IL23 inhibition may have niche applications for height growth(Tremfya)

Some questions that have to be answered for Tremfya that have to be answered to see if it influences longitudinal bone growth:

1: Does it inhibit IL-23 in an area that would affect height such as the growth plate, articular cartilage, or intervertebral discs? I don’t think reducing the action of inflammatory cytokines on bone would have any impact on height as we generally want more bone turnover to get more height.

2: Does IL-23 impact height? Is it biphasic where there needs to be an equilibrium amount. In which case Tremfya can help when IL-23 is too high.

According to the study Pro-Inflammatory Cytokines Produced by Growth Plate Chondrocytes May Act Locally to Modulate Longitudinal Bone Growth, inflammatory cytokine inhibition of IL-1Beta and TNF-Alfa increased growth. Inflammatory cytokines can cause chondrocyte apoptosis which too much of is bad but chondrocyte apoptosis is a needed a stage in endochondral ossification. It’s likely that inflammatory cytokines are needed in small quantities so knockout is bad but too much overall decreases height.

IL-23 Inhibits Osteoclastogenesis Indirectly through Lymphocytes and Is Required for the Maintenance of Bone Mass in Mice

“L-23 stimulates the differentiation and function of the Th17 subset of CD4+ T cells and plays a critical role in chronic inflammation. The IL-23 receptor-encoding gene is also an inflammatory disease susceptibility gene. IL-23 shares a common subunit with IL-12, a T cell-dependent osteoclast formation inhibitor, and we found that IL-23 also dose-dependently inhibited osteoclastogenesis in a CD4+ T lymphocyte-dependent manner. When sufficiently enriched, γδ T cells also mediated IL-23 inhibition. Like IL-12, IL-23 acted synergistically with IL-18 to block osteoclastogenesis but, unlike IL-12, IL-23 action depended on T cell GM-CSF production. IL-23 did not mediate IL-12 action although IL-12 induced its expression. Male mice lacking IL-23 (IL-23p19−/−) had ∼30% lower bone mineral density and tibial trabecular bone mass (bone volume (BV)/total volume (TV)) than wild-type littermates at 12 wk and 40% lower BV/TV at 26 wk of age; male heterozygotes also had lower bone mass. Female IL-23p19−/− mice also had reduced BV/TV. IL-23p19−/− mice had no detectable osteoclast defect in trabecular bone but IL-23p19−/− had thinner growth plate hypertrophic and primary spongiosa zones (and, in females, less cartilage remnants) compared with wild type. This suggests increased osteoclast action at and below the growth plate, leading to reduced amounts of mature trabecular bone. Thus, IL-23 inhibits osteoclast formation indirectly via T cells in vitro. Under nonpathological conditions (unlike inflammatory conditions), IL-23 favors higher bone mass in long bones by limiting resorption of immature bone forming below the growth plate.”

IL-23 knockout increases osteoclast action. It’s unclear how this would affect height at skeletal maturity.

“IL-23 is a heterodimeric cytokine structurally related to IL-12.”

“IL-23p19/ male mice develop shorter limb bones than WT:”<-so IL-23 knockout is bad as it reduces height when you’re skeletally immature. The difference in length was 8.6% which is fairly significant.

So if knockout of IL-23 is bad is too much IL-23 good or also bad(and IL-23 is biphasic)?

According to the study Linear growth and bone metabolism in pediatric patients with inflammatory bowel disease, chronic inflammation results in reduced longitudinal bone growth. But there are many inflammatory cytokines involved inflammatory bowel disease, not just IL-23.

According to Bone phenotypes in rheumatology – there is more to bone than just bone, IL-23 can cause bone destruction which may actually be good if you want to grow taller as bone is not capable of interstitial growth. Distraction osteogenesis after all begins with an osteotomy. Also of note in this study is that it’s mentioned that psoriatic osteoarthritis involves ossification of the enthesis. Tremfya is a treatment for psoriatic osteoarthritis. The study also mentions that psoriatic osteoarthritis can result in increased bone formation.

I could not find a direct link between IL-23 and longitudinal bone growth reduction just with inflammation in general. I’m going to conclude that Tremfya if it could be used as a way to increase longitudinal bone growth it is only in very niche cases where inflammation is very high.

It looks like corsets may actually cause plastic bone deformation

This is a huge find because it means that we may actually be able to pull on bones to make them longer.  Now it’s easier to deform bones by bending than it is by pulling on them but bending generates both tensile and compressive forces so you’d have to find a way to bend the bone in two parts at once to balance the compressive forces to achieve length.  Lateral compressive forces are axial tensile forces so this is why something like tapping can be beneficial to achieve length.  Don’t think that sleeping in a “rack” position can achieve this kind of pull the problem is that the pull forces are observed muscle by the muscles and ligaments which only pull the bone at the enthesis(which not surprising is longer and thicker than other parts of the bone), you’d have to find a way to generate pull directly on the bone itself.  Also, consider that sleeping in the rack position could potentially cut off circulation when you’re not awake to do anything about it.

