This blog is now a year old and represents an accumulation of 232 posts and 270 comments.  My favorite thing seems to be reporting recent research findings in context, providing discussion and a network of citations for understanding how newly-reported research fits in to what is already known.  This has required much thinking on my part and many ideas that are original to me have appeared here.  But there also have been two streams of brand-new original thinking that have appeared in this blog, ideas that did not exist “out there” before they appeared here.  The purpose of this post is to highlight those two streams and point to the posts that contain them.

Giuliano’s Law

The first stream relates to Giuliano’s Law, which is “Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period.  That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period.  Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population.

This law and some of the rationale for it was laid out in the March 2009 post Giuliano’s Law: Prospects for breaking through the 122 year human age limit.  It is an analog of Moore’s law for the power of computers and is valid for many of the same reasons.  The post Factors that drive Giuliano’s Law goes into those reasons in detail, a positive feedback loop  of interaction exists between societal need, market, marketing channels and economics, changes in user expectations, market vehicles, user applications, marketing channels, advancement in the relevant basic science, advancement in technology, advancement in manufacturing, and entrepreneurial environment. 

I argue that the juggernaut defined by these interacting factors is already immense, growing mightily in power and on the road just as surely as the computer revolution was on the road in 1958.  The same advances that further health and medicine will further the cause of longevity.  Anti-aging science is not some arcane discipline off to the side.  It is a natural byproduct of the life sciences revolution that is well underway.  

The blog post More on Giuliano’s Law; calculating my longevity prospects is a more personal one, looking at my own life expectancy assuming Giuliano’s law is correct under three scenarios: Case 1:  I discontinue my anti-aging firewalls program and go about living a normal life.  Case 2: I continue pursuing my existing anti-aging firewall program keeping it exactly as it is now and Case 3: I continue to follow all the relevant threads of anti-aging research, to update the Anti-Aging Firewalls Treatise weekly or more as I have been doing, and periodically update the firewalls and firewall program to reflect this emerging new knowledge.  Further, I incorporate new science-based anti-aging substances and procedures into the firewall program as they become available. As you might guess, the Case 3 projection is that I have a good shot at breaking the 123 years maximum age barrier.  I hope that I am right!

The stem cell supply chain theory of aging

After generating a number of blog posts related to stem cells and stem cell differentiation I started to see a whole new viewpoint on aging connected with stem cells.  I first laid this viewpoint out in my September 2009 blog post An emerging new view of aging – the stem cell supply chain.  The idea is that there is a hierarchy of stem cells in human bodies ranging from pluripotent embryonic-like stem cells at the top to specialized progenitor cells just above ordinary somatic cells, with senescent cells at the very bottom of the heap.  In a healthy living organism, a supply chain is in constant operation.  Cells at one level are replenished by differentiation of cells at a higher level.  In aging the pools of stem cells at the higher levels become exhausted, cell regeneration via differentiation of stem cells is compromised, and sickness and death follow. 

The blog entry The stem cell supply chain – closing the loop for very long lives suggests an approach that could conceivably transform the stem cell supply chain from being a once-through process to being a continuous loop.  The idea is to generate autologous induced pluripotent stem cells in order to keep the stem cell supply chain operating indefinitely.  I have created a large number of posts about stem cells and the stem cell supply chain is an underlying concept of several of them.

A follow-up posting will comment on how my views of aging and anti-aging interventions have evolved since starting this blog.

It seems like scarcely a day goes by now without new telomerase research news items showing up in the popular press, the latest having to do with fish oil.  I mention this news here but my purpose is to make a few broader points:

1.      Taking a number of popular supplements in the anti-aging firewalls Supplement Regimen like Vitamin E, fish oils, Vitamin D3 and resveratrol can lead to telomeres being longer than they otherwise might be, possibly because they induce the production of telomerase, possibly for other reasons.  As such, these supplements are quite possibly life-extending.

2.     Despite the popular conception, telomere lengths do not uniformly get shorter with advancing age.  Sometimes they get longer over substantial periods of time.  Nobody is quite sure of how or why.

3.     Many of the same supplements that lead to longer telomeres in healthy people seem to have the capacity to turn off telomerase and shorten telomeres in cancer cells and help kill them.

Fish Oil and longer telomeres

Yesterday’s news is based on a January 20 publication in JAMA: Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease.  “Context  Increased dietary intake of marine omega-3 fatty acids is associated with prolonged survival in patients with coronary heart disease. However, the mechanisms underlying this protective effect are poorly understood. ^— Objective  To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age. ^— Design, Setting, and Participants  Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years). ^— Main Outcome Measures  We measured leukocyte telomere length at baseline and again after 5 years of follow-up. — Results  Individuals in the lowest quartile of DHA+EPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17), whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08; P < .001 for linear trend across quartiles). –. Each 1-SD increase in DHA+EPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98). ^— Conclusion  Among this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.”

The temptation is to conclude that “taking fish oils leads to less telomere length shortening,” but that is not what the study says.  The conclusions of this study are based on levels of DHA and EPA measured at baseline and do not take possible supplementation during the study period into account.  Further, the study population was a very special one, people with coronary artery disease.  Another temptation is to conclude that fish oil leads to the expression of telomerase, but this conclusion is also not directly supported.  The study does not say why the rate of telomere shortening was less in those with higher baseline levels of the fish oils.  Nontheless, the popular press has yielded to these temptations with news story titles like Is Fish Oil the Elixir of Life? And  Stay young by eating fish oil, say scientists. I chalk this up to a general hunger in the population for anti-aging news.  And now, after Blackburn, Greider and Szostak  have received a Nobel prize for work on telomeres and telomerase, it is almost household news that longer telomeres are associated with longevity and are better for health.

Natural telomere lengthening with age

The report on omega-3 fish oils and telomeres was preceded two weeks ago by another PLoS ONE report based on data for the same 608 individuals in the Heart and Soul Study Telomere length trajectory and its determinants in persons with coronary artery disease: longitudinal findings from the heart and soul study.  “METHODOLOGY/PRINCIPAL FINDINGS: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0). CONCLUSIONS/SIGNIFICANCE: Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening.”

Note that this is not the first study to show average telomere length increasing for a substantial part of the study population over a substantial period of time. According to a large Swedish study, a third of the population experienced telomere lengthening over 9 to 11 year intervals(ref).

Fish Oil, other supplements and turning off telomerase in cancers

According to the 2005 report Polyunsaturated fatty acids inhibit telomerase activity in DLD-1 human colorectal adenocarcinoma cells: a dual mechanism approach “We investigated the inhibitory effect of various fatty acids on telomerase, with particular emphasis on those with antitumor properties, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  — In contrast, cis-unsaturated fatty acids significantly inhibited the enzyme, and the inhibitory potency was elevated with an increase in the number of double bonds. Accordingly, polyunsaturated fatty acids (PUFAs), like EPA and DHA, appeared to be powerful telomerase inhibitors. — Culturing DLD-1 cells with either EPA or DHA resulted in a remarkable decrease in telomerase activity. EPA and DHA inhibited telomerase by down-regulating human telomerase reverse transcriptase (hTERT) and c-myc expression via protein kinase C inhibition. These results indicate that PUFAs can directly inhibit the enzymatic activity of telomerase as well as modulate the telomerase at the transcriptional level.” 

So there we have it.  The same DHA and EPA fish oils that seem to be correlated with longer telomeres in the recent population study also clobber telomerase in a cancer cell line.  This property seems to be shared by several other popular supplements as well. 

Alpha-tocopherol (Vitamin E) seems to repress age-related telomere shortening(ref). Yet, the 2007 study Vitamin E suppresses telomerase activity in ovarian cancer cells concludes “Our data suggest that, by suppressing telomerase activity, Vitamin E may be an important protective agent against ovarian cancer cell growth as well as a potentially effective therapeutic adjuvant.”  

Another supplement that is both associated with longer telomere lengths and that inhibits telomerase expression in cancer cells is Vitamin D3.   The 2007 paper Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women reports ”Serum vitamin D concentrations were measured in 2160 women aged 18–79 y (mean age: 49.4)  — Serum vitamin D concentrations were positively associated with LTL (longer telomere length) (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging.” Yet, D3  is another substance that can help inhibit the expression of telomerase in cancer cells as pointed out in the 2003 publication Combination treatment with 1alpha,25-dihydroxyvitamin D3 and 9-cis-retinoic acid directly inhibits human telomerase reverse transcriptase transcription in prostate cancer cells.  Also, see Induction of Ovarian Cancer Cell Apoptosis by 1,25-Dihydroxyvitamin D3 through the Down-regulation of Telomerase.

Resveratrol is another supplement substance that seems to have a dual personality, on the one hand associated with enhancing telomerase activity in healthy cells(ref)(ref) and on the other hand inhibiting expression of telomerase in cancer cells(ref)(ref).   

The active ingredient in green tea EGCG appears to be yet another dietary substance with the dual personality characteristic.  Drinking ample quantities of green tea appears to slow down age-dependent telomere shortening on the one hand(ref),  and EGCG represses telomerase expression in cancer cells(ref)(ref).  I am sure the same point can be made for other substances in the anti-aging supplement regimen.

Telomerase regulation is in fact a very complex process(ref).   As I have put it in my treatise “These results suggests to me that telomere shortening is a complex process involving a balance of shortening due to cell division, lengthening due to natural telomerase expression and perhaps cell replacement due to differentiation of stem cells. And these in turn are affected by many lifestyle and dietary factors and moderated by cell-signaling feedback loops.” 

Yet, it could well be the case that management of telomere length is our best hope for realizing extraordinary longevity in the nearer future.  The 12^th theory of aging in my treatise Telomere Shortening and Damage forwards the hypothesis that longer telomere lengths are likely to be correlated with longer lifespans and that keeping one’s telomeres as long as possible through expression of telomerase is vital for health and longevity. Telomeres and telomerase are among my favorite subjects for treatment in this blog.  Among the many relevant blog postings are the recent postings Exercise, telomerase and telomeres, Timely telomerase tidbits, Breakthrough telomere research finding, and Telomere and telomerase writings. And, as time proceeds, I expect there will be more.

In researching the previous blog post Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, I discovered a fascinating set of relationships among the substances mentioned in the title of this post and promised to report further on them.  I do that here, requiring a review of some of the basic biochemistry involved.  Although I am not clear of all the implications involved, I flag a few of these in the areas of pain management, synapse development and learning, maintaining mental balance, sleep and mental acuity.   

GABA

GABA (gamma-Aminobutyric acid) “is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.^[1] (ref)”  The operation of GABA is complex.  “In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known: GABA_A in which the receptor is part of a ligand-gated ion channel complex, and GABA_B metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).  GABA_A receptors are chloride channels, that is, when activated by GABA, they allow the flow of chloride ions across the membrane of the cell (ref).” “GABA_B receptors (GABA_BR) are metabotropic transmembrane receptors for gamma-aminobutyric acid (GABA) that are linked via G-proteins to potassium channels.^[1] These receptors are found in the central and peripheral autonomic nervous system^[2](ref). 

Carnosine, homocarnosine, anserine and beta-alanine

Carnosine and homocarnosine are closely related dipeptide substances, both found in substantial quantities in the mammalian brain and muscles, and they are similar also to anserine found in bird muscles and brains as well as humans.  L-Carnosine is a dipeptide composed of the two amino acids L-histidine and beta-alanine.  And Homocarnosine is a dipeptide composed of the amino acids L-histidine and GABA.  The chemical structures of the two substances are remarkably similar; you can see them diagrammed here.  (Unfortunately, the way this blog software is set up it is hard for me to include diagrams here).  This little article L-Carnosine and Related Histamine-Derived Molecules comments further on the three substances. “Carnosine and homocarnosine are both produced by the same ATP-driven enzyme, carnosine synthetase, and both molecules exhibit very similar properties. The concentration of homocarnosine in the human brain, however, is about 100 times that of carnosine. It is manufactured by glial cells (oligodendrocytes) except in the olfactory bulb, where it is synthesized by neurons. The highest brain homocarnosine concentrations are found in the substantia nigra, dentate gyrus and olfactory bulb as well as in the cerebrospinal fluid.”

