review article an update on inflamm-aging: mechanisms...

Review ArticleAn Update on Inflamm-AgingMechanisms Prevention and Treatment

Shijin Xia1 Xinyan Zhang2 Songbai Zheng1 Ramin Khanabdali3

Bill Kalionis3 Junzhen Wu1 Wenbin Wan4 and Xiantao Tai5

1Department of Geriatrics Shanghai Institute of Geriatrics Huadong Hospital Fudan University Shanghai 200040 China2Department of Information Chengdu Military General Hospital Chengdu 610083 China3Department of Maternal-Fetal Medicine Pregnancy Research Centre and Department of Obstetrics and GynaecologyUniversity of Melbourne Royal Womenrsquos Hospital Parkville VIC 3052 Australia4Department of Neurology Zhongshan Hospital Fudan University Shanghai 200032 China5School of Acupuncture Massage and Rehabilitation Yunnan University of Traditional Chinese Medicine Kunming 650500 China

Correspondence should be addressed to Shijin Xia xiashijinhd163comSongbai Zheng songbai1009163com and Xiantao Tai taixiantao163com

Received 2 March 2016 Revised 16 May 2016 Accepted 14 June 2016

Academic Editor Lenin Pavon

Copyright copy 2016 Shijin Xia et alThis is an open access article distributed under theCreativeCommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunose-nescence Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases such as Alzheimerrsquosdisease atherosclerosis heart disease type II diabetes and cancer Mounting studies have focused on the role of inflamm-agingin disease progression and many advances have been made in the last decade However the underlying mechanisms by whichinflamm-aging affects pathological changes and disease development are still unclear Here we review studies of inflamm-agingthat explore the concept pathological featuresmechanisms intervention and the therapeutic strategies of inflamm-aging in diseaseprogression

1 Introduction

Inflamm-aging [1] was first named by Franceschi et al in2000 and it is a new addition to the types of aging studiesInflamm-aging plays an increasingly important role in therate of aging and age-related diseases Research in thisarea has attracted attention of scholars in many fields andsignificant progress has been made in the last decadeHere we review the concept of inflamm-aging and describevarious research strategies that have led to insights into itsinflammatory characteristics and mechanisms of action Wealso discuss the relationship of inflamm-aging with diseasesand novel interventions to delay or prevent inflamm-aging-related diseases

2 The Concept of Inflamm-Aging

A main feature of the aging process is a chronic progressiveincrease in the proinflammatory status which was originally

called ldquoinflamm-agingrdquo [1] Subsequently other similar termswere used such as ldquoinflammagingrdquo [2] ldquoinflamm-ageingrdquo [3]and ldquoinflammageingrdquo [4] Inflamm-aging is the expansion ofthe network theory of aging [5] and the remodeling theory ofaging [6 7] The network theory of aging posits that aging isindirectly controlled by the network of cellular andmoleculardefense mechanisms The remodeling theory which wasput forward to explain immunosenescence is the graduallyadaptive net result of the process of the body fighting malig-nant damage and is a dynamic process of optimization ofthe trade-off in immunity [6 7] In the process of agingsome researchers pointed out that the phenomenon whereadaptive immunity declines is called immunosenescencewhile the phenomenon where innate immunity is activatedcoupled with the rise of proinflammation is called inflamm-aging [8] Some regard the chronic inflammatory processwith age as inflamm-aging [9] while others proposed theoxidation-inflammation theory of aging [10] Despite the lack

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2016 Article ID 8426874 12 pageshttpdxdoiorg10115520168426874

2 Journal of Immunology Research

of agreement on definitions and terminology there is consen-sus that the primary feature of inflamm-aging is an increasein the bodyrsquos proinflammatory status with advancing ageFurthermore a new concept of ldquoanti-inflammagingrdquo was alsoproposed which influences progressive pathophysiologicalchanges as well as lifespan and acts along with inflamm-aging [11] In the next section the characteristics of inflamm-aging are described in more detail

3 The Inflammatory Characteristics ofInflamm-Aging

Thefive states of inflamm-aging are as follows [12] low-gradecontrolled asymptomatic chronic and systemic Howeverthe inflammation during inflamm-aging is not in a controlledinflammatory state We propose that inflammation in theprocess of inflamm-aging belongs to nonresolving inflam-mation [13] Inflammation is a series of complex responseevents which are caused by the host system facing a pathogeninfection or various types of tissue injury These responseevents are characterized by interactions between the cellsand factors in the microenvironment and by regulation ofthe balance between physiological and pathological signalingnetworks In common conditions inflammatory responsesdisappear when proinflammatory factors in infection andtissue injuries are eliminated and then change into a highlyactive and well regulated balanced state which is calledresolving inflammation [13] However in the presence ofsome as yet uncertain factors such as persistent and lowintensity stimulation and long-term and excessive responsein target tissues inflammation fails to move into a steadystate of anti-infection and tissue injury repair instead theinflammation continues andmoves to a nonresolving inflam-mation state [13] Given this background inflammation in theprocess of inflamm-aging belongs to the state of nonresolvinginflammation

4 The Relationship betweenInflamm-Aging and Diseases

Like the immune response inflammation has a physiolog-ical function in the normal body Moderate inflammatoryresponse is beneficial to the body but when excessive theresponse becomes harmful Changes in the inflammatorycytokine network control the direction of the developmentof inflammation The dynamic balance of the network ofproinflammatory cytokines and anti-inflammatory cytokinesmaintains the physiologic function of inflammation in thenormal body Tipping the balance from anti-inflammation toproinflammation can lead to pathological changes Persistentinflammation during the inflamm-aging process may causeinflammation-related diseases

Inflamm-aging is a determinant of the speed of the agingprocess and of lifespan and is highly related to Alzheimerrsquosdisease [2] Parkinsonrsquos disease acute lateral sclerosis multi-ple sclerosis atherosclerosis heart disease age-related mac-ular degeneration [14] type II diabetes [15] osteoporosis andinsulin resistance [16] cancer and other diseases Inflamm-aging also increases morbidity and mortality significantly

harming the health of patients and causes a decline in thequality of life of patients [16] Chronic subclinical inflamma-tion and immune disorders coexist in the process of inflamm-aging Epidemiological studies show that with age there isan imbalance in the loss of old bone and the formation ofnew bone Inflamm-aging may be one of the contributingfactors to the imbalance and to the subsequent excessive lossof bone Inflammatory markers of inflamm-aging provideclinicians with the necessary data for risk assessment ofosteoporosis Inflammatory cytokines may be therapeutictargets for improving the formation of bone in the elderlyafter bone operations [16] Excessive inflammation duringinflamm-aging increases the morbidity and mortality ofpatients after bone operations even though the mechanismfor this remains unclear [17] In the process of inflamm-agingthe pathophysiological changes in the colon are revealed atthe cellular and molecular levels and these culminate in theinflammation that leads to injury of the gastric mucosa andepithelium as well as a decrease in the epitheliumrsquos ability toregenerate [18] (Figure 1)

However inflamm-aging seems to be a double-edgedsword in that it decreases immune function but also increasesthe autoreactivity of the body [17] Inflamm-aging is benefi-cial to the body by neutralizing the harmful cytokines in theearly stage of the life but has a detrimental role in the later life[17]

Unfortunately the strong correlation between inflamm-aging and disease development is complex and unclearBecause immunosenescence and inflamm-aging coexist it isdifficult to distinguish whether the inflammation-related dis-eases are caused by inflamm-aging or immunosenescenceMoreover the crucial question is whether there is a causalrelationship between inflamm-aging and diseases whichneeds integrated biological and clinical research to resolve

5 The Mechanisms of Inflamm-Aging

While the mechanism of inflamm-aging is not completelyunderstood the current theories in the field are summarizedbelow

51 The Theory of Stress Generally stress is either beneficialor harmful to the body During inflamm-aging the body isconstantly in the stress environment which is caused by dif-ferent kinds of stressors that induce andmaintain the chronicproinflammatory status in the body Stress as one of regulatedfactors of immunity provokes the greatest immune responsein the bodies of young persons whereas it provokes thatweakest response in elderly persons with signs of immunose-nescence and inflamm-aging [19 20] According to a seriesof studies involving different species from invertebrates tohumans from an evolutionary perspective inflammation isclosely related to innate immunity and stress [20] Basedon evolutionary studies immune response stress responseand inflammation form a defensive network in the bodyHowever the compatibility between inflammatory status andlongevity and the paradoxical proinflammatory character inhealthy centenarians strongly suggest the existence of physi-ological inflammation [21] Therefore inflammation and the

