By Vince Giuliano
The human immune system provides our defenses against pathogens. This blog entry focuses on research on T-cells. a family of cells in the immune system. The research is relevant to aging because it challenges the traditional view that T-cell numbers and potency decrease with advanced aging making the body ever-more susceptible to diseases, and that essentially nothing can be done about this.
Overview – the immune systems and T cells
Like the US Departments of Defense and Homeland Security, our immune systems involve many complex interacting subsystems and components. In fact, humans have two interacting immune systems, the innate immune system which is older and common to more primitive species, a system that offers fixed responses to pathogens and an adaptive immune system that not only defends against pathogens but learns about them so as better to protect the body in the future. “The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. Innate immune systems provide immediate defense against infection, and are found in all classes of plant and animal life(ref).” “The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or “specific” immune system is activated by the “non-specific” and evolutionarily older innate immune system (which is the major system of host defense against pathogens in nearly all other living things). The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens (to generate immunity), and to mount stronger attacks each time the pathogen is encountered. It is adaptive immunity because the body’s immune system prepares itself for future challenges(ref).”
T cells along with B-cells are components of the adaptive immune system. “T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells (NK cells) by the presence of a special receptor on their cell surface called T cell receptors (TCR). The abbreviation T, in T cell, stands for thymus, since this is the principal organ responsible for the T cell’s maturation. Several different subsets of T cells have been discovered, each with a distinct function(ref).” Subsets are: 1.1 Helper, 1.2 Cytotoxic, 1.3 Memory, 1.4 Regulatory, 1.5 Natural killer, 1.6 γδ. Each plays its own specialized role in the adaptive immune system.
“The cells of the adaptive immune system are a type of leukocyte, called a lymphocyte. B cells and T cells are the major types of lymphocytes. The human body has about 2 trillion lymphocytes, constituting 20-40% of white blood cells (WBCs); their total mass is about the same as the brain or liver. The peripheral blood contains 20–50% of circulating lymphocytes; the rest move within the lymphatic system. B cells and T cells are derived from the same multipotent hematopoietic stem cells, and are morphologically indistinguishable from one another until after they are activated. B cells play a large role in the humoral immune response, whereas T-cells are intimately involved in cell-mediated immune responses. However, in nearly all other vertebrates, B cells (and T-cells) are produced by stem cells in the bone marrow. T-cells travel to and develop in the thymus, from which they derive their name. In humans, approximately 1-2% of the lymphocyte pool recirculates each hour to optimize the opportunities for antigen-specific lymphocytes to find their specific antigen within the secondary lymphoid tissues (ref).”
“In an adult animal, the peripheral lymphoid organs contain a mixture of B and T cells in at least three stages of differentiation:
· naive cells that have matured, left the bone marrow or thymus, have entered the lymphatic system, but that have yet to encounter their cognate antigen,
· effector cells that have been activated by their cognate antigen, and are actively involved in eliminating a pathogen.
“Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes (T cells)(ref).” The thymus provides a series of specialized microenvironments necessary for proper T-cell maturation. Complex transcription factors and miRNAs are involved in the selection of destination-type T-cells(ref)(ref). “Thymocytes must complete an elaborate developmental program in the thymus to ultimately generate T cells that express functional but neither harmful nor useless TCRs. Each developmental step coincides with dynamic relocation of the thymocytes between anatomically discrete thymic microenvironments, suggesting that thymocytes’ migration is tightly regulated by their developmental status. Chemokines produced by thymic stromal cells and chemokine receptors on the thymocytes play an indispensable role in guiding developing thymocytes into the different microenvironments(ref).”
Aging and the immune system
One of the hallmark of advanced aging is weakening adaptive immune systems, often referred to as immunosenescence. “These age-associated immune dysfunctions are the consequence of declines in both the generation of new naïve T and B lymphocytes and the functional competence of memory populations(ref).” This decline appears to be due to a variety of causes. For one matter, thymic involution starts at an early age. “The thymus begins to shrink (atrophy) after adolescence. By middle age it is only about 15% of its maximum size(ref). There are strong age-related changes in hormone production(ref). Older people may take anti-inflammatory medications like prednisone which inhibit immune function. And changes in patterns of epigenetic markers alter gene activation so as to reduce responsiveness of T cells with age.
