Abstract
The immune system is a dynamic whole system network that, as a result of the interaction between genes, lifestyle and environment, is constantly remodeling itself throughout our lifespan. The immune response is driven by the complex interactions of up- and downregulating cytokines and chemokines. These families of proteins fine-tune effective responses to infection or tissue damage, through multiple layers of activation and control, regulated by soluble receptors, receptor antagonists, and diverse serum mediators, in order to maintain homeostatic immune balance.
With age, the immune system shows a persistent low-grade inflammation, controlled by the balance between pro-inflammatory and anti-inflammatory cytokines. A loosening of this cytokine balance has been called “inflamm-aging” or sterile inflammation and underpins most age-related disease from atherosclerosis, to diabetes, to Alzheimer’s disease, and aging itself. “Inflamm-aging” may derive in part, from age-related increases in senescence-associated secretory phenotype cells, which secrete pro-inflammatory mediators, together with an age-related decline in homeostatic immune function, increased fragility of epithelial barriers, and changes in the gut microbiome. Cytokine expression is known to be influenced by the local cellular environment, which accumulates age-related damage from reactive oxygen species, DNA and lipid damage, or incorrectly folded proteins.
Increasing knowledge about the molecular pathways underpinning the pro-inflammatory cytokine network should allow the development of therapeutic tools to reduce senescence-associated secretory phenotype cells or the use of deacetylating and demethylation agents to modify gene expression. At the human level, emerging understanding of the importance of external environments and the epigenome suggests that behavioral changes in lifestyle through diet, exercise, or social networks can and do influence the immune system.
Susan E. McNerlan and I. Maeve Rea contributed equally to this work.
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Keywords
Introduction
The immune system is a dynamic network that is constantly remodeling throughout life as a result of the interaction between our genes, our lifestyles, and our environments (Govindaraju et al. 2015; Rea et al. 2015). With aging, the immune system is characterized by a persistent low-grade inflammatory response that is associated with changes in immune parameters, alterations in lymphocyte subsets, and cytokine dysregulation, all of which vary, depending on the state of immune cell activation and the surrounding tissue environment (Shaw et al. 2013). This phenomenon has been called “inflamm-aging ” (Franceschi and Campisi 2014; Franceschi et al. 2000).
The measurement of cytokines has been extensively investigated in elderly people, with at times conflicting results. This may be due in part to the number of different methodologies employed. Immunoassays have been used for the measurement of circulating cytokines in plasma but due to the detection limits of kits, and the presence of natural inhibitors, soluble receptors or antagonists, their presence in serum may be masked (Rose-John et al. 2006). Bioassays, involving in vitro stimulation of whole blood or separated mononuclear cells, have also been widely employed in the study of age-related changes in cytokine production. However, the response of cells to stimulants in an unnatural environment may not reflect what occurs in vivo. Neither bioassays nor immunoassays can give an indication of the exact cellular source of these cytokine factors. Intracellular cytokine methodology enables detection of cytokines at a single-cell level, thereby identifying the specific cell subsets producing these mediators (Damsgaard et al. 2009; McNerlan et al. 2002). The technique is performed in whole blood so cells can be kept in their natural environment. Multiple cytokine simultaneous immunoassays are becoming available in immunochips (Abe et al. 2013), and the advent of proteomic methods which can identify cytokine RNA arrays in physiological fluids promises to further interrogate and elucidate cytokine networks and their function in aging (Pilling et al. 2015). However, the interface between gene transcription and translation remains incompletely understood, and the presence and role of long-coding RNAs, siRNAs, and miRNAs makes interpretation of microarray data challenging (Battle et al. 2015). While each of these methodologies has their limitations, a great deal of information on the cytokine profile of the very elderly people has been and continues to be elucidated.
Cytokine expression is influenced by networks of genes and polymorphisms (reviewed in Minciullo et al. 2016; Murabito et al. 2012) and modified through our internal and external environment by diet and lifestyles (Periera et al. 2013; Carmago et al. 2012), with epigenetics considered an important modifying mechanism (Rea et al. 2016; Talens et al. 2012). While studies of cytokine gene polymorphisms suggest that certain cytokine genotypes are associated with a long life (reviewed Brooks-Wilson 2013), cytokine levels have also been associated with a whole range of chronic- and age-related diseases (Minciullo et al. 2016; Michaud et al. 2013) and increased morbidity and mortality (Ferruci et al. 1999; Harris et al. 1999). Comparator studies of cytokines and cytokine polymorphisms and increasingly genome-wide association studies (GWAs) with large number of nonagenarians and centenarians who show both health span and age span have been considered the most useful in determining the immunological fingerprint/s contributing to successful longevity (Soerensen et al. 2013; Skytthe et al. 2011; Franceschi et al. 2007a).
