Aging and immunity – Impact of behavioral intervention

Brain, Behavior, and Immunity xxx (2013) xxx–xxx

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Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi

Review

Aging and immunity – Impact of behavioral intervention Ludmila Müller a,⇑, Graham Pawelec b a b

Max Planck Institute for Human Development, Lentzeallee 94, D-14195 Berlin, Germany Center for Medical Research, University of Tübingen, Waldhörnlestr. 22, D-72072 Tübingen, Germany

a r t i c l e

i n f o

Article history: Available online xxxx Keyword: Immunosenescence

a b s t r a c t Immune responses to pathogens to which they were not previously exposed are commonly less effective in elderly people than in young adults, whereas those to agents previously encountered and overcome in earlier life may be amplified. This is reflected in the robust finding in many studies that the proportions and numbers of naïve B and T cells are lower and memory cells higher in the elderly. In addition to the ‘‘extrinsic’’ effects of pathogen exposure, ‘‘intrinsic’’ events such as age-associated differences in haematopoeitic stem cells and their niches in the bone marrow associated with differences in cell maturation and output to the periphery are also observed. In the case of T cells, the ‘‘intrinsic’’ process of thymic involution, beginning before puberty, further contributes to reducing the production of naïve T cells. Like memory T cell populations, innate immune cells may be increased in number but decreased in efficacy on a per-cell basis. Thus, superimposed on chronological age alone, remodelling of immunity as a result of interactions with the environment over the life course is instrumental in shaping immune status in later life. In addition to interactions with pathogens, host microbiome and nutrition, exercise and stress, and many other extrinsic factors are crucial modulators of this ‘‘immunosenescence’’ process. In this review, we briefly outline the observed immune differences between younger and older people, and discuss the possible impacts of behavioral variations thereon. Ó 2013 Elsevier Inc. All rights reserved.

1. Introduction The process of aging mostly reflects the biological consequences of unrepaired damage over time, and has a complex phenotype associated with progressive changes in many key physiological systems (Fig. 1). Aging influences an organism’s entire physiology, impacting on functions at the molecular, cellular and systemic levels and increasing susceptibility to many major chronic diseases. Many age-related diseases have multifactorial aetiology and aging is hypothesed to alter the highly coordinated interactions on the systemic level, leading to loss of homeostasis and to decreased ability to respond to extrinsic and intrinsic challenges, resulting in senescence. For this reason, a comprehensive explanation of how and why we age requires an understanding of events at the different levels of this decline. Further complexity is introduced particularly in studies on people due to the great diversity among individuals, which results from the dynamic interaction of genetics, environment, life style, nutrition and other factors (including those still not identified). One obvious example relates to differences between male and female gender, which influence life span for reasons that remain unclear (Nussinovitch and Shoenfeld, 2012; Tower and Arbeitman, 2009). Gender-specific differences ⇑ Corresponding author. Tel.: +49 3082406380.

in sex hormone secretion patterns and their changes over the lifespan are clearly candidates intimately involved in controlling aging trajectories, but their exact contributions to longevity in humans are not well-established. The modulating and reciprocal influence of sex hormones on major physiological responses to environmental and cellular stressors, and to oxidative damage, may play a role in longevity. Additional factors which are proposed to have an influence in this context include telomere and telomerase-related differences, as well as changes in mitochondrial DNA (Pan and Chang, 2012). Although the role of gender differences in the regulation of inflammatory and regulatory pathways (such as insulin/ IGF signalling and Target of Rapamycin (TOR) signalling) is not entirely elucidated, these pathways or factors clearly do play a role in longevity and aging-related diseases. Particularly chronic oxidative stress is known to affect those cells constituting central regulatory systems (such as the nervous, endocrine and immune systems) and lead to disturbed communication between them. This affects their functional capacity, deregulates homeostasis and thus may influence longevity (Fuente Mde et al., 2011). In some way associated with these events, low-level inflammatory status is commonly found to be elevated in the elderly, and is implicated in frailty and mortality. Numerous attempts to define the role of chronic inflammation in aging have implicated redox stress, mitochondrial damage, immunosenescence, endocrinosenescence, epigenetic modifications and other

E-mail address: [email protected] (L. Müller). 0889-1591/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbi.2013.11.015

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Body’s systems

Age-related changes

Lifespan Fig. 1. Aging alters the highly coordinated interactions on the systemic level, leading to loss of homeostasis and senescence.

phenomena. No single mechanism or theory is likely to be able to explain all aspects of aging – it is more likely that multiple processes contribute to this process; nonetheless, nearly all of them may be associated with inflammatory responses in some way (Jenny, 2012). Age-related inflammatory processes are intimately intertwined with changes in immune function. At the same time, they are regulated by neuroendocrine hormones, including glucocorticoids, dehydroepiandrosterone, and the catecholamines, epinephrine, and norepinephrine. During the life course, age-related changes in endocrine function can potentially lead to the disturbance of this regulation. Social, occupational and psychological stressors are a part of our daily life and the source of life-changing events. Chronic stress of this type is also known to cause harmful effects on both neuroendocrine and immune functions and may contribute (in combination with age) to further increases in morbidity and mortality among elderly individuals (Heffner, 2011; Hawkley and Cacioppo, 2004). Thus, accumulating evidence shows incontrovertibly that immune function changes with normal aging and independently with increased stress; and that chronic stress deregulates multiple components of innate and adaptive immunity, leading to what might be construed as premature aging of the immune system (Gouin et al., 2008). At the same time it is likely that the immune system impacts on the rate of organismal aging (Fuente Mde et al., 2011). Consistent with a central role of the immune system in this process, several lifestyle strategies such as intervening to provide an adequate diet, physical exercise, physical and mental activity, also result in improved immune functions, decreasing oxidative stress, and potentially increasing individual longevity. Finally, human beings may be considered as ‘metaorganisms’ as a result of a close symbiotic relationship with the intestinal microbiota (and indeed also systemic microbiota, such as persistent viruses). This assumption enforces an even more holistic view of the aging process where dynamics of the interaction between environment, intestinal microbiota and all physiological processes of the host must be taken into consideration (Biagi et al., 2012).

Here, we will briefly survey the cells and functions of the vertebrate immune system focussing on the human immune system, and the effects of aging thereon, before considering if and how behavioral interventions might be able to restore appropriate immune function in the elderly.

2. Age-related changes in the immune system Age-related physiological changes can be very well exemplified in the immune system, which is continuously remodelled over the life course. The most important task of the immune system is to defend the body’s integrity against external pathogens or altered internal factors, and to facilitate the maintenance of a beneficial microbiota (Pawelec, 2012). Various immune mechanisms of both the innate and adaptive arms of the immune system, including different cell populations, are available to respond to these challenges to bodily integrity. Recently, however, the strict distinction between these two arms of immunity, classically viewed as completely separate, has become less obvious. It has been shown that innate immune cells can demonstrate memory characteristics under certain conditions, and reciprocally that adaptive immune cells can express receptors characteristic of innate cells, especially at late stages of differentiation, i.e. commonly present in increased numbers later in life and with the appearance of age-associated, potentially senescent, changes (Lanier and Sun, 2009). The changes in the immune system that accompany human aging are very complex and are generally referred to as immunosenescence. Aging does not necessarily lead to unavoidable deteriorations in immune functions, but always affects their modulation. While many aspects of immune function decline with aging, some of them remain stable, and some become overactive. Hence, dysregulation rather than deterioration per se is likely to be the major explanantion for immunosenescence. Nevertheless, increased susceptibility to infections and autoimmune diseases, neoplasias, metabolic diseases, osteoporosis and neurological disorders are all in some way likely to be at least partly caused by immunosenescence.

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Macrophage

Neutrophil

Reduced expression and function of TLR

Reduced chemotaxis of neutrophils Pathogens

Reduced MHC-expression and signaling Reduced chemotaxis and phagocytosis

Blood vessel DC

Decreased cytokine production

Impaired signal transduction

Monocyte Inflammatory proteins

Decreased superoxide production

Cytokins

Reduced apoptosis

TC

Impaired distribution and migratory capacity of DC Ageing

Reduced expression of TLR and MHC

Macrophage Dendritic cell

Monocyte Ageing

Fig. 2. Age-related alteration in macrophages, monocytes, neutrophils and dendritic cells. TLR: toll-like receptor; MHC: major histocompatibility complex; DC: dendritic cells.