So, going back to the discussion of the previous blog entry, Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation, chemically, beta-alanine is one of the dipeptide components of l-carnosine, the wonderful stuff discussed in the blog entry The curious case of l-carnosine.  Homocarnosine, on the other hand, molecularly substitutes GABA for beta-alanine. 

The three dipeptides Carnosine, homocarnosine, and anserine, have a number of biological properties in common.  All appear to be antioxidants(ref).  All three are protective against peroxyl radical-mediated Cu,Zn-superoxide dismutase modification(ref).  Both carnosine and homocarnosine can detoxify the highly reactive aldehyde acrolein(ref).  Of particular note, all three are inhibitors of GABA metabolism.  That is, they lead to higher levels of GABA in the brain.  This was pointed out in a 1978 publication Homocarnosine, carnosine and anserine on uptake and metabolism of GABA in different subcellular fractions of rat brain.  “L-Carnosine, L-homocarnosine and L-anserine are inhibitors of GABA metabolism. They show differential action on GABA-transaminase from synaptosomes compared to the extrasynaptosomal enzyme.” A 2004 publication also identifies beta-alanine as a GABA uptake inhibitor. 

Much of the research literature on these substances was published prior to 2000. The more-recent literature has since been scanty and scattered as indicated in the 2005 title Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain.  

Carnosine and homocarnosine are degraded in the body by carnosinase, “An enzyme that hydrolyzes carnosine (amino-acyl-l-histidine) and other dipeptides containing l-histidine into their constituent amino acids(ref).”  Activity of carnosinase tends to increase with age, leading to lower levels of carnosine in older people, however a very recent publication suggests that the presence of homocarnosine tends to inhibit the degradation of carnosine by carnosinase.  “Activity of carnosinase (CN1), the only dipeptidase with substrate specificity for carnosine or homocarnosine, varies greatly between individuals but increases clearly and significantly with age. — Further, CN1 activity was dose dependently inhibited by homocarnosine. — Homocarnosine inhibits carnosine degradation and high homocarnosine concentrations in cerebrospinal fluid (CSF) may explain the lower carnosine degradation in CSF compared to serum. Because CN1 is implicated in the susceptibility for diabetic nephropathy (DN), our findings may have clinical implications for the treatment of diabetic patients with a high risk to develop DN. Homocarnosine treatment can be expected to reduce CN1 activity toward carnosine, resulting in higher carnosine levels.”

Further background information on carnosine, homocarnosine, anserine and other related nerve and muscle histidine can be found in the online monograph Carnosine and Oxidative Stress in Cells and Tissues. This monograph also describes several pathways through which these substances can be created as metabolic products of each other.

A few of the key points for the purpose of this discussion are:

·        While carnosine can play key health and longevity-supporting roles, it or beta-alanine are far from the only games in town.  Carnosine acts in synergy with homocarnosine and its levels are controlled by carnosinase. 

·        Although exogenous supplementation is possible with one or several of these dipeptides, they are created and broken down in the body in complex ways.  Homocarnosine can be formed when GABA replaces the beta-alanine component in carnosine.  It appears that carnosine and beta-alanine release is stimulated by glutamatergic receptors, at least in cultured rat oligodendrocytes(ref).  

·        Supplementation with carnosine and/or beta-alanine may be valuable for athletes and older people as described in the blog entry Changing the threshold for neuromuscular fatigue in the young and old, carnosine or beta-alanine supplementation.

·        Carnosine, beta-alanine and homocarnosine increase levels of GABA. 

Gabapentin

I have discussed the drug gabapentin in the blog entry Spinal cord injury pain – a personal story and a new paradigm. As pointed out there it has been both a very popular as well as controversial drug used as an antic-convulsant, for control of neuropathic pain and, off-label, for a number of other psychiatric and medical conditions.  Gabapentin, like carnosine, beta-alanine and homocarnosine, is a GABA agonist that increases GABA levels in the brain(ref)(ref).  Further, gabapentin increases brain levels of homocarnosine(ref)(ref).  The studies cited were on patients or on tissues from patients prone to seizures, but I would wager that at least some increases in GABA and homocarnosine levels due to taking gabapentin would apply in general.

In my blog entry on neuropathic pain, I highlighted the possible role of gabapentin in quieting pathological pain due to over-excited microglia.  A July 2009 e-publication suggests that carnosine and N-acetyl carnosine might possibly be able to accomplish a similar result.  “Chronic inflammation and oxidative stress have been implicated in the pathogenesis of neurodegenerative diseases. A growing body of research focuses on the role of microglia, the primary immune cells in the brain, in modulating brain inflammation and oxidative stress. One of the most abundant antioxidants in the brain, particularly in glia, is the dipeptide carnosine, beta-alanyl-L-histidine. — The aim of the present study was to examine the role of carnosine and N-acetyl carnosine in the regulation of lipopolysaccharide (LPS)-induced microglial inflammation and oxidative damage. –. The data shows that both carnosine and N-acetyl carnosine significantly attenuated the LPS-induced nitric oxide synthesis and the expression of inducible nitric oxide synthase by 60% and 70%, respectively.  — we demonstrated a direct interaction of N-acetyl carnosine with nitric oxide. LPS-induced TNFalpha secretion and carbonyl formation were also significantly attenuated by both compounds. N-acetyl carnosine was more potent than carnosine in inhibiting the release of the inflammatory and oxidative stress mediators. These observations suggest the presence of a novel regulatory pathway through which carnosine and N-acetyl carnosine inhibit the synthesis of microglial inflammatory and oxidative stress mediators, and thus may prove to play a role in brain inflammation.”

Having been on gabapentin for three months now has contributed to vanishing my neuropathic pain due to a spinal injury and keeps me sleeping soundly.  See my blog entry Spinal cord injury pain – a personal story and a new paradigm. 

However, there are a few things I don’t like about gabapentin, one being that it often leaves me sleepy in the mornings making it difficult to concentrate. More seriously, I recently discovered something that bothers me a lot: gabapentin inhibits neuron synapse formation and therefore probably impairs new learning.  This was reported in an October 2009 study Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. “We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin.“  As explained in the LA Times Booster Shots: “Stanford University researchers examined the interaction between neurons and brain cells called astrocytes. Previous studies showed that a protein that astrocytes secrete, thrombospondin, is critical to the formation of the brain’s circuitry. In the study, researchers found that thrombospondin binds to a receptor, called alpha2delta-1, on the outer membrane of neurons. In a study in mice, they showed that the neurons that lacked alpha2delta-1 could not form synapses in response to the presence of thrombospondin. — Alpha2delta-1 is the receptor for gabapentin. That has been known, although scientists did not understand how gabapentin worked. But the new research revealed that when gabapentin was given to mice, it prevented thrombospondin from binding to the receptor, thus stopping the synapse formation.  While gabapentin, which is sold under the trade name Neurontin, does not dissolve pre-existing synapses, it prevents the formation of new ones. That’s why the medication may be dangerous if given to pregnant women or young children, the authors said. The majority of the brain’s synapses are formed in uteri and early childhood.”  We now know that synapse formation goes on throughout life, and I don’t like the idea of it being stopped in me. 

Some of the questions I am left with are:

·        Is seizure control associated with taking gabapentin due to higher levels of brain homocarnosine or GABA, or due to some other effect of the drug?

·        Can l-carnosine or N-acetyl carnosine achieve some of the pain control and other benefits attributed to gabapentin?

·        What if any of the general health benefits of supplementation by l-carnosine are also achieved by supplementation with beta-alanine, by taking gabapentin?  Is gabapentin a “longevity drug?”

·        What are the actual implications on adult learning of gabapentin inhibiting new synapse formation?

·        What are the differential effects of supplementation with l-carnosine, supplementation with beta-alanine, supplementation with GABA or taking the drug gabapentin on brain neurons, in CNS glial cells and in muscle tissues? 

My current personal plans are 1. to stay on 500mg of l-carnosine twice daily, 2.   To phase off of gabapentin as soon as possible consistent with my neuropathic pain not returning; pursuant to this,I have just phased down from 900mg a day to 600mg, and 3. Of course to keep alert to any new research developments that might affect these decisions.

First of all, my thanks to reader Jeg3 who put me onto this topic via a comment to the blog post Exercise, telomerase and telomeres.  It seems that both younger people who participate in strenuous sports and old folks who are in danger because of loss of muscle strength can benefit considerably from increasing the carnosine levels in their muscles.  And this can be accomplished to some extent by eating meat, supplementation with l-carnosine or supplementation with beta-alanine.  This blog post reviews the research in this area and steps towards muscle strengthening that can be taken by both athletes and older folks like me. 

I am also planning a follow-up blog post that looks at a fascinating set of similarities and relationships in behavior of beta-alanine, l-carnosine and gabapentin in terms of actions on GABA receptors in nerves and glia.  This post will relate these substances to topics like pain management, maintaining mental balance, sleep and mental acuity. 

I fell in love with l-carnosine over ten years ago when I learned how it could delay or reverse cellular senescence.  It can triple the replicative lifespan of fibroblasts in culture.  For an introduction to this fascinating substance, see the blog post The curious case of l-carnosine.  L-carnosine has long been part of my personal supplement regimen and is in my suggested anti-aging Supplement Regimen.

Beta-alanine and carnosine

The research of relevance to this blog entry has to do with supplementation to increase muscle carnosine levels in two populations: those who participate in high-intensity exercise like long-distance running, and the elderly. The studies I cite are mostly concerned with beta-alanine supplementation, though I am not completely convinced that this is the best approach to building up carnosine levels in muscles.  Beta alanine “is a naturally occurring beta amino acid, — is a component of the naturally occurring peptides carnosine and anserine and also of pantothenic acid (vitamin B₅) which itself is a component of coenzyme A. Under normal conditions, β-alanine is metabolized into acetic acid. — β-Alanine is the rate-limiting precursor of carnosine, which is to say carnosine levels are limited by the amount of available β-alanine(ref).” 

Another source indicates “The greatest natural dietary sources of beta-alanine are believed to be obtained through ingesting the beta-alanine containing dipeptides: carnosine, anserine and balenine, rather than directly ingesting beta-alanine. These dipeptides are found in protein rich foods such as chicken, beef, pork and fish. It is predominantly through ingesting the dipeptide carnosine that we ingest most of our beta-alanine, as the two other dipeptides are not found nearly as plentiful in our typical coniferous diet. However, obtaining beta-alanine through these dipeptides is not the only way, as our bodies can synthesize it in the liver from the catabolism of pyrimidine nucleotides which are broken down into uracil and thymine and then metabolized into beta-alanine and B-aminoisobutyrate.” 

Simply put, in the body both carnosine and beta alanine create each other and the presence of one leads the body to create the other.  Beta alanine has been a very popular sports and body-building supplement but carnosine itself is just now emerging to be known as a sports supplement(ref). 

