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PHYSIOLOGY 23: 64–74, 2008; doi:10.1152/physiol.00040.2007
Aging of the Immune System as a
Prognostic Factor for Human Longevity
Anis Larbi,1 Claudio Franceschi,2
Dawn Mazzatti,3 Rafael Solana,4
Anders Wikby,5 and
Graham Pawelec6
1University
Accumulating data are documenting an inverse relationship between immune status,
response to vaccination, health, and longevity, suggesting that the immune system
becomes less effective with advancing age and that this is clinically relevant. The
mechanisms and consequences of age-associated immune alterations, designated
immunosenescence, are briefly reviewed here.
Average life expectancy at birth of Homo sapiens did
not exceed 40-45 years until a couple of centuries ago
even in the most developed countries, although the
survival of a small number of very old people even in
“primitive” societies is well documented. However,
aging of a large proportion of the population is a very
recent phenomenon that emerged as a consequence
of the reduction of infant mortality and improving
medical care and environmental conditions (127).
Infectious diseases have been a pervasive threat for
survival throughout evolution; thus strong immune
responses and inflammation in early life have played a
major role in the survival of humans in the unforgiving
environment that was common to our ancestors.
Accordingly, we can assume that genes and gene variants associated with strong immune responses and
inflammation have been positively selected, because
they likely contributed to ensure survival to reproductive age. Indeed, studies on the evolution of the
immune system indicate that stress responses, immunity, and inflammation are deeply interconnected and
constitute an integrated network of defense capable of
coping with most stressors, including microbial antigens (37, 79).
On this evolutionary background and on the basis of
data collected in the last 15 years on centenarians and
from longitudinal studies of free-living humans, two of
the best models to study healthy aging and longevity in
humans (34, 78), we argue that lifelong exposure to a
variety of infectious agents for a period much longer
than previously encountered during human evolution
(chronic antigenic load) is a major influence driving
the aging of the immune system (33, 85).
“Immunosenescence” is the term coined for the ageassociated decreased immune competence that renders individuals more susceptible to disease and
increases morbidity and mortality due to infectious
disease in the elderly compared with the young (18,
42, 60, 85, 123). The nature of immunosenescence will
be discussed in the next section. The main observed
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result at old age is a decrease in adaptive immunity
and increased low-grade chronic inflammatory status,
which has been referred to as Inflamm-aging (32), a
process that impacts on the internal milieu of the body
by changing its composition over time (27) (change
not only of the immune cells but also of their
“microenvironment”). Within this perspective, chronic antigenic load and inflamm-aging are strong candidates as major driving forces of the rate of aging and of
the pathogenesis of major age-related diseases (16, 17,
119). Inflamm-aging is the end result of such a process
characterized by activation of macrophages and
expansion of specific clones (megaclones) of T lymphocytes directed toward antigens of common viruses
such as cytomegalovirus (CMV) or Epstein-Barr virus
(EBV) (FIGURE 1; Refs. 31, 49, 81, 85, 116). All these
phenomena have a strong genetic component, as
shown by studies in old people and centenarians,
which collectively established that the frequency of
several variants (polymorphisms) of important genes
involved in immune responses and inflammation are
present at a different frequency in long-lived people
compared with young subjects (FIGURE 1; Refs. 23,
41, 96, 97, 116). Within this scenario, the age-related
changes in body composition (loss of muscle/bone
mass and increase of fat mass) (84), insulin growth factor 1/insulin pathway (36), as well as inflammatory
phenomena occurring in the central nervous system
are also emerging as critical influences on the development of frailty and major age-related diseases (59,
121, 124).
The genetics of aging and longevity are quite unusual and have specific and unexpected peculiarities (15).
First, for example, the same gene polymorphism can
have different (beneficial or detrimental) effects at different ages, a phenomenon we proposed calling “complex allele timing” (15). Indeed, gene variants that are
apparently neutral at young age show a greatly different biological role at old and very old age in terms of
phenomena such as apoptosis, cell proliferation, and
cell senescence. This is the case for a common polymorphism at codon 72 of the TP53 gene encoding p53,
1548-9213/08 8.00 ©2008 Int. Union Physiol. Sci./Am. Physiol. Soc.
