Missed blogging the first talk, by session chair Irina Conboy, because I was late coming back from a walk (during which time I had a really nice talk about ER stress, which is my old field as well as a subject that increasingly appears relevant to aging)
Heidi Scrable started her talk with the attention-getting introduction: “The stem cell theory of aging [the idea that loss of homeostasis (aging) occurs when stem cells can no longer maintain viability] and why we might not believe it anymore.” She described new results regarding her lab’s p44 transgenic mouse, which has a hyperactive p53 axis and exhibits signs of premature aging: p44, an isoform of p53, is strongly expressed in embryonic stem cells (indeed, it appears that ESCs require p44 in order to proliferate) but expression is lost with pluripotency. Therefore, Scrable argued, the lifespan effects of p44 in adult animals must be the result of effects the protein has during embryonic development. I’m not 100% sure that I think this buries the stem cell theory of aging, but this idea of genetic “action at a distance” is certainly thought-provoking.
Chong Chen then discussed the role of mTOR in the aging of hematopoietic stem cells. The mTOR pathway (whose homologs in yeast are involved in lifespan regulation) is highly activated in aged HSCs — and rather than a compensatory or protective response, this appears to be causative: experimentally activated mTOR interferes with the regenerative functions of HSCs, probably by increasing the level of reactive oxygen species (ROS). To seal the deal, treatment with the mTOR inhibitor rapamycin can improve the regenerative capacity of HSCs from old mice. (No comment on how or whether DNA damage, which is known to reduce HSC proliferative capacity, activates mTOR.)
Sean Curran (from Gary Ruvkun’s lab) described a novel phenotype of the long-lived worm IGF-I pathway mutants: an soma-to-germline transition in a subset of cells. Since germ line cells engage protective pathways (for the purpose of protecting posterity), this transition could explain the increased cellular stress resistance in long-lived mutants.
Henry Jasper is studying how activation of stress response pathways can limit tissue homeostasis and regenerative capacity, using the Drosophila gut as a model system. Old fly intestines exhibit functional degradation and increased activity of the stress response kinase JNK. Experimental activation of JNK accelerates the expansion of certain types of stem cells, potentially causing overproliferation (thereby exhausting the compartment) and misdifferentiation of a subclass of daughter cells.
Karl Rudolph, the other session chair, described the role of checkpoint controls in stem cells. In telomerase-deficient mice, DNA damage checkpoints limit the regenerative capacity of stem cells, thereby reducing repair and maintenance and interfering with tissue homeostasis — raising the issue of tradeoffs between cancer prevention and self-renewal.
Gonad time! Leanne Jones, whose work on the role of the stem cell niche in the Drosophila gonad we follow closely, described new results from her lab pertaining to the role of insulin signaling in stem cell aging. Her group has discovered a number of factors (genes as well as physical associations) involved in germline stem cell maintenance, and is now in the process of demonstrating that the major lifespan-regulation pathways are involved in controlling these factors.
Sticking with the “simpler organisms” for a moment, Shijing Luo (from Coleen Murphy’s lab) next described the mechanisms by which the TGF-ß/Smad pathway controls reproductive aging in the worm. Mutants in the pathway extend reproductive lifespan — as do mutations in the IGF-I signaling pathway, which are also long-lived — and the eggs they produce are more “youthful” later in life than in the wildtype.
Back down to the molecular nitty-gritty, Eric Verdin from UCSF discussed the regulation of SIRT1 expression in embryonic stem cells, one of two cell types (other than testis) where the protein is highly expressed. Note that I say “protein” — the SIRT1 mRNA is widely expressed, but in most differentiated cells the protein is not detectable, implying that the gene is post-transcriptionally regulated. Using a conditional knockout of the micro-RNA processing enzyme Dicer, Verdin’s group has shown that the SIRT1 mRNA is targeted by a several micro-RNAs that are upregulated over the process of differentiation.
Last but not least, Stephanie Xie (from David Scadden’s group) described the role of the spindle checkpoint kinase Mps1 in chromosomal instability, tumorigenesis and HSC aging. She started with a piece of information I didn’t have — that the number of HSCs (at least by immunophenotypic criteria) actually increases with age, even as their function is declining. (That made me wonder whether “useless” stem cells impose some kind of metabolic burden on an aging organism, and secondarily whether these same impotent cells might exert a “dominant negative” effect by crowding out and/or getting in the way of the few remaining functional cells.)
Session index:
Ouroboros 
Interesting, thanks for report,
Interestingly, with age we can see myeloid markers expression shift on HSC and progenitors, in the same time with age we see increase chance to develop myelogenous leukemias (AML). More of that AML blast express mTOR and there is an opinion that rapamycin can selectively kill AML stem cells (with high mTOR) expression, remain normal HSC untouchable. This concept testing on clinical trial right now.
So, seem like rapamycin can “clean” mutated HSC (with mTOR high expression) and increase regenerative capacity of normal HSC,
but I think it’s even more complicated and few players involved.
I wonder: instead of using it systemically, could sirolimus be used to enhace bone marrow cells and then implant them?
(and on the pl6vPl6 topic: wouldn´t a simmilar approach, as in, inhibiting Pl6 -such as with miRNA- be a good approach to temporally enhace the regenerative capabilities of the HSCs without actually removing the tumor-suppressor gene?)
Another thing: as you know, recently there have been updates on successful transplant tollerance. In one article I read some months ago, which was in the january edition of the NEJM, I think, they reported that if they mixed donor bone marrow with receptor bone marrow, and made the latter a marrow graft with the result along with the kidney transplant, they obtained induced tollerance . Part of the procedure involved using non-myeloablative immunosuppresion. I´m not profficient as to whether this involved sirolimus or not (can´t check. Could be. AFAIK sirolimus is non myeloablative, but if it did, might it have enhaced the results? (increasing the graft´s perfomance) It might also be behind some odd immune system activity that was detected in one of the patients.
The p16 miRNA is a nice idea but it wouldn’t work — once p16 has been turned on in a cell, the growth arrest is not reversible by knocking down p16. For data on this in fibroblasts, see Beauséjour et al.. I’m fairly sure this is also true in epithelial cells.
Hm, a pity. I wonder, is there any workaround? For instance: filtering out not-yet-senescent bone marrow cells (somehow), and cultivating those in the transient pl6 inhibiting medium? (or maybe, use an iPSC derived method to get some HSCs from scratch? *Is* it possible to get more limited stem cells from pluripotent ones?)
Also: In this post:
https://ouroboros.wordpress.com/2007/06/14/sucking-the-life-out-of-marrow-dna-damage-accumulation-in-aged-hematopoietic-stem-cells/
it seems that in hematopoietic cells, at least, it is linked to the cells themselves. (An idea linked to the Pl6 article: could it be that the reduced regen. rate is due to a high percentage of cells being non-functional due to Pl6 firing off in many of them, rather than DNA damage, at least directly?)
So I wonder, to what extent would a bone marrow transplant help the situation by itself? Would it result in enhaced immune activity and blood vessel regeneration? Or would it be still subject to some negative niche influence?