Sunday, July 17, 2011

Human Ageing and Immune System Deterioration


Immunogerontology, the study of the immune system in the elderly, is a relatively new field, and large amounts of data are not yet available on some key components of the immune system as it ages. Conclusions drawn from animal studies, tissue culture studies and human studies investigating the same topic often suggest conflicting conclusions, but these discrepancies will probably be resolved once more data become available. Controversy arises in part because gerontologists have not created commonly accepted definitions of when the aging process begins or at what point an individual is considered "aged." Traditional aging studies merely compared a population of "young" individuals against a population of "old" individuals without attempting to define "young" and "old." Without a clear definition of these terms it is difficult to determine whether immunological differences observed in the aged group result from age only or are instead the results of age-related disease. To work around this problem and develop a definition of what normal aging is for a healthy older population, several studies have focused exclusively on centenarians under the assumption that an individual who lives to be 100 must be exceptionally healthy. Even though this population is extremely limited, the conclusions from these studies have helped to lay the groundwork for broader studies that include a younger elderly population.

It is well-documented that immunocompetence declines with age; that is, as people age, the immune system begins to lose some of its functions and cannot respond as quickly or as efficiently to stimuli. Age-related changes in the immune system have been observed at all levels ranging from chemical changes within the cells, to differences in the kinds of proteins found on the cell surface, and even to alterations in entire organs. Studied separately, some of these changes may seem trivial, but when all of the changes are added up, they radically affect the overall health of the individual.

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Thymus Gland Deterioration

One major change that occurs as the body ages is a process termed "thymic involution." The thymus, located above the heart behind the breast bone, is the organ where T cells mature. T cells are an extremely important, highly-specialized population of lymphocytes that have many functions ranging from killing bacteria to assisting other cell types of the immune system. As humans age, the thymus naturally atrophies. The volume of thymic tissue in a 60-year-old adult is less that 5% that of a newborn, and it is postulated that if humans lived to be more than 120, the thymus would disappear altogether. Although T cells are produced continuously throughout life, over time this progressive decay of the thymus causes a sharp decrease in the number and type of T cells produced.

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It is not known why the thymus deteriorates in this fashion. The prevailing theory is that the thymus is an extremely energy-expensive organ that is most needed in the early stages of life when the body has not had time to develop resistance to foreign antigens. Once the immune system fully develops and can protect the host against a myriad of antigens, the thymus may be too costly to maintain, so it is evolutionarily advantageous to decrease the amount of thymic tissue and use the energy that would have supported the thymus for other purposes. However, because T cells play such a prominent role in immunity, longer-lived individuals still need a continuous supply of "fresh" T cells to protect against newly-encountered antigens, and this slow but progressive loss of thymic tissue has profound effects on the entire immune system of the aged.

Aging affects the functions of T cells in a myriad of ways. Several subpopulations of T cells are found in the thymus and in the blood circulation, among them, naive T cells and memory T cells. Naive T cells are quiescent T cells that have never been exposed to any foreign antigen, while memory T cells are long-lived antigen-activated cells that rapidly respond to a second exposure to the same antigen. When encountering a foreign antigen, naive T cells become activated, stimulate the immune system to eliminate the foreign antigens from the body, and convert into memory T cells. The memory T cells then become dormant and are only reactivated upon a subsequent exposure to that same antigen. A marked difference has been observed between young and old subjects in the subpopulations of naive and memory T cells. In newborns, the ratio of naive to memory T cells is quite high; in adults the ratio is reversed because most of the naive T cells have been exposed to antigen, and hence converted to memory cells. The elderly have almost no naive T cells at all, since as the thymus progressively deteriorates with age, fewer T cells are produced, and the naive T cell subpopulation is not replenished. Consequently, the stock of naive T cells becomes depleted and the aged immune system cannot respond as well as a young person to a "new" antigen.

In addition to the decline of certain subpopulations of T cells, important changes occur at the cell surface of all T cells. When a T cell, using T cell receptor proteins found on the cell surface, binds to an antigen, that environmental stimulus must be communicated to the interior of the T cell. Many molecules are involved in "signal transduction," the process of transmitting the antigen-binding signal across the cell membrane into the cell. Signal transduction is a cascade of chemical reactions, each dependent upon the preceding event. Aged T cells do not display the CD28 antigen, a molecule critical for signal transduction and T cell activation, on the cell surface. Without this protein, T cells remain quiescent and do not respond to foreign pathogens. One indication of a malfunctioning signal transduction pathway in T cells is that the presence of CD69 antigen on the cell surface is lower in elderly individuals. T cells are induced to display CD69 antigen only after antigen binds to the T cell receptor. If the antigen-binding signal is not transmitted to the interior of the T cell, CD69 antigen will not appear on the cell surface, and is an indication that in older people, less signal transduction is occurring.

