Stem cells


Racing toward its ultimate goal of being involved in every aspect of biology, the mammalian sirtuin SIRT1 has been the subject of a number of recent papers, each dealing with a different aspect of the protein’s role. (Abstracts are excerpted; ellipses, emphases, and interpolated commentary are mine.)

In energy metabolism and liver cirrhosis: Sirt1 is involved in energy metabolism: The role of chronic ethanol feeding and resveratrol, Oliva et al.:

These results support the concept that ethanol induces the Sirt1/PGC1α pathway of gene regulation and both naringin and resveratrol prevent the activation of this pathway by ethanol. However, resveratrol did not reduce the liver pathology caused by chronic ethanol feeding [In other words, it's probably not a good idea to get your resveratrol by drinking 1000 bottles of red wine a day.]

In diseases of protein aggregation: The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration, Chen et al. [a collaboration between the Lindquist and Guarente labs]:

We tested the role of SIRT1 in mediating the effects of CR in a mouse model of prion disease. … We report that the onset of prion disease is delayed by CR and in the SIRT1 KO mice fed ad libitum. CR exerts no further effect on the SIRT1 KO strain, suggesting the effects of CR and SIRT1 deletion are mechanistically coupled. In conjunction, SIRT1 is downregulated in certain brain regions of CR mice. … Surprisingly, CR greatly shortens the duration of clinical symptoms of prion disease and ultimately shortens lifespan of prion-inoculated mice in a manner that is independent of SIRT1. [i.e., CR isn't actually therapeutically beneficial since the mice die young.]

In inflammation, inflammaging, and HIV/AIDS: SIRT1 longevity factor suppresses NFκB -driven immune responses: regulation of aging via NFκB acetylation?, Salminen et al. (review):

HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NFκB complex. As a consequence, the transactivation efficiency of the NFκB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. … Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NFκB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.

In Notch regulation of stem cell aging: Sirt1, Notch and stem cell “age asymmetry”, Mantel et al. (review):

The protein-deacetylase, SIRT1, has received much attention because of its roles in oxygen metabolism, cellular stress response, aging, and has been investigated in various species and cell types including embryonic stem cells. However, there is a dearth of information on SIRT1 in adult stem cells, which have a pivotal role in adult aging processes. Here, we discuss the potential relationships between SIRT1 and the surface receptor protein, Notch, with stem cell self-renewal, asymmetric cell division, signaling, and stem cell aging.

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:

Ever since the discovery that loss-of-function daf-2 mutations extend lifespan in C. elegans (a phenotype for which the forkhead-like transcription factor daf-16 is required), biogerontologists have devoted a tremendous amount of attention to the pathway, both in worm and in mammal (where DAF-2 and DAF-16 have homologs: insulin-like growth factor receptor (IGF-I-R) and various FOXO proteins, respectively).

As I mentioned yesterday, this week I’m clearing the backlog of articles that has accumulated over the past couple of months. Lots has been happening on the IGF/FOXO front. As always, each of these papers probably deserves its own post, but time is not permitting. Quoted passages are excerpts from the abstracts.

Low IGF-I decreases cancer: Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels, Moore et al.:

These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

Downregulating IGF-I enhances stress tolerance: Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway, Chu et al.:

Interestingly, the insulin signaling pathway mediated by Akt was inhibited in the TSA-resistant cells, mirroring the effect of glucose deprivation on this pathway. … Together, these findings suggest that cellular conditioning with TSA may represent a useful approach to mimic the effects of caloric restriction.

Inflammation: Regulation of IGF-I function by proinflammatory cytokines: At the interface of immunology and endocrinology, O’Connor et al.:

Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-1β, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I).

Gonadal regulation: Drosophila germ-line modulation of insulin signaling and lifespan, Flatt et al.:

Here we report that eliminating germ cells (GCs) in Drosophila melanogaster increases lifespan and modulates insulin signaling. … These results suggest that signals from the gonad regulate lifespan and modulate insulin sensitivity in the fly and that the gonadal regulation of aging is evolutionarily conserved.

Target genes: Identification of Direct Target Genes Using Joint Sequence and Expression Likelihood with Application to DAF-16, Yu et al.:

We found that 189 genes were tightly regulated by DAF-16. In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification.

