Aging, DNA damage, and chronic inflammation?

Hi all,

Recently I found a research article that describes experiments that show for the first time a possible cause of the chronic inflammation that seems to be implicated in the etiology of so many chronic medical conditions. This chronic inflammation becomes more common and widespread as people age, or when they somehow sustain considerable damage to a particular tissue over time. One underlying cause of this age-associated inflammation turns out to be unrepairable DNA damage which accumulates in non-cycling cells of our bodies (either quiescent or senescent) as we age. This accumulation of DNA damage in cells as we age has been known for some time - but what this paper, by Campisi et. al. [1] at the Lawrence Berkeley National Laboratory, unexpectedly showed is that these damaged cells secrete a unique and powerful battery of inflammatory cytokines. As we age we constantly secrete more and more of these inflammatory cytokines in our tissues, which can lead to the development or exacerbation of all of the chronic inflammatory conditions which we have studied this semester

As an aside, I found this paper on the Faculty of 1000 Biology web-site (http://f1000biology.com/guardpages/evaluation/1145049//article/article.asp%253Fid%253D1145049%2526view%253D%2526style%253D). This web-site is a very cool service which provides a synopsis and critique of the most interesting current papers in biology, as judged by the "Faculty of 1000" - generaly recognized respected researchers in their fields. So, if you can afford the subcription fee, you can have the hottest papers in your research area identified and critiqued by experts and sent straight to your e-mailbox! You can also get a copy at the cool free-access Public Library of Science (PLoS) website, http://www.plosbiology.org/article/info:doi%2F10.1371%2Fjournal.pbio.0060301.

Anyways, back to the paper. In their experiments, the authors modified commercial antibody arrays to substantially improve their range and sensitivity, and then measured the proteins secreted by senescent cells in culture, as well as from tissue samples that were collected from prostate cancer patients both before and after completing a DNA-damaging form of chemotherapy. They found that different types of cells from different tissue all secrete a very similar set of proteins when they senesce in response to DNA-damaging radiation or chemotherapy. The authors propose to call this common response to DNA damage and senescence "senescence-associated secretory phenotype", or SASP. Importantly, they then showed that it occurs not only in cultured cells, but also to cells in vivo in response to exogenously introduced DNA damage (and by extension to normally produced endogenous oxidative DNA damage). The SASP develops slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. The SASP featured high levels of secreted inflammatory cytokines, immune modulators, and growth factors, all of which are associated with inflammation and malignancy (IL-6, IL-8, GRO-α, MCP-1, GM-CSF...).

Note: For those interested, the primary authors followed up this seminal line of experiments with further work clarify some of the molecular interactions involved in this inflammatory phenotype of aging and/or damaged cells, finding connections with the well characterized dna repair/maintenance genes ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb... [2]


- Brian P


1. Jean-Philippe Coppé, Christopher K. Patil, Francis Rodier, Yu Sun, Denise P. Muñoz, Joshua Goldstein, Peter S. Nelson, Pierre-Yves Desprez, Judith Campisi (2007) Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor, PloS Biology, www.plosbiology.org




2. Francis Rodier1,2, Jean-Philippe Coppé1, Christopher K. Patil1, Wieteke A. M. Hoeijmakers1,4, Denise P. Muñoz2, Saba R. Raza1,5, Adam Freund1,3, Eric Campeau1,6, Albert R. Davalos1 & Judith Campisi1,2 (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nature Cell Biology 11, 973 - 979.