Journal of Immunology Research 3

Inflamm-aging

Alzheimerrsquos disease

Parkinsonrsquos disease

Heartdiseases

Atherosclerosis

Age-related macular

degeneration

Multiple sclerosisIncrease of

morbidity and mortality

Acute lateral sclerosis

Insulin resistance

Osteoporosis

Type II diabetes

Cancer

Figure 1 The relationship between inflamm-aging and diseases

proinflammatory status in healthy persons and centenariansshow a beneficial response that helps the elderly deal withthe stimuli generated by chronic antigen stressors [19] How-ever excessive stress response as well as an accompanyingincreasingly high proinflammatory response leads to humaninflamm-aging

52 The Theory of Oxidation-Inflammation There are closerelationships between oxidative stress and inflamm-aging[21] Based on the close relationship between oxidative stressinflammation and aging the oxidation-inflammatory theoryof aging (oxi-inflamm-aging) was proposed [10] In this the-ory oxidative stress leads to inflamm-aging and influencesthe homeostasis and health of the body The relationshipbetween the redox state and the function of immune cellsinfluences the speed of aging and lifespan [10] Accordingto this theory sufficient antioxidants in food may improveimmune function decrease oxidative stress and extend thelifespan [22]

53 The Theory of Cytokines Proinflammatory cytokinesplay an important role in inflamm-aging caused by chronicinflammation [23] Type I cytokines (such as IFN-120574 andTNF-120572) and type II cytokines (IL-4) in unactivated and memoryCD4+ T lymphocytes participate in the proinflammatoryprocess [24] Further research shows that CD8+ and CD4+T lymphocytes play a pivotal role in the developing cytokinenetwork and this can lead to the chronic proinflamma-tory state and inflamm-aging [25] In animal experimentsincreased expression of IL-1120573 IL-15 IL-18 TNF-120572 mRNA

and TNF-120572 protein in the peripheral blood of elderly horsesappears to be a distinctive feature of inflamm-aging [26]

Elevated levels of IL-6 and TNF-120572 in the serum of theelderly are associated with disease disability and mortality[3] Studies employing large patient cohorts provide evidencethat the level of serum IL-6 is a reliable marker or apredictive index of inflamm-aging [3] Experiments withhealthy elderly people show that aging relates to increasedproinflammatory status The cause of the increased proin-flammatory status is elevated levels of proinflammatorycytokines in the circulation including IL-1 IL-6 TNF-120572 andPGE2 [27 28] Although the identity of cells that secreteproinflammatory mediators in elderly persons remains con-troversial the prevailing view is that during inflamm-aginghigh levels of proinflammatory cytokines in the circulationcreate an inflammatory environment for tissues and organs[29] However differences in levels of IL-10 and TNF-120572 inindividuals may play an important role in the final outcomeof inflammation [29] IL-6 and TNF-120572 are upregulated whilegrowth hormone and IGF-1 are downregulated in the processof aging The overall balance of cytokines such as IL-6 andTNF-120572 appears to play a decisive role in aging As wellgenetic variations in the promoter regions of proinflamma-tory and regulated cytokine genes have effects on inflamm-aging and susceptibility to age-related diseases [29]

Pes et al [30] found that the frequency of the -174Csingle nucleotide polymorphism (SNP) in the promoterregion of IL-6 gene is increased in Italian male centenariansand the frequency of the -1082G SNP at the 51015840 flankingregion of the IL-10 gene coding sequence is increased


among male centenarians These data indicate that differ-ent alleles in different cytokine gene coding regions forpro- (IL-6) or anti-inflammatory (IL-10) cytokines mayinfluence immune-inflammatory responses and individuallifespan expectancy suggesting that inflammatory cytokinegene polymorphisms for immune system genes may regulateimmune-inflammatory responses Gene polymorphisms ofproinflammatory cytokines associated with high levels ofIL-6 have decreased capacity to reach extremely old agewhereas genotypes associated with high levels of IL-10were increased in centenarians [30] Genetic polymorphismin proinflammatory cytokine genes is necessary and hasimportant consequences in the body On the one handmoderate levels of proinflammatory cytokines contribute toinducing a protective response when the body is invadedby pathogens On the other hand excessive proinflammatorycytokines may cause immune-inflammatory diseases andeven death Indeed the process of evolution has shaped theability of the body to fight and control pathogens Thereforethe proinflammatory response may be beneficial to the bodyin fighting potentially fatal infectionsThus high levels of IL-6 and low levels of IL-10 are associated with enhanced abilityagainst pathogens [30]

The vicious cycle of reciprocal causation between theproinflammatory cytokines and cellular senescence aggra-vates inflamm-aging On the one hand proinflamma-tory cytokines induce cellular senescence Proinflammatorycytokines such as TNF-120572 IFN-120574 and IFN-120573 induce cellularsenescence in epithelial cells by producing reactive oxygenspecies and activating the ATMP53P21 (WAF1Cip1) sig-naling pathway [31] CXCR2 a chemokine receptor inducescellular senescence of fibroblasts [32] DNAdamage producesproinflammatory cytokines (such as IL-1 IL-6 and IL-8) byactivating the NF-120581B signaling pathway blocking the cellularcycle and inducing andmaintaining the phenotype of cellularsenescence [32] On the other hand senescent cells secretegrowth factors proteases chemokines and cytokines such asIL-6 and IL-8 [33]

Most phenotypes of aging can be explained by animbalance between proinflammation and anti-inflammationwhich results in inflamm-aging with a low chronic proin-flammatory status However centenarians have high levelsof inflammatory mediators and more anti-inflammatorycytokines suggesting that inflamm-aging can coexist withlongevity even though the underlying mechanisms have notbeen uncovered [34]

54 The Theory of DNA Damage Sustained telomere DNAand mitochondrial DNA damage caused by exogenous andendogenous factors can induce errors of DNA replication ortranslation which leads to point mutations or chromosomalrearrangements and stress reactions via various signalingpathways which eventually contributes to cellular senes-cence Researchers found that in human senescent primarycells the shortest telomeres lack most of the telomere repeatsequence which leads to DNA damage accumulation andterminal cell cycle arrest and further induces replicativesenescence [35] A persistent DNA damage response (DDR)caused by telomere shortening is a key mechanism involved

in replicative senescence and aging process [36] New evi-dence indicates that DNA damage response (DDR) signalingis a major link between cell senescence and organism agingDDR activation of senescent cells contributes to an increasein the proinflammatory secretory phenotype (PSP) which inturn triggers the activation of adjacent cell DDR and PSPThis local inflammatory environment eventually becomessystemicThe increasing number of cells withDDR activationmay exacerbate inflamm-aging [37] These results suggestthat cells in an inflammatory environment induce aging at thesystemic level Stem cells and stromal fibroblasts differenti-ate into proinflammatory cytokine overexpressing cells andconsequently the cytokine network breaks down inducinginflamm-aging as a result of the accumulation of DNAdamage [38] Proinflammatory cytokines in the microenvi-ronment of cells with DNA damage further induce inflamm-aging Macrophages which mediate the main effects ofinflamm-aging amplify inflamm-aging self-propagation viaa cascade effect on the local and systemic proinflammatoryresponse [38]

55 The Theory of Autophagy Autophagy plays an impor-tant role in stress removing harmful substances in cellsto maintain homeostasis and normal metabolism [39 40]Autophagy transfers the abnormal substances of the cell tolysosomes for degradation and also plays a role in manypathophysiological processes [41] For example autophagyplays important roles in removing abnormal proteins adapt-ing to hunger and cancer More and more evidence showsthat autophagy is important in increasing longevity Forexample knocking out the autophagy gene Atg7 leads to theaccumulation of proteins and organelles in the cell causingcellular senescence [42]

The process of aging accompanies disorder in homeosta-sis However autophagy plays an important role in main-taining homeostasis and delaying aging In the processof aging autophagic cleansing capacity declines graduallywhich induces mitochondrion disordering and protein accu-mulation This leads to increased reactive oxygen species(ROS) and consequently oxidative stress Destabilized lyso-somes release ROS which activate Nod-like receptor 3(NLRP3) and this initiates an inflammatory cascade reactionDuring this process inactive precursors of IL-1120573 and IL-18 areincreased and IL-1120573 and IL-18 release is stimulated whichcauses an inflammatory reaction and accelerated aging [43]

56 The Theory of Stem Cell Aging Stem cell aging is closelyrelated to inflammation [44] Stem cell aging is the cellularbasis of aging and chronic inflammation is one of themain factors that induces stem cell aging In the chronicinflammatory process proinflammatory factors activate NF-120581BMAPKs TOR RIG-I and JAKSTAT signaling pathwaysto induce cells to synthesize and to secrete large amounts ofinflammatory cytokines such as TNF120572 and IL-1120573 [45] whichleads to a chronic low degree of inflammation in the environ-ment of cells thereby inhibiting the regenerative capacity ofstem cells This leads to dysfunctional differentiation of stemcells damage of the stem cell microenvironment (ie thatstem cell niche) homeostasis and stem cell aging [44]