If corsets generated bone shape increase via plastic deformation rather than traditional bone modeling with osteoclast absorption and osteoblast deposition that is a huge find because bone modeling is not likely to result in an increase in length unless osteoblast deposition occurs at the longitudinal ends of bones.

Here’s the citation:

Corsets and Skeletal Deformities: Anthropological Study

“The skeletons of 19th century corseted women were studied to see how their ribcages were flexibly bent into a more tapered shape from the corset. From the photos, you can see literal ‘bends’ in the ribs where the pressure from the corset formed the ribs into the shape of a circle. Also, the spinous processes seemed to be affected too: spinous processes are the small “spikes” humans have on their vertebrae; they look like spikes down a lizard’s back, but in humans these are small and one can occasionally see or feel them as the ‘bumps’ along one’s back. In the skeletons that showed rib shaping from a corset, these same skeletons also had “spikes” in the upper back that bent downward and overlapped like snaggleteeth.”

Corsets are basically lateral compressive loading on the ribs so should generate a minor longitudinal tensile force as well.  it’s not surprising that corsets also generate torsional and rotational forces which explain why the spinous process of the vertebrae were deformed.  But ribs are bent so it would be easier to generate stronger mechanical forces than it would be in straighter long bones.

“Gibson first chose skeletons showing classic deformation of the ribcage from the pressure of the corset (which in O’Followell’s study, pressure from the corset is shown to be measured up to 80psi). The ribs were more circular compared to an anatomically “normal” human ribcage (the “control” ribcage).”  1 psi is about 0.007 MPa.  Or about 0.56 MPa total.

Rickets can also cause deformation of the rib bones “rickets flattens the curves of the ribcage, and most of the ‘bend’ occurs at the costal joints, especially at the sternum (“pigeon chest” is common) – and in extreme cases of rickets, the pressure from one’s own arms laying at the side of the body can cause the ribcage to cave in at each side.”

 A pigeon chest looks longer than a regular chest so if we look at the principles that make a pigeon chest that may translate into longer bones.  Rickets results in less height but more bended bones.

  Since rickets bones would more malleable it would be interesting to try a bone loading deformation routine on someone with rickets.

“In the French [corset] skeletons, instead of seeing “flattened curves”, Gibson noted that the ribcage was more rounded, such that when the dimensions were measured, the coronal (front-to-back) and sagittal (side-to-side) diameters were identical (or close to it). Also, the area of the rib with the greatest bending was closer to the back of the body, not at the sides where the arms would be. Gibson said that formation was seen as high as the 4th rib (imagine right up in the armpit)  and the corset molded each successive rib consistently and uniformly. The floating ribs (11th and 12th) were sometimes affected even more.”

“I found Figure 6 of the article to be of particular interest, where a single pair of ribs shows plastic deformation of the rib (actual bending near the back), a broken area that had healed later in life, and a post-mortem breakage (obviously not healed), showing how different all of them appear.”  Now the usage of the term plastic deformation in the study studied may need indicate that plastic deformation actually occurred it may have been traditional bone modeling rather than mechanical loading resulting in permanent change in shape.

” throughout the thoracic spine, normal spinous processes are already angled slightly downward, although may not necessarily overlap. It would not be impossible for these processes to deform with regular pressure and a predisposition to softer bones,”<-it would be interesting if different shaped and designed corsets would have different affects on the shape of the spinous process.

Something like scoliosis bracing has always thought to only be beneficial during development as as a means to alter spinal development mainly through altering growth via compression and tension on the growth plate.  Something like artificial cranial deformation was thought only to work in the youth.  If something like the corset can change the spine as an adult than maybe bracing can too.

The key step is catabolism.  HGH increases bone turnover which involves both catabolism and anabolism of bone.  So we need to not only stimulate bone growth but bone degradation as well to allow the bone growth to be of a less mature cell type.

mTor: Is Rapamycin good or bad for height growth?

