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Gynecol Endocrinol, Early Online: 17

! 2013 Informa UK Ltd. DOI: 10.3109/09513590.2013.852531

REVIEW ARTICLE

The immune system and aging: a review

Camil Castelo-Branco1 and Iris Soveral2
1
Faculty of Medicine, Institut Clnic of Gynecology, Obstetrics and Neonatology, University of Barcelona, Barcelona, Spain and
2
Hospital Clinic-Institut dInvestigacions Biome`diques, August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Abstract Keywords
The concept of immunosenescence reflects age-related changes in immune responses, both Aging, immune system, immunosenescence,
Gynecol Endocrinol Downloaded from informahealthcare.com by 88.18.136.187 on 11/13/13

cellular and serological, affecting the process of generating specific responses to foreign and innate and adaptive responses
self-antigens. The decline of the immune system with age is reflected in the increased
susceptibility to infectious diseases, poorer response to vaccination, increased prevalence of History
cancer, autoimmune and other chronic diseases. Both innate and adaptive immune responses
are affected by the aging process; however, the adaptive response seems to be more affected Received 8 September 2013
by the age-related changes in the immune system. Additionally, aged individuals tend to Accepted 3 October 2013
present a chronic low-grade inflammatory state that has been implicated in the pathogenesis Published online 12 November 2013
of many age-related diseases (atherosclerosis, Alzheimers disease, osteoporosis and diabetes).
However, some individuals arrive to advanced ages without any major health problems,
referred to as healthy aging. The immune system dysfunction seems to be somehow mitigated
in this population, probably due to genetic and environmental factors yet to be described. In
this review, an attempt is made to summarize the current knowledge on how the immune
For personal use only.

system is affected by the aging process.

Introduction seems to be more affected by the age-related changes in the

Aging is a complex process that deeply affects the immune
system. The decline of the immune system with age is reflected in
the increased susceptibility to infectious diseases, poorer response
to vaccination, increased prevalence of cancer, autoimmune and
other chronic diseases characterized by a pro-inflammatory state
[15], such as atherosclerosis and diabetes mellitus.
The concept of immunosenescence reflects those age-related
changes in immune responses, both cellular and serological,
affecting the process of generating specific responses to foreign
and self-antigens.
The immune system is a complex system in which a multitude
of different cells throughout the organism interact with each other,
either directly or through a variety of soluble mediators, to
achieve a thorough defense of the organism against foreign
attacks while maintaining control of correct cell proliferation
within the body.
The mechanisms of the immune response have been divided
into an innate and an adaptive component (Figure 1). The innate
response comprises both the anatomical and biochemical barriers
and the unspecific cellular response mediated mainly by mono-
cytes, natural killer cells and dendritic cells. The adaptive
response provides an antigen-specific response mediated by
T and B lymphocytes. Both parts of the immune response are
affected by the aging process; however the adaptive response
immune system [6].
In this review, an attempt is made to summarize the current
knowledge on how the immune system is affected by the aging
process.
Methods
A systematic review was carried out of studies involving the aging
of the immune system. To identify the articles that describe a
relationship between aging and the immune system, the following
keyword-based search strategy was designed: (immunosenescense
or aging) and (immune system or immunity or immune) followed
by a specific search for every major component of the immune
system. This strategy was adapted and applied to several widely
used Internet search engines, to the MEDLINE database (1966
October 2013) and to Cochrane Controlled Trials Register. There
was no language or date restriction. This search was further
supplemented by a hand-search of reference lists of selected
review papers.
Immunosenescence theories and causes
The three major theories developed to explain immunosenescence
include the autoimmunity, the immunodeficiency and the
immunodysregulation. Table 1 shows some causes and factors
associated with immunosenescence.