The term immunosenescence is now well-established in the scientific literature and includes a number of profound changes that affect both the innate and adaptive arms of the immune system. The factors and mechanisms of immune senescence are multiple and include, among others, defects in the bone marrow (reflected in alterations in the proportions of lymphoid and myeloid cells exported to the periphery), thymus involution (decreasing the generation of new T cells) and intrinsic defects in formation, maturation, homeostasis and migration of peripheral lymphocytes (Gruver et al., 2007). The genetic background of aged individuals, epigenetic changes occurring during the life course, impaired interaction of innate and adaptive immune responses, continuous reshaping of the immune repertoire by persistent antigenic challenges, chronic low-grade inflammation and deregulation of hormonal pathways – all these factors might synergise, leading to the age-associated decline of immunity commonly seen in the elderly (Jenny, 2012). Age-dependent epigenetic changes in DNA methylation do occur in cells of the immune system in the same way that overall genomic methylcytosine levels decrease in other major tissues. More demethylation is known to occur in the brain, heart, liver, small intestine mucosa, spleen, and also in T lymphocytes in the elderly. These age-dependent changes in DNA methylation are likely to contribute in some way to T cell senescence (Calvanese et al., 2009; Gonzalo, 2010). Additional to these intrinsic factors, also extrinsic factors, like health-related behaviors and chronic stress exposure (Bauer, 2005) can accelerate immunosenescence and the process of aging as discussed later in this chapter. 3. Cells of the innate immune system and impact of aging Innate immune responses initially call adaptive immune responses into play and both arms act together to eliminate pathogens. Cells of the innate immune system, such as natural killer cells, macrophages, dendritic cells, and neutrophils, generate a more rapid but less finely antigen-specific immune response than the cells of the adaptive immune system. 3.1. Neutrophils Neutrophils are the most abundant population of circulating leukocytes and represent the first line of defence against most types of pathogens, such as bacteria, yeast and fungi (Fig. 2, right). These cells have a very high turnover and relatively short lifespan.

Nevertheless, a number of impairments in their function (such as chemotaxis, phagocytosis, production of free radicals as well as susceptibility to apoptosis) in aged individuals have been reported (Shaw et al., 2010). The expression and function of surface receptors recognizing pathogen-associated molecular patterns, such as Toll-like receptors, as well as cytokine production, and expression of other surface molecules like MHC class II antigens is also reduced (Fulop et al., 2004). Thus, impairments in these initial defences against infections could be very important in the elderly. 3.2. Monocytes and macrophages These cells also play multiple important roles in the immune system including key functions in phagocytosis and possibly antigen presentation (Fig. 2). Monocytes are very efficient in the elimination of bacterial infections, which occurs with high prevalence in the aged population. Macrophages are directly involved in the initiation of inflammatory responses, elimination of pathogens and tumor cells, and regulation of the adaptive immune response through the process of antigen presentation. They can destroy their targets directly, or they can act indirectly through release of immune mediators (such as IL-1, TNF-a, and IFN-c) that activate other inflammatory cells (Derhovanessian et al., 2008; Keller, 1993). The number of blood monocytes does not appear to change with advancing age, but a decreased percentage of macrophages in the bone marrow of aged individuals 80–100 years old has been reported, which can be explained by increased apoptosis and reduced cellularity. Expression of MHC-II molecules in macrophages is impaired with aging, and epigenetic mechanisms have been invoked in this decrease. The phagocytic and killing capacities of macrophages are also reduced with age, accompanied by lower production of reactive oxygen intermediates such as NO2 and H2O2, and decreased levels of macrophage-derived cytokines (TNF-a and IL-1), the expression of which is modulated by epigenetic mechanisms (Fernandez-Morera et al., 2010; Gonzalo, 2010). 3.3. Dendritic cells Dendritic cells (DCs) play crucial roles in the immune response and constitute an essential bridge between the innate and adaptive immune systems. They are responsible for recognizing pathogenassociated molecules, for taking up and processing pathogen antigens, and for presenting these antigens to T cells. They represent professional antigen-presenting cells, without which adaptive

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Compensatory increase in cell numbers

Virus-infected or modified cell

Reduced per-cell cytotoxicity Decreased signal transduction Reduced response to cytokines Impaired cytokine and chemokine production

NKT cell / iNKT cell

NK cell

NKT cell Decrease in frequency of iNKT

TCR IL-2 CD161

ARL

IFN-γ TNF-γ

AR

IFN-γ TNF-γ

NK cell

Reduced population doubling in iNKT

ARL

Impaired cytokine production

Perforin Granzyme

Ageing

Increase in NKT cell numbers

Virus-infected or tumour cell

Shift in cytokine profile: Th1 to Th2 Ageing

Fig. 3. Age-related changes in NK- and NKT-cells. NK: natural killer cells; NKT: natural killer T cells; iNKT: invariant natural killer T cells; IL: interleukin; IFN: interferon; TNF: tumor necrosis factor; TCR: T-cell receptor; CD: cluster of differentiation; AR: activation receptor; ARL: activation receptor ligand; Th: T-helper.

immune responses cannot take place. Moreover, the manner in which the DCs present antigen and costimulate T cells influences the type of T cell response initiated, and thus the quality and intensity of adaptive immune responses (Müller et al., 2013). This implies that age-associated decreased DC function leads unavoidably to reduced T cell activation and proliferation. DCs seem to be affected by aging in terms of their distribution and migratory capacity, in their antigen-processing ability as well as in costimulatory signal expression and cytokine production (Fig. 2, left). Although antigen presentation by DCs seems to be only subtly different in the elderly, fewer DC are found in peripheral blood and follicles, implying reduced efficiency of this line of defence against infections and tumors (Gonzalo, 2010; Della Bella et al., 2007; Derhovanessian et al., 2008). Similar to the results obtained from animal studies, the numbers of DCs, their distribution, and potentially their generation and development from hematopoietic precursors in vivo are markedly reduced in elderly humans (Adema, 2009).

3.4. Natural killer cells Natural killer (NK) cells are cytotoxic lymphocytes which are involved in early defence, recognizing virus-infected and virally or non-virally modified tumor cells in an MHC-unrestricted manner (Fig. 3, left). This outstanding competence of NK cells probably makes them particularly important for cancer immune surveillance during aging. Studies on healthy elderly individuals and centenarians demonstrate that the overall NK cell number tends to increase with age, but their function on a per-cell basis decreases and NK cells are also more likely to have a mature phenotype. NK cells from the elderly also produce lower levels of cytokines and chemokines (such as RANTES, MIP1a, and IL-8). Thus, the overall increase in number of NK cells can be considered as a compensatory mechanism to maintain an important level of functionality. An age-related impairment in perforin secretion, associated with defective polarization of lytic granules toward the immunological synapse was recently proposed to be a reason for the age-associated reduction in NK-cytotoxicity (Hazeldine et al., 2012). NK-cell production of IL-2, IFN-c, TNF-a and IL-12 is also diminished in elderly people and this may contribute, among other factors, to immune deficits associated with advanced age (Dewan et al., 2012).

3.5. Natural killer T cells Natural killer T (NKT) cells share attributes of both the innate and adaptive arms of the immune system. They are a unique and relatively rare (ca. 0.1%) subset of CD3-positive T cells that coexpress TCRs and CD161 (NKR-P1A), undergo maturation in the thymus and/or at extrathymic sites, and play an important role in viral and antitumor cytolytic activity (Fig. 3, right). A subset of so-called invariant NKT (iNKT) cells is characterized by a TCR with an invariant alpha chain. These two subsets of lymphocytes share some attributes, such as expression of CD16, CD56 and CD161 with NK-cells, but they are able to recognize antigens in both an MHC-restricted (peptides), as well as a CD1-restricted (lipids and glycolipids) manner. It has been reported that absolute numbers of NKT-cells increase with advancing age (Mahbub et al., 2011), whereas for the iNKT-cells reduced frequency and numbers has been found in aged individuals (DelaRosa et al., 2002) with no marked change in their phenotypes. It was also shown that iNKT cells underwent fewer population doublings compared to cells from young individuals (Peralbo et al., 2006), suggesting that they were already ‘‘older’’. With aging, the cytokine profile secreted by NKT-cells also changes. Recent studies indicate that cytokine profile of iNKT-cells from old individuals showed a shift from a T helper (Th)-1 toward a Th-2 pattern compared with iNKT-cells from young individuals (Mahbub et al., 2011). Although NKT-cells are known for their ability to influence immunological functions of APCs and T cells, only a few studies have examined the role of NKT-cells in immunosenescence.

