Sci. Aging Knowl. Environ., 7 January 2004
Vol. 2004, Issue 1, p. pe2
[DOI: 10.1126/sageke.2004.1.pe2]

PERSPECTIVES

Maintaining Your Immune System--One Method for Enhanced Longevity

Evi Wollscheid-Lengeling, Rolf-Joachim M�ller, Rudi Balling, and Klaus Schughart

The authors are in the German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany. E-mail: ewl{at}gbf.de (E.W.L.)

http://sageke.sciencemag.org/cgi/content/full/2004/1/pe2

Key Words: humoral immunity • cell-mediated immunity • inflammation • innate immunity • lymphocytes

From the moment we're born, death is unavoidable. Extending our life spans is important to humans, but maintaining one's health span is even more crucial for a high quality of life. The immune system is one of the most important determinants that influence not only how long we live but also how well we feel as we reach octogenarian status and beyond. In this Perspective, we discuss and integrate some of the current research findings related to the aging immune system.

Introduction to the Aging Immune System

What do we know about age-related changes in the immune system?

As a result of the mounting drive in recent years to understand the mechanisms of aging (see "Aging Research Grows Up"), scientists from a variety of research fields now study mechanisms of the aging process in diverse model organisms. From studies on mice, rats, and humans, it has become apparent that in addition to other factors, the declining immune system plays an important role in the onset of many age-related health problems, thus affecting life span. The progressive dysfunction of the immune system--immune senescence--is a major cause of the increased susceptibility to infections and deleterious autoimmune reactions observed in aging organisms, including humans.

Two complementary arms of the immune system protect humans from pathogens and cancer: natural (innate) immunity and adaptive (acquired) immunity. Both components interact closely with each other (1). Innate immunity is our first line of defense against pathogens. It is called to action immediately after the body encounters a pathogen and is supported by polymorphonuclear leukocytes (PMNs, also called neutrophils), dendritic cells (DCs) (Fig. 1), macrophages (also called mononuclear phagocytes), natural killer (NK) cells, and the complement system (see below).



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Fig. 1. Scanning electron microscope image of an immature human DC. [Credit: Manfred Rohde, GBF]

 
Adaptive immunity responds to trespassers in a more specific manner but takes longer to achieve results. The adaptive immune system, however, can "remember" an intruder and act more quickly to battle it when a second encounter ensues. This branch of the system is supported by white blood cells called T lymphocytes (which participate in so-called cellular immunity) and B lymphocytes (which generate specific antibodies against pathogens, the basis of so-called humoral immunity). The process of cellular immunity involves the direct binding of T lymphocytes to foreign antigens on the surface of infected or abnormal host cells, causing a cytotoxic response. Tumor cells exhibit foreign antigens on their surface and can thus prompt an immune reaction involving T lymphocytes, NK cells, and macrophages. Humoral immunity defends the body against bacterial and viral infections. B cells from the bone marrow, lymphatic tissue, and blood produce antibodies that interact with pathogens and their toxic products and initiate the bacterial or viral cell destruction.

The immune system can go awry and attack normal host cells and organs in a process called autoimmunity, which involves both the cellular and humoral branches of the immune system. For a more detailed description of B and T lymphocyte functions, see "Immunity Challenge".

The development and function of the immune system are tightly regulated to ensure the generation of protective immune responses against invading pathogens while avoiding autoimmunity. During the aging process, the humoral and cell-mediated immune systems lose some of their ability to battle a large variety of exogenous antigens, and lymphocyte clones with self-reactive potential accumulate (2). Therefore, the elderly suffer a reduced ability to fight infectious diseases and eliminate tumor cells, as well as an increased autoreactivity, with a possible increase in autoimmune diseases. Aged individuals also respond poorly to vaccines.

