Growth plate cellular senescence preceeds epiphyseal fusion.  It is the reason why people stop growing.  If we stop cellular senescence we can keep growing.  And this study states that stem cell growth is not based on demand.  Demand for stem cells too high to be kept up with may lead to cancer growth.  However, supplements, reduction of environmental stressors, and mechanical loading may be some ways to stimulate stem cell health and renewal.  The key to LSJL success on restoring growth renewal may be based on it’s ability to stimulate stem cell proliferation and impair cellular senescence.  As this study suggests that microcracks that occur during old age increase the demand for stem cells but the body doesn’t generate new stem cells or increase proliferation to compensate.  However, unlike microcracks due to degradation LSJL places forces directly on the cells themselves.  I will be posting some updates on the LSJL method as soon as the comments section is up(after Michael has resolved some legal issues).

Age-specific bone tumour incidence rates are governed by stem cell exhaustion influencing the supply and demand of progenitor cells

“Knudson’s carcinogenic model, which simulates incidence rates for retinoblastoma, provides compelling evidence for a two-stage mutational process. However, for more complex cancers, existing multistage models are less convincing. To fill this gap, I hypothesize that neoplasms preferentially arise when stem cell exhaustion creates a short supply of progenitor cells at ages of high proliferative demand. To test this hypothesis, published datasets were employed to model the age distribution of osteochondroma, a benign lesion, and osteosarcoma, a malignant one. The supply of chondrogenic stem-like cells in femur growth plates of children and adolescents was evaluated and compared with the progenitor cell demand of longitudinal bone growth. Similarly, the supply of osteoprogenitor cells from birth to old age was compared with the demands of bone formation. Progenitor cell demand-to-supply ratios are a good risk indicator, exhibiting similar trends to the unimodal and bimodal age distributions of osteochondroma and osteosarcoma, respectively. The hypothesis also helps explain Peto’s paradox and the finding that taller individuals are more prone to cancers and have shorter lifespans. The hypothesis was tested, in the manner of Knudson, by its ability to convincingly explain and demonstrate, for the first time, a bone tumour’s bimodal age-incidence curve.”

“Osteochondroma is the most common benign bone tumour, occurring as an abnormal osteocartilaginous outgrowth of the epiphyseal growth plate with a low rate (≤2%) of malignant transformation to secondary chondrosarcoma”

“In adolescents, growth plate senescence is followed by epiphyseal fusion when osteochondroma stop growing.”

“Osteosarcoma is the most common primary bone malignancy (excluding multiple myeloma), originating from the transformation of aberrant bone-forming mesenchymal stem cells (MSC), also known as marrow stromal cells”

“Differentiation is impaired by replicative senescence”

“Post-natal stem cell replication leads to telomere shortening in somatic tissues, as telomerase activity in humans is not at sustaining levels. At the Hayflick limit of cell division, telomeres reach a critical length, triggering cells to become senescent or apoptotic. A recent publication provides quantitative evidence that soft tissue organ mass loss in humans aged 25–70 is significantly associated with the log of shorter cell turnover times, implicating stem cell exhaustion and replicative senescence in normal ageing”

“MSC, like other stem cells, have been observed to have a self-renewal and proliferative capacity that diminishes with age, and that is regulated by different pathways, such as antioxidant defence, DNA repair, and protein turnover, before entering a senescence-associated proliferation arrest”

“There is a normal trade-off for a stem cell to self-renew or produce differentiated and differentiating progeny. High stem cell demand relative to supply appears to produce stem cell progeny with stopped differentiation but with self-renewal properties, perhaps triggered by senescent cell secretions”

Here’s a graph describing the stem cell pool:

“A good marker of the skeletal demand for osteoprogenitors involved in bone formation (as opposed to osteoclast bone resorption activity) is serum BALP activity. This marker is particularly sensitive to physiological changes such as adolescent growth spurt and menopause. The demand for progenitor cells participating in bone formation, as measured by BALP activity, is highest in newborns, slowly declines until early adolescence in girls and late adolescence in boys, then decreases rapidly to its lowest level in young adults, before increasing again in the latter half of adulthood to cope with the decline in osteocyte density and repair of accumulated damage related to ageing, e.g. bone microcracks”

“senescent cells can arise due to “epigenetic senescence” (initiated by histones altering activity of genes), stress-induced senescence or replicative senescence”<-Stress-induced sensescence is the easiest to avoid and epigenetic senescence can be affected by supplements.  Replicative senescence may be influenced by mechanical loading.

