Brain, Behavior, and Immunity 39 (2014) 8–22

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Brain, Behavior, and Immunity

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Review

Aging and immunity – Impact of behavioral intervention

Ludmila Müller a,⇑, Graham Pawelec b
a
Max Planck Institute for Human Development, Lentzeallee 94, D-14195 Berlin, Germany
b
Center for Medical Research, University of Tübingen, Waldhörnlestr. 22, D-72072 Tübingen, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Immune responses to pathogens to which they were not previously exposed are commonly less effective
Available online 4 December 2013 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
Keyword: and numbers of naïve B and T cells are lower and memory cells higher in the elderly. In addition to the
Immunosenescence ‘‘extrinsic’’ effects of pathogen exposure, ‘‘intrinsic’’ events such as age-associated differences in hae-
matopoeitic 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 invo-
lution, 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 dis-
cuss 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 lev-
els 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 genet-
ics, environment, life style, nutrition and other factors (including
those still not identified). One obvious example relates to differ-
ences 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.
E-mail address: lmueller@mpib-berlin.mpg.de (L. Müller).
in sex hormone secretion patterns and their changes over the life-
span 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 environmen-
tal 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 regu-
lation of inflammatory and regulatory pathways (such as insulin/
IGF signalling and Target of Rapamycin (TOR) signalling) is not en-
tirely 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 communi-
cation between them. This affects their functional capacity, dere-
gulates 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, immunosenes-
cence, endocrinosenescence, epigenetic modifications and other

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 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
Body’s systems
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 pro-
cesses contribute to this process; nonetheless, nearly all of them
may be associated with inflammatory responses in some way (Jen-
ny, 2012).
Age-related inflammatory processes are intimately intertwined
with changes in immune function. At the same time, they are reg-
ulated 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 mor-
tality among elderly individuals (Heffner, 2011; Hawkley and
Cacioppo, 2004).
Thus, accumulating evidence shows incontrovertibly that im-
mune function changes with normal aging and independently with
increased stress; and that chronic stress deregulates multiple com-
ponents 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 pro-
cess, 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 micro-
biota (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 envi-
ronment, intestinal microbiota and all physiological processes of
the host must be taken into consideration (Biagi et al., 2012).
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9
Age-related changes
Here, we will briefly survey the cells and functions of the verte-
brate 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 im-
mune 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 dif-
ferent cell populations, are available to respond to these challenges
to bodily integrity. Recently, however, the strict distinction be-
tween these two arms of immunity, classically viewed as com-
pletely separate, has become less obvious. It has been shown that
innate immune cells can demonstrate memory characteristics un-
der 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 immunose-
nescence. Aging does not necessarily lead to unavoidable deterio-
rations 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, dys-
regulation rather than deterioration per se is likely to be the major
explanantion for immunosenescence. Nevertheless, increased sus-
ceptibility to infections and autoimmune diseases, neoplasias, met-
abolic diseases, osteoporosis and neurological disorders are all in
some way likely to be at least partly caused by immunosenescence.
10 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
Macrophage
Reduced expression
and function of TLR
Pathogens
Reduced MHC-expres-
sion and signaling
DC
Reduced chemotaxis
and phagocytosis
Decreased cytokine
production
TC
Impaired distribution
and migratory capacity
of DC
Dendritic cell
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 sci-
entific 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 ex-
ported to the periphery), thymus involution (decreasing the gener-
ation 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, epige-
netic 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 de-
cline 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 geno-
mic 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 re-
sponses into play and both arms act together to eliminate patho-
gens. 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.
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Neutrophil
Reduced chemotaxis
of neutrophils
Impaired signal
Blood vessel transduction
Monocyte
Inflammatory Decreased superoxide
proteins production
Cytokins Reduced apoptosis
Macrophage Reduced expression of
TLR and MHC
Monocyte
Ageing
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 recep-
tors 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 re-
duced (Fulop et al., 2004). Thus, impairments in these initial de-
fences 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 anti-
gen presentation (Fig. 2). Monocytes are very efficient in the elim-
ination 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 im-
mune 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 re-
ported, which can be explained by increased apoptosis and re-
duced 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 epige-
netic 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 pathogen-
associated molecules, for taking up and processing pathogen anti-
gens, and for presenting these antigens to T cells. They represent
professional antigen-presenting cells, without which adaptive
 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
Compensatory
increase in cell
numbers
Reduced per-cell
cytotoxicity
Decreased signal IL-2
transduction
Reduced response to IFN-γ
cytokines TNF-γ
Impaired cytokine and
chemokine production
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 inten-
sity of adaptive immune responses (Müller et al., 2013). This im-
plies 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 periph-
eral 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 ob-
tained from animal studies, the numbers of DCs, their distribution,
and potentially their generation and development from hemato-
poietic 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 in-
volved 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 surveil-
lance during aging. Studies on healthy elderly individuals and cen-
tenarians 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 over-
all increase in number of NK cells can be considered as a compen-
satory 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-associ-
ated 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 el-
derly people and this may contribute, among other factors, to im-
mune deficits associated with advanced age (Dewan et al., 2012).
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11
NK cell NKT cell / iNKT cell
Increase in NKT cell
numbers
Virus-infected
NKT cell
or modified cell
Decrease in
TCR frequency of iNKT
Reduced population
CD161 doubling in iNKT
ARL
IFN-γ ARL
AR TNF-γ
Impaired cytokine
production
Perforin
Granzyme
Shift in cytokine
profile: Th1 to Th2
NK cell Virus-infected
or tumour cell
Ageing
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 co-
express 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 in-
crease 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 abil-
ity 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-lympho-
cytes) act in a highly antigen-specific manner and imbue the sys-
tem with immunological memory (Medzhitov and Janeway,
1997) as well as regulating immune homeostasis. The receptors
of these lymphocytes are generated through somatic recombina-
tion 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 essen-
tially all potential pathogens. Adaptive immunity comprises a
12 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
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 environ-
ments 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 (lym-
phoid and myeloid) components, is negatively modulated and
functionally affected by aging (Geiger et al., 2013). The stromal ma-
trix 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 compart-
ment 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 poten-
tial contribute to changes in the cellular composition of the HSC
compartment. The hematopoietic stem cell pool contains a hetero-
geneous mixture of HSCs, and aging is associated with a marked
Bone marrow Pluripotent HSC
Decrease of HSC
compartment
Pre-B cell
Transformation of Pro-B cell
HSC and shift to
myeloid lineage
Decreased frequency
of pro-B cells
IgG
Altered Ig-specificity,
-isotype and -idiotype
Reduced primary and
secondary response
IgG
Ageing Memory B 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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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 predispo-
sition 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 thymosuppres-
sive cytokines, such as IL-6, oncostatin M and leukaemia inhibitory
factor (Sempowski et al., 2000) and parallel decreases in IL-7 pro-
duction, known to be important for thymopoiesis. These changes
lead to the consequent decrease in the numbers of thymic epithe-
lial 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 immunose-
nescence (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 ex-
press the T-cell receptor (TCR) on their surfaces. Chronic thymus
involution is associated with a reduced efficiency of T-cell develop-
ment and with the reduced migration of naïve T cells in the periph-
ery. 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 poten-
tially also cancer and autoimmune disease (Lynch et al., 2009).
Changes in thymus activity may also be influenced by environmen-
tal 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
Young thymus Aged thymus
Aging
Development?
Reduced active area
of thymopoiesis
DNT
Up-regulation of
DPT thymus-suppressive
cytokines
CD8+T cell
Reduced population
of naÔve T cells
IgM
Oligoclonal TCR
repertoire
CD4+T cell Aggregation of
exhausted memory
T cells
Ageing
Memory CD4+T cell Memory CD8+T cell
 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22 13

Regular physical activity

and exercise

Reduced energy intake

Adipocyte
Practice of “healthy
behaviour” - Treg cell - Acvated
T cell
- M1-Macrophage - M2-Macrophage
- pro-inflammatory adipokines - an-inflammatory adipokines

Fig. 5. Impact of behavioral intervention on immunosenescence.

