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ScienceDirect Inflammation, ageing and chronic disease Graham Pawelec, David Goldeck and Evelyna Derhovanessian Acute inflammatory responses are essential for pathogen control and tissue repair but can also cause severe collateral damage. Tight regulation of the response is required to minimize host injury, but in the face of chronic infections and age-associated immune dysregulation, inflammatory processes may exert multiple detrimental effects on the organism. The signs of low level systemic inflammation commonly detectable in elderly people are associated with many chronic diseases of ageing and may even contribute to their causation. The purpose of this article is to review recent literature from the past two years providing new data on the inter-relationships between inflammatory status and chronic diseases of ageing. Addresses Tu¨bingen Ageing and Tumour Immunology Group, Second Department of Internal Medicine, Center for Medical Research, ZMF, Waldho¨rnlerstr. 22, D-72072 Tu¨bingen, Germany Corresponding author: Pawelec, Graham ([email protected], [email protected]) and

Current Opinion in Immunology 2014, 29:23–28 This review comes from a themed issue on Immune senescence Edited by Tamas Fu¨lo¨p and Ruth Montgomery

0952-7915/$ – see front matter, # 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.coi.2014.03.007

response once the pathogen has been eliminated (for a recent review on resolution of inflammation, see [2]). If the pathogen cannot be eliminated, or the immune response cannot be properly regulated, the immune pathology responsible for most of the symptoms associated with infections may also persist. The consequences of such persistent immune responses may be serious, ranging from tumorigenesis (e.g. in the case of HBV, HCV and HPV) to systemic inflammatory disease [3]. As mammals age, the complex regulatory circuits required to maintain appropriate immune homeostasis may become compromised, with the result that there is a dysbalance of immune control tending to favour innate responses. This manifests in humans as a state characterized by the presence of higher levels systemic inflammatory markers than generally seen in the young, some of which have been associated with detrimental health outcomes. This has been dubbed ‘inflammaging’, an umbrella term covering a multitude of phenomena first introduced by Claudio Franceschi in 2000 [4]. More recent iterations and extensions of this idea suggest the possible involvement of aberrant glycosylation [5] as well as accumulating tissue damage reflected in increasing amounts of mitochondrial DNA in the periphery which correlate with levels of inflammatory mediators [6]. The purpose of this opinion piece is to review the published literature from the last couple of years in an attempt to characterize inflammaging and assess its contribution to the development of age-associated chronic diseases in humans.

Detection of systemic chronic inflammation Introduction Inflammatory processes are evolutionarily ancient and are essential components of immune defense in all mammals, probably in all vertebrates and even invertebrates [1]. Acute inflammation is a rapid response to injury with which pathogen ingress is likely to be associated and which therefore prepares defenses in advance. It is caused by activation of specialized cells like granulocytes and mast cells which are present throughout the body and primarily recognize structures present in microorganisms that are absent in host cells. Multiple responses are triggered including cellular effectors that kill pathogens directly via highly toxic non-specific mediators such as reactive oxygen species. Such onslaughts also cause collateral damage to healthy host cells and need to be strictly controlled. Such control is achieved by influx of cells of the adaptive immune system which develop specific antipathogen responses and provide tight regulation of both the innate and adaptive immune response by means of regulatory (suppressor) cells of several different types. These are also present in order to terminate the immune www.sciencedirect.com

Most gerontological data in humans derive from studies of systemic levels of soluble mediators measured in plasma or serum, usually comparing cohorts of younger and older people in cross-sectional studies. In many different cohorts, these studies have repeatedly shown that elderly people tend to have higher levels of C-reactive protein (CRP), IL-6 and TNF in their blood [7]. There are certainly many other cytokines and chemokines that could also be informative in this context, particularly those that are present at very low levels or are undetectable in healthy young adult serum, including inflammatory factors such as IL-1b, CCL7 (MCP-3), and Lymphotoxin-a [8] but many of these have not yet been well-studied in the ageing context. These factors normally exert their biological effects locally; thus their presence in serum is likely to reflect ‘leakage’ into the periphery and their potentially inappropriate action at a distance. Hence, not only dysregulated production of these factors, but their improper localization, may contribute to deleterious health outcomes. Although the above consideration would place such systemic factors Current Opinion in Immunology 2014, 29:23–28

