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BIOLOGY OF AGING

IMMUNE RESPONSE An introduction to aging science brought to you by the American Federation for Aging Research The immune system is composed nodes marrow of an interdependent set of organs These small oval structures are The is the home of and cells, as well as the found along the . stem cells, the cells that and other chemicals they produce. Immune cells collect in them, and give rise to the various circulating Following is a brief review of what they filter out foreign substances. blood cells. The marrow produces these components are and what In and , red blood cells, which carry oxy- they do. they enlarge and are sometimes gen to our tissues, and , ­referred to as “swollen glands.” small cells critical for proper blood ORGANS OF THE They enlarge because the immune clotting. The marrow also pro- IMMUNE SYSTEM cells in them divide very rapidly, duces white blood cells, of which in order to multiply and defeat­ there are several different kinds, and mucous membranes ­infection. including B cells (B ), The skin is a critical barrier that which make . White helps to prevent invasion by blood cells are the critical immune germs and foreign substances. The thymus is an in the cells of the body. The various mucous membranes chest, under the breastbone. It that come into contact with the produces immune cells called CELLS OF THE outside world also serve to protect T cells and is important in their IMMUNE SYSTEM against invasion. , , and maturation. The thymus is critical contain antibacterial sub- for the development of the im- The various white blood cells stances. The small hairs or cilia mune system of . It also has ­include , lympho- that line the (windpipe) important functions in adult im- cytes, and . beat ­upwards to move foreign munity, but adults can live without Granulocytes matter that has been inhaled a thymus. The thymus drastically These constitute about half of your back out of the ­. shrinks with age and produces circulating white blood cells. They Germ-killing cells line the mucous only very small numbers of new contain granules, or little spots membranes and skin and prevent T cells after , potentially ­visible under a microscope. Types germs from establishing them- setting the stage for T-cell aging. of granulocytes include: selves as ­. Also, mucous New research shows that while membranes, and in particular the adults can live without the thymus, • those in the gut, are densely popu- removing thymus in early child- These are the most common lated by useful hood may accelerate the decline in white cells we have. They live (gut flora), which not only help us with aging. less than a day, and their job digest and maintain health is to react ­immediately to the but also serve as a barrier against presence of foreign matter. harmful microorganisms. The spleen is an organ in the They locate the foreign matter ­upper left quadrant of the through , a re- Lymphatic system ­abdomen that filters out foreign sponse to the release of chem- Lymph is a clear, watery fluid cells. It is an important con- icals in the presence of foreign which bathes cells of the body tainment area for white blood substances. They will surround and carries to them. After cells called lymphocytes. It is a germ or ­ (such supplying the cells with essential ­particularly important in ­protecting as a splinter), engulf it, and re- substances, lymph collects waste against infection with certain lease other chemicals such as and foreign materials and conveys ­, such as Pneumococcus­ , hydrogen peroxide to destroy them to the lymphatics, vessels that have cell capsules—­ it. Pus is simply a large volume that lead to the lymph nodes. After anatomical structures, layered of dead neutrophils and foreign being filtered through the lymph over the bacteria’s cell wall. Cell matter. nodes, lymph re-enters the blood ­capsules make germs slippery stream as plasma. This liquid and harder to kill. While a person • part of the blood is composed of can live without a spleen, he or These granulocytes account lymph, rather than of red and white she would be at a higher risk of for one to three percent of all blood cells. Plasma carries nutri- ­developing certain infections. white cells in the blood. Their ents from the blood to the cells. numbers rise in the presence of certain parasites. However, in the absence of parasites,

2 | Infoaging Guide to Immune Response hey also participate in allergic responses.

• These cells carry the chemical , the source of the woes associated with (hence the value of antihis- tamines). They participate in inflammation.

