Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

The immune system and aging: a review

Camil Castelo-Branco & Iris Soveral

To cite this article: Camil Castelo-Branco & Iris Soveral (2014) The immune system and aging: a
review, Gynecological Endocrinology, 30:1, 16-22, DOI: 10.3109/09513590.2013.852531

To link to this article: https://doi.org/10.3109/09513590.2013.852531

Published online: 12 Nov 2013.

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ISSN: 0951-3590 (print), 1473-0766 (electronic)

Gynecol Endocrinol, 2014; 30(1): 16–22

! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.852531

IMMUNE SYSTEM

The immune system and aging: a review

Camil Castelo-Branco1 and Iris Soveral2
1
Faculty of Medicine, Institut Clı́nic of Gynecology, Obstetrics and Neonatology, University of Barcelona, Barcelona, Spain and
2
Hospital Clinic-Institut d’Investigacions Biomèdiques, 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,
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, Alzheimer’s 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
system is affected by the aging process.

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

immune system [6].
Aging is a complex process that deeply affects the immune
In this review, an attempt is made to summarize the current
system. The decline of the immune system with age is reflected in
knowledge on how the immune system is affected by the aging
the increased susceptibility to infectious diseases, poorer response
process.
to vaccination, increased prevalence of cancer, autoimmune and
other chronic diseases characterized by a pro-inflammatory state
Methods
[1–5], such as atherosclerosis and diabetes mellitus.
The concept of immunosenescence reflects those age-related A systematic review was carried out of studies involving the aging
changes in immune responses, both cellular and serological, of the immune system. To identify the articles that describe a
affecting the process of generating specific responses to foreign relationship between aging and the immune system, the following
and self-antigens. keyword-based search strategy was designed: (immunosenescense
The immune system is a complex system in which a multitude or aging) and (immune system or immunity or immune) followed
of different cells throughout the organism interact with each other, by a specific search for every major component of the immune
either directly or through a variety of soluble mediators, to
13
system. This strategy was adapted and applied to several widely
20
achieve a thorough defense of the organism against ‘‘foreign used Internet search engines, to the MEDLINE database (1966–
attacks’’ while maintaining control of correct cell proliferation October 2013) and to Cochrane Controlled Trials Register. There
within the body. was no language or date restriction. This search was further
The mechanisms of the immune response have been divided supplemented by a hand-search of reference lists of selected
into an innate and an adaptive component (Figure 1). The innate review papers.
response comprises both the anatomical and biochemical barriers
and the unspecific cellular response mediated mainly by mono- Immunosenescence theories and causes
cytes, natural killer cells and dendritic cells. The adaptive
The three major theories developed to explain immunosenescence
response provides an antigen-specific response mediated by
include the autoimmunity, the immunodeficiency and the
T and B lymphocytes. Both parts of the immune response are
immunodysregulation. Table 1 shows some causes and factors
affected by the aging process; however the adaptive response
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 Clı́nic 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
[email protected] conditions linked to aging like arthritis, occur.
DOI: 10.3109/09513590.2013.852531 Immunosenescence 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, immune–neuroendocrine 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 hypothalamic–pituitary–thyroid axis can
be inhibited by IL-1, tumor necrosis factor and IL6 and
the hypothalamic–pituitary–adrenal axis may influence immune
functions with glucocorticoids suppressing the maturation,
differentiation and proliferation of immune cells. The hypothal-
Figure 1. Biological defense mechanisms that protect the body. The amic–pituitary axis can also modulate the immune function
immune system is a functional system rather than an organ system because Gonadotropin-releasing hormone is also involved in
involving hematopoietic, vasculature and lymphatic systems. (a) Innate the process of developing and modulating the immune system
defenses; (b) adaptive defenses.
(Figure 2).

Table 1. Immunosenescence: causes and associated factors. The innate response

Skin and mucous barriers
 Lifelong antigenic stress
 Filling of the immunological space Skin and mucous membranes constitute the first line of defense
 Accumulation of effector T and memory cells against pathogens, with both a barrier and mechanic function.
 Reduction of naı̈ve T cells With age, skin cell replacement declines, sweat and sebum
 Deterioration of clonotypical immunity
 Up-regulation of the innate IS
production decrease and structural changes such as flattening of
 Lifelong antigenic stress the dermoepithelial junctions, depletion of Langerhans cells and
 Filling of the immunological space melanocytes; dermal and subcutaneous atrophy occurs [7–10].
 Mitochondrial damage causing tissues dysfunction In mucous membranes, in which ciliated cells play an
 Micronutrient inadequacy accelerates aging because of important role by mechanically removing pathogens, changes in
 metabolic malfunctioning the ciliary beat frequency are controversial with some studies
 The number of telomeres is proportional to life
finding no differences with age [11] and others found a reduced
 expectancy. They avoid DNA damage
 Reactivity to self-antigens – risk of triggering autoimmune diseases 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
The immune deficiency theory
line of defense against pathogens that invade mucosal surfaces.
With increasing age, the immune system is no longer able to The levels of secretory IgA were found to increase with age up
defend the body from foreign invaders and detrimental changes to 60 years and then slightly decrease thereafter, at least in
result. saliva [13].