The autoimmnune theory

Address for correspondence: Camil Castelo-Branco, Faculty of Medicine,

As a person ages, the ability of the immune system to differentiate
Institut Clnic of Gynecology, Obstetrics and Neonatology, University of between invaders and normal tissues diminishes and immune cells
Barcelona, Barcelona, Spain. Tel: +34 932275534/932275436. E-mail: begin to attach normal body tissues. In these circumstances
castelobranco@ub.edu conditions linked to aging like arthritis, occur.
 2 C. Castelo-Branco & I. Soveral
Gynecol Endocrinol Downloaded from informahealthcare.com by 88.18.136.187 on 11/13/13
Figure 1. Biological defense mechanisms that protect the body. The
immune system is a functional system rather than an organ system
involving hematopoietic, vasculature and lymphatic systems. (a) Innate
defenses; (b) adaptive defenses.
Table 1. Immunosenescence: causes and associated factors.
For personal use only.
 Lifelong antigenic stress
 Filling of the immunological space
 Accumulation of effector T and memory cells
 Reduction of nave T cells
 Deterioration of clonotypical immunity
 Up-regulation of the innate IS
 Lifelong antigenic stress
 Filling of the immunological space
 Mitochondrial damage causing tissues dysfunction
 Micronutrient inadequacy accelerates aging because of
 metabolic malfunctioning
 The number of telomeres is proportional to life
 expectancy. They avoid DNA damage
 Reactivity to self-antigens risk of triggering autoimmune diseases
The immune deficiency theory
With increasing age, the immune system is no longer able to
defend the body from foreign invaders and detrimental changes
result.
The immune dysregulation theory
With aging, multiple changes in immune system occur disrupting
the regulation between multiple components of immune process
implying the progressive destruction of body cells.
The evolutionay point of view
The immune system is subject to evolutionary constraints.
Humans lived 3050 years a couple of centuries ago and
nowadays, 80120 years. This is longer than predicted. This
condition implies antigenic burden encompassing decades of
evolutionary unpredicted exposure.
Antagonistic pleiotropy
Natural selection has favored genes conferring short-term benefits
at the cost of deterioration in later life. Therefore, immune system
Gynecol Endocrinol, Early Online: 17
has probably been selected to serve individuals only until
reproduction and after that, biochemical processes proceed
freely without past selective pressure to improve the life of an
individual. Thymic involution in early age supports this
hypothesis.
The endocrine point of view
Several shared mechanisms highlight the interaction between the
endocrine and the immune systems: first, cells of immune and
endocrine systems have receptors to cytokines, neuropeptides and
neurotransmitters. Second, immuneneuroendocrine products are
described in both systems and third, endocrine mediators
modulate the immune system and immune structures mediators
may affect the endocrine system. Steroid hormones may affect
the immune response by influencing gene expression in cells that
have receptors for these hormones. Moreover, immune cells
via receptors may bind to steroids, growth hormone, estradiol
and testosterone. The hypothalamicpituitarythyroid axis can
be inhibited by IL-1, tumor necrosis factor and IL6 and
the hypothalamicpituitaryadrenal axis may influence immune
functions with glucocorticoids suppressing the maturation,
differentiation and proliferation of immune cells. The hypothal-
amicpituitary axis can also modulate the immune function
because Gonadotropin-releasing hormone is also involved in
the process of developing and modulating the immune system
(Figure 2).
The innate response
Skin and mucous barriers
Skin and mucous membranes constitute the first line of defense
against pathogens, with both a barrier and mechanic function.
With age, skin cell replacement declines, sweat and sebum
production decrease and structural changes such as flattening of
the dermoepithelial junctions, depletion of Langerhans cells and
melanocytes; dermal and subcutaneous atrophy occurs [710].
In mucous membranes, in which ciliated cells play an
important role by mechanically removing pathogens, changes in
the ciliary beat frequency are controversial with some studies
finding no differences with age [11] and others found a reduced
ciliary beat frequency [12]. Additionally, ultrastructural abnorm-
alities can also be found [11].
Secretory IgA, the main immunoglobulin in secretions, along
with the anatomical and mechanical barriers constitutes first
line of defense against pathogens that invade mucosal surfaces.
The levels of secretory IgA were found to increase with age up
to 60 years and then slightly decrease thereafter, at least in
saliva [13].
Dendritic cells
Dendritic cells (DCs) are responsible for the first recognition of
pathogens, their phagocytosis, processing of antigens, migration
to regional lymph nodes, priming of nave T cells and regulation
of B and NK cells response [14]. They represent the first alert of
pathogens presence and constitute a bridge between innate and
adaptive immune responses.
Two subsets of DCs are recognized: DC of myeloid origin
(conventional DC in the blood, interstitial DC in tissues,
Langerhan cells in the skin and monocyte-derived DC) and DC
of lymphoid origin (plasmacytoid DC).
Globally, the number of DC in the organism does not seem to
be affected by healthy aging, although their number diminishes in
specific subsets such as Langerhans cells in the skin [10]
and plasmacytoid DC [15] and in the presence of chronic
diseases [16].
 DOI: 10.3109/09513590.2013.852531 Immunosenescence 3
Figure 2. Relations between immune, endo- Thymic pepdes
crine and central nervous systems. Pathways