childhood leads to premature onset of many of these age associ-
ated 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 trigger-
ing signals of B-cell activation for antibody production. A counter-
balancing subset of the CD4 population consists of regulatory T
cells (Treg), which exert inhibitory activities on other T cells, sup-
pressing 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 im-
mune responses by progressive reduction of the TCR repertoires in
the CD4+ and CD8+ subsets contributing to highly restricted oli-
goclonal TCR repertoire in the periphery of the elderly (Kohler
et al., 2005). This could lead to age-dependent increase in suscep-
tibility to infectious, autoimmune, malignant diseases and de-
creased efficiency of vaccination.
At the single-cell level, T cells from aged individuals demon-
strate reduced functional potency compared to cells of the same
phenotype from young individuals. This reduced functional po-
tency of T cells was shown to be restored under some conditions
by the addition of IL-15 (Liu et al., 2002). Normally, after their re-
lease 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 differentia-
tion 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 contrib-
ute 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 de-
pends 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 influ-
ence their development. These factors can alter the epigenetic pro-
file of cells, and therefore have a direct effect on gene expression
profiles and on remodelling processes. Senescent immune remod-
elling 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 (Paw-
elec 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 CMV-
driven 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 ex-
hausted 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 low-
grade inflammation (inflamm-aging) commonly observed in el-
derly people (Franceschi et al., 2007; Bennett et al., 2012). How-
ever, the hypothesis that CMV is a significant driver in
inflammaging has been challenged in a recent cohort study (Bart-
lett et al., 2012) showing that levels of pro-inflammatory and
anti-inflammatory cytokines were changing equally in CMV-sero-
positive 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 (Paw-
elec et al., 2009). The accumulation of later-stage CD8 T cells char-
acterizing 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 immunose-
nescence may also be amplified in the context of both chronologi-
cal 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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14 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
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-inflam-
matory 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). Inflam-
maging 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 sta-
tus can be associated with patho-physiological conditions. How-
ever, 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 differen-
tiate 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 long-
term immunoglobulin-producing B lymphocytes is also impaired.
The numbers of functional immunoglobulin-secreting B cells and ti-
ters of antigen-specific immunoglobulins are decreased. B-cell sub-
sets, 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 second-
ary 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 in-
side 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 func-
tion 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 men-
tal, 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 ele-
vated levels of inflammatory markers (von Kanel et al., 2006; Jen-
ny, 2012).
Frailty is a common syndrome in the elderly and is character-
ized by poor mobility, weakness and low tolerance to psychologi-
cal 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 accu-
mulation 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 sub-
stances, 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 pro-
inflammatory immune cells and induction of a low-grade inflam-
matory 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 cyto-
kines 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, neu-
rodegeneration, 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 con-
cerning the dietary supply of certain nutrients but also in terms
of their altered metabolism (Duncan and Flint, 2013). Micronutri-
ent 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
 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
disorders, autoimmune diseases, age-related degenerative dis-
eases, 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 nutri-
tion in maintaining the immune response of the aged, but they also
indicate the need for a more in-depth, holistic approach to deter-
mining the optimal nutritional strategies that would maintain a
healthy immune system in elderly people and promote their resis-
tance 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 modifi-
cations in lifestyle, in nutritional behavior, and impaired function-
ality 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 fac-
tors impact upon health in old age, including effects on immunity.
However, the relative contribution of these factors to immunose-
nescence will have to be more accurately established. These vari-
ables 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 differ-
ent chronic infections. It will be necessary to build up a solid evi-
dence 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 develop-
ing 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 fol-
low-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 pre-
vent, improve or even reverse age-related impairments in immune
function, continues to accumulate. Lifestyle factors, such as exer-
cise 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 exer-
cises, have been proposed to restore immune function in elderly
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15
people. Some studies have shown that moderate exercise training
(5 days a week for 6 months) can improve Th-cell mediated im-
mune 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 resis-
tance 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 re-
sponses 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 im-
mune responsiveness to influenza vaccination in older adults.
Exercise-related increased antibody titre, T-cell function, macro-
phage 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 signifi-
cant increase in seroprotection 24 weeks after vaccination, provid-
ing 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 power-
ful 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 accu-
mulation of late-stage, possibly terminally differentiated T cells, of
which at least some may be truly senescent (mostly as a conse-
quence of persistent viral infection), coupled with greatly reduced
or absent entry of naïve T cells into the periphery (as a conse-
quence of thymic atrophy). This leads to a drastically shrinking
naïve T-cell repertoire. However, beneficial effects of the manipu-
lation 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 under-
stood (Simpson and Guy, 2010).
It has been suggested that habitual physical exercise can bene-
ficially modulate immunosenescence in two ways: first, by a pre-
ventive 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 abil-
ity 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 circulat-
ing lymphocyte numbers, with their rapid mobilization into the
blood at the beginning of exercise (lymphocytosis) and falling be-
low the resting values during the early phase of exercise recovery
16 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
(lymphocytopenia) (Simpson et al., 2008; Turner et al., 2010). By
mechanisms not very well understood, in particular the lympho-
cytes 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 subpopu-
lation of lymphocytes has been demonstrated to egress from the
circulation during exercise recovery (Simpson et al., 2008). Fur-
thermore, it was shown that in CMV-seropositive young individu-
als, mobilization and subsequent egress of total CD8+ lymphocytes
was nearly twice as great as in CMV-seronegative subjects, indicat-
ing that exercise may induce the mobilization of viral-specific CD8+
T cells (Turner et al., 2010). The same type of senescent and effec-
tor memory cells are believed to overcrowd the immune space dur-
ing aging and persistent CMV-infection. Therefore, it was
postulated that mobilization of senescent viral-specific T-cells to-
gether 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 sensi-
tive 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 express-
ing CD28, CD62L, or CD11a least susceptible (Wang and Lin,
2010). The subpopulation of CD45RA/CCR7-negative effector mem-
ory T cells has been demonstrated to be more sensitive to H2O2-in-
duced 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 exer-
cise-induced apoptosis is a systemic phenomenon and is not lim-
ited 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. Inter-
leukin-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 (Simp-
son 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. Further-
more, 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 in-
dex 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-inflamma-
tory cytokines, so called myokines, from contracted skeletal mus-
cles and (iii) reduced expression of TLRs on monocytes and
macrophages. A reduction in the numbers of circulating pro-
inflammatory-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 infiltra-
tion and by phenotypic switching from pro-inflammatory M1- to
anti-inflammatory M2-type macrophages (Fig. 5). Recent data sug-
gest 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 hor-
mone-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 lev-
els 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 tran-
sient 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 ner-
vous system. Impulses from the motor centers in the brain to-
gether with afferent impulses from working muscles seem to
evoke a rise in the sympathoadrenal activity in an intensity-depen-
dent manner. Therefore, increases in levels of cortisol (which is a
potent anti-inflammatory regulator) and adrenalin (which down-
regulates 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 cas-
cades (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 im-
mune-reactive molecules, which all contribute to anti-inflamma-
tory 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 ef-
fects, caloric restriction (CR) in humans might have beneficial ef-
fects in terms of lowering metabolism, reduction of visceral fat
and weight loss. CR has been shown to delay signs of immunose-
nescence 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 Weind-
ruch, 2012). Thus, in rodents and non-human primates CR leads
 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
to attenuation of the age-related shift from naïve to memory-phe-
notype T cells and maintains a higher number of naïve T cells in
aged animals (Nikolich-Zugich and Messaoudi, 2005). Further-
more, 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 re-
ported 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 restric-
tion 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 re-
sponse 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 hu-
mans 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’ func-
tional foods, containing probiotics and/or prebiotics, may help in
preventing the age-related disruption of the gut environment (Gui-
goz et al., 2008). In fact, it has been demonstrated that the mainte-
nance 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 Lactobacil-
lus and Bifidobacterium strains (Biagi et al., 2010; Blum et al.,
2002; Meydani and Ha, 2000). It has been shown that 3- and 6-
week 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 pro-
biotic yoghurt supplementation tested on elderly persons affected
intestinal bacterial overgrowth. This intervention was able to nor-
malize 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 peo-
ple. 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 pro-
duction 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 (con-
taining Lactobacillus casei) by elderly subjects for several weeks be-
fore 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 re-
duced (Boge et al., 2009; Goodwin et al., 2006).
