Fight Aging!

The open access paper I'll point out today covers some of the aspects of aging in the immune system, with a particular focus on the role of cytomegalovirus infection, and makes for interesting reading. The immune system is vital to health, not just in defending against pathogens such as bacteria, viruses, and fungi, but also because its agents work to destroy broken and harmful cells, such as those that have become cancerous, remove metabolic waste compounds where they accumulate outside cells, and help to regulate many necessary processes, from wound healing to the formation and destruction of synaptic structures in the brain. When the immune system declines into failure and dysfunction with advancing age, many other parts of our biology are dragged along with it into the downward spiral that ends in major organ failure and death. Finding ways to even partially reverse the progression of immune aging is obviously of great importance for the near future, a necessary part of the first generation of rejuvenation therapies. Fortunately, there are a few comparatively straightforward approaches that might bear fruit in the years ahead, despite the enormous and still incompletely mapped complexity of immune system biochemistry.

The immune system is broadly divided into innate and adaptive components, comprising different types of cell, different behaviors, and different vulnerabilities that lead to accumulated damage and disarray with time. The adaptive immune system is more recent in evolutionary terms, built atop the activities of the innate immune system. It is, as the name suggests, distinguished by being able to adapt to new threats rather than deploying the same set of armaments and strategies against every challenge, as is the case for the innate immune system. The adaptive immune system ultimately fails in large part because adaptation requires a memory of past actions, and over time the cells responsible for maintaining immune memory begin to crowd out the cells capable of taking action. Adults have a slow rate of creation of T cells, the cells of adaptive immunity. These cells are constructed in the bone marrow, but then migrate to the thymus to mature. That organ declines greatly shortly after childhood, and then further with increasing age, reducing its capacity for T cell maturation. This slow rate of replacement effectively puts a cap on the number of T cells present in the body under normal circumstances, and that combined with the lack of any effective limit on the numbers of memory T cells inevitably leads to disaster. Evolutionary processes are good at front-loading for success, producing biological systems that work very well in youth, but that hit architectural limits later in life.

The most effective near-term approach to this problem of misconfigured adaptive immunity is to improve upon and adapt the immune reboot therapies that are presenting being trialed successfully as treatments for severe autoimmune conditions. At the very high level, the age-damaged adaptive immune system is conceptually similar to an immune system fallen into autoimmunity: in both cases the problem is one of misconfiguration, the bad information recorded in immune cells leading to bad behavior. Wiping out these cells and starting over is a very promising approach. In the case of aging this doesn't deal with any of the forms of cellular damage that cause aging, but it should nonetheless do a great deal to restore effectiveness of the immune system in older people. The challenges are numerous: the present chemotherapies for immune ablation would need to be replaced with side-effect-free targeted cell killing technologies, such as that pioneered by Oisin Biotechnologies. Further, replacement of the immune system would likely have to be augmented with cell therapies in older people, as they would not be able to replace those cells rapidly enough on their own for safety. These are, however, very approachable challenges. The technologies largely exist already, and just need to be packaged, trialed, and moved into the clinic. Deploying this class of therapy will answer many of the questions asked in the paper linked below, and more rapidly than other forms of investigation.

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

The human immune system must fight diverse pathogens and provide sufficient host protection throughout life. Memory T cells, which differentiate from naïve T cells upon primary antigenic stimulation and enable a rapid and robust response to previously encountered pathogens, are key players in adaptive immunity. The generation and maintenance of pathogen-specific memory T cells is crucial for life-long immune protection and effective vaccination. However, profound changes occur in the human immune system over time, known as immunosenescence. These age-related changes contribute to decreased immune protection against infections and diminished responses to vaccination in the elderly. Changes in T cell immunity appear to be have the most impact.

Although T cell numbers remain more or less constant over the human lifespan, pronounced age-associated changes occur in T cell composition (naïve vs. memory T cell subsets). It is well accepted that the functional naïve T cell output decreases after puberty due to thymic involution, resulting in increased homeostatic proliferation of existing naïve T cells and eventually phenotypic conversion of naïve T cells into virtual memory cells. In contrast to the shrinking naïve compartment and its impaired ability to activate and differentiate with age, the proportion of memory T cells increases during early life, remains stable throughout adulthood, but starts to show senescent changes after about 65 years. In humans, circulating memory T cells can be subdivided into two major phenotypically and functionally distinct populations: central memory T cells (TCM), which are largely confined to secondary lymphoid tissues, and effector memory T cells (TEM), which can traffic to multiple peripheral compartments.

