The immune system plays a role in the aging process. As we age, the immune system becomes less effective at fighting infections and diseases. Specifically, the thymus shrinks and produces fewer T cells after age 50. Macrophages and Langerhans cells also become less effective at killing pathogens. Memory immunity declines such that secondary responses are weaker. Antibody production decreases as well. This weakened immune system allows for increased risk of cancer, infections, and autoimmune diseases in older age. While lifestyle factors like stress and sleep also impact immunity, the immune system ultimately has a finite lifespan, leading to its deterioration over time.

1. Jordan Williams
Professor Crawford
The Immune System and Aging
There are many theories that have been tested as the causes for aging. The Digiovanni text,
Human Aging: Biological Perspectives cites no fewer than eight plausible causes for aging, with
the immune system acting as one of the culprits. Specifically, this theory suggests that the
prevalence of autoimmunity and an overall weakened ability to fight off viral and bacterial
infections and diseases contribute to the breakdown of the body on a cellular and organic level.
Furthermore, this theory comments on "immune deficiency" which relates to the limited gene usage
theory which states that the body only has so long of an active capacity to function before the
continuous assault overwhelms the system and breakdown occurs on the cellular level. So, the
immune system presents a challenging obstacle to understanding what happens to the human body
with aging. This reports seeks to illuminate some of the mysterious aspects of aging and immunity
and what happens to the immune system well after the evolutionarily useful age of reproduction.
A good starting point would be to address what constitutes the immune system and what is
its purpose. Structures within the body constitute the immune system; these include: the thymus,
spleen, lymph nodes, bone marrow, and lymphatic tissues (i.e. GI tract). Cells that contribute to
immunity include: white cells (lymphocytes), macrophages, Natural Killer cells, Dendritic cells,
and Langerhans Cells, cytotoxic T cells, among others.
Organic systems provide aid in halting the assault of foreign intruders. The skin system
(called SALT in some texts) maintains a specific PH number that inhibits the growth of many
bacterial colonies. The many layers of epidermis prevent bacterial entry into the bloodstream. The

2. GI tract (A.K.A. GALT) maintains a high acid content to burn and dissolve any antigens that find
their way in by inhalation or consumption. Nasal cilia trap particles and bacteria such as
staphylococcus aureus. The conjunctivae neutralize the growth of many airborne bacteria, while
the super-cilia catch dead skin and other harmful product from entering the eye area. The mucosal
system (MALT) augments the immune response of a specific tissue or organ system.
Already, just naming the various components of immunity, a pattern becomes clear. The
main objective of the immune system is to relentlessly prevent, protect, and attack foreign materials
and rogue self-cells (e.g. cancerous cells, etc.). The mechanisms of antibodies, memory, and
acquired active immunity are very complex and intricate, but the scope of this report isn't to rehash
how memory B cells target and neutralize immunogens, but rather to investigate, through research
and prior understanding of the immune system, what happens to our immune systems with age.
The scientific community finds it difficult to cleave lifestyle habits, diseases, and medical
procedures from the natural aging phenomena's effect on the immune system. Even more
frustrating, disagreements within the immunological community about how to interpret data,
results, and testing methods vary greatly. All of these variables seek to perpetuate the smokescreen
that occludes the link between immunosenescence and biological aging. Digiovanni writes:
"Distinguishing age changes from other changes in the immune system is difficult for various
reasons, including limited understanding of this complex system…diverse and rapidly changing
methods of research…and the diversity of factors affecting it [the immune system]" (Digiovanni
303). These factors include sunlight exposure, malnutrition, chemotherapy, surgery, and stress,
among others.
However, acknowledging these roadblocks, there still is scholarly and scientific research