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17
Nutritional intervention including micronutrients and vitamins
has also been recognized as a practical, cost-effective approach to
attenuating age-associated declines in immune function, vaccina-
tion 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 proper-
ties of zinc may have significant therapeutic benefits in these dis-
eases. It has been shown that zinc supplementation enhances
innate immunity by increasing phagocytosis, and T-cell functional-
ity (Sheikh et al., 2010). Zinc supplementation was able to improve
the generation of NK cells from CD34+ cell progenitors through in-
creased 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 supplementa-
tion 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 enhance-
ment 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 con-
trol 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 infec-
tion and reduced incidence of upper respiratory infection in elderly
people (Pae et al., 2012).
Taken together, studies have shown that nutritional interven-
tion with the above-mentioned supplements, as well as many oth-
ers 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 lim-
itations are reviewed by Pae et al. concerning some nutritional reg-
iments. 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. Pro-
biotics are increasingly being demonstrated as a powerful, im-
mune-modulating nutritional factor, but, to be effective, they
require an adequate supplementation period. Moreover, their ef-
fects seem to be strain-specific and among some strains, a syner-
gistic effect is observed. Thus, the more in-depth holistic
approach is needed for determination the optimal nutritional strat-
egies that would maintain a healthy immune system in the elderly
and promote their resistance to infection and other immune-re-
lated diseases (Pae et al., 2012). Recent advances in this area sug-
gest 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’’ mix-
tures of different bacteria in order to achieve the desired effect.
Thus, Atarashi et al. (2013) entified 17 strains of bacteria preferen-
tially 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 tai-
lor-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
18 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
et al. found that of all the bacteria in a human fecal sample, only a
mixture of 17 Clostridia strains was effective at modulating immu-
nity in germ-free mice. The mechanism of action was via the induc-
tion 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 dis-
ease and atopy have been reported to contain relatively low
amounts of some of the same bacterial strains, suggesting their rel-
evance 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 accumu-
lating data from in vitro-, animal- and clinical studies provide evi-
dence 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 nutraceuti-
cals 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 differ-
ent stages of tumorigenesis, including tumor cell survival, prolifer-
ation, invasion and angiogenesis. The anticancer activities of spices
are mediated primarily through suppression of inflammation. Bio-
active 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 cinna-
maldehyde 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 die-
tary 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, pre-
sumably 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 (Bau-
er et al., 2009). Many of the same immunosenescence-related man-
ifestations, like decreased numbers of naïve T cells, increased
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For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
numbers of memory and regulatory T cells, diminished cell-medi-
ated immunity, restricted TCR-repertoire, elevated serum pro-
inflammatory markers have been demonstrated to be present dur-
ing 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; Trzon-
kowski et al., 2006; Wack et al., 1998).
It is known that aging is correlated with activation of the hypo-
thalamic–pituitary–adrenal (HPA) axis. Healthy older people have
an approximately twofold higher cortisol level and reciprocally to
the same extent lower dehydroepiandrosterone (DHEA) level rela-
tive to young adults (Luz et al., 2003; Bauer et al., 2009). DHEA acts
as an endogenous glucocorticoid antagonist, and the lack of appro-
priate levels of DHEA could lead to higher cortisol/DHEA ratio,
combined with the consequent deregulation of key allostatic sys-
tems 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 conse-
quences. 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 treat-
ment 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 pathol-
ogies. Moreover, amplified neuroinflammation negatively influ-
ences several aspects of neural plasticity (e.g., neurogenesis,
long-term potentiation, and dendritic morphology) that can con-
tribute 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 atten-
dant 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, pro-
moting the synthesis of pro-inflammatory cytokines, overproduc-
tion 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 impor-
tant 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 interven-
tions may also reduce the rise in cortisol and attenuate the decline
in DHEA, thus decreasing inflammatory effects. All these changes
 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
may possibly result in better immune responses (Jeckel et al.,
2010). For example, following a psychological enrichment pro-
gram, which was designed to counteract social isolation and pas-
sivity 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 interven-
tion would be associated with reduced chronic antigenic stimula-
tion (Gouin et al., 2008). Another study suggests that stress-
buffering strategies can lead to an improvement in cellular immu-
nity 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 IL-
6 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 man-
agement interventions and resilience factors seem to modulate dif-
ferent 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 reg-
ulating 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 dem-
onstrated 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 character-
istic 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, im-
prove 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 pro-
tection against dementia and cognitive decline, increasing the re-
lease of growth hormone, epinephrine, cortisol, prolactin, and
other factors, which have immunomodulatory effects (Handschin
and Spiegelman, 2008; Pedersen, 2011). Moreover, moderate train-
ing 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 im-
mune responses to vaccines (Simpson and Guy, 2010). In addition,
physical activity can improve mucosal immune responses in the el-
derly and has been shown to increase resistance to upper respira-
tory 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 infec-
tions. However, many questions remain to be investigated, includ-
ing 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,
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For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
19
whether the benefits of this intervention are extendable to all pop-
ulations 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 sys-
tems 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 con-
stantly remodelling immune system is most dynamic in childhood
as a result of responding to and generating memory for the diver-
sity 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 individuaĺs supply of naïve lympho-
cytes 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 pub-
erty 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 be-
come exposed to new pathogens by travel. The immune system is
simply not evolved to cope with these challenges. It is less remark-
able 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 immu-
nosenescence 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 circum-
stances 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 popula-
tion 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 envi-
ronmental pollutants, amount and type of exercise and other ex-
tremely 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 hu-
man populations, and that animal models are unlikely to be partic-
ularly 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,
20 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22

medical, genetic, nutritional, psychosocial and immunological fac- Boge, T., Remigy, M., Vaudaine, S., Tanguy, J., Bourdet-Sicard, R., van der Werf, S.,
2009. A probiotic fermented dairy drink improves antibody response to
tors in an effort to establish baseline conditions informative for
influenza vaccination in the elderly in two randomised controlled trials.
health and longevity over the lifespan (Bertram et al., 2013). Vaccine 27, 5677–5684.
Bonilla, F.A., Oettgen, H.C., 2010. Adaptive immunity. J. Allergy Clin. Immunol. 125,
S33–S40.
Acknowledgments Boscolo, P., Youinou, P., Theoharides, T.C., Cerulli, G., Conti, P., 2008. Environmental
and occupational stress and autoimmunity. Autoimmun. Rev. 7, 340–343.
This work was supported by the German Federal Ministry of Butcher, S.K., Killampalli, V., Lascelles, D., Wang, K., Alpar, E.K., Lord, J.M., 2005.
Raised cortisol:DHEAS ratios in the elderly after injury: potential impact upon
Education and Research (Bundesministerium für Bildung und Fors- neutrophil function and immunity. Aging Cell 4, 319–324.
chung, BMBF) under grant numbers #16SV5536K, #16SV5537, Calvanese, V., Lara, E., Kahn, A., Fraga, M.F., 2009. The role of epigenetics in aging
#16SV5538, and #16SV5837 and the BMBF Network ‘‘Geronto- and age-related diseases. Ageing Res. Rev. 8, 268–276.
Campbell, J.P., Riddell, N.E., Burns, V.E., Turner, M., van Zanten, J.J., Drayson, M.T.,
Shield’’ ((BMBF Gerontoshield 0315890F), as well as the European
Bosch, J.A., 2009. Acute exercise mobilises CD8+ T lymphocytes exhibiting an
Commission (EUFP7 IDEAL 259679) (to G.P.). LM would like to effector-memory phenotype. Brain Behav. Immun. 23, 767–775.
gratefully aknowlege Dr. Frank Schmidt for his competent help Chadalapaka, G., Jutooru, I., McAlees, A., Stefanac, T., Safe, S., 2008. Structure-
during the writing of the manuscript. dependent inhibition of bladder and pancreatic cancer cell growth by 2-
substituted glycyrrhetinic and ursolic acid derivatives. Bioorg. Med. Chem. Lett.