In particular, homeostatic mechanisms related to naïve T-cells tend to become deregulated with advancing age in primates and humans. A 2011 report Age-related deregulation of naive T cell homeostasis in elderly humans concludes “Our results show that lower naive T cell numbers were associated with a lower thymic function and higher activation and proliferating naive T cell levels. We then analyzed sjTREC numbers and relative telomere length from sorted naive T cells. Our results show that the aberrant activation and proliferation status was related to lower sjTREC numbers (a peripheral proliferation marker) and both, higher CD57 expression levels and shortened telomeres (replicative senescence-related markers). Elderly individuals show a greater contraction of the CD8 naive T cell numbers and all homeostatic alterations were more severe in this compartment. In addition, we found that low functional thymus show a CD4-biased thymocyte production. Taken together, our results suggest a homeostatic deregulation, affecting mostly the naive CD8 T cell subset, leading to the accumulation of age-associated defects in, otherwise, phenotypically naive T cells.”
The thymus is also extremely susceptible to diseases. Malnutrition, nutritional imbalances and other triggers of thymic involution. See The thymus is a common target organ in infectious diseases(2006) and The thymus is a common target in malnutrition and infection (2007). The 2010 publication Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses reports “The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4+CD8+ cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host’s immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4+CD8+ thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases.”
It may be possible to discover safe ways to halt or reverse thymic involution and therefore keep the thymus gland active in producing T-cells in aging people. For several years now researchers have been pursuing approaches to preserving age-related T-cell functionality via slowing, halting or reversing thymic involution.
The 2005 publication Insights into thymic aging and regeneration relates “The deterioration of the immune system with progressive aging is believed to contribute to morbidity and mortality in elderly humans due to the increased incidence of infection, autoimmunity, and cancer. Dysregulation of T-cell function is thought to play a critical part in these processes. One of the consequences of an aging immune system is the process termed thymic involution, where the thymus undergoes a progressive reduction in size due to profound changes in its anatomy associated with loss of thymic epithelial cells and a decrease in thymopoiesis. This decline in the output of newly developed T cells results in diminished numbers of circulating naive T cells and impaired cell-mediated immunity. A number of theories have been forwarded to explain this ‘thymic menopause’ including the possible loss of thymic progenitors or epithelial cells, a diminished capacity to rearrange T-cell receptor genes and alterations in the production of growth factors and hormones. Although to date no interventions fully restore thymic function in the aging host, systemic administration of various cytokines and hormones or bone marrow transplantation have resulted in increased thymic activity and T-cell output with age.”
A substantial body of subsequent research has been focused on strategies for restoring thymic function. The 2010 review publication Emerging strategies to boost thymic functionreports on some of these “In recent years, thymus-stimulatory, thymus-regenerative, and thymus-protective strategies have been developed to enhance and repair thymus function in the elderly and in individuals undergoing hematopoietic stem cell transplantation. These strategies include the use of sex steroid ablation, the administration of growth and differentiation factors, the inhibition of p53, and the transfer of T cell progenitors to alleviate the effects of thymus dysfunction and consequent T cell deficiency.”..
Male hormone blocking
One of the approaches to thymic renewal has been based on blocking male hormone since such hormones appear to be implicated in the process of thymic involution. Treatments that block male sex hormone have in some circumstances been shown to reverse age-related thymic involution but with side effects. According to the December 2010 e-publiction Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis, “Androgens contribute to the involution process of the aging thymus gland.– . We have investigated the influence of testosterone on the ectopic synthesis of glucocorticoids (GCs) in thymocytes, an activity recently shown by us to be important for the homeostatic regulation of these cells. — We provide here an unrecognized mechanism how androgens contribute to thymic involution by stimulating local synthesis and release of GCs in the thymus.”
The relationships of glucocorticoids to thymic function is complex and has been much-studied. It appears that glucocorticoids can play different roles. “Here, we summarize these data and suggest that GCs can mediate both positive and negative effects in the organ depending on the local hormonal concentration. Basal GC levels might promote growth of early thymocytes in young mice, and increased levels, generated through a stress reaction, apoptosis in these cells. A gradual loss of GC synthesis in TECs during aging might contribute to thymic involution, a process so far unexplained(ref).” See also Thymocyte-synthesized glucocorticoids play a role in thymocyte homeostasis and are down-regulated by adrenocorticotropic hormone,Different roles for glucocorticoids in thymocyte homeostasis?, Glucocorticoids delay age-associated thymic involution through directly affecting the thymocytes and Age-related synthesis of glucocorticoids in thymocytes.
Relative to reversing immune system aging, functional senescence of immune system cells may not be associated with telomere shortening and may be reversible.