Interleukin-1 (IL-1) Family
The IL-1 family of cytokines has 11 members that include IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, and the newer members IL-1F5–IL-1F10 (reviewed in Sims and Smith 2010). Three members of the IL-1 cluster have pro-domains; IL-1β and IL-18 pro-domains are activated to biologically active forms by the enzyme caspase 1, while the pro-domain of IL-1α is cleaved by the cysteine protease calpain.
Interleukin-1 (IL-1) is the name given to the two main cytokine peptides, IL-1α and IL-1β , which bind and activate the IL-1 receptor (IL-1R) and are produced by B lymphocytes, natural killer (NK) cells, tissue macrophages, fibroblasts, and dendritic cells. The IL-1 receptor antagonist (IL-1Ra) binds IL-1R and has a higher affinity for IL-1R than IL-1α or IL-1β and so limits pro-inflammatory IL-1 signaling by blocking its activation.
In early studies in elderly people, Rudd and Banerjee (1989) measured the IL-1 production by human monocytes in response to bacterial lipopolysaccharide (LPS) and found no difference in IL-1 secretion between well elderly and young subjects, but noted that those elderly subjects with recurrent infection without a temperature response produced significantly less interleukin-1 (IL-1). Many authors have described a general increase in all pro-inflammatory cytokines including IL-1 with increased age, while others described different values for IL-1α and IL-1β and IL-1Ra in healthy aged subjects compared to young controls. In a large study, Cavallone et al. (2003) reported an age-related rise in IL-1Ra plasma levels, whereas IL-1β plasma showed no detectable age-related trend, in 1,131 Italian subjects (including 134 centenarians). Similarly the large InCHIANTI study of subjects >65 years of age found no relationship between serum levels of IL-1β and age but found an association with heart failure and angina (Di Iorio et al. 2003). Most authors as exemplified by Sansoni et al. (2008) have described an increased pro-inflammatory response, which is detrimental to longevity and good quality aging. Westendorp et al. (1997) in a counterargument have suggested that an enhanced pro-inflammatory response may facilitate better quality aging in the very elderly group, if responses are adequately controlled (van den Biggelaar et al. 2004).
The main genes of the IL-1 family, including the agonists IL-1α and IL-1β, are inherited together as haplo-groups. IL-1 haplotype carriers have been reported to produce greater quantities of IL-1β in stimulated cells compared to carriers of other alleles and higher IL-1β in plasma, with higher concentrations of both IL-1α and IL-1β in gingival fluid. The same IL-1 gene variations have been associated with earlier onset or more severe disease expression of age-related diseases such as Alzheimer’s disease (Mrak and Griffin 2000; Trompet et al. 2008), cardiovascular disease (Zhou et al. 2012), and osteoporosis (Langdahl et al. 2000). A recent meta-analysis by Mun et al. (2016) reported that the 889C>T polymorphism in IL-1α may be a factor in Alzheimer’s disease , similar to previous studies.
The IL-1 gene cluster has been investigated with respect to longevity in very aged cohorts. Cavallone et al. (2003) found no significant differences in genotype and allele frequency distributions between large groups of young, elderly, and centenarian Italians subjects and suggested that no single polymorphism in the IL-1 gene cluster showed an advantage for survival in the last decades of life. Similar findings were reported in Finnish nonagenarians (Wang et al. 2001). In a follow-up of elderly people in Sweden with respect to gender, Cederholm et al. (2007) reported that elderly males carrying the high producing IL-1 β -511T allele of the IL-1 β -511C/T gene showed a shorter survival time compared to females in the study.
As with other cytokines, the interpretation of studies of associations between candidate gene variations and clinical disease is complicated, often due to the use of individual polymorphisms (SNPs) which do not adequately represent the variation in the candidate gene and the use of imprecise clinical criteria and endpoints. Dinarello et al. (2012) reviewed the use of drugs which have been used to block IL-1 in a broad spectrum of diseases and concluded that IL-1 gene variations were associated with overexpression of inflammatory mediators and increased the risk of age-related diseases and that recombinant drugs, such as IL-1RA blockers, can help in the understanding of disease processes and may have a role in the clinical control of inflammation.