24 Immune senescence

firmly in the realm of ‘biomarkers’, there are some intriguing results in animal models suggesting that soluble products in the serum of old animals can ‘age’ young animals, and vice versa (recently reviewed in [9]). These parabiosis experiments immediately offer the enticing possibility of developing interventions actually to reverse rather than ‘merely’ slowing or preventing ageing. Publications are already appearing setting out hypothetical protocols for applying this approach in humans (e.g. see [10]). Possibly, the identification and removal of factors present in the plasma would already do the job, without the necessity for such invasive apheresis techniques in the elderly. One such candidate is now under scrutiny: the chemokine CCL11 (eotaxin), at least in the context of neurodegeneration [11]. To focus on the current state of the art regarding systemic inflammatory marker studies in such a short piece as this, one needs to limit the range of factors to those bestaccepted as correlating with detrimental physiological effects (even then, each section below could be a whole chapter). Such studies in humans can only be observational, except in rare cases where, e.g. cytokine treatment for disease is considered, but these are not very relevant for normal ageing. The next sections will therefore mostly concern human studies on factors such as IL-6, TNF and CRP in chronic disease, considering the sources of these factors contributing to their higher levels in the elderly, the mechanisms by which they may exert their deleterious effects, and finally, efforts at remediation in old people.

matory markers. Multiple measurements in longitudinal studies were more informative for 10-year follow-up in over 3000 people [14]. As has repeatedly been found in other studies, it was again IL-6 that was the most informative factor in this analysis, and the authors concluded that it very significantly affected both cardiovascular and non-cardiovascular mortality, concluding that ‘chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy ageing phenotypes and a decreased likelihood of successful ageing. Our results suggest that assessing long-term chronic inflammation by repeat measurement of interleukin-6 has the potential to guide clinical practice’ [14]. However, the molecular mechanisms responsible for such associations are for the most part unclear. They are likely to be highly complex, but clearly important in major age-associated chronic diseases such as cardiovascular disease caused by arterial degeneration (e.g. see [15]), neurodegeneration (e.g. [16]) and cancer (e.g. [3]). One hypothesis is that the immune system is kept at a higher state of activation in a type of vicious circle which is adaptive in defense against pathogens but maladaptive when considered in the light of autoimmune manifestations. This is essentially what was proposed by Roy Walford in his prescient work on the ‘Immunologic Theory of Aging’ [17]. Despite our continued lack of knowledge on mechanisms, many anti-inflammatory interventions are being tested in the clinic, or are in routine use, as briefly discussed in the final section.

Sources of the inflammatory mediators Chronic infection

Inflammatory mediators and chronic disease Elevated systemic indicators of inflammation in the elderly are implicated in carcinogenesis, sarcopenia, atherosclerosis, diabetes, neurodegeneration and other chronic diseases of ageing. There is a large literature on this topic, mostly recently nicely reviewed by Michaud et al. [12]. Why chronically elevated low-level systemic inflammatory mediators are associated with disease and whether this is casual is not known. Is it a reflection of some other ageing process independently causing both disease and increased inflammation? Evidence that higher levels of inflammatory mediators themselves cause disease comes from therapies neutralizing specific cytokines in pathologies such as rheumatoid arthritis (see section on interventions below). Consistent with this, younger people with controlled HIV infection who show elevated levels of multiple markers of inflammation were found to suffer excess cardiovascular, neurologic and other diseases that usually occur at a later age. ‘Premature inflammaging’ in these patients predicts their risk of morbidity and mortality from these age-associated diseases [13]. It is likely that similar considerations apply not only to HIV-infected people; indeed, a recent study argues that the impact of chronic inflammation in ageing has been underestimated in the past, due to suboptimal study design using only single measurements of inflamCurrent Opinion in Immunology 2014, 29:23–28

The necessity for ongoing immunosurveillance of chronic infections might be expected to contribute to higher levels of pro-inflammatory mediators. These would be the same in the equally infected young and old, unless there was a problem with dysregulation of the local immune response in the elderly. Infection with persistent herpesviruses, notably HHV5 (Cytomegalovirus, CMV) is associated with dramatic changes in the distribution of CD8+ T cells, with marked increases of late-stage memory cells in the periphery, and it had been suggested that CMV-infected elderly had higher levels of inflammatory mediators than the (rare) CMV-seronegative elderly. However, recent studies have challenged this notion. In the Leiden 85+ study of free-living residents of this Dutch town >85 yr of age, CRP levels were identical in 435 CMV-seropositive subjects and the 114 seronegatives [18]. Another study followed 249 subjects longitudinally in the Hertfordshire Ageing Study from a mean age of 67.5 years at baseline. This revealed significant increases of CRP, TNF and IL-6 and decreased anti-inflammatory cytokine IL-10 over 10 years follow-up, but no difference in this respect between CMV-seropositive or seronegative subjects [19]. Thus, it appears that chronic infection with a virus known to have a marked impact on parameters of adaptive immunity does not necessarily contribute to the age-associated increased systemic www.sciencedirect.com