A 2009 study looks at how long carnosine stays in muscles, once its level has been built up by supplements, Carnosine loading and washout in human skeletal muscles. “The oral ingestion of β-alanine, the rate-limiting precursor in carnosine synthesis, has been shown to elevate the muscle carnosine content both in trained and untrained humans.– The β-alanine supplementation significantly increased the carnosine content in soleus by 39%, in tibialis by 27%, and in gastrocnemius by 23% and declined postsupplementation at a rate of 2–4%/wk. Average muscle carnosine remained increased compared with baseline at 3 wk of washout (only one-third of the supplementation-induced increase had disappeared) and returned to baseline values within 9 wk at group level. — It can be concluded that carnosine is a stable compound in human skeletal muscle, confirming the absence of carnosinase in myocytes. The present study shows that washout periods for crossover designs in supplementation studies for muscle metabolites may sometimes require months rather than weeks.” It is remarkably persistent stuff!

Beta alanine supplementation for endurance athletes

The 2007 publication β-Alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters states “The ingestion of β-alanine, the rate-limiting precursor of carnosine, has been shown to elevate the muscle carnosine content. We aimed to investigate, using proton magnetic resonance spectroscopy (proton MRS), whether oral supplementation with β-alanine during 4 wk would elevate the calf muscle carnosine content and affect exercise performance in 400-m sprint-trained competitive athletes. Fifteen male athletes participated in a placebo-controlled, double-blind study and were supplemented orally for 4 wk with either 4.8 g/day β-alanine or placebo. — In conclusion, 1) proton MRS can be used to noninvasively quantify human muscle carnosine content; 2) muscle carnosine is increased by oral β-alanine supplementation in sprint-trained athletes; 3) carnosine loading slightly but significantly attenuated fatigue in repeated bouts of exhaustive dynamic contractions; and 4) the increase in muscle carnosine did not improve isometric endurance or 400-m race time.”

The 2007 study Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity concludes: “Muscle carnosine was significantly increased by +58.8% and +80.1% after 4 and 10 wks beta-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks beta-alanine supplementation resulted in a significant increase in TWD (total work done) (+13.0%); with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.” 

The purpose of the 2009 study Effects of beta-alanine supplementation and high-intensity interval training on endurance performance and body composition in men; a double-blind trial “was to evaluate the effects of combining beta-alanine supplementation with high-intensity interval training (HIIT) on endurance performance and aerobic metabolism in recreationally active college-aged men. — CONCLUSION: The use of HIIT to induce significant aerobic improvements is effective and efficient. Chronic BA supplementation may further enhance HIIT, improving endurance performance and lean body mass.”

The 2006 study Effects of twenty-eight days of beta-alanine and creatine monohydrate supplementation on the physical working capacity at neuromuscular fatigue threshold looked at non-athletes. “ — findings suggested that b-Ala supplementation may delay the onset of neuromuscular fatigue. Furthermore, there appeared to be no additive or unique effects of CrM vs. b-Ala alone on PWCFT (neuromuscular threshold fatigue test).”

Beta-alanine supplementation for the elderly

Of course there is much to the conventional wisdom that exercise is an important part of any anti-aging program for the elderly as well as for the young(ref).   But what about muscular carnosine?

The 2008 study The effect of beta-alanine supplementation on neuromuscular fatigue in elderly (55-92 Years): a double-blind randomized study looked at a small sample of elderly people. In the introduction, the article makes a compelling argument for strengthening the carnosine concentrations in muscles of older people: “Carnosine (beta-alanyl-L-histidine), a dipeptide is an efficient hydrogen ion (H⁺) buffer over the physiological pH range [1,2]. In muscle, where its concentration is highest, carnosine makes an important contribution to the maintenance of intracellular pH, which is vital for normal muscle function during intense exercise [1]. While the dipeptide is found in both Type I and Type II muscle, its concentration is highest in Type II muscle. Studies in humans and rats have demonstrated an inverse relationship between age and muscle carnosine content [3,4]. Sarcopenia, the loss in muscle mass with age, is associated with significant reductions in strength, power, and the ability to resist fatigue in elderly men and women [5,6]. Significant decreases in skeletal muscle and decline in muscle function are clearly evident after the age of fifty [5,7]. Deterioration of motor coordination, as a result of losses in strength and/or fatigue, is related to an increase in the frequency of falls [6,8] which repeatedly lead to injury and even deaths among the elderly [9].”  — “Twenty-six elderly men and women (Table 1) from independent-living communities in South Florida volunteered to participate in the study. None of the participants had any previous history of BA supplementation and maintained their regular activity and dietary patterns throughout the study”

The study looked at Pre- to post-test values for physical working capacity (PWC) at fatigue threshold (PWC_FT) for BA and PL groups.  A significant difference was found.  “Data from this study suggest that ninety days of BA supplementation may increase physical working capacity in elderly men and women. These findings may be clinically significant, as a decrease in functional capacity to perform daily living tasks has been associated with an increase in mortality [18], primarily due to increased risk of falls [9]. Further, deVries et al. [13] and Alexander et al. [8] have suggested that falls may be related to fatigue-induced deterioration of motor coordination. Thus, an improved resistance to fatigue, as reported in this study, may be important to consider when working with a similar population.  — The results of this study suggest that ninety days of BA supplementation may have significantly increased intramuscular carnosine resulting in a 28.5% increase in PWCFT due to a greater H+ buffering capacity.” This study also contains an excellent set of hyperlinked references relating to muscular fatigue,  muscular carnosine and age-related muscle functioning. 

I surmise that changing the fatigue threshold for exercise via raising muscle carnosine levels would also change the point where telomere shortening due to exercise over-stress might occur.  However, none of the papers regarding muscular carnosine and beta-alanine supplementation shed direct light on this issue, an issue raised in the blog entry Exercise, telomerase and telomeres. 

The new-to-me citations listed above leave me impressed with how important carnosine augmentation in muscles might be for health and functionality in the elderly.  On the other hand I am not sure at this point that beta-alanine supplementation is the best way to go. 

Supplementation: beta-alanine vs. l-carnosine

Studies in the literature about augmenting muscular carnosine seem to be mostly about supplementation using beta-alanine.  I am not sure the reasons for that including possibly a) the sport-medicine oriented researchers have always thought in terms of using beta-alanine instead of directly taking carnosine, b) the research was motivated or influenced by commercial makers of beta-alanine supplements, no doubt large money-makers, or c) beta-alanine is in fact the best approach to augmenting muscular carnosine.

As mentioned earlier, muscle levels of carnosine can also be raised by eating meat or by directly taking carnosine supplements.  I have had difficulty finding any study that systematically compares the efficacy of these approaches vs beta-alanine supplementation.  I have seen claims on body-building sites that beta-alanine is possibly less expensive and more bioavailable  than directly taking carnosine. 

One such site recommends taking a combination of beta-alanine and Histidine.  On the other hand, the 2006 report The absorption of orally supplied beta-alanine and its effect on muscle carnosine synthesis in human vastus lateralis states “Dietary supplementation with I) 3.2 and II) 6.4 g . d(-1) beta-alanine (as multiple doses of 400 or 800 mg) or III) L-carnosine (isomolar to II) for 4 w resulted in significant increases in muscle carnosine estimated at 42.1, 64.2 and 65.8%.”

I also found a seemingly-credible blog entry relative to beta-alanine and carnosine: “Anti-crosslinking properties of carnosine: significance of histidine. — Hobart LJ, Seibel I, Yeargans GS, Seidler NW. Department of Biochemistry, University of Health Sciences, 1750 Independence Avenue, Kansas City, MO 64106-1453, USA.  Carnosine, a histidine-containing dipeptide, is a potential treatment for Alzheimer’s disease. There is evidence that carnosine prevents oxidation and glycation, both of which contribute to the crosslinking of proteins; and protein crosslinking promotes beta-amyloid plaque formation.  It was previously shown that carnosine has anti-crosslinking activity, but it is not known which of the chemical constituents are responsible. We tested the individual amino acids in carnosine (beta-alanine, histidine) as well as modified forms of histidine (alpha-acetyl-histidine, 1-methyl-histidine) and methylated carnosine (anserine) using glycation-induced crosslinking of cytosolic aspartate aminotransferase as our model. beta-Alanine showed anti-crosslinking activity but less than that of carnosine, suggesting that the beta-amino group is required in preventing protein crosslinking. Interestingly, histidine, which has both alpha-amino and imidazolium groups, was more effective than carnosine.  Acetylation of histidine’s alpha-amino group or methylation of its imidazolium group abolished anti-crosslinking activity. Furthermore, methylation of carnosine’s imidazolium group decreased its anti-crosslinking activity. The results suggest that histidine is the representative structure for an anti-crosslinking agent, containing the necessary functional groups for optimal protection against crosslinking agents. We propose that the imidazolium group of histidine or carnosine may stabilize adducts formed at the primary amino group.” 

At this time I will not stop taking l-carnosine as a supplement and substitute beta-alanine in its place because of the multiple demonstrated benefits of l-carnosine that are independent of its effects in muscle tissues(ref)(ref).   I am open, however, to the question of whether adding beta-alanine to my regimen could be useful or would be redundant, and will be on the lookout for further research on this issue. I am planning a follow-up blog entry that will go deeper into the biochemical actions of carnosine, beta-alanine and gabapentin insofar as they impact on GABA receptors in nerve cells and glia.

It has long been suspected that polymorphisms in the cholesterol ester transfer protein (CETP) gene confer important longevity benefits.  This post is prompted by recent news about the gene.  The post reviews what is known about the actions of the gene and its variants, and speculates about how this knowledge could lead to a new anti-aging intervention.

CEPT inhibition and coronary heart disease

The interest in the CEPT gene goes back a long time.  A 2000 publication states “Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that mediates the transfer of cholesteryl ester from high density lipoproteins (HDL) to triglyceride-rich lipoproteins in exchange for triglycerides. — Several genetic variants at CETP locus have been identified and they have been generally associated with increased HDL-cholesterol concentrations.”  Thus, it was originally thought that these gene variations could be life-extending because the higher HDL would be cardioprotective.   Interest developed in drugs that limit the expression of CEPT, the hope being that they would have a profound effect on raising HDL cholesterol.  “In our view, CETP inhibitors in combination with statins will be profoundly beneficial in reducing human atherosclerosis, primarily because they normalize HDL particles and prevent the transfer of cholesteryl ester from HDL to atherogenic lipoproteins(ref).” “A relative new strategy for raising HDL cholesterol, inhibition of cholesteryl ester transfer protein (CETP), is markedly effective. CETP inhibitors prevent the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride. One inhibitor, torcetrapib, binds to CETP on HDL, markedly increases HDL cholesteryl ester, — (ref) .“   

Unfortunately torcetrapib had serious problems.  “A large clinical trial in patients with CAD who were taking atorvastatin was recently stopped prematurely because of excess mortality in those receiving torcetrapib versus placebo, and 2 other trials reported no benefit of torcetrapib on coronary atherosclerosis or carotid intima-media thickness as compared with subjects on atorvastatin alone. The adverse effects of torcetrapib may be compound specific, and because the crystal structure of CETP is now known, it should be possible to develop more optimal CETP inhibitors that do not form a nonproductive complex with CETP on the HDL particle, as has been reported for torcetrapib(ref).”  A 2009 report indicates ”Recently, Phase III clinical studies of torcetrapib, one of the CETP inhibitors developed by researchers at Pfizer, were unexpectedly terminated because of an increase in cardiovascular events and mortality. Torcetrapib has some compound-specific and off-target effects, such as raising blood pressure and aldosterone, which could affect an increase in cardiovascular events and mortality.”