Interleukin-18 (IL-18)
IL-18, another member of the IL-1 family, is a potent pro-inflammatory cytokine which induces IFN-γ from macrophages and dendritic cells (Smith 2011) and is essential for host defense against severe infections. Like IL-1, IL-18 is considered an important mediator of inflammation associated with the aging process (Dinarello 2006). Serum IL-18 levels have been reported to be higher in centenarians compared to a young control group and also compared to a group of patients with chronic ischemic syndromes (Gangemi et al. 2003). These authors also reported a significant increase in circulating levels of IL-18 binding protein , a natural inhibitor, compared to the other two groups which could explain the apparent paradox of elevated IL-18 in these centenarians with no apparent vascular disease. Ferruci et al. (2005) also reported increased values of IL-18 in an aged cohort who demonstrated a reduced incidence of ischemic events. Conversely, both circulating plasma and myocardial tissue concentrations of IL-18 were higher in the heart failure patients than in the age-matched healthy control subjects with plasma IL-18 concentrations that were significantly higher in the patients who died than in survivors (Mallat et al. 2004). Increased IL-18 was produced in stimulated mononuclear cells and macrophages of peripheral blood from Alzheimer’s patients and was increased in the plasma of mild cognitively impaired patients and in the blood of patients with ischemic heart disease, type 2 diabetes, and obesity, all of which are risk factors for Alzheimer’s disease (Liu and Chan 2014), in keeping with studies showing increased IL-18 was present in the brain of Alzheimer’s patients. Novel gene variants have been reported to predict serum levels of cytokines IL-18 and Il-1Ra in older adults (Matteini et al. 2014). The pro-inflammatory IL-18 (rs1946519) alleles of IL-18 gene have been noted to be increased in patients from their South Asian population with premature coronary artery disease (Ansari et al. 2016).
IL-18 has also been associated with physical functioning (Thomas et al. 2009) and a frailty index in the English Longitudinal Study of Ageing (Mekli et al. 2015). In a study of 1,671 elderly subjects aged 65–80 years, elevated IL-18 levels were associated with a decline in physical function, and a polymorphism in the IL-18 gene that reduces Il-18 serum concentration was associated with improved walking speed (Frayling et al. 2007). Conversely there are reports of IL-18 having a protective role in some studies. In caspase-1-deficient mice subjected to dextran sulfate sodium administration, defects in mucosal tissue repair were observed and the mice were rescued by exogenous IL-18 administration (Dupaul-Chicione et al. 2010). In human studies, a similar protective role for both the inflammasome NPL3 and IL-18 was reported in the progression of age-related macular degeneration (Doyle et al. 2012).
Interleukin-6 (IL-6)
In 1993, Ershler intuitively described IL-6 as a “cytokine for gerontologists ” (Ershler 1993), and increasingly IL-6 is recognized as one of the main signaling pathways in aging and chronic disease, morbidity, and mortality . The physiological role of IL-6 has been mostly studied in the context of the acute phase response, although there is increasing evidence that it plays a pivotal role during the transition from innate to acquired immunity and is involved in metabolic control (Weiss et al. 2013), the regulation of many regenerative and neural processes (Scheller et al. 2011), and in the pathogenesis of almost all chronic diseases (Franceschi and Campisi 2014; Ferruci et al. 1999).
In the acute phase response, IL-6 plays a key role and displays both pro-inflammatory and anti-inflammatory activities. The acute phase response , rapidly induced by infection or any sort of tissue damage, prevents pathogen invasion and then damps down and controls tissue damage. IL-6 activates the hypothalamic–pituitary–adrenal axis; produces symptoms of fever, anorexia, and lethargy; and, in the immune system, promotes the expansion and activation of T cells, differentiation of B cells, and production of positive acute phase reactants such as C-reactive protein and serum amyloid protein and fibrinogen. The mechanisms through which IL-6 orchestrates both the containment and the resolution of the acute inflammatory response include suppression of TNF−α and IL-1β and production of increasing amounts of IL-1 receptor antagonist (IL-1 Ra) and soluble TNF receptor p55.
IL-6 is normally present in low levels in the blood. Increased levels have been widely reported in studies in very elderly subjects. In an early study, Hager et al. (1994) showed a linear correlation of 0.016 pg/ml for IL-6 per year of life, with other studies reporting similar changes in both IL-6 and soluble IL-6 receptor (sIL-6R) in aged cohorts (Rea et al. 2003). Many studies have shown significant differences for IL-6 between survivors and non-survivors in keeping with the reported association between IL-6 and markers of frailty and mortality (Puzianowska-Kuznicka et al. 2016; Jyhla et al. 2007; Harris et al. 1999).
A number of studies have linked polymorphisms of IL-6 genes to age-related disease . The G allele of the IL-6-174C/G polymorphism (rs1800795) shows higher stimulated and unstimulated levels of IL-6 for the G allele (Fishman et al. 1998) and has been associated not only with age-related diseases and disability but also with mortality from vascular-related disease (Spoto et al. 2014). Qi et al. (2012) in the PROSPER study and Mooijart et al. (2013) independently reported an association between IL-6 and cognitive decline in their study populations and in a meta-analysis; Dai et al. (2012) reported an association between the CC polymorphism of IL6-174G/C and the risk of Alzheimer’s disease in carriers of this genotype.
