Stem Cell Supply Chain Breakdown is the newest theory of aging described in my treatise and the one I am currently most excited about. According to a simplified model of this theory a newly-conceived human embryo consists of pluripotent stem cells (Type A), ones that can potentially divide into any body cells. With growth, these proliferate and, in a remarkably articulated manner, progressively differentiate into multipotent stem cells (Type B), progenitor cells (Type C), mature body somatic cells (Type E), and many eventually become senescent cells (Type E).
According to the best current understanding of stem cells this is an open-loop process. The above list is in order of increasing cell-type specificity and decreasing cell-type potency to differentiate into other cell types. Starting at conception and throughout life, all cells on this list except the senescent ones will selectively reproduce and possibly differentiate into cells of types further down in the list. The state of the body in terms of makeup of cell types continues to change through life and the process goes inexplicably from start (conception) leading to end (death).
At conception, the embryo is all Type A cells. At maturity there are relatively very few Type A cells and a mix of Type B, C and D cells, Type B and C cells typically live in protected stem cell niches where they reproduce and, as-needed differentiate to become the normal working body Type D cells. As Type D cells die from trauma or apoptosis they are replaced by new cells resulting from differentiation of Type B and Type C cells. Stem cell gene expression evolves with age. “In newborn mice, blood-forming cells (hematopoietic stem cells, HSCs) rely on a transcription factor known as Sox17 for self-renewal, but adult HSCs rely on a different transcription factor, Bmi-1(ref).” At an advanced age, the pools of Type B and Type C cells become depleted in part because of replicative senescence and the cells remaining in the pools lose their ability to differentiate as necessary to replace Type D cells.
Although in principle stem cells can replicate indefinitely, in fact they age as the organism ages, continuing to change their gene expression. And the gene expression changes in a way that favors protection against cancer over differentiation capability, e.g. expression of p16ink4a increases. Many Type D cells senesce and become Type E cells which make the corresponding organs shrivel and be susceptible to cancers and other disease processes.
That is the essence of the Stem Cell Supply Chain Breakdown theory of aging. In essence, early-on the body sets up pools of stem and progenitor cells to replace lost somatic cells. Cells in those pools replicate and differentiate throughout life. But when these pools become compromised or depleted or the cells in them lose their capability to differentiate – well – to be blunt soon its curtains. “Every day, billions of new blood cells are produced in the body, each one derived from a hematopoietic stem cell (HSC). Because most mature blood stem cells have a limited life span, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells for the lifetime of an organism is critical to sustaining life(ref).” I suggest here the possibility that the stem cell supply chain process could someday be made into a continuing closed loop one where at some point in life the balance of the difference types of cells reaches an equilibrium and stays at that equilibrium and that the consequence could possibly be extremely long lives.
To get the full depth of this post, please review the Stem Cell Supply Chain Breakdown section of my treatise. There is a lot of research background described there that I cannot repeat here.
This post picks up with the closing remark in my treatise regarding stem cells: There is a possibility of keeping the stem cell supply chain active indefinitely. The key idea is to use induced Pluripotent Stem cells (iPSCs) which are fully pluripotent and equivalent to embryonic stem cells(ref)(ref)(ref) as feedstock Type A cells in adults to make the stem cell supply chain as a continuous loop process instead of a once-through process. I have described the process several times before. 1. A few human skin, fat, blood or spit cells are corrected for any known genetic diseases defect are taken from an individual, 2. These cells are reverted by known means to a state of epigenomic ground-zero, that is into iPSCs for that individual, 3. These corrected cells are replicated outside the body, and 4. They are re-introduced into the body of the same individuals so as to differentiate into vital Type B and Type C stem cells in their niches refreshing the existing pools of stem cells and revitalizing the cells in them. Because they are cells derived from the same individual, there should be no graft versus host disease immune system rejection or reaction to them. The stem cell supply chain becomes closed loop. Further, the Type A source cells are free of any original genetic disease susceptibility. Steps 1-3 have been tried out although many issues connected with them are still being worked out.
The balance of this post is devoted to reviewing the state of research progress related to such an overall loop-closing process focusing on Step 4 where the major challenge is. I discuss issues connected with the proliferation and differentiation of Type B and C cells extensively in my treatise and will not repeat those discussions here. Finally I comment on the kinds of research needed to allow closing the loop.
Some known things:
· Both proliferation and differentiation of Type A, B, and C stem and progenitor cells decreases with aging.
· Adult stem cells live in niches – stem cell microenvironments and the health of the stem cells and their ability to reproduce or differentiate both depend upon and condition the states of their niches.
These last two points are discussed further in the Stem Cell Supply Chain Breakdown section of my treatise, as are the following points.
· iPSCs can be cured of genetic defects, induced to produce hematopoietic and other Type B and C stem and progenitor cells, and re-introduced into the same animal so as to cure diseases. For example, they have been used to cure mice of sickle cell anemia(ref). Other researchers recently reported “Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free(ref).” Very recently, research has been reported in applying this general approach to “familial dysautonomia (FD), a rare but fatal neuropathy that has been impervious to functional analysis and drug validation(ref).”