4. The adaptive immune system and immunosenescence The cells of the adaptive immune system (T- and B-lymphocytes) act in a highly antigen-specific manner and imbue the system with immunological memory (Medzhitov and Janeway, 1997) as well as regulating immune homeostasis. The receptors of these lymphocytes are generated through somatic recombination of segments of their encoding sequences (Bonilla and Oettgen, 2010) and in this way provide an extremely diverse repertoire of receptor specificities capable of recognizing components of essentially all potential pathogens. Adaptive immunity comprises a

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highly regulated interplay between innate cells like DCs or other antigen-presenting cells, and T and B lymphocytes, which activate and promote pathogen-specific immunologic effector pathways and generate immunologic memory. During the first encounter with a pathogen, sets of long-lived memory T and B cells are established. In subsequent encounters with the same pathogen, the memory cells are quickly activated to yield a more rapid and robust protective response (Cooper, 2010). 5. Development of lymphocytes and impact of aging Development of lymphocytes occurs in the specialized environments of the bone marrow and thymus. The lymphoid precursors of T- and B-cells originate from the pluripotent hematopoietic stem cells in the bone marrow. 5.1. Immunosenescence and the haematopoietic stem cell compartment The haematopoietic stem cell (HSC) compartment, which is the source of the continuous replenishment of blood and the immune system throughout life (Fig. 4, left), giving rise to all cellular (lymphoid and myeloid) components, is negatively modulated and functionally affected by aging (Geiger et al., 2013). The stromal matrix of the aging bone marrow, which normally nurtures and drives stem cell production, also exhibits structural changes in terms of the numbers of stromal cells and diminished IL-7 production. The bone marrow haematopoietic compartment changes with age and is increasingly composed of fatty adipose tissue (Compston, 2002; Gruver et al., 2007). Age-related changes within the HSC compartment may be partly dependent on ‘‘intrinsic’’ cellular aging of HSCs themselves. Accumulation of DNA damage, telomere attrition and epigenetic deregulation, combined with an increase in intracellular reactive oxygen species characterizes aged HSCs (Dykstra and de Haan, 2008; Warren and Rossi, 2009). These events of genomic instability may also lead to malignant transformation of HSCs and to myeloproliferative disorders. Age-associated decreased homing efficiency, and a myeloid skewing of differentiation potential contribute to changes in the cellular composition of the HSC compartment. The hematopoietic stem cell pool contains a heterogeneous mixture of HSCs, and aging is associated with a marked

Bone marrow

Pluripotent HSC

shift in the proportions of these HSC subsets. Such changes in the lymphoid and myeloid lineage are believed by some investigators to be central to the decline of immune competence and predisposition to myeloproliferative diseases in the elderly (Beerman et al., 2010; Dykstra and de Haan, 2008).

5.2. Thymic involution Another major feature contributing to immunosenescence is thymic involution (Fig. 4, right). During this process a progressive age-related reduction in the size of the thymus takes place by replacement of lymphoid tissue by fatty tissue and by reducing the active areas of thymopoiesis (Aspinall et al., 2010). This process was shown to be mediated by the upregulation of thymosuppressive cytokines, such as IL-6, oncostatin M and leukaemia inhibitory factor (Sempowski et al., 2000) and parallel decreases in IL-7 production, known to be important for thymopoiesis. These changes lead to the consequent decrease in the numbers of thymic epithelial cells and impairment in thymopoiesis. The reduction of thymic output and therefore diminished replacement of circulating naïve T cells as they respond to pathogens or other antigens is thought to be a major contributory event in the development of immunosenescence (Aspinall et al., 2010). Normally, T cell precursors migrate from the bone marrow to the thymus (Fig. 4), where they proliferate and differentiate into immature double-negative CD4 CD8 thymocytes (Schwarz and Bhandoola, 2006). During T-cell development, rearrangement of the antigen receptor genes takes place, so that the cells now express the T-cell receptor (TCR) on their surfaces. Chronic thymus involution is associated with a reduced efficiency of T-cell development and with the reduced migration of naïve T cells in the periphery. The loss or great reduction of thymic function, although occurring early in life and therefore a developmental rather than senescence process, results in contraction of the T cell repertoire and contributes to the increased incidence of infections and potentially also cancer and autoimmune disease (Lynch et al., 2009). Changes in thymus activity may also be influenced by environmental conditions (prenatally and during the early period of life), genetics, sexual dimorphism (males and females show different patterns of thymic involution) and the thymic stroma (Gui et al., 2012). Sauce and colleagues showed that thymectomy during

Aged thymus

Young thymus Aging Development?

Decrease of HSC compartment Pre-B cell

Transformation of HSC and shift to myeloid lineage

Reduced active area of thymopoiesis

DNT

Up-regulation of thymus-suppressive cytokines

Pro-B cell DPT CD8+T cell

Reduced population of naÔve T cells

Decreased frequency of pro-B cells Altered Ig-specificity, -isotype and -idiotype

IgM

IgG

Oligoclonal TCR repertoire CD4+T cell

Reduced primary and secondary response IgG

Ageing

Memory B cell

Aggregation of exhausted memory T cells Ageing

Memory CD4+T cell

Memory CD8+T cell

Fig. 4. Development of lymphocytes and impact of aging. HSC: haemotopoietic stem cell; IgG: immunoglobulin G; IgM: immunoglobulin M; DNT: doppel-negative thymocyte; DPT: doppel-positive thymocyte; CD: cluster of differentiation.

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Regular physical activity and exercise

Reduced energy intake Adipocyte Practice of “healthy behaviour” - M1-Macrophage - pro-inflammatory adipokines

- Treg cell

- Acvated T cell

- M2-Macrophage - an-inflammatory adipokines

Fig. 5. Impact of behavioral intervention on immunosenescence.

childhood leads to premature onset of many of these age associated changes in the immune system (Appay et al., 2010; Sauce and Appay, 2011), underlining the importance of vigorous naïve T cell output in early life to build a reserve for later use. 5.3. Age-related changes of T cells Circulating CD4+ T cells act mostly as T-helper cells, by triggering signals of B-cell activation for antibody production. A counterbalancing subset of the CD4 population consists of regulatory T cells (Treg), which exert inhibitory activities on other T cells, suppressing excessive or misguided immune responses. The number of peripheral regulatory T cells can increase during aging as well as under conditions of chronic stress (Bauer et al., 2009). The process of immune aging seems to represent a remodelling of adaptive immune responses by progressive reduction of the TCR repertoires in the CD4+ and CD8+ subsets contributing to highly restricted oligoclonal TCR repertoire in the periphery of the elderly (Kohler et al., 2005). This could lead to age-dependent increase in susceptibility to infectious, autoimmune, malignant diseases and decreased efficiency of vaccination. At the single-cell level, T cells from aged individuals demonstrate reduced functional potency compared to cells of the same phenotype from young individuals. This reduced functional potency of T cells was shown to be restored under some conditions by the addition of IL-15 (Liu et al., 2002). Normally, after their release from the thymus, naïve T-cells may be activated by binding of their TCR to the appropriate MHC-peptide complex presented by APCs, such as dendritic cells. The crucial initial step in this T-cell activation is the reorganisation of the plasma membrane, in which membrane rafts cluster to the T cell/APC site. This process of lipid raft polarization is impaired in T cells from older people. It was shown that the higher cholesterol content in these aged cells may influence the motility of their rafts and thereby may reduce recruitment of signalling molecules following activation (Larbi et al., 2011). Naïve T cells from elderly people exhibit impaired differentiation into effector cells following antigen stimulation, as well as other functional defects such as reduced cytokine production, as well as a restricted TCR repertoire (Ferrando-Martinez et al., 2011; Weiskopf et al., 2009). Epigenetic age-associated alterations, such as methylation of cytokine gene promoters can also contribute to perturbed immune function (Calvanese et al., 2009; Gonzalo, 2010). Both immune-specific genes (such as surface molecules or the cytokines IL-2 and IFN-c) and genes involved in general cell homeostasis pathways, show altered DNA methylation profiles during aging (Fernandez-Morera et al., 2010; Shanley et al., 2009). Appropriate differentiation and activation of T cells partly depends on the integrity of the genes encoding key factors, which may be associated with an environmental component, viral