Lymphocytes These white blood cells are called into action to defeat bacterial and viral infections. There are two ma- jor categories of lymphocytes: B lymphocytes and T lymphocytes, often called simply B cells and T cells. Unlike granulocytes and monocytes, which will respond to any infection, each T or is highly specific and will respond Antibodies are shaped like the letter Y. The very tips of the only to one or a handful of similar arms of the Y vary and can stick to the foreign invader at microorganisms. which they are aimed. • B cells B cells mature in the bone Monocytes Y. There are five major forms of marrow. They “recognize” These cells are produced in the ­antibodies or immunoglobulin specific microorganisms, (i.e. bone marrow and released into (abbreviated Ig): IgG, IgD, IgE, bacteria , , etc.), and in the . They make IgA, and IgM. The base of the the presence of those specific their way to various organs in Y-shaped is similar for , reproduce rapidly the body and mature into mac- all within these five as identical clones. B cells rophages. “eat” ­categories. The very tips of the eventually mature into plasma foreign matter such as bacteria, arms of the Y vary and can stick to cells, which are responsible parasites, inhaled fibers and dusts, the foreign invader at which they for producing antibodies, and anything else they find in are aimed, making them easier for infection-fighting proteins also organs that does not belong there, macrophages to find. specific to the particular germs including pus. Unlike neutrophils, that have invaded the body. they are hardier and much larger, • IgD able to “eat” more efficiently and This immunoglobulin is found • T cells without being destroyed them- on the surface of B cells and T cells. T cells also come in selves in the process. is involved in activating them subcategories. The two main to participate in the immune types are the killer (or cytotox- PROTEINS AND CHEMICALS OF response. ic) T cells, which can kill tumor THE IMMUNE SYSTEM cells and -infected cells, • IgE and helper T cells, which pro- The various immune cells This immunoglobulin partici- vide help to the killer T cells, to make a variety of proteins and pates in the allergic response. B cells, and to macrophages ­chemicals that are also important • IgA (see below). Some T cells also ­components of the immune and IgA molecules generally come serve as regulators to stop inflammatory responses. These in pairs and are found in body immune responses before they include: , such as saliva. go too far. Like B cells, they Antibodies or immunoglobulin They are also found inside the “recognize” specific microor- Antibodies are proteins, made and intestines. ganisms. by B cells, shaped like the ­letter

Infoaging Guide to Immune Response | 3 • IgM IgM molecules gather in The virus, or ­clusters and are involved in HIV, destroys helper T cells, limiting the killing bacteria. body’s ability to fight infection. and These are chemicals that are secreted by cells of the immune system. Chemokines are chemi- cal messengers that recruit other immune cells to where they are needed to fight infection and even . Cytokines are used to augment or diminish the im- mune response and inflammation, and some can also directly kill or ­inhibit germs. Because they ­communicate between white blood cells, also called leukocytes, cytokines are sometimes called .

Complement proteins These proteins are manufactured in the . They circulate in the bloodstream and are activated by the presence of antibodies (thus they complement their activity). They act to puncture and thus burst, or lyse, foreign cells.

Antigens DNAAntigens damage are the alsochemicals contrib on -the Autoimmune AIDS The loss of the recognition of The human immunodeficiency utessurfaces to theof microorganisms development or of foreign cells that are recognized some body as “self” is part ­virus or HIV destroys helper T age-relatedby the immune , system. Antibodies such of . Antibod- cells, limiting the body’s ability to asare heartcreated disease, to specific . can- ies and T cells attack the body’s fight infection. B cells have - own tissue. Some examples of this and its treatments cer,sites andon their . surfaces, which are include some forms of diabetes, Cancer is a disease of out-of-con- proteins that recognize those an- , and . trol cell proliferation. Sometimes tigens. T cells have more sophis- disease this disease becomes manifest ticated antigen-sensing systems Normally, the clumps of antibodies because of a failure of the immune and do not recognize “naked” and antigens that form as we fight system to destroy cancerous cells. antigen. Instead, they recognize infection or invasion are cleared Also, and radia- chopped pieces of an antigen that from the circulation and destroyed. tion given to people with cancer has been processed by other im- If that clearance does not occur, can destroy or weaken the cells mune cells. those clumps can lodge in tissues and organs of the immune system IMMUNE-RELATED DISEASES or small blood vessels and cause as an inadvertent side effect, and damage. this can reduce our resistance to There are a few diseases that are infection. Boosting the ability of related to disorders within the im- the immune system to fight cancer mune system. Among these are: is one of the newest forms of anti- cancer .

4 | Infoaging Guide to Immune Response CHARACTERIZATION OF AGE-RELATED CHANGES IN able to destroy as many microor- IMMUNE RESPONSE THE IMMUNE SYSTEM ganisms. Dendritic cells are a cell type that senses infection, picks Scientists characterize the immune Some scientists refer to immune up the germ, and fragments it to response based on which aspects senescence, a term that describes activate T-cells. It is unclear at the of it they are studying. Those the progressive decline in function present whether and to what ex- ­aspects include: of the immune system with age. tent aging impairs their function. Various aspects of the immune Innate immunity system respond to aging in differ- Adaptive immunity and aging This is the nonspecific part of ent ways. While some components The thymus gland is the organ immunity, or the generalized re- lose function, others increase in the chest that assists in the sponse the body has to the pres- function inappropriately. maturation of T cells. The ­thymus ence of an invader. But innate im- involutes, or shrinks, and these munity also alerts the T and B cells Natural, or innate, changes are already evident by that they should mount an immune immunity and aging puberty. As we mature, the thy- response to eradicate infection. One component of natural im- mus can become nonfunctional munity is the , the by age 50 to 60. How significant Adaptive or acquired immunity cell whose job it is to engulf and This refers to the very specific this is to immunity in is destroy invading cells. With aging, under investigation. How signifi- response that comes in the pres- the balance between the macro- ence of specific antigens. This cant this is to immunity in old age phages that enhance the immune is ­under investigation. While many includes the recruitment of B cells response and the ones that sup- that make the antibodies aimed T cells are made by the thymus press it is altered, and suppressive before the thymus shrinks and at those antigens, and activated macrophages tend to dominate. T cells that also recognize the ­involutes, the problem remains Also, weak T cells in older adults how to maintain these cells for six specific invader. While very spe- can slow the of macro- cific, adaptive immunity also takes to seven ­decades or longer. There phages. function de- is compelling evidence that the much longer to develop than the clines with aging, and they are not nearly immediate innate immunity. naive T cells, which are made by Thus, very often, innate immunity holds and slows down the germ until adaptive immune response We might be fortunate enough to outgrow our allergies develops and is ready to eradicate as we age. the infection.