18, 2633–2639.
References Chainy, G.B., Manna, S.K., Chaturvedi, M.M., Aggarwal, B.B., 2000. Anethole blocks
both early and late cellular responses transduced by tumor necrosis factor:
effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis. Oncogene 19, 2943–
Adema, G.J., 2009. Dendritic cells from bench to bedside and back. Immunol. Lett.
2950.
122, 128–130.
Chang, S.S., Weiss, C.O., Xue, Q.L., Fried, L.P., 2012. Association between
Ademokun, A., Wu, Y.C., Dunn-Walters, D., 2010. The ageing B cell population:
inflammatory-related disease burden and frailty: results from the Women’s
composition and function. Biogerontology 11, 125–137.
Health and Aging Studies (WHAS) I and II. Arch. Gerontol. Geriatr. 54, 9–15.
Adzersen, K.H., Jess, P., Freivogel, K.W., Gerhard, I., Bastert, G., 2003. Raw and cooked
Chasapis, C.T., Loutsidou, A.C., Spiliopoulou, C.A., Stefanidou, M.E., 2012. Zinc and
vegetables, fruits, selected micronutrients, and breast cancer risk: a case-
human health: an update. Arch. Toxicol 86, 521–534.
control study in Germany. Nutr. Cancer 46, 131–137.
Colonna-Romano, G., Bulati, M., Aquino, A., Vitello, S., Lio, D., Candore, G., Caruso, C.,
Aggarwal, B.B., Shishodia, S., 2006. Molecular targets of dietary agents for
2008. B cell immunosenescence in the elderly and in centenarians.
prevention and therapy of cancer. Biochem. Pharmacol. 71, 1397–1421.
Rejuvenation Res. 11, 433–439.
Ames, B.N., Wakimoto, P., 2002. Are vitamin and mineral deficiencies a major cancer
Compston, J.E., 2002. Bone marrow and bone: a functional unit. J. Endocrinol. 173,
risk? Nat. Rev. Cancer 2, 694–704.
387–394.
Anderson, R.M., Weindruch, R., 2012. The caloric restriction paradigm: implications
Cooper, M.D., 2010. 99th Dahlem conference on infection, inflammation and chronic
for healthy human aging. Am. J. Hum. Biol. 24, 101–106.
inflammatory disorders: evolution of adaptive immunity in vertebrates. Clin.
Andersson, D., Liu, J.J., Nilsson, A., Duan, R.D., 2003. Ursolic acid inhibits
Exp. Immunol. 160, 58–61.
proliferation and stimulates apoptosis in HT29 cells following activation of
Corona, A.W., Fenn, A.M., Godbout, J.P., 2012. Cognitive and behavioral
alkaline sphingomyelinase. Anticancer Res. 23, 3317–3322.
consequences of impaired immunoregulation in aging. J. Neuroimmun.
Appay, V., Sauce, D., Prelog, M., 2010. The role of the thymus in immunosenescence.
Pharmacol. 7, 7–23.
lessons from the study of thymectomized individuals. Aging (Albany NY) 2, 78–
Damjanovic, A.K., Yang, Y., Glaser, R., Kiecolt-Glaser, J.K., Nguyen, H., Laskowski, B.,
81.
Zou, Y., Beversdorf, D.Q., Weng, N.P., 2007. Accelerated telomere erosion is
Arnetz, B.B., Theorell, T., Levi, L., Kallner, A., Eneroth, P., 1983. An experimental
associated with a declining immune function of caregivers of Alzheimer’s
study of social isolation of elderly people: psychoendocrine and metabolic
disease patients. J. Immunol. 179, 4249–4254.
effects. Psychosom. Med. 45, 395–406.
Deeks, S.G., Verdin, E., McCune, J.M., 2012. Immunosenescence and HIV. Curr. Opin.
Arnold, C.R., Wolf, J., Brunner, S., Herndler-Brandstetter, D., Grubeck-Loebenstein, B.,
Immunol. 24, 501–506.
2011. Gain and loss of T cell subsets in old age–age-related reshaping of the T
Delarosa, O., Tarazona, R., Casado, J.G., Alonso, C., Ostos, B., Pena, J., Solana, R., 2002.
cell repertoire. J. Clin. Immunol. 31, 137–146.
Valpha24+ NKT cells are decreased in elderly humans. Exp. Gerontol. 37, 213–
Ashwell, J.D., Lu, F.W., Vacchio, M.S., 2000. Glucocorticoids in T cell development
217.
and function⁄. Annu. Rev. Immunol. 18, 309–345.
Della bella, S., Bierti, L., Presicce, P., Arienti, R., Valenti, M., Saresella, M., Vergani, C.,
Aspinall, R., Pitts, D., Lapenna, A., Mitchell, W., 2010. Immunity in the elderly: the
Villa, M.L., 2007. Peripheral blood dendritic cells and monocytes are differently
role of the thymus. J. Comp. Pathol. 142 (Suppl 1), S111–S115.
regulated in the elderly. Clin. Immunol. 122, 220–228.
Atarashi, K., Tanoue, T., Oshima, K., Suda, W., Nagano, Y., Nishikawa, H., Fukuda, S.,
Derhovanessian, E., Maier, A.B., Hahnel, K., Beck, R., de Craen, A.J., Slagboom, E.P.,
Saito, T., Narushima, S., Hase, K., Kim, S., Fritz, J.V., Wilmes, P., Ueha, S.,
Westendorp, R.G., Pawelec, G., 2011. Infection with cytomegalovirus but not
Matsushima, K., Ohno, H., Olle, B., Sakaguchi, S., Taniguchi, T., Morita, H.,
herpes simplex virus induces the accumulation of late-differentiated CD4+ and
Hattori, M., Honda, K., 2013. Treg induction by a rationally selected mixture of
CD8+ T-cells in humans. J. Gen. Virol. 92, 2746–2756.
Clostridia strains from the human microbiota. Nature 500, 232–236.
Derhovanessian, E., Solana, R., Larbi, A., Pawelec, G., 2008. Immunity, ageing and
Bartlett, D.B., Firth, C.M., Phillips, A.C., Moss, P., Baylis, D., Syddall, H., Sayer, A.A.,
cancer. Immun. Ageing 5, 11.
Cooper, C., Lord, J.M., 2012. The age-related increase in low-grade systemic
Derhovanessian, E., Theeten, H., Hahnel, K., van Damme, P., Cools, N., Pawelec, G.,
inflammation (Inflammaging) is not driven by cytomegalovirus infection. Aging
2013. Cytomegalovirus-associated accumulation of late-differentiated CD4 T-
Cell 11, 912–915.
cells correlates with poor humoral response to influenza vaccination. Vaccine
Bauer, M.E., 2005. Stress, glucocorticoids and ageing of the immune system. Stress
31, 685–690.
8, 69–83.
Dewan, S.K., Zheng, S.B., Xia, S.J., Bill, K., 2012. Senescent remodeling of the immune
Bauer, M.E., Jeckel, C.M., Luz, C., 2009. The role of stress factors during aging of the
system and its contribution to the predisposition of the elderly to infections.
immune system. Ann. N. Y. Acad. Sci. 1153, 139–152.
Chin. Med. J. (Engl.) 125, 3325–3331.
Bauer, M.E., Muller, G.C., Correa, B.L., Vianna, P., Turner, J.E., Bosch, J.A., 2013.
Dishman, R.K., Berthoud, H.R., Booth, F.W., Cotman, C.W., Edgerton, V.R., Fleshner,
Psychoneuroendocrine interventions aimed at attenuating immunosenescence.
M.R., Gandevia, S.C., Gomez-Pinilla, F., Greenwood, B.N., Hillman, C.H., Kramer,
a review. Biogerontology 14, 9–20.
