An emerging new view of aging – the stem cell supply chain

This is a long and important blog entry, going to the heart of “What is aging and what can be done about it?”

Stem cell research, churning along at a ferocious rate, is revealing a new view of aging from the cellular level – one that renders older concepts obsolete.  While that view is still being formed, my purpose here is to identify what that view generally looks like and some of the research evidence supporting it. I also look at a few of the existing theories of aging from this new viewpoint and touch on implications for anti-aging interventions.

The new view looks at aging as a cellular supply-chain phenomenon.  In a simplified model, think of the 210 kinds of cells found in the human body as falling in five categories:

A.  Human embryonic stem cells (hESCs) which are pluripotent and capable of differentiating into any cells; induced pluripotent stem cells (iPSCs) are also in this category,

B.  Relatively undifferentiated multipotent somatic stem cells, such as may exist in bone marrow or vascular walls (e.g. hematopoietic stem cells, mesenchymal stem cells and pericytes).  These multipotent cells are each capable of differentiating into a variety of kinds of somatic cells.

C.  More differentiated stem and progenitor cells (e.g. endothelial progenitor cells, myoblasts or satellite cells in muscle tissue).  These are cells capable of differentiating only into specific somatic cell types.  

D.  Normal body somatic cells (e.g.  cardiomyocytes, red blood cells, leukocytes, keratinocytes, melanocytes, and  Langerhans cells)

E.  Senescent cells, ones which no longer can divide.

Cells in all categories except Type E can divide to make new cells.  They are all subject to mutation, cell damage, oncogenesis and, it is thought, are subject to replicative senescence due to telomere attrition.  Cells of Type A in the early embryo progressively differentiate to make all cells of Types B, C or D. All cells of Type D result from differentiation of cells of Type A, B and/or C, possibly via intermediary stem cell types. Some cells of Type B may differentiate through several intermediate forms before creating Type D cells.  Hierarchy in differentiation is always preserved under natural conditions, although it may or may not necessarily be the case that intermediate stem cell types are involved depending on the kind of cell.

An early embryo consists of mostly A-Type cells.  This supply-chain process continues through life although in aging there may be more and more cells of Types D and E and fewer and fewer active cells of Types B and C. and virtually no active Type A cells left.  Healthy normal aging is thus a matter or cellular supply chain management.  The body must assure that there are not too many Type E cells around for they create havoc.  Type D cells are the workhorses of day-to-day functioning and the key factors involved are insuring a good supply of them by avoiding damage-related or replicative senescence, taking care of their need for nutrition and a healthy intra-cellular environment, and making sure that damaged or proto-cancerous cells are eliminated through proper apoptosis.  Also, it is important to assure that Type B and C cells are able to differentiate properly to provide a reliable source of replacements for them. 

The issues for Types B and C cells include seeing that they are in sufficient supply and health so as to be able to differentiate into Type D cells and making sure that the differentiating option is readily available when needed.  Other issues for Types B and C cells are similar to those for Type D cells – preventing damage-related or replicative senescence, and preventing oncogenesis.  The unique problem is that in aged individuals there are few active Type A cells around to replace them.

Before looking further at anti-aging interventions given this new perspective, let’s review some of the recent relevant research.

• Both proliferation and differentiation of Type A, B and C stem and progenitor cells decreases with aging due to the existence of niches (stem cell microenvironments) of more-differentiated cells.  That is, they reduce their regenerative potential.  “Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches(ref).”  This is important because it says that the very existence of differentiated cells in their niches acts to inhibit the proliferation and differentiation of stem cells. “– the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches(ref).”
• 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.  “In adult skeletal muscle, where the resident dedicated stem cells (“satellite cells”) are capable of rapid and highly effective regeneration in response to injury, there is just such a loss of regenerative potential with age. Satellite cell activation and cell fate determination are controlled by the Notch signaling pathway that is initiated by the rapid increase in expression of the Notch ligand, Delta, following injury. In old muscle, this upregulation of Delta is blunted and thus satellite cell activation is markedly diminished. However, by indirectly inducing Notch activity, the regenerative potential of aged satellite cells can be restored.  In old muscle, this upregulation of Delta is blunted and thus satellite cell activation is markedly diminished. However, by indirectly inducing Notch activity, the regenerative potential of aged satellite cells can be restored. Furthermore, exposure of aged satellite cells to serum from young mice, either in vivo by heterochronic parabiotic pairings or in vitro, rejuvenates the satellite cell response. This restorative potential suggests that tissue-specific stem cells do not lose their ability to participate in tissue maintenance and repair. Therefore, it may be that even very old stem cells may be capable of maintaining and repairing aged tissues if provided with optimal environmental cues (ref).”

