AGINGSCIENCES™ – Anti-Aging Firewalls™

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.

In the human body, of course everything is connected to everything else.  But some of these connections are intelligent and keep body parts working well together.  In particular, there are certain systems that detect problems such as the presence of disease or other stressors, compute solutions designed to maximize the survival of the organism, and send messages out to other body systems and components telling them what to do to get in step with a new or revised survival system. 

One such system is the hypothalamic-pituitary-adrenal axis. “The stress system coordinates the adaptive responses of the organism to stressors of any kind. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival.”  The effects of signaling from this system are widespread. “The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them (ref).”  If you get badly startled the adrenalin kicks in and the whole cascade process is kicked off.

Recent research is revealing that the skin provides another quite similar system.  “Described as the body’s largest organ, the skin is strategically located at the interface with the external environment where it has evolved to detect, integrate and respond to a diverse range of stressors. A flurry of recent findings has established the skin as an important peripheral (neuro)endocrine organ that is tightly networked to central stress axes. This capability is contributing to the maintenance of body homeostasis, and in this way could be harnessed for therapeutic strategies(ref).”

Central actors in this regard are our old friends, melanocytes.  “More than 15 years ago, we have proposed that melanocytes are sensory and regulatory cells with computing capability, which transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis. This concept is substantiated by accumulating evidence that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, express corresponding receptors and these processes are modified and/or regulated by ultraviolet radiation, biological factors or stress(ref).” Melanocortins produced by melanocytes have widespread impacts including cardiovascular regulatory effects(ref).  Regarding melanocytes, also see the previous posts Anti-inflammatory effects of the hormone alpha-MSH and  More research insight on gray hair and adult stem cell reproduction .

In fact, hair follicles just by themselves play an important role(ref)(ref).  And see Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.   “Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops(ref).”  Who would think a lowly hair follicle could do things like that  – things that regulate my temperament and how I react?

To sum it up: “We are currently experiencing a spectacular surge in our knowledge of skin function both at the organ and organismal levels, much of this due to a flurry of cutaneous neuroendocrinologic data, that positions the skin as a major sensor of the periphery. As our body’s largest organ, the skin incorporates all major support systems including blood, muscle and innervation as well as its role in immuno-competence, psycho-emotion, ultraviolet radiation sensing, endocrine function, etc. It is integral for maintenance of mammalian homeostasis and utilizes locally-produced melanocortins to neutralize noxious stimuli. In particular, the cutaneous pigmentary system is an important stress response element of the skin’s sensing apparatus—(ref).”

I am planning another blog entry where I will discuss another topic related to melanocytes – the afamelanotide analog of alpha-MSH that has been in clinical trials and the “melanotan” commercial products that may or may not work like alpha-MSH and may or may not be safe.

This morning, several news items appeared in the world press on a study relating the impact of mental exercises to the incidence of dementia in the elderly.  The new study, reported the Aug. 4 issue of the journal Neurology, involved following 488 elderl y people aged 75 to 85 (mean age 79.5)  for an average of five years.  The participants did not have dementia when they enrolled in the study and 101 of them developed dementia during the study period. “We assessed the influence of self-reported participation in cognitively stimulating leisure activities on the onset of accelerated memory decline.” (The activities reported on were daily reading, writing, group discussions, playing music, doing crossword puzzles, and playing board or card games.)  “Results: Each additional self-reported day of cognitive activity at baseline delayed the onset of accelerated memory decline by 0.18 years (66 days)(ref).”  “”The point of accelerated decline was delayed by 1.29 years for the person who participated in 11 activities per week compared to the person who participated in only four activities per week,” said study author Charles B. Hall of Albert Einstein College of Medicine in Bronx, NY(ref).”

The link between mental activity and a reduced risk of dementia is not new.  “In one study, Dr Valenzuela, a clinical neuroscience research fellow at the University of NSW school of psychiatry, looked at almost 29,000 people.”   (The study combined data from 22 studies worldwide.) “He found that a lifetime of complex mental activity almost halved the risk of dementia. — A separate study conducted over three years used repeated brain scans of healthy people aged over 60. It found those who led mentally stimulating lives had “less shrinkage of the hippocampus”, the area of the brain associated with memory and the first area affected by Alzheimer’s(ref).”