overlap between them. ACTH, adrenocorti- interferons
cotropic hormone; CRH, corticotrophin- ACTH
releasing hormone; TNF, tumour necrosis Central Nervous o rph in s
System -end Endocrine System
factor; VIP, vasoactive intestinal peptide. CRH
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In order to effectively play their role as sentinels in the entry
points of the organism, DCs recognize conserved pathogen-
associated molecular patterns using pattern recognition receptors
(PRRs) [17], including Toll-like receptors whose function has
been shown to be compromised in the elderly [18]. Phagocytosis
and migration are also negatively affected by old age via the
phosphoinositide 3-kinase-signaling pathway [19].
The effects of aging on the inflammatory response and T cell
priming by DCs remain unclear [16], although most studies show
an impaired inflammatory response that might be related to a
decrease in IL-15, tumor necrosis factor (TNF)-a and IFN-a
expression in response to viral infections and vaccines [1921].
Natural killer cells
Natural killer cells (NK cells) play an important role within the
innate immune response. They recognize and eliminate cells
lacking MHC class I molecules without previous sensitization or
activation by other cells; they play a role in maintaining innate
and adaptive immune responses by secreting a variety of
cytokines [22,23]. These two main mechanisms, cell cytotoxicity
and cytokine secretion, are carried out by two main subpopula-
tions: CD56dimCD16 NK cells, which are truly cytotoxic cells
with low cytokine production and CD56brightCD16- NK cells,
which are less differentiated cells whose main response upon
activation is cytokine and chemokine production [24].
It is widely accepted that there is an increase in the number of
NK cells in the elderly [22,23,25]. This increase seems to be the
result of an accumulation of mature cells in the organism and as
such, results in an increase in the CD56dim population [26].
Nonetheless, this increase in NK cells is not associated with an
increase in global cytotoxicity. It can be that this increase in NK
cells constitutes a compensation mechanism of the reduced per-
cell cytotoxicity that seems to be secondary to a decreased
perforin secretion [27].
In murine models NK cells migration has been shown to be
affected [28,29], although in human studies no age-related
differences have been observed in the expression of adhesion or
chemokine receptors [23,30,31]. Cytokine secretion by NK cells
also seems to be reduced [31] as well as variably diminished
proliferative response to stimulation with IL-2 [26].
Neutrophils
Neutrophils are short-lived phagocytic cells circulating in blood
vessels until they are recruited to site of infection by cytokines
and chemokines, mainly IL-1 and IL-8. They are the first
responders to microbial and parasitic infections and act by three
main mechanisms: phagocytosis (requiring opsonization), gener-
ation of reactive oxygen species and degranulation (releasing
enzymes and antimicrobial peptides) and neutrophil extracellular
traps [32,33].
Most studies suggest that age does not affect the number of
neutrophils, but it seems that their ability to increase their life
span in response to survival signals (IFN-1, GM-CSF) produced
at the site of infection is decreased [34,35]. Chemotaxis results in
adhesion to endothelial cells and migration through them into the
affected tissue. The mechanisms of adhesion and migration seem
to remain unaffected [36,37], but it remains unclear whether
chemotaxis is affected by age [33,3638]. In regards to phago-
cytosis, most authors agree that the phagocytic function and the
intracellular respiratory burst necessary to kill bacteria are
reduced in the elderly [36,3943]. The defect in phagocytosis of
opsonized bacteria and superoxide generation seems to depend on
a reduced expression of CD16 (Fc receptor) [41]. How age affects
the generation of neutrophil extracellular traps remains to be
clarified [44].
Macrophages
Macrophages are tissue resident phagocytes, derived from
circulating monocytes and like the DCs possess abundant Toll-
like receptors being, therefore, capable of recognizing pathogens
with conserved pathogen-associated molecular patterns and
 4 C. Castelo-Branco & I. Soveral
initiating the inflammatory response. Tissue-macrophages play an
important role in the recruitment of neutrophils by synthetizing
pro-inflammatory cytokines and chemokines, such as TNF-a,
IL-1, IL-6 and IL-8 [32]. They are also capable of processing and
presenting antigens to T cells and participate in the regulation of
the adaptive immune response [38].
In older people, macrophages present a reduced production of
cytokines such as TNF-a and IL-6 in response to TLR1/2 but not
other TLR that might be responsible for a less potent recruitment
of neutrophils and other cells [45]. Additionally, TLR-induced
expression of B7 (B7 CD80 and CD86 unite to either CD28 or
CD152 in the T cell producing a co-stimulatory signal) is
decreased in the elderly [46]. Also, they show an altered
expression of MHC class II molecules (with decreased
HLA-DR/DQ and increased HLA-DQ), whose significance
remains unclear but can contribute to a poorer T cell response
[47]. Studies on mouse models have shown that macrophages
from aged individuals express less MHC class [48] after
stimulation with IFN-gamma II, show impaired phagocytosis
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[49,50] and present a decreased ability to produce reactive oxygen
species [51], although these findings are yet to be replicated
in humans.
The adaptive response
Lymphoid progenitors
Hematopoietic stem cells (HSCs) are found mainly in the bone
marrow and are responsible for the continuous supply of both
myeloid and lymphoid progenitors necessary for an adequate