The abandonment  of torcetrapib due to side effects dealt a mighty blow to the area of pharmacologic CETP inhibition, although not necessarily a fatal one.  See JTT-705: is there still future for a CETP inhibitor after torcetrapib? Also, “Dalcetrapib (JTT-705) and anacetrapib, which have not been reported to have the off-target effects of torcetrapib, are currently in Phase III. They are expected to reveal whether CETP inhibition is beneficial for atherosclerosis-related diseases(ref).”  Results of the safety and tolerability study of Dalcetrapib were promising(ref).  A clinical trial of the Tolerability and Efficacy of Anacetrapib for patients with coronary heart disease is ongoing(ref).

CEPT gene variations and cardiovascular diseases

Most of the studies of CEPT have looked at the CEPT gene and its variants in the context of HDL and impact on cardiovascular disease processes.  The 2009 report Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18 245 initially healthy women from the Women’s Genome Health Study looks at whether CEPT and HDL-C have causal roles in atherothrombosis. “One method to evaluate this issue is to examine whether polymorphisms in the CETP gene that impact on HDL-C levels also impact on the future development of myocardial infarction. METHODS AND RESULTS: In a prospective cohort of 18 245 initially healthy American women, we examined over 350 000 singe-nucleotide polymorphisms (SNPs) first to identify loci associated with HDL-C and then to evaluate whether significant SNPs within these loci also impact on rates of incident myocardial infarction during an average 10-year follow-up period. Nine loci on 9 chromosomes had 1 or more SNPs associated with HDL-C at genome-wide statistical significance (P<5×10(-8)). However, only SNPs near or in the CETP gene at 16q13 were associated with both HDL-C and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the CETP gene was associated with a per-allele increase in HDL-C levels of 3.1 mg/dL and a concordant 24% lower risk of future myocardial infarction (age-adjusted hazard ratio, 0.76; 95% CI, 0.62 to 0.94), consistent with recent meta-analysis. Independent and again concordant effects on HDL-C and incident myocardial infarction were also observed at the CETP locus for rs4329913 and rs7202364. Adjustment for HDL-C attenuated but did not eliminate these effects. CONCLUSIONS: In this prospective cohort of initially healthy women, SNPs at the CETP locus impact on future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDL-C mediated pathway.”

A 2006 study I405V polymorphism of the cholesteryl ester transfer protein (CETP) gene in young and very old people reports “We recruited 100 healthy young people (median age 31 years) and 100 very old people (median age 89 years) and analysed their DNA for the presence of I405V polymorphism. — The frequency of the VV genotype in very old people was more than double that in the young population. Subjects with this genotype had lower serum concentrations of CETP. Young people with the V/V genotype had a less atherogenic lipoprotein profile (lower total cholesterol, LDL cholesterol, Apo B, and Apo B/Apo A-I ratio) than those with the I/V or I/I genotypes. The older subjects, particularly the older women with the V/V genotype, had larger LDL than the young people. The prevalence of clinical endpoints was much lower among the very old people with the V/V genotype. In conclusion, the V/V genotype of the I405V CETP polymorphism is more frequent among very old people than young ones, and is associated with a lower incidence of vascular damage.”

A number of other studies have supported a possible life-extending role for CEPT polymorphisms, but always in the contexts of lipids, raising HDL, and preventing cardiovascular diseases.  See, for example, this list of citations.  

Latest news: CEPT and dementia

A break in the pattern was reported two days ago.   Going back a couple of years, researchers at the Albert Einstein College of Medicine of Yeshiva University conducted a study where they searched for the presence of “longevity genes” in a cohort of aged Ashkenazi Jews.  As reported in a 2008 Science Daily article “Participating in the study were 305 Ashkenazi Jews more than 95 years old and a control group of 408 unrelated Ashkenazi Jews. — All participants were grouped into cohorts representing each decade of lifespan from the 50’s on up. Using DNA samples, the researchers determined the prevalence in each cohort of 66 genetic markers present in 36 genes associated with aging. — The Einstein researchers were able to construct a network of gene interactions that contributes to the understanding of longevity. In particular, they found that the favorable variant of the gene CETP acts to buffer the harmful effects of the disease-causing gene Lp(a).” 

A January 13 2010 report ‘Longevity Gene’ Helps Prevent Memory Decline and Dementia in Science Daily discusses a January report on JAMA describing further investigations by the same researchers relating the CEPT gene in the Ashkenazi Jews to the risks of Alzheimer’s Disease.  The JAMA report is entitled Association of a Functional Polymorphism in the Cholesteryl Ester Transfer Protein (CETP) Gene With Memory Decline and Incidence of Dementia.  “Objective  To test the hypothesis that a single-nucleotide polymorphism (SNP) at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including Alzheimer disease (AD).”  “The researchers of the current study hypothesized that the CETP longevity gene might also be associated with less cognitive decline as people grow older. To find out, they examined data from 523 participants from the Einstein Aging Study, an ongoing federally funded project that has followed a racially and ethnically diverse population of elderly Bronx residents for 25 years. — At the beginning of the study, the 523 participants — all of them 70 or over — were cognitively healthy, and their blood samples were analyzed to determine which CETP gene variant they carried. They were then followed for an average of four years and tested annually to assess their rates of cognitive decline, the incidence of Alzheimer’s disease and other changes.  – – “We found that people with two copies of the longevity variant of CETP had slower memory decline and a lower risk for developing dementia and Alzheimer’s disease,” says Amy E. Sanders, M.D., assistant professor in the Saul R. Korey Department of Neurology at Einstein and lead author of the paper. “More specifically, those participants who carried two copies of the favorable CETP variant had a 70 percent reduction in their risk for developing Alzheimer’s disease compared with participants who carried no copies of this gene variant. — The favorable gene variant alters CETP so that the protein functions less well than usual(ref).”

The new news is in fact not completely new.  A  December 2006 news report states “An Israeli study involving 158 people who lived to 95 or beyond has found that those who inherit a particular version of the gene CETP are twice as likely to have a sharp and alert brain when they are elderly. — They are also five times less likely than people with a different version of CETP to develop Alzheimer’s disease and other forms of dementia, according to the study by a team at the Albert Einstein College of Medicine at Yeshiva University. — About 8 per cent of people aged 70 have the CETP variant, but this rises to 25 per cent among centenarians. This is thought to play a key role in explaining why some people live to very old ages.  The research, published in the journal Neurology, found that those with CETP VV were twice as likely as the others to have good brain function. — A separate investigation of 124 Ashkenazi Jews aged between 75 and 85 found that CETP VV appeared to protect against dementia: those with the variant were five times less likely to suffer from it.”

The researchers at the Albert Einstein College of Medicine also have found that telomere maintenance plays a very important role in maintaining the longevity of the centenarian Ashkenazi Jews, as reported in the November 2009 blog entry Timely telomerase tidbits. From a November 2009 Science Daily story: “As we suspected, humans of exceptional longevity are better able to maintain the length of their telomeres,” said Yousin Suh, Ph.D., associate professor of medicine and of genetics at Einstein and senior author of the paper. “And we found that they owe their longevity, at least in part, to advantageous variants of genes involved in telomere maintenance. — More specifically, the researchers found that participants who have lived to a very old age have inherited mutant genes that make their telomerase-making system extra active and able to maintain telomere length more effectively. For the most part, these people were spared age-related diseases such as cardiovascular disease and diabetes, which cause most deaths among elderly people.” 

So, variants in the CEPT gene appear to be protective against cardiovascular diseases and also protective against memory decline and dementia. Further, drugs are in Phase III clinical trials that may mimic the effects of these gene variants.   As usual several questions are still to be answered including: 

·        Do variations in the CEPT gene actually confer overall additional longevity or simply accompany longevity conferred by other genes?  If so, which variations are most effective and how much additional longevity can they provide? 

·        In the centenarians, what is the relationship between having extraordinary telomerase- maintenance genes and CEPT polymorphic genes?  Is it coincidental or in any sense causative that some centenarians have both of these kinds of gene variations?

·        In the event that effective and safe pharmacological means are established to inhibit CEPT expression (Dalcetrapib or Anacetrapib), will these be longevity-enhancing drugs? 

·        If so, how will they work: by maintaining high HDL levels and protecting cardiovascular health, by protecting mental functioning and preventing dementia, and/or by additional means yet to be characterized?

·        Are there nutraceuticals that inhibit CEPT expression and that could provide similar benefits?

A new study reported in the press this week looks at the relationship of exercise to expression of telomerase and telomere lengths in athletes and non-athletes.  Other studies on the same topic have appeared in the last year or so.  My purpose here is to review these studies in the context of some earlier studies. It is not just a simple matter of “the more and the harder the exercise, the better.”

The 12^th theory of aging in my treatise Telomere Shortening and Damage forwards the hypothesis that longer telomere lengths are likely to be correlated with longer lifespans and that keeping one’s telomeres as long as possible through expression of telomerase is vital for health and longevity. I have devoted numerous blog entries to telomeres and telomerase, including most recently Timely telomerase tidbits, Breakthrough telomere research finding, and Telomere and telomerase writings. On the other hand, it is also well established that regular exercise is also strongly supportive of longevity(ref)(ref)(ref).  The mechanisms through which exercise improves health and life expectancy hitherto appeared to be complex and unclear.  The new research suggests that telomere extension may be a key mediator of the health and longevity benefits of regular exercise.

Sustained exercise can keep leukocytes younger

The latest study, an e-publication dated January 8 2010 from a University of Colarado group, is Leukocyte Telomere Length is Preserved with Aging in Endurance Exercise-Trained Adults and Related to Maximal Aerobic Capacity.  “To determine if age-associated reductions in TL (telomere length) are related to habitual endurance exercise and maximal aerobic exercise capacity (maximal oxygen consumption, VO(2)max), we studied groups of young (18 – 32 years; n = 15, 7m) and older (55 – 72 years; n = 15, 9m) sedentary and young (n = 10, 7m) and older endurance exercise-trained (n = 17, 11m) healthy adults. Leukocyte TL (LTL) was shorter in the older (7059 +/- 141bp) vs. young (8407 +/- 218) sedentary adults (P < 0.01). LTL of the older endurance-trained adults (7992 +/- 169bp) was approximately 900bp greater than their sedentary peers (P < 0.01) and was not significantly different (P=0.12) from young exercise-trained adults (8579 +/- 413). — Our results indicate that LTL is preserved in healthy older adults who perform vigorous aerobic exercise and is positively related to maximal aerobic exercise capacity. This may represent a novel molecular mechanism underlying the “anti-aging” effects of maintaining high aerobic fitness.”

So, older folks who vigorously exercise keep up their leukocyte telomere lengths and folks who sit around watching TV instead do not.  This message seems repeated in several other research reports. A 2009 study, this time from a German group, is: Beneficial Effects of Long-term Endurance Exercise on Leukocyte Telomere Biology.  “This study examines telomere biology and senescence-associated factors in endurance athletes and matched controls without physical activity. –Methods: Leukocytes where isolated from the peripheral blood of professional young track & field athletes (n=32, age 20.4 years, running 73±5 km/week), aged athletes performing regular endurance training (n=25, age 51.1 years, running 80±8 km/week, 35 years training history) and two control groups of age-matched, physically inactive healthy volunteers (26 young and 21 aged subjects).  –Results: Telomere repeat amplification protocols revealed an activation of leukocyte telomerase in young athletes to 256±19% and in elderly athletes to 182±11% compared to controls. Western blots showed an up-regulation of the telomere-capping protein TRF2 in young (179±1%) as well as in aged athletes (176±10%). FlowFISH assays and real-time PCR measurements of leukocyte telomere length showed no difference between young athletes and young controls. Sedentary elder controls exhibited a significant reduction of leukocyte telomere length (FF: 53±3%; PCR: 70±8%; vs. young controls). Importantly, there was a striking conservation of telomere length in aged athletes (FF: 88±4%; PCR: 84±7%; vs. young controls). Further analysis of telomere-associated proteins and cellular senescence regulators demonstrated an increase of TRF2, Ku70 and Ku80 mRNA and a reduced protein expression of Chk2, p16 and p53 in aged athletes compared to untrained elder controls.”