6 Regulatory Signaling Pathways ofInflamm-Aging

In principle the pathways controlling inflammation arepotential regulatory signaling pathways of inflamm-agingThe NF-120581B and TOR signaling pathways in particular havebeen investigated

61 NF-120581B Signaling Pathway NF-120581B a nuclear transcriptionfactor is regarded as the main molecular switch of inflam-matory pathways The NF-120581B signaling pathway may alsoregulate inflamm-aging [8] However the longevity geneSIRT1 can be combined with a subunit of NF-120581B Relp65to deacetylate K310 and inhibit the transcriptional activityof NF-120581B [46 47] NF-120581B can regulate the occurrence ofaging whereas SIRT1may regulateNF-120581B to delay aging [48]Thus NF-120581B can regulate both aging and inflammation [49]NF-120581B can also inhibit inflammatory reactions by regulatingSIRT1 (Sir2 homolog) and FoxODAF-16 [8]

62 TOR Signaling Pathway TOR a highly conserved ser-inethreonine protein kinase plays an important role in theregulating growth and proliferation of cells [50] According toits different functions TOR can be divided into TORC1 andTORC2The former is sensitive to rapamycin participating inthe biological process of transcription and translation in cellsThe latter is insensitive to rapamycin and mainly regulatesremodeling the cytoskeleton [51]TheTOR signaling pathwayregulates longevity When TOR signaling is decreased orinactivated the lifespan of wireworms and Drosophila isextended Similarly the lifespan of yeast can be increased byexposure to a low dose of rapamycin [52] At present it isbelieved that TORC1 participates in regulating aging S6K is apositive regulation target of TORC1 In the mouse knockoutof the S6K gene lifespan is extended 4E-BP is a gene that isnecessary to lifecycle and is a negative regulator of TORC1When 4E-BP is overexpressed lifespan is prolonged [53]

In terms of the physiological function of TOR signalregulation TOR regulates growth during embryonic develop-ment and in maturity TOR regulates metabolism Howeverin old age TOR signaling regulation is excessively acti-vated and is associated with many age-related diseases Theexcessive production of cytokines and inflammatory factorsinduces aging and the changes to the local microenviron-ment causing age-related diseases TOR regulates inflamm-aging by activating NF-120581B [54]

63 RIG-I Signaling Pathway Retinoic-acid-inducible gene-I(RIG-I) may be involved in inflamm-aging RIG-I is inducedvia the ataxia telangiectasia mutated interferon regulatoryfactor-1 (ATM-IRF1) axis in senescent cells and interactswith increased levels of IL-6 and IL-8 The activation ofRIG-I signaling pathway upregulates IL-6 expression [55]RIG-I is a caspase recruitment domain- (CARD-) containingprotein that functions as a cytoplasmic RNA sensor [55]Liu et al [55] showed that IL-6 and IL-8 levels increasein replicating senescent cells They reported that senescentcells transfected with RIG-I show increased secretion of IL-6 However knockdown of RIG-I in senescent cells leads to

the extension of the lifespan of cells which shows that RIG-I-induced inflammation plays a role in promoting and main-taining aging Interfering with RIG-I expression significantlydecreases the levels of inflammatory cytokines in senescentcells [55] This imbalance in the inflammatory process maycause chronic inflammation during aging

64 Notch Signaling Pathway The Notch signaling pathwayis a major intercellular communication pathway that ishighly conserved through evolution Notch signaling playsan essential role in aging [56] At the cellular level aging ofvascular endothelial cells (EC) leads to senescence SenescentEC secrete proinflammatory cytokines and this is oftenaccompanied by a low-grade chronic upregulation of certainproinflammatory responses [56] Constitutive activation ofNotch signaling induces EC senescence Consistent withthese results HeyL a Notch downstream target is elevated inaged compared to young EC Notch activation also triggersEC inflammatory responses by upregulating expression of apanel of proinflammatory cytokineschemokines and adhe-sion molecules in EC This has revealed a novel functionof Notch1 signaling in EC biology and may shed light onthe mechanism whereby Notch signaling may contribute tosome age-related vascular diseases characterized by chronicinflammation

65 Sirtuin Signaling Pathway Silent information regulator(Sir) proteins regulate lifespan in multiple model organ-isms [57] Sir2 (SIRT1ndash7 in mammals) is a NAD-dependentdeacetylase that has been implicated in aging and inflamma-tion in yeast worms and flies SIRT1 the most extensivelystudied inmammals has a highly conservedNAD-dependentsirtuin core domain and is a good candidate lifespan regulatoralong with the other six homologs Recent studies showedthat SIRT1 is a potent anti-inflammatory protein and inhibitsthe COX-2MMP pathway via suppression of the potentproinflammatory factor NF-120581B NF-120581B signaling is limited bySIRT6 which is recruited to NF-120581B target gene promoters bya physical interaction with the NF-120581B subunit RelA SIRT6deacetylates histone H3 lysine 9 on target gene promotersthereby altering the chromatin structure to facilitate NF-120581B destabilization and signal termination SIRT1 activationdecreases the proinflammatory effects induced by TNF-120572 Inaddition treatment with SIRT1 activators such as resveratrolor overexpression of SIRT1 inhibits the expression and acti-vation of the main proinflammatory regulator NF-120581B whichis increased by TNF-120572 When SIRT1 is overexpressed theanti-inflammatory action of SIRT1 is similar to that exerted byresveratrol Resveratrol as an SIRT1 activator inhibits TNF-120572-induced inflammatory factor release Resveratrol effec-tively inhibits the activation of proinflammatory factors byactivating SIRT1 leading to the deacetylation of NF-120581B p-65and subsequent downregulation of TNF-120572-induced COX-2and MMP expression [58]

66 TGF-120573 Signaling Pathway Sequence variations in a vari-ety of pro- or anti-inflammatory cytokine genes have beenfound to influence successful aging and longevity TGF-1205731


has been shown to have an essential role in inflammation andin the maintenance of immune response homeostasis TGF-1205731 belongs to the group of cytokines with anti-inflammatoryeffects and is a deactivating factor ofmacrophageswith potentanti-inflammatory properties Because of the role played bythe transforming growth factor 1205731 (TGF-1205731) in inflammationand the regulation of immune responses variability of theTGF-1205731 gene may affect longevity by playing a role ininflamm-aging The potential role of TGF-1205731 in aging andlongevity has been suggested by many in vitro and in vivostudies In particular TGF-1205731 gene overexpression has beenobserved in human fibroblasts that display a senescent-likephenotype following exposure to oxidative stress which mayhelp to seek a new proposal to treat disease-related aging [59]

67 Ras Signaling Pathway Ras is an important signalingmolecule involved in atherogenesis and is a proinflamma-tory molecule involved in inflammation and aging Raspromotes aging in yeast and cellular senescence in primaryhuman fibroblasts Activation of Ras drastically increases theexpression of proinflammatory cytokines in part throughextracellular signal-regulated kinase activation Introductionof Ras into arteries enhances vascular inflammation andsenescence [60]

Ang II promotes reactive oxygen species (ROS) pro-duction cell growth apoptosis cell migration and differen-tiation and extracellular matrix remodeling Ang II regu-lates gene expression and can activate multiple intracellularsignaling pathways leading to tissue injury Ang II alsomediates several key events in the inflammatory processBlocking Ang II signaling protects against neurodegenerativeprocesses and promotes longevity in rodents Ang II-inducedROS production via the AT1 receptor promotes the onset ofvascular senescence associated with functional and structuralchanges to blood vessels that contribute to age-related vascu-lar diseases [60]

At present the mechanisms of inflamm-aging remainunclear because the methods and tools used for researchinto the mechanisms of inflamm-aging are not sufficientlysophisticated to explain inflammatory reactions caused bycomplex inflammatory cytokine cascades during inflamm-aging Unfortunately an adequate and reliable assessmentsystem for aging has not yet been established Furthermorethe causal relationships between inflammation and aginghave not yet been elucidated Moreover the mechanismsreferred to above need to be further verified Inflamm-aginginfluences all levels of function from cells to tissues organsand the whole body Inflamm-aging also involves aberrantgene regulation and an imbalance in energy metabolism aswell as interactions between these two factors The mech-anisms of inflamm-aging are very complicated and requiremultidisciplinary research to further investigate the interac-tions at multiple levels from cells to the whole body (Figure 2and Table 1)