Age-Related Changes in Innate Immunity

Cells of the innate immune system

Invasions by pathogens are initially battled by the innate immune system, which exists in all vertebrates and acts within minutes of infection. The innate immune system is supported by two major families of phagocytic cells: PMNs (short-lived, abundant white blood cells) and macrophages, which arise from continuous maturation of circulating monocytes that, when mature, migrate into tissues throughout the body. Both cell types recognize pathogenic microorganisms through cell surface receptors that can distinguish pathogen from host. Once the bacterium is engulfed by the macrophage, it induces the secretion of cytokines: proteins that act as intercellular mediators in a paracrine or autocrine fashion, including chemokines (cytokines that are chemotactic for leukocytes and monocytes circulating in the bloodstream). These proteins then initiate a process known as inflammation, the body's response to bacterial constituents (see below). The PMNs and macrophages are further assisted by DCs, NK cells, and the complement system.

DCs are long-lived, specialized phagocytic cells that migrate from the bone marrow to peripheral locations to inspect the environment for pathogens. When they travel to the lymph nodes through the lymph they interact with na�ve lymphocytes. If the DCs have been in contact with bacteria or viruses, they degrade these organisms intracellularly and present the pathogen's antigens to T lymphocytes in the lymphoid organs (Fig. 2). Thus, the DC is activated by the uptake of a pathogen and becomes an antigen-presenting cell (APC). NK cells circulate in the blood and, if activated through interferon or macrophage-derived cytokines, bind to infected or foreign target cells and kill these cells by releasing cytotoxic granules on their surface that penetrate the cell membrane and induce programmed cell death.



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Fig. 2. Adhesion to and invasion of a human DC by the bacteria Listeria monocytogenes. The bacterial cells (yellow) adhere to and invade the DC (red). [Credit: Manfred Rohde, GBF]

 
The complement system consists of a variety of distinct plasma proteins that are activated through enzymatic cleavage. After cells of the innate immune system recognize the invasion of foreign organisms, complement proteins are activated locally, at the site of infection, and induce a series of potent inflammatory events. Inflammation is characterized by pain, redness, heat, and swelling at the site of an infection. It causes the conveyance of additional effector molecules and cells to sites of infection to support the killing of invading microorganisms by macrophages. The second role of inflammation is to prevent the spread of infection, and the third is to aid in tissue repair.

PMN function in the elderly

Of the various reactions carried out by components of the innate immune system, the first is mediated through PMNs. These white blood cells are recruited to tissue sites in response to inflammation or infection, and they release toxic oxygen metabolites and proteolytic enzymes that defend against invading bacteria and parasites. In young adults ages 22 to 32, cytokines [such as interferon-{gamma} (IFN-{gamma}) and interleukin-2 (IL-2)], growth factors [such as granulocyte-macrophage colony-stimulating factor (GM-CSF)], and bacterial products [such as lipopolysaccharide (LPS)] rescue PMNs from apoptosis, thereby allowing these cells to continue to produce the superoxide anions needed to kill the pathogens they have engulfed. In the elderly, PMN function is sensitive to the concentrations of these cytokines and growth factors at the site of inflammation, and thus the killing ability of PMNs can be mitigated by increased apoptosis. PMNs show an age-related diminution in their capacity to be rescued from apoptosis by proinflammatory mediators (such as GM-CSF and LPS) after in vitro activation by Fas antigen, a cell surface protein that mediates apoptosis (3). This change may prevent PMNs from accumulating in inflamed tissues and be partially responsible for the increased susceptibility of elderly individuals to infections.

As part of the inflammatory response, circulating PMNs undergo both random and directed migration from the blood to sites of infection by binding to adhesion molecules expressed on the surface of endothelial cells that line the blood vessels. This process was studied in vivo and in vitro in 10 healthy elderly people (4). These experiments revealed that PMN mobilization provoked through skin abrasion is significantly reduced in elderly patients as compared with a younger control group. Further, expression of CD11 (a molecule that is critical for leukocyte adhesion) on the plasma membrane of PMNs was found to be significantly higher in unstimulated PMNs isolated from the younger cohort. After stimulation, CD11 expression was increased in PMNs from elderly individuals, but not as much as in young cells.