More or less the same story.  Among the younger people exercise seems to have a strong effect on leukocyte telomerase expression but no effect on telomere lengths.  But in the older folks, only those who exercised kept up most of their telomere lengths.  Further, their cells showed markedly lower levels of senescence markers.  As far as leukocytes are concerned, vigorous regular exercise definitely seems to keep them young. 

A 2009 mouse and human study Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall looks a bit further at the molecular dynamics of exercise and comes to a consistent conclusion.  “Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle–checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls. — Conclusions— Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis.”

Watch out for your muscle satellite cells

There is a caution however, for more or harder exercise is not always better.  And leukocytes are not the only relevant cells to consider.  Earlier studies indicate that too strenuous or prolonged exercise can lead to serious depletion of telomerase in muscle satellite cells.  Muscle satellite cells “are small mononuclear progenitor cells with virtually no cytoplasm found in mature muscle. They are found sandwiched between the basement membrane and sarcolemma (cell membrane) of individual muscle fibres, and can be difficult to distinguish from the sub-sarcolemmal nuclei of the fibres. Satellite cells are able to differentiate and fuse to augment existing muscle fibres and to form new fibres. These cells represent the oldest known adult stem cell niche, and are involved in the normal growth of muscle, as well as regeneration following injury or disease.”   

Under conditions of hard exercise satellite cells can be forced into multiple rounds of duplication and differentiation leading to telomere shortening.  The 2003 publication Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres tells the story. “Although the beneficial health effects of regular moderate exercise are well established, there is substantial evidence that the heavy training and racing carried out by endurance athletes can cause skeletal muscle damage. This damage is repaired by satellite cells that can undergo a finite number of cell divisions. — In this study, we have compared a marker of skeletal muscle regeneration of athletes with exercise-associated chronic fatigue, a condition labeled the “fatigued athlete myopathic syndrome” (FAMS), with healthy asymptomatic age- and mileage-matched control endurance athletes. — Three of the FAMS patients had extremely short telomeres (1.0 +/- 0.3 kb). The minimum TRF lengths of the remaining 10 symptomatic athletes (4.9 +/- 0.5 kb, P < 0.05) were also significantly shorter that those of the control athletes. CONCLUSION: These findings suggest that skeletal muscle from symptomatic athletes with FAMS show extensive regeneration which most probably results from more frequent bouts of satellite cell proliferation in response to recurrent training- and racing-induced muscle injury.”

The 2008 study The effects of regular strength training on telomere length in human skeletal muscle looked at power lifters and showed that long-term exercise is not necessarily associated with satellite cell telomere loss although lifting heavier loads mean more loss.  “These results show for the first time that long-term training is not associated with an abnormal shortening of skeletal muscle telomere length. Although the minimum telomere length in PL (power lifters) remains within normal physiological ranges, a heavier load put on the muscles means a shorter minimum TRF length in skeletal muscle.”

The effect of exercise on telomeres in satellite cells is further reported in the 2009 publication The biology of satellite cells and telomeres in human skeletal muscle: effects of aging and physical activity.  “New insights suggest that telomeres in skeletal muscle are dynamic structures under the influence of their environment. When satellite cells are heavily recruited for regenerative events as in the skeletal muscle of athletes, telomere length has been found to be either dramatically shortened or maintained and even longer than in non-trained individuals. This suggests the existence of mechanisms allowing the control of telomere length in vivo.”  Whether satellite cell telomeres get shorter or longer or stay the same with exercise depend, among other matters, on the expression of telomerase in the satellite cells as a result of the exercise, and this in turn depends on several factors including physical condition of the person and the nature of the exercise.

Finally a late 2008 study report Relationship between physical activity level, telomere length, and telomerase activity looks at the results of exercise on telomeres in peripheral blood mononuclear cells (PBMCs). “A Peripheral Blood Mononuclear Cell (PBMC) is any blood cell having a round nucleus. For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells (CD4 and CD8 positive ~75%), B cells and NK cells (~25% combined)(ref).”  According to the report:  “The purpose of this study was to examine the relationship of exercise energy expenditure (EEE) with both telomere length and telomerase activity in addition to accounting for hTERT C-1327T promoter genotype. — Sixty-nine (n = 34 males; n = 35 females) participants 50-70 yr were assessed for weekly EEE level using the Yale Physical Activity Survey. Lifetime consistency of EEE was also determined. Subjects were recruited across a large range of EEE levels and separated into quartiles: 0-990, 991-2340, 2341-3540, and >3541 kcal x wk(-1). Relative telomere length and telomerase activity were measured in peripheral blood mononuclear cells (PBMC). — CONCLUSION: These results indicate that moderate physical activity levels may provide a protective effect on PBMC telomere length compared with both low and high EEE levels.”

These studies leave me tentatively concluding:

·        Regular mildly cardiovascular exercise is likely to protect telomere lengths with aging across the three cell categories studied.

·        Vigorous aerobic exercise approaching “maximal aerobic exercise activity” may further serve to keep telomere lengths at youthful levels in leukocytes.

·        However, excessively strenuous exercise such as lifting very heavy weights or leading to exercise-associated fatigue may lead to compromised telomere lengths in muscle and/or PBMC cells and be life-shortening.

So, I believe moderation should be the rule.  See the suggestions for regular exercise in my treatise.

In the January 5 post Important new mesenchymal stem cell therapies, I promised this post specifically devoted to research on use of stem cells for cartilage regeneration.  It is a long and fairly thorough post with focus on regeneration of cartilage damage due to osteoarthritis, the toughest kind to deal with.

About cartilage and osteoarthritis

From Wikipedia, “Cartilage is a stiff yet flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs. It is not as hard and rigid as bone but is stiffer and less flexible than muscle. — Cartilage is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix composed of collagen fibers, abundant ground substance rich in proteoglycan, and elastin fibers. Cartilage is classified in three types, elastic cartilage, hyaline cartilage and fibrocartilage, which differ in the relative amounts of these three main components. — Unlike other connective tissues, cartilage does not contain blood vessels. The chondrocytes are supplied by diffusion, helped by the pumping action generated by compression of the articular cartilage or flexion of the elastic cartilage. Thus, compared to other connective tissues, cartilage grows and repairs more slowly.” Hyaline Cartilage lines the ends of bones in joints in the body where there is movement, such as in the elbow or knee.  A synovial fluid bathes the joint continuously so as to provide a frictionless interface.

Osteoarthritis (OA) is classically thought to be a “wear and tear” disease where the cartilage gradually wears out, like brake shoes do in a car, leaving bones rubbing directly on bones.  It can occur in the knees, hands, hips and the spinal areas of the lower back and neck.  “In osteoarthritis of the spine, the spaces between the vertebrae narrow. Bone spurs often form. When bone surfaces rub together, the vertebral joints (facets) and areas around the cartilage become inflamed and painful. Gradually, your spine stiffens and loses flexibility. Once these changes appear on X-rays, osteoarthritis has already started(ref).”  Osteoarthritis can create stiffness, be very painful, and be seriously debilitating. 

The classical view is that osteoarthritis is an incurable disease of progressing age: “Osteoarthritis gradually worsens with time, and no cure exists. But osteoarthritis treatments can relieve pain and help you remain active. Taking steps to actively manage your osteoarthritis may help you gain control over your symptoms(ref).”  According to this view, if the osteoarthritis situation gets bad enough your best recourse might be surgery such as total knee replacement.    

The classical view of osteoarthritis is evolving in that it is increasingly being seen as a disease that can arise from multiple causes in younger as well as older people and in that there is an increasingly brighter prospect for cartilage regeneration, even of seriously damaged joints, without need for drastic surgery.   Osteoarthritis can arise from mutated genes, traumatic injury or an operation as well as from wear and tear. It is not uncommon for people in their 40s and 50s to have a serious osteoarthritis problem.  Osteoarthritis can frequently arise in young people and even in children, such as when associated with a mutation in the type II procollagen gene (COL2A1)(ref)(ref).

Osteoarthritis can create collateral damage besides loss of cartilage.  In the case of the spine, for example, “Sometimes, the wear-and-tear of osteoarthritis puts pressure on the nerves leaving the spinal column. This can cause weakness and pain in the arms or legs. Osteoarthritis might also cause bone spurs to form in the spinal area. Osteoarthritis of the spine sometimes is called spinal spondylosis if the damage affects the facet joint and the disks in the spine(ref).”

Osteoarthritis involves a number of degenerative processes and any effective regenerative treatment must be able to deal with these. From the 2008 review article Technology Insight: Adult Mesenchymal Stem Cells for Osteoarthritis Therapy:  “Much research into the pathophysiology of OA has focused on the loss of articular cartilage, caused by mechanical and oxidative stresses, aging or apoptotic chondrocytes.  Articular chondrocytes within diseased cartilage synthesize and secrete proteolytic enzymes, such as matrix metalloproteinases and aggrecanases, which degrade the cartilaginous matrix. The proinflammatory cytokine interleukin 1 (IL-1) is the most powerful inducer of these enzymes and of other mediators of OA in articular chondrocytes. The induction of these factors leads to matrix depletion through a combination of accelerated breakdown and reduced synthesis.  Other proinflammatory cytokines, such as tumor necrosis factor, are also involved in cartilage breakdown and, together with biomechanical factors implicated in OA etiopathophysiology, contribute to induction of the disease.” 

First-generation cartilage regeneration using implanted chondrocytes

The objective of cartilage regeneration in the case of a joint where the cartilage is seriously compromised by OA is to induce new cartilage to grow in the joint, modeling  and organizing itself correctly in the process so as to restore the original functionality of the joint.  The area of therapy is sometimes called cartilage tissue engineering.  Hyaline cartilage is formed by chondrocytes, specialized cells that reside in and “produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans.”    So, first-generation attempts at joint cartilage regeneration have been focused on introduction of new chondrocytes into osteoarthritis-compromised joints. The method has become known as ACT (or ACI), standing for Autologous Chondrocyte Transplantation (or implantation) and its use goes back to 1987.  “In ACT, a cartilage biopsy is taken from the patient and articular chondrocytes are isolated. The cells are then expanded after several passages in vitro and used to fill the cartilage defect. Since its introduction, ACT has become a widely applied surgical method with good to excellent clinical outcomes. More recently, classical ACT has been combined with tissue engineering and implantable scaffolds for improved results. However, there are still major problems associated with the ACT technique which relate mainly to chondrocyte de-differentiation during the expansion phase in monolayer culture and the poor integration of the implants into the surrounding cartilage tissue(ref).”

Results of ACT, when it could be applied, were often not bad.  According to a 2000 publication reported on a number of ACT papers, regarding one study  “The Swedish clinical experience with ACT now extends to more than 800 patients, including 200 patients with a minimum follow-up of 2 years. — Treatment of chondral and osteochondral lesions with ACT appears to produce new tissue similar in histologic and mechanical characteristics to hyaline cartilage, resulting in good clinical outcomes in more than 75% of patients. Results are best in lesions of the distal femur, including multiple defects. Patellar lesions require strict attention to alignment, and trochlear results are size-dependent.”  Regarding another paper “The multicenter results presented in this paper appear to parallel the Swedish experience and demonstrate a durable repair out to 36 months. ACT appears to be an efficacious and safe treatment for full-thickness chondral lesions of the femoral condyles and trochlea.” However regarding a third paper “Osteochondral grafts improve symptoms, but may increase risk of osteoarthritis.”   