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immune response.
With age, the proliferative capacity of the HSC diminishes [52]
and a shift is seen toward the production of myeloid progenitors
[53,54]. Several mechanisms have been proposed, including the
shortening of telomeres [55], epigenetic changes secondary to a
decreased DNA methylation in the HSC that could be responsible
for the shift toward the myeloid series (as myeloid progenitors
present lower DNA methylation than the lymphoid progenitors)
[5658] and changes in the HSC niche including the cytokine
milieu [59].
B cells
B cells main function is the production of specific antibodies in
response to a specific antigen and this function is crucial to the
effective response against bacterial infections and vaccination
[60]. High-affinity-specific antibodies are generated by somatic
hypermutation of immunoglobulin genes in the germinal center of
secondary lymphoid tissue after which professional antibody
secreting plasma cells migrate to the blood stream [61].
In line with the reduced ability of HSCs to generate new B
lymphocytes, the total number of B cells seems to diminish with
age [62,63]. Additionally, a decrease in diversity of the B cell
repertoire is seen in older people, characterized by a decrease in
nave B cells (CD27; with few somatic mutations in immuno-
globulin genes) and an increase in memory B cells (CD27; with
multiple somatic mutations) [60,62,64]. These memory B cells
present an increased resistance to apoptosis. Furthermore, some
studies describe a subtype of B cell called aging-associated
B-cell that accumulates with age (possibly displacing nave
B cells) [58] that respond to innate but not adaptive immunity
stimuli [65], although more studies are needed to clarify their role
in humans.
Consistent with the change in B cell subsets, antibody
production is also affected by age. In response to vaccines,
older people present a slower response, a reduced clonal
expansion of plasma cells that correlates with a decrease in
Gynecol Endocrinol, Early Online: 17
immunoglobulin production and these present lower affinities
toward the antigens [66]. Although fewer plasma cells are
generated, their individual antibody secreting function seems to
be intact [66] and the somatic hypermutation apparatus seems to
be preserved [67].
Additionally, when a primary antibody response is needed in
the presence of new antigens, a delayed response with lower levels
of high-affinity antibodies is observed in the elderly that is
compensated later by clonal expansion, which can be explained
by the decrease in nave B cell pool [68]. Globally, the
circulating immunoglobulins become dominated by those with
somatic mutations compatible with their generation primarily
by memory B cells and an increase in auto-antibodies is
observed [69].
Accompanying the decrease in high-affinity antibodies, the
ability of the humoral response to produce antibodies capable of
opsonizing bacteria for neutralization by phagocytosis is also
impaired in older people [70].
It would seem that three major impairments affect B cells with
aging: a decrease in the number of nave B cells and therefore an
impaired capacity for response to new antigens; a reduced clonal
expansion capability of memory B cells that correlates with a
lower level of circulating antibodies after contact with a
previously known antigen and functionally impaired antibodies
with lower affinities and decreased opsonizing abilities.
T cells
T cells are characterized by the presence of T cell receptors
(TCRs) and can be categorized in two main subsets by the cell
surface expression of either CD4 or CD8. CD4 cells, which
recognize antigens in the context of Class II major histocompati-
bility complex (MHC), are mainly regulatory cells, whereas
CD8 cells are mainly cytotoxic cells that recognize antigen
presented within Class I MHC molecules. Both functions are of
vital importance in the adaptive and innate immune responses.
The absolute number of T cells decrease with age and, as in
B cells, this decrease affects more importantly the nave subset
[71]. T cell differentiation takes place in the thymus and results in
the production of CD4 or CD8 nave cells, which are then
exported to the periphery [72]. During maturation, T cells
rearrange TCR genes resulting in the production of DNA
fragments known as T cell receptor excision circles (TRECs)
that have been used as an indirect measure of thymopoietic
potential [73,74]
Thymic involution has been well established in the literature
and is considered to be the main mechanism by which the pool of
nave T cells declines with age [72,75]. This decline affects
CD4 and CD8 cells differently with a greater contraction in
CD8 numbers and a better preserved population of nave CD4
cells [74,7678]. Accompanying the numeric defect in nave
T cells, functional defects (especially in the CD8 subset) have
been described such as antigen-independent activation and
proliferation rates. These cells that maintain a nave phenotype
are less capable of producing an adequate response when
presented with a new antigen [77].
Activation of both nave and memory T cells is a complex
process that requires the intervention of co-stimulatory molecules
after the binding of TCR to MHC molecules [72]. CD28 is an
important co-stimulatory molecule present in T cells and the
binding of CD28 to its co-receptor (B7, present in antigen
presenting cells) results in potent activation stimuli for T cells
[79]. CD28 presence in T cells decreases with cell differentiation
from naive to central memory to effector memory cells as a result
of persistent antigenic stimulation and repeated proliferation
cycles [80]. The activation of T cells via TCR-CD28 does not
 DOI: 10.3109/09513590.2013.852531 Immunosenescence 5