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Human Longevity, Genetics,
and Inflammation
of Tübingen, Center for Medical
Research,Tübingen, Germany;
Centre “L. Galvani” (CIG),
University of Bologna, and
Department of Gerontological Research,
Italian National Research Centre on Aging (INRCA), Ancona,
3Unilever Corporate Research, Colworth Park,
Italy;
Sharnbrook, United Kingdom; 4Department of Cellular
Biology, Physiology, and Immunology, University of
Cordoba, Cordoba, Spain; 5Department of Natural Science
and Biomedicine, School of Health Sciences, Jönköping
University, Jönköping, Sweden; and 6University of Tübingen,
Center for Medical Research, Tübingen, Germany
[email protected]
2Interdepartmental
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Even if we still do not know how general these phenomena (complex allele timing and age-related
increase of homozygosity) can be, it is reasonable to
envisage that the genetics of longevity is likely much
more complex than previously anticipated.
Centenarians are able to counteract the damaging
effects of Inflamm-aging by activating a variety of
anti-inflammatory networks, such as those involving
interleukin-10 (IL-10) and transforming growth factor-␤1, but still benefit from the action of immunity
necessary to maintain health by resisting infectious
disease (27, 114).
Thus centenarians are equipped with gene variants
that allow them to optimize the balance between proand anti-inflammatory cytokines and other mediators
involved in inflammation (11, 35). Indeed, genetic
markers related to a pro-inflammatory phenotype
associated with the major age-related diseases have
been found to be underrepresented in centenarians,
whereas those associated with anti-inflammatory
activity are more highly represented in centenarians,
confirming that the balancing of pro- and anti-inflammatory mechanisms during aging is largely under
genetic control (114). Accordingly, it can be anticipated that a genetic propensity to produce excessive
amounts of inflammatory factors associated with an
insufficient anti-inflammatory response will play a
major role in the development of frailty and age-related pathologies in later (post-reproductive) life, despite
being protective in earlier (reproductive) life.
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a protein playing a crucial role in DNA repair, apoptosis, cell cycle arrest, and senescence. This substitution
of arginine (Arg) for proline (Pro), located in the
polyproline-rich domain, modulates cell growth arrest
and activation of apoptosis and has been studied in
relation to cancer biology and extreme longevity (113).
The Arg variant is associated with a higher susceptibility to oxidative stress-induced apoptosis, whereas the
Pro variant is associated with a higher tendency to cell
cycle arrest and senescence. However, this applies
only to cells from old donors in whom it becomes progressively more evident with age but is not seen in
young donors’ cells (7). Second, an increased homozygosity, likely correlated with the profound age-related
remodelling, has been found at several polymorphic
sites in DNA from old people and centenarians (contrary to the accepted advantage of heterozygosity for
survival at younger age) (10, 15). An example is the
recent identification and characterization of a previously “anonymous” inter-Alu polymorphism associated with human longevity as a TG/CA microsatellite in
the fourth intron of the YTHDF2 gene. Genotyping a
total of 285 subjects of different ages (17-109 years)
revealed that a significant increase of homozygosity
was found in centenarians (10).
Recent methodological improvements have led to a
better understanding of the genetic basis of
immunosenescence. Using recombinant inbred mice,
it is possible to detect quantitative trait loci (QTLs) that
underlie age-related thymic involution. Approaches
have been developed to enable higher resolution mapping of these QTLs and to carry out direct identification
of candidate genes. It is likely that, given the complexity of immune system development, the number of cells
involved in an immune response (and especially the
changes in the immune system with aging), multiple
genetic loci, and many genes will contribute to agerelated changes in immunity (46). Furthermore, recent
studies investigating the molecular mechanisms associated with thymic aging showed the necessity of taking
biological variables such as gender and diet into
account when studying the role of genomics in the
molecular pathways responsible for thymic involution
(62). The use of model organisms facilitates testing different hypotheses regarding the role of genetics in
immune responses. Using several chromosome substitution lines of Drosophila melanogaster derived from a
natural population, Lesser et al. (58) found significant
genetic variation among lines in the immune response
to E. coli, showing improvement, no change, or a
decline with age. Overall, their data suggest that different loci contributed to variation in immune responses
at each age, consistent with the mutation accumulation model of senescence. In mice, following LPS challenge, it was found that 500 genes were activated in
macrophages from young and old individuals, but
more than 150 were activated only in the old or only in
the young (12).