• The gene expression profiles in Type A human embryonic stem cells offer regenerative anti-aging potential not found in more mature stem cells.  “Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo (ref).”  I comment at this point that the same regenerative potential is likely to be found in induced pluripotent stem cells.  See the post Rebooting cells and longevity and additional discussions of iPSCs in other posts in the blog.
• More is being learned about the relationships between stem cells and their niches and environmental messaging relating to stem cell division and differentiation.  Stem cells of Types B and C have been known for some time to live and thrive within specific tissue stem cell niches, microenvironments that interact with stem cells and are necessary for their survival and mobilization for differentiation.  Recently it was discovered that stem cells of type A in vivo also live in their autonomously derived niches(ref).  “Understanding how extrinsic factors control hESC self-renewal and differentiation will allow us to culture and differentiate these pluripotent cells with higher efficiency. This knowledge will be essential for clinical applications using human pluripotent cells in regenerative medicine(ref).”
• Stem cells are subject to replicative senescence, although niche signaling and telomerase expression may have strong influences on their replicative lifespan.  This 2008 study looked at replicative senescence of mesenchymal stem cells in vitro and found it to be “a continuous and organized process.”  “Within 43 to 77 days of cultivation (7 to 12 passages), MSC demonstrated morphological abnormalities, enlargement, attenuated expression of specific surface markers, and ultimately proliferation arrest. Adipogenic differentiation potential decreased whereas the propensity for osteogenic differentiation increased. mRNA expression profiling revealed a consistent pattern of alterations in the global gene expression signature of MSC at different passages. These changes are not restricted to later passages, but are continuously acquired with increasing passages. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages.”  This form of replicative senescence occurring at each reproduction cycle appears to be absence-of-niche related and not to be driven by telomere shortening, the usual cause of replicative senescence. It highlights the importance of understanding what is going on in stem cell niches. Proliferation and differentiation of stem cells involves a bimolecular dance with their niches.
• Highlighting the importance of stem-cell environment signaling, a recent finding is that Co-Culture with Mesenchymal Stromal Cells Increases Proliferation and Maintenance of Hematopoietic Progenitor Cells.  Stem cells seem to be very social animals.
• As I have previously pointed out, buildup of levels of Ink4a/P16 associated with aging slows down the rate of differentiation of adult stem cells.  “Recent evidence shows that loss of Bmi-1, a polycomb transcriptional repressor of theInk4a-Arf locus, results in progressive loss of HSCs in adult mice with subsequent failure of hematopoiesis.” – “ These results show that either both p16Ink4a and p19Arf can inhibit HSC self-renewal in a serial transplant setting, or that only p16Ink4a is necessary(ref).“
• Researchers are starting to look harder at the links between cellular senescence, aging, and bone marrow-derived cells.  See this review article.
• See the recent blog post Research evidence for the Decline In Adult Stem Cell Differentiation theory of aging.

Implication for anti-aging interventions

First of all, the required shift in emphasis seems to be expansion from what is going on with normal body cells to encompass also what is going on with stem cells in the supply chain.  If this view of aging is correct, a program of effective anti-aging interventions is needed that applies across the entire cell supply chain.   Simply extending the telomeres of Type D cells and extending their replicative life spans is unlikely to lead to extraordinary longevity if they are not being reliably replaced by stem cell differentiation.  And convincing Type B and Type C cells to differentiate more readily into Type D cells won’t achieve that end either if these stem cell stocks are aging and losing inherent capability.  Of course, both of these interventions could still help.  See the discussions for the Telomere shortening and damage and the Decline of adult stem cell differentiation theories of aging in my treatise.

Of the interventions in the combined anti-aging firewalls dietary regimen, a key one seems to be taking supplements that enhance the expression of telomerase.  That may have three positive anti-aging effects: 1. promoting differentiation of stem cells through a mechanism independent of telomere extension, 2.  extending the replicative lifespan of Type D somatic cells through extending their telomeres, and 3.  possibly similarly extending the replicative lifespan of Type B,  C and even possibly A stem cells through telomere extension.  The last point is a conjecture on my part since I am not aware of any direct research on that topic.  See the blog post Extra-telomeric benefits of telomerase – good news for telomerase activators.

The above-cited research also suggests a new possible anti-aging supply chain intervention: re-activating Type A cells at the head end of the entire supply chain to start producing new and vital Type B and Type C stem cells in a controlled fashion.  Whether this is to be accomplished by factors that enable the controlled expression hESCs already in the body or through use of iPSCs is yet to be seen.  The above-cited research provides clues.  For example, rejuvenating hESCs through increasing the expression of Oct4 in them to overcome mature niche signaling, hESC proliferation and differentiation might be increased. Oct4 is one of the transcription factors introduced to generate iPSCs from normal somatic cells.

Other supply chain anti-aging interventions may be possible, such as induction of notch activity in satellite cells to restore their regenerative capabilities.  Also, the fact that serum from young mice rejuvenates stem cell activity in old mice provides important clues for where to look further.

I expect there will be a lot more to say regarding this supply chain view of longevity interventions.