The immune dysregulation theory Dendritic cells

With aging, multiple changes in immune system occur disrupting Dendritic cells (DCs) are responsible for the first recognition of
the regulation between multiple components of immune process pathogens, their phagocytosis, processing of antigens, migration
implying the progressive destruction of body cells. to regional lymph nodes, priming of naı̈ve T cells and regulation
of B and NK cells’ response [14]. They represent the first alert of
The evolutionay point of view pathogen’s presence and constitute a bridge between innate and
adaptive immune responses.
The immune system is subject to evolutionary constraints.
Two subsets of DCs are recognized: DC of myeloid origin
Humans lived 30–50 years a couple of centuries ago and
(conventional DC in the blood, interstitial DC in tissues,
nowadays, 80–120 years. This is longer than predicted. This
Langerhan cells in the skin and monocyte-derived DC) and DC
condition implies antigenic burden encompassing decades of
of lymphoid origin (plasmacytoid DC).
evolutionary unpredicted exposure.
Globally, the number of DC in the organism does not seem to
be affected by healthy aging, although their number diminishes in
Antagonistic pleiotropy
specific subsets – such as Langerhans cells in the skin [10]
Natural selection has favored genes conferring short-term benefits and plasmacytoid DC [15] – and in the presence of chronic
at the cost of deterioration in later life. Therefore, immune system diseases [16].
18 C. Castelo-Branco & I. Soveral Gynecol Endocrinol, 2014; 30(1): 16–22

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 β-end Endocrine System
factor; VIP, vasoactive intestinal peptide. CRH
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Circulang Molecules
Messenger Molecules
glands
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In order to effectively play their role as sentinels in the entry differences have been observed in the expression of adhesion or
points of the organism, DCs recognize conserved pathogen- chemokine receptors [23,30,31]. Cytokine secretion by NK cells
associated molecular patterns using pattern recognition receptors also seems to be reduced [31] as well as variably diminished
(PRRs) [17], including Toll-like receptors whose function has proliferative response to stimulation with IL-2 [26].
been shown to be compromised in the elderly [18]. Phagocytosis
and migration are also negatively affected by old age via the Neutrophils
phosphoinositide 3-kinase-signaling pathway [19].
The effects of aging on the inflammatory response and T cell Neutrophils are short-lived phagocytic cells circulating in blood
priming by DCs remain unclear [16], although most studies show vessels until they are recruited to site of infection by cytokines
an impaired inflammatory response that might be related to a and chemokines, mainly IL-1 and IL-8. They are the first
decrease in IL-15, tumor necrosis factor (TNF)-a and IFN-a responders to microbial and parasitic infections and act by three
expression in response to viral infections and vaccines [19–21]. main mechanisms: phagocytosis (requiring opsonization), gener-
ation of reactive oxygen species and degranulation (releasing
Natural killer cells enzymes and antimicrobial peptides) and neutrophil extracellular
traps [32,33].
Natural killer cells (NK cells) play an important role within the Most studies suggest that age does not affect the number of
innate immune response. They recognize and eliminate cells neutrophils, but it seems that their ability to increase their life
lacking MHC class I molecules without previous sensitization or span in response to survival signals (IFN-1, GM-CSF) produced
activation by other cells; they play a role in maintaining innate at the site of infection is decreased [34,35]. Chemotaxis results in
and adaptive immune responses by secreting a variety of adhesion to endothelial cells and migration through them into the
cytokines [22,23]. These two main mechanisms, cell cytotoxicity affected tissue. The mechanisms of adhesion and migration seem
and cytokine secretion, are carried out by two main subpopula- to remain unaffected [36,37], but it remains unclear whether
tions: CD56dimCD16þ NK cells, which are truly cytotoxic cells chemotaxis is affected by age [33,36–38]. In regards to phago-
with low cytokine production and CD56brightCD16- NK cells, cytosis, most authors agree that the phagocytic function and the
which are less differentiated cells whose main response upon intracellular respiratory burst necessary to kill bacteria are
activation is cytokine and chemokine production [24]. reduced in the elderly [36,39–43]. The defect in phagocytosis of
It is widely accepted that there is an increase in the number of opsonized bacteria and superoxide generation seems to depend on
NK cells in the elderly [22,23,25]. This increase seems to be the a reduced expression of CD16 (Fc receptor) [41]. How age affects
result of an accumulation of mature cells in the organism and as the generation of neutrophil extracellular traps remains to be
such, results in an increase in the CD56dim population [26]. clarified [44].
Nonetheless, this increase in NK cells is not associated with an
increase in global cytotoxicity. It can be that this increase in NK
Macrophages
cells constitutes a compensation mechanism of the reduced per-
cell cytotoxicity that seems to be secondary to a decreased Macrophages are tissue resident phagocytes, derived from
perforin secretion [27]. circulating monocytes and like the DCs possess abundant Toll-
In murine models NK cells migration has been shown to be like receptors being, therefore, capable of recognizing pathogens
affected [28,29], although in human studies no age-related with conserved pathogen-associated molecular patterns and
DOI: 10.3109/09513590.2013.852531 Immunosenescence 19