A separate study assessed other parameters of PMN function, such as adherence of PMNs to endothelial cells and chemotaxis, including directed and random migration of PMNs. Chemotaxis was defined experimentally as migration through a filter that had endotoxin-activated serum on one side and as movement into a second filter that did not have endotoxin-activated serum on either side. None of these functions differed significantly between PMNs isolated from old and young people.

Functions of other cells of the innate immune system in the elderly

Within the innate immune system, the macrophages represent an evolutionarily old defense mechanism. Invading and replicating microorganisms or tumor cells in the host tissue are, in most cases, recognized by macrophages via cell surface receptors. The key functions of tissue macrophages include phagocytosis of foreign organisms and infected cells, killing of tumor cells, and activation of other macrophages. After maturation from circulating monocytes, which is induced by their interaction with pathogens, macrophages activate other macrophages to release cytokines, chemokines, and other products, such as IL-1, IL-6, IL-12, IL-8, IL-10, IFN-{gamma}, prostaglandin E2, tumor necrosis factor-{alpha} (TNF-{alpha}), and reactive oxygen and nitrogen intermediates. The production of cytokines by macrophages is important for stimulating the activation of and interactions among other cells of the immune system to initiate an adaptive immune response and, when the pathogen is defeated, for turning these immune pathways off.

Impairment of macrophage activation in aged mice leads to an increased susceptibility to parasitic infection and a decrease in tumor cell lysis, both of which result from a dampened response to IFN-{gamma} or bacterial LPS (1). A reduction in the lysis of tumor cells has also been detected in elderly humans as a result of decreased production of reactive oxygen and nitrogen intermediates by macrophages (5). This age-related reduction in the immune system's ability to fight pathogens and tumor formation may lead to a compensatory continuous stimulation of macrophages and be followed by a subclinical chronic inflammatory process in aged individuals (6). The occurrence of age-associated degenerative diseases, such as Alzheimer's disease, atherosclerosis, and rheumatoid arthritis, with chronic inflammation implies that, once triggered, the activity of the innate immune system may contribute to disease pathology (see McGeer Review).

NK cells derive from hematopoietic stem cells and are crucial for the recognition and killing of tumor cells and virus-infected cells, which is done without the need for immunization or preactivation (7). With age, NK cell activity decreases, but the effect is partially compensated for by an increase in their number (1, 2).

From the Innate to the Adaptive Immune System

The production and signal strength of a variety of cytokines produced by distinct cells of the innate immune system are crucial to the initiation of the adaptive immune response. Thus, when the innate immune system is impaired, as in the elderly, the efficiency of the adaptive immune system is affected as well.

Activated APCs are necessary to initiate an adaptive immune response. Tissue-resident DCs travel through the lymph to regional lymph nodes, where they interact with na�ve lymphocytes. Initiation of the adaptive immune response starts with the engulfment of a pathogen by DCs. DCs that have taken up a pathogen become activated and are highly effective APCs. These APCs travel to a nearby lymph node to present the pathogen's antigens to T lymphocytes. This process activates the T cells, causing a clonal expansion of na�ve T cells and their differentiation into armed effector T cells (8). This maturation and mobilization of DCs can be demonstrated both in vitro in tissue culture and in vivo with immature DCs of the skin. Nonactivated DCs possess the ability to tolerize T cells to self-antigens, thus avoiding autoimmune reactions that otherwise could lead to diseases such as multiple sclerosis and diabetes.

Age-Related Changes in Adaptive Immunity

DCs and APCs

Mature DCs synthesize large amounts of IL-12, which enhances NK-, B cell-, and T cell-mediated immunity (8). In frail elderly people [that is, older individuals with clinical signs of infection, inflammation, malignancy, or abnormal organ function, or those who take medication for the treatment of defined diseases or have made unhealthy lifestyle choices (9)], there is a reduction in antigen presentation and in the production of IL-12 and T cell stimulatory molecules by DCs (9). IL-12 drives T cells to proliferate and synthesize and secrete IFN-{gamma}. IL-10, a key cytokine that can suppress cell-mediated immunity and the maturation of DCs, is produced by T cells, monocytes, and macrophages; and in human T cells, IL-10 production is induced by IL-12 (probably mainly through initial IL-12 overproduction by monocytes and macrophages) (10). IL-10 is elevated in the elderly and probably is involved in age-related impairment of immune function (9).