“cell proliferation is not in itself a risk factor for tumogenesis; instead, neoplastic promotion or progression occurs preferentially when, for example, stem cell exhaustion creates a short supply of progenitor cells at ages of high mitogenic demand.”

” Ionizing radiation exposures produce free radicals and reactive oxygen species that excite a high proliferative demand on MSC involved in inflammation and subsequent fibrosis. When bone marrow is subjected to a high dose, there is an increase in expression of the ageing and senescent cell biomarker p16INK4a reducing the capacity for stem cell renewal and, consequently, causing a decline in cellularity commensurate with premature ageing”

Alexander Teplyashin Explains How To Regrow Severed Fingers

I have talked before how there are already at least two research professors and teams in universities in the United States who have developed ways to regrow severed fingers. One of them developed this unique blend of “stem cell pixie dust” which is sprinkled like grounded pepper over the wound area of a severed finger. As much as the entire distal area of a finger can be cut off but the stem cell pixie dust would still work. Refer to the much older post “The Fingertips Of Young Human Children Can Regenerate If The Wound Is Not Closed And A Blastema Can Form” for more information. Others have figured out which genes are turned on when say a finger or arm of a salamander is cut off and the amphibian starts to regenerate their limbs back.

It seems that our old friend the plastic surgeon Alexander Teplyashin has also been getting in on the field. He know how to regrow finger bones and make them longer.

(BTW: I have seen this type of thing being advertised in the Subway Stations in Gangnam Station in Seoul, South Korea when I was living there too. There would be these posters showing how the plastic surgeon company managed to correct their patients bow leggedness and how they figured out how to lengthen a finger bone with almost no surgery.)

Not only that, Teplyashin seems to be using a minimally invasive type of ilizarov distraction device. It looks similar to design and idea as what the Chinese Limb Lengthening Orthopedic Surgeon Dr. Bai Helong talked about back in 2010 about his rather original redesign of the older circular type external fixator model perfected back in the 80s in the former Soviet Union. 

You can see what the design of the new limb lengthening device looked like on the website news aggregator website entitled “Chinese doctor pioneers height-increase surgery“

Notice how the distractor used by Teplyashin for bone lengthening is quite minimally invasive. We will be posted up something relevant to it in the coming days.

Note: To figure out where I am getting this information from go to the Russian/Cyrillic Based websites like Yandex.com or Rambler.Ru and type in the term александр тепляшин кость

кость is the cyrillic term for “bone” and хрящ is the cyrillic term for “cartilage”. Play around with it on the russian based search enginer Yandex.com to see what you guys can find on this guy. I’ve already found 4-5 different Russian based patents on this guy which I have translated using Google translator to see what he has been up to. Also search for his research partners Korjikoff Svetlana and this other person who I forgot the name of currently . I am guessing that it is the female researcher that shows up right next to Teplyashin’s name who is the real brains of the work. I found her Ph. D Thesis and the subject is on stem cell work. In comparison, Teplyashin’s Ph.D Thesis was on the prevention and treatment of septic complications that results from sugery. (Refer to the link here) 

Nate Robinson’s New Book “Heart Over Height” Reveals How To Deal With Heightism and Discrimination

I found out that Nate Robinson, who is one of the shortest players in the NBA, released his own book about his trials and tribulations recently. It is called “Heart Over Height“. I might have found out about the book from some online news aggregator but it gives a lot insight about how he at just around 5′ 9″ has had to compete and deal with the amount of “hate” and discrimination he has met choosing the career he has and being the size he is at.

