birth (Ferrucci et al., 2010). Atrophy
even in the most energetically demanding tissues, such as the cardiac occurs in various parts of the brain at different rates especially after the
muscle and the brain (Du et al., 2008; Ferrucci and Studenski, 2012; age of 60 years (Raz et al., 2007). Brain atrophy, for instance in the
Yaniv et al., 2013). ATP is constantly resynthesized since the storage of thalamus, is often accompanied by microglial activation and neuroin-
ATP is enough for only a few seconds (Casey and Greenhaff, 2000). In flammation and may be a contributor to cognitive age-related declines
muscle cells and neurons such stability is supported by the phospho- as well as some brain diseases such as Alzheimer's disease (Cagnin et al.,
creatine buffering system that accumulates chemical energy to be 2001). With aging, microglia acquires a predisposition to reactive in-
promptly used when the demand suddenly increases (Christie, 2007). flammation and the brain tissue from older persons contains a higher
Most of the energy used by muscle is generated through aerobic me- level of proinflammatory cytokines and a lower level of anti-in-
tabolism (though some is generated through anaerobic glycolysis) and, flammatory cytokines than the brain of younger individuals. Higher
hence, energy consumption can be estimated indirectly by oxygen inflammation has been associated with lower cognition and reduced
consumption (indirect calorimetry). Fitness, or the maximum energy neuronal plasticity, expressed as a reduced capacity of adaptation and
that can be produced by a person, can hence be estimated indirectly compensation (Norden and Godbout, 2013). Because the brain is cap-
from peak oxygen consumption (MVo2peak) using a maximal treadmill able of reorganization and compensation, extensive neurodegeneration
test. MVo2peak declines with age (Fleg et al., 2005) and is accelerated may occur without any clinically evident functional consequence. Brain
with chronic disease or those who are sedentary (Ferrucci et al., 2010). pathology such as amyloid plaques and neurofibrillary tangles con-
Older individuals with multiple comorbidities have lower available sidered the hallmarks of Alzheimer's disease are found in autopsy of
energy and require more energy at rest and during physical activity. many older individuals who were cognitively normal (Ferrucci and
This can be manifested as fatigue and through exercise tolerance Studenski, 2012). How the brain changes and adapts with age is still the

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A. Bektas et al. Experimental Gerontology xxx (xxxx) xxx–xxx

What are the processes by which aging and disease affect


aging phenotypes and longevity?

Environment (External and Internal) Genetics

Biological Genomic Epigenetic Telomere Mitochondrial


Mechanisms Instability Alterations Attrition Dysfunction
of Aging

Loss of Cellular Altered Intercellular Stem Cell Dysregulated


Proteostasis Senescence Communication Exhaustion Nutrient Sensing

Inflammation

Domains of Changes in Energy Imbalance Homeostatic Neurodegeneration /


the Aging Body Composition Production / Utilization Dysregulation Neuroplasticity
Phenotype

Disease

Disease Susceptibility Adapted from:


Reduced Functional Reserve Physical and
Ferrucci L, Studenski S. Clinical Problems of Aging.
Reduced Healing Capacity and Stress Resistance Cognitive Harrison’s Principles of Internal Medicine, 18 th Ed. 2012
Unstable Health FRAILTY Lopez-Otın C et al. The Hallmarks of Aging. Cell. 2013
Failure to Thrive

Fig. 1. The processes by which aging and disease affect aging phenotypes and longevity.
Environmental stressors, especially those that affect inflammation and metabolism, and individual genetics determine the dysfunction of biological mechanisms associated with aging,
ultimately converging to a chronic low-grade state of inflammation, often referred to as "inflammaging". This proinflammatory state amplifies systemic and localized changes that
contribute to the development of aging phenotypes, with consequential increased disease susceptibility and risk of multimorbidity as well as physical and cognitive decline, frailty, and
decreased longevity. Many of these interactions are cyclical in nature and further accelerate processes and mechanisms that lead to aging phenotypes and age-related functional decline.

subject of intense research. For instance, in one representative fMRI reduced functional reserve, reduced healing capacity and stress re-
study, while there was significant activation of the left hippocampus in sistance, unstable health and finally failure to thrive. Ultimately, phy-
young participants during autobiographical event memory retrieval, sical and cognitive decline will result, leading to frailty (Fig. 1). In turn,
there was significant bilateral hippocampi activation in older in- frail older persons tend to develop multiple chronic diseases resulting in
dividuals suggesting that older adults may be compensating in recall by a vicious cycle of increased multimorbidity and worsening frailty
recruiting additional neural circuits (Maguire and Frith, 2003). (Vetrano et al., 2017).