3. that strongly suggests a link between immune collapse and senescence. To begin, Langerhans cell
production seems to fall dramatically with age, and this decrease of cells leads to an impaired ability
for "presentation of antigens in the epidermis, causing increasing risks of skin infection and
cancer…" (Digiovanni 303). The thymus begins to shrink after puberty and appears to reach a
lifetime minimum size by age 50. Naturally, the hormone production of the thymus declines in
accordance to the shrinking organ. These declines occurring in tandem blunt the overall production
and conversion of non-specific lymphocytes into mature T cells. The heterogeneous nature of
homo sapiens problematizes the reckoning of an exact number, but "Up to 25% of older people
may show no decrease in T cell functioning, while approximately 50% have moderate declines.
The remaining 25% experience major decreases…" (Digiovanni 304). B cells behave similarly in
the aged, with these numbers circulating throughout the body for life with relative numerical
stability but with some special cases of decline in some individuals.
The aging of processing and presentation mechanisms are more transparent and easily
explained. The presentation and processing stages appear unaffected by natural aging. Yet,
macrophages become less effective at killing because of a reduction of IL-2 stimulation from
Helper T cells, while Langerhans cells' effectiveness wanes because of an overall reduction in their
numbers occurring with age.
The aging process directly affects the T-cell participation in cell-mediated and humoral
immunity. Fewer numbers of T-cells and IL-2 production reduce the immune system as a whole.
For example, a decrease in IL-2 receptors leads to a cascade effect where "the intensity of both cell-
mediated and humoral parts of an immune system" are diminished alongside delayed-
hypersensitivity responses (Digiovanni 304). Furthermore, the production of autoantibodies

4. increases, however modern science cannot discern an immediate health consequence from this
unusual increase of autoantibodies. Autoantibodies arising outside the parameters of aging may be
indirectly involved in exacerbating the symptoms of such autoimmune diseases like Rheumatoid
Arthritis.
B-cell participation diminishes across the spectrum with advanced age. Because IL-2
stimulation from T-helper cells is not as strong, "antibody production is slower…ends sooner, a
lower peak antibody concentration…level declines faster…." (Digiovanni 305). Worse still,
antibodies cannot bind to antigens as tightly in earlier ages, and there is an all-inclusive reduction of
antibody variability (e.g. IgE, IgA). With the fall of certain immunoglobulins, allergic reactions
slow down. All of these changes develop slowly until around 60 years of age, wherein the decline
becomes more rapid.
Finally, the status of memory in the immune system becomes precarious with age. The
swiftness and intensity of secondary responses subsides at ages above 60. An antigen that never
tested the immune system in earlier ages will do much more damage at higher ages. Also, it may
take several battles with an aged immune system before memory immunity sets it; this can cause
much damage on the cellular and organic level. Vaccinations administered for the first time in later
ages provide less help with cell-mediated immunity; however, vaccines administered in youth
continue to yield residual immunity without much apparent deterioration due to age. Vaccines
continue to be highly necessary in old age because older immune systems and organ systems (like
cardiopulmonary) are extremely susceptible to pneumonia and most strains of influenza. As a side
note, autoantibodies that were once advantageous at younger ages continue to do cellular damage
until older age when this collective damage may manifest itself as deleterious autoimmune diseases

5. such as Rheumatic heart disease, Myasthenia Gravis, or Crohn's disease (Digiovanni 306-7).
One aspect of aging with immunity not yet explored is the prevalence of cancer in the well-
aged. For instance:
"The importance of the immune system in preventing tumor formation, termed
immunosurveillance, has been repeatedly shown in animal models and is supported by
epidemiological evidence, such as increased frequency of certain cancer types in immuno-
suppressed individuals." (Derhovanessian et al 2008)
This opening statement by this team of researchers links cancer to immunosenescence and
senescence in general. As cited by Digiovanni, low numbers of naïve T cells allow for cancerous
cells to grow out of control. Also, there is a "reduction in the diversity of naïve T-cell receptors
(TCR) repertoire" which may account for an senescent immune system's inability to resist bacterial
infection or subdue tumor antigens (Derhovanessian et al 2008). Another component of cancer
susceptibility lies in the lessened integrity of CD4+ and CD8+ T-cells; this loss of structural
integrity most likely accounts for the inability to continuously combat carcinogens and antigens
which increase the likelihood of cancer growth.
Curiously enough, this published finding brings up an old theory that may look familiar to
students taking this course. "Immune exhaustion" is named as a possible term to describe the
incessant viral, bacterial, fungal, and protozoan assaults that overwhelm the immune system and
thus leads to cancer prevalence (Derhovanessian et al 2008). Additionally, the prolonged presence
of some viruses like cytomegolovirus (CMV) coupled with undetectable protozoa may help in the