Humoral immunity This describes the production of antibodies by B cells.

Cellular immunity This refers to the immunity that is controlled by T cells.

Mucosal immunity This is a term that refers to the immune cells and tissues found within the mucous membranes (mouth, intestines).

Allergic reactivity This is the immune system’s ­response to , substances such as pollen or that incite an inflammatory response. the thymus, disappear in old age; also, these cells protect against new infection, and it is precisely those infections (a new strain of flu or a new germ we have not seen before, such as the West Nile virus or SARS) that are most dangerous to older adults. of the thymus is therefore regarded by some as the “holy grail” of pre- venting immune decline in old age.

Older adults not only produce fewer T helper cells, but the ones they do have are often less effec- tive than they were in earlier . Others show aberrant function.

Finally, it appears that many ­autoimmune diseases arise in ­older adults, though the ­incidence of new cases likely peaks in our 30s and 40s. The immune ­system’s ability not to attack “self” diminishes as we age, and we can begin to produce ­autoimmune ­antibodies. This may be due to age-related changes that take place within cells, such as oxida- tive damage from free radicals and glycation, the ­inappropriate are available to protect against some infectious ­insertion of glucose (sugar ­molecules) into DNA and other cell diseases that are particularly deadly for older adults. components. Such small changes to our cells may cause our ­immune colonize the gut (and possibly DISEASES CAUSED BY systems to fail to recognize them other mucosal membranes). ­CHANGES IN THE IMMUNE as our own, and lead to the SYSTEM ­production of auto-antibodies. It is ALLERGIC RESPONSE not clear whether these auto-anti- AND AGING In addition to autoimmune bodies produce disease as often in ­diseases (described above) other older adults as they do in younger This is perhaps the only instance in types of diseases also become adults. which there is good news for older more prevalent as we grow older adults. We tend to produce less because of our aging immune MUCOSAL IMMUNITY IgE, the associated with systems. AND AGING the allergic response to such items as pollen and ­danders. Infectious diseases IIn , the production of anti- Thus, we might be fortunate Immune senescence can permit bodies by cells located in mucosal enough to outgrow our allergies the reactivation of old infections, tissues, such as those found in as we age. such as Herpes zoster or , the mouth and intestines, falls with which is caused by the chicken age, reducing mucosal immunity. pox virus. Immune senescence Also, changes occur in the normal can also cause the reactivation of gut flora, so that different bacteria . less compatible with health now

