DR. PETER VICKERS UNIVERSITY OF HERTFORDSHIRE, UK

 ‘Last scene of all, That ends this strange eventful history, Is second childishness and mere oblivion, Sans teeth, sans eyes, sans taste, sans everything’. ( William Shakespeare – As You Like It )  ‘None are so old as those who have outlived enthusiasm.’ ( Henry David Thoreau )  ‘And in the end, it’s not the years in your life that count. It’s the life in your years.’ ( Abraham Lincoln )

 The phenomenon of aging has not been conceived by nature, because both human and animal organisms are constructed so that they function optimally up to the time of reproduction.  Beyond that time they (we) have passed their (our) ‘sell by date’.  That is why, in the natural environment, old animals are very rarely seen.  Only exceptions are pets, zoos, and ‘civilisation’ (for humans).  Aging is a multifactorial process for which no simple explanation or cause can be identified and to which no treatment can be offered.

 What happens?  In the elderly, we know that:  The incidence of severe infections increases  The protective effect of vaccination is low  The incidence of malignancies increases  Why is this?  The function of the immune system declines with age.  So, in what ways does it decline?

 The thymus where T lymphocytes mature begins to shrink (atrophy) after adolescence.  By middle age it is only about 15% of its maximum size.

 As the thymus atrophies, there is a fall in the thymic production of naïve T cells.  A naïve T cell is a T cell that has successfully undergone the positive and negative processes of central selection in the thymus.  A naïve T cell, unlike activated T cells or memory T cells has not encountered its cognate antigen within the periphery.  This means that the proliferation of T cells in the periphery of the body is responsible (by means of dividing - cloning ) for maintaining adequate T-cell numbers in adults and the elderly, but cannot respond to new antigens.  Consequently, although the actual circulating numbers of T cells may be impaired, their functioning certainly will be.

 This (along with changes in B-cells) leads to a failure to generate long lasting immunity to vaccination, e.g. smallpox  Nairn & Helbert (2007)

 Reduced T-cell numbers  Increase in memory cells  Decrease in naïve cells  Decrease in proliferative responses to antigens.  Decrease in CD4+ (T-helper cells) and CD8+ (T-cytotoxic cells, although the CD4/CD8 ratio is generally the same no matter what the age.  Decrease in the expression of CD3+ cells (CD3 is required for T cell activation).  Decrease in expression of CD28 (responsible for the activation of naïve T cells; helps to activate CD4+ and CD8+ cells).  NB. People who live 100 years have higher numbers of CD8+ T-cells expressing CD28 – suggests that prolonged survival could be linked to numbers of functioning CD + 28 T-cells.

 Aging is associated with both quantitative and qualitative changes in humoral immunity (B-cell lymphocytes).  Primary antibody responses in the elderly are often weak and short-lived.  In addition, the antibody that is produced binds the lower affinity antigens less well than those produced in young adults – basically, although there appear to be more circulating antibodies in the elderly, they actually do not work too well.  Also, many of these antibodies are actually autoantibodies!

 All this leads to a decline in specific antibodies – although total Immunoglobulin levels are maintained, as can be seen in the table below .. From: Lydyard et al. (2004), page 292

 In the elderly, when the body is exposed to bacterial or other microorganisms (either by natural exposure or by immunisation), although antibodies may be formed, there are fewer of them and they are formed at a lower rate.  Also, when antibodies are produced, the duration of their response is shorter than that of young adults.  Some of these problems may be related to the problems with T-cells already discussed, as well as a reduction in their ability to facilitate the B-cell immune response (linked to co-stimulation).  They may also be related to a failure of development of the precursor B-cells that are to be found in bone marrow.

 Aged phagocytes show an impaired respiratory burst alongside a decreased ability to destroy pathogens because their ability to phagocytose infectious microorganisms is compromised.  Aged dendritic cells are less efficient in activating both T- and B-cell populations.  Aged NK cells show a decreased ability in the killing of tumour cells  Thus many elderly patients are unable to effectively deal with microbial infections – particularly staphylococcus infections (hence being very much at risk of MRSA in hospitals, etc., as well as being at an increased risk of malignancies

 The numbers of NK cells generally increase in the elderly – which is good.  Also, as well as their cytotoxic function, NK cells produce cytokines and chemokines – producing large amounts of IFN-gamma, which in turn primarily promotes TH1-mediated immune responses.  Unfortunately, in the elderly, the NK cells only release about 25% of the INF-γ produced by younger adults  However, it appears that age-related functional defects in NK cells is compensated for by the increased numbers of mature NK cells, so that total NK activity remains intact.

 As well as a decrease in immunity, aging also affects inflammation and wound healing.  Many older people heal more slowly, and this may be directly related to changes in the immune system, brought about by the factors mentioned previously – but not exclusively so.  For example, it may be a consequence of other problems such as diabetes or arteriosclerosis – which lead to a decreased blood flow to arts of the body, particularly the lower extremities.  Remember, also, that many older people take anti-inflammatory drugs (e.g. for arthritis), which can slow down the rate at which wounds heal.

 There is an association between immune deficiency and increased malignancy events.  In the elderly, because of, amongst other things – inappropriate DNA translational events, such as shortening of telomeres and exhaustion of DNA material, there is a higher risk of cancer occurring (70% of all malignancy-related deaths are in people aged 65+ years).  This is due to the elderly immune system (particularly the T-cells) not working properly and so leading to a defective immune system.  Consequently, the elderly are more at risk of developing malignancies, such as, amongst others, bowel cancers, prostate cancer and lung cancer

 Lydyard et al. (2004) state that immunological features of aging include: 1. Increased NK cell numbers. 2. Increased IL-6 and IL-10 production by monocytes. 3. Increase in pro-inflammatory cytokines. 4. Lower density of MHC molecules being expressed 5. Fewer T-cells expressing CD28 (important for T- cell signalling. 6. Lower affinity of antibody responses. 7. Autoantibodies found more frequently. 8. Haemopoiesis impaired and fewer progenitor cells produced. 9. Thymic atrophy is well established leading to fewer T-cells entering the vascular pool with a consequent decrease in their functioning ability.

 In spite of what has been discussed in this presentation, it is important not to run away with the idea that this decline in immune competence is solely the result of a defective immune system.  It can also result from changes in the endocrine and nervous systems as we age.  We must also not forget the changes that may occur in nutritional, environmental, sensation to pain and heat, etc., as well as changes in mobility and gait (way of walking), changes in skin structure along with other ‘normal aging changes’ which can increase the risk of injury following which bacteria can enter broken skin.

 Lydyard P. et al. (2004) Instant Notes: Immunology (2 nd. Ed.) Abingdon, Garland Science  Nairn R. & Helbert M. (2007) Immunology for Medical Students. 2 nd. Ed. Philadelphia, Mosby Elsevier  Grubeck-Loebenstein B. & Wick G. (2002) The aging of the immune system. Advances in Immunology 80:  Gupta S. et al. (2005) Life and death of lymphocytes: a role in immunosenescence. Immunity & Ageing 2:12  Linton P. J. & Dorshkind K. (2004) Age-related changes in lymphocyte development and function. Nature Immunology 5:  Mazzola P. et al. (2012) Aging, Cancer and Cancer Vaccines. Immunity & Ageing 9:4  Steinman G. G. (1986) Changes in the human thymus during aging. Current Topics in Pathology 75:  Weksler M.E. (2000) Changes in the B-ell repertoire with age. Vaccine 18:

 Do not go gentle into that good night,  Old age should burn and rage at close of day:  Rage, rage against the dying of the light.  (Dylan Thomas)  Thank You For Listening