The classical American hero story has always been about how the smaller guy managed to triumph over the larger, more dominant opponent and Nate’s story is a good example of it.

This last few days I have been out of town on an outdoors retreat with no laptop so I just picked up the book off of Amazon using the itunes app on my iphone at just $3.50 for Kindle just to see what this average sized man can tell us about how to deal with the internal issues that one might have from always being around people much bigger than him.

The thing is that Nate is not really short. He might be slightly below average when compared to the Average Caucasian Male these days, which is probably around 5′ 10″, but he is not that small. It is his chosen work that puts him in the type of unique situation (which he is forced to deal with internal issues over an aspect on who he is which he can’t control) every day. It is mentioned that his father is 6′ 1″ so he expected to be at least as big as his dad but that didn’t happen.

I do feel bad for the guy, since he didn’t get that 2nd big growth spurt that he hoped for. He has been 5′ 9″ since the age of 15-16.

Then again, we can’t all be 6′ 8″ like Lebron James. For every person who is blessed with the genetic lottery, 9 other person will loss out. It just means that for the people who weren’t so lucky at birth, we are forced to work much harder to get to where we want in life, just to break even with the luckier ones.

I will just quote some study (which everyone uses but can’t find the original study from) which said that for men, for every inch that they increase in height, they will earn about $800 more per year. Of course that is only in the area of life known as professional life. When it comes to our personal lives, it is much, much worst.

Yes, it is NOT FAIR. Yes, there is of course some type of double standard. Yes, there is an unequal distribution of reward to effort ratio when we compare the top 1% to the rest on the bottom, but that there is little that most of us can do about it. We are all sort of waiting for a Superman, who can rise up and save us from ourselves. Most of us feels so powerless to make the sweeping, all pervasive decisions which can really make a huge change in the world. Sure, some people like Kim Jung Un being dictators can change the little nation that they completely rule over but most of us don’t have that type of power.

I do read Reddit and the subreddit groups (like r/short) so I have an idea on what they talk about. This book might really help some people who are on those groups and want some type of light reading material to help get more validation or feedback on the issues they might have on being below average in height. There is not going to be any solutions, but it might be a good motivation and gives some inspiration. (You can read the summary of it here)

What 7 Feet Tall Isaiah Austin Having Marfan Syndrome Suggest To Professional Basketball Players

So I was not able to write much in the last 2 weeks due to a combination of issues: legal, technical, and health related. Hopefully most of those issues have been resolved.

The news that is making the rounds in the NBA and the basketball world in the last 2 days is that Current Baylor University’s Basketball Center and NBA Draft hopeful Isaiah Austin was diagnosed with Marfan’s Syndrome. It might be surprising news for some people but for people like me, it was almost sort of expected.

I became aware of Austin for a couple years now since I am a fan of basketball. It is always interesting to see what types of players are coming up in the annual NBA Drafts. Austin was a potential game changer for the NBA team who would draft him for his amazing length. When I first saw this kid, who was obviously tall, it did strike me as a little strange that a person would be as skinny as him, even for the ectomorphic body shape of most professional basketball players. Add in the fact that he always wore plastic goggles, and it just made him look slightly strange. It would turn out that he lost the use of one of his eyes in recent years due to a detached retina stem.

I have been aware of Marfan Syndrome for a long time, ever since I was doing research on the various genetic pathologies which can lead to tall stature like Klinefelter Syndrome, Ehlers Danlos Syndrome, Proteus Syndrome, the condition affecting the late Siah Khan and Zech Devits,  and Marfans and found pictures and threads on TheTallestMan.com forums suggesting that Abraham Lincoln most likely had Marfan Syndrome. Lincoln was shown to have the average length of torso but his legs and arms were very disproportionally long. When Lincoln would sit down, his sitting height would be the same as most men of his time.