FIGURE 1. Effect of the genetic background and
aging on the immune system
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Immunosenescence and Inflamm-aging, by intimately changing the body microenvironment, have systemic effects on a variety of organs and systems and
must be envisaged and conceptualized within a broad
perspective, such as that proposed by Systems Biology,
an approach that can help us to grasp its complexity
and possibly to formulate rational anti-immunosenescence strategies (9, 106). To this end, an overview of
the multiple facets of immunosenescence will be
given in the next section on age-related changes in
innate and adaptive immune functions.
First Line of Defense:
Innate Immunity
NK cells
NK cells are cytotoxic cells that play a significant role
in innate defense against virally infected cells and possibly tumors, and recent studies support the hypothesis that high NK cytotoxicity associates with healthy
aging and longevity, whereas low NK cytotoxicity associates with increased morbidity and mortality due to
infections, atherosclerosis, and poor response to
influenza vaccination (FIGURE 2; Refs. 8, 72, 99, 76).
Inefficient signal transduction was found to be associated with decreased NK cell cytotoxicity in the aged
(65, 99). For example, it has been shown that the
CD94-NKG2A inhibitory signaling pathway is intact in
NK cells from elderly individuals despite a decrease in
CD94-NKG2A expression (63), suggesting an
increased inhibitory signaling efficiency and
decreased activating signaling at the cellular level.
Moreover, the expression of killer-inhibitory receptors
(KIR), which are more specific to NK cells, was shown
to increase in aging (110). NK cells express a complex
array of activating and inhibitory receptors, detailed
knowledge of which is just now emerging, which is
required to form a clear idea of the role of changes in
NK cells in the elderly (8, 63, 99). So far, only one study
has established the frequency of the KIR
genes/pseudogenes and KIR genotypes in healthy
aged and young people (in the Irish population).
However, no significant associations between KIR
gene expression and aging were found. It is hypothesised that alterations of KIR functions may increase
susceptibility to infections or cancers, and thus a similar study needs to be performed in non-healthy, old
individuals compared with healthy individuals (67).
Other aspects of NK cell function, such as the secretion of chemokines or interferon-␥ (IFN-␥) in
response to IL-2 are also decreased in the aged (66).
NK cells have an important role in immuno-surveillance, and any alterations in their function will influence susceptibility to pathogens and the control of
cancer development (77).
Neutrophils
FIGURE 2. Impaired function of innate immunity in aged individuals
Only dysregulated functions discussed in this review are displayed. Broken lines indicate a decrease in the function, whereas solid lines indicate an over-activation of the
function. NK, natural killer cells; TLR, toll-like receptors; GM-CSF, granulocyte
macrophage-colony stimulator factor; TREM-1, triggering receptor expressed on
myeloid cells-1; ROS, reactive oxygen species; PGE2, prostaglandin-E2; DC, dendritic
cells; PI3K, phosphoinositide-3 kinase; MHC, major histocompatibility complex.
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The number and phagocytic capacity of neutrophils is
well preserved in the elderly. However, certain other
functional characteristics of neutrophils from elderly
individuals, such as superoxide anion production,
chemotaxis, and apoptosis in response to certain stimuli, are reduced (FIGURE 2; Ref. 40). It has been suggested that a decrease in signal transduction of certain
receptors could be involved in the defective function
of neutrophils with advancing age (30). In particular,
the triggering of activating receptors such as Toll-like
receptor-4 (TLR4), granulocyte macrophage colony
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Immunosenescence is the name given to the global
age-associated immune dysfunctions (23, 33, 42, 51,
82). There are several hypotheses to explain the aging
process; the same is true for immunosenescence (41,
85). Virtually all cells of the immune system can
undergo immunosenescence, which can lead to the
general erosion of the immune capacities. Different
animal (4, 38) and in vitro models (75, 86) substantiate
the existence of immunosenescence in humans.
Although it has been generally accepted that some
aspects of innate immunity are well preserved in aging
(87, 100), cumulative evidence in the last decade supports the existence of age-associated changes in the
cellular components of the innate immune system,
including natural killer (NK) cells, phagocytes, and
dendritic cells (DC), which are important in the
increased susceptibility of elderly individuals to infectious diseases.
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stimulating factor (GM-CSF), and triggering receptor
expressed on myeloid cell-1 results in a decreased
response in elderly individuals associated with altered
signal transduction and changes in the structure,
dynamics, and function of lipid raft-dependent signaling in these cells (28, 107). Similarly, anti-apoptotic
signals delivered by GM-CSF failed to rescue
neutrophils from apoptosis in the elderly (29).