6. dismantling of immunosurveillance of cancer antigens and autoantigens.
Other ways in which the immune system is affected by age are clearly defined. Pro-
inflammatory cytokine production increases, which worsens any underlying autoimmune issues.
Production of and response to IL-12 falls in conjunction with the falling of naïve CD4 T-cell
stimulation. The number of antibodies declines, as well as chemotaxis and phagocytosis by
macrophages. Surprisingly, 60-65 year olds retain enough TCR diversity to not notice much of a
difference in immunity. But around the age of 75, thymic output completely ceases and the TCR
diversity is severely reduced (Derhovanessian et al 2008).
Despite the loss of thymus function and TCR diversity in 65 to 75 year olds, peripheral T-
cells continue to circulate throughout the body for an amazingly long time. Naturally, if this
individual lives long enough, even these peripheral T-cells exhaust their energy. These exhausted
cells lack CD27, CD28, and telomerase expression. These lacking components contribute to
"higher levels of Tregs in cancer patients…believed to be a bad prognostic sign…interfere with
immunotherapy," (Derhovanessian et al 2008).
In preclinical animal models, age-associated changes in tumor immunity become more
apparent. In a mouse breast cancer model, the anti-cancer immune responses in young animals was
characterized by cell-mediated responses. In the older animals, the less effective response of innate
immunity (inflammation, etc) seemed to be the major response component. This reflects the trend
of inflammation-related immunity working well into octogenarian ages for humans while T-cell
immunity falls to the wayside several years beforehand. This retention of inflammatory responses
"may enhance immunopathology and carcinogenesis," (Derhovanessian et al 2008). Logically,
centenarians "enjoy" less aggressive cancers because of the decrease in inflammation as first

7. immune defense; this lessening of inflammation retards angiogenesis and depresses the metastatic
nature of advancing cancers. The authors conclude by stating that the exact mechanisms of
immunosenescence elude modern science, but they suspect that thymic regeneration, proliferation
of Natural Killer cells, medical reintroduction of telomerase, and removal of CMV or dangerous
protozoa may decelerate the ride to immunosenescence.
So what is to make of the immune system and aging? Other areas of aging seem to be
more clear cut. As we age, vision, hearing, taste, and touch all deteriorate and we have very
plausible and well-researched explanations for these losses. However, with the immune system so
little can be observed or reproduced in a laboratory. Even animal models only provide a glimpse
into how complex the immune system in the aged is.
Even more troubling, it remains difficult to separate lifestyle habits from natural aging. For
instance, longitudinal studies strongly suggest stress factors (cortisol, etc), low quantity and quality
of sleep, lack of physical activity, and poor intake of protein influence the speed and severity of
immunosenescence (Larbi et al 2008). This team of scientists found that Natural Killer cells, T-
helper cells, Tumor Necrosis Factor receptors, and Interferon levels all fluctuated greatly in animal
model rats that were sleep deprived and sedentary (Larbi et al 2008). In reference to lifestyle
habits, the comprehensive suspicion of unknowability is succinctly stated: "the enormous
redundancy and pleiotropy of the immune system makes it hard to predict the consequences at the
organismal level," (Larbi et al 2008).
Notwithstanding this scientific stymie, a consensus arises from many members of the
scientific community. Many argue that "Lymphocytes are thought to have a finite replicative
lifespan" and that "Telomere length may act as the ultimate limit for the number of divisions that a

8. human lymphocyte can undergo," (Weng 2006). Weng's research alludes to the growing curiosity
that surrounds telomeric attrition and the use of telomerase to reestablish a coherent and effective
immune system. Scientists worldwide remain faithful to the idea that the human body can only
sustain its natural defenses for a limited time and that drug therapies and surgeries only prolong the
inevitable. Therefore, the answer to the question posed early in this paper: what happens to the
immune system as we age, is the same answer to what happens to humans as we age; things get
worse, less effective, turn upon you, and then you die.

9. Works Cited
Derhovanessian, E et al. September 2008 "Immunity, Ageing, and Cancer." Immunity & Ageing
5: 1-16.
Digiovanni, Augustine Gaspar. Human Aging: Biological Perspectives. McGraw Hill 2000.
Larbi, A et al. 2008 "Aging of the Immune System as a Prognostic Factor for Human Longevity."
Physiology 23: 64-74.
Weng, Nan-ping. May 2006 "Aging of the Immune System: How Much Can the Adaptive
Immune System Adapt?" Immunity 24: 495-499.