7 Potential Markers of Inflamm-Aging

One of the constraining factors of aging research is thelack of recognized accurate and reliable biological markers

StressOxidation-

inflammationCytokines

DNA damageAutophagy

Stem cell aging

NF-120581B signaling pathwayTOR signaling pathway RIG-1 signaling pathwayNotch signaling pathway Sirtuins signaling pathwayTGF-120573 signaling pathway

Ras signaling pathway

Imbalance ofinflammation homeostasisA chronic

progressive increase in the

proinflammatorystatus

Inflamm-aging

Activation

Figure 2 The mechanisms and regulated signaling pathways ofinflamm-aging

The main biological markers of aging can be categorized asfollows (1) the marker is related to age (2) the marker doesnot change with disease (3) the marker does not changewith metabolic and nutrient conditions (4) the marker isinfluenced by the process of aging (5) the marker does notchange in immortalized cells Unfortunately the biologicalmarkers of aging have not yet been defined and need to befurther investigated This will facilitate the evaluation of thedegree of inflamm-aging and assist in identifying the molec-ular mechanisms underlying inflamm-aging The potentialmarkers of inflamm-aging may include immune cellmarkersserum cytokinemarkers and microRNAs

71 Immune Cell Markers A main characteristic of theimmune system in the elderly is antigenic T cell accu-mulation The shortage of naive CD8+ T lymphocytes isregarded as a reliable biological marker related to the risk ofdeath The increase in CD8+ T cells a decrease in CD4+ Tcells and CD19+ B cells and inhibition of mitogen-inducedproliferation of T cells may be predictors of inflamm-aging[3]

72 Serum Cytokine Markers The increase in serum IL-6 inthe elderly is related to diseases disability and mortality Astudy on a large cohort showed that IL-6 in the serum is a reli-able marker of disability in the elderly and contributes to thepredictive index of disability andmortality [3]The functionsof some cytokines such as IL-10 and TNF-120572 are complex andplay opposing roles in the systemic inflammatory reactionIL-10 inhibits inflammatory reactions while TNF-120572 activatesinflammatory reaction locally and systemically Differentregulation of IL-10 and TNF-120572 may be essential to the finaloutcome of the inflammatory reaction Therefore levels ofIL-6 TNF-120572 and IL-10 may be regarded as serum markersof inflamm-aging [3]

73 MicroRNA Markers MicroRNAs (miRs) are a class ofmolecules involved in the regulation of gene expression and


Table 1 Inflamm-aging-related mechanisms and regulated signaling pathways

Mechanisms Effects Signaling pathways References

Stress Chronic antigen stressors lead to excessive stress response andcontribute to inflamm-aging Ras [19 20]

Oxidation-inflammation Oxidative stress and inflammation influences the homeostasis andhealth of body

NF-120581B Notch TGF-120573sirtuin [10]

Cytokines High levels of proinflammatory cytokines result in inflamm-agingand age-related diseases mTOR RIG-I Notch [29 30 52 53]

DNA damage DNA damage response increases proinflammatory cytokines NF-120581B [36]

Autophagy Autophagic function dysfunction leads to increased oxidativeproducts and oxidative stress NF-120581B [40 41]

Stem cell aging Chronic inflammation induces stem cell aging and inhibits theregenerative capacity of stem cells NF-120581B mTOR RIG-I [42]

are emerging as modulators of biological pathways includingNF-120581B mTOR sirtuins TGF-120573 and Wnt miRs may beassociated with inflammation cellular senescence and age-related diseases and they can be classified as inflammation-associated (inflamm-miRs) and senescence-associated (SA-miRs) [61] miR-based anti-inflammatory mechanisms mayplay a crucial role during aging where a chronic low-levelproinflammatory status is likely sustained by the cell senes-cence secretome and by progressive activation of immunecells over time Circulating miRs seem to be promisingbiomarkers ofmajor age-related diseases [60] SomemiRs arefound in plasma and leukocytes in centenarians Some miRssuch asmiR-21 miR-126 andmiR-146a which targetmRNAsbelonging to the NF-120581B pathway can be considered as bothSA-miRs and inflamm-miRs [61] Thus specific inflamm-miRs may be regarded as biomarkers of inflamm-aging [62]

8 Intervention in Inflamm-Aging

A significant feature of inflamm-aging is that there is achronic low-grade microinflammatory state in the bodyTherefore drugs used for the treatment of inflamm-agingmust be effective safe nontoxic and appropriate forlong-term use Calorie restriction zinc (Zn) resveratrolEpimedium total flavonoids and icariin have these character-istics and may be candidate drugs to treat inflamm-aging

81 Calorie Restriction Calorie restriction (CR) also knownas dietary restriction (DR) has been regarded as the goldstandard ofmany aging interventions to counteract aging CRtogether with adequate nutrient intake prolongs maximumlifespan possibly through beneficial metabolic hormonaland functional alterations [63] The antiaging action of CRmay be based largely on its ability to suppress oxidative stressrelated alterations and oxidative stress induced age-relateddiseases [64 65] CR can modulate many important inflam-matory signaling pathways involved in aging and inflam-mation such as NF-120581B mTOR and MAPK [66] The age-related upregulation of NF-120581B IL-120573 IL-6 and TNF-120572 in theproinflammatory states of the aging process is attenuated byCR [67]

82 Zn Zn is an especially important necessary microele-ment for the human body and has an important impact onregulating the balance between the genetic expression ofmet-alloproteinases (MPs) and MPs inhibitors on maintaininginducible nitric-oxide synthase (iNOS) activity and on manybiochemical functions The interaction between Zn and IL-6 TNF-120572 or heat shock protein 70 (Hsp70) regulates theimmune-inflammatory reaction The elderly frequently lackadequate levels of Zn A moderate amount of Zn added tothe dietmay expand the lifespan of the elderly which suggeststhat Zn may intervene in inflamm-aging [68]

83 Resveratrol Some studies have found that resveratrolaffects aging and lifespan in mammals [22] Researchersreported that this potent natural compound is a SIRT1 acti-vator and may help in preventing the aging-related declinein heart function and neuronal loss through stimulatingSIRT1 activation [69] Moreover resveratrol decreases ovar-ian inflammation via inhibition of NF-120581B by upregulation ofPPAR-120574 and SIRT1 expression [70] Furthermore resveratrolcan suppress tumorigenesis at least in part by targetingSirt1 and suppressing NF-120581B activation [71] Resveratrolsuppresses the upregulation of proinflammatory molecules(such as IL-1120573 and IL-6) by TNF-120572 in 3T3 cells in a dose-dependent manner However knockdown of Sirt1 by RNAinterference makes 3T3 cells susceptible to TNF-120572 stimula-tion and decreases the anti-inflammatory effect of resveratrolThe potential anti-inflammatory mechanisms of resveratrolinvolve a reduction in NF-120581B subunit RelAp65 acetylationwhich is notably Sirt1 dependent Resveratrol also attenuatesthe phosphorylation of the mammalian target of rapamycin(mTOR) and S6 ribosomal protein (S6RP)while amelioratinginflammation [72] These data demonstrate that resveratrolmay have inhibitory effect on inflamm-aging

84 Epimedium Total Flavonoids and Icariin In our previousstudies based on the neuroendocrine-immunological net-work we used an inflammatory cytokine and genetic receptorchip-based assay to detect critical genes in the hippocampushypothalamus hypophysis adrenal gland and spleen ofelderly rats We also detected the proteins corresponding


to the genes referred to above The findings showed thatoverexpression of some proinflammatory cytokines at thetranscription and protein level may be involved in thehighly proinflammatory reactive state during inflamm-agingAdditionally our experiments showed that Epimedium totalflavonoids (EF) and icariin (Ica) reduced the proinflamma-tory response enhanced the anti-inflammatory response andreestablished the equilibrium between proinflammatory andanti-inflammatory reactions in the process of inflamm-aging[73 74]

85 Metformin The biguanide drug metformin a type ofhypoglycemic drug is widely prescribed to treat type 2diabetes and metabolic syndrome Researchers have alsonoted the effect of metformin on delaying aging an effectvalidated in rodents [75] and in the nematode Caenorhab-ditis elegans [76] Recently Hall conducted a clinic trialcalled ldquoMetformin Anti-agingrdquo which was supported bythe US Food and Drug Administration (FDA) [77] Thiswas a landmark event in the history of aging research andshowed that metformin may be used as an antiaging drugto improve the health span of humans The mechanismsunderlying the antiaging effects ofmetformin remain unclearSeveral lines of evidence support that metformin may actby inducing metabolism associated with dietary restriction(DR) to increase lifespan and thereby limit the onset ofage-associated diseases across species [78 79] A potentialmediator of metformin benefits is the AMP-activated kinase(AMPK) and metformin can be viewed as DR-like com-pound [76] Cabreiro et al reported that metformin disruptsthe bacterial folate cycle leading to reduced levels of S-adenosylmethionine (SAMe) and decelerated aging in Celegans [80] Meanwhile Moiseeva et al showed that met-formin inhibits the expression of genes coding for multipleinflammatory cytokines seen during cellular senescence andmetformin blocks the activity of NF-120581B [81] The effectsof metformin on anti-inflammation and antiaging imply itspotential on inflamm-aging

