Stem cells

While stem cells exhibit the capacity to differentiate and self- renew, their ability to do so is now known to decline with age. The stem cell niche plays a key role in this decline, particularly in the case of embryonic stem cells. At the level of individual cells, replicative capacity is to reason that telomere dynamics should be intimately involved with this age-related decline in stem cell function. To this end, Holmes et al. have recently investigated telomere dynamics in a longitudinal study of fetal and early post-natal subjects:

Telomere length dynamics differ in foetal and early post-natal leukocytes in a longitudinal study

Haemopoietic stem cells (HSC) undergo a process of self renewal to constantly maintain blood cell turnover. However, it has become apparent that adult HSC lose their self-renewal ability with age. Telomere shortening in peripheral blood leukocytes has been seen to occur with age and it has been associated with loss of HSC proliferative capacity and cellular ageing. In contrast foetal HSC are known to have greater proliferative capacity than post-natal stem cells. However it is unknown whether they undergo a similar process of telomere shortening. In this study we show a more accentuated rate of telomere loss in leukocytes from pre term infants compared to human foetuses of comparable age followed longitudinally for 8-12weeks in a longitudinal study. Our results point to a difference inHSC behaviour between foetal and early postnatal life which isindependent of age but may be influenced by events at birth itself.

To compare telomere dynamics between fetal and adult stem cells, theauthors carried out a longitudinal analysis of peripheral blood. Obtaining serial fetal samples from healthy subjects would be fraught with ethical issues, hence alloimmune fetuses (AF) undergoing intrauterine transfusion were utilized. Venous samples from age-matched fetuses undergoing termination of pregnancy (TOP) for non-hematological reasons served as controls; no significant differences in terms of MNC behavior were noted, hence the AF samples were considered to be representative.

MNC telomere length in the AF samples was then compared with pre-term infants (PTI) of equivalent gestational age to assess the impact of the different environments (in utero vs. post-natal). In 7 of the 8fetal samples, comparison between the first and last serial samples revealed either an increase in mean telomere length, or no “detectable“ change in length (overall, the average gain in length was 19 bp/week). A similar analysis was performed on the PTI samples with equivalent gestational ages; in contrast to the fetal samples, 4 out of 5 PTI samples demonstrated considerable age-related telomere length decline (238bp/week). No significant changes in sub-sets of peripheral blood cells occurred between time points or between AF and PTI groups.

The paper supports the notion that stem cells lose efficacy with increasing age — even very early age. Furthermore, regarding the environmental influence on stem cell efficacy, these data extend the scope of the term “environment” beyond the stem cell niche and into the macroscopic world: in utero, fetuses continue to extend their telomeres — even though their cells are rapidly dividing –whereas once they are ex utero, babies start to shorten their telomeres.

During the discussion, the authors suggest that “different mechanisms of telomere length maintenance operate…in foetal compared to post-natal life”. Unfortunately, these differences are not investigated further in this study. I would have liked to see the authors measure telomerase activity and correlate this with the differing rates of attrition. Furthermore, the physical weight of the PTI samples should be included: it is recognized that babies born small-for-gestation age (SGA) are prone to developing problems in adulthood (including hypertension), possibly as a result of increased growth (with concurrent telomere loss) during the first year of life. In light of this, omission of weight data makes the interpretation of the results less robust.

Leaving the mechanisms aside for the moment, the data indicate that fetal HSCs may provide a superior source of cells for use in the clinical setting — assuming, that is, that removing them from the in utero context isn’t the event that flips the switch from telomere elongation to telomere attrition.


via The Niche: The stem cell blog:

The pharmaceutical giant made it official today. It has launched a regenerative medicine unit co-located in Cambridge, UK and Cambridge, MA. It will have about 70 full-time employees, but the cheery news for stem-cell start-ups is the focus on deal-making. The company’s press release hinted that several scientific collaborations would be announced this week, and Pfizer’s head of bio-innovation reportedly said that this initiative might very well help some young companies stay alive through the financial crisis. (See the Wall Street Journal blog. For a broader view, see In search of a viable business model.)

The company press release (linked in the excerpt above) manages to go on for 500 words without mentioning aging, but I’d bet that targeting age-related decline in tissue function is near the top of the list for planned cell-based therapeutics. It is, after all, a potentially bigger market than any one disease.

In universities across the USA today, we are breathing a collective sigh of relief — the long national nightmare of an anti-science administration will soon come to a close.

We knew that the Bush administration’s days were numbered, of course, but I’m pleased that our next chief executive does not come from a party whose scientific judgment is dictated by the “moral” strictures of its religious fringe.

As a biogerontologist, here’s what I’m most interested to know: How soon after his inauguration President Obama will overturn GWB’s executive order banning the use of federal funds in embryonic stem cell research?

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.

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