In longevity studies, studies of IL-6 polymorphisms have produced conflicting findings. In Italian centenarians, the GG genotype of the 174G>C associated with increased IL-6 levels, was decreased in male but not female centenarians, suggesting that this genotype producing high levels of IL-6 might be detrimental to long life, at least in men (Bonafe et al. 2001). Conversely studies in Danish, Irish, Finnish, and Swedish nonagenarians showed the GG genotype somewhat increased in the elderly nonagenarian cohorts, suggesting modest survival advantage (Christiansen et al. 2004; Ross et al. 2003a; Cederholm et al. 2007), with other studies showing no change (Pes et al. 2004). A meta-analysis of IL-6 genotypes and longevity in studies of European nonagenarians and centenarians showed different allele frequencies of the IL-6-174 G/C polymorphisms, stratified north to south in Europe, but no change in frequency of the risk G allele in the combined European aged cohorts (Di Bona et al. 2009). The reasons for these discrepancies are unclear but may depend on cultural and lifestyle differences between the populations studied in Northern and Southern Europe, with evidence that the IL-6 gene polymorphisms could be modulated by the Mediterranean diet, similar to cellular studies (Camargo et al. 2012) with the Mediterranean diet contributing to differences between Northern and Southern European incidence, and mortality from vascular disease (De Lorgeril and Salen 2006; Fung et al. 2009).
Tumor Necrosis Alpha (TNF-α)
TNF-α, another pro-inflammatory cytokine and an important mediator of the immune response, is widely reported as being elevated in the plasma of elderly people. Increased production has been reported from unstimulated monocyte monolayers, but LPS-stimulated leukocytes have yielded conflicting results (Bruunsgaard et al. 1999). Using flow cytometry intracellular cytokine detection, the percentage and absolute counts of CD3+ T cells producing TNF-α were significantly higher in the study of healthy octo-/nonagenarians compared to young controls (McNerlan et al. 2002), similar to results reported by O’Mahoney et al. (1998), for slightly younger individuals. In a Danish study, high levels of TNF-α were seen in centenarians and octogenarians with atherosclerotic CVD (Bruunsgaard et al. 2000; 2003a), and elevated TNF-α was associated with mortality (Bruunsgaard et al. 2003b). An age-related increase in plasma TNF-α was reported in Senieur-recruited BELFAST octo-/nonagenarian subjects (Armstrong et al. 2001).
TNF-α initiaties the inflammatory cascade and evidence suggests that TNF−α contributes to age-related diseases (Rea 2017). Ridker et al. (2000) reported persistently elevated plasma TNF-α among post-MI patients at increased risk for recurrent coronary events. In rheumatoid arthritis, where TNF-α is an important contributor to the pathogenesis of the disease and increased vascular risk, anti-TNF-α therapy was shown to improve both disease symptoms and vascular risk, in a pooled meta-analysis of 23 studies, (Barnabe et al. 2011). In keeping with the finding of TNF-α-associated vascular risk , an updated meta-analysis (Wang et al. 2015) has confirmed the numerous reports which describe the A allele of the of TNF-α G-308-A gene (rs1800629) as having a role in coronary heart disease and myocardial risk. TNF-α has also been reported in association with Alzheimer’s disease . Increased levels of TNF-α were found in moderate to severe dementia in a cohort of Danish centenarians (Bruunsgaard et al. 2003b) and considered potentially predictive markers for the development of Alzheimer’s disease at 7 years (Tan et al. 2007). Certain polymorphisms of the TNF-α, as well as the IL-1, and IL-6 genes, increase the risk of developing Alzheimer’s disease (McCusker et al. 2001; Collins et al. 2000). However, it remains unclear whether TNF-α’s role is directly causative as a result of an increased immune activation caused by the underlying pathologic processes, or whether, as has been variously described; risk is increased in association with atherosclerosis.
TNF-α also has also been described as important in the metabolic syndrome . It was elevated in a study of 70-year-old men with type 2 diabetes mellitus compared to age-matched controls, and TNF-α levels were correlated with the severity of insulin resistance (Nilsson et al. 1998). The inflammatory syndrome and TNF-α have been associated with increased muscle catabolism and high levels of both TNF-α and IL-6 associated with lower muscle mass and muscle strength in older men and women (Reviewed in Michaud et al. 2013).
Polymorphisms of the TNF-α gene have been studied with respect to good quality aging and long life and do not appear to be associated with longevity. Three studies in Finnish nonagenarians, Italian centenarians, and Irish nonagenarians showed no difference in the frequency of the TNFα-308A/G polymorphism compared to young controls (Ross et al. 2003b; Lio et al. 2003; Wang et al. 2001) with no significant sex differences.
Other Pro-inflammatory Cytokines
Interleukin 7 (IL-7)
IL-7 is a pro-inflammatory cytokine essential for the development and survival of T cells. It is involved at all stages of T cell development , from early days in the thymus, when it is important for the survival, proliferation, and rearrangement of some TCR genes, to a later stage, when it is involved in the selection of CD8+ cells. Mature T cells, upon leaving the thymus, also require IL-7 for survival and proliferation, and IL-7 expression levels are one of the factors determining the size of the peripheral T cell pool (Aspinall 2006). IL-7 acts via its cell surface receptor IL-7R which consists of the IL-7R alpha chain and a common chain IL-7Rgamma, both of which are shared by IL-2, IL-4, IL-9, IL-15, and IL-21 receptors (Jiang et al. 2005).