Rapamycin is looked at a lot in longevity research. So if rapamycin helps help height growth then it could be a supplement worth looking into. Previously looking into mtor and rapamycin showed that rapamycin made bone growth slower. However, it is conceivable that rapamycin may make bone growth slower but increase height at skeletal maturity. Although based on the information presented in the study it seems that rapamycin can not increase long bone growth

Look who’s TORking: mTOR-mediated integration of cell status and external signals during limb development and endochondral bone growth

“the role of mTOR signaling in three aspects of tetrapod limb development: 1) limb outgrowth; 2) chondrocyte differentiation after mesenchymal condensation and 3) endochondral ossification-driven longitudinal bone growth. We conclude that, given its ability to interact with the most common signaling pathways, its presence in multiple cell types, and its ability to influence cell proliferation, size and differentiation, the mTOR pathway is a critical integrator of external stimuli and internal status, coordinating developmental transitions as complex as those taking place during limb development.”

“mTOR stands for mechanistic (formerly mammalian) target of rapamycin, a macrolide produced by Streptomyces Hygroscopicus bacteria. Rapamycin was named after the island of Rapa Nui, where it was discovered in the early 1990 s during a genetic screen in the budding yeast, where TOR1 and TOR2 were identified as the toxic agents of rapamycin”

“mTORC1 signaling in the limb mesenchyme is required for the normal size of both the limb bud and its individual cells, but relatively dispensable for skeletal patterning”

“MPs have been shown to induce mTORC1 activation via the ALK3 receptor and Smad4-mediated inhibition of PTEN. mTORC1, in turn, is required for the translational control of SOX9, a key transcription factor in the progression towards cartilage. mTORC1 has been shown to upregulate HIF-1α protein levels in the cartilage, which is critical for the control of glucose metabolism, proliferation and differentiation in chondrocytes”

“mTORC1 inhibition impaired fetal chondrocyte differentiation and response to insulin, but not proliferation. Similarly, genetic deletion of either Mtor or Raptor in the mouse cartilage impaired skeletal growth through reduced matrix production, decreased chondrocyte size and delayed chondrocyte hypertrophy”

“The size of the proliferative zone is controlled by a well characterized negative feedback loop between IHH and PTHrP. In this loop, IHH produced by pre-hypertrophic chondrocytes induces PTHrP expression in resting chondrocytes, whereas PTHrP secreted from the resting zone promotes chondrocyte proliferation and delays differentiation, including Ihh expression. mTOR is likely involved in this feedback loop in two different ways: via mechanotransduction-dependent Ihh expression, and via regulation of PTHrP signaling. Regarding the former, mechanical loading is an important regulator of chondrocyte maturation, and experiments in chicken embryos showed that elimination of muscle contraction results in mTOR inhibition in the cartilaginous growth plate”

“On the other hand, mTORC1 activation has been shown to reduce expression of the PTHrP receptor in articular cartilage, which could potentially happen in the growth plate cartilage as well{perhaps it is thus mechanisms by which rapamycin could potentially increase height at skeletal maturity?}. S6K1, a downstream effector of mTORC1, phosphorylates and allows nuclear translocation of HH-signaling transducer GLI2, leading to transcription of Pthlh, encoding PTHrP. The mTOR/PTHrP interaction also works in reverse. Studies of skeletal dysplasia syndromes characterized by constitutive activation of PTH/PTHrP showed reduced activities of salt inducible kinase 3 (SIK3), which caused accumulation of DEPTOR, in turn inhibiting mTORC1 and 2 activity, biasing skeletal progenitor differentiation towards fat instead of bone. This new PTH/PTHrP-SIK3-mTOR axis has been recently explored further, showing that, in the presence of nutrients, DEPTOR directly interacts with PTH1R to regulate PTH/PTHrP signaling, whereas in the absence of nutrients it forms a complex with TAZ (an effector of the Hippo pathway), to prevent its translocation to the nucleus and therefore inhibit its transcriptional activity”

“Wnt10b overexpression causes enlargement of calvarial tissue and phosphorylation of S6, both of which effects were abrogated by rapamycin”<-obviously we want enlargement so rapamycin in that case is bad.

Interesting paper on how periosteal stem cells impact growth plate development

I’m not sure how this can be applied in practice but since periosteum is on the surface of the bone and it is easier to stimulate the surface of the bone than the interior of the bone this could have some practical implications.  For example, a foam roller could be used to stimulate the periosteum.

Periosteal stem cells control growth plate stem cells during postnatal skeletal growth

“The ontogeny and fate of stem cells have been extensively investigated by lineage-tracing approaches. At distinct anatomical sites, bone tissue harbors multiple types of skeletal stem cells, which may independently supply osteogenic cells in a site-specific manner. Periosteal stem cells (PSCs) and growth plate resting zone stem cells (RZSCs) critically contribute to intramembranous and endochondral bone formation, respectively. However, it remains unclear whether there is functional crosstalk between these two types of skeletal stem cells. Here we show PSCs are not only required for intramembranous bone formation, but also for the growth plate maintenance and prolonged longitudinal bone growth. Mice deficient in PSCs display progressive defects in intramembranous and endochondral bone formation, the latter of which is caused by a deficiency in PSC-derived Indian hedgehog (Ihh). PSC-specific deletion of Ihh impairs the maintenance of the RZSCs, leading to a severe defect in endochondral bone formation in postnatal life. Thus, crosstalk between periosteal and growth plate stem cells is essential for post-developmental skeletal growth.”