A.F., Levin, B.E., Moran, T.H., Russo-Neustadt, A.A., Salamone, J.D., van
Beerman, I., Bhattacharya, D., Zandi, S., Sigvardsson, M., Weissman, I.L., Bryder, D.,
Hoomissen, J.D., Wade, C.E., York, D.A., Zigmond, M.J., 2006. Neurobiology of
Rossi, D.J., 2010. Functionally distinct hematopoietic stem cells modulate
exercise. Obesity (Silver Spring) 14, 345–356.
hematopoietic lineage potential during aging by a mechanism of clonal
Dock, J.N., Effros, R.B., 2011. Role of CD8 T Cell Replicative Senescence in Human
expansion. Proc. Natl. Acad. Sci. U.S.A. 107, 5465–5470.
Aging and in HIV-mediated Immunosenescence. Aging Dis. 2, 382–397.
Bennett, J.M., Glaser, R., Malarkey, W.B., Beversdorf, D.Q., Peng, J., Kiecolt-Glaser,
Dockray, S., Steptoe, A., 2010. Positive affect and psychobiological processes.
J.K., 2012. Inflammation and reactivation of latent herpesviruses in older adults.
Neurosci. Biobehav. Rev. 35, 69–75.
Brain Behav. Immun. 26, 739–746.
Duncan, S.H., Flint, H.J., 2013. Probiotics and prebiotics and health in ageing
Bertram, L., Bockenhoff, A., Demuth, I., Duzel, S., Eckardt, R., Li, S.C., Lindenberger, U.,
populations. Maturitas 75, 44–50.
Pawelec, G., Siedler, T., Wagner, G.G., Steinhagen-Thiessen, E., 2013. Cohort
Dykstra, B., de Haan, G., 2008. Hematopoietic stem cell aging and self-renewal. Cell
Profile: The Berlin Aging Study II (BASE-II). Int. J. Epidemiol. [Epub ahead of
Tissue Res. 331, 91–101.
print].
Effros, R.B., Dagarag, M., Spaulding, C., Man, J., 2005. The role of CD8+ T-cell
Biagi, E., Candela, M., Fairweather-Tait, S., Franceschi, C., Brigidi, P., 2012. Aging of
replicative senescence in human aging. Immunol. Rev. 205, 147–157.
the human metaorganism: the microbial counterpart. Age (Dordr) 34, 247–267.
Elenkov, I.J., Chrousos, G.P., 1999. Stress hormones, Th1/Th2 patterns, pro/anti-
Biagi, E., Nylund, L., Candela, M., Ostan, R., Bucci, L., Pini, E., Nikkila, J., Monti, D.,
inflammatory cytokines and susceptibility to disease. Trends Endocrinol. Metab.
Satokari, R., Franceschi, C., Brigidi, P., de Vos, W., 2010. Through ageing, and
10, 359–368.
beyond: gut microbiota and inflammatory status in seniors and centenarians.
Es-Saady, D., Simon, A., Ollier, M., Maurizis, J.C., Chulia, A.J., Delage, C., 1996.
PLoS One 5, e10667.
Inhibitory effect of ursolic acid on B16 proliferation through cell cycle arrest.
Blum, S., Haller, D., Pfeifer, A., Schiffrin, E.J., 2002. Probiotics and immune response.
Cancer Lett. 106, 193–197.
Clin. Rev. Allergy Immunol. 22, 287–309.

Downloaded for dr laqif abdurrahman (laqif.abdurrahman@gmail.com) at Universitas Indonesia from ClinicalKey.com by Elsevier on May 20, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
Fernandez-Morera, J.L., Calvanese, V., Rodriguez-Rodero, S., Menendez-Torre, E.,
Fraga, M.F., 2010. Epigenetic regulation of the immune system in health and
disease. Tissue Antigens 76, 431–439.
Ferrando-Martinez, S., Ruiz-Mateos, E., Hernandez, A., Gutierrez, E., Rodriguez-
Mendez Mdel, M., Ordonez, A., leal, M., 2011. Age-related deregulation of naive
T cell homeostasis in elderly humans. Age (Dordr) 33, 197–207.
Ford, E.S., Bergmann, M.M., Kroger, J., Schienkiewitz, A., Weikert, C., Boeing, H.,
2009. Healthy living is the best revenge: findings from the European
Prospective Investigation Into Cancer and Nutrition-Potsdam study. Arch.
Intern. Med. 169, 1355–1362.
Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., de Luca, M., Ottaviani, E., de
Benedictis, G., 2000. Inflamm-aging. An evolutionary perspective on
immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254.
Franceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panourgia, M.P.,
Invidia, L., Celani, L., Scurti, M., Cevenini, E., Castellani, G.C., Salvioli, S., 2007.
Inflammaging and anti-inflammaging: a systemic perspective on aging
and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–
105.
Fuente Mde, L., Cruces, J., Hernandez, O., Ortega, E., 2011. Strategies to improve the
functions and redox state of the immune system in aged subjects. Curr. Pharm.
Des. 17, 3966–3993.
Fulop, T., Larbi, A., Douziech, N., Fortin, C., Guerard, K.P., Lesur, O., Khalil, A., Dupuis,
G., 2004. Signal transduction and functional changes in neutrophils with aging.
Aging Cell 3, 217–226.
Geiger, H., de Haan, G., Florian, M.C., 2013. The ageing haematopoietic stem cell
compartment. Nat. Rev. Immunol. 13, 376–389.
Glaser, R., Kiecolt-Glaser, J.K., Bonneau, R.H., Malarkey, W., Kennedy, S., Hughes, J.,
1992. Stress-induced modulation of the immune response to recombinant
hepatitis B vaccine. Psychosom. Med. 54, 22–29.
Gleeson, M., Bishop, N.C., Stensel, D.J., Lindley, M.R., Mastana, S.S., Nimmo, M.A.,
2011. The anti-inflammatory effects of exercise: mechanisms and implications
for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615.
Globerson, A., Effros, R.B., 2000. Ageing of lymphocytes and lymphocytes in the
aged. Immunol. Today 21, 515–521.
Gonzalo, S., 2010. Epigenetic alterations in aging. J. Appl. Physiol. 109, 586–597.
Goodwin, K., Viboud, C., Simonsen, L., 2006. Antibody response to influenza
vaccination in the elderly: a quantitative review. Vaccine 24, 1159–1169.
Gouin, J.P., Hantsoo, L., Kiecolt-Glaser, J.K., 2008. Immune dysregulation and chronic
stress among older adults: a review. Neuroimmunomodulation 15, 251–259.
Grant, N., Hamer, M., Steptoe, A., 2009. Social isolation and stress-related
cardiovascular, lipid, and cortisol responses. Ann. Behav. Med. 37, 29–37.
Gruver, A.L., Hudson, L.L., Sempowski, G.D., 2007. Immunosenescence of ageing. J.
Pathol. 211, 144–156.
Gui, J., Mustachio, L.M., Su, D.M., Craig, R.W., 2012. Thymus size and age-related
thymic involution: early programming, sexual dimorphism, progenitors and
stroma. Aging Dis. 3, 280–290.
Guigoz, Y., Dore, J., Schiffrin, E.J., 2008. The inflammatory status of old age can be
nurtured from the intestinal environment. Curr. Opin. Clin. Nutr. Metab. Care
11, 13–20.
Hajat, A., Diez-Roux, A., Franklin, T.G., Seeman, T., Shrager, S., Ranjit, N., Castro, C.,
Watson, K., Sanchez, B., Kirschbaum, C., 2010. Socioeconomic and race/ethnic
differences in daily salivary cortisol profiles: the multi-ethnic study of
atherosclerosis. Psychoneuroendocrinology 35, 932–943.
Handschin, C., Spiegelman, B.M., 2008. The role of exercise and PGC1alpha in
inflammation and chronic disease. Nature 454, 463–469.
Harmand, P.O., Duval, R., Delage, C., Simon, A., 2005. Ursolic acid induces apoptosis
through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu
melanoma cells. Int. J. Cancer 114, 1–11.