I have written about mental exercise before in this blog.  See the post Brain fitness, Google and comprehending longevity.  Repeating something I said there, “Try and get your arms around longevity research and I can personally guarantee you will get ample mental exercise.” Physical exercise too powerfully helps postpone or prevent dementia – but that will be the subject of another blog posting.

The brain contains white matter, grey matter and black matter.  “White matter is composed of bundles of myelinated nerve cell processes (or axons), which connect various grey matter areas (the locations of nerve cell bodies) of the brain to each other, and carry nerve impulses between neurons(ref).”  “A 20 year-old male has around 176,000 km of myelinated axons in his brain.^[1]”  Stretched end-to-end, that would be enough to go around the world more than four times. 

Health of white matter in older people seems to be a strong predictor of general functionality and probability of death.  A few weeks ago, a report appeared on a “3 year follow-up study of 639 non-disabled older patients (mean age 74.1 (SD 5.0), 45.1% men) in whom brain magnetic resonance imaging showed mild, moderate, or severe age related changes in white matter.”  –“The annual rate of transition or death was 10.5%, 15.1%, and 29.5%, respectively, for patients with mild, moderate, or severe age related changes in white matter.”   The conclusion of the study was “The three year results of the LADIS study suggest that in older adults who seek medical attention for non-disabling complaints, severe age related changes in white matter independently and strongly predict rapid global functional decline.(ref)”

The relationship between age-related white matter change and serious health problems is multi-faceted.  For example, age-related white matter changes stroke death(ref) and such changes negatively affect cognitive functioning(ref). 

From an anti-aging viewpoint the three critical questions appear to be 1.  What are the typical age-related changes in the white matter?  2.  What causes the changes?  and 3. What can be done to avert the changes?

As to the first question, one answer is “– the appearance, starting around age 60, of “white-matter lesions” among the brain’s message-carrying axons — significantly affect cognitive function in old age. White-matter lesions are small bright patches that show up on magnetic resonance imaging (MRI) of the brain(ref).  The technical term for the change is Leukoaraiosis, involving  “changes in the cerebral white matter that can be detected with high frequency by CT and MRI in aged individuals. It is a descriptive term for rarefaction of the white matter. It is also commonly referred to as white matter hyperintensities (WMH) due to its bright white appearance on T2 MRI scans(ref).”  Myelin degeneration appears to be another cause of age-related white matter changes(ref).  There appears to be a correlation between Leukoaraiosis and  small vessel disease.

As to the second question, what exactly causes the white matter changes is only now being established.  An earlier hypothysis is that leukoaraiosis may be associated with decreaserd cortical oxygen metabolism(ref). “The result is consistent with the view that primary cortical hypoperfusion (decreased blood flow) plays a role, at least in part, as a pathogenesis of impaired cortical metabolism in hypertensive patients with extensive deep white matter lesions.”   That view is also supported by this study.  Whatever the basic cause of leukoaraiosis may be, those who have it seem to have decreased regional cerebral blood volume and, most likely, circulation. One research report colorfully states about the cereberal vascular system “Adding to the difficulties, tortuosities develop in some of these vessels with aging. According to some calculations, hypertensive levels of blood pressure would be required to maintain irrigation through some of these vessels.”  Also, it appears that “Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well.”

Another earlier hypothysis links the white matter lesions with apoptosis(ref). “Nonetheless, because the number of oligodendroglia within the area of leukoaraiosis is greatly depleted, the percentage of cells caught in the act of apoptosis is actually quite high(ref).”   A 2009 report links the vascular-defect hypothysis with the apoptosis hypothysis giving a more complete picture.   “We explain the vascular changes in LA (leukoaraiosis) as follows. LA induces apoptosis with loss of oligodendrocytes. Capillaries and neuropil are lost. Increased oxygen extraction from the blood in the deep white matter in LA implies that there are too many cells for the remaining capillaries. Thus, the capillaries appear to die first(ref).”  Oligodendrocytes play a central role in the white matter.  They are a kind of neuroglia cells that provide insulation of and protection for the axons.  Oliodendrocytes play a role in the central nervous system similar the role that Schwann cells play in the peripheral nervous system, a topic I discussed in the previous post on Nerve regeneration.  