T lymphocytes

In mammals, T lymphocytes are trained in the thymus, a gland that lives behind the breastbone. The development of T lymphocytes is divided into three phases: pre-thymus, thymus, and post-thymus. In the bone marrow of adult mammals (and, in early embryos, in the liver), stem cells differentiate into lymphatic cells. A proportion of the lymphocyte precursors migrate to the thymus, where T cells are generated. After arrival, the pre-lymphocyte migrates to the medulla of the thymus, where, under the influence of thymus hormones, the pre-lymphocyte begins to express membrane markers (that is, membrane antigens). In the thymus, these cells come into contact with endogenous and foreign antigens. This contact is the basis for the ability of T cells to distinguish between self and nonself. Interaction with foreign antigens on the surfaces of APCs activates the T cells (see above). The various T cell maturation steps are characterized by the expression on the cell surface of different versions of the T cell receptor (TCR), an antigen recognition molecule. Most T cell maturation is completed in the cortex of the thymus gland. The epithelial cells of the cortical stroma express major histocompatibility complex (MHC) class I and II molecules, which, when in contact with the receptor on the surface of developing T cells, is important for their maturation.

After birth, the thymus begins to atrophy in a process called thymic involution. This lifelong progression continues until the thymus becomes largely dormant in elderly people. The decline in T cell function with age is the result of this developmental process (1). In addition, bone marrow stem cells are subject to age-related changes that result in a decrease in the number of na�ve T cells and an accumulation of memory T cells. Memory T cells are long-lived cells that respond to specific antigens. With age, the remaining population of memory T cells consists of normally functioning and hypofunctioning cells (1).

As a result of thymus involution and the consequent decrease in the number of na�ve T lymphocytes, the ratio of antigen-experienced memory T lymphocytes to na�ve T lymphocytes increases with age (1, 2). In addition, older people display a significant decrease in T lymphocyte response to mitogens and antigens. Also decreased is T cell cytotoxicity (that is, the ability of the T cell to kill infected target cells) (11). It is not clear whether changes in the TCR repertoire contribute to age-related immunological deficiencies; although in humans, there is a reduction in the expression of the TCR, which is needed for functional T cell activation (12).

B lymphocytes

B cells develop from precursor cells in the bone marrow with the help of nonlymphoid stromal cells, which adhere to the B cell precursors. The stromal cells secrete growth factors that induce the B cell precursors to differentiate and proliferate. Final maturation of immature B cells occurs in peripheral lymphoid organs through the rearrangement and expression of immunoglobulin genes, and this process generates a wide repertoire of antigen receptors on the surface of B cells. Activation of mature B cells is initiated by the binding of foreign antigens expressed on the surface of activated T cells to the antigen receptors on the surface of B cells. Activated B cells then differentiate into antibody-secreting cells, and the secreted antibodies flood the extracellular space to protect the host from extracellular microorganisms and the spread of intracellular infection.

B cells from older animals show impaired activation and proliferation, a decrease in the amount of antibody production, and less display of membrane-bound antibodies than do B cells from younger animals (12). Some of the age-dependent decline in B cell function is caused by a decline of the expression of a molecule, CD40, on the surface of T cells, which is essential for the activation and differentiation of B cells. Furthermore, the increase in the production of specific antibodies by B cells in response to vaccination is significantly impaired (1).