infections, exposure to chemicals or hormones, etc., which influence their development. These factors can alter the epigenetic profile of cells, and therefore have a direct effect on gene expression profiles and on remodelling processes. Senescent immune remodelling is a significant contributing factor to the increased risk and severity of infections in the elderly (Dewan et al., 2012; Larbi et al., 2008; Solana et al., 2006; Fernandez-Morera et al., 2010). 5.4. Changes in T-cell populations and impact of Cytomegalovirus (CMV) As a consequence of decreased thymopoiesis with advancing age and other age-related modulating factors, a shift in the ratio of naïve to memory T cells takes place, in order to maintain T-cell homeostasis in the periphery. Additionally, repetitive antigen exposure contributes to the continuous reshaping of the immune repertoire by persistent antigenic challenge, modulating the T-cell pool and contributing to immunosenescence in older adults (Pawelec et al., 2009; Lang et al., 2013). Nearly 25% of the total CD8 T cells in CMV-positive elderly persons may be specific for a single CMV-immunodominant epitope (Pawelec et al., 2009); this CMVdriven expansion of CD8-positive T cells is accompanied by the loss of the costimulatory CD28 molecule, the process being considered as a key predictor of immune incompetence in older individuals (Müller et al., 2013). The age-dependent accumulation of exhausted memory T cells, releasing the pro-inflammatory cytokines CRP, IL-6, TNF-a and IFN-c, together with components and factors of the innate immune system, is thought to contribute to the lowgrade inflammation (inflamm-aging) commonly observed in elderly people (Franceschi et al., 2007; Bennett et al., 2012). However, the hypothesis that CMV is a significant driver in inflammaging has been challenged in a recent cohort study (Bartlett et al., 2012) showing that levels of pro-inflammatory and anti-inflammatory cytokines were changing equally in CMV-seropositive and CMV-seronegative subjects over time, suggesting that CMV might be not a primary causative factor in inflammaging. The increased presence of exhausted CD28 T cells in elderly people, together with other parameters, such as an altered CD4/ CD8 ratio and CMV-seropositivity, has led to the definition of the so-called ‘‘immune risk phenotype’’ predicting a higher 2-year mortality in a longitudinal study of octa- and nonagenarians (Pawelec et al., 2009). The accumulation of later-stage CD8 T cells characterizing the IRP was not seen in people not infected with CMV, even when they were infected with other persistent herpesviruses (Derhovanessian et al., 2011). However, the process of immunosenescence may also be amplified in the context of both chronological aging and HIV-infection; thus, also during chronic HIV disease the proportion of senescent CD8 T cells increases progressively with age and often consists of oligoclonal populations (Deeks et al., 2012). These cells gain suppressive functions and may also

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contribute to carcinogenesis. Interestingly, even in HIV disease, a high proportion of late-differentiated, senescent, memory CD8 T cells are nonetheless specific for CMV antigens (Dock and Effros, 2011). 6. Inflammaging As mentioned above, chronic low-grade inflammation has been repeatedly identified in seemingly healthy individuals during aging and is characterized by increased levels of circulating pro-inflammatory cytokines, such as TNF-a, IL1Ra, IL-6 and markers of inflammation such as C-reactive protein (CRP). It was postulated that this so-called ‘‘inflammaging‘‘ process appears to be a key phenomenon associated with different age-related diseases and their pathological features (Franceschi et al., 2000, 2007). Inflammaging seems to be a universal phenomenon accompanying aging, and is associated with frailty, morbidity and mortality in elderly individuals (Jenny, 2012). Thus, age-related pro-inflammatory status can be associated with patho-physiological conditions. However, it is often difficult to identify whether the inflammation is the causative agent for these co-morbidities or the consequence (Rymkiewicz et al., 2012). 7. Humoral immunity Humoral immunity in an aged organism is known to be both qualitatively and quantitatively different than in the young. There is a lower frequency and absolute number of pro-B lymphocytes in the bone marrow, along with a reduction in their ability to differentiate into pre-B lymphocytes (Fig. 4, left). Immunoglobulin diversity and affinity are reduced in the elderly because of impaired somatic hypermutation inside the germinal center (GC), which is the main site of B cell proliferation and maturation. The generation of longterm immunoglobulin-producing B lymphocytes is also impaired. The numbers of functional immunoglobulin-secreting B cells and titers of antigen-specific immunoglobulins are decreased. B-cell subsets, and thus the antibody repertoire, are altered in specificity and isotype. The result is a shortened duration of humoral response and reduced B-cell ability to establish specific primary and secondary responses in elderly people (Colonna-Romano et al., 2008; Ademokun et al., 2010). This process is also dependent on cognate interactions between antigen-activated B cells and CD4+ T cells inside the GCs. Therefore, age-related deficits in T cells can modulate cognate interactions between B and T cells and in this way reduce antibody avidity (Dewan et al., 2012). Aging-associated changes in epigenetic status might also be responsible for altered B-cell function in elderly people, because of modifications in the differentiation pathways and in regulation and rearrangement of BCR/Ig genes (Shanley et al., 2009; Colonna-Romano et al., 2008). Taken together, one can conclude that the quality of the humoral immune response declines with progressing age. 8. Impact of life style factors on immunosenescence Many lifestyle factors are known or suspected to contribute to perceived deleterious age-associated changes to immunity. These include psychosocial parameters, stress responsiveness, physical inactivity, macro- and micro-nutrition, all of which may play important roles in immunosenescence. Stress may play a crucial role in mediating inflammation and age-associated impairments of immunity. Stress may be induced by a variety of factors, including situations both physical and mental, such as caregiving or low socioeconomic status. The latter in the elderly, depending on previous education and low income, has been shown to be associated with higher levels of inflamma-

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tory markers (Hajat et al., 2010; Nazmi et al., 2010). It has also been demonstrated that psychosocial stress may be responsible for accelerated telomere attrition, with shorter leukocyte telomere lengths in persons with lower socioeconomic status (Shiels et al., 2011). Stress has been shown to be associated with increased risk of frailty and cardiovascular diseases, apparently as result of elevated levels of inflammatory markers (von Kanel et al., 2006; Jenny, 2012). Frailty is a common syndrome in the elderly and is characterized by poor mobility, weakness and low tolerance to psychological or/and physiological stress, and results from accumulation of multiple functional declines in various systems. Frailty may be considered as a kind of exhaustion of physiological reserves of the organism, leading to decreased overall physical function, which can be characterized by weight loss (primarily at the cost of muscle loss), decline in muscle function and their reduced strength due to sarcopenia. As mentioned before, inflammatory status seems to play a decisive role in the frailty that is associated with higher prevalence of inflammatory diseases (Chang et al., 2012). 8.1. Impact of physical inactivity on inflammatory status An inactive life style and sedentary behavior promote the accumulation of visceral fat and lead to obesity. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and development of systemic metabolic dysfunction that appears to be aetiologically associated with obesity-linked disorders. Adipose tissue acts as a key endocrine organ by releasing bioactive substances, known as adipokines, that have pro-inflammatory or anti-inflammatory activities (Ouchi et al., 2011). The production of pro-inflammatory adipokines in expanding fat tissue, such as TNF, leptin, retinol-binding protein 4, lipocalin 2, IL-6, IL-18 and angiopoietin-like protein 2 increases, while the concentrations of anti-inflammatory cytokines are reduced (Ouchi et al., 2011). This process is accompanied by infiltration of adipose tissue with proinflammatory immune cells and induction of a low-grade inflammatory state (Fig. 5, left), which is characterized by elevated levels of circulating inflammation markers, such as IL-6, TNF and CRP. Adipose tissue is infiltrated with macrophages in two separate polarization states: M1, which produce pro-inflammatory cytokines and M2, producing anti-inflammatory cytokines. Therefore, it has been proposed that in adipose tissue a phenotypic switch takes place toward macrophages of M1-phenotype, promoting the inflammatory state. This low-grade systemic inflammation is known to be associated with development of atherosclerosis, neurodegeneration, insulin-resistance and promotion of tumor growth (Gleeson et al., 2011). While these phenomena are not limited to the elderly, they often tend to be exacerbated in older people who for one reason or another exercise less than the young. 8.2. Impact of nutrition on immunosenescence Aging represents a major nutritional challenge, not only concerning the dietary supply of certain nutrients but also in terms of their altered metabolism (Duncan and Flint, 2013). Micronutrient deficiencies, which are very common in the elderly, have been found to be associated with a physiological decline in various body functions, which can lead to a higher morbidity and mortality. Among other micronutrients, zinc has an essential significance to health; its deficiency is responsible for various diseases. Zinc is one of the most important trace elements in the organism, with three major biological roles, as catalyst, structural, and regulatory ion. It plays a critical role in organism homeostasis, in immune function, in oxidative stress, in apoptosis and other areas (Chasapis et al., 2012). Thus, zinc deficiency may influence progression of many chronic diseases, including atherosclerosis, neurological