Haugen, F., Norheim, F., Lian, H., Wensaas, A.J., Dueland, S., Berg, O., Funderud, A.,
Skalhegg, B.S., Raastad, T., Drevon, C.A., 2010. IL-7 is expressed and secreted by
human skeletal muscle cells. Am J Physiol Cell Physiol 298, C807–C816.
Hawkley, L.C., Cacioppo, J.T., 2004. Stress and the aging immune system. Brain
Behav. Immun. 18, 114–119.
Hazeldine, J., Hampson, P., Lord, J.M., 2012. Reduced release and binding of perforin
at the immunological synapse underlies the age-related decline in natural killer
cell cytotoxicity. Aging Cell 11, 751–759.
Heffner, K.L., 2011. Neuroendocrine effects of stress on immunity in the elderly:
implications for inflammatory disease. Immunol. Allergy Clin. North Am. 31,
95–108.
Hong, S., 2011. Can we jog our way to a younger-looking immune system? Brain
Behav. Immun. 25, 1519–1520.
Hsu, Y.L., Kuo, P.L., Lin, C.C., 2004. Proliferative inhibition, cell-cycle dysregulation,
and induction of apoptosis by ursolic acid in human non-small cell lung cancer
A549 cells. Life Sci. 75, 2303–2316.
Jeckel, C.M., Lopes, R.P., Berleze, M.C., Luz, C., Feix, L., Argimon, I.I., Stein, L.M., Bauer,
M.E., 2010. Neuroendocrine and immunological correlates of chronic stress in
‘strictly healthy’ populations. Neuroimmunomodulation 17, 9–18.
Jenny, N.S., 2012. Inflammation in aging: cause, effect, or both? Discov. Med. 13,
451–460.
Jolly, C.A., 2007. Is dietary restriction beneficial for human health, such as for
immune function? Curr. Opin. Lipidol. 18, 53–57.
Keller, R., 1993. The macrophage response to infectious agents: mechanisms of
macrophage activation and tumour cell killing. Res. Immunol. 144, 271–273,
discussion 294-8.
Khanfer, R., Lord, J.M., Phillips, A.C., 2011. Neutrophil function and cortisol:DHEAS
ratio in bereaved older adults. Brain Behav. Immun. 25, 1182–1186.
Downloaded for dr laqif abdurrahman (laqif.abdurrahman@gmail.com) at Universitas Indonesia from ClinicalKey.com by Elsevier on May 20, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
21
Kiecolt-Glaser, J.K., Preacher, K.J., Maccallum, R.C., Atkinson, C., Malarkey, W.B.,
Glaser, R., 2003. Chronic stress and age-related increases in the
proinflammatory cytokine IL-6. Proc. Natl. Acad. Sci. U.S.A. 100, 9090–9095.
Kim, D.H., Kim, C.H., Kim, M.S., Kim, J.Y., Jung, K.J., Chung, J.H., An, W.G., Lee, J.W., Yu,
B.P., Chung, H.Y., 2007. Suppression of age-related inflammatory NF-kappaB
activation by cinnamaldehyde. Biogerontology 8, 545–554.
Kim, S.S., Oh, O.J., Min, H.Y., Park, E.J., Kim, Y., Park, H.J., Nam Han, Y., Lee, S.K., 2003.
Eugenol suppresses cyclooxygenase-2 expression in lipopolysaccharide-
stimulated mouse macrophage RAW264.7 cells. Life Sci. 73, 337–348.
Kohler, S., Wagner, U., Pierer, M., Kimmig, S., Oppmann, B., Mowes, B., Julke, K.,
Romagnani, C., Thiel, A., 2005. Post-thymic in vivo proliferation of naive CD4+ T
cells constrains the TCR repertoire in healthy human adults. Eur. J. Immunol. 35,
1987–1994.
Kohut, M.L., Cooper, M.M., Nickolaus, M.S., Russell, D.R., Cunnick, J.E., 2002. Exercise
and psychosocial factors modulate immunity to influenza vaccine in elderly
individuals. J. Gerontol. A Biol. Sci. Med. Sci. 57, M557–M562.
Kohut, M.L., Senchina, D.S., 2004. Reversing age-associated immunosenescence via
exercise. Exerc. Immunol. Rev. 10, 6–41.
Kruger, K., Frost, S., Most, E., Volker, K., Pallauf, J., Mooren, F.C., 2009. Exercise affects
tissue lymphocyte apoptosis via redox-sensitive and Fas-dependent signaling
pathways. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1518–R1527.
Kwak, J.H., Lee, J.H., Ahn, C.W., Park, S.H., Shim, S.T., Song, Y.D., Han, E.N., Lee, K.H.,
Chae, J.S., 2010. Black soy peptide supplementation improves glucose control in
subjects with prediabetes and newly diagnosed type 2 diabetes mellitus. J. Med.
Food 13, 1307–1312.
Lang, P.O., Govind, S., Aspinall, R., 2013. Reversing T cell immunosenescence. why,
who, and how. Age (Dordr) 35, 609–620.
Lanier, L.L., Sun, J.C., 2009. Do the terms innate and adaptive immunity create
conceptual barriers? Nat. Rev. Immunol. 9, 302–303.
Larbi, A., Franceschi, C., Mazzatti, D., Solana, R., Wikby, A., Pawelec, G., 2008. Aging
of the immune system as a prognostic factor for human longevity. Physiology
(Bethesda) 23, 64–74.
Larbi, A., Pawelec, G., Wong, S.C., Goldeck, D., Tai, J.J., Fulop, T., 2011. Impact of age
on T cell signaling: a general defect or specific alterations? Ageing Res. Rev. 10,
370–378.
Li, Y., Daniel, M., Tollefsbol, T.O., 2011. Epigenetic regulation of caloric restriction in
aging. BMC. Med. 9, 98.
Liu, K., Catalfamo, M., Li, Y., Henkart, P.A., Weng, N.P., 2002. IL-15 mimics T cell
receptor crosslinking in the induction of cellular proliferation, gene expression,
and cytotoxicity in CD8+ memory T cells. Proc. Natl. Acad. Sci. U.S.A. 99, 6192–
6197.
Luz, C., Dornelles, F., Preissler, T., Collaziol, D., da Cruz, I.M., Bauer, M.E., 2003.
Impact of psychological and endocrine factors on cytokine production of
healthy elderly people. Mech. Ageing Dev. 124, 887–895.
Lynch, H.E., Goldberg, G.L., Chidgey, A., van den Brink, M.R., Boyd, R., Sempowski,
G.D., 2009. Thymic involution and immune reconstitution. Trends Immunol. 30,
366–373.
Mahbub, S., Brubaker, A.L., Kovacs, E.J., 2011. Aging of the innate immune system:
an update. Curr. Immunol. Rev. 7, 104–115.
Maninger, N., Wolkowitz, O.M., Reus, V.I., Epel, E.S., Mellon, S.H., 2009.
Neurobiological and neuropsychiatric effects of dehydroepiandrosterone
(DHEA) and DHEA sulfate (DHEAS). Front. Neuroendocrinol. 30, 65–91.
Medzhitov, R., Janeway Jr., C.A., 1997. Innate immunity: the virtues of a nonclonal
system of recognition. Cell 91, 295–298.
Meydani, S.N., Barklund, M.P., Liu, S., Meydani, M., Miller, R.A., Cannon, J.G., Morrow,
F.D., Rocklin, R., Blumberg, J.B., 1990. Vitamin E supplementation enhances cell-
mediated immunity in healthy elderly subjects. Am. J. Clin. Nutr. 52, 557–563.
Meydani, S.N., Ha, W.K., 2000. Immunologic effects of yogurt. Am. J. Clin. Nutr. 71,
861–872.
Mocchegiani, E., Muzzioli, M., Giacconi, R., Cipriano, C., Gasparini, N., Franceschi, C.,
Gaetti, R., Cavalieri, E., Suzuki, H., 2003. Metallothioneins/PARP-1/IL-6 interplay
on natural killer cell activity in elderly: parallelism with nonagenarians and old
infected humans. Effect of zinc supply. Mech. Ageing Dev. 124, 459–468.