2.5. The phenotype of aging common pathway 3. Chronic inflammation

The systemic changes of aging (changes in body composition; bal- Aging is characterized by the development of a mild proin-
ance between energy availability and demand; signaling networks that flammatory state (Howcroft et al., 2013; Morrisette-Thomas et al.,
maintain homeostasis; and neurodegeneration and neuroplasticity) all 2014). Dysregulation of inflammation with age is found in almost every
will lead in some combination to increased disease susceptibility, living organism. However, exact mechanisms of such dysregulation are

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not well understood. In normal situations, inflammation is essential to which in general are environmentally sensitive, can provoke progeroid
health since it helps organisms to fight the invasion of microorganisms syndromes, and experimental manipulation in animal models can either
and it plays essential roles in repair and maintenance of organs. When extend or decrease lifespan (Lopez-Otin et al., 2013). For instance, a
inflammation is transient, meaning it rises when needed and fades reduction of SIRT6, which through histone H3K9 signaling regulates
down when it is no longer needed, there are no long-term con- genomic stability, NF-κB signaling and glucose homeostasis, can reduce
sequences. However, when inflammation becomes prolonged, either longevity in mice (Mostoslavsky et al., 2006), while an increase of
because of an intrinsic dysregulation of the immune system, or because SIRT6 can increase lifespan (Kanfi et al., 2012). MiRNAs, which are
the cause that triggered the inflammatory reaction is not removed, in- epigenetic regulators that circulate in the blood, appear to change with
flammation can lead to the accumulation of damage that eventually age (Franceschi et al., 2017). Several have been linked to inflammation
becomes manifest as pathology. This state of chronic inflammation that (inflamma-miRs), including miR-21, -126 and -146a which target the
correlates with aging but with substantial heterogeneity across in- NF-κB pathway (Olivieri et al., 2013). Metabolic changes also can have
dividuals, is sometimes referred to as “inflammaging” and is a strong a profound effect on epigenetic alterations that have been linked to
risk factor for the occurrence, progression, and complication of many aging (Lopez-Otin et al., 2016). Peters et al. (2015) showed that the
chronic diseases including obesity, cardiovascular disease, and neuro- difference between the calculated “transcriptomic age” of an individual
degenerative diseases (Bektas et al., 2017; Franceschi and Campisi, based on gene expression profiles and chronological age was associated
2014; Franceschi et al., 2007). Hence, the causal pathways and mole- with signs of the metabolic syndrome including high blood pressure,
cular mechanisms that connect inflammaging and chronic diseases re- elevated cholesterol levels, abnormally high fasting glucose, and being
main very little understood. Clinically, inflammaging is characterized overweight or obese. Telomeres are particularly susceptible to age-re-
by increased blood levels of several inflammatory biomarkers, in- lated deterioration through exogenous or endogenous damage
cluding CRP, IL-6, IL-18 and tumor necrosis factor-α (TNF-α) (Scheller (Blackburn et al., 2006) and through inflammation (Jurk et al., 2014).
et al., 2011). Importantly, IL-6 serum levels also predict incident dis- Anti-inflammatory diets such as the Mediterranean diet have been
ability and frailty (Soysal et al., 2016). In particular, the risk of de- shown to slow leukocyte telomere length shortening and to be asso-
veloping mobility disability appears to be increasing linearly for IL-6 ciated with reduced cardiovascular disease and mortality (Garcia-
levels higher that 2.5 pg/ml and these findings have been replicated in Calzon et al., 2015). Interestingly, obesity and in particular central
multiple studies, although there is some uncertainty on the specific obesity (which is at the core of the metabolic syndrome) is one of the
value for the critical threshold (Ferrucci et al., 1999). Also, elevated strongest known correlates of inflammaging (Schrager et al., 2007).
levels of IL-6 have been tied to many of the systemic changes of aging. Mitochondrial dysfunction has been shown to lead to accelerated
High IL-6 scores are related to lower walking speeds, which is con- aging in various mouse models (Kujoth et al., 2005; Trifunovic et al.,
sistent with multifactorial origin of this phenotype (Ferrucci et al., 2004; Vermulst et al., 2008) and to the overproduction of amyloid
2002). precursor protein and oxidative damage in the brain with memory loss