Inflammation, ageing and chronic disease Pawelec, Goldeck and Derhovanessian 25

inflammatory status in the elderly. A corollary to this is that the often-reported negative consequences of CMV infection must be mediated by mechanisms other than effects on increasing inflammation. Data analysis from the NHANES study suggested detrimental effects of CMV infection together with higher CRP levels primarily on cardiovascular mortality, but obviously did not show that CMV caused the higher CRP levels [20]. The NHANES cohort was relatively young but a smaller study of 511 people at least 65 years of age reported a marked impact of CMV infection. This increased the annual mortality rate by as much as 42% after adjusting for age, sex and baseline socioeconomic and health variables, corresponding to a 3.7 year lower life expectancy after age 65. As in the NHANES study, cardiovascular deaths but not mortality from other causes, was increased by CMV infection [21]. According to a most recent small study, for an accurate assessment of the relative impact of inflammation on CMV-associated mortality, we may have to look beyond the purely humoural indications of CMV infection. Thus, a recent analysis of data from the Baltimore WHAS study showed that anti-CMV IgG titers remained constant over a 12 year follow-up and were not associated with inflammatory status. However, subjects with detectable CMV DNA in their blood cells did have significantly higher IL-6 levels than CMV DNAnegative individuals, both at baseline and follow-up. Moreover, CMV-specific CD8+ T cells were expanded in only those who were CMV DNA-positive [22]. Thus, CMV serology is probably too blunt a tool to allow comparisons and more sophisticated dissection of CMV–host interactions will be required to dissect out meaningful parameters. Again, it is also conceivable that detrimental effects of CMV infection are discernible locally but not systemically, indirectly by being immune-mediated. Thus, proinflammatory cytokines released by CMV-reactive T-cells damage endothelial cells and promote migration of immune cells, which could have numerous knock-on effects [23]. Other recent example of such local effects may include the proinflammatory effects noted on CMV infection of macrophages and monocytes, possibly not reflected at the systemic level [24,25]. Other chronic infections such as HBV and HCV certainly do cause local inflammation, increase IL-6 levels in the liver and affect systemic CRP, but these infections may be unusual in that they are localized to the liver, which is the source of IL-6-stimulated CRP production [26]. The likelihood may be that many or most chronic infections do not cause much systemic inflammation. What then is responsible for the observed increased levels of systemic inflammatory mediators in the elderly?

elderly, which are a rich source of pro-inflammatory factors collectively termed the ‘Senescence-associated secretory phenotype’ (SASP). Cellular senescence is a fascinating phenomenon which could actually be a misnomer in that strictly controlled ‘senescence’ may be essential for embryonic development [27,28], although there may be different molecular pathways controlling ‘senescence’ under different circumstances [29]. Be that as it may, replicatively senescent cells have been shown to accumulate with age in different tissues, as reviewed many years ago by one of the foremost in the field [30]. A recent intriguing example of this found that the chronological age-related accumulation of senescent fibroblasts may also be under genetic control [31]. Senescence is most likely a response to DNA damage, although possibly not to DNA breaks but to chromatin remodeling [32], and the SASP a cocktail of cytokines and chemokines essentially a wound-healing response. Many of these are pro-inflammatory and share characteristics with factors produced by that other form of ‘wound that does not heal’, cancer. Indeed, it is reported that the SASP supports the promulgation of cancer ‘stem cell’ phenotypes, at least in multiple myeloma [33]. Other similarities recently coming to light include paracrine action to induce senescence in other cells [32], paralleling the effects of cancerous cells on the surrounding microenvironment. Due to the accumulation of senescent cells with chronological age (and also due to environmental exposures such as pollution, radiation, etc.) and the fact that the aged immune system appears not to be able to eliminate them as effectively as in the young [34], systemic inflammation may reach noticeable levels [35]. Indeed, the elimination of senescent cells (albeit in an artefactual model of murine premature ageing) improved function and extended lifespan [36]. Thus, the accumulation of replicatively senescent cells has multiple effects on the near environment, as well as systemically, and may contribute both directly and indirectly to age-associated disease. Although most work has been done with fibroblasts, there is an accumulating wealth of information on similar processes and pathologies in quite different cell types, as diverse as astrocytes [37], cholangiocytes [38] and osteoblasts [39]. However, as always, the situation is not so clear-cut: there is also evidence that senescence in some cell types may have opposing effects, as in the recently reported anti-inflammatory properties of senescent endothelial cells [40]. Thus, it is more than likely that not only will different cells and tissues senesce at different rates, with unclear consequences, but also that there may be more nuanced interactions between different cells in which senescence results in varying outcomes. Obesity

Cellular senescence

Recently, much work has focused on the accumulation of replicatively senescent cells, mostly fibroblasts, in the www.sciencedirect.com

