Fight Aging!

Today I thought I'd point out an interesting and very readable open access paper on immune system aging and the contribution of cytomegalovirus to that process. The authors outline the generation of a large set of data on immune aging, sampling a few hundred healthy individuals to obtain a range of measures of immune function, and discuss the results. It makes for interesting reading if you've been following research into cytomegalovirus in immune aging, and there are even online data visualization tools for the results published in this paper.

The immune system grows simultaneously overactive and ineffective in old age, generating chronic inflammation while failing to respond adequately to threats such as pathogens and potentially cancerous cells. A growing consensus in the researcher community sees exposure to cytomegalovirus (CMV) as an important contribution to this dysfunction. CMV is a very prevalent herpesvirus; near everyone has it in their system by the time they are old, and like all herpesviruses it resists clearance, reemerging from hiding to challenge the immune system repeatedly. In the old immune system there is an expansion of memory T cells, and especially memory T cells devoted to CMV. This expansion takes place at the expense of naive T cells needed to respond to new threats.

There is more than just this one form of dysfunction in the aged immune system, but this particular problem might be addressed in the near future in a variety of ways: clear out the useless duplicated memory T cells to free up space, or deliver a much larger supply of new T cells, such as by rejuvenating the thymus, the organ responsible for T cell maturation, or simply culturing new immune cells from a patient's own tissues and periodically delivering them. It is also possible to work towards a reliable way to clear CMV permanently - better ways to treat all herpesviruses are certainly needed. Even if completely successful this won't undo the damage done to the immune system's balance of cell populations, however. It only prevents the accumulation of more damage.

This paper can be taken as one of many that illustrates the magnitude of the effect of CMV on immune aging. It also makes some other interesting points regarding the scale of variations between individuals as compared to variations over the course of aging. It is possible to be old and still have a comparatively effective immune system by some measures: there is considerable overlap in the range of values across a given age and the range across all ages. The trend is still downhill and we need the development of rejuvenation treatments to reverse that, but all is not hopeless.

Large-Scale and Comprehensive Immune Profiling and Functional Analysis of Normal Human Aging

In this study, we describe a large immunological data set based on about 240 individuals from a clinical cohort of 740 healthy aging adults. Data from cellular, protein, and genomic assays are described, with particular emphasis on stimulation-response assays (analysis of cytokine signaling, and cytokine production and gene expression from stimulated peripheral blood mononuclear cells). Our emphasis in this paper was to describe the features of each assay with regard to discovering differences based on age, sex, and CMV status. Further analysis of the data is welcomed, via a parallel coordinates visualization tool.

One common theme among nearly all our immunological readouts is that there is considerable heterogeneity at every age, which is generally greater than the mean change across ages. This is exemplified by the CD27+CD8+ subset of T cells. While the downward trend with age is highly significant, the breadth of values at every age is very high. In this regard, there are essentially no "clock" analytes, which would accurately and independently predict age, since there is so much overlap in the distributions among young and old individuals. The corollary to this is that many, if not most, elderly individuals still fall within the range of the younger adults. In fact, we often observed a broadening of the distribution with age.

In this regard, it is important to note that this study had strict exclusion criteria, such that overt diseases of aging were not clinically present. Although our data provide a relatively clean description of the range of immunological values associated with healthy aging, they represent a cross sectional analysis and as such may include individuals at risk for or developing disease.

As a result of quantifying significant readouts by age, sex, and CMV status, one can pose the question, "Which of these three variables has the greatest impact on the immune system as we measured it?" From our data, it seems reasonable to conclude that age, then sex and CMV status, show the greatest effects. Taken another way, it is impressive to see that the changes in the immune system brought about by a single pathogen, CMV, rival the differences seen between the sexes, in terms of the number of significantly affected analytes. Another conclusion from our data is that there is a clear interaction of age, sex, and CMV status. For example, T cell subsets are highly influenced by all three. In this case, the effect of CMV appears to be a downward broadening of the distribution, such that a subset of CMV positive individuals shows markedly lower levels of these cells.