in a mouse model of Alzheimer's disease (Morley et al., 2012). Human
4. Mechanisms of aging and the environment aging is similarly thought to be linked to mitochondrial deterioration
(Wang and Hekimi, 2015). Patients with mitochondrial diseases can
Influences of the environment on chronic inflammation and the have signs or symptoms related to age-related diseases including muscle
other above-described domains of the aging phenotypes probably im- weakness, diabetes, and sensorineural hearing loss, frequently are
pact physiological and functional trajectories of aging across the whole multisystem in nature, and often affect the heart, liver and kidney
lifespan. The role of the environment can be examined in the context of (DiMauro et al., 2013). The role of ROS generation, DNA damage, and
specific processes influencing inflammaging using the novel framework inflammation associated with mitochondrial dysfunction has been well-
described by Lopez-Otin et al. as hallmarks of aging (Lopez-Otin et al., studied especially in relation to insulin resistance and cardiovascular
2013). The hallmarks of aging are considered biological mechanisms disease (Faria and Persaud, 2017). The mitochondrial-derived peptide
that in model organisms have been associated with biological and MOTS-c, for instance, regulates, in mice, insulin sensitivity and meta-
physiological changes that are typical of the aging process. Although it bolic homeostasis via AMPK, and prevents age-dependent and high fat
is currently unknown where these same mechanisms drive aging in diet-induced insulin resistance and diet-induced obesity (Lee et al.,
mammals, and particularly in humans, nonetheless they represent a 2015). A polymorphism of MOTS-c may be involved in increased
useful platform for research. Specific hallmarks include genomic in- longevity of the Japanese (Fuku et al., 2015). Obesity and insulin re-
stability, epigenetic alterations, telomere attrition, mitochondrial dys- sistance are altered in advancing age and together are linked to chronic
function, loss of proteostasis, cellular senescence, altered intercellular low grade inflammation, leading to age-related systemic metabolic
communication, stem cell exhaustion, and dysregulated nutrient sen- dysfunction, physical limitations and frailty (Stout et al., 2017). Mi-
sing (Lopez-Otin et al., 2013). An “American version” of the same topic tochondrial hormesis (mitohormesis) may also play a role in aging,
was published soon after, and included inflammaging as one of the where mild mitochondrial toxicity may trigger beneficial compensatory
“pillars” of aging (Kennedy et al., 2014). responses that improve cellular fitness (Lopez-Otin et al., 2013; Schulz
There is no doubt that environmental stressors, especially those that et al., 2007). Possible examples of this include resveratrol and met-
affect inflammation and metabolism, can strongly affect the “hall- formin that inhibit cellular energy metabolism through increase of
marks” (or pillars) of aging. Chemical, biologic, and physical agents can AMP, activation of AMPK, and decreased oxygen uptake (Hawley et al.,
challenge the stability and integrity of DNA, while intrinsic DNA re- 2010). Metformin, a biguanide hypoglycemic, promotes lifespan in C.
plication errors and ROS further increase the risk of internal genetic elegans through peroxiredoxin-2 by which oxidative stress is translated
lesions (Hoeijmakers, 2009). Genetics and diet have been shown to be into a downstream prolongevity signal (De Haes et al., 2014). Also,
associated with DNA damage levels and DNA repair capacity in in- metformin mitohormesis retards aging in C. elegans by altering micro-
dividuals (Slyskova et al., 2014). Levels of DNA damage were found to bial folate and methionine metabolism (Cabreiro et al., 2013). It ap-
be associated with sex (higher in women), fruit consumption (inversely pears that metformin's effect on diabetics is mediated by short-chain
associated) and XPG genotype; while DNA repair capacity (nucleotide fatty acid production and an increase in Escherichia species with a de-
excision repair) was increased with higher plasma levels of ascorbic pletion of butyrate-producing taxa in their human gut microbiome
acid and α-carotene. Evidence supports that epigenetic changes, such as (Forslund et al., 2015). Resveratrol, a polyphenol found in wine, and
enrichment of enhancer and insulator regions of genes with functional metformin importantly have anti-inflammation effects (Bektas et al.,
CpG methylation sites (Peters et al., 2015), accompany aging, and 2016; Saisho, 2015).
perturbations such as DNA methylation and histone modifications, Maintaining the stability and functionality of proteins are