Without going on further about the causes of leukoaraiosis, let me turn to the third question: what can be done to prevent or mimize it?  Looking at the causes of this condition it seems that what would help includes:

·        Insuring good circulation to the brain.  This implies maintaining a healthy vascular system.  For practical steps, have a look at my Susceptibility to cardiovascular disease firewall.

·        Maintaining healthy oliodendrocytes.  This implies continuing regeneration of oliodendrocytes: assuring differentiation of oliodendrocyte progenitor/precursor cells – a partially diffferentiated type of adult stem cell.  For a practical approach have a look at the firewall for the Decline in Adult Stem Cell Differentiation theory of aging. 

·        Maintaining  a balanced pattern of oligodendroglial apoptosis.  A number of research studies suggest that the effects of TNF-alpha and inflammation often play key roles in initiating unwanted oligodendroglial apoptosis(ref)(ref).  “These results demonstrate that aberrant local TNF/p55TNF receptor signaling in the central nervous system can have a potentially major role in the aetiopathogenesis of MS demyelination, particularly in MS subtypes in which oligodendrocyte death is a primary pathological feature, and provide new models for studying the basic mechanisms underlying oligodendrocyte and myelin loss(ref).”  Again, practical measures are suggested in the firewall for the Chronic or Excess Inflammation theory of aging.  Also inflammatory gene-activation associated with TNF-alpha activation can be inhibited by inhibiting the expression of NF-kappaB, an effect of 36 substances in the combined anti-aging firewall.  This topic is discussed as part of the firewall for the Programmed Epigenomic Changes  theory of aging.

The bottom line is that the combined anti-aging firewall program should provide protection for the heath of white brain matter in aging individuals.  How much protection I cannot say, but it may well be a lot.

The previous blog post pointed out how defects in two genes, Fas and FasL are implicated in a number of diseases and may cause such diseases or increase susceptibility to them.  It left open the question of what can be done for people with such defective genes and suffering from associated diseases.  I speculate that the treatment process will turn out to be something like this:  

1.  As a first step, a few drops of blood or a tiny piece of skin would be taken from a person suffering from a disease known to be associated with certain defective genes that have been detected in the patient. For example the defective genes could include Fas and FasL in the case Lupus or Lymphoma .  

2. The cells in the blood or skin would be reverted to being induced pluripotent stem cells, known as iPSCs.  Technolgy to do this is now being perfected. See the post Rebooting cells and longevity and several subsequent posts related to iPSCs in this blog.  

3.  Using laboratory techniques of gene splicing, sometimes called DNA editing, the defective Fas, FasL and/or possibly other defective genes will be stripped out of the chromosomes in these cells, and good versions of the same genes pasted in their place.  This is accomplished by established techniques of genetic engineering.  The results will be the patient’s own pluripotent stem cells with good genes in place of the defective ones. Call these corrected induced pluripotent stem cells ciPSCs.   

4.  The ciPSCs will be encouraged to reproduce in the laboratory to increase their numbers. This is something commonly done. 

5.  The ciPSCs will be introduced back into the patient under conditions that they will differentiate into the stem cell types and somatic cell types involved in the disease process.  Discovering exactly how to do this is probably the major challenge involved in the whole process.  Success has already been realized in getting embryonic stem cells which are like iPSCs to differentiate into certain cell tyles.  See the July blog post Embryonic Stem cell research news.  Also, we know no immune reaction can be expected because the ciPSCs are the patient’s own cells.   

6.  As the ciPSCs reproduce and differentiate in the body, they will produce adult stem cells and differentiated tissue cells that are free of the genetic defect.   The genetically corrected cells will supplement and possibly in time replace the genetically defective ones.  In principle at least, as fewer and fewer body cells possess the genetic defect and more and more are normal, susceptibility to the disease should decrease, the hope being that the disease will go away.  The process can be compared to replacing defective car parts with rebuilt ones from the original manufacturer. 

Why such a complicated process using corrected induced pluripotent stem cells?  If the disease is in T-lymphocytes for example , why not just collect some T-lymphocytes from the patient, correct the genetic defects in them, reproduce them and introduce them back into the body?  I think a major problem would be that the body’s hematopoietic stem cells that make new  T-lymphocytes would continue to have the genetic defect in them and  would continue differentiating and producing new defective t lymphocytes.  So, I believe it will be necessary to go to the stem-cell level to have a lasting fix.  Many genetic engineering experiments have been tried with ordinary cells but with only poor or mixed success. 