Monocytes/macrophages
Dendritic cells
Dendritic cells (DC) are the major antigen-presenting
cells (APC) responsible for initiating an adaptive
immune response. It has been shown that DC retain
their antigen presentation function with healthy aging
(61), whereas DC from frail elderly people display
changes in costimulatory molecules (FIGURE 2; Ref.
1). Moreover, aging is associated with a reduction in
the number of DC derived from myeloid precursors
(18), which also have a more mature phenotype and
an impaired ability to produce IL-12 with age (17, 108).
Other functions such as macropinocytosis, endocytosis, response to chemokines, and cytokine secretion
are impaired, probably as a consequence of decreased
activation of the phosphoinositide-3 kinase pathway
(2). Together, these data suggest that some age-associated immune dysfunctions can originate from
impaired DC functions.
Lymphocyte Senescence
Longevity and lymphocytes: what we learned
from longitudinal studies
The OCTO and NONA immune longitudinal studies
represent population studies of Swedish octo- and
nonagenarians to establish predictive factors for
longevity (123) in the context of functional and disability parameters also measured in these studies. The
OCTO immune study identified an immune risk profile
(IRP) predictive of subsequent mortality (FIGURE 3).
The IRP was characterized by immune parameters
consisting of high levels of CD8+ T cells, low levels of
CD4+ T cells and CD19+ B cells, an inverted CD4-toCD8 ratio, and poor proliferative response to concanavalin A (26). In the subsequent NONA study, the
IRP included characteristics of immunosenescence,
recognized as increased numbers of late differentiated
memory and effector CD8+CD28– T cells and depleted
numbers of naive cells that are able to recognize and
combat new antigens (FIGURE 3; Ref. 121). Extensive
analysis to search for associations between this IRP
and various psychosocial parameters revealed that the
IRP was associated only with evidence of persistent
CMV infection, becoming prevalent in the very old
(78, 121). Therefore, CMV seems to have a more insidious impact on the immune system than previously
believed and also compared with other herpes viruses
examined in these studies (78). The accumulation of
large numbers of CMV-specific CD8+ T cells (122), as
well as the finding that a majority of clonal expansions
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The number of monocytes in peripheral blood does
not change substantially with age, although there is a
decreased number of macrophage precursors and
bone marrow macrophages (90). In macrophages,
phagocytosis, production of reactive oxygen species,
chemotaxis, and response to TLR function are altered
with aging (42, 90). A recent evaluation of TLR expression and function in monocytes from older adults concluded that TLR1/2 function is altered probably due to
defects in signaling (FIGURE 2; Ref. 112). These consequences of aging on human TLR expression and
function may impair activation of the immune
response and contribute to poorer vaccine responses
and greater morbidity and mortality from infectious
diseases in older adults. The reduction of class II
major histocompatibility (MHC) expression is thought
to be responsible for decreased antigen presentation
by macrophages with age (44, 90, 117). The hyper-production of prostaglandin E2 by activated macrophages
at least partly explains the reduced surface expression
of class II MHC (90).
humans and are therefore termed invariant NKT
(iNKT) cells. These cells have been implicated in
diverse immune reactions, ranging from self-tolerance
and development of autoimmunity to responses to
pathogens and tumors. Recent studies showed a
reduced number of iNKT cells with aging (72, 89), suggesting their contribution to decreased protection
against certain pathogens such as gram-negative
bacteria (125).