Stem cells: FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System, Tothova and Gilliland:

… FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems.

As therapeutic targets: OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins, Malese et al.:

Forkhead transcription factors have a ‘winged helix’ domain and regulate processes that range from cell longevity to cell death. … Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.

There’s plenty to chew on. Tomorrow: telomeres.

Welcome to the first installation of Hourglass, a blog carnival devoted to the biology of aging. This first issue corresponds with the second blogiversary of Ouroboros, but mostly I consider it a celebration of the excellent (and growing) community of bloggers who are writing about biogerontology, lifespan extension technologies, and aging in general.

Without further ado, then, let’s get started:

Reason at Fight Aging! reports on AnAge, a curated database of longevity, aging, and life history in a wide range of animals. The database contains information about average and maximum longevity within species, and also cool features like lists of the “world-record” holders for the longest-lived organisms on the planet. AnAge will be a great tool for anyone interested in studying evolution of negligible senescence or exploiting lifespan diversity across related species to learn about mechanisms of aging. For those who are interested in databases of this kind, AnAge is a component of a larger project, the Human Ageing Genomic Resources.

The most widely studied technique for extending the lifespan of diverse animals is calorie restriction (CR), whose benefits in humans are still under careful study. One of the disadvantages of studying humans, of course, is that you can’t keep them in completely controlled environments, free from temptation to cheat on their defined diets — but this may be more than adequately compensated by the main advantage of human subjects, namely, that they can tell you how they’re feeling about the study while it’s underway. Over at Weekly Adventures of a Girl on a Diet, Elizabeth Ewen describes her experiences as a subject in the CALERIE study, a large-scale test of the effects of CR on humans (we’ve discussed CALERIE here before). In her post, Elizabeth describes the CALERIE study in detail, and also critically assesses some of its specific features — something that no mouse, however talented, could ever do.

While methods like CR may delay aging, or at least aspects thereof, they can’t stop it dead in its tracks — and they certainly can’t reverse large-scale age-related decline in tissue function. For those applications, we will have to look to more dramatic interventions, such as tissue engineering. In this exciting new field, biomedical engineers are seeking, essentially, to grow new organs for people whose originals have worn out due to injury, disease, or aging itself. One of the major challenges of tissue engineering is morphology: Even assuming that the appropriate sorts of stem cells are available, and that one can induce them to differentiate appropriately, how would one guarantee that they grow into the appropriate spatial architecture for efficient function? According to Attila Csordás at Partial Immortalization, one solution would be to use the “decellularized matrix hack“: to chemically or enzymatically remove the cells from cadaver organs, and then regrow new cells over the extracellular matrix left behind. (Since ECM is much more highly conserved than cell-surface markers, I suspect that such an approach could also be used to overcome immune rejection issues.) Attila’s post includes a video of the application of this concept to the heart.

Moving from the heart to the brain, we’re going to finish up with two huge posts about aging, mental fitness, and age-related changes in neurological function.

Ward Plunet at BrainHealthHacks writes about recent evidence that smarter people live longer. This is true whether your metric of intelligence is education (which could be problematic, as education levels are often correlated with lifelong affluence and access to medical care) or whether you’re looking at individual genetic variations correlated with both longevity and intelligence. It’s a giant post that quotes several articles from the primary literature as well as studies by international organizations. Nature, nurture, Ward has it all.

Assuming for the moment that long life and intelligence are associated — in which direction does the causal arrow point? We’re still unsure about that at the level of the whole organism, but in the case of brain health we know a bit more. At SharpBrains, Alvaro Fernandez interviews U. of Illinois’ Prof. Art Kramer, who describes ways that everyone can extend their mental healthspans and even delay the onset of age-related neurological dysfunction such as Alzheimer’s disease. That’s just the beginning of the lengthy interview, which goes on to talk about people’s desire for magical solutions to age-related declines in mental function, the results of prior studies, and the synergy between physical and cognitive exercise — among many other subjects.

Thanks for reading. I’m going to try to make Hourglass a monthly carnival on the second Tuesday of every month, so the next one will be held on August 12th. If you’re interested in hosting, please email me.

One major barrier to the therapeutic use of pluripotent and totipotent cells is that by the time a patient needs them, their body has become less able to use them. The stem cell niche (i.e., those factors in the tissue microenvironment that stem cells require in order to function normally) changes with age, and not for the better: for example, embryonic stem cells lose proliferative capacity when confronted with aged niches.