9 Novel Research Strategies in Inflamm-Aging

Research into inflamm-aging is still at an early stage Themechanisms biomarkers evaluation method research mod-els and intervention methods of inflamm-aging have notbeen fully elucidated Moreover inflamm-aging involvescells organs and the whole body and this requires an exten-sive and varied range of research investigations

Based on the essential effects and our understanding ofinflammatory cytokine pathways in the process of inflamm-aging we can begin to explore the inflammatory cytokinenetwork and perform a quantitative evaluation of inflamm-aging Inflammatory cytokines including interleukins tumornecrosis factor and interferon mediate their effects bybinding to their receptors and competing in a complex cell-cell network These cytokines act in both paracrine andautocrine ways to exert direct effects on the microenvi-ronment This plays an important regulatory role by acti-vating inflammatory and immune cells and by releasingcytokines In addition inflammatory cytokines induce the

systemic inflammatory response in the circulation Inter-actions between many inflammatory cytokines comprisethe inflammatory cytokine network which features poly-phyletism pleiotropy and overlapping effects Inflammatorycytokines form a complex network which extends in alldirections and throughout the whole bodyThe inflammatorycytokine network can be divided into the proinflammatorycytokine network and anti-inflammatory cytokine networkAs with the immune reaction the inflammatory reactionis also a normal defense function A moderate inflamma-tory reaction is advantageous to the body whereas a highreaction is harmful and the outcome of these reactionsis determined by changes in the inflammatory cytokinenetwork The dynamic balance between the proinflamma-tory cytokine network and the anti-inflammatory cytokinenetwork maintains the normal function of inflammation inbody Once the balance is broken pathological inflammationoccurs [82 83]Therefore we infer that the cause of inflamm-aging is an imbalance in the proinflammatory cytokineand anti-inflammatory cytokine networks which leads to aproinflammatory status with increasing age This may be themechanism of inflamm-aging

The changes in the inflammatory cytokine network havethree characteristics parallelity multilevel action and non-linearity Unraveling the inflammatory cytokine network willrequire nonlinear research methods such as systems biologymethods The inflammatory cytokine network is a typicalsystems biology issue which needs to replace the modelinvolving individual genes with a systems biology model

Systems biology is an interdisciplinary field integratingmultiple disciplines such as biology medicine mathemat-ics physics and chemistry It integrates many kinds ofexperimental data and biological information to build amathematical model tested and verified by experimentaldata and finally predicts the behavior of biological systems[84] Systems biology provides an excellent opportunity toelucidate the essential features of the inflammatory cytokinenetwork It also provides a theoretical guide and new waysto illustrate the relevant mechanisms and build a quantitativeevaluation system for the inflammatory cytokine networkwhich may provide a breakthrough in research on inflamm-aging

Aging (including inflamm-aging) is also a systems biol-ogy issue involving a complex process that results from thecombined effects of many factors Cellular senescence is thebasic unit of biological aging Organ aging is not only themacropresentation of cellular senescence but also a bridgethat connects cellular senescence and integral aging Cellularsenescence organ aging and integral aging form a chain ofaging and cellular senescence is the critical link in the chainof aging In the aging process at all levels (ie genes proteinsmetabolites cells and tissues) the organism undergoesvarying degrees of change in these structures such that thebodyrsquos systems (eg the nervous system endocrine systemcardiovascular system respiratory system digestive systemurinary system and motor system) undergo a significantfunctional decline Aging is not the result of a unilateralfactor but a systemic decline in body function and thedistinctive features of aging are systemic [85] The systemic


features of aging strongly reflect the gradual changes in bodyfunction Functional changes in the process of aging appeargradually with age and all the changes are the results ofprogressive accumulation time is the driving factorThebodyis composed of various tissues and organs so aging is agradual process not a point but an evolution of tissues andorgans over time

Multidisciplinary research including the fields ofmedicine biology mathematics computer science and sys-tems biology should be applied and developed to investigatethe mechanisms of inflamm-aging and the relationshipbetween inflamm-aging and age-related diseases Specificallythe important scientific problems that need to be addressedare the following (1) the regulatory mechanisms responsiblefor the development of inflamm-aging and (2) the molecularmechanisms the regulatory network and the key role of thetransformation from inflammation to age-related diseases inthe process of inflamm-aging

In summary inflamm-aging and the inflammatorycytokine network are both classical systems biology issuesThe inflammatory cytokine network is involved in the processof inflammation and senescence and may be the ideal break-through point of research into inflamm-aging Omics such asgenomics transcriptomics proteomics and metabolomicsare excellent methods to solve systemic biology problemsTherefore under the guidance of systems biology it would benovel strategy to conduct basic research into inflamm-agingusing omics methods to identify characteristic inflammatorycytokine genes in the process of aging and to uncovernew mechanisms to regulate inflammatory cytokines duringinflamm-aging This will also illustrate the mechanism ofinflamm-aging and provide new ways to assess inflamm-aging

10 A Novel Concept ofImmuno-Inflamm-Aging

There is an essential relationship between inflammation andimmunity Both the inflammatory steady state and immunesteady state have defense functions protecting the body frominjury [86]However when the inflammatory steady state andimmune steady state are broken excessive inflammation andpathological immunity ensue and the normal physiologicalfunction of the body is compromised which causes immune-inflammatory diseases Inflammation and immunity coexistin the same pathological process the two sides of a wholeand are inseparable In a sense inflammatory cells areimmune cells [87] therefore they have the same cellularfoundation Many inflammatory and immune cells have thesame cytokine receptors [88] which mediate cell-cell andcell-cytokine interactions The internal relationship betweeninflammation and immunity is not known and the causes andpathological mechanisms of immune-inflammatory diseasesare not understood and this limits effective treatments forimmune-inflammatory diseases [86]

EF and Ica anti-inflammatory immunomodulatory Chi-nese traditionalmedicines not only reduce inflammation butalso regulate immunity As anti-inflammatory immunomod-ulatory Chinese traditional medicines EF and Ica have the

double effects of intervening in immunosenescence andinflamm-aging suggesting an intimate relationship betweenimmunosenescence and inflamm-aging [73 74]

Based on the integrated relationship between oxidativestress and inflammatory stress De La Fuente and Miquelproposed an innovative oxidation-inflammation theory ofaging (oxi-inflamm-aging) [10] The oxi-inflamm-aging the-ory posits that chronic oxidative stress affects all immunecells and particularly regulatory systems such as neuralendocrine and immune systems as well as the mutualinteractions among these systems These events lead tostable internal environment disorders that are harmful tohealthThe relationship between the redox state and immunefunction affects the speed of aging and lifespan A diet withsufficient antioxidants improves immune function reducesoxidative stress and prolongs lifespan which supports thenotion that the inflammatory response of immune cellsand the immune system play an important role in oxi-inflamm-aging [10] Inflamm-aging and immunosenescenceare connected and they cause and affect each other This canresult in a vicious cycle that further aggravates the occur-rence and development of age-related diseases includingatherosclerosis metabolic syndrome type 2 diabetes insulinresistance osteoporosis bone arthritis muscle mass andmuscle weakness cancer and neurodegenerative diseases

It is currently not possible to distinguish whether diseasesare caused by inflamm-aging alone or immunosenescencealone [30 89] Therefore we propose that inflamm-agingis accompanied by immunosenescence and they occurtogether We propose the novel concept of immuneinflam-matory aging (immuno-inflamm-aging) instead of the indi-vidual concepts of inflamm-aging and immunosenescence

Competing Interests

The authors declare that they have no competing interestsregarding the publication of this paper

Authorsrsquo Contributions

Shijin Xia andXinyan Zhang contributed equally to this workand should be considered the first authors

Acknowledgments

This work was supported by the National Natural ScienceFoundation of China (Grant nos 81460748 31171129 and81000859) and Shanghai Municipal Commission of Health(Grant no 2013ZYJB0801)

