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.

Osteoperosis study with resistance and impact training shows height gain

There a few possibilities as to why the height gain occurs:

  1. Improvement in posture
  2.  Increase in bone density reducing bone compression
  3.  Longitudinal bone growth

High‐Intensity Resistance and Impact Training Improves Bone Mineral Density and Physical Function in Postmenopausal Women With Osteopenia and Osteoporosis: The LIFTMOR Randomized Controlled Trial

“Optimal osteogenic mechanical loading requires the application of high‐magnitude strains at high rates{I’m not sure this is the case given fluid flow models}. High‐intensity resistance and impact training (HiRIT) applies such loads but is not traditionally recommended for individuals with osteoporosis because of a perceived high risk of fracture. The purpose of the LIFTMOR trial was to determine the efficacy and to monitor adverse events of HiRIT to reduce parameters of risk for fracture in postmenopausal women with low bone mass. Postmenopausal women with low bone mass (T‐score < –1.0, screened for conditions and medications that influence bone and physical function) were recruited and randomized to either 8 months of twice‐weekly, 30‐minute, supervised HiRIT (5 sets of 5 repetitions, >85% 1 repetition maximum) or a home‐based, low‐intensity exercise program (CON). Pre‐ and post‐intervention testing included lumbar spine and proximal femur bone mineral density (BMD) and measures of functional performance (timed up‐and‐go, functional reach, 5 times sit‐to‐stand, back and leg strength). A total of 101 women (aged 65 ± 5 years, 161.8 ± 5.9 cm, 63.1 ± 10.4 kg) participated in the trial. HiRIT (n = 49) effects were superior to CON (n = 52) for lumbar spine (LS) BMD (2.9 ± 2.8% versus –1.2 ± 2.8%, p < 0.001), femoral neck (FN) BMD (0.3 ± 2.6% versus –1.9 ± 2.6%, p = 0.004), FN cortical thickness (13.6 ± 16.6% versus 6.3 ± 16.6%, p = 0.014), height (0.2 ± 0.5 cm versus –0.2 ± 0.5 cm, p = 0.004){0.2 cm is pretty significant.  If the gain is due to posture then wouldn’t the low intensity exercise program gain posture as the low intensity group would also build functional strength?}, and all functional performance measures (p < 0.001). Compliance was high (HiRIT 92 ± 11%; CON 85 ± 24%) in both groups, with only one adverse event reported (HiRIT: minor lower back spasm, 2/70 missed training sessions). Our novel, brief HiRIT program enhances indices of bone strength and functional performance in postmenopausal women with low bone mass. Contrary to current opinion, HiRIT was efficacious and induced no adverse events under highly supervised conditions for our sample of otherwise healthy postmenopausal women with low to very low bone mass.”

One thing to consider is that there may be a load threshold for bone strengthening.  Since the women were so weak 85% of 1RM was needed to get above the load but for a stronger individual a smaller percentage of the 1RM may theoretically be needed.

” Resistance exercises (deadlift, overhead press, and back squat) were performed for the remainder of the intervention period in 5 sets of 5 repetitions, maintaining an intensity of >80% to 85% 1 RM. Participants performed up to 2 sets of deadlifts at 50% to 70% of 1 RM to serve as a warm‐up, as required. Impact loading was applied via jumping chin‐ups with drop landings. Participants were instructed to grasp an overhead bar with their shoulders and elbows flexed to 90 degrees, and their hands shoulder width apart with an underhand grip. The participant then jumped as high as possible while simultaneously pulling themselves as high as possible with their arms. At the peak of the jump, the participant dropped to the floor, focusing on landing as heavily as comfortably possible. Each exercise session was performed in small groups with a maximum of 8 participants per instructor, who was an exercise scientist and physiotherapist.”

I’m not sure if impact loading would be superior to tapping.  Tapping applies the load directly to the bone and whole body impact can damage soft tissue(although so can tapping).  I feel it more in the bone when tapping than whole body impact.

“Participants allocated to CON undertook an 8‐month, twice‐weekly, 30‐minute, home‐based, low‐intensity (10 to 15 repetitions at <60% 1 RM) exercise program designed to improve balance and mobility but provide minimal stimulus to bone. The CON program consisted of walking for warm‐up (10 minutes) and cool down (5 minutes), low‐load resistance training (lunges, calf raises, standing forward raise, and shrugs) and stretches (side‐to‐side neck stretch, static calf stretch, shoulder stretch, and side‐to‐side lumbar spine stretch). The intensity of resistance exercises was progressed from body weight to a maximum of 3 kg hand weights for the final month of the program.”<-I think this exercise regime would improve posture.  But if you look at table 2 this group lose 0.2cm of height.  Although if you look at the back extensor strength increase in table 5 the amount is far more in the high intensity group which would look to posture.