Molano, A., Meydani, S.N., 2012. Vitamin E, signalosomes and gene expression in T
cells. Mol. Aspects Med. 33, 55–62.
Morimoto, S.S., Alexopoulos, G.S., 2011. Immunity, aging, and geriatric depression.
Psychiatr. Clin. North Am. 34, 437–449, ix.
Müller, L., Fulop, T., Pawelec, G., 2013. Immunosenescence in vertebrates and
invertebrates. Immun. Ageing 10, 12.
Muzzioli, M., Stecconi, R., Moresi, R., Provinciali, M., 2009. Zinc improves the
development of human CD34+ cell progenitors towards NK cells and increases
the expression of GATA-3 transcription factor in young and old ages.
Biogerontology 10, 593–604.
Nazmi, A., Diez Roux, A., Ranjit, N., Seeman, T.E., Jenny, N.S., 2010. Cross-sectional
and longitudinal associations of neighborhood characteristics with
inflammatory markers: findings from the multi-ethnic study of
atherosclerosis. Health Place 16, 1104–1112.
Nikolich-Zugich, J., Messaoudi, I., 2005. Mice and flies and monkeys too: caloric
restriction rejuvenates the aging immune system of non-human primates. Exp.
Gerontol. 40, 884–893.
Nussinovitch, U., Shoenfeld, Y., 2012. The role of gender and organ specific
autoimmunity. Autoimmun. Rev. 11, A377–A385.
Ornish, D., Lin, J., Chan, J.M., Epel, E., Kemp, C., Weidner, G., Marlin, R., Frenda, S.J.,
Magbanua, M.J., Daubenmier, J., Estay, I., Hills, N.K., Chainani-Wu, N., Carroll,
P.R., Blackburn, E.H., 2013. Effect of comprehensive lifestyle changes on
telomerase activity and telomere length in men with biopsy-proven low-risk
22 L. Müller, G. Pawelec / Brain, Behavior, and Immunity 39 (2014) 8–22
prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol. 14,
1112–1120.
Ornish, D., Lin, J., Daubenmier, J., Weidner, G., Epel, E., Kemp, C., Magbanua, M.J.,
Marlin, R., Yglecias, L., Carroll, P.R., Blackburn, E.H., 2008. Increased telomerase
activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 9,
1048–1057.
Ouchi, N., Parker, J.L., Lugus, J.J., Walsh, K., 2011. Adipokines in inflammation and
metabolic disease. Nat. Rev. Immunol. 11, 85–97.
Pae, M., Meydani, S.N., Wu, D., 2012. The role of nutrition in enhancing immunity in
aging. Aging Dis. 3, 91–129.
Pan, Z., Chang, C., 2012. Gender and the regulation of longevity: implications for
autoimmunity. Autoimmun. Rev. 11, A393–A403.
Pathak, A.K., Bhutani, M., Nair, A.S., Ahn, K.S., Chakraborty, A., Kadara, H., Guha, S.,
Sethi, G., Aggarwal, B.B., 2007. Ursolic acid inhibits STAT3 activation pathway
leading to suppression of proliferation and chemosensitization of human
multiple myeloma cells. Mol. Cancer Res. 5, 943–955.
Pawelec, G., 2012. Hallmarks of human ‘‘immunosenescence’’: adaptation or
dysregulation? Immun. Ageing 9, 15.
Pawelec, G., Derhovanessian, E., Larbi, A., Strindhall, J., Wikby, A., 2009.
Cytomegalovirus and human immunosenescence. Rev. Med. Virol. 19, 47–56.
Pedersen, B.K., 2011. Exercise-induced myokines and their role in chronic diseases.
Brain Behav. Immun. 25, 811–816.
Peralbo, E., Delarosa, O., Gayoso, I., Pita, M.L., Tarazona, R., Solana, R., 2006.
Decreased frequency and proliferative response of invariant Valpha24Vbeta11
natural killer T (iNKT) cells in healthy elderly. Biogerontology 7, 483–492.
Prasad, S., Sung, B., Aggarwal, B.B., 2012. Age-associated chronic diseases require
age-old medicine: role of chronic inflammation. Prev. Med. 54 (Suppl), S29–S37.
Rickman, A.D., Williamson, D.A., Martin, C.K., Gilhooly, C.H., Stein, R.I., Bales, C.W.,
Roberts, S., Das, S.K., 2011. The CALERIE Study: design and methods of an
innovative 25% caloric restriction intervention. Contemp. Clin. Trials 32, 874–881.
Rymkiewicz, P.D., Heng, Y.X., Vasudev, A., Larbi, A., 2012. The immune system in the
aging human. Immunol. Res. 53, 235–250.
Sakamoto, Y., Ueki, S., Kasai, T., Takato, J., Shimanuki, H., Honda, H., Ito, T., Haga, H.,
2009. Effect of exercise, aging and functional capacity on acute secretory
immunoglobulin: a response in elderly people over 75 years of age. Geriatr.
Gerontol. Int. 9, 81–88.
Sauce, D., Appay, V., 2011. Altered thymic activity in early life: how does it affect the
immune system in young adults? Curr. Opin. Immunol. 23, 543–548.
Schiffrin, E.J., Morley, J.E., Donnet-Hughes, A., Guigoz, Y., 2010. The inflammatory
status of the elderly: the intestinal contribution. Mutat. Res. 690, 50–56.
Schwarz, B.A., Bhandoola, A., 2006. Trafficking from the bone marrow to the
thymus: a prerequisite for thymopoiesis. Immunol. Rev. 209, 47–57.
Sempowski, G.D., Hale, L.P., Sundy, J.S., Massey, J.M., Koup, R.A., Douek, D.C., Patel,
D.D., Haynes, B.F., 2000. Leukemia inhibitory factor, oncostatin M, IL-6, and
stem cell factor mRNA expression in human thymus increases with age and is
associated with thymic atrophy. J. Immunol. 164, 2180–2187.
Shanley, D.P., Aw, D., Manley, N.R., Palmer, D.B., 2009. An evolutionary perspective
on the mechanisms of immunosenescence. Trends Immunol. 30, 374–381.
Shaw, A.C., Joshi, S., Greenwood, H., Panda, A., Lord, J.M., 2010. Aging of the innate
immune system. Curr. Opin. Immunol. 22, 507–513.
Sheikh, A., Shamsuzzaman, S., Ahmad, S.M., Nasrin, D., Nahar, S., Alam, M.M., Al
tarique, A., Begum, Y.A., Qadri, S.S., Chowdhury, M.I., Saha, A., Larson, C.P., Qadri,
F., 2010. Zinc influences innate immune responses in children with
enterotoxigenic Escherichia coli-induced diarrhea. J. Nutr. 140, 1049–1056.
Shiels, P.G., McGlynn, L.M., Macintyre, A., Johnson, P.C., Batty, G.D., Burns, H.,
Cavanagh, J., Deans, K.A., Ford, I., McConnachie, A., McGinty, A., McLean, J.S.,
Millar, K., Sattar, N., Tannahill, C., Velupillai, Y.N., Packard, C.J., 2011. Accelerated
telomere attrition is associated with relative household income, diet and
inflammation in the pSoBid cohort. PLoS One 6, e22521.
Shimizu, K., Kimura, F., Akimoto, T., Akama, T., Tanabe, K., Nishijima, T., Kuno, S.,
Kono, I., 2008. Effect of moderate exercise training on T-helper cell
subpopulations in elderly people. Exerc. Immunol. Rev. 14, 24–37.
Shimizu, K., Suzuki, N., Imai, T., Aizawa, K., Nanba, H., Hanaoka, Y., Kuno, S., Mesaki,
N., Kono, I., Akama, T., 2011. Monocyte and T-cell responses to exercise training
in elderly subjects. J. Strength Cond. Res. 25, 2565–2572.
Shishodia, S., Potdar, P., Gairola, C.G., Aggarwal, B.B., 2003. Curcumin
(diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB
activation through inhibition of IkappaBalpha kinase in human lung epithelial
cells: correlation with suppression of COX-2, MMP-9 and cyclin D1.