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paramount to the proper functioning of all organisms. Protein home- unknown.


ostasis (proteostasis) involves mechanisms to avoid and correct errors Intercellular communication such as that of neurohormonal sig-
in transcription, splicing and translation, as well as disaggregate and naling (e.g. insulin-IGF1 and renin-angiotensin signaling) becomes de-
refold misfolded proteins, and degrade damaged, misfolded, or ag- regulated in aging and corresponds to an increase in inflammatory re-
gregated proteins by the ubiquitin-proteasome system or lysosome actions and declines in immunosurveillance (Lopez-Otin et al., 2013).
(Lopez-Otin et al., 2013; Sala et al., 2017). There is some evidence that Inflammaging contributes to increased activation of the NLRP3 in-
proteostasis is dysregulated by aging (Koga et al., 2011) and protein flammasome and other proinflammatory processes, which leads to in-
impairment contributes to the development of age-related diseases such creased secretion of IL-1β, interferons, and tumor necrosis factor
as cataracts, Alzheimer's disease and Parkinson's disease (Powers et al., (Salminen et al., 2012). Individuals with atherosclerosis have increased
2009). Healthy centenarians are able to maintain high levels of pro- aortic expression of NLRP3 that correlated with coronary severity
teasomal activity (Chondrogianni et al., 2000). Proteolytic systems such (Zheng et al., 2013) and there was increased expression of NLRP3 in
as the autophagy-lysosomal system and the ubiquitin-proteasome peripheral blood monocytes from patients with coronary artery disease
system decline with aging (Rubinsztein et al., 2011; Tomaru et al., (Wang et al., 2014). Genetic ablation of the NLRP3 inflammasome in
2012) and defects in these and other disposal systems for organelles or mouse models was shown to reduce age-associated inflammation and
cellular debris may contribute to inflammaging through increased consequent insulin resistance, cognitive decline, and frailty (Goldberg
production of proinflammatory compounds (Franceschi et al., 2017). and Dixit, 2015). Aging has also been linked to changes in circadian
Both dietary/nutrient supplementation of a macroautophagy inducer, control. Decreases in circadian oscillation of the “respiratory exchange
the polyamine spermidine, and gut flora producing spermidine lead to ratio” reflecting the relative use of carbohydrates or lipids for energy
increased longevity in mice (Matsumoto et al., 2011; Soda et al., 2009) metabolism correlate with aging with a preference of old mice for lipids
while dietary supplementation of omega-6 polyunsaturated fats in- and a loss of “metabolic flexibility” (Lopez-Otin et al., 2016). Decreased
creases longevity through autophagy activation in C. elegans (O'Rourke circadian oscillations in transcriptional processes in the aging brain
et al., 2013). Autophagy plays an important role in modulating in- have also been noted (Chang and Guarente, 2013). It has also been
flammation, mostly through the regulation of inflammasome activation. demonstrated that polyamines are involved in communication between
There is evidence that damaged mitochondria release ROS and other circadian clocks and metabolic pathways influencing feeding behavior
signaling molecules that activate the inflammasome and results in and age-related reduction in polyamines that have been linked to in-
caspase-1-dependent secretion of the inflammatory cytokines IL-1β and creased circadian periodicity can be reversed with polyamine supple-
IL-18. Adequate recycling of dysfunctional mitochondria through au- mentation (Zwighaft et al., 2015).
tophagy prevents such proinflammatory mechanistic responses (Netea- The ability for the body to be able to regenerate cells and tissues is
Maier et al., 2016). In addition, other inflammatory pathways are af- important for maintaining homeostasis and can be strongly affected by
fected by autophagy including a reduction of NF-κB activation by de- aging. For example, the phenomenon of immunosenescence which is
gradation of BCL10 complexes (Paul et al., 2012). Genetic variations in characterized by chronic inflammation, and inadequate dynamic re-
genes linked to autophagy, such as IRGM, are linked to chronic in- sponse to proinflammatory stimuli is considered a defect of intercellular
flammatory disorders, like Crohn's disease, and in the case of ATG5 are signaling (Bektas et al., 2017). An important role in the impairment of
