Telomerase as a cure for immune senescence

Hot on the heels of reports that calorie restriction slows immunological aging comes this theoretically motivated suggestion that expressing telomerase in T cells might delay senescence in immune cells themselves. From a UCLA‘s Rita Effros:

Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3–5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8+CD28 T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation.

Lymphocytes are particularly attractive targets for gene therapy because they can be removed from the body via extraction of blood (a relatively non-invasive technique, as invasive techniques go), propagated in culture, and even positively selected for successful genetic modification — this last point being particularly easy in this case, since telomerase-positive cells don’t have a built-in limit on the number of divisions they can undergo.

The clinical ramifications of the strategy are clear, not only for the treatment of specific diseases (in the work here, the author focused on HIV-reactive CD8+alternative pathway.

Hence, giving telomerase to cells removes one roadblock on the path to full-blown neoplasia. Does we really want our blood crawling with lymphocytes that are all one step closer to oncogenic transformation?

On the other hand, telomerase expression is just one of the roadblocks; there are many more. And there are tissues of the body that express telomerase throughout the lifespan but are not riddled with tumors, i.e., the germ line.

So while more study is clearly required before this enters the clinic, I’d count Dr. Effros’ suggestion as one with considerable promise.

Advertisements

4 comments

  1. […] Telomerase, Immune Senescence Beyond the reduction in number of naive T cells, the immune system also ages through an accumulation of senescent T cells that behave in suboptimal or damaging ways. Via Ouroboros, a look at the science of doing something about the latter problem: “Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age … high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8+CD28- T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging.” View the Article Under Discussion: https://ouroboros.wordpress.com/2006/12/22/telomerase-as-a-cure-for-immune-senescence/ Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/ Published Saturday, December 23, 2006 9:45 AM by Longevity Meme News and Commentary Tags: Medicine, Biotech, Research […]

  2. I’ve been thinking about this for a while. I think the best way to keep from adding a “hit” to the lymphocytes is to transiently x-fect the t-cells with telomerase and to put it under an inducible promoter and/or negive selection (suicide) for protection against expression in cells incorporating it by random integration. Then you passage the cells ex-vivo long enough to regenerate their telomeres before transplanting them back in.

    I’m glad to hear Rita talking about this. Any chance she’s actually working on it?

  3. And also: does the suggestion of human-telomerase engineered T-cells evade the “Two times” limit that it mentions at the beggining of the article? (“T by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase”)

Comments are closed.