References

[1] C FranceschiM Bonafe S Valensin et al ldquoInflamm-aging Anevolutionary perspective on immunosenescencerdquo Annals of theNew York Academy of Sciences vol 908 pp 244ndash254 2000

[2] B Giunta F Fernandez W V Nikolic et al ldquoInflammaging asa prodrome to Alzheimerrsquos diseaserdquo Journal of Neuroinflamma-tion vol 5 article 51 2008


[3] M De Martinis C Franceschi D Monti and L GinaldildquoInflamm-ageing and lifelong antigenic load as major determi-nants of ageing rate and longevityrdquo FEBS Letters vol 579 no 10pp 2035ndash2039 2005

[4] M J Day ldquoAgeing Immunosenescence and Inflammageing inthe dog and catrdquo Journal of Comparative Pathology vol 142 no1 pp S60ndashS69 2010

[5] C Franceschi ldquoCell proliferation cell death and agingrdquo AgingMilano vol 1 no 1 pp 3ndash15 1989

[6] C Franceschi D Monti P Sansoni and A Cossarizza ldquoTheimmunology of exceptional individuals the lesson of centenar-iansrdquo Immunology Today vol 16 no 1 pp 12ndash16 1995

[7] C Franceschi and A Cossarizza ldquoIntroduction the reshapingof the immune system with agerdquo International Reviews ofImmunology vol 12 no 1 pp 1ndash4 1995

[8] A Salminen J Huuskonen J Ojala A Kauppinen K Kaarni-ranta and T Suuronen ldquoActivation of innate immunity systemduring aging NF-120581B signaling is the molecular culprit ofinflamm-agingrdquo Ageing Research Reviews vol 7 no 2 pp 83ndash105 2008

[9] M Mishto A Santoro E Bellavista M Bonafe D Monti andC Franceschi ldquoImmunoproteasomes and immunosenescencerdquoAgeing Research Reviews vol 2 no 4 pp 419ndash432 2003

[10] M De La Fuente and J Miquel ldquoAn update of the oxidation-inflammation theory of aging the involvement of the immunesystem in oxi-inflamm-agingrdquo Current Pharmaceutical Designvol 15 no 26 pp 3003ndash3026 2009

[11] C Franceschi M Capri D Monti et al ldquoInflammagingand anti-inflammaging a systemic perspective on aging andlongevity emerged from studies in humansrdquo Mechanisms ofAgeing and Development vol 128 no 1 pp 92ndash105 2007

[12] S Giunta ldquoIs inflammaging an auto[innate]immunity subclin-ical syndromerdquo Immunity and Ageing vol 3 article 12 2006

[13] C Nathan and A Ding ldquoNonresolving inflammationrdquo Cell vol140 no 6 pp 871ndash882 2010

[14] E Boren and M E Gershwin ldquoInflamm-aging autoimmunityand the immune-risk phenotyperdquo Autoimmunity Reviews vol3 no 5 pp 401ndash406 2004

[15] C Franceschi S Valensin F Lescai et al ldquoNeuroinflammationand the genetics of Alzheimerrsquos disease the search for a pro-inflammatory phenotyperdquo Aging Clinical and ExperimentalResearch vol 13 no 3 pp 163ndash170 2001

[16] P Lencel and D Magne ldquoInflammaging the driving force inosteoporosisrdquo Medical Hypotheses vol 76 no 3 pp 317ndash3212011

[17] C Miki M Kusunoki Y Inoue et al ldquoRemodeling of theimmunoinflammatory network system in elderly cancerpatients implications of inflamm-aging and tumor-specifichyperinflammationrdquo Surgery Today vol 38 no 10 pp 873ndash8782008

[18] F Sipos K Leiszter and Z Tulassay ldquoEffect of ageing on colonicmucosal regenerationrdquo World Journal of Gastroenterology vol17 no 25 pp 2981ndash2986 2011

[19] S K Butcher and J M Lord ldquoStress responses and innateimmunity aging as a contributory factorrdquo Aging Cell vol 3 no4 pp 151ndash160 2004

[20] E Ottaviani and C Franceschi ldquoThe neuroimmunology ofstress from invertebrates to manrdquo Progress in Neurobiology vol48 no 4-5 pp 421ndash440 1996

[21] E S Cannizzo C C Clement R Sahu C Follo and L San-tambrogio ldquoOxidative stress inflamm-aging and immunose-nescencerdquo Journal of Proteomics vol 74 no 11 pp 2313ndash23232011

[22] J Marchal F Pifferi and F Aujard ldquoResveratrol in mammalseffects on aging biomarkers age-related diseases and life spanrdquoAnnals of the New York Academy of Sciences vol 1290 no 1 pp67ndash73 2013

[23] S Salvioli M Capri S Valensin et al ldquoInflamm-agingcytokines and aging state of the art new hypotheses on the roleof mitochondria and new perspectives from systems biologyrdquoCurrent Pharmaceutical Design vol 12 no 24 pp 3161ndash31712006

[24] S Alberti E Cevenini R Ostan et al ldquoAge-dependent mod-ifications of Type 1 and Type 2 cytokines within virgin andmemory CD4+ T cells in humansrdquo Mechanisms of Ageing andDevelopment vol 127 no 6 pp 560ndash566 2006

[25] C Franceschi S Valensin M Bonafe et al ldquoThe network andthe remodeling theories of aging Historical background andnew perspectivesrdquo Experimental Gerontology vol 35 no 6-7pp 879ndash896 2000

[26] A A Adams C C Breathnach M P Katepalli K Kohlerand D W Horohov ldquoAdvanced age in horses affects divisionalhistory of T cells and inflammatory cytokine productionrdquoMechanisms of Ageing andDevelopment vol 129 no 11 pp 656ndash664 2008

[27] H Bruunsgaard K Andersen-Ranberg J V BHjelmborg B KPedersen and B Jeune ldquoElevated levels of tumor necrosis factoralpha and mortality in centenariansrdquo The American Journal ofMedicine vol 115 no 4 pp 278ndash283 2003

[28] M Cesari BW Penninx M Pahor et al ldquoInflammatory mark-ers and physical performance in older persons the InCHIANTIstudyrdquo Journals of GerontologymdashSeries A Biological Sciences andMedical Sciences vol 59 no 3 pp 242ndash248 2004

[29] D Lio L Scola A Crivello et al ldquoInflammation genetics andlongevity further studies on the protective effects in men ofIL-10-1082 promoter SNP and its interaction with TNF-120572-308promoter SNPrdquo Journal of Medical Genetics vol 40 no 4 pp296ndash299 2003

[30] GM Pes D Lio C Carru et al ldquoAssociation between longevityand cytokine gene polymorphisms A study in Sardinian cente-nariansrdquo Aging Clinical and Experimental Research vol 16 no3 pp 244ndash248 2004

[31] M Sasaki H Ikeda Y Sato and Y Nakanuma ldquoProinflamma-tory cytokine-induced cellular senescence of biliary epithelialcells is mediated via oxidative stress and activation of ATMpathway a culture studyrdquo Free Radical Research vol 42 no 7pp 625ndash632 2008

[32] J Bartek Z Hodny and J Lukas ldquoCytokine loops drivingsenescencerdquo Nature Cell Biology vol 10 no 8 pp 887ndash8892008

[33] A Freund A V Orjalo P-Y Desprez and J Campisi ldquoInflam-matory networks during cellular senescence causes and conse-quencesrdquo Trends in Molecular Medicine vol 16 no 5 pp 238ndash246 2010

[34] G Candore C Caruso and G Colonna-Romano ldquoInflamma-tion genetic background and longevityrdquo Biogerontology vol 11no 5 pp 565ndash573 2010

[35] A Meier H Fiegler P Munoz et al ldquoSpreading of mammalianDNA-damage response factors studied by ChIP-chip at dam-aged telomeresrdquo The EMBO Journal vol 26 no 11 pp 2707ndash2718 2007


[36] G Hewitt D Jurk F D Marques et al ldquoTelomeres are favouredtargets of a persistent DNA damage response in ageing andstress-induced senescencerdquo Nature Communications vol 3article 708 2012

[37] F Olivieri M C Albertini M Orciani et al ldquoDNA damageresponse (DDR) and senescence shuttled inflamma-miRNAson the stage of inflamm-agingrdquo Oncotarget vol 6 no 34 pp35509ndash35521 2015

[38] M Bonafe G Storci and C Franceschi ldquoInflamm-aging ofthe stem cell niche breast cancer as a paradigmatic examplebreakdown of the multi-shell cytokine network fuels cancer inaged peoplerdquo BioEssays vol 34 no 1 pp 40ndash49 2012

[39] N Mizushima T Yoshimori and B Levine ldquoMethods inmammalian autophagy researchrdquo Cell vol 140 no 3 pp 313ndash326 2010