If the kind of treatment process I outlined can be realized and fine-tuned, it could possibly be used to control or vanish most diseases related to genetic defects, not just defects in Fas or FasL.  I don’t think it will be very long before we start seeing positive results using this kind of process in laboratory animals.

This is going to be a rather technical post about the Fas and FasL  cell surface receptors and what happens when the genes that produce them are defective.  I offer it because Fas is so often mentioned in research studies related to cancers, auto-immune diseases and, in fact, in most discussions of molecular pathways concerned with cell birth, reproduction and death. 

Fas is a glycoprotein molecule, 43 kDa in size.  It is a surface receptor molecule that is expressed on the surface of Fas-activated lymphocytes. When Fas is paired up with another surface molecule, the ligand Fas L sitting on the surface of another cell, the lymphocyte cell bearing Fas commits apoptosis; it kills itself(ref).  So, a cell with Fas mating with another cell with Fas L is a dance of death.

Well-functioning of Fas and FasL is important for health.  “In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction(ref).”  

Here are some examples of disease conditions in relationship tp defects in the Fas/ FasL system: 

·        Going back to 1998 it was observed “Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma.” – “Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity(ref).”

·        Fas and FasL are implicated in many lymphoma cancers. “FasL mRNA was detected by reverse transcriptase-polymerase chain reaction in 38 out of 63 lymphoma biopsy specimens representative of various subtypes of non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease. FasL was co-expressed with Fas mRNA in most cases(ref).”  It appears that if there is a defect in Fas/FasL pathway, the normal reactive cells are more sensitive to Fas-induced apoptosis than the cancerous ones in the case of lymphomas(ref). 

·        A 2008 study was coducted “to investigate the impact of functional polymorphisms in the Fas and Fas L genes on the survival of early stage non–small cell lung cancer (NSCLC) patients.”  338 patients with NSCLC were involved.  The authors concluded “The Fas -670A>G polymorphism may affect survival in early-stage NSCLC. The analysis of the Fas -670A>G polymorphism can help identify patients at high risk for a poor disease outcome(ref).”

·        “A polymorphism in the Fas gene promoter region influences the susceptibility to systemic sclerosis(ref).”

·        Defects in the Gene encoding Fas is correlated with systemic lupus erythematosus (SLE).  “In the murine MRL/Ipr-Ipr model of systemic lupus erythematosus (SLE), the lymphoproliferation (lpr) mutation results in defective transcription of the gene that codes for the Fas protein.” – “Interest in the importance of Fas in SLE has risen with the observation that 60% of human subjects with lupus have elevated levels of the soluble Fas receptor in their serum and that the abnormal presence of this molecule may protect lymphocytes from undergoing apoptosis(ref).”  The link of FAS to autoimmune diseases goes back over a decade, considering the 1998 paper Human autoimmune lymphoproliferative syndrome, a defect in the apoptosis-inducing Fas receptor: a lesson from the mouse model.

·        Another 2008 study, Differential expression of Fas system apoptotic molecules in peripheral lymphocytes from patients with Graves’ disease and Hashimoto’s thyroiditis, looked at whether whether “the Fas system apoptotic molecules are differentially expressed in Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), the two opposite phenotypes of autoimmune thyroid disease (AITD).”  The conclusion was “The Fas system apoptotic molecules appear to be differentially expressed on peripheral lymphocytes in the two opposite phenotypes of AITD.”

The above is just a sampler.  Polymorphism veriations of the Fas and Fas L genes are also implicated in and perhaps causative of many other cancers and pathological processes. For a background discussion of gene veriations and how they impact disease processes see the blog post Gene variations and diseases – far from simple. 

What can be done for people with defective Fas or FasL genes?  I think the ultimate solution will involve gene splicing.  See the following blog post Treating genetic diseases with corrected induced pluripotent stem cells.