“Currently, more than 12,000 ACIs are documented. Different studies showed a permanence of clinical results that were gained in a period of about 10 years [14–16]. Despite good clinical results, some disadvantages hamper the prevalence of ACI: (a) the nonuniform spatial distribution of chondrocytes and the lack of initial mechanical stability, (b) the suture of the periosteal flap into the surrounding healthy cartilage and the necessity of a perifocal solid cartilage shoulder that limits ACI to the treatment of small defects and excludes the treatment of OA diseased cartilage, and (c) the arthrotomic surgery(ref).”

The last decade showed the emergence of Arthroscopic treatment regimens for osteoarthritis of the knee, with some degree of success.  “Arthroscopic treatment included joint insufflation, lysis of adhesions, anterior interval release, contouring of cartilage defects to a stable rim, shaping of meniscus tears to a stable rim, synovectomy, removal of loose bodies, and removal of osteophytes that affected terminal extension. — CONCLUSIONS: This arthroscopic treatment regimen can improve function and activity levels in patients with moderate to severe osteoarthritis. Of 69 patients, 60 (87%) patients had a satisfactory result. However, in this group of 60, 11 patients needed a second procedure, resulting in a 71% satisfactory result after 1 surgery.”  There was also some degree of success reported in implanting scaffolds in osteoarthritis-damaged knees and using a modified form of ACT to regenerate knee cartilage(ref).  “Tissue regeneration was found even when implants were placed in joints that had already progressed to osteoarthrosis. Cartilage injuries can be effectively repaired using tissue engineering, and osteoarthritis does not inhibit the regeneration process.”

However, ACT has several limitations and often can’t be used when severe cartilage loss is due to degenerative arthritis or osteoarthritis.  An excellent summary of the limits of ACT can be found in the write-up of a clinical trial of a second-generation stem cell therapy.  “this treatment requires the extraction of chondrocytes directly from the patient and thus causes trauma in healthy articular cartilage. Also, this type of treatment cannot be applied to large lesions, nor is the efficacy satisfactory in patients over the age of 40 whose cellular activation levels are low. Thus, autologous chondrocyte transplant is rather limited in the number of cells harvested and their activation level and is therefore restricted in terms of treatment site, severity of the condition, and the size of lesion. The current technology allows the application of treatments in local cartilage defects but not in degenerative arthritis or rheumatoid arthritis. The technology needs to be taken up to another level in order to benefit such prevalent arthritic disorders. Treatments using stem cells do not cause damage to healthy articular cartilage as they don’t require the harvesting of healthy cartilage tissues from the patients. Moreover, the number of successfully cultured cells is larger due to the excellent proliferation capability of stem cells and thus, mass supply is possible(ref).”

Second -generation cartilage regeneration using mesenchymal stem cells

Problems and limitations of ACT have led to interest in a better alternative as outlined in the March 2009 publication Mesenchymal stem cells in connective tissue engineering and regenerative medicine: applications in cartilage repair and osteoarthritis therapy. Animal experiments have demonstrated that under appropriate signaling conditions, mesenchymal stem cells (MSCs) differentiate into chondrocytes and can produce hyaline cartilage replacing that lost in injured sites.  I have discussed a number of attractive properties of mesenchymal stem cells in the post Important new mesenchymal stem cell therapies.  These properties are highly relevant to cartilage regeneration, including freedom from an immune or inflammatory response, donor independence, easy duplication in-vitro, homing capability and, particularly, that MSCs seem to be the body’s own natural means for cartilage renewal(ref). 

I mentioned the 2007 publication Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology, indicating that neither the ability to collect sufficient numbers of MSCs nor the capability of those MSCs to differentiate into chondrocytes is affected by age of the person contributing the MSCs or whether or not they have osteoarthritis.  “No correlation of age or OA etiology with the number of mononuclear cells in BM, MSC yield, or cell size was found. Proliferative capacity and cellular spectrum of the harvested cells were independent of age and cause of OA.”  So, a patient’s own MSCs can be used for cartilage regeneration, even if the patient has osteoarthritis which destroyed the original cartilage.  Despite this publication’s conclusions,  some researchers are still concerned as to whether MSCs from an old sick person are as good as ones from a young healthy person.  I personally wonder whether the telomere lengths of MSCs from old people are equal to those from younger people, and whether the epigenetic markers of MSCs from sick people allow those cells to be good candidates for tissue regeneration.

The 2009 publication Tissue engineering in the rheumatic diseases is an excellent treatise covering both the first and second generation tissue engineering approaches for osteoarthritis cartilage damage and I suggest it for anyone wishing to go into further depth than possible in this post.  “Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Here, most likely, cartilage formation is impaired and engineered neocartilage will be degraded. Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases.”  The following selective quotes are from the same paper.

“Diseases like rheumatoid arthritis (RA) or degenerative arthritis (osteoarthritis, OA) are accompanied by a progressive reduction of extracellular matrices (ECMs) in joint cartilage and bone and, eventually, loss of joint function and excessive morbidity. Current pharmacological treatment of RA focuses on alleviating symptoms and/or modifying the disease process. Despite recent success in controlling pain and inflammation, marginal cartilage regeneration has been observed.”  The last comment is important: there is a natural process of cartilage regeneration, though usually inadequate.  The passage goes on “Obviously, suppression of inflammation is not sufficient to restore joint structure and function. Probably, cartilage repair may be achieved only by triggering local cartilage tissue responses leading to recovery of chondrocyte remodeling. An imbalance in joint cartilage, subchondral bone, and synovial membrane remodeling is one important characteristic of OA.”

“Besides clinically applied tissue-specific chondrocytes, undifferentiated mesenchymal stem cells (MSCs) are of special interest as cell candidates. In particular, bone marrow MSCs are comprehensively characterized and represent promising candidates [5]. They are easy to isolate and expand, they differentiate into various tissues like cartilage [6] and bone [7], and therefore they are able to regenerate osteochondral defects. Additionally, as they target diseased organs and secrete many bioactive factors, such as immunosuppressives for T cells facilitating their allogeneic use, they serve as vehicles capable of presenting proteins with therapeutic effects.“

“In this regard, secreted bioactive factors provide a regenerative environment, referred to as trophic activity, stimulating, for instance, mitosis and differentiation of tissue-intrinsic repair or stem cells (reviewed in [8]). Because of their anti-inflammatory and immunosuppressive properties, MSCs have been used as agents in autoimmune diseases (ADs) and have been applied in arthritis animal models (reviewed in [9]).”

The 2008 review article Technology Insight: Adult Mesenchymal Stem Cells for Osteoarthritis Therapy also provides a good summary of the reasons for basing therapies for large areas damaged by osteoarthritis on use of MSCs.  “Unlike chondrocytes, the use of MSCs is not hindered by the limited availability of healthy articular cartilage or an intrinsic tendency of the cells to lose their phenotype during expansion. The use of MSCs also obviates the need for a cartilage biopsy and, thereby, avoids morbidity caused by damage to the donor-site articular surface.”

Mesenchymal stem cell delivery modes for tissue regeneration

A number of approaches have been suggested for obtaining and delivering MSCs to a site requiring regeneration(ref). 

1.      Get the MSCs from the patient or some other source (another person or umbilical cord blood), multiply them and inject them directly into the site requiring regeneration, e.g. intra-articular injection, perhaps with hyaluronic acid,

2.     Same but first implanting a biodegradable synthetic or natural scaffold, perhaps employing a collagen hydrogel,

3.     Attraction of autologous MSCs within the body using microfractures, an established technique, and

4.     Attraction of autologous MSCs within the body using scaffolds and stem-cell attracting and differentiating factors.

Microfractures and mobilizing the body’s MSCs

Microfracturing was the first MSC cartilage regeneration technique and has been used clinically for years with some success.   “Finally, it should be mentioned that ACI treatment is still controversial. In a prospective randomized controlled trial (level of evidence: therapeutic level I), no significant advantage for the complex ACI compared with standard self-repair-stimulating microfracture could be measured after 2 and 5 years [18].”  Standard self-repair-stimulating microfracture is a technique in which microfractures are deliberately introduced in compromised cartilage to stimulate the body’s own cartilage regeneration capabilities.  As I understand the procedure, a surgeon drills a number of small holes (2mm in diameter) in the cartilage down the point where there is bleeding from the bone marrow.  The theory is that the holes provide access to the cartilage of MSCs from the bone marrow.  See Chondral Resurfacing of Articular Cartilage Defects in the Knee with the Microfracture Technique.  The results of applying this technique are not too shabby. “At the time of the latest follow-up, knee function was rated good to excellent for thirty-two patients (67%), fair for twelve patients (25%), and poor for four (8%). — Microfracture repair of articular cartilage lesions in the knee results in significant functional improvement at a minimum follow-up of two years.” 

Apparently, the microfractures mobilize the body’s own mesenchymal stem cells to regenerate cartilage.  It appears that this process can be enhanced by adding a bit of hyaluronic acid.  “Following microfracture in rabbit knee cartilage defects, application of hyaluronic acid gel resulted in regeneration of a thicker, more hyaline-like cartilage(ref).”  The technique is quite different than removing stem cells from the bone marrow of a patient, growing them in culture and then re-introducing them into the body where the repair is needed.  It depends instead on a) stimulating a part of the body needing cartilage regeneration to send out signals that naturally mobilizes a patient’s own MSCs to multiply, swarm to the cartilage site and do the regeneration job that is needed, and b) providing easy physical access for the stem cells to reach the cartilage area involved. 

The future direction

A distinct possibility is that similar results can be achieved in the future without a need for microfractures, using chemotactic agents, substances that can get MSCs moving to the right place and differentiating into cartilage tissue.  “So, the next generation of tissue engineering focuses on in situ approaches [44]. Here, for joint repair, scaffolds combined with chemotactic molecules and joint tissue formation-stimulating factors are transplanted, resulting in the in situ recruitment of bone marrow MSCs to the defect sites of degenerated cartilage and bone and their subsequent use for factor-guided joint repair. — Although MSC migration factors and their mechanisms are not known yet, molecules such as chemokines [48], bone morphogenetic proteins and platelet-derived growth factor [49], and hyaluronan [50] have been shown to have a dose-dependent chemotactic effect(ref).“ Recent research shows that transforming growth factor TGF-β3 has a capacity to mobilize and initiate the differentiation of the body’s MSCs(ref)(ref). 

Clinical Trials

As to clinical investigations of using MSCs for OA cartilage damage, there is the trial   Autologous Transplantation of Mesenchymal Stem Cells (MSCs) and Scaffold in Full-Thickness Articular Cartilage.  It is a small study started in August 2998 and originally scheduled for completion in May 2010. Another relevant clinical trial just posted and now enlisting participants is Study to Compare the Efficacy and Safety of Cartistem® and Microfracture in Patients With Knee Articular Cartilage Injury or Defect.  “The purpose of the study is to assess and compare the safety and efficacy of the allogeneic-unrelated umbilical cord blood-derived mesenchymal stem cell product (Cartistem®) to that of a microfracture treatment in patients with articular cartilage defect or injury. — This clinical trial for the stem cell therapies is essential because treatment of cartilage defects with umbilical cord blood-derived mesenchymal stem cells, known to have the highest level of activity among all adult stem cells, opens the possibility of articular cartilage regeneration even for aged patients and patients with large lesions unable to benefit from existing treatments.”