seem to be impaired in old people [81]. However, with age, CD28 Telomere shortening
Thymus
expression decreases in both CD4 and CD8 T cells [82,83], Oxidave stress
involuon
consistent with a decreased naive cell pool and the accumulation
of highly differentiated T cells. CD27, a TNF receptor, suffers the Immunosenescence
same changes as CD28 with decreased expression as T cells
differentiate [71,72,77]. As such, CD27/CD28 T cells repre- Hormonal Decreased
sent highly differentiated effector T cells that accumulate in old Chronic infecons T cell funcon
changes
Autoimmune diseases
age. They have limited proliferative capability but as they are
apoptosis resistant, an accumulation is seen with age, mainly in
CD8 cells [84]. However, the proliferative capability of these Increased inammatory acvity
CD27/CD28 cells seems to be better preserved in the CD4
population, because these cells maintain a certain antigen-induced
telomerase activity [85].
Type 2 Diabetes
Another change seen in differentiated T cells in old age is the Demena Atherosclerosis
Osteoporosis
acquisition, mainly in CD8 cells but also in CD4, of NK
markers, such as CD56 [8688]. The presence of the NK cell Figure 3. Inflamm-aging consequences.
markers is associated with an increased presence of cytotoxic
molecules [89] and allows CD28 T cells to be activated
independently of TCR and maintaining their cytotoxic capabil- Table 2. Shift in cytokines with age.
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ity although their proliferative capability remains diminished