Another defect of T cell activation among the elderly is characterized by a decrease in calcium. Calcium is a vital element that is absolutely crucial for many biochemical reactions, including signal transduction. A calcium deficiency in T cells effectively halts signal transduction by failing to stimulate enzymes, including protein kinase C, MAPK and MEK, that require calcium for proper function. Decreased amounts of calcium can also inhibit production of cytokines, proteins responsible for coordinating the interaction with antigen and amplifying the immune response.

Ageing and Infectious Diseases

Aging brings on an increased vulnerability to infectious diseases. Central nervous system (CNS) inflammation is associated with various disease processes and neurotrauma. Burns and Goodwin (1997) state "Aging is associated with decline in multiple areas of immune function, but to date no single mechanism has emerged as being responsible for all the observed changes…. It is being increasingly acknowledged that autoimmune processes play a proinflammatory role in the development of many pathological conditions….". Erschler, in an article in Experimental Gerontology (1998), suggests that healthy individuals evidence age-related increases in plasma Interleukin-6 levels, a cytokine, which parallel the vulnerability of the central nervous system to injury. Cytokines are intercellular communicating proteins in the immune system and their measurement may provide a sensitive index of inflammatory processes.

Increased serum levels of cytokines are commonly found in infections. In some way activated cells in the aged CNS are primed to be more hypersensitive to infection and at the same time may be too damaged to react normally to invading pathogens. The damage (hypersensitivity) may be the result of free radical involvement with cell membranes.

Free radical damage to immune cell membrane lipids may ultimately impair the ability of immune cells to respond normally to challenge. Cells have to maintain general conditions necessary for life’s chemistry, insulating them from the local environment. The lipid membrane plays this role. It is equipped with pumps and transporters that manage the transportation of molecules in and out of the cell. The cell membrane has surface receptors conducive to chemical reactions.

Normally, oxidation involves the transfer of a pair of electrons from one atom to another. When an unpaired electron escapes, called a free radical, it can cause damage to the molecules in nearby cell membrane. These single electrons, the free radicals, are highly reactive, seeking to capture another electron to complete a pair and in doing so they damage or destroy the function of another molecule. This type of damage could be a major contributing factor to aging and to infectious diseases.

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Free radical damage is cumulative, building up with age. The cell membrane lipids, an important role player in nerve function, are oxidized, resulting in impaired cell-to-cell communication and transmission. The immune alert systems are slow to react and the memory to deal with the invading pathogen is impaired. Vulnerability to infections occurs.

This oxidative damage changes the local cellular environment, disrupts cellular signals, changes metabolic pathways, and interferes with immunological functions, with resulting potential for infection. A struggle results, with the body repair system trying to repair the damage. The strength of this repair system is compromised with age and the infection takes over.

Oxidative damage has stimulated interest in antioxidants in preventing the development of infectious diseases. Many healthy individuals are now taking vitamins and other supplements for their "protective effect". Maxwell (1999), in a review of the literature states: "a number of long term, prospective, randomized, placebo-controlled trials examining the protective effect of antioxidant supplements have now been completed. The results have been generally disappointing and have provided little evidence of efficacy." He also goes on to warn that certain antioxidants, namely beta-carotine, might increase the risk of cancer in those individuals who are at high risk for developing this disease.

Another substance that has been implicated in immune system deterioration is DHEA (dehydroepiandrosterone), the most abundant adrenal steroid in young healthy individuals. It is released from the zona reticularus of the adrenals after birth, increasing throughout puberty until maximum serum levels are reached in the third decade of life. Then a slow, steady decline commences of about 2% per year in circulating blood levels. By the time one reaches the eighth decade of life, the levels are at 10-15% of the maximum. This information is arrived at by doing a challenge test (adrenocorticotropic hormone challenge test) on different age groups which indicates that the decline is not the result of a change in the metabolism of DHEA, but instead appears to be affected by a diminished adrenal secretory rate. This is contrasted with the cortisol secretion, which is maintained throughout life. The resulting increase in cortisol/DHEA ratio in the blood may be another culprit partially responsible for the vulnerability that develops during aging. This is further confounded by the loss of receptors for DHEA that arise with aging such that there is an irreversible process rapidly overcoming any attempts to enhance the immune system.