Summary

While MSCs offer great promise for tissue regeneration based on both theoretical understandings and experiments with animal models, many questions regarding human use remain incompletely resolved, e.g. use of allogeneic vs. autologous cells, mode of implantation and use of scaffolds, use of chemotactic and messenger molecules, and even nagging issues of whether age and arthritic status of donors are really irrelevant.  In any event, now in 2010 the myth that nothing basic can be done about OA cartilage deterioration has lost credibility.  Clinical trials of MSCs are getting underway and even more can be expected to be launched soon.  My own guess is that in 5-10 years tissue-engineering regeneration of osteoarthritic and other forms of cartilage damage will be in widespread clinical use.  It is the dawn of the age or tissue engineering and regenerative medicine.

One of the great things about following longevity research is that surprises are around every corner.  But I have not imagined a surprise of major importance about vitamin C supplementation.  Yesterday I would have said such a surprise is very unlikely because the stuff has been studied for more than 50 years including the Linus Pauling C-advocacy era.  There is a long history of controversy regarding therapeutic use of vitamin C, especially in megadose amounts(see the citations in ref).  Having been an aficionado of C megadosing back in the 70s, I have long since given up on the substance being other than an important antioxidant supplement.   Well, wrong again!  A 2010 research study just published in the FASEB Journal indicates that vitamin supplementation C cures mice with Werner’s Syndrome and could possibly be very important for the longevity of people with related genetic defects(ref)(ref).  What did we miss and what new is to be learned about vitamin C?

Werner’s Syndrome is a form of adult progeria (premature aging) due to a mutation in the WRN gene, a helicase deficiency.  For background on the disease and its genetic causes see the blog post Werner Syndrome – another model for aging.  

The new study is entitled Vitamin C restores healthy aging in a mouse model for Werner syndrome.  “Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-kappaB, as well as protein kinase C and Hif-1 transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPAR . Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.”  In other words, vitamin C supplementation delivers on restoring a Wrn mutant mice to normal healthy mouse status and the researchers think it might do the same for human patients with WS.

The important implication of the study is that vitamin C could be extremely important for prolonging the lives of people with WS or related genetic defects who normally show accelerated aging around 20 and die by 50.  A discussion of the new result in EurekAlert quotes an author of the study:”Our study clearly indicates that a healthy organism or individuals with no health problems do not require a large amount of vitamin C in order to increase their lifespan, especially if they have a balanced diet and they exercise,” said Michel Lebel, Ph.D., co-author of the study from the Centre de Recherche en Cancerologie in Quebec, Canada. “An organism or individual with a mutation in the WRN gene or any gene affected by the WRN protein, and thus predisposes them to several age-related diseases, may benefit from a diet with the appropriate amount of vitamin C.”

The reports I have read of this study do not make it clear how exactly vitamin C works to overcome the multiple effects of accelerated aging  due to mutation in the WRN gene, and I suspect this is unknown.  I would like to learn more about that  since I doubt only a simple antioxidant effect is involved.  And, if we knew how vitamin C can halt extraordinary aging due to WS, that just possibly might give us a clue as to how something else could halt normal aging.

There is apparently a lot more to learn about the workings of that wonderful, familiar and cheap ascorbic acid stuff.   “Vitamin C has become one of the most misunderstood substances in our medicine cabinets and food,” said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “This study and others like it help explain how and why this chemical can help to defend some, but certainly not all, people from premature senescence(ref).”  

Rapidly curing a roaring case of hepatitis back in 1970 using megadoses of vitamin C is what started my interest in anti-aging science.  I will continue popping at least 3 grams a day of C as I have been doing for decades now.

On January 21, this blog will celebrate its first birthday.  The purpose of this post is to review how the blog has evolved from its original intent, to review the ways it has been heading recently, and to discuss whether those ways make sense for the future.  Specifically, I am asking for your feedback on the kinds of content that you would find most useful in the coming months and year and how to make this blog most interesting and useful for you.

How the blog has evolved so far

The original introduction to this blog stated “The purpose of this Blog is to provide a frequently-updated plain-language companion to my Anti-Aging Firewalls treatise site ANTI-AGING FIREWALLS THE SCIENCE AND TECHNOLOGY OF LONGEVITY.   This blog is for people interested in living  longer and better lives by taking advantage of developments on the frontiers of longevity science.  I plan to post comments on recent aging-related developments  from time to time, and welcome any and all discussion by others.”  So, now after 224 posts and 236 comments, what has actually happened?

Where the blog has been going

·        It is frequently updated, several times a week, and still positioned as a companion to the treatise although it frequently goes into far greater scientific depth in topics discussed in the treatise and includes content related to aging that is not in the treatise.  The blog has assumed a life and importance of its own, in many ways exceeding that of the relatively static treatise.

·        The blog is still positioned to address the audience mentioned but is not for the general public.  It is targeted to informed science-minded people, professionals in the medical arts, researchers in the many areas of science covered in the blog, and laypeople with serious interests in anti-aging developments.  It often goes into fairly great technical depth.  I have given up on sticking to “plain language” for that would be incompatible with responsibly covering “developments on the frontiers of longevity science.”  Instead, I have been introducing more and more advanced technical concepts from the disciplines involved.

·        The purpose of the blog is to fill in the pieces of the large puzzle that constitutes aging, and to address fundamental issues related to aging based on hard current scientific research : What are the mechanisms of aging?  How do they relate to each other?  Which ones are primary?  What anti-aging interventions are possible now?  Which ones are coming along, and how far off are they likely to be?.  This requires following and digging ever-deeper into a number of streams of research involving molecular biology, genetics, genomics, proteomics and other “omics.”  And it requires keeping current with research related to a number of aging theories (19 as of now) and ongoing research developments relating to a number of aging-related genes and pathways with names like mTOR, NF-kappaB, Akt, P53, P21, hTERT, and Notch and MAPK signal transduction pathways.

·        Scientific and intellectual integrity are essential characteristics of the blog.  I research the science items in depth before writing them and it sometimes requires several days to do this.  I provide numerous links to research citations and often quote direct passages from research publications.  When I have a personal opinion, I identify it as such. I avoid fringe or cult science.  If an ancient Chinese or Indian herb is reputed to have incredible curative powers I am interested in it only if the claims are supported by a body of reputable Western scientific research.

·        Freedom from commercialism is another important aspect of the blog.  I do not accept advertising though I could probably earn some cash by doing that given blog’s  growing popularity.  Further, I don’t cover commercial products such as supplement combinations except in very rare cases when such a product has a unique scientific character.  I am beholden to no commercial interest and own no stake in nor am I employed by any company selling anti-aging products or services.

·        In the interest of providing depth, new blog items are usually highly hyperlinked with related past blog items and relevant items in my treatise.

·        Current “unique visits” to the blog and treatise typically range from 700 to 1,000 per day.  My ISP defines these visits as unique user URLs that visit at least two pages in a session, e.g. two blog posts or a blog post and my treatise.  These numbers correspond to 1,400+ page views per day.  There has been a slow and irregular upwards trend in usage, perhaps amounting to 5% to 10% per month.  Based on these statistics I estimate that there are probably a few thousand people who occasionally visit the blog, and perhaps a few hundred regular avid readers.  Increasing numbers of international users are being attracted, probably via personal networks.  I would like to see these numbers increased by an order of magnitude during 2010.  This will require ways of making the existence of the blog known to wider audiences.

Blog items seem to fall in the following categories:

–         Coverage of news items and new research discoveries and “breakthroughs.”  Unlike the popular press and many other blogs, I like to provide citations to the original publication whenever possible, citations to previous relevant publications and some discussion of how the discovery fits into the bigger picture and what it means.  An example is the recent post Ginkgo Biloba supplementation has no effect on cognitive decline (but it does have other impacts).

–         Mini-treatises on topics relevant to longevity.  The purpose is usually to provide a review picture of the state of research and research knowledge in a particular area.  These are the postings that usually require the most background research work.  An example is the three-part post Autoimmune diseases and lymphoma: Part I: focus on Lupus, Part II: focus on inflammation and Part III: focus on lymphomas. Another example is DNA demethylation – a new way of coming at cancers. A few of these mini-treatises have been motivated by a personal medical concern, Spinal cord injury pain – a personal story and a new paradigm being a case in point.

–         Original research and intellectual contributions. These are my own ideas not found in the existing literature but representing a synthesis of knowledge and trends that are definitely “out there.”  I have made two major contributions and some minor ones in this regard.  One of the major contributions is the Stem Cell Supply Chain theory of aging, originally written up in this blog and now part of my treatise. Many later posts refer back to this one.  The other major contribution is Giuliano’s Law, related to the exponential acceleration in anti-aging science and the implication of this for personal longevity.  Again, this was a three-part series starting with Giuliano’s Law: Prospects for breaking through the 122 year human age limit and going on to More on Giuliano’s Law; calculating my longevity prospects and Factors that drive Giuliano’s Law. Occasionally I will develop an original insight  while writing a blog post  and mention it in that post.  An example from yesterday’s post Important new mesenchymal stem cell therapies was that acupuncture might work because it mobilizes  mesenchymal stem cells to migrate to a problematic location where they do their job of tissue regeneration.   I plan to research that particular speculation further, incidentally, and report on it in a future blog entry.

–         Humorous pieces.  An example is P38, P39 and P40 channel receptor functions inhibit activities of BF-110, HE111 and HE177 leading to reduced expression of (SC)1000 in BOB which seems to be a typical jargon-filled paper title from a molecular biology journal but in fact describes World War II fighter plane action.  Another example is the Avoidance Magazine stories.

–         Review and housekeeping posts, like this one and the recent post Genes discussed or mentioned in this blog.

–         Only selective reviews of supplements: While many supplements are suggested in my treatise and are of great personal interest to me and to many of my readers, I do not usually review them because they are mostly already well-reviewed in other on-line resources.  I make a few exceptions to this rule when the science is unusual, however, such as in The curious case of l-carnosine.

–         More and more-sophisticated comments: During the first 9 months of the blog’s existence, the number of posts exceeded the number of comments.  Currently more comments are coming in than posts and the comment-to-post ratio is continuing to grow. And the comments are tending to be more sophisticated contributions.

Why these directions?

I believe the above profile gives the blog a unique character and market positioning, different than the many aging and anti-aging sites out there.  The blog strives for both technical depth and true multi-disciplinary breadth and provides viewpoints not normally found in focused research studies.   As I add entries, I believe I am constructing an important database of longevity-related articles, again a key adjunct to my treatise.  As time goes on the blog gains value because of its retrospective as well as current content.  Even  now, if a doctor or scientist wants to learn about aging, the blog is an excellent way to start.

Further there is another, personal, agenda involved.  Researching these articles, writing this blog and updating my treatise is a full-time job for me, and it is a full-time self-educational process.  Eighteen months ago I looked at two options: 1.  entering a full time graduate level program in the life sciences at MIT or Harvard, with the four-year objective of obtaining a second Ph.D. focusing on longevity sciences and writing a Ph.D. in that area, and 2. Pursuing the course I am now pursuing of self-education and communication, using the discipline of blog writing and treatise updating to keep me focused, on track, and constantly digging deeper and learning more.  And, in the process, building an equivalent of the Ph.D. thesis as I move along, constantly improving it – (that is my treatise and the collective writings in this blog).  