[89,90]. " IL-1, IL-6, TNF-a
In conclusion, T cells are deeply affected with aging but CD8 " Cytokine production imbalance
cells seem to be affected to greater extent, which suggests that # IL-2
CD4 cells are subject to stricter homeostatic mechanisms given " IL-8 (which can recruit macrophages and may lead to lung
inflammation dysfunctional IL-8)
the importance of these cells in the maintenance of the immune # Interferon-g
system function [91].
Altered cytokine responsiveness of NK cells
The degree of T cell impairment is also variable among " IL-10 and IL-12 up-regulated by antigen processing cells
individuals and a T cell immune risk profile has been established,
characterized by an inverted CD4/CD8 ratio, an accumulation of
CD8/CD28 cells and CMV infection [88,92]. This immune
For personal use only.

Table 3. Changes affecting the innate immune system with age.

profile is associated with increased mortality and age-related
diseases [92].
Inflamm-aging
Inflamm-aging refers to a chronic state of low-grade inflamma-
tion that accompanies the aging process characterized by
increased levels of circulating cytokines and pro-inflammatory
markers [93]. It is associated with many age-related diseases, such
as atherosclerosis, Alzheimers disease, osteoporosis and diabetes
(Figure 3) [93]. Among such pro-inflammatory cytokines TNF-a
[94], IL1 [95] and IL6 [96] seem to play a major role. Table 2
records the shift in cytokines with aging. However, in healthy
aging these pro-inflammatory states seem to be somewhat
inhibited by anti-inflammatory cytokines such as IL-10 [97].
Conclusions
Immunosenescence is a complex process that affects the
immune system on the whole (summarized in Tables 3 and 4)
and reflects upon the organisms ability of adequately respond-
ing to pathogens. There is no single impairment to be blamed;
instead it is a multilevel dysfunction that affects individuals to a
different extent. As a result, elderly people present increased
susceptibility to infections [98], decreased responses to vac-
cination [66] and poorer responses to known and new
antigens. Additionally, aged individuals tend to present a chronic
low-grade inflammatory state that has been implicated in the
pathogenesis of many age-related diseases (atherosclerosis,
Alzheimers disease, osteoporosis, diabetes) [9597]. Also, the
increased prevalence of cancer has been associated with an age-
related impairment of the immune surveillance function [22].
However, some individuals arrive to advanced ages without any
major health problems, referred to as healthy aging. The immune
system dysfunction seems to be somehow mitigated in this
population, probably due to genetic and environmental factors yet
to be described.
Impairment of anatomical barriers
# Number of Langerhan cells
# Pathogen recognition by DCs
" Numbers of less functional NK cells
# Neutrophil survival in response to stimuli
# Neutrophil phagocytic function and respiratory burst generation
# Cytokine production by macrophages
# T cell activation by macrophages
Table 4. Changes affecting the adaptive immune system with age.
# Lymphoid progenitors production
# Number of B cells, specially nave cells
" Apoptosis resistance of memory B cells
# Antibody production, with lower affinities and decreased opsonizing
abilities
Delayed antibody response to new antigens
# Number of T cells, specially nave and CD8 cells
" Antigen-independent activation and proliferation of nave T cells
# CD28 T cells as a result of accumulation of mature cells
" Apoptosis resistance of memory T cells
Acquisition of NK cell markers by T cells
# Cytotoxic capability of CD8 cells
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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