“After four weeks of the PSC deletion, the mice exhibited an impaired periosteal bone formation with a compensatory increase in endosteal bone formation”<-this is interesting as it means that the bone compensates in growth in a mechanism in which it is not impaired.

“Ihh was among the genes highly specific to PSCs and is known to be involved in the regulation of endochondral bone formation”<-so then an interesting study would be to compensated for PSC deletion via increasing IHH levels and see how much that rescues the impaired bone formation of the PSC deletion phenotype.  According to the study osteoclasts were not impacted so we know that inability to remodel is not one of the factors.

“During development, growth plate-derived Ihh acts on cells in the periosteum/perichondrium, leading to the activation of PTHrP expression in the periarticular chondrocytes through a poorly understood mechanism. PTHrP then maintains chondrocytes in a proliferative, less differentiated state and inhibits the production of Ihh from the growth plate. This Ihh/PTHrP loop coordinates the synchronized chondrocyte differentiation in the growth plate during early life stages”<-manipulation of IHH-PTHrP production may be able to manipulate height but it is unlikely to totally be able to do it due to other factors like for example of other nutrients required for the growth plate to grow and eventually the cells will no longer be able to divide due to things like methylation and telomeres etc.

 

Your gut microbiome may have an impact on how tall you grow

Thus, during development it may be important to optimize your gut microbiome via possibly avoiding antibiotics, modifying diet, etc.  This also means that there is the possibility of modification of the microbiome via transfer, etc.  Although there doesn’t seem to be any clear degree of optimization as of yet.

The microbiome: A heritable contributor to bone morphology?

“Bone provides structure to the vertebrate body that allows for movement and mechanical stimuli that enable and the proper development of neighboring organs. Bone morphology and density is also highly heritable. In humans, heritability of bone mineral density has been estimated to be 50–80%. However, genome wide association studies have so far explained only 25% of the variation in bone mineral density, suggesting that a substantial portion of the heritability of bone mineral density may be due to environmental factors. Here we explore the idea that the gut microbiome is a heritable environmental factor that contributes to bone morphology and density. The vertebrae skeleton has evolved over the past ~500 million years in the presence of commensal microbial communities. The composition of the commensal microbial communities has co-evolved with the hosts resulting in species-specific microbial populations associated with vertebrate phylogeny. Furthermore, a substantial portion of the gut microbiome is acquired through familial transfer{so what the mother eats during pregenancy may affect a childs height}. Recent studies suggest that the gut microbiome also influences postnatal development. Here we review studies from the past decade in mice that have shown that the presence of the gut microbiome can influence postnatal bone growth regulating bone morphology and density. These studies indicate that the presence of the gut microbiome may increase longitudinal bone growth and appositional bone growth, resulting differences cortical bone morphology in long bones. More surprising, however are recent studies showing that transfer of the gut microbiota among inbred mouse strains with distinct bone phenotypes can alter postnatal development and adult bone morphology. Together these studies support the concept that the gut microbiome is a contributor to skeletal phenotype.”

“The majority of the mammalian microbiome is present in the gastrointestinal system. The mammalian gut microbiome consists of hundreds of distinct microbial species (bacteria, archea, viruses, single celled eukaryotes) interacting with one another and with host cells at the gut endothelial barrier. The body is first colonized by microbes soon after birth. Over the first few years of life the composition of the gut microbial community fluctuates considerably until achieving a relatively stable composition”

“The gut microbiome is also heritable: maternal transfer of the microbiome soon after birth is among the most influential contributors to the establishment of the gut microbiome; and later in life components of the gut microbiota are transferable through close contact such as that occurring within households and due to familial dietary habits. The composition of a mature gut microbiota can fluctuate on an hourly or daily basis due to variations in diet. However, the overall composition of an established gut microbiota are robust to perturbations; the vast majority of the microbial composition returns to its prior state following a mild or temporary perturbation. Hence, the composition of the gut microbiota is partially heritable and, once established, does not change substantially without a large or prolonged stimulus. That the gut microbiota is established at an early age suggests that heritable components of the gut microbiota may contribute to the patterns of bone mass accrual that determine adult bone morphology and density.”