linked to autoimmune disorders, such as systemic lupus erythematosus tissue repair and renewal is played by loss of potential of stem cells with
(Netea-Maier et al., 2016). aging which has been found in nearly all adult stem cell compartments
Chronic cellular stressors including those from a persistent DNA and has been associated with DNA damage, INK4a, telomere short-
damage response, telomere shortening, and derepression of the ening, and chronic inflammation (Lopez-Otin et al., 2013). More re-
CDKN2A locus (producing p16INK4A and ARF) with age, lead to chronic cently, metabolic ties to stem cell exhaustion involving the balance
cellular senescence, a persistent hyporeplicative state (Childs et al., between glycolysis, oxidative phosphorylation and response to oxida-
2015; He and Sharpless, 2017). A meta-analysis of over 300 genome- tive stress has been explored (Shyh-Chang et al., 2013) and autophagy
wide association studies has identified the INK4a/ARF locus as being and deregulated nutrient sensing including the insulin receptor,
the genomic locus linked to the highest number of age-associated dis- mTORC1, and AMPK may play a role (Lopez-Otin et al., 2016). Rapa-
eases including cardiovascular disease, diabetes, and Alzheimer's dis- mycin, for instance, which inhibits mTORC1 and mimics a state of
ease (Jeck et al., 2012). Other genes associated with cellular senescence limited nutrient availability, has been shown to postpone aging through
and advancing age in man, include ATM, a regulator of the DNA da- improving proteostasis and affecting deregulated nutrient sensing and
mage response pathway, which was found to have an inhibitory role in appears to improve stem cell function in the epidermis, hematopoietic
expression of certain splicing factors (Holly et al., 2013). Overall, the system and the intestine (Lopez-Otin et al., 2013), all compartments
number of senescent cells more than doubles in very old mice to ~ 17% with rapid cell turnover.
but varies between tissues with some tissues such as the heart, skeletal Various signaling pathways, especially the insulin and IGF1 sig-
muscle, and kidney showing no change (Wang et al., 2009). Strong naling pathway, that monitor and regulate the compartmentalization of
evidence that senescent cells accumulate with aging in humans is lim- nutrients appear to be deregulated in aging and also in metabolic dis-
ited to the skin, and has not been associated with important age-related orders and many studies have shown that caloric restriction which
outcomes such as Alzheimer's disease and intervertebral disk degen- suppresses the insulin and IGF1 signaling pathway, coupled with acti-
eration (Childs et al., 2017), with the exception of skin appearance, vation of members of the FOXO protein family, and mTOR inhibition
though causal links of age-related diseases and cellular senescence are extend lifespan (Efeyan et al., 2015; Lopez-Otin et al., 2016). Poly-
being explored (Childs et al., 2017). Cells that become senescent un- morphisms in the IGF-1 receptor gene, in female centenarians (Barzilai
dergo profound alterations of their secretome which becomes highly et al., 2010), and especially a polymorphism in FOXO3A, which has
enriched for proinflammatory cytokines, matrix metalloproteinases, been replicated in eight independent groups (Barzilai et al., 2012), have
and growth factors: a change known as “senescence-associated secre- been linked to longevity in humans. It should be noted that two other
tory phenotype” (SASP) (Childs et al., 2015). SASP result from a DNA nutrient sensors, AMPK and sirtuins, signal nutrient scarcity and cata-
damage response which induces inflammation and senescence by in- bolism, rather than nutrient abundance and anabolism as the insulin
hibiting autophagy of GATA4. GATA4 accumulates in multiple tissues and IGF1 signaling pathway and mTOR do (Lopez-Otin et al., 2013).
and likely contributes to aging through its associated inflammation Interestingly, the CALERIE study, the only randomized controlled trial
(Kang et al., 2015). The removal of senescent cells in a mouse model of caloric restriction in humans, demonstrated that a 25% calorie re-
reduces inflammaging (Baker et al., 2016) but the extent to which ac- striction significantly reduced several biomarkers of inflammation in
cumulation of senescent cells causes inflammaging in humans is the circulation (Fontana et al., 2016).

