If extremely long lives are going to become possible, it will be necessary to discover effective means for averting or delaying immunosenescence, the process of the immune system losing functionality with advanced aging. This is a mini-treatise on immunosenescence. It looks at immunosenescence from a few key perspectives and discusses possible approaches for delaying it and possibly averting it entirely in the future.
“Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement. It involves both the host’s capacity to respond to infections and the development of long-term immune memory, especially by vaccination . This age-associated immune deficiency is ubiquitous and found in both long- and short-living species as a function of their age relative to life expectancy rather than chronological time . It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly(ref).”
Immunology is a complex subject so let me set the context for this discussion. There is an innate immune system involving cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner, and an adaptive immune system that learns about specific threats, develops means to deal with these threats and remembers the threats and responses to them. Aging affects both immune systems but I am concerned here mostly with the adaptive immune system.
What happens in immunosenescence is that with aging the immune system becomes less capable of dealing with new disease challenges and at the same time typically becomes more autoimmune reactive. Observable biological changes are many including deregulation of T cell functions, decline in rates of T cell progenitor reproduction and differentiation resulting in reduced rates of T cell renewal, decline in the antigen-presenting function of dendritic cells resulting in T-lymphocytes having a reduced capability to generate an adaptive immune response , decline in the toxicity of Natural Killer (NK) cells, and resulting in a decline in cell-mediated immunity. See here for more details.
Starting with the philosophical, from an evolutionary perspective immunosenescence is the result of design compromises favoring younger animals over older ones. According to this time-worn argument, survival is best optimized for animals which are young enough to be still engaged in child rearing. From the publication “Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load:” “On the whole, immunosenescence can be taken as a proof that the beneficial effects of the immune system, devoted to the neutralization of dangerous/harmful agents early in life and in adulthood, turn to be detrimental late in life, in a period largely not foreseen by evolution. This perspective fits with basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy.” The antagonistic pleiotropy theory of aging holds that “if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution.”
This all reminds me of the traditional Detroit auto-company philosophy of building cars: “We build them so they last and look good for 2-3 years; after that, we don’t care. In fact, we want to build-in obsolescence so our customers will have to come back and buy newer models.” Japanese-initiated total-quality engineering finally required Detroit to drop that approach in favor of much longer-lived cars. We can possibly do something similar for people.
In the blog entry Social Ethics of Longevity, I pointed out that the antagonistic pleiotropy way of thinking takes biological evolution into account but not social evolution, and that social evolution is reflecting back on biological evolution in a way that is making human lifespan longer and longer. So whatever the genetic shortcuts have been that lead to early immunosenescence, they are already being re-engineered by evolution so our immune systems last longer. The question is whether they can be re-engineered consciously so our immune systems last a lot longer.
Cellular memory perspective
From a cellular memory perspective, put crudely the immune systems of older people are too clogged up with memories of older threats and not sufficiently open to newer threats and ready and able to deal with them. Immunological memory is a function of the adaptive immune system. “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(ref). “ The operation of the adaptive immune system is quite complex(ref) involving interactions of multiple immune system cells including antigen-presenting cells like dendritic cells, B cells and macrophages with T cells. “Adaptive immunity is triggered in vertebrates when a pathogen evades the innate immune system and generates a threshold level of antigen. The major functions of the adaptive immune system include:
- The recognition of specific “non-self” antigens in the presence of “self”, during the process of antigen presentation.
- the generation of responses that are tailored to maximally eliminate specific pathogens or pathogen infected cells.
- the development of immunological memory, in which each pathogen is “remembered” by a signature antibody. These memory cells can be called upon to quickly eliminate a pathogen should subsequent infections occur(ref).”
Vaccination is one way of deliberately introducing immunological memory.
“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(ref).”
With aging, the adaptive immune system develops a memory bank of antigens representing potential threats identified over a lifetime, and at the same time loses capability to recognize and deal with new threats. There are too many irrelevant old memories. “In this review, recent data are discussed under the hypothesis that human immunosenescence is the consequence of the continuous attrition caused by chronic antigenic overload/stress. — Thus, immunosenescence can be envisaged as a global reduction of the “immunological space(ref).”