I did not like the first track for it would have been a massive digression requiring me to take too many courses and learn too much material only marginally relevant to longevity.  And I would miss keeping up with key longevity developments that were unfolding day-to-day.  While I would have earned a new Ph.D. and a certain amount of institutional credibility, I would have missed much of the party and most likely would have prepared myself for a relatively narrow career.  I compared myself to being a guy with an electrical engineering degree who found himself in a fairly exciting job in a computer industry lab in 1955, already making important contributions, say in the area of storage technology and knowing a lot about computers and where they were heading.  Should that guy drop out for four years to get an academic degree in computer sciences?  Probably not since most of his professors would know less about what was really important about computers and storage than he did, and he too would have missed the most exciting part of the party.

An advantage of this approach is sharing my education with my readers, making my learning far from a lonely process.

My choice of the current educational track often requires me to stop and backfill knowledge, however.  I find it easier and more satisfying to work backwards from current research than to take courses or read entire books which would give me a broader base of mostly-irrelevant knowledge.  For example, suppose I encounter research relating to protein folding and how this effects P53 gene activation in the presence of co-activators under certain conditions of histone acetylation.  I want to understand what the new research means.  This requires digging into these areas to the degree necessary to understand what is going on.  And because these areas are new research frontiers, I am not going to find what I want to know all neatly packaged in a course anywhere or even in one book.  If the area is complex and important, I may decide to generate a blog post about it as a way of forcing my own learning.  I can’t write clearly about something unless I understand it.  So several blog posts are about such “backfill” areas of knowledge, an example being MicroRNAs, diseases and yet-another view of aging.

All of this is to say that as I am learning more and the state of knowledge advances my blog entries have been tending to become more complex, technical and sophisticated, and this tendency is likely to continue.  I am also spending more and more time addressing comments.

Future of the blog

My current plan is to continue the blog along the paths identified above, but I have some questions for my readers:

·        What do you think about the current mix of posts?  Which kinds would you like to see more or less of?

·        What area of content are you most interested in?

·        Do you know how to find all the past items, to use the search features to find past blog entries?  I could write a short post on this.

·        Do you make much use of the hyperlinks?

·        Are you satisfied with how I respond to comments?

·        Do you find this site too personal, not personal enough or are you OK with the current mix?

·        Right now there is backwards hyper linking of blog entries to previous relevant ones, but no forward hyper linking, say linking an early article on telomerase to the many subsequent ones.  Do you think it would be worth the time and effort required for me to generate such forward links?

·        What forms of networking or joint activities would you suggest for me with aging research institutions?  Any specific links you can suggest? People you know who I should contact?

·        Any ideas of how radically to expand the readership of the site?  I already have pretty good search engine placement on Google.

·        Any other suggestions?

While embryonic stem cell therapies are still barely getting off the ground (see the post It’s a long  way to stem cell treatment), several important therapeutic applications of Mesenchymal stem cells (MSCs) are now getting to be well along in the development pipeline and could soon become part of mainline medicine.  

In this post I first enumerate some recently-discovered and exciting properties of MSCs that make these applications possible.  Then, to illustrate that mesenchymal stem cell therapies are going prime-time, I provide a current listing of clinical trials involving MSCs with hyperlinks to further information about each trial.     

Mesenchymal stem cells are multipotent cells that can differentiate into a variety of cell types including chondrocytes, osteoblasts,  myocytes, adipocytes and beta-pancreatic islets cells.  “Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration(ref).” Some of the properties of these cells are amazing, making them a good platform for a variety of new emerging disease therapies. 

Properties of Mesenchymal stem cells 

·        “MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential(ref).”

·        MSCs inhibit immune response.  “Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions(ref).” MSCs suppress lymphocyte proliferation(ref).   Implications are that MSCs might be useful in treating autoimmune diseases,  and that MSCs could work in treating Graft vs Host Disease (GvHD), a major problem encountered in organ transplantation.

·        Because of their freedom from immune responses, MSCs work fine no matter where you get them.  “ Most interestingly, there was no difference in the response rates or side effects between patients receiving mesenchymal stem cells from third-party mismatched donors compared with those patients receiving cells from HLA-identical siblings or from haploidentical family members(ref).

·        MSCs tend to inhibit the inflammatory response. “Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases(ref).”

·        MSCs prolong the survival of haemopoietic stem cells(ref).

·        MSCs automatically home in on diseased or damaged tissues requiring regeneration.  “It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear(ref).”

·        Arriving at a site having tissue damage and requiring regeneration, MSCs can and “know how to” differentiate into a variety of different types of cell tissues as needed, ranging from heart muscle cells to cartilage osteoclasts, and integrate themselves into a functioning organ so as to renew it.  

·        A 2010 study suggests that one of the communications strategies utilized by MSCs is that they they secrete therapeutic paracrine factors (signaling molecules that affect nearby cells) and also secrete RNA-containing microparticles(ref).

·        There is strong evidence that a number of known medical conditions can be treated with MSCs, and new ones are still being discovered.  “Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction(ref).”

·        Amazingly, Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology.  This means that the MSCs from an old person with osteoarthritis whose knee or hip cartilage is severely eroded by that osteoarthritis can be used to regenerate new cartilage.  “We conclude that, irrespective of age and OA etiology, sufficient numbers of MSCs can be isolated and that these cells possess an adequate chondrogenic differentiation potential. Therefore, a therapeutic application of MSCs for cartilage regeneration of OA lesions seems feasible.”  This will be the subject of another blog post to follow within a few days.

·        Several non-surgical ways are being experimented with for working with MSCs including site injection, topical application possibly with a structure matrix, and injection with substances that accelerate the natural migration of MSCs to a site requiring restoration. “Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo(ref).” 

·        I even speculate that one of the main ways acupuncture could work is by creating minor damage that generates chemical messages that attract MSCs to an injury site requiring attention.

Previous blog posts have highlighted various aspects and other potential applications of MSCs.  See the blog posts Terminator stem cells in the early pipeline, Stem cell differentiation and nanotubes, Trojan-horse stem cells might offer an important new cancer therapy.  The blog post State of autologous stem cell therapies is relevant.  However it is already partially obsolete though only 8 months old.  Also, MSCs can be found in other body locations besides bone marrow, like in teeth.  See the post Dental Pulp Stem Cells – the big needle vs the tooth fairy.

Clinical trials involving Mesenchymal stem cells 

A good sign that  a drug or technology is probably headed for big-time medical use is when it is in several clinical trials.  The following  listing is mostly based in information from www.clinicaltrials.gov, “a registry of federally and privately supported clinical trials conducted in the United States and around the world.”  Clicking on any trial heading will lead you to further information about the objectives, methodology and status of the trial involved.   

1.     Safety Study of Adult Mesenchymal Stem Cells (MSC) to Treat Acute Myocardial Infarction  Also see ref.

2.     A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation

3.     Mesenchymal Stem Cell Transplantation in Decompensated Cirrhosis

4.     Allogeneic Mesenchymal Stem Cell for Graft-Versus-Host Disease Treatment (MSCGVHD

5.     Mesenchymal Stem Cell Infusion as Treatment for Steroid-Resistant Acute GVHD or Poor Graft Function

6.       Prochymal™ Adult Human Mesenchymal Stem Cells for Treatment of Moderate-to-Severe Crohn’s Disease

7.     Safety and Efficacy Study of Umbilical Cord Blood-Drived Mesenchymal Stem Cells to Promote Engraftment of Unrelated Hematopoietic Stem Cell Transplantation (for treating acute leukemia).     

8.  Mesenchymal Stem Cell Infusion as Prevention for Graft Rejection and Graft-Versus-Host Disease (for treating Hematological Malignancies)

9.     Mesenchymal Stem Cells and Subclinical Rejection (related to Organ Transplantation)

10.            Autologous Transplantation of Bone Marrow Mesenchymal Stem Cells on Diabetic Foot

11.   Allogeneic Mesenchymal Stem Cells Transplantation for Primary Sjögren’s Syndrome (pSS)

12.            Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS)

13.            Mesenchymal Stem Cells in Critical Limb Ischemia

14.            The Use of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Articular Cartilage Defects (for treating Degenerative Arthritis; Chondral Defects;  Osteochondral Defects)

15.  Safety and Efficacy Study of Allogenic Mesenchymal Stem Cells to Treat Extensive Chronic Graft Versus Host Disease ((for combined treatment with prednisone and cyclosporine as primary treatment) 

16.            Mesenchymal Stem Cell Transplantation in the Treatment of Chronic Allograft Nephropathy  (for Kidney Transplant; prevention of Chronic Allograft Nephropathy)

17.            Extended Evaluation of PROCHYMAL[tm] Adult Human Stem Cells for Treatment-Resistant Moderate-to-Severe Crohn’s Disease

18.  Autologous Transplantation of Mesenchymal Stem Cells (MSCs) and Scaffold in Full-Thickness Articular Cartilage (for treating Knee Cartilage Defects;   Osteoarthritis)

19.            Evaluation of the Role of Mesenchymal Stem Cells in the Treatment of Graft Versus Host Disease

20.            Mesenchymal Stem Cell for Osteonecrosis of the Femoral Head

21.            Mesenchymal Stem Cells Under Basiliximab/Low Dose RATG to Induce Renal Transplant Tolerance

22.            Intravenous Stem Cells After Ischemic Stroke

23.            Effect of Mesenchymal Stem Cell Transplantation for Lupus Nephritis

24.            Safety and Efficacy Study of Adult Human Mesenchymal Stem Cells to Treat Acute GHVD

This listing may not be complete but should make the point that MSC therapies are probably heading for big-time.  Yet, I need point out that most of these trials are either just getting off the ground or are Phase I studies focused on safety and dosage rather than on efficacy.  And some of the trials could produce negative results and be aborted.  So it may be a while before most of these therapeutic applications are actually integrated in as part of mainline medicine. 

A few of the studies are in or already beyond Phase II, however, and moving along nicely through the pipeline.  The following is from a report in Medical News Today on a Phase II study:  “A phase II multicenter study performed within the European Group for Blood and Marrow Transplantation (EBMT) Mesenchymal Stem Cell Expansion Consortium, shows that mesenchymal stem cells provide a therapeutic potential for the treatment of acute steroid-refractory GvHD (graft-versus-host disease). — Allogeneic stem-cell transplantation is the treatment of choice for many malignant and non-malignant disorders. Severe graft-versus-host disease (GvHD) is a life-threatening complication which could arise following this treatment. Especially if patients with GvHD do not respond to steroids, therapeutic options are limited and the success uncertain. This publication in one of the leading scientific journals opens new exciting possibilities for patients with GvHD. — The study was launched to assess whether mesenchymal stem cells could reduce the risk of GvHD after stem cell transplantation. Between October 2001 and January 2007, 55 patients were treated. From this, 30 patients had a complete response and nine showed improvement. No patients had side effects during or immediately after infusions of mesenchymal stem cells. This response was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. — This phase II study shows that the infusion of mesenchymal stem cells expanded in vitro, irrespective of donor, might be an effective therapy for patients with steroid-resistant, acute GvHD. Most interestingly, there was no difference in the response rates or side effects between patients receiving mesenchymal stem cells from third-party mismatched donors compared with those patients receiving cells from HLA-identical siblings or from haploidentical family members. This finding makes the logistical requirements for this approach more convenient, because the establishment of local banks of mesenchymal stem cells would enable unproblematic and rapid availability of mesenchymal stem cells without the need of HLA typing.”

I am optimistic.  In a follow-up blog post, I will focus on research relating to one specific possible therapeutic role of MSCs – cartilage regeneration, an application for those who are suffering from lost cartilage in their knees, hips or elsewhere, a cure that can be done without need for surgery.  It works even if the patient has ongoing osteoarthritis which caused the problem in the first place.  I believe we are finally entering the new era of regenerative medicine. What incredible good news for longevity!