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Though many environmental factors influence these mechanisms of genetic factors (Bektas et al., 2013; Lin et al., 2014; Pilling et al., 2015)
aging, it is clear that DNA damaging agents, ROS, and metabolic factors and can theoretically be examined also in a behavioral and environ-
influenced by diet or the microbiome play a seminal role. For instance, mental context. While most scientists would agree with this theoretical
many metabolic interventions through nutrient manipulation have ex- view, empirical evidence supporting it in humans is lacking because
tended health span or lifespan in mice. These include acarbose (α-gly- clinical studies, especially cross-sectional ones, have limitations in de-
cosidase inhibitor), branched amino acid mix (valine, leucine, iso- tecting gene-environment interactions (Manolio et al., 2006). Long-
leucine), butyrate supplementation, D-glucosamine (glycolysis itudinal and prospective cohort studies can characterize exposures and
inhibitor), methionine restriction, metformin, nicotinamide mono- risk factors before disease onset, therefore reducing some common
nucleotide, protein restriction, rapamycin, resveratrol, spermidine, and biases of case-control studies and also the assessment of environmental
tryptophan restriction (Lopez-Otin et al., 2016). risk factors (Manolio et al., 2006). Some markers of inflammation
In the previous part of this text we have described evidence from the though have been validated in cross-sectional as well as longitudinal
literature that inflammation is involved in the molecular, phenotypic studies. For instance, IL-6 has been shown to be both a cross-sectional
and functional consequences of aging. Although most of the available and longitudinal predictor of comorbidity. Cross-sectionally, higher
evidence in humans is correlational, nonetheless questions arise of levels of IL-6 are correlated with a higher number of chronic diseases,
whether the proinflammatory state of aging can be modulated by in- however a high baseline of IL-6 is associated with a faster increase in IL-
terventions and whether reducing inflammation can prevent the aging 6 over time and a higher number of chronic diseases (Fabbri et al.,
phenotypes and their functional consequences. One logical place to 2015). Also high IL-6's correlation with lower walking speed cross-
start is to examine lifestyle factors. Diet, microbiome changes, vitamin sectionally is also correlated with a greater decrease in walking speed
D deficiency, stress and dioxins are all examples that can lead to over the following three years (Ferrucci et al., 2002). It is difficult to
proinflammatory factors such as obesity, altered gut microbiota, de- link all the manifestations of aging with dysregulated inflammation and
fective immunoregulation, and proinflammatory cytokines (Rook, high levels of cytokines, especially at the cellular level. However, it is a
2010). Gene-environment interactions have been found between poly- fact that many of the phenotypic changes as well as many biological
morphisms in genes coding for proinflammatory cytokines such as IL-1β changes at the cellular and tissue levels that occur with aging have been
and air pollution (NO2 exposure) which are correlated to inflammation associated with inflammation in the literature. In addition, it is possible
and increase the likelihood of Parkinson's disease diagnosis (Lee et al., that part of the proinflammatory state often found in older persons are
2016). Persistent organic pollutants that are stored in adipose tissues reactive to “normal” daily activities such as eating behaviors and
have been linked to inflammatory pathway genes involved in metabolic physical activity. However, the evidence that these behaviors con-
pathways (Kim et al., 2012). Epigenome (DNA methylation)-environ- tribute to chronic inflammation is still limited and need further con-
ment interactions have linked, in the elderly, traffic-related pollutants sideration in longitudinal studies.
(NO2, CO, black carbon, PM (2.5) and sulfite) with fibrinogen (a marker The power of analyses conducted on longitudinal studies can be
of coagulation), CRP, and endothelial function markers intercellular summarized by the extraordinary productivity of the Baltimore
adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 Longitudinal Study of Aging (BLSA), a prospective cohort study fol-