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disorders, autoimmune diseases, age-related degenerative diseases, various malignancies, and adversely affect immunological status, increase oxidative stress, and lead to the generation of inflammatory cytokines (Chasapis et al., 2012). Zinc deficiency is known to decrease innate immunity. Particularly, zinc deficiency impairs the lytic activity of NK cells, reduces NKT cell cytotoxicity and immune signalling, influences the neuroendocrine immune pathway, and alters cytokine generation in mast cells (Mocchegiani et al., 2003; Muzzioli et al., 2009). The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, holistic approach to determining the optimal nutritional strategies that would maintain a healthy immune system in elderly people and promote their resistance to infection and other immune-related diseases (Pae et al., 2012). Therefore, we will need a more holistic view of the aging process where dynamics of the interaction between environment, intestinal microbiota and host must be taken into consideration. We should take into account also the age-associated physiological changes in the gastrointestinal tract, as well as age-related modifications in lifestyle, in nutritional behavior, and impaired functionality in the immune system of the elderly population. 9. Impact of behavioral interventions on immunosenescence It is now clear that a variety of genetic and environmental factors impact upon health in old age, including effects on immunity. However, the relative contribution of these factors to immunosenescence will have to be more accurately established. These variables clearly include nutrition (micro and macro) and obesity, as well as gender and ethnicity, genetic background, psychosocial parameters (including stress), mental wellbeing, socioeconomic status, early life events and exposures, physical activity, and different chronic infections. It will be necessary to build up a solid evidence base in order to develop effective personalized interventions, both lifestyle and pharmacologic, to extend health span. Few current studies are attempting to meet this challenge, but according to the findings of a recent study on more than 23,000 adults, a healthy lifestyle alone lowered the risk in developing chronic diseases with known inflammatory aetiology by 78% (Ford et al., 2009). Thus, many chronic diseases can be prevented by changing lifestyle and behavioral habits, particularly dietary habits, and exercise. For example, a positive effect of 3 months of a regimen of comprehensive lifestyle changes (moderate exercise, plant-based diet, stress management and improved social support) on increased telomerase activity was demonstrated in men with low-risk prostate cancer (Ornish et al., 2008). After 5 years follow-up, relative telomere lengths of lymphocytes had increased in the lifestyle intervention group and decreased in the control group. Although such changes are thought to be beneficial, more investigations are needed to confirm whether this is really the case and the full biological implications remain to be determined in large randomised, controlled trials (Ornish et al., 2013). 9.1. Effect of physical exercise on the immune system Evidence that long-term behavioral changes, including reduced energy intake together with increased physical activity, may prevent, improve or even reverse age-related impairments in immune function, continues to accumulate. Lifestyle factors, such as exercise and diet have been established as playing an important role in immunosenescence, and the practice of ‘‘healthy’’ behavior may minimize the age-associated decline of immune function (Fig. 5). Several interventions, including different types of exercises, have been proposed to restore immune function in elderly

people. Some studies have shown that moderate exercise training (5 days a week for 6 months) can improve Th-cell mediated immune functions associated with up-regulation of CD28 expression on the surface and by improving the Th1/Th2 balance (Shimizu et al., 2008). The training sessions (2 days a week for 3 months), consisting of stretching and endurance exercise as well as resistance training using an exercise machine, led to increased numbers of CD28+CD8+ cells as well as CD80+CD14+ cells in the periphery (Shimizu et al., 2011), indicating that such training sessions might upregulate monocytes and dendritic cells, thereby possibly improving T-cell mediated immunity in elderly people. In recent years, the role of exercise in modulating immune responses has been examined using models that may have clinical relevance, such as the response to vaccines and novel antigens (Kohut and Senchina, 2004; Kohut et al., 2002). It has been shown, for example, that regular exercise is associated with improved immune responsiveness to influenza vaccination in older adults. Exercise-related increased antibody titre, T-cell function, macrophage response, improvement of the Th1/Th2 cytokine balance, the level of pro-inflammatory cytokines, and changes in naïve/ memory cell ratio have also been reported (Kohut and Senchina, 2004). An 10-month interventional trial with 144 participants (aged 60–83 years) has demonstrated that cardiovascular, but not flexibility and balance exercise intervention, resulted in a significant increase in seroprotection 24 weeks after vaccination, providing improved protection throughout the entire influenza season and reduced respiratory tract infections (Woods et al., 2009). Thus, accumulating data suggest that exercise may be a powerful approach to restoring immune function in old populations. However, more rigorous standardisation of procedures is required to use them in the prevention of disease and in the modulation of the immune system in order to reduce disease prevalence (Walsh et al., 2011; Hong, 2011). 9.2. Impact of exercise on senescent and virus-specific T lymphocytes As already mentioned above, aging is characterized by the accumulation of late-stage, possibly terminally differentiated T cells, of which at least some may be truly senescent (mostly as a consequence of persistent viral infection), coupled with greatly reduced or absent entry of naïve T cells into the periphery (as a consequence of thymic atrophy). This leads to a drastically shrinking naïve T-cell repertoire. However, beneficial effects of the manipulation of certain life style factors, especially the benefits of regular physical exercise, on markers of immunosenescence have been repeatedly reported, although the mechanisms underlying these potentially positive effects on immunity are not very well understood (Simpson and Guy, 2010). It has been suggested that habitual physical exercise can beneficially modulate immunosenescence in two ways: first, by a preventive mechanism (restricting the opportunity for latent viral reactivations), and second, by a restorative mechanism (Simpson, 2011). For the latter process to take place, three distinct phases were proposed: (i) a selective mobilization of senescent T cells from peripheral organs into the blood, occurring during exercise; (ii) extravasation of senescent T cells from the circulation and their enhanced apoptosis in peripheral tissue, occurring during exercise recovery; (iii) subsequent generation of naïve T cells to replace the deleted senescent cells. However given thymic involution, the ability to regenerate naïve cells in most elderly people will be limited, perhaps only to homeostatic proliferation of pre-existing naïve cells. Acute exercise normally induces a biphasic change in circulating lymphocyte numbers, with their rapid mobilization into the blood at the beginning of exercise (lymphocytosis) and falling below the resting values during the early phase of exercise recovery

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(lymphocytopenia) (Simpson et al., 2008; Turner et al., 2010). By mechanisms not very well understood, in particular the lymphocytes with high cytotoxic capacity are preferentially mobilized into the circulation. It has been shown that these cells consist of highly differentiated effector-memory T-cell subsets, expressing surface markers that may be shared with senescent cells, such as KLRG1 and CD57 (Simpson et al., 2007). High-intensity exercise was found to mobilise higher numbers of late-differentiated effector memory cells in comparison to low-intensity exercise (Campbell et al., 2009). The same subpopulation of lymphocytes has been demonstrated to egress from the circulation during exercise recovery (Simpson et al., 2008). Furthermore, it was shown that in CMV-seropositive young individuals, mobilization and subsequent egress of total CD8+ lymphocytes was nearly twice as great as in CMV-seronegative subjects, indicating that exercise may induce the mobilization of viral-specific CD8+ T cells (Turner et al., 2010). The same type of senescent and effector memory cells are believed to overcrowd the immune space during aging and persistent CMV-infection. Therefore, it was postulated that mobilization of senescent viral-specific T-cells together with frequent T-cell shifts in response to exercise may be the first step toward a restoration of the naïve T-cell repertoire (Simpson et al., 2012). In support of this suggestion, it has been demonstrated that lymphocytes mobilized by acute bouts of exercise are more sensitive to in vitro apoptosis induced by physiological concentrations of pro-oxidant H2O2. The most apoptosis-susceptible subpopulation was found to be KLRG1+ and CD57+ with subpopulations expressing CD28, CD62L, or CD11a least susceptible (Wang and Lin, 2010). The subpopulation of CD45RA/CCR7-negative effector memory T cells has been demonstrated to be more sensitive to H2O2-induced apoptosis than CD45RA/CCR7-positive naïve T cells (Takahashi et al., 2005), indicating that senescent T cells might be less resistant to apoptosis induction. Kruger et al. (2009)have demonstrated and quantified lymphocyte trafficking and death in peripheral tissues of mice after exercise. They found that exercise-induced apoptosis is a systemic phenomenon and is not limited to the peripheral blood. It occurs in various lymphoid and non-lymphoid tissues, such as lung, spleen, bone marrow, lymph nodes and Peyer’s patches and is dependent on the type of exercise and its intensity. The apoptosis-inducing mechanisms, as well as kinetics, have a tissue-specific character. The transient periods of lymphocytopenia caused by exercise normally last 6–24 h, and peripheral blood lymphocyte counts are normally restored to baseline within that period of time. Interleukin-7, which is known to play a crucial role in homeostasis of naïve T cells, has been shown to be released from active skeletal muscles (Haugen et al., 2010), possibly contributing to increased thymopoiesis and exercise-induced immune enhancement (Simpson et al., 2012). The impact of maximal aerobic capacity as a measure of aerobic fitness on the age-related accumulation of potentially senescent T cells and on the proportion of naïve T cells has been examined in another recent study (Spielmann et al., 2011). This showed that the proportion of senescent CD4+ and CD8+ T cells increased with advancing age at the rate of ca. 10% per decade, accompanied by a proportional reduction of CD4+ and CD8+ naïve T cells. Furthermore, it was demonstrated that participants with higher aerobic fitness possessed less senescent CD4+ and CD8+ T cells and had more naïve CD8+ T cells, than those with low aerobic fitness. This association was stable even after adjusting for age, body mass index and percentage of body fat. Very interesting and important was the finding that the association between age and the proportion of senescent cells disappeared when adjusted for scores of high aerobic fitness, demonstrating that the aerobic fitness may be a stronger determinant of phenotypic shift of T-cell