Other cells
Other cells participating in innate immunity also need
further investigation to fully understand the role of
each and the biological significance of any age-associated alterations. Natural killer T (NKT) cells that
express a CD1d-restricted T-cell receptor (TCR) have a
semi-invariant TCR using the V␣24J␣18 genes in
FIGURE 3. Interplay between the IRP, low grade inflammation, and cognitive impairment in mortality
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Table 1. Age-related changes in T- and B-cell markers and functions
Decreased
Increased
CD28
CD27
ICOS
CCR7
Proliferation with mitogens
IL-2 production
Telomere length
Telomerase activity
Th1 response: IL-2, IFN-␥
Delayed-type hypersensitivity
TCR signal transduction
Proteosome activity
Membrane fluidity
TCR repertoire
CD45+ T cells
Cytoskeleton rearrangement
Thymic output
Efficient response after vaccination
B-cell-derived antibody affinity
B-cell cass swith
Antibody somatic recombination
Lymphopoiesis (B and T cells)
Naïve B cells
Generation of immature B cells
KLRG1
ILT-2 (CD85j)
CD57
CD49d
KIR-positive T cells
KLRF1
CD244
CD45RO+ T cells
Memory B cells
CMV-specific CD8+ T cells
CMV-specific CD4+ T cells
DNA damage
Anergic T cells
The decrease or increase in surface markers, subpopulation frequencies, functions,
activities, and damages displayed are the most accepted. The corresponding citations can be found in the reference section. ICOS, inducible T-cell costimulator;
CCR7, chemokine (C-C motif) receptor 7; KLRG1, killer cell lectin-like receptor
subfamily G member 1; ILT-2, Ig-like transcript 2; KIR, killer cell Ig-like receptor;
KLRF1, killer cell lectin-like receptor subfamily F, member 1.
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expansions, a decrease in the number of CD4+ T cells,
and eventually the development of an IRP (FIGURE 3).
This is accompanied by a low-grade inflammatory
process in very late life, supporting the hypothesis that
immunosenescence is driven by a chronic antigen
load, CMV in particular.
T cells at the population level
The progressively reduced number of naive cells in the
periphery with increasing age is associated with the
thymic atrophy that occurs with aging. However, it is
still debated whether thymic atrophy is responsible for
reduced lymphopoiesis (21). Nevertheless, treating
aged mice with IL-7 has been reported to increase
thymic output, suggesting that intrathymic levels of IL7 have a critical effect on the production of T cells (5).
Old rhesus macaques also respond positively to this
treatment, as shown by increased CD4+ and CD8+ T
cells and a transient increase in the number of the
naive subset, suggesting that the same may be true of
humans. IL-7-treated old monkeys responded significantly better to influenza vaccine than controls (4).
Although some T-cell functions are decreased with
age, others are maintained or increased, the latter
exemplified by the CMV-specific memory T-cell population, which can occupy a quarter or more of the
whole T-cell repertoire (81, 82). These cells display the
CD8+CD28–CCR7–CD45RA+KLRG+CD57+ phenotype
of late-differentiated T cells (Table 1; Ref. 80).
Nevertheless, some of these cells, which include the
CMV-specific CD8+ T cells, still respond to certain
stimuli (3). Recent results indicate that CMV antigens
induce greater production of IFN-␥ in CD4+ T cells in
very old compared with young subjects. The comparative analysis of pp65-specific responses in long-term
carriers revealed that CD8+ and to a lesser degree CD4+
CMV-specific memory T cells do expand during life
(115). It is likely that immune mediators such as
cytokines may play a role in the maintenance of memory T-cell functionality and survival. IL-15 is known to
promote CD8+ memory cell survival and expansion
and was recently shown to induce CD28 downregulation (13). Although IL-15 can be considered as a factor
associated with the accumulation of CD8+ T cells, it
has been recently shown that the late-stage differentiated CD8+ population is the only one to turn over more
slowly in the elderly compared with the young and
therefore accumulate in the periphery (120). Globally,
expansion of CMV-specific T cells does not favor the
delivery of naive T cells to the periphery (49). One
putative intervention to restore a balanced T-cell subset distribution would be to deplete excess and possibly dysfunctional CMV-specific T cells but at the same
time to maintain strict control of this potentially dangerous viral infection. Because CMV infection is
asymptomatic in healthy individuals, it is difficult to
know the time of first infection except in the case of
CMV-seronegative patients receiving an organ from a
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in the very old are associated with CMV, has provided
additional support for the hypothesis that CMV contributes markedly to the development of an IRP and
thus constitutes a good biomarker of immunosenescence in the elderly (81, 93).