· “Embryonic stem (ES) cells have the potential to serve as an alternative source of hematopoietic precursors for transplantation and for the study of hematopoietic cell development(ref).” Also, “hESCs possess indefinite proliferative capacity in vitro, and have been shown to differentiate into the hematopoietic cell fate, giving rise to erythroid, myeloid, and lymphoid lineages using a variety of differentiation procedures(ref)”. The same point is made in this research report. Since iPSCs are relatively new, there is a lot more research out there on ESCs than on iPSCs.
· To the extent that iPSCs are truly equivalent to ESCs, they should have the same differentiation potential. This report is on a study that looked at the hematopoietic and endothelial differentiation potential of different iPSC lines. “Although we observed some variations in the efficiency of hematopoietic differentiation between different hiPSCs, the pattern of differentiation was very similar in all seven tested lines obtained through reprogramming of human fetal, neonatal, or adult fibroblasts with three or four genes(ref).”
· Technologies have been developed for generating a number of specific cell types from ESCs in-vitro using hematopoietic cell intermediaries and probably can be adopted for generating those cell types starting with iPSCs. “– we have developed a protocol for efficient generation of neutrophils, eosinophils, macrophages, osteoclasts, DCs, and Langerhans cells from human embryonic stem cells (hESCs). As a first step, we generated lin-CD34+CD43+CD45+ hematopoietic cells – “Morphologic, phenotypic, molecular, and functional analyses revealed that hESC-derived myelomonocytic cells were comparable to their corresponding somatic counterparts. In addition, we demonstrated that a similar protocol could be used to generate myelomonocytic cells from induced pluripotent stem cells (iPSCs)(ref).
In other words, techniques have been worked out to get ESCs to transform into hematopoietic progenitors and a variety of other stem types in-vitro, and these techniques will probably work equally well with iPSCs. This is not quite the same, however, as getting iPSCs to regenerate new supplies of multipotent and progenitor cells in their in-vivo niches. There the situation is much more complex involving niche-dependent signaling, age-dependent gene expression and related epigenomic DNA transformations in both stem cells and their supporting cells.
One approach might involve in-vivo creation of iPSCs through forced gene induction, as outlined in this research plan. “Here we propose that one important application is to produce neural stem cells from differentiated neurons in vivo in the central nervous system, and to repair the dysfunctional neural circuits, whether caused by aging, disease or a knife cut.” – “The first step will be the induction of neurons or glial cells in culture into neural stem cells or pluripotent stem cells, using similar transcription factors that have succeed in skin cells, for example, or to indentify extra transcription factors required. Then either viral transfection or electroporation could be adopted for in vivo gene transfer, “inducing” neural cells inside the brain into stem cells. Lastly the therapeutic values of these newly generated neurons have to be tested, to see if they can bring any functional outcomes(ref).” If this approach works, it could conceivably be applied to renewing Type B cells in their niches.
I will be looking for research news on using iPSCs to regenerate new supplies of multipotent and progenitor cells in their in-vivo niches. For now, closing the loop in the natural stem cell supply chain is an incomplete story, to be continued.
these supply chains can be rejuvenated by any supplements?
An excellent question, Res. My current take is that the effective life of the supply chain can probably be significantly extended by all the usual anti-aging steps and could conceivably be extended by a lot through telomerase activation. However as things stand it is a once-through open-loop process. This post suggests that in the future it could possibly be modified to being a continuous closed-loop process via introduction of autologous disease-corrected pluripotent stem cells – so that stem cells themselves at every level are constantly being renewed. No supplement I know of can do that although it is conceivable that someday one could be developed which accomplishes that end in-vivo.
Scientists discover clues to what makes human muscle age
Someday may be as soon as this UC Berkeley research becomes a biochemical pathway available for humans– Eric
Berkeley — A study led by researchers at the University of California, Berkeley, has identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, the researchers were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.
The findings will be reported in the Sept. 30 issue of the journal EMBO Molecular Medicine, a peer-reviewed, scientific publication of the European Molecular Biology Organization.
“Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals,” said Professor Irina Conboy, a faculty member in the graduate bioengineering program that is run jointly by UC Berkeley and UC San Francisco, and head of the research team conducting the study. “This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging, and perhaps other tissue degenerative disorders as well.”
Previous research in animal models led by Conboy, who is also an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), revealed that the ability of adult stem cells to do their job of repairing and replacing damaged tissue is governed by the molecular signals they get from surrounding muscle tissue, and that those signals change with age in ways that preclude productive tissue repair.
Those studies have also shown that the regenerative function in old stem cells can be revived given the appropriate biochemical signals. What was not clear until this new study was whether similar rules applied for humans. Unlike humans, laboratory animals are bred to have identical genes and are raised in similar environments, noted Conboy, who received a New Faculty Award from the California Institute of Regenerative Medicine (CIRM) that helped fund this research. Moreover, the typical human lifespan lasts seven to eight decades, while lab mice are reaching the end of their lives by age 2.