Obesity is a condition that tends to increase in frequency with age [41]. It is clearly associated with systemic elevated inflammatory markers and adipose tissue (AT) itself Current Opinion in Immunology 2014, 29:23–28

26 Immune senescence

may represent a major source of immune cell-derived inflammatory factors, as the white AT variety is commonly infiltrated not only by macrophages and T cells, but also B cells and mast cells [42]. Systemic alterations are also seen in cellular markers of inflammation in that leucocyte numbers are increased due to elevated neutrophil levels, as well as soluble factors including TNF, IL-1, IL-6, IL-8 and others, as well as CRP. However, it remains a puzzle why an energy storage system should manifest what could be considered dysregulated immune functions [43]. Visceral AT may be regarded as a pathological organ akin to a non-metastatic tumour, with some of the same mechanisms involved, namely stimulation of innate immunity by danger signals resulting from cell death (e.g. the macrophages surrounding adipocytes could be activated by released fatty acids) and activation of T cells with restricted antigen receptor repertoires, suggesting targeting of autoantigens or conserved microbial antigens [44,45]. Also similar to tumours, there is a reduction in NKT regulatory cells in obese AT [46]. It is particularly striking that obesity even in adolescents is also associated with increased immune dysregulation and the appearance of a ‘senescent’ T cell profile [47]. Thus obesity-linked inflammation and earlier development of features of immunosenescence could be a major contributor to the increasing burden of chronic disease in the developing as well as the developed world [48].

Finally, exercise, which is also relatively cheap and easy to promulgate, clearly has multiple health benefits, including alterations in peripheral immune parameters believed to signify improved immunological function (less ‘immunosenescence’) [55]. Much attention has recently been paid to the influence of nutrition on gut microbiota and associated effects on systemic inflammation and immune function, as reviewed by [56]. Some attempts to modulate these interactions using prebiotic and probiotic are ongoing (for recent review, see [57]).

Perspectives Appropriate control of inflammatory processes and their resolution is essential for the well-being of the host, but in the face of persistent infections or dysregulated responses resulting in sterile inflammation, the insidious phenomenon of systemic ‘inflammaging’ may chronically damage healthy tissues and contribute to multitudinous age-related diseases (Figure 1). Focusing future work on interventions that address dysregulated immune control in the ageing host rather than treating symptoms of disease or attempting to Figure 1

Injury

Interventions General interventions having multiple health effects, including reducing inflammatory markers, are caloric restriction, exercise programs, nutritional modifications and pharmaceutical anti-inflammatories. The latter include agents specifically targeting a certain cytokine, particularly anti-cytokine antibodies. These are in common use for treating autoimmune diseases, with some success, as documented for example in a recent metaanalysis of rheumatoid arthritis [49]. It was initially unexpected, but given the considerations regarding inflammation and chronic disease discussed above, perhaps comes as no surprise that some drugs used to treat diseases like diabetes should also have anti-inflammatory activity. A prime example is metformin which, strikingly, was only recently reported to inhibit macrophage IL-1 production in obese diabetics [50]. Moreover, it now seems that metformin supplementation may even increase lifespan in animal models [51]. Caloric restriction also increases lifespan in experimental animals, but it is not yet clear whether the same is true for primates, let alone humans [52], although it is self-evident that prevention of obesity has enormous health implications, including reduction of inflammatory markers [53]. Other contributions to disease including poor oral health, which should theoretically be easy to resolve, may play previously unsuspected roles, as illustrated by the associations between oral hygiene, systemic inflammation and Alzheimer’ disease [54]. Current Opinion in Immunology 2014, 29:23–28

Pathogen infiltration

Acute inflammation

Activation of immune cells and local response

Ageing, age-associated diseases and “Inflammaging”

Recruitment of cells into infected tissue via chemotaxis

Collateral damage to healthy host cells

Defence mechanisms, such as phagocytosis and production of reactive oxygen species

Immune exhaustion and “senescence”

Elimination of the pathogen

Persistent viruses

Control mechanisms, such as suppressor activity by regulatory cells

Termination of the immune response Current Opinion in Immunology

Immune homeostasis and age-related dysbalance. www.sciencedirect.com

Inflammation, ageing and chronic disease Pawelec, Goldeck and Derhovanessian 27

block the effects of the inflammatory mediators themselves, will offer improved therapeutic opportunities.

18. Chen S, de Craen AJ, Raz Y, Derhovanessian E, Vossen AC, Rudi WG, Pawelec G, Maier AB: Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus Study. Immun Ageing 2012, 9:18.

References and recommended reading

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Inflammation, ageing and chronic disease.

Acute inflammatory responses are essential for pathogen control and tissue repair but can also cause severe collateral damage. Tight regulation of the...
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