The increase in circulating inflammatory mediators
such as cytokines and acute phase proteins seems to
contribute to the low-grade inflammation observed
with aging. Age-related alterations in responses to
stimulation also contribute to low-grade inflammation
by changing the level of pro-inflammatory mediators
such as TNF-␣ and IL-6. Because of their association
with pathological cases and chronic diseases, inflammatory mediators can also act as biomarkers or risk
factors for age-associated diseases and predictors of
mortality (reviewed in Ref. 52). In the NONA immune
study, the IRP was also examined in the context of lowgrade inflammation (124). The IRP and low-grade
inflammation were found to be major independent
predictors of survival, an outcome that was not significantly affected by the individuals’ health status. The
results suggest that the physiological aging processes
of T-cell immunosenescence and low-grade inflammation are of crucial importance in late-life survival
(124) and suggest a sequence of stages for IRP individuals that seems to begin in early life with CMV infection, followed by homeostatic T-cell changes with the
generation of large CD8+CD28– effector cell
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CMV seropositive donor (95). One approach to better
understand the role of CMV or other pathogens in
remodeling the immune system is to assess the T-cell
repertoire. We know from the OCTO/NONA longitudinal studies that the number of clonal expansions
inversely correlates with remaining survival time (93).
More studies are needed to clarify whether this is
CMV-specific or a more general phenomenon
occurring with aging.
T-cell function, activation, and signaling at
the cellular level
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Major functions known to decrease with age are IL-2
production and T-cell proliferation (Table 1; Ref. 60).
This in vitro evidence would suggest an in vivo clonal
expansion deficiency following antigen recognition
partly explaining age-associated increased suscepti-
bility to infections, auto-immune diseases, and cancers. Although T-cell receptor expression is maintained with age, other co-receptors such as the
co-stimulatory molecule CD28 are lost (25) and would
explain the lower activation levels (109). A full state of
T-cell activation is achieved only when an immune
synapse is formed, which facilitates the ligation of
small numbers of T-cell receptors and other molecules
(39). To this end, membrane microdomains called
“rafts,” which are highly motile through the membrane, allow protein polarization at the site of the
immune synapse (39, 103). Thus achieving the activation threshold is dependent on raft functions rather
than purely dependent on the number of molecules
expressed at the cellular level (22). However, a deficiency in raft functions would explain, at least in part,
downstream signaling alterations such as those
FIGURE 4. Age-associated changes at the immuno-synaptic level
For activation, T-cells require sustained physical contact with APC. The closest contacts occur in the central supramolecular activation cluster
(cSMAC) where positive signaling is facilitated by membrane raft-associated structures (22). Other receptors/molecules are located in the peripheral
SMAC and migrate into the cSMAC to regulate activation (39). Here, only the signaling molecules/pathways that are known to display age-related
changes are shown (53). CD4- or CD8-associated Lck recruits and activates Zeta-associated protein of 70 kDa (ZAP-70) and phospholipase C␥-1
(PLC␥-1) on exclusion of CD45. PLC␥-1 is involved in calcium metabolism and protein kinase C activation, whereas ZAP-70 phosphorylates the linker
of activated T-cells (LAT). The last is associated with several molecules including Vav, influencing cytoskeletal rearrangements (22). Together, these
changes in expression (E), phosphorylation (P), or recruitment (R) cause differential activation of mitogen-activated protein kinases (MAPK) and
translocation of transcription factors including NF-␬B, NF-AT, and AP-1 into the nucleus (53, 54). This is decreased in aged T-cells and directly affects
clonal expansion due to decreased IL-2 production. All these downstream events are dependent on upstream alterations such as membrane viscosity
and integrity, which also change with age (75). Unbalanced negative signaling involving inhibitory receptors such as KIR2DL2 or NK receptors can
explain defects in signal transmission. The role of senescence-associated markers such as killer cell lectin-like receptor G1 (KLRG1), programmed
death 1 (PD-1), and CD57 as well as the Src homology region 2 domain-containing phosphatase 1 (SHP-1) in age-related impaired activation is still
unknown (30).
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observed in the initial signaling cascade, translocation
of transcription factors to the nucleus, and gene transcription (53, 54, 75). The signaling events impaired in
aged individuals, which interfered with the formation
of the immune synapse, are depicted in FIGURE 4.
“Although an association between aging and cortisol
levels is observed, the precise mechanism by which
alterations in the neuroendocrine system can impact on
immunity in aging is not clearly identified."
The age-associated immune dysfunctions described
above may partly influence the efficiency of vaccination strategies in the elderly (74, 104). Although
70-90% of individuals <65 years old are efficiently protected after influenza vaccination, only 10-30% of frail
elderly are protected (43). This is partly due to the fact
that antibodies produced by old B cells are commonly
of low affinity, providing less efficient protection compared with young individuals (Table 1; Ref. 56). The
class switching and somatic recombination necessary
for antibody production and diversity are both
impaired in aged humans (38). B-cell lymphopoiesis is
also reduced, which leads to an increase in the percentage of antigen-experienced cells compared with
newly produced naive B cells, parallel to the situation
with T cells. There is an inappropriate differentiation
of pre-B cells from pro-B cells, which is associated
with the reduced generation of immature B cells (71).