The Center for Disease Control reports that infections are the fifth most common cause of death in the elderly. Most common infections are viral and bacterial. This vulnerability is most likely linked to deterioration in the immune system called immunosenescence. ("Immunosenescence is a complex remodeling of the immune system which may contribute significantly to the morbidity and mortality in the elderly. Immunosenescence due to the accumulation of chromosomal damage and induction of gene products that inhibit cell-cycle progression." (Ginaldi, 1999).

Our protective immunity system shows declines in the formation of affinity antibodies, the generation of long-lasting memory immune responses after vaccination and the expression of delayed-type hypersensitivity reaction to antigens initially encountered earlier in life. Virtually every human being that survives into advanced age expresses this immunodeficiency (immunosenescence) to some extent. The goal now is to map underlying cellular and molecular changes and develop ways to stop the deterioration of the immune system or to beef up this system so that deterioration does not take place.

Antioxidants are not the final answer, but may have a part in immune stimulation, increasing the body's capacity to respond to antigens. DHEA may play a functional role in the maintenance of an immune competent state, reversing some aspects of immunosenescence. In some cases, this may be enough to beef-up the effects of vaccinations. No robust evidence of either role exists in the literature. More research is needed to develop appropriate and effective prevention and intervention protocols to reduce the incidence of infectious disease. This calls for long term prospective studies that are not the "fashionable" studies funded in our society, but are valuable because they can supply answers to the challenge of prevention of infectious diseases and give us insight into reversing the process of aging.


It is well-documented that the elderly do not respond as well to vaccinations as young people. The purpose of a vaccine is to "educate" the immune system against an infectious agent. Vaccines provide a non-infectious substance containing the same antigens as the foreign pathogen to teach the immune system to recognize that foreign pathogen by creating populations of memory T cells and antibody-producing B cells and thus prevent future infection. Some vaccines, like the vaccine for smallpox, only need to be administered once to confer lifetime immunity. Other vaccines, such as vaccines for influenza, need to be administered annually because there are multiple strains of influenza virus and the dominant strain changes each year. Influenza and pneumonia are two diseases that particularly affect the elderly, and providing vaccinations is a high priority in eldercare.

However, there are special challenges involved in developing vaccines targeted for older adults. In the elderly, antibody responses to vaccines are slower, and not as strong as in younger people, and T cell subpopulations are not very responsive to vaccines. For reasons that are not yet clear, memory T cells from aged individuals do not react as quickly or for as great a duration as cells from younger subjects. Numerous studies have examined means of improving the efficacy of vaccines for the aged. Novel types of vaccine delivery using, for example, liposomes or naked DNA to create a more powerful immune response, are being developed. Alternative adjuvants such as IL-2 are being tested to boost vaccine efficacy. New methods of vaccination, like using nasal sprays or oral vaccines to stimulate mucosal immunity, instead of the traditional injections, are also being explored.

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Nutrition plays a prominent role in immune response, and the elderly often suffer from malnutrition. Reduced caloric intake is known to slow the aging process and help maintain higher numbers of naive T cells and levels of IL-2. Vitamin E and zinc in particular are important nutrients for the proper functioning of the immune system. Long-term zinc deficiency in the elderly causes a decrease in cytokine production and impaired regulation of helper T cell activity. Vitamin E has recently been in the news as a possible treatment for Alzheimer's disease, and it seems that vitamin E supplements may also boost the immune system. In both mice and humans, a daily dose of vitamin E significantly higher than the U.S. Recommended Daily Allowance improved T cell function in cell-mediated immunity. Vitamin E is also an antioxidant that can protect lymphocytes, the brain, and other tissues from destructive free radicals.

Cheese –common food found in many households – was proved to act as a carrier for probiotic bacteria, which can aid in restoring your immune system’s power. The latest Finnish research confirmed that cheese significantly enhances the immunity and defensive system of an elderly, and offered data that consuming the probiotics from cheese on a daily basis can help one cope up and tackle age related changes in one’s immune system.

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