About four years ago I suffered an accident that resulted in significant loss of nerve sensation in two fingers.  I was carrying a bottle of wine by the neck to a friend’s house, slipped on a wet slimy board, fell down and smashed the bottle on the board.  I suffered a slash from the broken glass that nearly caused me to lose two fingers.  The surgeon was very skilled.  He sewed the tendons and the severed nerves together as best he could.   After several surgeries and a long period of recovery the two fingers were saved but the tendon in one finger and the nerve sensation in both fingers were left compromised, a situation that persists to this day.  The fingers constantly feel like I am starting to recover from a Novocain shot in them.  During my final appointment with the surgeon I asked him “How about injecting a nerve growth factor in my two fingers to restore full sensation in them?”  He knew of no such thing and looked at me as if I came from Mars.  He said absolutely nothing further could be done. 

I look at research related to nerve regeneration in this post, still anticipating the day when the nerves in these fingers can be fully restored.  First of all, I need mention that peripheral nerve regrowth can occur naturally after an accident .  “Human axon growth rates can reach 2 mm/day in small nerves and 5 mm/day in large nerves(ref).”  There is increasing understanding of the factors that impact on nerve growth, such as the role of Schwann cells.  “Regeneration of peripheral nerve involves an essential contribution by Schwann cells (SCs) in collaboration with regrowing axons. — Reforming peripheral nerve trucks involves a very close and intimate relationship between axons and Schwann cells that must proliferate and migrate, facilitated by laminin(ref).” 

“Schwann cells (also referred to as neurolemnocytes) are a variety of glial cell that keep peripheral nerve fibres (both myelinated and unmyelinated) alive. In myelinated axons, Schwann cells form the myelin sheath(ref)”  “During peripheral nerve development the Schwann cell population is expanded so that adequate numbers are available for ensheathment of both nonmyelinated and myelinated nerve fibres. As ensheathment of these fibres progresses each axon–Schwann cell unit becomes surrounded by a basal lamina, providing a unique microtubular framework within the peripheral nerve trunk(ref).”   

A plentiful supply of Schwann cells is therefore important to support repair of severed peripheral nerves.  So adequate differentiation of stem cells into Schwann cells is required for nerve regeneration, bringing us back to the discussion of the Decline in Adult Stem Cell Differentiation theory of aging.  Hair follicle stem cells can be induced to differentiate into Schwann cells and such induction might be an approach to improving nerve regeneration(ref).  You might want to read the recent post Hair stem cells and hair growth if you have not already done so.

The process of nerve regrowth can be facilitated or inhibited by various glycoproteins..  For example “Myelin-associated glycoprotein (MAG), a carbohydrate-binding protein on the myelin sheaths that coat nerve cells, inhibits regeneration of damaged neurons by binding to gangliosides on axon surfaces. This interaction causes gangliosides to cluster together, generating a signal that inhibits axon regrowth(ref).”  Another nerve growth-inhibiting substance can be “chondroitin sulphate proteoglycans (CSPGs). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity.”  — “To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons(ref).”

One important thread of current research involves the use of spinal chord stem cells (ependymal stem cells) to repair spinal chord injuries, a major challenge of nerve regeneration.  From a 2007 report of work:  “We know that stem cells are present within the spinal cord, but it was not known why they could not function to repair the damage. Surprisingly, we discovered that they actually migrate away from the lesion and the question became why – what signal is telling the stem cells to move.” “The researchers then tested numerous proteins and identified netrin-1 as the key molecule responsible for this migratory pattern of stem cells following injury. In the developing nervous system, netrin-1 acts as a repulsive or attractive signal, guiding nerve cells to their proper targets. In the adult spinal cord, the researchers found that netrin-1 specifically repels stem cells away from the injury site, thereby preventing stem cells from replenishing nerve cells. “When we block netrin-1 function, the adult stem cells remain at the injury site(ref).”

A December 2007 report indicates “A study carried out by researchers at the Kyoto University School of Medicine has shown that when transplanted bone marrow cells (BMCs) containing adult stem cells are protected by a 15mm silicon tube and nourished with bio-engineered materials, they successfully help regenerate damaged nerves(ref).”   Another experiment with laboratory animals reported in January of 2009 “found that transplantation of stem cells from the lining of the spinal cord, called ependymal stem cells, reverses paralysis associated with spinal cord injuries(ref).”  Finally, I mention that in January 2009, the Geron company got FDA approval for a clinical trial of its embryonic stem cell product GRNOPC1 in patients with acute spinal cord injury(ref).