This appears to be a general problem in metazoans, and is conserved between humans and relations as distant as arthropods — fortunately for us, because it means that the tools and genius of the Drosophila community can be brought to bear on the problem. In the fruit fly, age-related changes in the stem cell niche are well-documented, especially in the reproductive system, and the molecular players are starting to be individually identified (see our previous post on Dpp, this one on BMP, unpaired and cadherins, and this nice review of the whole story). There are one or two tissues in which stem cells actually become more numerous with age, but the consensus seems to be that the aged microenvironment is generally not beneficial for stem cells. At least in the fly.

But what about species nearer and dearer to us? Fortunately, the human case is starting to be fleshed out in equally fine detail, and the state of the art has been thoroughly and artfully reviewed by Stefanie Dimmeler and Annarosa Leri. (The article is open access, so the full text is available to everyone.) The authors focus on the heart but also address more general (and less tissue-specific) issues along the way:

Aging and Disease as Modifiers of Efficacy of Cell Therapy

Cell therapy is a promising option for treating ischemic diseases and heart failure. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia, and clinical trials have confirmed that autologous cell therapy using bone marrow—derived or circulating blood–derived progenitor cells is safe and provides beneficial effects. However, aging and risk factors for coronary artery disease affect the functional activity of the endogenous stem/progenitor cell pools, thereby at least partially limiting the therapeutic potential of the applied cells. In addition, age and disease affect the tissue environment, in which the cells are infused or injected. The present review article will summarize current evidence for cell impairment during aging and disease but also discuss novel approaches how to reverse the dysfunction of cells or to refresh the target tissue. Pretreatment of cells or the target tissue by small molecules, polymers, growth factors, or a combination thereof may provide useful approaches for enhancement of cell therapy for cardiovascular diseases.

The bad news about the impact of aging and disease factors on the prospects for cell therapy is tempered with good news — the final quarter of the piece is devoted to therapeutic strategies for overcoming the negative effects of the aged niche, with the ultimate goal of using stem cells even in suboptimal tissue microenvironments — i.e., in patients who need them.

It is widely accepted that stem cells are involved in tissue regeneration. It is also widely accepted that (in most organs) stem cells are vanishingly rare. So: if there doesn’t happen to be a stem cell adjacent to a site of damage, how can stem cells be involved in the process of tissue repair?

One possible answers: There might be more stem cells than we think, because we’ve been missing them for some reason. This possibility is strongly supported by the recent findings of Zuba-Surma et al., who have discovered a population of tiny pluripotent cells (termed, appropriately, very small embryonic-like, or VSELs) scattered throughout the body.

Very small embryonic-like stem cells in adult tissues—Potential implications for aging
Recently our group identified in murine bone marrow (BM) and human cord blood (CB), a rare population of very small embryonic-like (VSEL) stem cells. We hypothesize that these cells are deposited during embryonic development in BM as a mobile pool of circulating pluripotent stem cells (PSC) that play a pivotal role in postnatal tissue turnover both of non-hematopoietic and hematopoietic tissues. During in vitro co-cultures with murine myoblastic C2C12 cells, VSELs form spheres that contain primitive stem cells. Cells isolated from these spheres may give rise to cells from all three germ layers when plated in tissue specific media. The number of murine VSELs and their ability to form spheres decreases with the age and is reduced in short-living murine strains. Thus, developmental deposition of VSELs in adult tissues may potentially play an underappreciated role in regulating the rejuvenation of senescent organs. We envision that the regenerative potential of these cells could be harnessed to decelerate aging processes.

Note that both VSEL number and potency diminish with age, consistent with the decrease in proliferative and regenerative capacity that we see in older animals. (And recall that diminishing stem cell potency is just one side of the story: over the course of aging, tissue microenvironments themselves grow more hostile to stem cell growth and function).

The small size of the VSELs, along with their dispersal throughout the body, might explain why they’d been missed up until now. It makes sense that cells devoted to long-term storage of regenerative potential would be very little: other than surviving and maintaining the ability to respond to proliferative signals, they wouldn’t really have much in the way of functional requirements, and wouldn’t need much more than a nucleus, a membrane, and extremely vigilant signal-transduction pathways — the latter ready to awaken the dormant cell when it’s time to turn into a proper stem cell, divide, and differentiate. In a sense, then, these VSELs are not so much progenitors as “progenitor progenitors”, the of regenerative capacity lying silent until they are needed.