Diseases of the Aged

Immune cells are involved in age-related diseases such as osteoporosis, Alzheimer's disease, and rheumatoid arthritis (see "Autoimmune Diseases and Aging" below). The decline in estrogen during menopause leads to an increased synthesis rate of IL-1 by monocytes/macrophages, resulting in an increased production of IL-6 by osteoblasts, cells that regulate new bone formation (see "The Plot Thickens on Thin Bones"). IL-6 induces bone resorption and may therefore be responsible for the development of osteoporosis.

As mentioned briefly above, inflammatory reactions are known to be involved in the pathogenesis of Alzheimer disease (see McGeer Review). Lesions characteristic of Alzheimer's disease are amyloid depositions in the brain parenchyma and its vasculature (see Honig Case Study). {beta}-amyloid deposits were found to be closely associated with complement components and microglial cells that secrete larger amounts of TNF-{alpha} and IL-1 than normal (11). The elevated amount of TNF-{alpha} might mediate the neurotoxicity. And IL-1 stimulates the production of amyloid precursor protein, which in turn leads to the generation of amyloidogenic metabolites (11, 13). The immune system tries to protect against Alzheimer's disease through the generation of cytokines: IL-1, IL-3, IL-6, and TNF-{alpha} all exist in high concentrations in the Alzheimer's disease brain and probably affect the survival of neurons, although the precise mechanism is not yet known (14). Furthermore, inflammatory molecules, such as cytokines, prostaglandins, and acute phase reactants (for example, C-reactive protein), which are produced by brain cells, including neurons, are thought to play an important role in the pathogenesis of Alzheimer's disease. Inflammatory factors might be involved in the development of and are responsible for the spread of the pathology to surrounding brain tissue (9). However, there are also indications that the immune system possesses the ability to degrade the substances that accumulate to form senile plaques, even when these proteins are already in their immobilized forms (11).

Autoimmune Disease and Aging

As the body ages, the ability of the immune system to properly distinguish between self and nonself diminishes, and immune cells begin to produce antibodies to components of the resident organism, so-called autoimmune- or autoantibodies. This happens in diseases such as rheumatoid arthritis and atherosclerosis (11). The initiating event is an autoimmune reaction against the stress factor heat shock protein 60 (Hsp60), which binds to proteins and prevents their unfolding or targets them for degradation (see "Stress for Success", Lithgow Perspective, and Gray Review). Activated T cells are the first cells found in the arterial intima at sites predisposed to develop atherosclerosis. In order to understand the development of atherosclerosis as an immune reaction, it is important to emphasize that Hsp60 is highly conserved throughout species from bacteria to human, and human Hsp60 is >95% similar to bacterial Hsp60 at the DNA level. Further, HSPs in general and Hsp60 in particular are quantitatively important and highly immunogenic components of viruses, bacteria, and parasites. Thus, atherosclerosis likely appears as a side effect that results from antibody cross-reactivity with human Hsp60 when our immune systems attempt to protect us against exogenous Hsp60.

Another cause of the increase in autoimmune antibodies with age may result from immune responses against self molecules that have been altered by abnormal age-related modifications of macromolecules, such as oxidation or glycosylation. In their new states, the macromolecules are now recognized as nonself, and the immune system goes to work to eliminate them from the body.

Does a Healthy Immune System Have an Effect on Life Span?

A study with centenarians shows that youthful and efficient immune defense mechanisms play an important role in the extension of an organism's life span and the absence of diseases (15). These well-preserved individuals reach the extreme limit of human life, while at the same time escaping major age-related diseases. For example, most centenarians are free of diseases such as cancer, dementia, diabetes, cardiovascular diseases, and cataracts. Immunological studies have shown that centenarians exhibit important differences in their immune systems when compared with other elderly persons between the ages of 65 and above. Centenarians are virtually free of organ-specific autoantibodies, indicating the absence of significant autoimmune responses. Their T cells retain full proliferative capability, and the only difference centenarian T cells show when compared with T cells from people in their first three decades of life is a delay in peak responsiveness (that is, more time is needed to reach the point of highest lymphocyte proliferation) (15).