There are reports also of non stem-cell approaches for dealing with spinal chord injuries, ones that might come under a broad heading of “tissue engineering.”  For example, “Northwestern University researchers have shown that a new nano-engineered gel inhibits the formation of scar tissue at the injury site and enables the severed spinal cord fibers to regenerate and grow. The gel is injected as a liquid into the spinal cord and self -assembles into a scaffold that supports the new nerve fibers as they grow up and down the spinal cord, penetrating the site of the injury.  When the gel was injected into mice with a spinal cord injury, after six weeks the animals had a greatly enhanced ability to use their hind legs and walk(ref).”  Another approach to nerve regeneration reported in March of this year involves engineered transplantable living nerve tissue.  ““We have created a three-dimensional neural network, a living conduit in culture, which can be transplanted en masse to an injury site,” explains senior author Douglas H. Smith, MD, Professor, Department of Neurosurgery and Director of the Center for Brain Injury and Repair at Penn. Smith and colleagues have successfully grown, transplanted, and integrated axon bundles that act as ‘jumper cables’ to the host tissue in order to bridge a damaged section of nerve(ref).”

My fantasy is still going back to visit my hand surgeon who will this time give me an injection in each of my semi-numb fingers and assure me that in a couple of months the nerves will have completely grown back.  I don’t know when that day will be but I think we are getting closer to it.

Experiments extending the lives of mice up to about 35% have been reported, and that is about it.  However, last year an experiment was reported that extended the life span of baker’s yeast by a factor of 10.  Certain genes and genetic pathways involved in longevity of primitive species like yeast are conserved by evolution in higher species including humans.  “Genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution(ref).”  Studies of longevity-promoting genetic interventions are relatively easy in yeast because its life span is very short, and the hope is that insights can be realized through such studies that can eventually be applied to higher species including our own.    

The latest research involved ”knocking out two genes, known as RAS2 and SCH9, which promote ageing in yeast and cancer in humans, and putting the microbes on a diet low in calories(ref).”  The researchers reported “The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.” — “Our study also showed that by combining the genetic manipulation and calorie restriction intervention, yeast can reach a life span ten times that of those grown under standard conditions. This extreme longevity requires Rim15 and also depends on other yet-to-be identified mechanisms. Our findings provided new leads that may help to elucidate the mechanisms underlying the anti-aging effect of calorie restriction in mammals(ref).”    

There is a long history of longevity-related experiments on yeast.  Back in 2005 some of the same researchers looked at the role of SIR2 in aging in yeast.  “Rather than adding copies of SIR2 to yeast, Longo’s research group deleted the gene altogether. –The result was a dramatically extended life span – up to six times longer than normal – when the SIR2 deletion was combined with caloric restriction and/or a mutation in one or two genes, RAS2 and SCH9, that control the storage of nutrients and resistance to cell damage. — Human cells with reduced SIR2 activity also appear to confirm that SIR2 has a pro-aging effect, Longo said, although those results are not included in the Cell paper(ref).”  

A 10-fold increase in longevity in humans would bring our average life spans up to about 800 years, more than enough to satisfy any contemporary anti-aging zealot.   But, will the life-extending interventions used on the yeast also work for more advanced species?  My answer is that the knowledge gained in the yeast experiments has been valuable though the anti-aging interventions used on yeast may not work or be inappropriate.  I wrote about one of the two pathways involved in the cited experiment in an earlier blog post Longevity genes, mTOR and lifespan.  I wrote that “With respect to humans, much of the machinery of TOR signaling found in more primitive species is conserved.”  “The longevity function of SIR2 is conserved in at least one multicellular organism, Caenorhabditis elegans(ref)” and SIR1 appears to play a similar role in mammals.  SIR2 and its mammalian  counterpart SIR1 are involved in the calorie-restriction anti-aging pathway and have been the subject of much recent research(ref)(ref)(ref).  

The cited yeast research studies are interesting because they are  based on simultaneously altering two longevity-related genetic pathways to achieve extraordinary longevity, something not yet systematically studied in higher animals.   So the yeast research might ultimately prove to be very valuable for us. 