The August 2011 publication Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells relates: “Persistent viral infections and inflammatory syndromes induce the accumulation of T cells with characteristics of terminal differentiation or senescence. However, the mechanism that regulates the end-stage differentiation of these cells is unclear. Human CD4+ effector memory (EM) T cells (CD27−CD45RA−) and also EM T cells that re-express CD45RA (CD27−CD45RA+; EMRA) have many characteristics of end-stage differentiation. These include the expression of surface KLRG1 and CD57, reduced replicative capacity, decreased survival, and high expression of nuclear γH2AX after TCR activation. A paradoxical observation was that although CD4+ EMRA T cells exhibit defective telomerase activity after activation, they have significantly longer telomeres than central memory (CM)-like (CD27+CD45RA−) and EM (CD27−CD45RA−) CD4+ T cells. This suggested that telomerase activity was actively inhibited in this population. Because proinflammatory cytokines such as TNF-α inhibited telomerase activity in T cells via a p38 MAPK pathway, we investigated the involvement of p38 signaling in CD4+ EMRA T cells. We found that the expression of both total and phosphorylated p38 was highest in the EM and EMRA compared with that of other CD4+ T cell subsets. Furthermore, the inhibition of p38 signaling, especially in CD4+ EMRA T cells, significantly enhanced their telomerase activity and survival after TCR activation. Thus, activation of the p38 MAPK pathway is directly involved in certain senescence characteristics of highly differentiated CD4+ T cells. In particular, CD4+ EMRA T cells have features of telomere-independent senescence that are regulated by active cell signaling pathways that are reversible.”
Regarding this research, an August 2011 Science Daily article Possibility of Temporarily Reversing Aging in the Immune System reports: “Researchers have discovered a new mechanism controlling aging in white blood cells. The research, published in the September issue of the Journal of Immunology, opens up the possibility of temporarily reversing the effects of aging on immunity and could, in the future, allow for the short-term boosting of the immune systems of older people. — Weakened immunity is a serious issue for older people. Because our immune systems become less effective as we age we suffer from more infections and these are often more severe. This takes a serious toll on health and quality of life. — Professor Arne Akbar of UCL (University College London), who led this research, explains “Our immune systems get progressively weaker as we age because each time we recover from an infection a proportion of our white blood cells become deactivated. — This is an important process that has probably evolved to prevent certain cancers, but as the proportion of inactive cells builds up over time our defenses become weakened. “What this research shows is that some of these cells are being actively switched off in our bodies by a mechanism which hadn’t been identified before as important in aging in the immune system. Whilst we wouldn’t want to reactivate these cells permanently, we have an idea now of how to wake them from their slumber temporarily, just to give the immune system a little boost.”
The Science Daily article goes on relating to the telomere-shortening hypothesis of immune cell senescence: “Until now, aging in immune cells was thought to be largely determined by the length of special caps on the ends of our DNA. These caps, called telomeres, get shorter each time a white blood cell multiplies until, when they get too short, the cell gets permanently deactivated. This means that our immune cells have a built-in lifespan of effectiveness and, as we live longer, this no longer long enough to provide us protection into old age. — However when Professor Akbar’s team took some blood samples and looked closely at the white blood cells they saw that some were inactive and yet had long telomeres. This told the researchers that there must be another mechanism in the immune system causing cells to become deactivated that was independent of telomere length. — Professor Akbar continues “Finding that these inactive cells had long telomeres was really exciting as it meant that they might not be permanently deactivated. It was like a football manager finding out that some star players who everyone thought had retired for good could be coaxed back to play in one last important game.” — When the researchers blocked this newly identified pathway in the lab they found that the white blood cells appeared to be reactivated. Medicines which block this pathway are already being developed and tested for use in other treatments so the next step in this research is to explore further whether white blood cells could be reactivated in older people, and what benefits this could bring. — Professor Akbar continues “This research opens up the exciting possibility of giving older people’s immune systems a temporary boost to help them fight off infections, but this is not a fountain of eternal youth. It is perfectly normal for our immune systems to become less effective and there are good evolutionary reasons for this. We’re a long way from having enough understanding of aging to consider permanently rejuvenating white blood cells, if it is even possible.” — Professor Douglas Kell, Chief Executive of the Biotechnology and Biological Sciences Research Council, said: “This is a fantastic example of the value of deepening our understanding of fundamental cell biology. This work has discovered a new and unforeseen process controlling how our immune systems change as we get older. Also, by exploring in detail how our cells work, it has opened up the prospect of helping older people’s immune systems using medicines that are already being tested and developed. By increasing the incidence and severity of infection, weakened immunity seriously damages the health and quality of life of older people so this research is very valuable.”