There is also evidence suggesting a shift in B-cell
selection leading to increased frequencies of autoreactive cells with aging (48). This directly impacts on
humoral immunity. Vaccination is the best prophylactic treatment for the aged population, and future
research needs to take into account the characteristics
of aged individuals for the design of new vaccines. One
good example is the use of adjuvants in vaccine composition to increase its efficiency. In the next section,
we will review some of the important extrinsic mediators of immunity that can be most easily targeted for
use in the elderly for the prevention of immune senescence because they belong to the lifestyle rather than
the pharmacological category.
Extrinsic Influence on Immunity
Stress
Although factors that initiate psychological and physical stress differ, the ways in which they impact the
immune system are similar and include activation of
the hypothalamic-pituitary-adrenal (HPA axis) and
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Sleep/physical activity
Age-associated sleep dysregulation is a common phenomenon (6). Sleep-deprived rats display a number of
physiological abnormalities, eventually leading to
death. A loss of host defenses has been suggested
based on the occurrence of sepsis in long-term sleepdeprived rats (24) as well as changes in immune mediators, including increased plasma levels of IL-1␤ (20),
soluble tumor necrosis factor-␣ receptor 1 and IL-6
(98), and fluctuations in IFN-␥ (20). Acute sleep loss
also appears to be a potent stimulus of stress hormone
release, including cortisol (69). Additionally, metabolic changes associated with sleep deprivation include
hyperphagia, increased fasting blood glucose levels,
and insulin resistance (101). This last parameter associated with high levels of markers of inflammation is
well documented in elderly populations (73).
One of the most-utilized strategies to improve
immunocompetence in older adults is through moderate
physical activity (126). The immunomodulatory effects of
exercise include a shift in the production of T helper1 and
T helper 2 cytokines, enhanced NK cell and T-cell activity, and improved antibody responses (50). Moreover,
physical activity may enhance immunity through the
release of neuroendocrine factors (88). Additionally,
exercise may enhance immunity through indirect effects
on psychosocial variables such as depression and mood,
thereby attenuating the negative influence of these
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B-cell function and vaccination
the sympathetic-adrenal-medullary (SAM) axis, both
of which influence the immune system (128).
Increased psychological stress in aging occurs in parallel with significant activation of the HPA axis (19, 64,
111). The persistent activation of the SAM axis in
chronic stress responses and in depression impairs the
immune response and contributes to the development
and progression of some types of cancer (92). Stressed
and depressed patients have reduced mitogen-stimulated lymphocyte proliferation, high levels of acutephase proteins, IL-1, IL-6, and TNF-␣. Both stress and
depression are associated with decreased cytotoxic Tcell and NK activities, which could affect immunosurveillance of tumors, and the events that modulate the
development and the accumulation of somatic mutations and genomic instability (64, 92) altogether
influencing longevity (118).
Although an association between aging and cortisol
levels is observed, the precise mechanism by which
alterations in the neuroendocrine system can impact
on immunity in aging is not clearly identified. There is
evidence suggesting that cortisol can act by increasing
T-cell susceptibility to apoptosis as in the case of
immunocompromised individuals (93). The glucocorticoid (GC) cascade is a putative candidate when its
major role in suppressing the synthesis of pro-inflammatory cytokines by the innate arm following trauma
is considered (83), and it may be useful for reducing
age-associated low-grade inflammation.
REVIEWS
factors on immunocompetence. Human exercise intervention studies show a causal reduction in inflammatory
markers, including C-reactive protein (14). Due to the
many other beneficial health benefits associated with
regular moderate exercise, recommendations to improve
levels of physical activity are widely prescribed in the
aging population (51).
Nutrition
Concluding Remarks
Immunosenescence is a complex phenomenon occurring as a consequence of incompletely understood
multiple alterations in hematopoiesis, immune cell
development and differentiation, and cell function. The
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Nutritional factors play a major role in the immune
responses of healthy as well as immunocompromised
individuals. Protein energy malnutrition is common in
the elderly and may be an important factor in influencing diminished immune responses (45, 57, 68).