6 | Infoaging Guide to Immune Response The decline in adaptive immunity Pneumococcal tion in the feet, as can happen with can cause infectious agents to The Pneumococcus bacterium diabetes or poor circulation, can be far more potent in older adults ( pneumoniae) is the mean that a dirty wound may go than in younger people. This major cause of bacterial pneumo- unnoticed, increasing the risk for is seen in the high death rates nia. It can be lethal in older adults the tetanus bacterium to penetrate ­associated with and (and in some younger ones as broken skin. influenza in older adults. well). Pneumococcus is called an encapsulated , and such Of all the vaccines above, not a Other physical changes associ- organisms can be filtered out of single one has been produced to ated with aging contribute to the the bloodstream by the spleen. protect older adults specifically decline in resistance to infection. The pneumococcal vaccine pro- and take into account the changes These include the decreased tects against 23 different forms of occurring in an aging immune sys- cough reflex, which allows bac- pneumococcus. When it was first tem. As we now have more knowl- teria entry into the , and used, it covered fewer subtypes, edge about the challenges that changes in function, and in and its protection was thought can plague an old immune system, men, enlargement, which to be lifelong. We know now that we should be able to improve the can lead to an increased risk of the duration of protection by that above vaccines and generate new urinary tract infections. Loss of vaccine is more limited, and older ones, that will be tailored specifi- the ­ability to secrete in the adults at particular risk should be cally for seniors. stomach in older adults can also revaccinated. Those at particular ­predispose the digestive tract to risk include those with diabetes AND AGING certain ­infections. and other chronic illnesses that Autoimmunity refers to the Cancer can reduce immune response. ­unfortunate phenomenon in which There is speculation that the Influenza vaccine our bodies start attacking our increasing incidence of cancer Influenza (the flu) is caused by a own organs and cells as if they in aging adults may be related to virus. How deadly the flu virus is were foreign materials. Research the decreased ability of the aging depends on what strain is ­passing ­suggests that autoimmunity immune system to recognize and through a population in a given increases as we age, though the destroy cancerous cells before year, and the immune strength of incidence of new autoimmune they proliferate to uncontrollable those who contract the illness. The ­diseases peaks in middle age. levels. most infamous influenza outbreak occurred in 1918 and killed some- Autoimmune diseases VACCINES FOR AGE-RELATED where between 20 and 40 million There are a great many autoimmune DISEASES people worldwide. diseases that can occur when the human immune system turns on No vaccines yet exist for The flu vaccine is an annual itself. Some of these include rheu- ­disease, diabetes, cancer, ­. That is, a new matoid arthritis, lupus, autoimmune ­Alzheimer’s disease, or other ­vaccine is developed each year in thyroiditis, ­, diseases most often associated ­response to the variant of the virus giant cell arteritis, and a host of with aging, although ­vaccines that has arisen for that year; thus, others with long, often difficult-to- for Alzheimer’s disease and individuals need re-inoculation pronounce names. certain types of cancer are every year. in ­development. Fortunately, Some of the autoimmune diseases ­vaccines are available to protect Tetanus seen more commonly among against some infectious diseases Tetanus, a bacterial infection, older adults include polymyalgia that are particularly deadly for can be deadly, especially in rheumatica, which produces older adults. Unfortunately, even older adults. The vaccine against and muscle pains, and temporal the best current vaccines are less ­tetanus is given in multiple doses arteritis, an inflammatory problem effective in older adults. Among in infancy, with boosters given that damages the near the them are: about every ten years in adults. temples. While rheumatoid arthritis It is important for older adults can occur in young adults, there is to remain up to date on tetanus a recognized, late-onset rheuma- ­, since loss of sensa- toid arthritis as well.

Infoaging Guide to Immune Response | 7 Many scientists recommend that the best diet comprises a wide variety of fruits and vegetables, which contain natural antioxidants.

Some background that organ-specific auto-anti- ­attempted to boost immunity Antibodies are proteins our bodies, the ones that can cause through a variety of interventions. ­immune system makes to ­attack ­clinically significant disease, are Most research into adding vitamin foreign substances, such as bac- found at the highest rate among and antioxidant supplements to teria and viruses. the older adults. Centenarians the diet has not shown that these Auto-antibodies are immune had about the same number of supplements improve immunity. It proteins that we ­mistakenly make organ-specific auto-antibodies as is clear, however, that against some part of ourselves. the younger subjects. Non-organ- contributes to the depression of We can ­sometimes erroneously specific auto-antibodies, ­however, the immune response. Thus, many make antibodies against our own were found at relatively high scientists recommend that the DNA ­(anti-nuclear antibodies or levels among the centenarians. best diet, for a variety of ­reasons— ANA); our own mitochondria, The study suggests a provocative perhaps including ­maintaining the ­powerhouses of our cells theory: that those older adults with immune response—comprises (AMA); and cells in our stomachs organ-specific auto-antibodies are a wide variety of fruits and called parietal cells (PCA), among less likely to ­survive to ­become ­vegetables, which contain natural other tissues. When these auto-­ centenarians. The authors also antioxidants. antibodies are organ-specific, speculate that the non-organ Other lifestyle changes can they attack our organs and cause ­specific auto-antibodies the ­improve immune function, as well. disease. When they are not organ- ­centenarians have were not made For example, it is never too late specific, they appear to circulate to ­attack native tissue ­erroneously, to quit smoking. Smoking raises harmlessly in our blood. but perhaps were made in the risk of a variety of infectious ­response to damage in those diseases, such as pneumonia Aging-related changes ­tissues as a result of aging. More and bronchitis, as well as a whole In a small study that compared research, of course, is needed to raft of age-related diseases and younger subjects (under age 60) further clarify these ideas. ­conditions including heart disease to older adults (up to age 93) and cancer. and centenarians (six men and Boosting the immune 20 women, ages 101 to 106), system as we age ­scientists in Palermo, Italy, found Many experimenters have

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