IMAGE: Human muscle stem cell regenerative activity is depicted in green and red. Stem cell responses were incapacitated when researchers inhibited the activation of key biochemical pathways, making the young muscle…
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Working in collaboration with Dr. Michael Kjaer and his research group at the Institute of Sports Medicine and Centre of Healthy Aging at the University of Copenhagen in Denmark, the UC Berkeley researchers compared samples of muscle tissue from nearly 30 healthy men who participated in an exercise physiology study. The young subjects ranged from age 21 to 24 and averaged 22.6 years of age, while the old study participants averaged 71.3 years, with a span of 68 to 74 years of age.
In experiments conducted by Dr. Charlotte Suetta, a post-doctoral researcher in Kjaer’s lab, muscle biopsies were taken from the quadriceps of all the subjects at the beginning of the study. The men then had the leg from which the muscle tissue was taken immobilized in a cast for two weeks to simulate muscle atrophy. After the cast was removed, the study participants exercised with weights to regain muscle mass in their newly freed legs. Additional samples of muscle tissue for each subject were taken at three days and again at four weeks after cast removal, and then sent to UC Berkeley for analysis.
Morgan Carlson and Michael Conboy, researchers at UC Berkeley, found that before the legs were immobilized, the adult stem cells responsible for muscle repair and regeneration were only half as numerous in the old muscle as they were in young tissue. That difference increased even more during the exercise phase, with younger tissue having four times more regenerative cells that were actively repairing worn tissue compared with the old muscle, in which muscle stem cells remained inactive. The researchers also observed that old muscle showed signs of inflammatory response and scar formation during immobility and again four weeks after the cast was removed.
“Two weeks of immobilization only mildly affected young muscle, in terms of tissue maintenance and functionality, whereas old muscle began to atrophy and manifest signs of rapid tissue deterioration,” said Carlson, the study’s first author and a UC Berkeley post-doctoral scholar funded in part by CIRM. “The old muscle also didn’t recover as well with exercise. This emphasizes the importance of older populations staying active because the evidence is that for their muscle, long periods of disuse may irrevocably worsen the stem cells’ regenerative environment.”
At the same time, the researchers warned that in the elderly, too rigorous an exercise program after immobility may also cause replacement of functional muscle by scarring and inflammation. “It’s like a Catch-22,” said Conboy.
The researchers further examined the response of the human muscle to biochemical signals. They learned from previous studies that adult muscle stem cells have a receptor called Notch, which triggers growth when activated. Those stem cells also have a receptor for the protein TGF-beta that, when excessively activated, sets off a chain reaction that ultimately inhibits a cell’s ability to divide.
The researchers said that aging in mice is associated in part with the progressive decline of Notch and increased levels of TGF-beta, ultimately blocking the stem cells’ capacity to effectively rebuild the body.
This study revealed that the same pathways are at play in human muscle, but also showed for the first time that mitogen-activated protein (MAP) kinase was an important positive regulator of Notch activity essential for human muscle repair, and that it was rendered inactive in old tissue. MAP kinase (MAPK) is familiar to developmental biologists since it is an important enzyme for organ formation in such diverse species as nematodes, fruit flies and mice.
For old human muscle, MAPK levels are low, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly, the researchers said.
When levels of MAPK were experimentally inhibited, young human muscle was no longer able to regenerate. The reverse was true when the researchers cultured old human muscle in a solution where activation of MAPK had been forced. In that case, the regenerative ability of the old muscle was significantly enhanced.
“The fact that this MAPK pathway has been conserved throughout evolution, from worms to flies to humans, shows that it is important,” said Conboy. “Now we know that it plays a key role in regulation and aging of human tissue regeneration. In practical terms, we now know that to enhance regeneration of old human muscle and restore tissue health, we can either target the MAPK or the Notch pathways. The ultimate goal, of course, is to move this research toward clinical trials.”
Other co-authors of the EMBO Molecular Medicine paper include Abigail Mackey at the University of Copenhagen in Denmark, and Per Aagaard at the University of Southern Denmark.
eric25001: A fascinating report. In my treatise I say “Although the mobilization responsiveness of Type C stem cells declines with age, it appears that their regenerative capability can be restored through environmental messages or induction of Notch activity” and include a quote on this subject from a 2005 paper by the same researcher, Conboy. Thanks for pointing out this latest progress report. I expect to continue monitoring research relating Notch expression, MAPK and stem cell mobilization. In particlar, this new report stimulates me to see who else is focusing on MAPK and stem cells. Please keep your ideas coming.
Thanks for posting this, lifted my day.
Self Storage Mere
Thanks. And you just lifted my day.
I too am battling a major spam attack. I am not sure which comments including yours are real and which are spam. Had about 300 comments yesterday, mos if not all being spam. I am working on a solution.
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