Accelerated Immune System Aging That Illustrates Normal Immune System Aging

The study of forms of accelerated aging often provides insight into the biochemical processes of normal (and equally undesirable) degenerative aging. Here, we'll look at the aging of the immune system, a comparatively structured form of degeneration that might be viewed as the natural consequence of evolutionary selection:

Evolution is a harsh but efficient mistress; you can consider yourself surprisingly well optimised as a piece of machinery, but your warranty only goes so far as the number of years in which your recent ancestors contributed to the success of their offspring. After that, you're on your own - biochemical processes unwind and break down free from any past selective pressure to do better.

Take the immune system, for example, one of many absolutely vital components in the very complex system that supports your life. It is remarkably well optimized for reliable and effective use of resources in early and mid-life, but the rules that govern that optimization lead to a system that breaks down badly after extended usage.

For a low cost in biological resources you get a good immune system at the very start of your life - but that system's prowess is all front-loaded. It is not set up for the long term. There are two principle issues at work here:

1) The supply of new immune cells diminishes as the thymus involutes:

The immune system undergoes dramatic changes with age - the thymus involutes, particularly from puberty, with the gradual loss of newly produced naive T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells.

2) The immune system is limited in the number of cells it can support:

Throughout our lives, we have a very diverse population of T cells in our bodies. However, late in life this T cell population becomes less diverse ... [one type of cell] can grow to become more than 80 percent of the total [T-cell] population. The accumulation of this one type of cell takes away valuable space from other cells, resulting in an immune system that is less diverse and thus less capable in effectively locating and eliminating pathogens.

...

One main reason your immune system fails with age appears to be that chronic infections by the likes of cytomegalovirus (CMV) cause too many of your immune cells to be - uselessly - specialized.

Your immune system is set up to fail - it's only a matter of time. At one end of the candle burns the lack of new immune cells, while at the other end CMV and its ilk ensure that limited resources are increasingly (and uselessly) devoted to combatting them. With that in mind, let me point you to a recent open access paper that illustrates both of these root causes by looking at people who lost their thymus in younger life:

While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4+ and CD8+ T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells.

A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus.

Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

The next step in immune research should be to do something about these problems. On the one hand, we would want to understand how to safely keep the thymus active, and on the other hand establish methodologies to regularly eliminate CMV-specific immune cells and thus free up capacity. Fortunately, both of these goals look to be very plausible for the next decade of development. Researchers in the cancer science community have been demonstrating methods of safely killing specific cell populations identified by their surface markers for some years now, using either nanoparticles or engineered viruses. Killing specific immune cells should be well within the capabilities of this emerging field. As to the thymus, we can look to regenerative medicine and tissue engineering, a vast and well funded field devoted to restoring and recreating fully functional organs using a patient's own cells. If you can build a heart from scratch, a thymus can't be many years behind.

From a technology perspective, the future is bright and restoring an aged immune system looks very viable in the near term. Unfortunately this is yet another of those longevity science line items that few groups are working on. Like all aspects of "normal" aging, the FDA does not consider immune degeneration in late life a disease, and therefore will not approve treatments for it. Since there is no prospect of bringing such a treatment to market in the US, there is little funding for development, and little interest amongst researchers in undertaking work that will relegate them to an economic backwater.

In this, as in so many areas of medicine, we must look to other strategies and other regions of the world if we wish to see the potential of present scientific understanding and capacities of biotechnology fully realized.

ResearchBlogging.orgSauce, D., Larsen, M., Fastenackels, S., Duperrier, A., Keller, M., Grubeck-Loebenstein, B., Ferrand, C., Debré, P., Sidi, D., & Appay, V. (2009). Evidence of premature immune aging in patients thymectomized during early childhood Journal of Clinical Investigation DOI: 10.1172/JCI39269

Comments

Unlike some of the other, potential anti-aging treatments on the horizon, a pharma might be able to get the FDA to approve an immune booster/regenerative (if/when it becomes available) for the elderly by demonstrating that the drug/procedure is able either to lower cancer rates or to decrease the incidence of infectious diseases in the elderly, ie. reducing the number of deaths from flu.

If I were trying to get this type of drug through FDA trials, that is how I would market it. I think the FDA would allow a company to vet the drug through clinical trials if the firm takes that approach.

Posted by: Anthony at September 24th, 2009 2:44 PM

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