With aging, certain naïve T cells selectively survive longer than others and are more protective.
Also published in August 2011, the publication Non-random attrition of the naïve CD8+ T-cell pool with aging governed by TCR:pMHC interactions reports “Immunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and diversity of naive CD8+ T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor:pMHC avidity, and preferentially acquired “memory-like” phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and diversity defects in old T cells.”
An August 2011 Science Daily article Aging: T Cells That Survive the Longest May Better Protect Against Infections Such as the Flu reports on the same research: “Aging brings about a selective decline in the numbers and function of T cells — a type of white blood cell involved in the immune system’s response to infection — and T cells that survive the longest may better protect against infections such as the flu, according to a study led by researchers from the University of Arizona College of Medicine — Tucson. The finding may lead to targeting these cells with vaccinations that increase their number and improve protection against disease in older adults. — The decline in immune function with age is viewed as the most important contributing factor to older adults’ increased susceptibility to infections and decreased responses to vaccinations. Improving T cell function can result in improved immunity. –”We have discovered that aging brings about selective attrition of those T cells that defend us against new infections that we have not encountered before. Not all T cells age the same and the ones that will survive the longest have special features that may allow them to best protect against infections such as flu,” says study senior author Janko Nikolich-Žugich, MD, PhD, chairman of the Department of Immunobiology, co-director of the Arizona Center on Aging, and Elizabeth Bowman Professor in Medical Research at the UA College of Medicine, and a member of the UA BIO5 Institute. “We now know that there are a few good cells that can be targeted by vaccination to expand their numbers and achieve protection.”
Autologous bone marrow transplantation
Autologous bone marrow transplantation is another strategy for restoration of thymic function and prolongation of the production of naïve T-cells. See Restoration of the thymic cellular microenvironment following autologous bone marrow transplantation.
It appears that thymic involution like so many other aging-related changes is to a large extent dependent on epigenetic factors, so age-related changes are potentially stoppable or reversible by epigenetic interventions.
There appears to be a significant amount of current research related to epigenetic mechanisms and gene-activation pathways relating to T-cell genesis and homeostasis. For example, a number of publications have been concerned with Foxp3 and NF-kappaB expression in regulatory T-cells. From DNA methylation controls Foxp3 gene expression: “Together, our data suggest that TSDR is an important methylation-sensitive element regulating Foxp3 expression and demonstrate that epigenetic imprinting in this region is critical for establishment of a stable Treg (regulatory T-cell) lineage.” Other related publications include Epigenetic mechanisms of regulation of Foxp3 expression, Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome, Nuclear Factor – kappa B modulates regulatory T-cell development by directly regulating expression of Foxp3 transcription factor, and the 2011 publications Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription. Cell-intrinsic NF-κB activation is critical for the development of natural regulatory T cells in mice.
Certain dietary supplements appear to be protective against thymic involution and facilitate thymopoiesis in aged individuals
One such supplement is zink, as suggested in the 2006 publication Correlation between zinc status and immune function in the elderly. The 2009 publication Zinc supplementation increases zinc status and thymopoiesis in aged mice reports “Our goal in this study was to understand how dietary zinc supplementation affects thymopoiesis in aged mice. We hypothesized that impaired zinc status associated with aging would mediate the decline in thymic function and output and that restoring plasma zinc concentrations via zinc supplementation would improve thymopoiesis and thymic functions. — Taken together, our results showed that in mice, zinc supplementation can reverse some age-related thymic defects and may be of considerable benefit in improving immune function and overall health in elderly populations.” The 2009 publication The immune system and the impact of zinc during aging reported “The trace element zinc is essential for the immune system, and zinc deficiency affects multiple aspects of innate and adaptive immunity. There are remarkable parallels in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance toward T helper type 2 cells, decreased response to vaccination, and impaired functions of innate immune cells. Many studies confirm a decline of zinc levels with age. Most of these studies do not classify the majority of elderly as zinc deficient, but even marginal zinc deprivation can affect immune function. Consequently, oral zinc supplementation demonstrates the potential to improve immunity and efficiently downregulates chronic inflammatory responses in the elderly. These data indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence.”