“Although not originally a primary outcome measure, we observed that HiRIT improved stature compared with CON. The observed improvement in stature after HiRIT is likely to be a consequence of increased BES(back extensor strength), as BES is inversely associated with magnitude of kyphosis. Our results add support to the findings of other exercise intervention studies that have demonstrated improvements in BES by 21% and corresponding kyphosis reductions of 5° to 6° in postmenopausal hyperkyphotic women”

Now we don’t want the height gain to be due to back extensor strength.  We want the height to be due to longitudinal bone growth.

According to Short-term and long-term site-specific effects of tennis playing on trabecular and cortical bone at the distal radius, “In children, no significant difference was observed between the dominant and nondominant forearm lengths (21.6 cm on both sides). In adults, the respective values were 25.3 ± 1.6 cm and 25.0 ± 1.6 cm, with a significant side-to-side difference”.  So also a bone density increase correlates with about a .3cm gain and you can’t account for this gain in terms of posture.

More on tennis increasing bone length can be found here.

Whole-body morphological asymmetries in high-level female tennis players: A cross‑sectional study

“This cross-sectional study aimed to examine the degree of whole-body morphological asymmetries in female tennis players. Data were collected in 19 high-level female tennis players (21.3 ± 3.4 years). Based on anthropometric measurements (upper arm, lower arm, wrist, upper leg and lower leg circumferences as well as elbow and knee widths) and dual x-ray absorptiometry research scans (bone mineral density (BMD), bone mineral content (BMC), lean mass (LM), fat mass (FM) as well as humerus, radio-ulnar, femur and tibia bone lengths), within-subject morphological asymmetries for both upper (dominant vs. non-dominant) and lower (contralateral vs. ipsilateral) extremities were examined. Upper arm (p = 0.015), lower arm (p < 0.001) and wrist circumferences (p < 0.001), elbow width (p = 0.049), BMD (p < 0.001), BMC (p < 0.001), LM (p = 0.001), humerus (p = 0.003) and radio-ulnar bone length (p < 0.001) were all greater in the dominant upper extremity. BMC (p < 0.001) and LM (p < 0.001) were greater in the contralateral lower extremity, whereas FM (p = 0.028) was greater in the ipsilateral lower extremity.”

“Humerus bone length (cm) 27.6 ± 1.1(dominant)26.9 ± 1.2(non-dominant) Radio-ulnar bone length (cm) 25.0 ± 1.2(dominant)24.3 ± 1.3(non-dominant)”

I don’t think we can rule out that bone density can increase bone length.  It’s possible that since gains are typically small 0.2cm-1cm that they aren’t considered.  You’ll remember above that that the tennis study found the increase in bone length only in adult and not in children.  I don’t know if whole body impact is the best just based on personal testing I think direct impact is the best.  Tennis is pretty close to direct impact but the load is very inconsistent being based on how the game is going.  It may be possible to get larger increases with direct impact.  Whole body impact is skill dependent, runs risk of soft tissue injury, and you may land wrong.  It’d be interesting if a bone density regime like osteostrong has any impact on bone length or height parameters.

 

One more study that shows that milk may help you grow taller

 


“Bone is constantly balanced between the formation of new bone by osteoblasts and the absorption of old bone by osteoclasts. To promote bone growth and improve bone health, it is necessary to promote the proliferation and differentiation of osteoblasts. Although bovine milk is known to exert a beneficial effect on bone formation, the study on the effect of bovine milk extracellular vesicles (EVs) on osteogenesis in osteoblasts is limited. In this study, we demonstrated that bovine milk EVs promoted the proliferation of human osteogenic Saos‐2 cells by increasing the expression of cell cycle‐related proteins. In addition, bovine milk EVs also induced the differentiation of Saos‐2 cells by increasing the expression of RUNX2 and Osterix which are key transcription factors for osteoblast differentiation. Oral administration of milk EVs did not cause toxicity in Sprague‐Dawley rats. Furthermore, milk EVs promoted longitudinal bone growth and increased the bone mineral density of the tibia. Our findings suggest that milk EVs could be a safe and powerful applicant for enhancing osteogenesis.”