(Extending this admitted over-interpretation — small size, after all, does not mean low metabolism, but I’m reasoning by analogy to spores and other very small totipotent cellular forms — another advantage of keeping stem cells metabolically inactive is that they would be less likely to suffer mutations or other damage that could convert them into cancer stem cells.)

Required skepticism: VSELs are both brand new and (so far as I can tell) idiosyncratic to a single group’s work. Before we get too worked up about this, I’d like to see the work reproduced by other labs and in other systems. Hopefully that sort of confirmation is already underway.

Lately, we’ve made much of the stem cell niche, the combination of tissue microenvironment and signaling factors in which stem cells thrive (or not). In both human and fly, the niche is critical to proper stem cell functioning. As we age, stem cells begin to fail; an accumulating body of evidence suggests that alterations in the niche are partially responsible.

But what is the stem cell niche, exactly? (Since there’s one for each type of stem cells, I should have asked “what are stem cell niches?”) If you’re wondering the same thing, you’re in luck: Here’s a big review of the niche in multiple organisms, by Morrison and Spradling. The piece includes not only a thorough discussion of age-related change to the niche but also a great introduction to “normal” niche function — what biogerontologists might call the “pre-aged” case:

Stem Cells and Niches: Mechanisms That Promote Stem Cell Maintenance throughout Life

Niches are local tissue microenvironments that maintain and regulate stem cells. Long-predicted from mammalian studies, these structures have recently been characterized within several invertebrate tissues using methods that reliably identify individual stem cells and their functional requirements. Although similar single-cell resolution has usually not been achieved in mammalian tissues, principles likely to govern the behavior of niches in diverse organisms are emerging. Considerable progress has been made in elucidating how the microenvironment promotes stem cell maintenance. Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood.

Suckers for punishment will be pleased to see, in the same issue of Cell, another stem cell-related review, this one by Rossi et al. on the relationship between stem cell decline and age-related pathologies, including cancer.

When we discuss the effect of aging on stem cell populations, we invariably lament the decrease in stem cell number and proliferative capacity that occurs in late life. It’s therefore newsworthy when anyone observes an age-related increase in stem cell populations — and this is just the case in the Drosophila midgut, where intestinal stem cells (ISCs) become more numerous with age. From Choi et al.:

Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor

Age-associated changes in stem cell populations have been implicated in age-related diseases, including cancer. However, little is known about the underlying molecular mechanisms that link aging to the modulation of adult stem cell populations. Drosophila midgut is an excellent model system for the study of stem cell renewal and aging. Herein, we describe an age-related increase in the number and activity of intestinal stem cells (ISCs) and progenitor cells in Drosophila midgut. We determined that oxidative stress, induced by paraquat treatment or loss of catalase function, mimicked the changes associated with aging in the midgut. Furthermore, we discovered an age-related increase in the expression of PVF2, a Drosophila homologue of human PDGF/VEGF, which was associated with and required for the age-related changes in midgut ISCs and progenitor cell populations. Taken together, our findings suggest that PDGF/VEGF may play a central role in age-related changes in ISCs and progenitor cell populations, which may contribute to aging and the development of cancer stem cells.

To my knowledge, this is the first report of any stem cell compartment expanding with age in the fly. In the gonad, the situation is quite reversed, with germ line stem cells diminishing over the lifespan. Nonetheless, there are similarities: in the intestine, we see another case where intercellular signaling between stem cells and theirniche playing a critical role in determining the age-related changes in a stem cell compartment. In the gonad, the key factors were cadherins and unpaired signaling; in the intestine, the PDGF/VEGF homolog is essential.

The authors speculate that the expansion of the stem cell compartment in late life could result in the appearance of cancer stem cells. I would agree. Especially given the ability of oxidative DNA damage to mimic the effects of age in this system, the phenomenon might be less analogous to beneficial regeneration and more analogous to pre-cancerous hyperplasia. The obvious question, then: Do flies lacking the PGDF/VEGF homolog develop fewer intestinal tumors?