IL-7 has been associated with longer life. Passtoors et al. (2012) found lower expression levels of both IL-7 and IL-7R in the elderly people. In contrast, the middle-aged children of the nonagenarian siblings showed lower levels of IL-7R but not IL-7. In other studies, higher levels of IL-7R in middle-aged controls correlated with immune-related disease (Passtoors et al. 2015).
Interleukin-8 (IL-8)
IL-8 is a neutrophil chemotactic factor and inflammatory cytokine that brings neutrophils to the site of inflammation in order to contain infection (Baggiolini and Clarke-Lewis 1992). Increased levels have been detected after LPS stimulation of leukocytes from elderly individuals (Rink et al. 1998). IL-8 has been proposed as a possible key to longevity in a small study of centenarians. A study of 30 young people (21–37 years), 30 healthy elderly (65–87 years), and 10 centenarians found levels of IL-8 to be elevated in the serum of the centenarians compared to the other two groups (Wieczorowska-Tobis et al. 2006), while IL-6 levels were unchanged. This might suggest that increased serum IL-8 alongside low IL-6 might be related to longevity, although larger studies are needed to confirm this finding. In a study of IL-8 polymorphisms, Ross et al. (2003a) found no significant difference in IL-8 intron 1-251 A/T polymorphism in a group of nonagenarians compared to young controls, but the study was relatively small.
Interleukin 12 (IL-12) Family
IL-12 is a cytokine acting on T and NK cells and directing proliferation of activated T cells toward a Th1 phenotype (Trinchieri 1993). IL-12p70 and IL-23 are important co-members of the same family and play a crucial role in both the innate and adaptive immune systems. They are heterodimeric cytokines composed of a common IL-12/23 p40 subunit and specific alpha subunits IL-12 p35 and IL-23 p19. The heterodimer IL-12p70 equates to biological activity, whereas the homodimer IL-12p40 acts as an IL-12 antagonist in vitro (Mattner et al. 1993).
Total IL-12, IL-12p40, and the IL-12p40/IL-12p70 ratio but not IL-12p70 increased significantly with age in healthy elderly individuals (Rea et al. 2000). Studies investigating age-related IL-12 production by mitogen-stimulated PBMCs in elderly groups have produced conflicting results. Compte et al. (2013) reported that reduced IL-12p70 and IL-23 production by LPS-stimulated dendritic cells was strongly correlated with a frailty and dependence phenotype. In keeping with this finding, Vom Berg et al. (2012) and Tan et al. (2014) showed an increased production of IL-12/23 p40 by microglia in Alzheimer’s disease and suggested that inhibition of this pathway may attenuate disease pathology.
IL-21 is a linked member of the type 1 cytokine family which also includes IL-2 and IL-15 (Leonard and Spolski 2005). Agrawal et al. (2012) showed that CD4+ T cells from healthy aged individuals (>65 years) secreted higher levels of IL-21 on priming with aged and young dendritic cells, despite the fact that these dendritic cells produced comparable levels of IL-12. Aging therefore affects Tfh cell responses in a manner that may contribute to age-associated inflammation and immune dysregulation.
Ross et al. (2003a) considered that alleles of IL-12 gene might have an important role in explaining conflicting results for IL-12 in aging studies. In their group of BELFAST octo-/nonagenarians compared to a younger cohort, there were no reported differences in IL-12A/C polymorphisms . However it is possible that the variable response, which has been measured in studies of aging, may be related to an age-related imbalance in the transcription of the p40 and p70 subunits that are encoded on different genes.
Anti-inflammatory Cytokines
Interleukin 10 (IL-10)
There are nine members of the IL-10 family of cytokines (Commins et al. 2008), which can be subdivided into three groups with different biological functions : (1) the immune-regulatory cytokine IL-10; (2) the IL-20 subfamily members IL-19, IL-20, IL-22, IL-24, and IL-26 which play a role in host defense mechanisms against bacteria and fungi; and (3) the type III interferons IL-28A, IL-28B, and IL-29 which induce antiviral responses. Some cytokines have dual effects with both pro- and anti-inflammatory capacities though the biological function and significance during immune responses for some newer cytokines remain to be fully determined. The expanded class 11 cytokines share the same IL-10R2 chain (Donnelly et al. 2004).