If I paid more attention to the videos on Isaiah Austin and how his body looked, I would have been able to diagnose him within a minute of having Marfan. However, since he is not playing professional sports yet, there was only a small handful of videos on this kid.

His body shape is similar to what we see in other super sized humans like Mamadou N’Diaye and Shagari Alleyne, who have more than just height but also unusually long wingspans. While N’Diaye has been diagnosed only this year with having an overactive pituitary gland condition, I am not sure if anyone has checked Alleyne yet. There are people who are tall from genetics and others who have become large due to a medical condition or genetic mutation.

It is a good thing that at least these days all prospects who want to play professional basketball are required to also get a full body physical and even blood work done to check for some hidden/unknown genetic predisposition towards some type of illness. Marfan Syndrome is one of those illnesses which are a type of silent killer. The syndrome causes connective tissue to be lossened, thus the extra height, but also the muscle tissue around the body.

The general medical concern is that the muscles that makes up the arteries and/or aorta is enlarged. If the body of the player playing a high intensity level physical stressful game gets pushed too much, that region of the heart can actually rupture, instantly killing the person from the loss of blood and internal bleeding.

Apparently Austin went to get an standard EKG (Electro Cardio Gram) and there seemed to have been some type of abnormality in the rhythm of the heartbeat noticed on the graph. Further tests showed he had marfan.

What all this news indicates is that there is a very good chance that a shocking high percentage of the people who player professional basketball have marfan syndrome, and they just don’t know it.

Generally, people who are above average in height are pushed into playing the sport. I would suspect that maybe even 1 out of 100 people who play professional basketball of any team in any country suffer from the disorder, but they just don’t realize it. This news that has come out should be a sign that people who notice that maybe their body is ectomorphic or have a very thin torso should get themselves checked out. They don’t have to be 7 feet tall like Austin but if they have that unique body shape, it would be a good sign to do something. The regular checkup with the GP (General Practitioner) is not enough since the family doctor and the nurses using even the best regular stethescope or Sphygmomanometer would be able to catch a heart murmur or rhythm irregularity.

Predicting and Validating the Pathway of Wnt3a-Driven Suppression of Osteoclastogenesis.

“we examined Wnt3a-driven regulation of osteoclast development. Mouse bone marrow-derived cells were incubated with RANKL in the presence and absence of Wnt3a. Using microarray mRNA expression data, we conducted a principal component analysis and predicted transcription factor binding sites (TFBS) that were potentially involved in the responses to RANKL and Wnt3a. The principal component analysis predicted potential Wnt3a responsive regulators that would reverse osteoclast development, and a TFBS prediction algorithm indicated that the AP1 binding site would be linked to Wnt3a-driven suppression. Since c-Fos was upregulated by RANKL and downregulated by Wnt3a in a dose-dependent manner, we examined its role using RNA interference. The partial silencing of c-Fos suppressed RANKL-driven osteoclastogenesis by downregulating NFATc1, a master transcription factor of osteoclast development. Although the involvement of c-Myc was predicted and partial silencing c-Myc slightly reduced the level of TRAP, c-Myc silencing did not alter expression of NFATc1. Collectively, the presented systems-biology approach demonstrates that Wnt3a attenuates RANKL-driven osteoclastogenesis by blocking c-Fos expression and suggests that mechanotransduction of bone alters the development of not only osteoblasts but also osteoclasts through Wnt signaling.”

LSJL upregulates c-Fos.  In all likelihood LSJL alters Wnt3a expression but there wasn’t any evidence in the LSJL gene expression study.  Fluid flow upregulates Wnt3a and LSJL does involve fluid flow although this was only in osteocytes and we’d want to know the effects on stem cells or chondrocytes for height growth purposes.  No evidence that LSJL alters Nfatc1 expression but it likely does and Salubrinal alters Nfatc1 expression.  According to a diagram, from that study LSJL would increase Nfactc1 expression but it reduces levels of phosphorylated eif2a.