Various explanations of the underlying molecular mechanisms have been put forward. An early (1997) explanation was “that aging is associated with the emergence of an unusual CD4 T cell subset characterized by the loss of CD28 expression.” –. “We propose that the emergence of CD28-deficient CD4 T cells in the elderly can partially explain age-specific aberrations in immune responsiveness(ref).” A 1997 mouse study suggested “Importantly, addition of IL-2 restores proliferation of aged naive T cells, restores efficient effector generation and results in effectors seemingly indistinguishable from those derived from young CD4 cells.” “– the loss of optimal IL-2 production may participate in the aging process and may represent the main antigen-independent defect in the CD4 T-cell population(ref).”
Another explanation is suggested in the publication Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might provide a clue. A 2003 publication Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1) suggest that “the expression of KLRG1 identifies a subset of NK cells and antigen-experienced T cells in humans that lack proliferative capacity.” Another study casts a lot of the blame on herpes viruses. “Thus, T cell responses are altered in the aged by an accumulation of replicatively senescent dysfunctional T cells carrying receptors for persistent herpes viruses. The presence of clonal expansions of such virus-specific cells may shrink the available repertoire for other antigens and contribute to the increased incidence of infectious disease in the elderly(ref) Another study implicates cytomegalovirus in a somewhat similar fashion. “At the same time, it was established that cytomegalovirus (CMV) seropositivity was associated with many of the same phenotypic and functional alterations to T-cell immunity that were being reported as biomarkers associated with aging. It was discovered that CMV was the prime driving force behind most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells. Independently, longitudinal studies of a free-living population of the very old in Sweden over the past decade have led to the emerging concept of an ‘immune risk phenotype’ (IRP), predicting mortality, which was itself found to be associated with CMV seropositivity. — In this sense, then, we suggest that immunosenescence is contagious (ref).”
From an evolutionary viewpoint, the difficulty experienced by mature adaptive immune systems when dealing with brand new pathogens is explained by the fact that until recent years there was very little mobility of people and therefore of human pathogens. Human diseases traveled by foot or ox cart. There was no such thing as a disease originating in Borneo and spreading all over the world in weeks because of air travel. So, the adaptive immune system rarely had to deal with new off-the-wall challenges like the new H1N1 virus.
Some of the responsibility for immunosenescence is associated with changes in antigen-presenting cells. “Recent findings suggest that interleukin-10, a key cytokine that can suppress cell mediated immunity and maturation of DC subsets, is elevated in the very healthy elderly. However, production of IL-12, required for the initiation of T cell immune responses, declines in frail elderly along with DC antigen presenting function. These findings suggest that shifts in IL-10 and IL-12 may not only directly influence immune response but may also alter the balance and maturation of DC subsets(ref). Another early study related to antigen presenting cells provided a clue of things to be explained later – that there is something about young immune system cells that invigorates older ones. “Surprisingly, co-culture of APC (antigen presenting cells) from healthy elderly donors with purified T cells from young donors enhanced T cell proliferation(ref).”
Whatever the age-associated mechanisms, there are a few recurring themes in the earlier literature (pre 2006): 1. too many antigen memories producing overload, 3. Cellular senescence of T and B cells, 3. insufficient proliferation of new T cells, and 4. Decline in the antigen presenting function.
Stem cell proliferation perspective
From the stem cell perspective the main issue of immunosenescence is decline of proliferation of new T cells as identified earlier. But the focus is on decline of the rate of differentiation of hematopoietic stem cells into immune system progenitor cells and subsequent proliferation and differentiation of those cells into immune system cells in the thymus. “The thymus is the site of production of mature T lymphocytes and thus is indispensable for the development and maintenance of the T cell–mediated arm of the immune system. Thymic production of mature T cells is critically dependent on an influx of bone marrow-derived progenitor T cells that undergo replication and selection within the thymus. Thymus cellularity and thymic hormone secretion reach a peak during the first year of life and then decline gradually until the age of 50–60 years, a process known as “thymic involution(ref).” In this regard, immunosenescence falls under the 14th theory of aging outlined in my treatise, Stem Cell Supply Chain Breakdown. In fact, decline of thymus function has long been thought to be associated with aging(ref).
