(Please welcome our newest contributor, okee.)
I recently attended a great meeting entitled Translational Research at the Aging and Cancer Interface, held by the American Association for Cancer Research (AACR) and organized by Judith Campisi, Harvey Cohen, and William Ershler. Here’s a synopsis based on my impressions. Fair Warning: this is by no means objective or comprehensive. It’s just what struck me as interesting and I have good enough notes on to talk about.
I’d say that there were 5 major themes to the meeting:
- Senescent environment
- Genomic predictors of cancer
- Models of Accelerated Aging
Judy Campisi has been championing this model for years now. The idea is this: some cells in the body proliferate too much or get too much DNA damage and undergo cell senescence. These cells cause aging, not because we run out of cells, but because these cells stick around indefinitely and poison the environment with nasty factors that they secrete into the extracellular space. Judy’s group has now identified many of these factors and analyzed the phenotype and underlying pathways to a great extent. The secreted proteins fall into two main categories: Inflammatory cytokines and proteases. Inflammation has been popular in recent years (with good reason), because it is involved in all kinds of bad stuff ranging from heart disease to arthritis to Alzheimer’s. Dr. Campisi now believes that the primary culprit in the inflammatory response is IL-6. Furthermore, senescent cells secrete proteases, break down the extracellular space and cause all kinds of localized trouble. The major player in this part of the story was reported to be matrix metalloproteinase 3.
Albert Davalos gave a great talk on HMGB1, a weird chromatin protein that is involved in cell senescence. It is secreted by senescent cells through some strange pathway that will give you a headache if I try to explain it. The important stuff is this:
- HMGB1 binds the RAGE receptor which activates the inflammatory response, including IL6;
- Both overexpression and knockdown of HMGB1 induce senescence;
- This is all happening downstream of telomeres and p16, but knocking down p53 can rescue the senescence induction;and
- HMGB1 forms a complex with the pro-apoptotic protein Bak.
Here’s the shortest talk summary ever: Massimiliano Bonafe reported that IL-6 activates Notch, which in turn promotes breast cancer malignancy. (Are you starting to see a trend here? IL-6 sucks!)
Norm Sharpless talked about the recent much celebrated senescence factor p16. The new and weird/interesting things is that he observes p16 to be upregulated in early aging – before the time we would consider to be even middle-aged for a mouse. He interprets this as an indication that p16 is one of those elusive causes of aging that heralds the coming decline. I’m pretty sure the story will be more complicated this, but it’s really interesting anyway.
Whew! That was a lot of stuff! Don’t worry though, that was probably the major theme of the meeting and the rest is lighter.
Arguably, this belongs under the senescence section, but I had to break it up somehow…
Elizabeth Blackburn presented the discovery of extremely short telomeres (which she coins T-Stumps) being maintained in some proliferating cancer cell lines. This is another peek into the mysterious world of what telomere capping really is and what the thresholds for replicative senescence really are.
Mark Eller (Gilchrest lab) gave an update to the story about how transfection of telomere sequence oligonucleotides can induced cell senescence. It turns out that they cause the cell to form DNA damage foci (TIFs) at actual telomeres.
There was some amount of discussion (though not much data) about the current idea (being touted by James Watson as the impetus behind the Cancer Genome Project) of using genomics and gene expression profiling in the treatment of cancers. Let’s hope that this becomes the standard of care sooner rather than later!
Along these lines, Christopher Benz reported that breast cancer recurrence is more well predicted by estrogen receptor expression than by the age of the patient.
The mitochondrial theory of aging took a blow at this meeting, with speakers casting doubt on some of the popular ideas. Tom Prolla reported that mutations in mitochondrially encoded genes have no affect on rates of tissue culture cell senescence. Arlan Richardson reiterated that MnSOD +/- mice have normal lifespan (when cancer is discounted).
Animal models of accelerated aging were poorly represented at this meeting. George Hinkal (Donehower lab) gave an excellent talk, however, on his work on the p53m mouse. Recall that the m-allele is thought to behave as a gain of function mutation in the presence of a wild-type allele of p53. These animals “age” prematurely, but don’t get cancer. Among other findings, George reported that the m-mouse has better defense against low level radiation, but a very poor reaction to high doses of radiation.
There you have it! It’s very exciting to go to meetings like this and see whole new paradigms emerging. It’s gotten to the point that it’s impossible to attend all of the many aging meetings that happen each year, so I hope that if you didn’t get the chance to attend this one, that you enjoyed reading about it here.