initiating the inflammatory response. Tissue-macrophages play an immunoglobulin production and these present lower affinities
important role in the recruitment of neutrophils by synthetizing toward the antigens [66]. Although fewer plasma cells are
pro-inflammatory cytokines and chemokines, such as TNF-a, generated, their individual antibody secreting function seems to
IL-1, IL-6 and IL-8 [32]. They are also capable of processing and be intact [66] and the somatic hypermutation apparatus seems to
presenting antigens to T cells and participate in the regulation of be preserved [67].
the adaptive immune response [38]. Additionally, when a primary antibody response is needed in
In older people, macrophages present a reduced production of the presence of new antigens, a delayed response with lower levels
cytokines such as TNF-a and IL-6 in response to TLR1/2 but not of high-affinity antibodies is observed in the elderly that is
other TLR that might be responsible for a less potent recruitment compensated later by clonal expansion, which can be explained
of neutrophils and other cells [45]. Additionally, TLR-induced by the decrease in naı̈ve B cell pool [68]. Globally, the
expression of B7 (B7 – CD80 and CD86 – unite to either CD28 or circulating immunoglobulins become dominated by those with
CD152 in the T cell producing a co-stimulatory signal) is somatic mutations compatible with their generation primarily
decreased in the elderly [46]. Also, they show an altered by memory B cells and an increase in auto-antibodies is
expression of MHC class II molecules (with decreased observed [69].
HLA-DR/DQ and increased HLA-DQ), whose significance Accompanying the decrease in high-affinity antibodies, the
remains unclear but can contribute to a poorer T cell response ability of the humoral response to produce antibodies capable of
[47]. Studies on mouse models have shown that macrophages opsonizing bacteria for neutralization by phagocytosis is also
from aged individuals express less MHC class [48] after impaired in older people [70].
stimulation with IFN-gamma II, show impaired phagocytosis It would seem that three major impairments affect B cells with
[49,50] and present a decreased ability to produce reactive oxygen aging: a decrease in the number of naı̈ve B cells and therefore an
species [51], although these findings are yet to be replicated impaired capacity for response to new antigens; a reduced clonal
in humans. 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
The adaptive response
with lower affinities and decreased opsonizing abilities.
Lymphoid progenitors
Hematopoietic stem cells (HSCs) are found mainly in the bone T cells
marrow and are responsible for the continuous supply of both
T cells are characterized by the presence of T cell receptors
myeloid and lymphoid progenitors necessary for an adequate
(TCRs) and can be categorized in two main subsets by the cell
immune response.
surface expression of either CD4 or CD8. CD4þ cells, which
With age, the proliferative capacity of the HSC diminishes [52]
recognize antigens in the context of Class II major histocompati-
and a shift is seen toward the production of myeloid progenitors
bility complex (MHC), are mainly regulatory cells, whereas
[53,54]. Several mechanisms have been proposed, including the
CD8þ cells are mainly cytotoxic cells that recognize antigen
shortening of telomeres [55], epigenetic changes secondary to a
presented within Class I MHC molecules. Both functions are of
decreased DNA methylation in the HSC that could be responsible
vital importance in the adaptive and innate immune responses.
for the shift toward the myeloid series (as myeloid progenitors
The absolute number of T cells decrease with age and, as in
present lower DNA methylation than the lymphoid progenitors)
B cells, this decrease affects more importantly the naı̈ve subset
[56–58] and changes in the HSC niche including the cytokine
[71]. T cell differentiation takes place in the thymus and results in
milieu [59].
the production of CD4þ or CD8þ naı̈ve cells, which are then
exported to the periphery [72]. During maturation, T cells
B cells
rearrange TCR genes resulting in the production of DNA
B cells’ main function is the production of specific antibodies in fragments known as T cell receptor excision circles (TRECs)
response to a specific antigen and this function is crucial to the that have been used as an indirect measure of thymopoietic
effective response against bacterial infections and vaccination potential [73,74]
[60]. High-affinity-specific antibodies are generated by somatic Thymic involution has been well established in the literature
hypermutation of immunoglobulin genes in the germinal center of and is considered to be the main mechanism by which the pool of
secondary lymphoid tissue after which professional antibody naı̈ve T cells declines with age [72,75]. This decline affects
secreting plasma cells migrate to the blood stream [61]. CD4þ and CD8þ cells differently with a greater contraction in
In line with the reduced ability of HSCs to generate new B CD8þ numbers and a better preserved population of naı̈ve CD4þ
lymphocytes, the total number of B cells seems to diminish with cells [74,76–78]. Accompanying the numeric defect in naı̈ve
age [62,63]. Additionally, a decrease in diversity of the B cell T cells, functional defects (especially in the CD8 subset) have
repertoire is seen in older people, characterized by a decrease in been described such as antigen-independent activation and
naı̈ve B cells (CD27; with few somatic mutations in immuno- proliferation rates. These cells that maintain a naı̈ve phenotype
globulin genes) and an increase in memory B cells (CD27þ; with are less capable of producing an adequate response when
multiple somatic mutations) [60,62,64]. These memory B cells presented with a new antigen [77].
present an increased resistance to apoptosis. Furthermore, some Activation of both naı̈ve and memory T cells is a complex
studies describe a subtype of B cell – called aging-associated process that requires the intervention of co-stimulatory molecules
B-cell – that accumulates with age (possibly displacing naı̈ve after the binding of TCR to MHC molecules [72]. CD28 is an
B cells) [58] that respond to innate but not adaptive immunity important co-stimulatory molecule present in T cells and the
stimuli [65], although more studies are needed to clarify their role binding of CD28 to its co-receptor (B7, present in antigen
in humans. presenting cells) results in potent activation stimuli for T cells
Consistent with the change in B cell subsets, antibody [79]. CD28 presence in T cells decreases with cell differentiation
production is also affected by age. In response to vaccines, from naive to central memory to effector memory cells as a result
older people present a slower response, a reduced clonal of persistent antigenic stimulation and repeated proliferation
expansion of plasma cells that correlates with a decrease in cycles [80]. The activation of T cells via TCR-CD28 does not
20 C. Castelo-Branco & I. Soveral Gynecol Endocrinol, 2014; 30(1): 16–22