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subpopulations than the chronological age (Spielmann et al., 2011). Thus, more experimental work is required, to determine the mechanisms playing a role in enhanced immunity associated with regular exercise (Walsh et al., 2011). 9.3. Anti-inflammatory effects of physical exercise Gleeson et al. (2011) reviewed three possible mechanisms for the anti-inflammatory effects of exercise: (i) reduction of visceral fat mass, (ii) increased production and release of anti-inflammatory cytokines, so called myokines, from contracted skeletal muscles and (iii) reduced expression of TLRs on monocytes and macrophages. A reduction in the numbers of circulating proinflammatory-type monocytes and an increase in the numbers of circulating regulatory T cells has been found in the peripheral blood of individuals following exercise (Timmerman et al., 2008; Yeh et al., 2006). It is possible that chronic exercise can attenuate inflammation in adipose tissue by reducing macrophage infiltration and by phenotypic switching from pro-inflammatory M1- to anti-inflammatory M2-type macrophages (Fig. 5). Recent data suggest that contracting skeletal muscles are able to release myokines, such as IL-6, IL-8, IL-15, BDNF and others, which may act in a hormone-like fashion, generating specific endocrine effects on visceral fat or mediating direct anti-inflammatory effects. Some of them may locally influence signalling pathways involved in fat oxidation (Pedersen, 2011). During exercise an exponential rise in muscle-derived IL-6 levels takes place, which seems to be responsible for a subsequent elevation in circulating concentrations of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist, IL-1R, as well as transient increased release of cortisol (Steensberg et al., 2003). Unlike macrophage-derived IL-6, the muscle-produced IL-6 mediates anti-inflammatory functions (Pedersen, 2011). Transient increases in levels of circulating cortisol and adrenalin during exercise is dependent on activation of the HPA-axis and the sympathetic nervous system. Impulses from the motor centers in the brain together with afferent impulses from working muscles seem to evoke a rise in the sympathoadrenal activity in an intensity-dependent manner. Therefore, increases in levels of cortisol (which is a potent anti-inflammatory regulator) and adrenalin (which downregulates production of IL-1b and TNF) in plasma, are related to intensity and duration of exercise (Simpson et al., 2008). It is also known that prolonged exercise results in decreased TLR expression with a subsequent deregulation of downstream inflammatory cascades (Stewart et al., 2005). Taken together, one might conclude that physical activity, such as regular exercise, activates the release of hormones, myokines and cytokines, as well as modulating expression of various immune-reactive molecules, which all contribute to anti-inflammatory effects and possible attenuation of immunosenescence. The reduction of visceral fat mass alone already leads to a decreased production and release of pro-inflammatory adipokines from fat tissue (Fig. 5). 9.4. Caloric restriction At least in the context of adiposity and inflammation mentioned above, as well as via multiple other postulated physiological effects, caloric restriction (CR) in humans might have beneficial effects in terms of lowering metabolism, reduction of visceral fat and weight loss. CR has been shown to delay signs of immunosenescence in animals and is considered today as the only known method to prolong median as well as maximal lifespan in several tested species, from invertebrates to rodents and even including non-human primates (Arnold et al., 2011; Anderson and Weindruch, 2012). Thus, in rodents and non-human primates CR leads

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to attenuation of the age-related shift from naïve to memory-phenotype T cells and maintains a higher number of naïve T cells in aged animals (Nikolich-Zugich and Messaoudi, 2005). Furthermore, the age-associated rise of pro-inflammatory cytokines, such as IL-6, IFN-c, and TNF-a, and the resulting pro-inflammatory state of an aged immune system can be reversed by CR. It has been reported that the age-related decrease in proliferative capacity of T cells (due to the shift from naïve to memory-phenotype T cells) can be reversed by CR (Arnold et al., 2011). Applying caloric restriction in rodents resulted in 50% increases in lifespan compared to animals which have been ‘‘free-choice’’ feeded (Li et al., 2011). Nevertheless, there are still many open questions concerning CR, which has been shown to be effective at improving the immune response in unchallenged animals, although it might compromise the host’s defence against pathogenic infection and result in higher morbidity and mortality outside of the lab. Moreover, CR has been shown to delay immunosenescence in animals, but this effect needs to be verified in humans. Furthermore, short-term CR may well be feasible, whereas dietary restriction long-term might have detrimental psychological and other effects in humans, making its practicality questionable (Jolly, 2007). Nevertheless, some indirect evidence for a positive effect of prolonged caloric restriction in humans has been found in the population of Okinawa, Japan, reported to consume fewer calories than the mainland Japanese population and with a larger proportion of centenarians (Anderson and Weindruch, 2012). More extensive studies are needed, some of which are currently underway, investigating effects of the CR in humans (Rickman et al., 2011).

9.5. Other nutritional interventions and their impact on Immunosenescence Optimization of nutrition is one of the first and theoretically easiest and cheapest strategies that can be employed to preserve health during aging. The development of ‘elderly-specific’ functional foods, containing probiotics and/or prebiotics, may help in preventing the age-related disruption of the gut environment (Guigoz et al., 2008). In fact, it has been demonstrated that the maintenance of a ‘healthy’ gut microbiota during aging could help to delay or prevent the inflamm-aging process (Biagi et al., 2012). Immunostimulatory properties, such as modulation of cytokine production or adjuvant effects on T lymphocytes and NK activity, have been demonstrated for various health-promoting Lactobacillus and Bifidobacterium strains (Biagi et al., 2010; Blum et al., 2002; Meydani and Ha, 2000). It has been shown that 3- and 6week interventions in elderly people can have positive effects, such as measurable increases of NK cells, tumoricidal activity and monocyte phagocytic capacity (Takeda and Okumura, 2007). A probiotic yoghurt supplementation tested on elderly persons affected intestinal bacterial overgrowth. This intervention was able to normalize the response to endotoxin and modulate inflammatory markers in blood phagocytes (Schiffrin et al., 2010) as well as decreasing the incidence of infections in this group of elderly people. Furthermore, a significant increase of phagocytosis, NK-cell activity and production of IL-10 were also demonstrated following probiotic supplementation in the elderly, as well as reduced production of the pro-inflammatory cytokines IL-6, IL-1b and TNF-a (Guigoz et al., 2008; Vulevic et al., 2008). Boge et al. showed in two clinical trials that the consumption of a probiotic drink (containing Lactobacillus casei) by elderly subjects for several weeks before and after influenza vaccination led to a significant increase in the influenza-specific antibody titre, demonstrating the potential of probiotics in improving the protective efficacy of vaccination in the elderly population, in which it is usually considerably reduced (Boge et al., 2009; Goodwin et al., 2006).