[40] K Y Hur H S Jung and M S Lee ldquoRole of autophagy in 120573-cell function and massrdquo Diabetes Obesity and Metabolism vol12 no 2 pp 20ndash26 2010

[41] E White and S W Lowe ldquoEating to exit autophagy-enabledsenescence revealedrdquo Genes and Development vol 23 no 7 pp784ndash787 2009

[42] G Juhasz B Erdi M Sass and T P Neufeld ldquoAtg7-dependentautophagy promotes neuronal health stress tolerance andlongevity but is dispensable for metamorphosis in DrosophilardquoGenes and Development vol 21 no 23 pp 3061ndash3066 2007

[43] A Salminen K Kaarniranta and A Kauppinen ldquoInflammag-ing disturbed interplay between autophagy and inflamma-somesrdquo Aging vol 4 no 3 pp 166ndash175 2012

[44] D L Jones and T A Rando ldquoEmerging models and paradigmsfor stem cell ageingrdquoNature Cell Biology vol 13 no 5 pp 506ndash512 2011

[45] H Bruunsgaard M Pedersen and B K Pedersen ldquoAging andproinflammatory cytokinesrdquo Current Opinion in Hematologyvol 8 no 3 pp 131ndash136 2001

[46] H Y Cohen CMiller K J Bitterman et al ldquoCalorie restrictionpromotes mammalian cell survival by inducing the SIRT1deacetylaserdquo Science vol 305 no 5682 pp 390ndash392 2004

[47] A Salminen A Kauppinen T Suuronen and K KaarnirantaldquoSIRT1 longevity factor suppresses NF-120581B-driven immuneresponses regulation of aging via NF-120581B acetylationrdquo BioEs-says vol 30 no 10 pp 939ndash942 2008

[48] A Salminen J Ojala JHuuskonenAKauppinen T Suuronenand K Kaarniranta ldquoInteraction of aging-associated signalingcascades inhibition of NF-120581B signaling by longevity factorsFoxOs and SIRT1rdquo Cellular and Molecular Life Sciences vol 65no 7-8 pp 1049ndash1058 2008

[49] X-Y Liu Q Wang S-J Xia J-H Huang Z-Y Shen andH Xu ldquoCharacteristics of lymphocyte nuclear factor-120581B signaltransduction kinase expression in aging process and regulatoryeffect of Epimedium flavonoidsrdquo Chinese Journal of IntegrativeMedicine vol 17 no 9 pp 704ndash709 2011

[50] S M Schieke and T Finkel ldquoTOR and aging less is morerdquo CellMetabolism vol 5 no 4 pp 233ndash235 2007

[51] Z D Sharp and R Strong ldquoThe role of mTOR signaling incontrolling mammalian life Span what a fungicide teaches usabout longevityrdquo Journals of GerontologymdashSeries A BiologicalSciences and Medical Sciences vol 65 no 6 pp 580ndash589 2010

[52] P Kapahi B M Zid T Harper D Koslover V Sapin and SBenzer ldquoRegulation of lifespan in Drosophila by modulation ofgenes in the TOR signaling pathwayrdquo Current Biology vol 14no 10 pp 885ndash890 2004

[53] X Wang and C G Proud ldquomTORC1 signaling what we stilldonrsquot knowrdquo Journal of Molecular Cell Biology vol 3 no 4 pp206ndash220 2011

[54] M N Stanfel L S Shamieh M Kaeberlein and B K KennedyldquoThe TOR pathway comes of agerdquo Biochimica et Biophysica Acta(BBA)mdashGeneral Subjects vol 1790 no 10 pp 1067ndash1074 2009

[55] F Liu S Wu H Ren and J Gu ldquoKlotho suppresses RIG-I-mediated senescence-associated inflammationrdquo Nature CellBiology vol 13 no 3 pp 254ndash262 2011

[56] T Quillard and B Charreau ldquoImpact of Notch signaling oninflammatory responses in cardiovascular disordersrdquo Interna-tional Journal of Molecular Sciences vol 14 no 4 pp 6863ndash6888 2013

[57] M C Haigis and L P Guarente ldquoMammalian sirtuinsmdashemerging roles in physiology aging and calorie restrictionrdquoGenes and Development vol 20 no 21 pp 2913ndash2921 2006

[58] M-H Moon J-K Jeong Y-J Lee J-W Seol C J Jackson andS-Y Park ldquoSIRT1 a class III histone deacetylase regulates TNF-120572-induced inflammation in human chondrocytesrdquoOsteoarthri-tis and Cartilage vol 21 no 3 pp 470ndash480 2013

[59] G Carrieri E Marzi F Olivieri et al ldquoThe GC915 poly-morphism of transforming growth factor 1205731 is associated withhuman longevity a study in Italian centenariansrdquo Aging Cellvol 3 no 6 pp 443ndash448 2004

[60] T Minamino T Yoshida K Tateno et al ldquoRas induces vascularsmooth muscle cell senescence and inflammation in humanatherosclerosisrdquo Circulation vol 108 no 18 pp 2264ndash22692003

[61] F Olivieri M R Rippo V Monsurro et al ldquoMicroRNAslinking inflamm-aging cellular senescence and cancerrdquo AgeingResearch Reviews vol 12 no 4 pp 1056ndash1068 2013

[62] F Olivieri M R Rippo A D Procopio and F FaziolildquoCirculating inflamma-miRs in aging and age-related diseasesrdquoFrontiers in Genetics vol 4 article 121 2013

[63] L Fontana and S Klein ldquoAging adiposity and calorie restric-tionrdquoThe Journal of the American Medical Association vol 297no 9 pp 986ndash994 2007

[64] W Cai J C He L Zhu et al ldquoOral glycotoxins determinethe effects of calorie restriction on oxidant stress age-relateddiseases and lifespanrdquo The American Journal of Pathology vol173 no 2 pp 327ndash336 2008

[65] D-H Hyun S S Emerson D-G Jo M P Mattson and R deCabo ldquoCalorie restriction up-regulates the plasma membraneredox system in brain cells and suppresses oxidative stressduring agingrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 103 no 52 pp 19908ndash199122006

[66] K W Chung D H Kim M H Park et al ldquoRecent advancesin calorie restriction research on agingrdquo Experimental Geron-tology vol 48 no 10 pp 1049ndash1053 2013

[67] H Y Chung H J Kim J W Kim and B P Yu ldquoTheinflammation hypothesis of aging molecular modulation bycalorie restrictionrdquoAnnals of the New York Academy of Sciencesvol 928 pp 327ndash335 2001

[68] E Mocchegiani L Costarelli R Giacconi et al ldquoNutrient-geneinteraction in ageing and successful ageing A single nutrient(zinc) and some target genes related to inflammatoryimmuneresponserdquoMechanisms of Ageing and Development vol 127 no6 pp 517ndash525 2006

[69] F J Alcaın and J M Villalba ldquoSirtuin activatorsrdquo ExpertOpinion onTherapeutic Patents vol 19 no 4 pp 403ndash414 2009


[70] R S Said E El-Demerdash A S Nada and M M KamalldquoResveratrol inhibits inflammatory signaling implicated inionizing radiation-induced premature ovarian failure throughantagonistic crosstalk between silencing information regulator1 (SIRT1) and poly(ADP-ribose) polymerase 1 (PARP-1)rdquo Bio-chemical Pharmacology vol 103 pp 140ndash150 2016

[71] C Buhrmann P Shayan B Popper A Goel and M ShakibaeildquoSirt1 is required for resveratrol-mediated chemopreventiveeffects in colorectal cancer cellsrdquoNutrients vol 8 no 3 p E1452016

[72] X Zhu Q Liu MWang et al ldquoActivation of Sirt1 by resveratrolinhibits TNF-120572 induced inflammation in fibroblastsrdquo PloS onevol 6 no 11 article e27081 2011

[73] S Xia Y ShenW Yu et al ldquoStudy onmechanism and interven-tion of inflamm-aging in ratsrdquo Chinese Journal of Gerontologyvol 29 no 20 pp 2595ndash2598 2009

[74] S Xia Y Shen W Yu et al ldquoInfalmm-aging related genesexpression in aged rat hippocampus and Icariin interventionoutcomerdquo Geriatrics amp Health Care vol 14 no 6 pp 340ndash3442008

[75] V N Anisimov L M Berstein I G Popovich et al ldquoIfstarted early in life metformin treatment increases life span andpostpones tumors in female SHR micerdquo Aging vol 3 no 2 pp148ndash157 2011