seem to be impaired in old people [81]. However, with age, CD28 Telomere shortening
Thymus
expression decreases in both CD4þ and CD8þ 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
CD8þ cells [84]. However, the proliferative capability of these Increased inflammatory acvity
CD27/CD28 cells seems to be better preserved in the CD4þ
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 CD8þ cells but also in CD4þ, of NK
markers, such as CD56 [86–88]. 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.
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 CD8þ " Cytokine production imbalance
cells seem to be affected to greater extent, which suggests that # IL-2
CD4þ 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
CD8þ/CD28 cells and CMV infection [88,92]. This immune
Table 3. Changes affecting the innate immune system with age.
profile is associated with increased mortality and age-related
diseases [92]. Impairment of anatomical barriers
# Number of Langerhan cells
Inflamm-aging # Pathogen recognition by DCs
" Numbers of less functional NK cells
Inflamm-aging refers to a chronic state of low-grade inflamma- # Neutrophil survival in response to stimuli
tion that accompanies the aging process characterized by # Neutrophil phagocytic function and respiratory burst generation
increased levels of circulating cytokines and pro-inflammatory # Cytokine production by macrophages
markers [93]. It is associated with many age-related diseases, such # T cell activation by macrophages
as atherosclerosis, Alzheimer’s 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 Table 4. Changes affecting the adaptive immune system with age.
records the shift in cytokines with aging. However, in healthy
aging these pro-inflammatory states seem to be somewhat # Lymphoid progenitors production
# Number of B cells, specially naı̈ve cells
inhibited by anti-inflammatory cytokines such as IL-10 [97]. " Apoptosis resistance of memory B cells
# Antibody production, with lower affinities and decreased opsonizing
Conclusions abilities
Immunosenescence is a complex process that affects the Delayed antibody response to new antigens
# Number of T cells, specially naı̈ve and CD8þ cells
immune system on the whole (summarized in Tables 3 and 4)
" Antigen-independent activation and proliferation of naı̈ve T cells
and reflects upon the organism’s ability of adequately respond- # CD28þ T cells as a result of accumulation of mature cells
ing to pathogens. There is no single impairment to be blamed; " Apoptosis resistance of memory T cells
instead it is a multilevel dysfunction that affects individuals to a Acquisition of NK cell markers by T cells
different extent. As a result, elderly people present increased # Cytotoxic capability of CD8þ cells
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 Declaration of interest
low-grade inflammatory state that has been implicated in the The authors report no conflicts of interest. The authors alone are
pathogenesis of many age-related diseases (atherosclerosis, responsible for the content and writing of this article.
Alzheimer’s disease, osteoporosis, diabetes) [95–97]. Also, the
increased prevalence of cancer has been associated with an age-
related impairment of the immune surveillance function [22]. References
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