Another dietary supplement possibly capable pf protecting against glutocortocoid-induced thymic involution is DHEA. This was suggested in-vitro studies some time ago. The 1990 publication Protection from glucocorticoid induced thymic involution by dehydroepiandrosterone reports: “Dehydroepiandrosterone (DHEA), the most abundantly secreted human adrenal steroid, has no known specific function. In spite of this fact there is an abundance of data associating DHEA with “health” in both man and experimental animals. Research in our laboratory has demonstrated evidence for an antagonistic interaction between DHEA and glucocorticoids (GC) in liver and brown adipose tissue. We hypothesized that DHEA also antagonized effects of GC on the immune system and that this “immune protective effect” might explain the diffuse positive effects of DHEA reported in the literature. Effects of GC on the immune system include involution of the thymus when given in animals in vivo and death of thymic lymphocytes in vivo with exposure to these steroids. We hypothesized that DHEA would block this GC mediated thymocyte destruction in vivo and in vitro. Pretreatment with DHEA for three days blocked approximately 50% of the thymic involution seen with dexamethasone. Results of in vitro experiments confirmed protective effects of DHEA in pretreated animals. (less than 50% of cell death in lymphocytes from pretreated mice compared with lymphocytes from control mice.) We conclude from these studies that DHEA protects against at least one GC anti-immune effect, thymic lymphocyte lysis.” Also relevant to the thymic effects of DHEA are the 2010 publication DHEA and testosterone therapies in Trypanosoma cruzi-infected rats are associated with thymic changes
Melatonin is another hormonal supplement which may exercise a positive effect on an aging immune system. The 2008 publication Melatonin and the immune system in aging relates: “diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. Circulating melatonin decreases with age, and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes and macrophages. It also stimulates the production of natural killer cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from natural killer cells and T helper lymphocytes are enhanced by melatonin. Melatonin has the potential therapeutic value to enhance immune function in aged individuals.”
Walter Pierpaoli, writer of several popular books on melatonin, has for very many years been a supporter of a theory that aging is governed by a circadian program of melatonin expression operative in the pineal gland which also governs immunity. From his 1998 publication Neuroimmunomodulation of aging. A program in the pineal gland: “We have investigated for 35 years the relationship between the neuroendocrine and the thymo-lymphatic, immune system. In the last decade we have shown that the pineal gland is a main adapter and fine synchronizer of environmental variables and endogenous messages into physiological modifications of basic functions. In particular the pineal gland itself seems to regulate, via circadian, night secretion of melatonin, all basic hormonal functions and also immunity. We have shown with several in vivo models that this fundamental role of the pineal gland decays during aging. Aging itself seems to be a strictly pineal-programmed event similar to growth and puberty.” Although this theory and Pierpaoli’s popular works have not been taken seriously by many longevity researchers, it does now seem clear that there is some kind of operative circadian immune-response cycle and that melatonin has an affect on T-cell production or expression.
Some commercial cocktails of herbal substances are claimed to have thymus-strengthening and immunity-enhancing powers. I have not so far undertaken to investigate these. For the moment I tend to be skeptical about such concoctions always taking the position “Show me the research.” I do know that some familiar herbal substances have thymic impacts. For example, the publication Tumor-induced oxidative stress perturbs nuclear factor-kappaB activity-augmenting tumor necrosis factor-alpha-mediated T-cell death: protection by curcumin suggests” Curcumin could prevent tumor-induced thymic atrophy by restoring the activity of NF-kappaB. Further investigations suggest that neutralization of tumor-induced oxidative stress and restoration of NF-kappaB activity along with the reeducation of the TNF-alpha signaling pathway can be the mechanism behind curcumin-mediated thymic protection. Thus, our results suggest that unlike many other anticancer agents, curcumin is not only devoid of immunosuppressive effects but also acts as immunorestorer in tumor-bearing host.”
Wrapping it up
A great deal of research effort has been devoted to understanding T-cell development and homeostasis, and approaches to preserving T-cell competency with advancing aging. There has been limited progress with hormonal and transplantation approaches to thymic renewal and much has been learned. However, it appears that we are not really there yet in terms of advanced immune competency-extending interventions. However, our knowledge of epigenetic factors affecting T-cell genesis and homeostasis is rapidly increasing and this could lead to new approaches or finer tuning of older ones. For now, it appears that the best approach to maintaining strong immunity with aging is maintenance of general health. Also, dietary supplementation with zink, DHEA and melatonin may be of some benefit.