It is considered that a sizable component of the disarray of the aged immune system is caused by cytomegalovirus infection, and here I thought I'd note a couple of recent papers that touch on the intersection between this topic and the measurement of telomere length. The herpesvirus cytomegalovirus cannot be cleared from the body by the immune system; it lurks and reappears again and again, but causes few or no obvious issues in the vast majority of individuals beyond this one long-term problem. It is pervasive, and more than 90% of the population is infected by the time they reach old age. Ever more immune cells become specialized to attack cytomegalovirus, that number expanding rapidly in later life. The immune system operates with only a low rate of replacement cells, which makes it act very much like a space-limited system, with a ceiling on the number of cells it can support at once. Too much of its limited count of cells becomes taken up by cytomegalovirus-specific cells that are incapable of performing all the other necessary tasks, such as destroying cancerous cells, or attacking novel, unrecognized pathogens. At present telomere length is usually measured in immune cells taken from a blood sample. Considered over a population, average telomere length via this measure tends to trend down over the course of a lifetime. Individuals can vary considerably, however, and average length bounces up and down quite dynamically with health changes and other short-term environmental factors. It isn't much use as a metric for any sort of individual assessment. What does telomere length even signify? Well, every time a cell divides, telomeres shorten a little. When they get too short, the cell self-destructs or becomes senescent, ceases to divide, and is then usually destroyed by the immune system. Stem cells, however, maintain long telomeres via use of telomerase, and carry out their task of tissue maintenance by delivering a supply of new daughter cells with long telomeres. So average telomere length in any cell population is a smeared-out metric that reflects something of cell division rates and something of stem cell activity rates. We know that stem cell activity declines with age, and this would be enough for us to expect some sort of fall in average telomere length. Immune cells division rates are greatly influenced by many factors that are not relevant in other cell types: the presence of pathogens; the degree to which tissues are generating inflammatory signals; and so forth. In particular, we would expect persistent pathogens such as herpesviruses and HIV to push the immune system into greater replication, shorter telomeres, high rates of senescence, and general exhaustion as a result - which appears to be the case. What can be done about the issue, however? The most promising line of attack for cytomegalovirus, a mostly harmless pathogen aside from its decades-long grinding down of the immune system, appears not to be to tackle the virus itself, but to periodically destroy and replace all of the problem immune cells. Getting rid of cytomegalovirus would be a nice bonus on top of that, but not of any great use in and of itself for old people. The damage has already been done. Immune destruction and recreation isn't pie in the sky: it is already being accomplished in the context of curing serious autoimmune conditions. However, the therapeutic approaches used are presently fairly damaging, akin to chemotherapy in impact on the patient. Given better and more gentle methodologies of selective cell destruction - such as those under development at Oisin Biotechnologies, among others - then this will become a very plausible prospect. Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. Unlike normal memory T cells, which persist due to the levels of interleukin-7 (IL-7) and IL-15, exhausted T cells only require the presence of viral antigen to continue proliferating. This is partly due to losses in interleukin-2 receptor-? (CD122) and interleukin-7 receptor (CD127) that limit generation of virus specific T cells. Because viral antigen is intermittently or constantly supplied to these cells, viral specific T cells never cease proliferating. Depending on the length of infection, this could result in progressively shorter telomeres and an age-related decline in T-cell responses. A deleterious consequence of excessive telomere shortening is the premature induction of replicative senescence of CD8+ T cells. While senescent cells are unable to expand, they can survive for extended periods of time, occupying immunological space where functional immune cells could exist. The accumulation of senescent CD8+ T cells has been proposed to play a role in failed immune surveillance and in facilitating the development of metastasis of certain cancer types. Interestingly, some studies proposed that it may be possible to reverse this phenotype by reactivating telomerase expression. Evidence is mounting that high levels of antigen stimulation result in excessive proliferation, driving cells into a state of replicative senescence due to telomere attrition. The benefits for addressing viral T-cell exhaustion and immune senescence in patients with chronic viral infections and chronic inflammatory or auto-immune diseases are great so as to finally eradicate the chronic virus. Therefore, it is relevant to the ongoing efforts to develop therapeutic vaccines aimed at stimulating CD8+ T-cell responses and current immunotherapy based on adoptive transfer of expanded virus-specific CD8+ T cells. There are still many questions when it comes to the therapeutic potential of blocking T-cell exhaustion. One concern is whether fully exhausted T cells can be reactivated. If exhausted T cells have reached a state of terminal differentiation, they may have undergone permanent cell cycle arrest and irreversible cellular senescence. In this case, it is important that anti-exhaustion therapy (such as drugs to block immune inhibitory markers) be given at the proper time, before the cells become permanently differentiated. In the latter case, it would then be imperative to target these cells for removal through enhanced cell death, since reactivation is not possible. Telomere Shortening, Inflammatory Cytokines, and Anti-Cytomegalovirus Antibody Follow Distinct Age-Associated Trajectories in Humans Chronic infection with cytomegalovirus (CMV) has a profound impact on the immune system and is considered one of the causes of immunosenescence in the elderly. The serum titer of CMV-specific IgG has been widely used as an indicator of CMV infection status, but its significance in immunosenescence is less well defined. Age-associated increase in anti-CMV IgG has been reported from cross-sectional studies, but its trajectory has not been analyzed in longitudinal studies. Although a recent study found no difference of telomere length in subjects between CMV seropositive and negative from a cross-sectional analysis, it is unknown whether the rates of changes of these age-associated biomarkers in vivo are correlated or independent. In this study, we sought to measure the in vivo changes of telomere length, inflammation-related cytokine and anti-CMV antibody titer with age and to determine the trajectory of these age-associated immune changes and their inter-relationship using longitudinal analysis over an average of 13 years. Specifically, we assessed the individual longitudinal trajectories of peripheral blood mononuclear cell (PBMC) telomere length, eight pro-inflammatory cytokines, and anti-CMV IgG titer in 456 subjects. Strikingly, aging-associated changes in these variables occur with a distinct trajectory in each individual. Thus, immune aging is a heterogeneous process across individuals, and an assessment of immunosenescence requires a combinatorial evaluation of multiple age-associated biomarkers. Although aging affects multiple organs and tissues, the rates of age-related changes display a remarkable degree of variation within the human population. Our previous longitudinal studies of aging of the immune system assessed immune cell composition and telomere length, and demonstrated highly individualized changes. Overall, the results of our longitudinal studies suggest that the manifestations of aging-associated changes in the immune system are multifaceted and exhibit independent trajectories. These findings suggest that there is no dominant integrator among the three classes of age-related change studied here: telomere attrition in PBMCs, increased circulating IFN-? and IL-6, and increased titers of anti-CMV IgG. In contrast to the disassociation among age-related changes in telomere length of PBMCs, circulating inflammatory cytokines, and titer of anti-CMV IgG, the changes of various inflammatory cytokines with age show a number of positive correlations. The rate of increase in IL-6 is positively correlated with the rate of change in IL-4, and the rate of IL-1? is positively correlated with the rates of IL-13, IL-12p70, and IL-2. Although not all these cytokines displayed statistically significant age-associated changes, this suggests that the expression of these multiple pro-inflammatory cytokines may be regulated by common stimulators and/or that these cytokines may regulate one another in an autocrine and paracrine fashion. This mutual enhancement of inflammatory cytokine expression may explain why the increase in pro-inflammatory cytokines with age is rarely limited to a single cytokine.