Nutritional intervention including micronutrients and vitamins has also been recognized as a practical, cost-effective approach to attenuating age-associated declines in immune function, vaccination efficiency, and resistance to infectious and neoplastic diseases. The importance of micronutrients and vitamins in proper immune functioning is clear, and among them, zinc is an essential element the significance of which to health is undisputable, as discussed above. It is therefore important that status of zinc is assessed in any case and zinc deficiency is corrected, since the unique properties of zinc may have significant therapeutic benefits in these diseases. It has been shown that zinc supplementation enhances innate immunity by increasing phagocytosis, and T-cell functionality (Sheikh et al., 2010). Zinc supplementation was able to improve the generation of NK cells from CD34+ cell progenitors through increased expression of GATA-3 transcription factor (Muzzioli et al., 2009). It was demonstrated that addition of zinc could modulate T cell-dependent immune reactions. For example, zinc supplementation to PBMC produces T cell activation through an indirect effect that is mediated by cytokine production by other immune cells; but it has also been shown that higher concentrations of zinc can also directly suppress T cell function (Wellinghausen et al., 1997). Vitamin E supplementation has been demonstrated to improve immune responsiveness in healthy elderly individuals by enhancement of cell-mediated immunity (Meydani et al., 1990). It was also able to reverse many of the T-cell age-associated defects, including reduced levels of phosphorylation of critical signalling proteins as well as to improve defective immune synapse formation. Vitamin E also enhances IL-2 production, expression of several cell cycle control proteins, and T-cell proliferation (Molano and Meydani, 2012). Intake of vitamin E above recommended levels has been shown to enhance T cell function in aged animals and humans. This effect is believed to contribute to improved resistance to influenza infection and reduced incidence of upper respiratory infection in elderly people (Pae et al., 2012). Taken together, studies have shown that nutritional intervention with the above-mentioned supplements, as well as many others being tested, may be a promising approach to restoring at least some elements of impaired immune function and countering diminished resistance to infection with aging. However, some limitations are reviewed by Pae et al. concerning some nutritional regiments. For example, zinc deficiency, common in the elderly can be amended by zinc supplementation. However, taken in higher doses than recommended, it may adversely affect immune function. Probiotics are increasingly being demonstrated as a powerful, immune-modulating nutritional factor, but, to be effective, they require an adequate supplementation period. Moreover, their effects seem to be strain-specific and among some strains, a synergistic effect is observed. Thus, the more in-depth holistic approach is needed for determination the optimal nutritional strategies that would maintain a healthy immune system in the elderly and promote their resistance to infection and other immune-related diseases (Pae et al., 2012). Recent advances in this area suggest means of improving the outcomes of some of these approaches. A recent seminal advance has been the realization that probiotic supplementation is likely to require ‘‘tailor-made’’ mixtures of different bacteria in order to achieve the desired effect. Thus, Atarashi et al. (2013) entified 17 strains of bacteria preferentially inducing colonic regulatory T cells (Tregs) and which reduced symptoms in models of colitis and allergic diarrhea in mice. Whereas single strains or even mixtures of less than the 17 was not or not as effective as all 17 together, supplementation with tailor-made mixtures of probiotics may be effective at modulating immune responses where use of single strains is ineffective. This may be one reason why the results of the many human probiotics supplementation trials have often been equivocal, since mostly a single strain was used, even if it was the ‘‘right’’ strain. Atarashi

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et al. found that of all the bacteria in a human fecal sample, only a mixture of 17 Clostridia strains was effective at modulating immunity in germ-free mice. The mechanism of action was via the induction of CD4+ CD25+ FOXP3+ Tregs by bacterial antigens at the same time as stimulating intestinal epithelial cells to produce TGF-ß1 but not IL 6 and TNF via bacterial production of short-chain fatty acids. Fecal samples from patients with inflammatory bowel disease and atopy have been reported to contain relatively low amounts of some of the same bacterial strains, suggesting their relevance to human disease as well as in the animal model. 9.6. Impact of nutraceuticals on immune system In the context of supporting the ‘‘right’’ balance of gut bacteria, reversing our nutritional habits ‘‘back to mother Nature’’ might represent an additional solution for modulation of age-related inflammatory status and associated chronic diseases. The accumulating data from in vitro-, animal- and clinical studies provide evidence that greater consumption of fruits, cereals, vegetables, legumes and spices is associated with a lower risk of many diseases (Adzersen et al., 2003; Ames and Wakimoto, 2002; Chadalapaka et al., 2008; Kwak et al., 2010; Prasad et al., 2012; Zhang et al., 2010). Consumption of diets consisting of natural foods can also raise the amounts of plant-based nutraceuticals in the body, such as antioxidants and anti-inflammatory agents. These nutraceuticals are known to cope with free radicals and to modulate the inflammatory signalling pathways in cells suppressing the onset of age-related chronic conditions (Aggarwal and Shishodia, 2006; Prasad et al., 2012). Here, we can provide only a few examples, limited to spices and fruits and their bioactive components, known to modulate different stages of tumorigenesis, including tumor cell survival, proliferation, invasion and angiogenesis. The anticancer activities of spices are mediated primarily through suppression of inflammation. Bioactive components of spices, such as eugenol prevent the release of TNF-a and IL-b (Kim et al., 2003) (6)-gingerol blocks production of TNF-a in in vitro stimulated macrophages (Tripathi et al., 2007). Curcumin has been shown to suppress the inflammatory mediators NF-jb and COX-2 (Shishodia et al., 2003), anethole inhibits NF-jb activation and cytokine production (Chainy et al., 2000) and cinnamaldehyde blocks age-related activation of NF-jb and targets inflammatory COX-2 and induces nitric oxide synthase (Kim et al., 2007). Ursolicacid, which is present in many fruits, including apple, pear, plum, bearberry, loquat, jamun and rosemary, has been found to exert antitumor activity against colon cancer (Andersson et al., 2003), breast cancer (Es-saady et al., 1996), non-small cell lung cancer (Hsu et al., 2004), pancreatic cancer (Chadalapaka et al., 2008), melanoma (Harmand et al., 2005), multiple myeloma (Pathak et al., 2007), cervical cancer (Yim et al., 2006) and prostate cancer (Zhang et al., 2010). Also several other nutraceuticals have been shown to exert anti-inflammatory and antitumor activities. More clinical studies are needed to determine amounts of the dietary agents needed to delay aging and age-related diseases, and to investigate their effects on different age groups (Prasad et al., 2012). 9.7. Chronic stress and aged immune system External factors such as chronic psychological stress are thought to accelerate the aging process of the immune system, presumably because stress hormones are immunosuppressive. The immunological changes, normally detected during aging, are also found to be affected to a similar degree, following chronic stress or prolonged glucocorticoid exposure in younger individuals (Bauer et al., 2009). Many of the same immunosenescence-related manifestations, like decreased numbers of naïve T cells, increased

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numbers of memory and regulatory T cells, diminished cell-mediated immunity, restricted TCR-repertoire, elevated serum proinflammatory markers have been demonstrated to be present during chronic stress or/and glucocorticoid-rich conditions (Ashwell et al., 2000; Damjanovic et al., 2007; Effros et al., 2005; Elenkov and Chrousos, 1999; Franceschi et al., 2000; Globerson and Effros, 2000; Kiecolt-Glaser et al., 2003; Sauce and Appay, 2011; Trzonkowski et al., 2006; Wack et al., 1998). It is known that aging is correlated with activation of the hypothalamic–pituitary–adrenal (HPA) axis. Healthy older people have an approximately twofold higher cortisol level and reciprocally to the same extent lower dehydroepiandrosterone (DHEA) level relative to young adults (Luz et al., 2003; Bauer et al., 2009). DHEA acts as an endogenous glucocorticoid antagonist, and the lack of appropriate levels of DHEA could lead to higher cortisol/DHEA ratio, combined with the consequent deregulation of key allostatic systems in aged individuals. The HPA axis plays a critical role in the homeostasis of the immune system; therefore a neuroendocrine imbalance of the HPA axis leads to negative immunological consequences. Due to the fact that all leukocytes express receptors for the neuroendocrine molecules of the HPA sympathetic-adrenal medullary axes, it seems plausible that an increased cortisol/DHEA ratio contributes to the immunological changes observed during aging. Indeed, similar changes have also been seen during chronic psychological stress and in the course of in vitro and in vivo treatment with glucocorticoids (Butcher et al., 2005; Khanfer et al., 2011; Maninger et al., 2009). Thus, detrimental additive effects of immunosenescence along with chronic stress may accelerate organismal aging and development of stress/aging-related pathologies. Moreover, amplified neuroinflammation negatively influences several aspects of neural plasticity (e.g., neurogenesis, long-term potentiation, and dendritic morphology) that can contribute to the severity of neurological disorders, such as prolonged sickness, cognitive impairment and depressive-like complications (Corona et al., 2012). Geriatric depression often occurs in persons exposed to chronic stress – a state, which accelerates the geriatric depression and triggers pro-inflammatory processes with attendant amplified immunosenescence. Geriatric depression is known to exacerbate the symptoms of comorbid pathologies and disorders (Morimoto and Alexopoulos, 2011). Thus, the immune system and the neuroendocrine system appear to modulate each other, promoting the synthesis of pro-inflammatory cytokines, overproduction of which, in turn, negatively influences behavior. On the contrary, a positive psychological situation has been associated with better heath, involving reduced activation of neuroendocrine, as well as immune and inflammatory pathways. Positive wellbeing improved several immunological biomarkers, including not only positive changes in the numbers of the immune cells, but also their improved functionality. Increased cellular immune competence has been linked with positive affect, including stronger NK-cell cytotoxicity and increased secretory IgA responses to antigenic challenge. Positive affect has also been associated with increased numbers of helper T cells. There is also consistent evidence for the beneficial influence of positive affect on antibody titers and antibody responses to antigens, as well as on levels of such important cytokines as IL-2, IL-3, IL-6 and TNFa (Dockray and Steptoe, 2010). 9.8. Stress-reducing interventions and their influence on immunity Stress-buffering psychosocial interventions have accordingly been shown to be effective in attenuating stress and in promoting a better neuroendocrine balance in the elderly. By reducing stress levels and supporting healthy behaviors, psychosocial interventions may also reduce the rise in cortisol and attenuate the decline in DHEA, thus decreasing inflammatory effects. All these changes