[76] B Onken and M Driscoll ldquoMetformin induces a dietaryrestriction-like state and the oxidative stress response to extendC elegans healthspan via AMPK LKB1 and SKN-1rdquo PLoS ONEvol 5 no 1 Article ID e8758 2010

[77] S S Hall ldquoA trial for the agesrdquo Science vol 349 no 6254 pp1274ndash1278 2015

[78] L PartridgeMDW Piper andWMair ldquoDietary restriction inDrosophilardquo Mechanisms of Ageing and Development vol 126no 9 pp 938ndash950 2005

[79] E J Masoro ldquoCaloric restriction and aging an updaterdquo Experi-mental Gerontology vol 35 no 3 pp 299ndash305 2000

[80] F Cabreiro C Au K-Y Leung et al ldquoMetformin retardsaging in C elegans by altering microbial folate and methioninemetabolismrdquo Cell vol 153 no 1 pp 228ndash239 2013

[81] O Moiseeva X Deschenes-Simard E St-Germain et al ldquoMet-formin inhibits the senescence-associated secretory phenotypeby interfering with IKKNF-120581B activationrdquo Aging Cell vol 12no 3 pp 489ndash498 2013

[82] Z Frankenstein U Alon and I R Cohen ldquoThe immune-body cytokine network defines a social architecture of cellinteractionsrdquo Biology Direct vol 1 article 32 2006

[83] M C Wichers G Kenis G H Koek G Robaeys N A Nicol-son andMMaes ldquoInterferon-120572-induced depressive symptomsare related to changes in the cytokine network but not tocortisolrdquo Journal of Psychosomatic Research vol 62 no 2 pp207ndash214 2007

[84] H Kitano ldquoSystems biology a brief overviewrdquo Science vol 295no 5560 pp 1662ndash1664 2002

[85] T B L Kirkwood ldquoA systematic look at an old problemrdquoNaturevol 451 no 7179 pp 644ndash647 2008

[86] G Kramer D Mitteregger and M Marberger ldquoIs benign pro-static hyperplasia (BPH) an immune inflammatory diseaserdquoEuropean Urology vol 51 no 5 pp 1202ndash1216 2007

[87] R Macaulay A N Akbar and S M Henson ldquoThe role of the Tcell in age-related inflammationrdquoAge vol 35 no 3 pp 563ndash5722013

[88] K Nie Y Zhang R Gan et al ldquoPolymorphisms in immuneinflammatory cytokine genes are related to Parkinsonrsquos diseasewith cognitive impairment in the Han Chinese populationrdquoNeuroscience Letters vol 541 pp 111ndash115 2013

[89] G Candore C R Balistreri G Colonna-Romano et alldquoGender-related immune-inflammatory factors age-relateddiseases and longevityrdquo Rejuvenation Research vol 13 no 2-3pp 292ndash297 2010

Submit your manuscripts athttpwwwhindawicom

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EndocrinologyInternational Journal of



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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


of agreement on definitions and terminology there is consen-sus that the primary feature of inflamm-aging is an increasein the bodyrsquos proinflammatory status with advancing ageFurthermore a new concept of ldquoanti-inflammagingrdquo was alsoproposed which influences progressive pathophysiologicalchanges as well as lifespan and acts along with inflamm-aging [11] In the next section the characteristics of inflamm-aging are described in more detail

3 The Inflammatory Characteristics ofInflamm-Aging

Thefive states of inflamm-aging are as follows [12] low-gradecontrolled asymptomatic chronic and systemic Howeverthe inflammation during inflamm-aging is not in a controlledinflammatory state We propose that inflammation in theprocess of inflamm-aging belongs to nonresolving inflam-mation [13] Inflammation is a series of complex responseevents which are caused by the host system facing a pathogeninfection or various types of tissue injury These responseevents are characterized by interactions between the cellsand factors in the microenvironment and by regulation ofthe balance between physiological and pathological signalingnetworks In common conditions inflammatory responsesdisappear when proinflammatory factors in infection andtissue injuries are eliminated and then change into a highlyactive and well regulated balanced state which is calledresolving inflammation [13] However in the presence ofsome as yet uncertain factors such as persistent and lowintensity stimulation and long-term and excessive responsein target tissues inflammation fails to move into a steadystate of anti-infection and tissue injury repair instead theinflammation continues andmoves to a nonresolving inflam-mation state [13] Given this background inflammation in theprocess of inflamm-aging belongs to the state of nonresolvinginflammation

4 The Relationship betweenInflamm-Aging and Diseases

Like the immune response inflammation has a physiolog-ical function in the normal body Moderate inflammatoryresponse is beneficial to the body but when excessive theresponse becomes harmful Changes in the inflammatorycytokine network control the direction of the developmentof inflammation The dynamic balance of the network ofproinflammatory cytokines and anti-inflammatory cytokinesmaintains the physiologic function of inflammation in thenormal body Tipping the balance from anti-inflammation toproinflammation can lead to pathological changes Persistentinflammation during the inflamm-aging process may causeinflammation-related diseases

Inflamm-aging is a determinant of the speed of the agingprocess and of lifespan and is highly related to Alzheimerrsquosdisease [2] Parkinsonrsquos disease acute lateral sclerosis multi-ple sclerosis atherosclerosis heart disease age-related mac-ular degeneration [14] type II diabetes [15] osteoporosis andinsulin resistance [16] cancer and other diseases Inflamm-aging also increases morbidity and mortality significantly

harming the health of patients and causes a decline in thequality of life of patients [16] Chronic subclinical inflamma-tion and immune disorders coexist in the process of inflamm-aging Epidemiological studies show that with age there isan imbalance in the loss of old bone and the formation ofnew bone Inflamm-aging may be one of the contributingfactors to the imbalance and to the subsequent excessive lossof bone Inflammatory markers of inflamm-aging provideclinicians with the necessary data for risk assessment ofosteoporosis Inflammatory cytokines may be therapeutictargets for improving the formation of bone in the elderlyafter bone operations [16] Excessive inflammation duringinflamm-aging increases the morbidity and mortality ofpatients after bone operations even though the mechanismfor this remains unclear [17] In the process of inflamm-agingthe pathophysiological changes in the colon are revealed atthe cellular and molecular levels and these culminate in theinflammation that leads to injury of the gastric mucosa andepithelium as well as a decrease in the epitheliumrsquos ability toregenerate [18] (Figure 1)

However inflamm-aging seems to be a double-edgedsword in that it decreases immune function but also increasesthe autoreactivity of the body [17] Inflamm-aging is benefi-cial to the body by neutralizing the harmful cytokines in theearly stage of the life but has a detrimental role in the later life[17]

Unfortunately the strong correlation between inflamm-aging and disease development is complex and unclearBecause immunosenescence and inflamm-aging coexist it isdifficult to distinguish whether the inflammation-related dis-eases are caused by inflamm-aging or immunosenescenceMoreover the crucial question is whether there is a causalrelationship between inflamm-aging and diseases whichneeds integrated biological and clinical research to resolve

5 The Mechanisms of Inflamm-Aging

While the mechanism of inflamm-aging is not completelyunderstood the current theories in the field are summarizedbelow

51 The Theory of Stress Generally stress is either beneficialor harmful to the body During inflamm-aging the body isconstantly in the stress environment which is caused by dif-ferent kinds of stressors that induce andmaintain the chronicproinflammatory status in the body Stress as one of regulatedfactors of immunity provokes the greatest immune responsein the bodies of young persons whereas it provokes thatweakest response in elderly persons with signs of immunose-nescence and inflamm-aging [19 20] According to a seriesof studies involving different species from invertebrates tohumans from an evolutionary perspective inflammation isclosely related to innate immunity and stress [20] Basedon evolutionary studies immune response stress responseand inflammation form a defensive network in the bodyHowever the compatibility between inflammatory status andlongevity and the paradoxical proinflammatory character inhealthy centenarians strongly suggest the existence of physi-ological inflammation [21] Therefore inflammation and the


Inflamm-aging



Heartdiseases

Atherosclerosis

Age-related macular

degeneration




Insulin resistance

Osteoporosis

Type II diabetes

Cancer



































StressOxidation-


DNA damageAutophagy

Stem cell aging






Inflamm-aging

Activation











































Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Inflamm-aging



Heartdiseases

Atherosclerosis

Age-related macular

degeneration




Insulin resistance

Osteoporosis

Type II diabetes

Cancer



































StressOxidation-


DNA damageAutophagy

Stem cell aging






Inflamm-aging

Activation











































Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































StressOxidation-


DNA damageAutophagy

Stem cell aging






Inflamm-aging

Activation











































Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















































Competing Interests




Acknowledgments


References


































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article an update on inflamm-aging: mechanisms...

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