These findings suggest that centenarians carry a well-preserved and efficient immune defense system. The fit immune systems of centenarians likely result from a healthy lifestyle (high-quality nutrition, acceptable working conditions, avoiding smoking) and/or a favorable genetic background, which accounts for about 35% of the variance in invertebrate and mammalian life spans (15, 16).

The hypothesis that the remaining immune capacity in an elderly individual might be an indication of his or her mortality risk also has arisen from a variety of other studies with humans and mice. For example, studies with humans with Down syndrome show that NK cell activity is persistently low and might be an indicator of threatening morbidity, because this disease is an example of precocious aging. Research on the MHC, which controls immunoregulatory cell functions and interactions, has shown that congenic mice that are genetically identical except for the short MHC region of the genome show considerable variation in maximum life span. Also in mice, high concentrations of CD8+ T cells have been shown to be associated with short survival times (12). These are just a few hints as to the central role of the immune system in the aging process.

Finally, the role of immune responsiveness in the context of aging also has been investigated in genetically selected mice that exhibit either a high or a low (Biozzi mice) antibody response, as compared with normal mice (17). Results from the genetic selection of over 1000 mice demonstrate that genes expressed in cells of the immune system affect life span and disease. Specifically, the study measured the antibody response against agglutinin, the occurrence of lymphomas, and mean life span. Mice with a high antibody response exhibited a longer life span and a lower incidence of lymphomas than did mice with a low response (2, 18). These results provide further indications that the fitness of the immunological defense system greatly influences the longevity and quality of life of aging mammals (2) (see also Lithgow Perspective).

Should Health Care Workers Vaccinate the Elderly?

Vaccines introduce foreign antigens (a pathogen or components of a pathogen) into the host and cause the multiplication of specific T and B cell clones that can be recruited the next time the host encounters the antigen. Thus, the vaccine recipient acquires long-term protection against the pathogen through long-lived antigen-specific lymphocytes. The environment and the possibility of vaccination influence one's chances of acquiring a disease caused by infection with a viral, bacterial, or protozoan pathogen. However, whether to vaccinate elderly patients is currently under debate. Some scientists observed a poor response to vaccines in the elderly, because of a diminished magnitude and duration of the antibody response (1, 11) (see "Battle Scars"). Most important for the elderly is protection against pneumococcal pneumonia, influenza, and tetanus (11). For influenza, the situation is complicated. In a fairly recent study (19), 153 elderly humans aged 65 to 98 were immunized with a trivalent, inactivated influenza vaccine that contained three hemagglutinin antigens. Scientists observed that 46% of the elderly exhibited no vaccine response (which was defined as a fourfold increase in antibody production) to any of the three strains, in contrast to younger control patients, indicating that the ability to respond to the vaccine declines with age. Fortunately, an influenza vaccine that contains adjuvants significantly boosts the immune response in both young and elderly patients.

These observations raise many questions, including the following: When might humans be too old for vaccination, and how long does a vaccination protect against infections? However, there are no simple answers to these questions, because the outcome depends on a number of different factors, such as age, a background of chronic illnesses, and preexisting immunity.

Conclusions

It is necessary to understand the basic mechanisms of aging in order to satisfactorily decrease the medical, economic, and social problems associated with advancing years. Thus far, much attention has been paid to gene mutations and calorie restriction, but a better understanding of the aging immune system may provide the most important clues for slowing the inevitable decline associated with the passage of time.

Revealing research on the adaptive immune system has brought it front and center with respect to understanding immune changes in the elderly. And the innate immune system, once neglected by researchers, has recently come into focus because of its role as initiator and modulator of the adaptive immune response. Researchers are now able to obtain cells of the innate immune system in sufficient quantities to study their function and thus characterize the changes that occur with age.


January 7, 2004
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Citation: E. Wollscheid-Lengeling, R.-J. M�ller, R. Balling, K. Schughart, Maintaining Your Immune System--One Method for Enhanced Longevity. Sci. Aging Knowl. Environ. 2004 (1), pe2 (2004).




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