“Wnt5a activates noncanonical Wnt signaling through a receptor tyrosine kinase-like orphan receptor and stimulates osteoclastogenesis. Wnt10b is required for maintenance of mesenchymal progenitors, and its deficiency leads to loss of bone mass. Wnt14 enhances endochondral ossification and accelerates chondrocyte maturation”<-Wnt14 may alter height.  However, Wnt14 does suppress chondrogenic genes and I couldn’t find any studies stating that Wnt14 transgenes or knockout causes overgrowth or undergrowth.  Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males., says that Wnt10b may have an effect on height but more testing needs to be done.

“Mouse bone marrow cells isolated from long bones (femur and tibia) as well as RAW264.7 mouse pre-osteoclast cells [were used in the study]”.  If mouse bone marrow cells were used it may have ramifications for how stem cells are affected by stimuli and finding the right stimuli is the key for height growth.

“Administration of RANKL to bone marrow cells significantly increased the number of TRAP-positive multi-nucleated cells{osteoclast cells are trap-positive}. In response to 100 or 200 ng/ml of Wnt3a, the number of TRAP-positive cells was reduced in a dose-dependent manner. The observed suppression of osteoclast development by Wnt3a was associated with a decrease in the phosphorylated form of β-catenin (p-β-catenin) as well as NFATc1 ”

“Wnt3a-induced reduction of the relative mRNA expression levels of the genes (NFATc1, TRAP, OSCAR, MMP9, and cathepsin K) linked to osteoclastogenesis on days 1 and 2 in bone marrow cells”<-Note that none of these levels were lower than control(The cells that were not exposed to RANKL) and the reduction was dose dependent until at least 200ng/ml.

Wnt3a downregulates C-Fos and C-Fos may be an important part in LSJL induced growth.

Wnt3a upregulated Egr1, Notch1, and Tgif1 at greater levels than control so excess levels of Wnt3a may have an effect on stimulating on those genes even without altering cells exposed to RANKL.  It downregulated Hmga1, Smad3, Dnmt3a, and Bach1 versus control.  Smad3 is involved in TGF-Beta induced chondrogenesis.  Dnmt3a promotes DNA methylation.

RECENT RESEARCH ON THE GROWTH PLATE: Mechanisms for growth plate injury repair and potential cell-based therapies for regeneration

“[The growth plate] functions to produce a mineralised cartilaginous scaffold to which new trabecular bone is formed via a tightly controlled two-step process (called endochondral ossification) involving chondrogenesis and osteogenesis ”

“The resting zone has previously been thought to play a very minimal role during endochondral ossification as the pre-chondrocytes/cells within this zone proliferate minimally. However, studies have indicated the importance of the resting zone as it acts as a reservoir of stem cells/pre-chondrocytes for the chondrocytes in the adjacent proliferative zone”

“The proliferative zone is responsible for matrix production (including collagen-2 and aggrecan) and cellular division during endochondral ossification. The height of the proliferative zone directly correlates with the extent of longitudinal growth that can be achieved by the long bone. As regulated by various signalling pathways including parathyroid hormone-related protein, insulin-like growth factor (IGF1), bone morphogenic protein (BMP), Wnt/B-catenin, fibroblast growth factor (FGF) and others , chondrocytes cease to proliferate and become hypertrophic. The hypertrophic chondrocytes produce collagen-10 which is involved with matrix mineralisation. Together with the action of angiogenic factor vascular endothelial growth factor (VEGF) produced by hypertrophic chondrocytes and a low oxygen tension, the lower hypertrophic zone attracts blood vessel invasion from the adjacent metaphyseal bone, which brings along mineralised cartilage-resorptive cells (chondroclasts), bone-forming cells (osteoblasts) and bone-resorptive cells (osteoclasts) to convert the mineralised cartilage scaffold into trabecular bone in metaphysis.”