IL-10 is considered an important anti-inflammatory cytokine that has been reported to increase in elderly people and in cellular studies related to ageing. IL-10 has both anti-inflammatory and B-cell stimulatory activities, and its production shows cell-specific regulation in inflammation and disease (Hedrich and Bream 2010). It is produced by activated T cells, B cells, monocytes, macrophages, dendritic cells, and NK cells and released upon activation of these cells by endogenous and exogenous mediators such as lipopolysaccharides and catecholamines. IL-10 is considered to block the ability of monocytes/macrophages to act as antigen-presenting cells by downregulating the MHC and has been shown to prevent the differentiation of monocytes into dendritic cells, which are important antigen-presenting cells in the immune system (Buelens et al. 1997). The pathway, by which IL-10 inhibits gene expression in monocytes, was identified by Williams et al. (2004) and Donnelly et al. (1999), as associated with the ability of IL-10 to induce the synthesis of SOCS-3 genes.
In human studies, Forientino et al. (1991) reported that IL-10 inhibited cytokine production in human-activated macrophages. This was followed by a series of cellular studies where IL-10 was shown to control the inflammatory processes by suppressing pro-inflammatory cytokines including TNF-α, interleukin-6, and interleukin-8 (reviewed in Ouyang et al. 2011). Stimulated lymphocytes from elderly subjects were reported to produce higher IL-10 compared to younger controls (Rink et al. (1998). In centenarians and long-lived individuals, Sansoni et al. (2008) reported an increase in both pro-inflammatory cytokines and IL-10 in serum. Hirokawa et al. (2013) conversely reported an age-related decline in IL-10 production in cellular stimulation studies and a differential decline of IL-10 in women compared with men.
More recent studies suggest a role for IL-10 in age-related diseases including atherosclerosis, following on studies in mice age models showing that IL-10 seemed to play a key role in vascular disease . Didion et al. (2009) demonstrated that endogenous IL-10 limits angiotensin II-mediated oxidative stress and vascular dysfunction both in vitro and in vivo, and Kinzenbaw et al. (2013) reported that IL-10 could act as a potent anti-inflammatory cytokine, protecting against aging-induced endothelial dysfunction. Small clinical studies found conflicting results, with IL-10 levels reported to be unchanged, increased, or decreased in stable and unstable angina patients relative to controls. Larger later studies in two groups of elderly subjects, the ERA study (Lakoski et al.2008) and the PROSPER study (Welsh et al. 2011), concluded that baseline circulating levels of the anti-inflammatory IL-10 were positively associated with risk of CVD among the elderly groups, without prior CVD events and that the involvement of IL-10 should warrant further investigation with respect to primary risk management.
The IL-10 gene has several described functional polymorphisms. Some alleles produce higher or lower amounts of IL-10, with variable responses to lipopolysaccharide (LPS) between individuals and ethnicities (Damgaard et al. 2009; Moraes et al. 2003; Westendorp et al. 1997). The GG 1082 allele of the IL-10 promoter polymorphism, which is associated with increased IL-10 production, was found increased in male centenarians in Sicily compared to young controls, with suggestions that an increased anti-inflammatory state might be the key to longevity in male though not female centenarians (Lio et al. 2002), with similar findings in healthy elderly Bulgarians (Naumova et al. 2004). These findings were not replicated in Finnish and Irish nonagenarian studies (Ross et al. 2003a; Wang et al. 2001) or in centenarians from Sardinia (Pes et al. 2004). Unlike Sicilian centenarians, where high IL-10 producers appeared to have a survival advantage, patients who were high IL-10 producers, who became ill with an acute illness, had a 20-fold higher chance of a fatal outcome compared to low producers (Westendorp et al. 1997). In studies in elderly people with high infectious burden, Westendorp et al. (1997) has argued that high IL-10 producers may have immunological advantages (Kuningas et al. 2009; Moraes et al. 2003). An enhanced anti-inflammatory genotype might be advantageous later in life, when a chronic pro-inflammatory state or the phenomenon called inflamm-aging is increasingly recognized associated with aging (Franceschi et al. 2007b, 2014).
Interleukin 19 (IL-19)
IL-19 is a relatively new member of the IL-10 family, whose full function remains to be determined. IL-19 induces the production of IL-10, and IL-19 itself, from PBMCs (Jordan et al. 2005). It also stimulates production of IL-6 and TNF-α from monocytes in vitro (Liao et al. 2002), suggesting it may exhibit pro-inflammatory activities. As increased production of both IL-6 and TNF-α is reported in aging, IL-19 may play a role in the aging process. A Japanese study of 500 subjects aged between 19 and 100 years has shown an association between IL-19 gene polymorphisms and age, though with no change in IL-19 levels (Okayama et al. 2007).
Interleukin 22 (IL-22)
In contrast to IL-10, IL-22 does not act on immune cells but rather on cells at the epithelium and cells at the outer barriers of the digestive system, skin, respiratory system, and kidney. It is not induced or produced by either resting or stimulated immune cells, and its production does not involve the STAT tyrosine phosphorylation pathway. The target cells of IL-22 are tissue cells of the digestive tract, skin, respiratory system, and kidney.