“most bacteria associated with vertebrates reside in the gastrointestinal tract, where densities can reach ~1011 cells per milliliter, yet relatively few of the constituents of this gut microbiota are known to cause disease in their hosts.”

“the composition of the gut microbiota can be influenced by environmental variation, including host diet, geography, and temperature ”

“transplantation of gut microbiota from Gairdner’s shrewmouse (Mus pahari) into germ-free house mice stunts host growth rate relative to transplantation of house-mouse gut microbiota”

“The ability of the gut microbiome to influence bone morphology has been recognized since the first animal studies of oral antibiotics in the 1920–30s which reported alterations in whole body growth as well as bone length and morphology following chronic oral antibiotic dosing”

According to Identifying Components of the Gut Microbiome that Regulate Bone Tissue Mechanical Properties, disruption in the gut microbione results in a femur length reduction.

“the absence or depletion of the gut microbiota, while potentially influencing the acquisition of trabecular bone at the growth plate, likely has little effect on the amounts of trabecular bone present at skeletal maturity.”

“Schwarzer and colleagues found that young (two month-old) germ-free mice were much smaller than conventionally raised mice in terms of whole body mass, whole body length, whole bone length and femoral cortical area”

“Yan and colleagues found that adult (10 month old) germ-free mice had smaller endosteal and periosteal diameter at the femur midshaft and shorter whole bone length in adulthood than mice that had been conventionalized at two months of age, in part leading to their conclusion that exposure to the gut microbiota leads to a net increase in bone acquisition during life. Guss and colleagues and Luna and colleagues found that disruption (but not decimation) of the gut microbiota in mice using narrow spectrum antibiotics from 1 to 4 months of age was associated with small but significant reductions in femur length “

What is the mewing equivalent for other parts of the body?

Mewing is basically putting the tongue on the roof of the mouth.    Now does the force of the tongue actually push the maxilla forward advancing it over time?  It’s possible.  But I think the majority of the benefits of mewing are due to the fact that actively putting the tongue on the roof of the mouth achieves lateral pterygoid muscle activation.   You see it’s been shown in orthodontal work via forced mouth opening and bite jumping appliance that lateral pterygoid muscle activation can simulate cartilage and endochondral ossification of the mandibular condyle.

The lateral pterygoid muscle attaches directly to the cartilage and by stimulating and activating by placing the tongue on the roof of your mouth you’re constantly pulling on the cartilage throughout the day.  Now it’s possible that mewing also has other benefits.  But if a large portion of mewings benefits are due to the lateral pterygoid muscle activation then it doesn’t matter if you’re mewing if you’re instead doing something else that activates the lateral pterygoid muscle such as talking or chewing.  But placing the tongue on the roof of the mouth is is something that can be done during sleep and I have successfully done this during sleep.  Thus your cartilage can be stimulated more frequently.

So, to apply the mewing principle to the other parts of the body?   How do we make alterations in posture and position such we can stimulate cartilage and growth throughout the day?

Chest up, shoulders back.  Shoulders back activates the upper back muscles.  Chest up activates the lower back muscles.  Now you don’t have to do this in a ridiculous way.  You just have to do enough so that the muscles are activated.  If if you at the the above pictures you see that most of the back muscles are angled upward so if you achieve muscle contraction it will pull all the spinal components upward too.

Now you may think if I round my shoulders forward and round my back that will stretch the back components too?  But if you do that the back will be stretched in an an unnatural way and out of alignment?  ie. scoliosis.  Like I said the muscles are already slanted and will pull upward if activated and it will pull in proper alignment.

If you want better results than get stronger back muscles(stronger lateral pterygoid muscle for the jaw).   Unfortunately, the back muscles do not attach directly to the cartilage but they do attach to soft tissues that will indirectly pull on the spine.  You can’t really mimic this with a back device you really want to do it yourself to achieve back muscle activation.

Now height gains won’t be much but a lot of people sit down for a lot of the day and don’t have good posture.  On an individual level the height gains probably won’t be significant(unless you have incredibly strong back muscles) but if everyone did it there would probably be small significant height gains.

If you’re worried about looking ridiculous then just find the minimal amount to pull your shoulders back and your chest up to achieve back muscle activation,  Ideally you’d want to sleep in this posture so your muscles pull while you sleep to.  So you would sleep on your back with your shoulders back and your back slightly arched.  Now you’re trying to sleep so you want to find the minimal amount of effort you can do to do this.  It cannot be achieved with a device as that will reduce muscle activation.

So think tongue on the roof of your mouth, shoulders back, chest up(or back arched).  Ideally while you sleep too.