We will be hearing more and more about chimeras.  In genetics, a chimera is an animal that has two or more different populations of genetically distinct cells that originated in different zygotes(ref).    The word was adopted from Greek mythology where the description is more colorful and gets down to the nitty-gritty.  According to Wikipedia  “the Chimera (Greek Χίμαιρα (Chímaira); Latin Chimaera) was a monstrous fire-breathing creature of Lycia in Asia Minor, composed of the parts of multiple animals: upon the body of a lion with a tail that terminated in a snake’s head, the head of a goat arose on its back at the center of its spine. The Chimera was one of the offspring of Typhon and Echidna and a sibling of such monsters as Cerberus and the Lernaean Hydra.”  Get the idea?

The news this week was two reports from Chinese researchers of making chimeric mice using induced pluripotent stem cells (iPSCs).  The mice were made by taking skin cells from mice, reverting these cells to iPSC status where they become virtually identical to embryonic stem cells (see the blog post Rebooting cells and longevity), and injecting them back into into eary-stage mouse embryos.  On of the reasons this work is important is that it established the true pluripotency of the iPSCs used.  After all, if you can make a whole living mouse out of them, they must be capable of differentiating into any mouse tissue.  “The generally accepted “gold standard” for determining whether a mouse iPSC line has been fully reprogrammed is to show that when injected into an early embryo (or blastocyst), the iPSCs can contribute to many different tissues in the resulting chimeric mouse, including the germline(ref).”  One of the chimeric mice made this way is reported to have mated with a normal mouse resulting in the birth of a normal mouse pup. Of course this is all on the level of the mouse.  Ethical and legal considerations are in the way of making chimeric “designer people,” but the results still give hope that iPSCs can be used for any purpose embryonic stem cells (eSCs) could be used for.

However, other stem cell research reported earlier this month indicates that the gene expression profiles of iPSCs and eSCs are different.  The study compared eSCs and iPSCs made by reprogramming skin cells. “The data from the study suggest that embryonic stem cells and the reprogrammed cells, known as induced pluripotent stem (iPS) cells, have overlapping but still distinct gene expression signatures. The differing signatures were evident regardless of where the cell lines were generated, the methods by which they were derived or the species from which they were isolated(ref).”  The researchers do not know what the practical implications of this finding are.  Whatever they are, they seem to be not enough to get in the way of making whole living chimeric mice. 

Chimeras, hybrid animals, have been around for some time and are interesting curiosities. According to Wikipedia “Chimeras are formed from four parent cells (two fertilized eggs or early embryos fused together) or from three parent cells (a fertilized egg is fused with an unfertilized egg or a fertilized egg is fused with an extra sperm). Each population of cells keeps its own character and the resulting animal is a mixture of tissues.”  Moreover people may be chimeras and not know it.  “As the organism develops, the resulting chimera can come to possess organs that have different sets of chromosomes. For example, the chimera may have a liver composed of cells with one set of chromosomes and have a kidney composed of cells with a second set of chromosomes. This has occurred in humans, and at one time was thought to be extremely rare, though more recent evidence suggests that it is not as rare as previously believed. Most will go through life without realizing they are chimeras. The difference in phenotypes may be subtle (e.g., having a hitchhiker’s thumb and a straight thumb, eyes of slightly different colors, differential hair growth on opposite sides of the body, etc) or completely undetectable . Another telltale of a person being a chimera is visible Blaschko’s lines(ref).”

A study published in the latest issue of the online journal Cell Stem Cell provides additional research evidence supporting the Decline in Adult Stem Cell Differentiation theory of aging, the 14^th theory treated in my treatise.  This theory holds that aging is due to a slowing rate of organ regeneration due to declining somatic cell differentiation activity.  This theory states that in addition to or perhaps instead of being concerned that aging is due to cells being damaged or reaching their reproductive  limit (such as according to the Oxidative Damage or the Telomere Shortening and Damage theories  of aging), we should be concerned that cells are not being replaced by freshly minted cells created by differentiating stem cells. 

The new study report TAp63 Prevents Premature Aging by Promoting Adult Stem Cell Maintenance  indicates that “that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely.” “TAp63 / mice (mice with TAp63 knocked out) age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis.” – “These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging(ref).” 

Again the message is that if you are worried about aging, be concerned with the supply chain for new somatic cells.  Start focusing on what is happening to adult stem cells.