Although the members of IL-10 family of cytokines share many similarities, they have different biological functions. IL-10, IL-20, and IL-22 appear to play an important role in the pathogenesis of some chronic inflammatory diseases. Rapid pro-inflammatory responses to pathogens are essential for effective host defense and to contain infection, but untimely control of infection results in chronic inflammation, autoimmunity, and death. Treatment with IL-10 has been shown to reduce inflammation and organ damage in models of systemic inflammation and sepsis (Hedrich and Bream 2010). However, in diseases where IL-10 is overproduced, IL-10 can produce immunosuppression and contribute to tumor growth or metastases. Conversely, a relative deficiency of IL-10 can cause persistent immune activation as is seen in some age-related diseases such as rheumatoid arthritis or after organ transplantation (Hofmann et al. 2012). The importance of an immune system which is able to maintain a finely balanced orchestration and expression of pro- and anti-inflammatory cytokines cannot be overemphasized, in order to prevent overwhelming infection or progression to uncontrolled “inflamm-aging .”
TGF-β
Transforming growth factor beta (TGF-β) is secreted by both immune and non-hematopoietic cells and has an important role in aging. It has wide effects across the immune system and is recognized as an important anti-inflammatory cytokine, which limits the acute response. While TGF-β plays an essential role in the suppression of inflammation, it also has an activating role in the repair of tissue and organs after damage, injury, and infection (Yoshimura et al. 2010).
TGF-β is always produced as an inactive complex that must be activated to exert functional effects, and this activation of latent TGF-β provides a crucial layer of regulation that controls TGF-β function (Grainger et al. 1999). Increased levels of TGF- β were reported in a study by Forsey et al. (2003) in octogenarians. Two studies in Italian centenarians showed that the bioactive TGF-β increased with age (Cavallone et al. 2003). Increased levels of active TGF-β were also reported in healthy octo-/nonagenarian subjects in the BELFAST study with an apparent anti-inflammatory effect on killer immunoglobulin receptors (KIR) on natural killer (NK) cells reported (Rea et al. 2013).
TGF-β has been considered to have an important downregulating effect in containing septic shock. In a study comparing genes involved in the immune response in elderly and young people with sepsis, Vieira da Silva Pellegrina et al. (2015) detected several genes, including genes related to TGF-β signaling, whose expression could be used to differentiate immune responses of the elderly individuals from those of young people. This group further proposed that increased activation of the TGF-β pathway in elderly septic patients might induce a prolonged downregulation of adaptive immunity and an increased Th17 response, presumably related to regulatory T (Treg) cell induction.
Various studies have implicated TGF-β with aging-related disease and obesity (Krieglstein et al. 2012). Investigating potential mechanisms, Yan et al. (2014) reported that obesity, atherosclerosis, and aging potentiated RNA stress-related TGF-β transcripts centrally in the hypothalamus, with the potential for diabetic development. Doyle et al. (2010) reported increased TGF-β signaling after stroke, involving astrocytes, activated microglia, and macrophages and interpreted this finding as suggesting that increased TGF-β after stroke likely regulated glial scar formation. Reports also link TGF-β and/or its polymorphisms with atherosclerosis and Alzheimer’s disease (Mallat er al. 2001; Luedecking et al. 2000), though Ross et al. (2003a) did not note any change in TGF-β gene frequency in their cohort of octo-/nonagenarians compared to younger controls.
Several members of the TGF-β family have been shown to be important in maintaining muscle mass . The maintenance of normal muscle mass and function depends on a normal balance between positive and negative regulators which includes TGF-β and its family member myostatin. TGF-β has been identified as preventing satellite cell differentiation and contributing to fibroblast growth that have been related to the development of muscle loss and sarcopenia (Burks and Cohn 2011).
Transforming growth factor (TGF-β1) is a pleiotropic cytokine , which maintains immune homeostasis by acting as a potent immune suppressor through inhibition of proliferation, differentiation, activation, and effector function of immune cells. While the importance of TGF-β’s role in active immune suppression is widely acknowledged, it also has paradoxical pro-inflammatory functions and is involved in multiple pathologies (Kubiczkova et al. 2012). In infections, TGF-β protects against excessive damage caused by the activated immune system but can also allow immune evasion with progression of chronic infections and tumors. In autoimmune diseases, TGF-β dysfunction leads to the loss of tolerance to self-antigens. In cancer, at the beginning of tumor development, TGF-β is a potent inhibitor of cell proliferation and tumor suppressor but in later disease can stimulate tumor development and metastases (Itoh and Itoh 2012; Wilson et al. 2011). Studies on TGF-β and Tregs are beginning to shed light on possible mechanism through which their interactions control immune responses (Tran et al. 2012) and which may be able to be translated into clinical benefits.