“The initial inflammatory response involves an influx of key inflammatory cells into the growth plate injury site and up-regulation of inflammatory cytokines/mediators and some growth factors (A). The fibrogenic phase involves an influx of fibrogenic and progenitor cells containing MSC-like cells (B). The osteogenic phase involves the osteogenic and chondrogenic differentiation, formation of bony trabeculae together with angiogenesis within the injury site (C). The remodelling phase involves the maturation and active remodelling of the newly formed bony trabeculae as well as disappearance of cartilaginous repair tissue (D).”<-Cinc1 is also known as IL8 or CXCL1{Which is upregulated by LSJL}

“neutrophil-mediated inflammatory response was found to modulate downstream injury repair events. Following the depletion of neutrophils with a neutralising antibody, an increase in the undesirable bony repair tissue [occurred] with increased expression in bone-related genes such as Runx2 and osteocalcin, but decreased expression in cartilage-related genes Sox9 and collagen-2 ”

“Blocking TNFa resulted in a clear delay in the subsequent mesenchymal infiltration response and a reduction of the proliferation of these cells”

“At the growth plate injury site, some of these cells were found to express growth factors including BMPs, platelet-derived growth factor (PDGF) and FGF2 and receptors for BMPs and PDGF. In addition, some of these cells were found to be MSC like as they expressed the stem cell marker alpha-smooth muscle actin{acta2 which is upregulated by LSJL}”

“this influx of mesenchymal cells may contain a myriad of cells including MSC-like cells, osteoprogenitor cells, pre-osteoblasts, and/or pre-chondroblasts (either pre-existing or newly derived from the infiltrated MSCs).”

“significant peak in the mRNA expression of platelet-derived growth factor (Pdgf) and fibroblast growth factor 2 (Fgf2){up} following the initial inflammatory phase, suggesting a potential regulatory role for these two growth factors during this phase”

“In rats with growth plate injury, the inhibition of PDGF signalling caused a significant reduction in the amount of mesenchymal infiltrate, decreased amounts of bony and/or cartilage repair tissues, and thus an overall delay in bony repair 14 days post-injury”

“At the injured growth plate, bone formation has been observed to commence around day 7 with the appearance of bony trabeculae, and bone remodelling has been observed by day 14 with the appearance of bone marrow cells in between bony trabeculae”

“During the osteogenic phase of the growth plate injury repair process, the cells within the fibrogenic infiltrate differentiate into Runx2 and alkaline phosphatase-immunopositive osteoblasts and produce increased levels of bone matrix protein osteocalcin (both mRNA and protein) during days 8–14”

“after a ‘fibrous tissue’ is formed from the infiltrated stromal cells at an injured growth plate, its invasion by new blood vessels is a prerequisite for its osseous transformation”

“the absence of VEGF delayed bone formation by halting the initial soft callus from being converted into hard bony callus. ”

“osterix over-expression can induce bone healing”

“PKD up-regulates osterix and [is] important for osteoblast differentiation. Inhibition of PKD suppressed bony repair but induced more chondrogenic differentiation at the injury site”

“over-expression of osterix in osteochondroprogenitor cells resulted in a decrease in chondrogenic transcription factor Sox9.”

“In a rat tibial drill hole growth plate injury model, levels of Bmp2 mRNA expression were found notably increased in the early part of the fibrogenic phase and then again later during the osteogenic phase”

“synovium-derived MSCs in particular had the greatest capability to enhance the chondrogenic differentiation potential when compared with any other mesenchymal tissue-derived cells. However, other studies have reported that bone marrow-derived MSCs (BMMSCs) are most suitable for cartilage tissue engineering, as they possess higher proliferation rates and higher levels of expression of cartilage-specific genes, when compared with MSCs derived from other tissues”

“MSCs were successfully isolated directly from murine epiphysis.  This novel type of MSCs could potentially be better than BMMSCs as they have shown greater capacities in growth and differentiation potential as well as possessing immunosuppressive and anti-inflammatory properties”