One of the most prominent T cell changes to occur with age is the loss of the co-stimulatory molecule CD28 and the progressive accumulation of highly differentiated CD28- TEM cells, mainly in the CD8+ T cell population. These cells are characterized by decreased proliferative capacity, shortened telomeres, a reduced TCR repertoire, and enhanced cytotoxic activity. As CD28 is crucial for complete T cell activation, CD28 loss is associated with increased susceptibility to infections and a weakened immune response to vaccination in older people. It is thought that the memory T cells generated in youth are well preserved and remain strongly protective over decades, while T cell memory responses first derived in old age are severely impaired.

The ability to generate protective immune responses largely depends on the generation and maintenance of a diverse and well-balanced T cell repertoire. Several studies have shown contraction in T cell diversity corresponding to a shrinkage in the naïve T cell compartment in elderly individuals due to thymic involution. However, these studies do not take the dramatic influence of latent persistent infection into account, particularly cytomegalovirus (CMV) infection, which is known to be associated with age-related alterations in the T cell pool and function. Recent evidence suggests that homeostatic proliferation maintains the naïve CD4+ T cell compartment and its diverse repertoire, but not naïve CD8+ T cells, in CMV-negative individuals. A decline in naïve CD4+ T cell subsets occurs in the presence of CMV, but there is no depletion of naïve CD8+ T cells. In principle, thymic involution should have an equal impact on both CD4+ and CD8+ T cells. Therefore, the differences seen between the two subsets suggest that shrinkage of the naïve CD8+ T cell pool is more likely to be due to increased development of virtual memory T cells than the defective regeneration ability of an aged thymus. Moreover, unprimed "innate/memory-like" CD8+ T cells have recently been identified in humans. Taken together, these data imply that thymic involution might be less important for maintaining T cell diversity than previously thought.

Despite intensive studies of T cells providing some insights into immune system aging, they have a number of limitations that need to be taken into consideration in future investigations. First, most of our current knowledge on T cell aging is based on studies of circulating peripheral blood T cells, which only represent 2% of the total T cell pool. Circulating memory T cells predominantly reside in tissues other than the blood. Finally, human memory T cells are generated and maintained in the context of exposure to diverse viral infections throughout life, particularly CMV infection (over 90% of young people in developing countries). It is well-known that CMV plays an important role in human memory T cell function with aging. Therefore, distinguishing CMV seropositive individuals from others is important to provide a more accurate understanding of age-related memory T cell immunity.

Cytomegalovirus (CMV) is an ubiquitous β-herpesvirus that has co-evolved with humans over millions of years. Human CMV (HCMV) is a prevalent human pathogen, infecting 40-100% of world's population. CMV has the capacity to induce both lytic and latent infections to establish lifelong persistence in human hosts following primary infection. Long-term HCMV persistence has a profound impact on the immune system's composition and function, even in healthy HCMV-infected individuals, especially with respect to CD8+ T cells. One hallmark of latent HCMV infection is the progressive and substantial expansion of HCMV-specific memory CD8+ T cells over time, with HCMV-specific memory CD4+ T cells accumulating to a lesser extent. This accumulation of HCMV-specific memory T cells during viral persistence is termed "memory inflation." HCMV-specific memory T cells tend to gradually increase in number with age: in HCMV-infected elderly individuals, the CD8+ T cell response to HCMV antigens occupies nearly 50% of the entire memory CD8+ T cell compartment in peripheral blood, while approximately 30% of total circulating CD4+ T cells can be HCMV responsive.

Human cytomegalovirus (HCMV) persistence is thought to be a driver of immunosenescence in humans. The majority of HCMV-specific inflationary T cells are TEM cells with the typical age-related senescent T cell phenotype. It is widely accepted that late-stage differentiated CD28- T cells are a major characteristic of T cell aging, suggesting that persistent HCMV infection is associated with immunosenescence. This is further supported by the fact that the large population of HCMV-specific CD8+CD28- TEM cells that usually accumulate during HCMV persistence are absent in HCMV-seronegative elderly individuals, even those infected with other persistent herpes viruses. There is increasing evidence to suggest that memory inflation in HCMV infection is associated with impaired T cell immunity in elderly hosts. Despite the CD8+ T cell repertoire being diverse enough to recognize different viral epitopes soon after primary HCMV infection, clonal diversity starts to shrink with age, with a large proportion of the repertoire limited to a few high-avidity clones with a replicative senescent phenotype.

Taken together, HCMV infection in the elderly is implicated in immunosenescence and might have a deleterious impact on host immunity and enhance the aging process. Nevertheless, there remains considerable uncertainty regarding the causative role of CMV in immunosenescence. Although it is well-known that HCMV is a common cause of severe morbidity and mortality in immunocompromised individuals, we cannot exclude the possibility that HCMV might improve the polyfunctionality of CD8+ T cells and consequently benefit the host immune system, at least in young healthy individuals. Moreover, it is still unclear whether HCMV re-activation occurs more frequently in the elderly than in younger individuals. Hence, whether expansion of HCMV-specific CD8+ T cells over time is really deleterious in old age remains unknown.