Summary and Future Consideration
The immune system is a dynamic whole system network that is constantly remodeling throughout life as a result of the interaction between our genes, our lifestyles, and our environments (Govindaraju et al. 2015; Rea et al. 2015), with epigenetics considered an important modifying mechanism (Rea et al. 2016; Talens et al. 2012). Our immune response to bacterial, viral, or other injury is driven by a complex network of interactions between upregulating and downregulating cytokines and chemokines, with the cytokine network always striving to manage the infection or damage effectively and achieve a homeostatic balance after the stress/danger threat has been quenched.
Research using multiple cytokine simultaneous immunoassays (Abe et al. 2013) shows a highly complex network with multiple layers of activation and control mediated through soluble receptors, receptor antagonists, and diverse serum mediators, which become more heterogenous with increasing age. Cytokine gene polymorphisms and gene splicing, which are subject to epigenetic modification, also variably influence cytokine expression and production. Proteomics and transcriptomics show large numbers of long-coding RNAs, siRNAs, and microRNAs involved in modulating cytokine production which make interpretation of cytokine data challenging (Battle et al. 2015). Although the interface between gene transcription and translation remains incompletely understood, these methodologies promise to further interrogate and elucidate cytokine networks and improve our understanding of their function in aging (Pilling et al. 2015).
Many cytokines appear able to act paradoxically, or in more than one way, with TGF-β identified as an excellent servant but a bad master by Kubiczkova et al. (2012) or by Tran (2012) who has described TGF-β: the sword, the wand, and the shield of FOXP3 + regulatory T cells, signifying TGF-β’s context-specific variable action. Cytokine expression appears to be influenced by local cellular microenvironments , suggesting that multiple pathways exist to achieve homeostatic immunologic control and effectiveness or conversely accentuation of chronic immune activation. However what seems clear is that mirroring other body systems, the homeostatic control, titration and modulation of immune responsiveness becomes more fragile and less tightly focused with increasing age. This loosening of the cytokine balance between the pro-inflammatory and anti-inflammatory control mechanisms, or inflamm-aging (Franceschi 2007c), is a characteristic feature of aging and aging-related disease.
Despite much ongoing research, there is no clear understanding about the cause(s) of “inflamm-aging” or “sterile inflammation” which underpins most major age-related diseases from atherosclerosis to diabetes, to Alzheimer’s disease , cancer (Franceschi et al. 2014; Chung et al. 2009), and aging itself. It may derive, in part, from an age-related decline in homeostatic immune function , a change to the balance of the gut microbiome, more fragile less efficient skin, a leaky gut, or less competent urogenital epithelial and mucosal barriers. Senescent cells, which increase with age, are considered to play a role. They secrete a combination of pro-inflammatory cytokines, chemokines, and proteases, called the senescence-associated secretory phenotype (SASP) , in response to DNA damage, protein misfoldings/aggregations, and reactive oxygen species (ROS), which accumulate in the cellular microenvironment (Coppé et al. 2008). These SASP-secreting cells respond by switching on a self-perpetuating intracellular pro-inflammatory signaling loop, centering around the NF-κB, TGF-β, IL-1α, IL-6, pathway.
These findings therefore suggest that aging may be a potentially modifiable risk factor and that it may be possible to delay age-related diseases , by modulating molecular mechanisms, evidenced through a pro-inflammatory phenotype. One therapeutic opportunity may be to adopt behavioral interventions in lifestyle and modification of diet to include more omega-3-containing foods, fruit, and vegetables as in the Mediterranean diet (Carmago et al. 2012; De Longeril et al. 2006), engage in regular moderate exercise routines (Carvalho et al. 2014; Elosua et al. 2005), and maintain more social connections in daily lives (Rea et al. 2016) or best of all a combination of lifestyle factors (Knoops et al. 2004). Other therapeutic opportunities may arise through better understanding of the molecular mechanisms that induce senescence and SASP in the cellular environments of chronic disease or using the increasing knowledge of the role of deacetylation and demethylating drugs and nutrachemicals to modify gene expression, with the potential for developing paths or drug targets toward useful clinical interventions (Dinarello 2010).
Whether inflammation in aging is different from inflammation associated with age-associated disease remains a subject of much debate. Much more research needs to be carried out to answer these challenging questions about the molecular pathways underpinning the pro-inflammatory aging phenotype. Ongoing large global and European studies of centenarians and nonagenarians (Deelen et al. 2014; Beekman et al. 2013; Murabito et al. 2012; Sebastiani et al. 2012; Willcox et al. 2006), which are currently being carried out, should have the organizational breadth of ability and the statistical weight, to help answer some of these unanswered questions. Understanding how to delay or modify the pro-inflammatory aging phenotype, the hallmark aging and age-related disease (Franceschi and Campisi 2014; Dinarello 2010; Rea 2017), will give hope of a better quality aging and longevity for all.
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McNerlan, S.E., Ross, O.A., Maeve Rea, I. (2018). Cytokine Expression and Production Changes in Very Old Age. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_40-1
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