(VCAM-1) (Bind et al., 2012). Many examples of environmental links to lowing a pool of individuals who reside in the Baltimore, MD-
chronic inflammation and age-related diseases have been shown in- Washington, DC area since 1958. For example, a study was conducted
cluding, as a recent example, total urinary phthalate concentration that that examined white blood counts (WBC) in 1298 adults over the years.
has been shown to be associated with CRP, IL-6 and TNF-α levels and Noteworthy, patterns of WBC were different among the age groups, but
cardiovascular disease, type-2 diabetes and hypertension (Bai et al., the pattern was also influenced by a secular trend (personal commu-
2017). A recent theory known as the “hygiene hypothesis” poses that nication). There is a declining pattern between individuals age
the recent increase in chronic inflammatory disorders may be partially 20–40 years old compared to those ages 81 years and older for the
a result of immune dysregulation that results from the lack of exposure cohorts measured in 1958–1970 and 1971–1980; whereas there is a
to microorganisms that play key roles in immune system function rising pattern of WBC counts between individuals age 20–40 years old
(Rook, 2010). Preliminary studies suggest that consumption of pro- compared to those ages 81 years for cohorts measured in 1991–2000
biotic bacteria such as those found in yogurt and other fermented milk and 2000+. WBC count has been shown to correspond to CRP and an
products can alter the composition of the gut microbiome beneficially age-independent rise of inflammatory score (CRP) or WBC has been
altering the hosts' metabolism (Wen and Duffy, 2017). shown to be related to the number of chronic diseases and hence be
indicative of accelerated aging (Stepanova et al., 2015). The total WBC
5. Why longitudinal studies level has also been shown to be associated with significant stepwise
increases in four escalating quartiles of IL-6 levels (Leng et al., 2005)
Caleb Finch (National Research Council, 2008) and others (Kuh and and high WBC counts and IL-6 levels were independently associated
New Dynamics of Ageing Preparatory, 2007) have argued that aging with prevalent frailty in older women (Leng et al., 2007).
begins at the beginning of life, including the period prior to birth.
Supporting this view, life course and historical cohort studies have 5.2. Example longitudinal studies
shown that environmental processes in early life, including in utero,
influence adult function and the propensity to acquire age-related There are many studies that can be exploited to examine how en-
chronic diseases (Gluckman and Hanson, 2004; Kuh and New Dynamics vironmental exposures and inflammation additively and synergistically
of Ageing Preparatory, 2007). affect the aging process. For example, the BLSA, the Genetic and
Epigenetic Signatures of Translational Aging Laboratory Testing
5.1. Dealing with different lifetime exposures (GESTALT), Health ABC, InCHIANTI Study (Invecchiare in Chianti,
aging in the Chianti area) and the Women's Health and Aging Study
Chronic diseases are caused by more than an individual's genetic (WHAS) are studies funded by the National Institute on Aging (NIA),
variants (Chakravarti and Little, 2003), and most likely result from National Institutes of Health (NIH) that are particularly suited for this
environmental and behavioral stressors interacting with genetic pre- purpose. The Environmental Polymorphisms Registry (EPR) at the
disposition (Manolio et al., 2006). Inflammaging can be viewed as a National Institute of Environmental Health Sciences Institute (NIEHS),
reactive response positioned at the crossroad between genetic sus- NIH is another example. Many of these studies are partially archived in
ceptibility and intervening stressors that are behavioral and environ- public domains and have developed mechanisms for investigators to
mental in nature. The inflammatory cytokine IL-6 is strongly affected by access them. Although none of these studies is “ideal” for testing the

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The authors declare no conflicts of interest. Ferrucci, L., Studenski, S., 2012. Chapter 72. Clinical problems of aging. In: Longo, D.L.,
Fauci, A.S., Kasper, D.L., Hauser, S.L., Jameson, J.L., Loscalzo, J. (Eds.), Harrison's
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