A major emerging theme in stem cell biology is that the tissue microenvironment or “niche” — the cells that surround, support, and communicate with stem cells — are critical for their proper function, and in particular for their persistence and health over the course of aging. Stem cells seem to fare poorly in aged niches — an observation with major ramifications regarding the prospects of treating late-life diseases (or aging per se) by simply re-introducing stem cells to decrepit organs.

The fruit fly gonad is an important model system for stem cell and niche aging: in both males and females, the organ undergoes dramatic changes over the course of the lifespan, and in both sexes, decreases in the numbers and capacity of functional germline stem cells (GSCs) occurs at least in part due to deterioration of the niche. (For an excellent and fairly current review of the subject, see here.)

Late last year, we learned that declining BMP and E-cadherin signaling from ovarian niche cells appears to be responsible for the decline in GSCs in the female gonad. (In the testis, E-cadherin is also important, along with another signaling molecule, unpaired.) Now a new player has been revealed: Zhao et al. report that decapentaplegic signaling from the ovarian niche also declines with age, and that this may have a causative role in the diminution of GSC number and proliferative capacity:

Age-related changes of germline stem cell activity, niche signaling activity and egg production in Drosophila

Adult stem cells are important in replenishing aged cells to maintain tissue homeostasis. Aging in turn may exert profound effects on stem cell’s regenerative potential, but to date the mechanisms of such stem cell aging are poorly understood, and it is not clear to what extent stem cell aging contributes to tissue or organ aging. Here we show in female Drosophila, that germline stem cell (GSC) division rate progressively declines with age, which is accompanied by reduced decapentaplegic (dpp) niche signaling pathway activation within GSCs. Egg production also rapidly declines with age, which is accompanied by both decreased stem cell division and increased incidence of cell death of developing eggs, especially in the oldest females. Genetically increasing dpp expression delays GSC activity decline and transiently increases egg production. We conclude that age-related decline of reproduction is caused by both decreased GSC activity and increased incidence of cell death during oogenesis, while decreased GSC activity is attributed to declined signaling from the regulatory niche. We suggest that niche functional decay may be an important mechanism for stem cell aging and system failure.

Taken together with last year’s results, this paper informs us that — perhaps not surprisingly — there are multiple signals between the niche and the GSCs. I find it somewhat curious that both BMP and decapentaplegic overexpression can delay GSC aging; this observation suggests that the two factors may be rate-limiting at different stages of the aging process — or alternately, that they ultimately converge on the same intracellular signal relevant to GSC viability.

(continued from Morning session 1)

Back from bagels and coffee.

Bill Mobley (Stanford) began with the bold claim that all neurodegenerative illnesses are ultimately breakdowns of neural circuitry — if not etiologically, then symptomologically. He went on to summarize and review the body of evidence supporting the view that axonal dysfunction contributes to Alzheimer’s Disease (AD) pathology, focusing especially on the idea that decreases in neurotrophic factor signaling and retrograde transport play a causative role in AD. The talk concluded with breathtaking tomography and fluorescence video microscopy of intact circuits manipulated in culture.

Mobley turned over the microphone to a collaborator (Tony Wyss-Coray) who argued that age- and AD-related changes in autophagy (e.g., decreases in the level of the autophagy protein beclin) could explain how receptors and transport factors might get “stuck” in axons, further contributing to pathology and neurodegeneration. Consistent with this, both Aß plaque deposition and APP accumulation are dramatically increased in beclin+/- mice. The collaborator was senior author of the recent paper about a serum cytokine profile of AD, and he said some more about the possibility that the factors shown to be associated with AD are actually contributing to disease pathology.

Changing gears from the brain to the pancreas (half the LLHF’s mission is devoted to diabetes), Alberto Hayek and C. C. King from the Whittier Institute for Diabetes described efforts to derive populations of insulin-producing beta cells, suitable for transplant, from stem cells and other sources. Quick version: So far, not so good, but researchers are learning a ton about the basic regulatory biology of pancreatic cells (especially the miRNA, proteomic and epigenetic/methylation profiles of beta cells), and hopes are high that at some point in the not-too-distant future, stem cell-based approaches will indeed fulfill their oft-cited promise in potential treatments for diabetes.

(continued in Afternoon session)

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