Carcinogenesis 24, 1269–1279.
Simpson, R.J., 2011. Aging, persistent viral infections, and immunosenescence. Can
exercise ‘‘make space’’? Exerc. Sport Sci. Rev. 39, 23–33.
Simpson, R.J., Cosgrove, C., Ingram, L.A., Florida-James, G.D., Whyte, G.P., Pircher, H.,
Guy, K., 2008. Senescent T-lymphocytes are mobilised into the peripheral blood
compartment in young and older humans after exhaustive exercise. Brain
Behav. Immun. 22, 544–551.
Simpson, R.J., Florida-James, G.D., Cosgrove, C., Whyte, G.P., Macrae, S., Pircher, H.,
Guy, K., 2007. High-intensity exercise elicits the mobilization of senescent T
lymphocytes into the peripheral blood compartment in human subjects. J. Appl.
Physiol. (1985) 103, 396–401.
Simpson, R.J., Guy, K., 2010. Coupling aging immunity with a sedentary lifestyle: has
the damage already been done? – a mini-review. Gerontology 56, 449–458.
Downloaded for dr laqif abdurrahman (laqif.abdurrahman@gmail.com) at Universitas Indonesia from ClinicalKey.com by Elsevier on May 20, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
Simpson, R.J., Lowder, T.W., Spielmann, G., Bigley, A.B., Lavoy, E.C., Kunz, H., 2012.
Exercise and the aging immune system. Ageing Res. Rev. 11, 404–420.
Solana, R., Pawelec, G., Tarazona, R., 2006. Aging and innate immunity. Immunity
24, 491–494.
Spielmann, G., McFarlin, B.K., O’Connor, D.P., Smith, P.J., Pircher, H., Simpson, R.J.,
2011. Aerobic fitness is associated with lower proportions of senescent blood T-
cells in man. Brain Behav. Immun. 25, 1521–1529.
Steensberg, A., Fischer, C.P., Keller, C., Moller, K., Pedersen, B.K., 2003. IL-6 enhances
plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol. Endocrinol. Metab.
285, E433–E437.
Stewart, L.K., Flynn, M.G., Campbell, W.W., Craig, B.A., Robinson, J.P., McFarlin, B.K.,
Timmerman, K.L., Coen, P.M., Felker, J., Talbert, E., 2005. Influence of exercise
training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4.
Brain Behav. Immun. 19, 389–397.
Takahashi, A., Hanson, M.G., Norell, H.R., Havelka, A.M., Kono, K., Malmberg, K.J.,
Kiessling, R.V., 2005. Preferential cell death of CD8+ effector memory (CCR7-
CD45RA-) T cells by hydrogen peroxide-induced oxidative stress. J. Immunol.
174, 6080–6087.
Takeda, K., Okumura, K., 2007. Effects of a fermented milk drink containing
Lactobacillus casei strain Shirota on the human NK-cell activity. J. Nutr. 137,
791S–793S.
Timmerman, K.L., Flynn, M.G., Coen, P.M., Markofski, M.M., Pence, B.D., 2008.
Exercise training-induced lowering of inflammatory (CD14+CD16+) monocytes:
a role in the anti-inflammatory influence of exercise? J. Leukoc. Biol. 84, 1271–
1278.
Tower, J., Arbeitman, M., 2009. The genetics of gender and life span. J. Biol. 8, 38.
Tripathi, S., Maier, K.G., Bruch, D., Kittur, D.S., 2007. Effect of 6-gingerol on pro-
inflammatory cytokine production and costimulatory molecule expression in
murine peritoneal macrophages. J. Surg. Res. 138, 209–213.
Trzonkowski, P., Szmit, E., Mysliwska, J., Mysliwski, A., 2006. CD4+CD25+ T
regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-
impact of immunosenescence. Clin. Immunol. 119, 307–316.
Turner, J.E., Aldred, S., Witard, O.C., Drayson, M.T., Moss, P.M., Bosch, J.A., 2010.
Latent cytomegalovirus infection amplifies CD8 T-lymphocyte and egress in
response to exercise. Brain Behav. Immun. 24, 1362–1370.
von Kanel, R., Dimsdale, J.E., Mills, P.J., Ancoli-Israel, S., Patterson, T.L., Mausbach,
B.T., Grant, I., 2006. Effect of Alzheimer caregiving stress and age on frailty
markers interleukin-6, C-reactive protein, and D-dimer. J. Gerontol. A Biol. Sci.
Med. Sci. 61, 963–969.
Vulevic, J., Drakoularakou, A., Yaqoob, P., Tzortzis, G., Gibson, G.R., 2008. Modulation
of the fecal microflora profile and immune function by a novel trans-
galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. Am. J.
Clin. Nutr. 88, 1438–1446.
Wack, A., Cossarizza, A., Heltai, S., Barbieri, D., D’Addato, S., Fransceschi, C.,
Dellabona, P., Casorati, G., 1998. Age-related modifications of the human
alphabeta T cell repertoire due to different clonal expansions in the CD4+ and
CD8+ subsets. Int. Immunol. 10, 1281–1288.
Walsh, N.P., Gleeson, M., Shephard, R.J., Gleeson, M., Woods, J.A., Bishop, N.C.,
Fleshner, M., Green, C., Pedersen, B.K., Hoffman-Goetz, L., Rogers, C.J., Northoff,
H., Abbasi, A., Simon, P., 2011. Position statement. Part one: immune function
and exercise. Exerc. Immunol. Rev. 17, 6–63.
Wang, J.S., Lin, C.T., 2010. Systemic hypoxia promotes lymphocyte apoptosis
induced by oxidative stress during moderate exercise. Eur. J. Appl. Physiol. 108,
371–382.
Warren, L.A., Rossi, D.J., 2009. Stem cells and aging in the hematopoietic system.
Mech. Ageing Dev. 130, 46–53.
Weiskopf, D., Weinberger, B., Grubeck-Loebenstein, B., 2009. The aging of the
immune system. Transpl. Int. 22, 1041–1050.
Wellinghausen, N., Martin, M., Rink, L., 1997. Zinc inhibits interleukin-1-dependent
T cell stimulation. Eur. J. Immunol. 27, 2529–2535.
Woods, J.A., Keylock, K.T., Lowder, T., Vieira, V.J., Zelkovich, W., Dumich, S.,
Colantuano, K., Lyons, K., Leifheit, K., Cook, M., Chapman-Novakofski, K.,
McAuley, E., 2009. Cardiovascular exercise training extends influenza vaccine
seroprotection in sedentary older adults: the immune function intervention
trial. J. Am. Geriatr. Soc. 57, 2183–2191.
Wrosch, C., Schulz, R., Heckhausen, J., 2002. Health stresses and depressive
symptomatology in the elderly: the importance of health engagement control
strategies. Health Psychol. 21, 340–348.
Wrosch, C., Schulz, R., Miller, G.E., Lupien, S., Dunne, E., 2007. Physical health
problems, depressive mood, and cortisol secretion in old age: buffer effects of
health engagement control strategies. Health Psychol. 26, 341–349.
Yeh, S.H., Chuang, H., Lin, L.W., Hsiao, C.Y., Eng, H.L., 2006. Regular tai chi chuan
exercise enhances functional mobility and CD4CD25 regulatory T cells. Br. J.
Sports Med. 40, 239–243.
Yim, E.K., Lee, K.H., Namkoong, S.E., Um, S.J., Park, J.S., 2006. Proteomic analysis of
ursolic acid-induced apoptosis in cervical carcinoma cells. Cancer Lett. 235,
209–220.
Zhang, Y.X., Kong, C.Z., Wang, L.H., Li, J.Y., Liu, X.K., Xu, B., Xu, C.L., Sun, Y.H., 2010.
Ursolic acid overcomes Bcl-2-mediated resistance to apoptosis in prostate
cancer cells involving activation of JNK-induced Bcl-2 phosphorylation and
degradation. J. Cell. Biochem. 109, 764–773.