The stem cell perspective of immunosenescence started to emerge into prominence in recent years. A 2006 publication indicates “The differentiation state of CD8+ T cells has emerged as a crucial determinant of their ability to respond to tumor and infection. Signals from T-cell receptors, co-stimulatory molecules and cytokine receptors direct the differentiation process. These signals ‘program’ sustained and heritable gene expression patterns that govern progressive differentiation and lineage commitment. The epigenetic mechanisms by which T cells are programmed are just beginning to be elucidated. Understanding the mechanisms that control CD8+ T-cell differentiation is important in the development of novel immunotherapy strategies(ref).” As time goes on, more is being learned about aspects of the stem cell supply chain that ends up in production of T cells. See, for example, the publications Differentiation of memory B and T cells, Major T Cell Progenitor Activity in Bone Marrow–derived Spleen Colonies, and Identification of an early T cell progenitor for a pathway of T cell maturation in the bone marrow.
It appears clear that averting immunosenescence requires a continuing high level of healthy operability of the stem cell supply chain leading from hematopoietic stem cells to operating immune system cells, T cells in particular. Further, it is important to avert depletion of the stocks of hematopoietic stem cells themselves. These topics are treated at some length in my treatise as part of the discussion of the Stem Cell Supply Chain Breakdown theory of aging. See particularly the discussion in the subsection on Exhaustion of critical pools of healthy adult stem cells.
The accumulation of too-many memories in immune cells mentioned earlier as well as the operation and evolution of the stem cell supply chain that makes new immune system cells are both epigenomic phenomena. They have to do with histone acetylation and DNA methylation and protein folding changes in the DNA of cells that profoundly affect gene expression but that are not in the genes themselves. As elaborated in my treatise “The Deterioration of the Stem Cell Supply Chain and the Programmed Epigenomic Changes and the candidate Epigenomic Changes In DNA Methylation and Histone Acetylation theories of aging are completely compatible and complementary.
What can be done about immunosenescence?
I have previously discussed one possible approach for combating immunosenescence: promotion of the expression of telomerase. This could produce three desirable consequences: 1. Extending the replicative lifespan of existing immune system cells, 2. Promoting the chain of differentiation starting with hematopoietic stem cells leading through neural progenitor cells and ending with operable immune system cells, and 3. Possibly expanding the replicative lifespan of hematopoietic stem cells thus assuring greater longevity of the pools of those cells. See the discussion in my treatise in the Telomere Shortening and Damage Firewall section and some of the publications that Rita Effros and her team have produced related to telomerase activation in immune system cells like this one, this one and this one. “Our research has documented that maintaining high levels of the telomere-extending enzyme, telomerase, by either genetic manipulation or exposure of T cells to chemical telomerase activators, not only retards telomere loss but also restores a more youthful functional profile to the T cells. These observations suggest possible novel telomerase-based therapeutic approaches to enhancing health span in the elderly population(ref).” Also, I have written before on how telomerase expression can promote the differentiation of stem cells independently of telomere extension. See, for example, the post Extra-telomeric benefits of telomerase.
Speculations on preventing or significantly delaying immunosenescence
I speculate here on possible future approaches that could conceivably prevent immunosenescence completely, or at least delay its onset for a very long time. I need stress that right now exactly how to go about these procedures is unknown
- One approach would be focus further on the stem and progenitor differentiation function and determine whether there may be ways to modify Notch and possibly mTOR and other pathway signaling to keep open the differentiation pathway leading from hematopoietic stem cells to mature T cells. Hints about how to go about doing this are buried in some of the research studies referenced above.
- Another approach would involve changing epigenomic markers within T cells so as selectively to erase recordings of possibly irrelevant antigens from the far past. I have no idea of how this could specifically be done but the current intense research focus on epigenomics and the other “omics” might show the way(ref)(ref). We do know how to erase epigenomic memory completely in cells(ref). The challenge is how to erase it part way in a controlled manner.
- Another approach would be to focus on the health of pools of hematopoietic stem cells and possibly employ a form of induced pluripotent stem cell (ref)(ref) technology to prime the pump at the head of the stem cell supply chain by creating a continuing new supply of healthy hematopoietic stem cells. In other words, we probably need to tackle the problem upstream of where most current research focus is. That is how I think aging needs to be addressed.
Time will tell if any of these approaches will make sense.