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may possibly result in better immune responses (Jeckel et al., 2010). For example, following a psychological enrichment program, which was designed to counteract social isolation and passivity by increasing social activation, competence, and independence, elderly individuals showed increased levels of DHEA, testosterone, estradiol and growth hormone (Arnetz et al., 1983). Another study demonstrated that older adults who practiced relaxation techniques had reduced antibody titers to latent herpes simplex virus-1 (HSV-1). Lower viral antibody titers suggest fewer episodes of viral-reactivation, implying that this lifestyle intervention would be associated with reduced chronic antigenic stimulation (Gouin et al., 2008). Another study suggests that stressbuffering strategies can lead to an improvement in cellular immunity involved in the control of latent viruses (Bauer et al., 2013). Individuals with a positive type of personally have been found to have lower plasma cortisol levels and lower concentrations of IL6 und CRP. These reduced levels of inflammatory markers have been favourably associated with blood pressure and heart rate (Grant et al., 2009). Also, the outcome of the immune response to vaccination (even in stressed elderly) appeared to be influenced by better social support (Glaser et al., 1992). Therefore, stress management interventions and resilience factors seem to modulate different aspects of immunosenescence, most likely by modulation of neuroendocrine factors. It seems that regular exercise may play an important role also for stress-reducing purposes. Physical activity is associated with many advantageous effects on stress management, immunity, well-being and health. Regular physical activity attenuates neural responses to stress in brain circuits, which are responsible for regulating peripheral sympathetic activity, and could contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity (Dishman et al., 2006). It also has the important advantage of being non-invasive, low-cost and easy to implement (Bauer et al., 2013). For example, elderly individuals committed to a physical activity program demonstrated low levels of emotional distress (Wrosch et al., 2002) and had more moderate concentrations of salivary cortisol (Wrosch et al., 2007). Higher levels of blood NK cell activity were characteristic for individuals with a relaxed life style and healthy mental condition. Physically active behaviors would, thus, improve the quantity, as well as the quality of blood NK cells, and, in turn, improve the mental health status by restraining anxiety and avoiding depression (Boscolo et al., 2008). Moderate-intensity exercise has been reported to be associated with anti-inflammatory effects, including lowering serum TNF and IL-6 levels, and improving IL-10 and Treg counts (Simpson et al., 2008). Active lifestyle and regular exercise appear to provide protection against dementia and cognitive decline, increasing the release of growth hormone, epinephrine, cortisol, prolactin, and other factors, which have immunomodulatory effects (Handschin and Spiegelman, 2008; Pedersen, 2011). Moreover, moderate training in the elderly has been shown to improve T cell proliferation, to increase IL-2 production and expression of the IL-2 receptor on T cells, to reduce the frequency of senescent T cells, and has been associated with longer leukocyte telomeres and better in vivo immune responses to vaccines (Simpson and Guy, 2010). In addition, physical activity can improve mucosal immune responses in the elderly and has been shown to increase resistance to upper respiratory infections (Sakamoto et al., 2009). Thus, the enhanced mucosal immune response together with improved T-cell responses may build up stronger immunity to control bacterial and viral infections. However, many questions remain to be investigated, including the mechanisms which are involved in these processes, the appropriate type and dose of exercise, the potential clinical impact in dependency to this type and this particular dose, and finally,

whether the benefits of this intervention are extendable to all populations including frail, older people (Kohut and Senchina, 2004; Hong, 2011; Simpson et al., 2012). Taken together, the data obtained from different studies and interventions suggest that both immune and neuroendocrine systems are plastic and immunosenescence can be attenuated through different kinds of behavioral, psychological and nutritional interventions.

10. Conclusions A current evolutionary understanding of immunosenescence as postulated in this review is based on the consensus that the constantly remodelling immune system is most dynamic in childhood as a result of responding to and generating memory for the diversity of pathogens to which the person is most exposed in early life (in order to survive childhood and still be around in later life). The individual therefore invests heavily in expensive (and potentially dangerous) adaptive immune responses to the most prevalent pathogens. By puberty, the individual´s supply of naïve lymphocytes will have been converted into memory cells for the most important pathogens in that particular environment, increasing protection and fitness for reproduction. Further investments in generating more naïve cells, especially in the resource-intensive process of T-cell production, are no longer worthwhile and are also dangerous in terms of immune pathology and autoimmunity. This is the reason why output of lymphocytes from the bone marrow is reduced (but myeloid cells maintained or increased to facilitate sufficient innate immunity) and thymic involution occurs at puberty to greatly reduce naïve T-cell processing). In the modern world, however, most people commonly survive for much longer than in the past and may be exposed to emerging pathogens, or become exposed to new pathogens by travel. The immune system is simply not evolved to cope with these challenges. It is less remarkable that immunosenescence occurs than it is that there is so much reserve capacity in our immune systems that function may still be retained for over 100 years. The impact of behavioral variations on immune status within this ‘‘narrow window of opportunity’’ may nonetheless be great but by the nature of things cannot overcome the intrinsic programming which evolved during speciation. A prime example of how we should not generalize too much comes from our own work on exceptional survivors in the Leiden 85 + Study. Here, contrary to the generalized statement that immunosenescence is characterized by few naïve T cells, more memory cells and higher pro-inflammatory status and that this is associated with worse survival, we found the opposite: under the circumstances in which these people were living, having fewer naïve T cells and more memory cells (responding to CMV antigens in a pro-inflammatory manner) was prospectively associated with a significant 8-year survival benefit (Derhovanessian et al., 2013). This underlines the importance of considering each study population in the context of the local situation. This ‘‘local situation’’ is obviously hard to define, but certainly includes nutritional factors, pathogen exposure, stresses of multiple types, exposures to environmental pollutants, amount and type of exercise and other extremely heterogeneous factors that will be very difficult or impossible to control for in people. It is our conviction that further insight into which of these multifarious factors may be most important for assuring maintenance of appropriate immunity into late life will only be obtained by establishing large databases attempting to correlate as many of these factors as possible in human populations, and that animal models are unlikely to be particularly helpful in this respect. For example, to this end, the Berlin BASE II study is surveying 2200 Berlin residents at early middle age and older age and collating data on psychological, cognitive,

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medical, genetic, nutritional, psychosocial and immunological factors in an effort to establish baseline conditions informative for health and longevity over the lifespan (Bertram et al., 2013). Acknowledgments This work was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) under grant numbers #16SV5536K, #16SV5537, #16SV5538, and #16SV5837 and the BMBF Network ‘‘GerontoShield’’ ((BMBF Gerontoshield 0315890F), as well as the European Commission (EUFP7 IDEAL 259679) (to G.P.). LM would like to gratefully aknowlege Dr. Frank Schmidt for his competent help during the writing of the manuscript. References Adema, G.J., 2009. Dendritic cells from bench to bedside and back. Immunol. Lett. 122, 128–130. Ademokun, A., Wu, Y.C., Dunn-Walters, D., 2010. The ageing B cell population: composition and function. Biogerontology 11, 125–137. Adzersen, K.H., Jess, P., Freivogel, K.W., Gerhard, I., Bastert, G., 2003. 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