Furthermore, infections (increasingly prevalent in the
elderly), even when mild, can compromise nutritional
status or lead to recompartmentalization of trace elements as part of the acute adaptive response. This can
lead to a spiral of impaired immunity and exacerbated
infections.
More recently, it was suggested that lipids are very
important mediators of cellular functions (47, 102).
Because cell membranes are primarily composed of
phospholipids, fatty acids, and cholesterol and
because these are the first elements in contact with
free radicals, a change in the composition or quality of
membrane lipids can influence cell fate.
Eicosapentaenoic acid (EPA) infusion induced a dosedependent decrease in neutrophil respiratory burst
only in old individuals associated with a higher incorporation of EPA into plasma and mononuclear cells
than in younger subjects (91). Defects in signaling
associated with aging (FIGURE 4) have a common origin, i.e., the membrane. Changing the extrinsic lipid
composition will directly influence intrinsic events
because of the natural diffusion of lipid into cell membranes (42). Each lipid has a specific effect on cell
functions, and the same lipid may have different
effects depending on the individual’s age (55, 91).
Although nutrition, immune function, and infection
are clearly interrelated, it is no simple matter to quantify these relationships (70). Some agents used in
intervention studies are listed in Table 2. Most of our
current understanding relates to nutrient deficiency
states and acute infections, and often investigations
occur in hospitalized patient settings. Very few studies
have been conducted on primary outcomes, such as
infection/inflammation severity/resistance or quality
of life end points. Although these are potentially highly relevant, the enormous redundancy and pleiotropy
of the immune system makes it hard to predict the
consequences at the organismal level.
adaptive immune system is particularly affected by
thymic involution, reducing the generation of new T
cells, and by the effects of long-term exposure of
peripheral T cells to a variety of antigenic stimuli for a
period much longer than that expected on the basis of
the evolutionary history of H. sapiens. The combination
of the accumulation of molecular and cellular defects at
several levels of immune responses with such chronic
antigenic load results in the paradoxical situation of an
immune system that is concomitantly hyper-activated
(Inflamm-aging) and defective. We suggest that a unifying hypothesis to explain these changes is to be found
within the paradigm of retention or exacerbation of
innate immunity coupled with dysregulation or dysfunction of adaptive immunity. Dissecting biomarkers
used to distinguish healthy aging from age-associated
pathologies or phenomena such as frailty, dementia,
cancer, auto-immune diseases, and increased susceptibility to infections indicates that most of these are
immune-related and are good indicators for survival/mortality. The above hypothesis requires rigorous
testing in humans, from which the performance of longitudinal studies with detailed immunological and
non-immunological follow-up and cause-of-death data
are urgently required. In this context, available data
Table 2. Attempts to restore immunity in the elderly
Intervention
Effects
Vitamin B6
+ Lymphocyte proliferation
Vitamin E
+ PPAR-␣
- Free radical production
- Prostaglandin-E2
- Inflammation
DHEA
- NF-␬B
- Pro-inflammatory molecules
Vitamin D
- IFN-␥ transcription
- Th1/Th2 response
Zinc
+ Vaccine responses
Folate
+ Proliferative response to mitogens
+ Distribution of T cells
+ Cytokine production in the spleen
PUFA
- T-cell activation
- T-cell signalling
- Lymphocyte proliferation
Probiotic
+ Number of CD4+ and CD25+ T cells
(Bifidobacterium lactis HN019)
+ Number and activity of natural killer
cells
+ Phagocytic capacity
The different strategies to restore age-associated immune dysfunctions are shown
(57, 70, 91, 102). An increase or activation of the pathway/process is represented
by + and a decrease/inhibition by -. DHEA, dehydroepiandrosterone; PUFA,
polyunsatured fatty acids; PPAR-␣, peroxisome proliferator-activated receptor
alpha; NF-␬B, nuclear factor-␬ B; IFN-␥, interferon-␥.
PHYSIOLOGY • Volume 23 • April 2008 • www.physiologyonline.org
71
REVIEWS
This work was supported by DFG PA 361/11-1 and SFB
685 B04 and EU contracts QLK6-2002-02283 (T-CIA),
LSHG-CT-2007-036894 (LIFESPAN). R. Solana was supported by grants FIS03/1383, FIS06/1320, and Junta de
Andalucia. C. Franceschi was supported by FP6, Project
GEHA LSHM-CT-2004-503270.
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