Can you grow taller with Lithium Salts?

Previously, I have written about the possibility of Lithium being used as a supplement to help you grow taller during development.  Not much was written about it other than that Lithium inhibits GSK3 beta which inhibits cellular proliferation.  I've been taking Lithium and my Lithium levels are about .26 while effective lithium blood levels are reported to range from 0.5-1.0 mM.  I'm not sure if that benefit is only for the neuronal advantages of Lithium.  Since Lithium increases stem cell proliferation it could also be used to augment LSJL related growth.  Lithium also inhibits Thyroid hormone and I wanted to explore that as well to see if that had any negative impacts on growth.

A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation.

"Sulfation is an important biological process that modulates the function of numerous molecules. It is directly mediated by cytosolic and Golgi sulfotransferases, which use 3'-phosphoadenosine 5'-phosphosulfate to produce sulfated acceptors and 3'-phosphoadenosine 5'-phosphate (PAP). Golgi-resident PAP 3'-phosphatase (gPAPP) is potently inhibited by lithium in vitro. The inactivation of gPAPP in mice led to neonatal lethality, lung abnormalities resembling atelectasis, and dwarfism characterized by aberrant cartilage morphology. The phenotypic similarities of gPAPP mutant mice to chondrodysplastic models harboring mutations within components of the sulfation pathway lead to the discovery of undersulfated chondroitin in the absence of functional enzyme. Loss of gPAPP leads to perturbations in the levels of heparan sulfate species in lung tissue and whole embryos. Clearance of the nucleotide product of sulfotransferases within the Golgi plays an important role in glycosaminoglycan sulfation, provide a unique genetic basis for chondrodysplasia, and define a function for gPAPP in the formation of skeletal elements derived through endochondral ossification."

Remember in the article about FGF, proteoglycan desulfation was a critical component in maximizing height growth.  Sulfated GAGS like chondroitin sulfate consumed like lysosomes which remove waste molecules that can reduce your height growth.  This article says that sulfated chondroitin(and other GAGs) is needed for height.  What's likely is that the ability to remove sulfate chains from GAGs(like Chondroitin) and add new sulfate chains is critical for certain stages of endochondral ossification.  Too much lithium is bad just like other beneficial compounds like BMP-2 or Estrogen etc.  That doesn't mean a little lithium is bad just like a little BMP-2 is bad(it's critical).

"Establishment of the cartilaginous template is a tightly ordered process that involves the function and interplay of: (i) specific transcription factors; (ii) chondrocyte-modulatory ligand pathways; (iii) extracellular matrix (ECM) structural proteins; (iv) core proteins of proteoglycans and their covalently linked glycosaminoglycans (GAGs), such as chondroitin sulfate (CS) chains; and correspondingly (v) gene products essential to the appropriate synthesis and sulfation of GAGs"

"Members of this phosphatase family are functionally inhibited in vitro and in vivo by clinically appropriate doses of lithium "<-Although lower doses of Lithium may not have this effect.

"The extent of gPAPP influence on GAG sulfation likely depends on multiple factors, including: (i) the metabolic load of specific sulfation reactions and thus how the consumption of PAPS by one gSULT may influence that of another, (ii) the inherent kinetic properties of individual gSULTs, (iii) the relative availability of PAPS and sulfate-acceptor substrates, (iv) tissue and cell expression patterns of gPAPP and the various gSULTs, and (v) possible compensation by other phosphatases. "<-So even if Lithium inhibits gPAPP which may have height reducing effects if there's compensation by other phosphatases and/or the height beneficial effects of Lithium are greater than gPAPP inhibition then Lithium may lead to a net increase in height.


Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway.

"To determine the effects and mechanism of action of lithium chloride (LiCl) on cartilage destruction induced by the pro-inflammatory cytokines IL-1, IL-1 + oncostatin M and TNF-α.
The release of collagen was assessed in bovine cartilage explant cultures, whereas collagenolytic activities (active and total) in conditioned culture supernatants were determined by bioassay.
LiCl, but not selective glycogen synthase kinase 3 (GSK-3) inhibitor compounds SB-415286 and TDZD-8, significantly decreased pro-inflammatory cytokine-induced collagen release from bovine cartilage via the down-regulation of collagenolytic activity. MMP-1 and MMP-13 expression was reduced in both bovine and human chondrocytes. LiCl selectively inhibited activation of the p38 mitogen-activated protein kinase pathway; effects that were recapitulated by specific p38 pathway inhibition.
LiCl can protect against cartilage damage induced by pro-inflammatory cytokines, and LiCl-mediated cartilage protection is not via a GSK-3-dependent mechanism, but potentially via inhibition of the p38 pathway."

Remember that inflammatory particles like TNF-alpha can reduce height by causing chondrocyte apoptosis.  So lithium can increase height by inhibiting inflammatory particles like TNF-alpha.

"we found that LiCl blocked cartilage collagen degradation in a bovine model and reduced levels of MMPs including the collagenases MMP-1 and MMP-13"

"LiCl reduced the level of activation of the p38 pathway substrate HSP27"<-It's speculated that Lithium Chloride stops IL-1 inflammatory cytokine collagen release through the p38 MAPK pathway.

"HSP27 was shown to be required for the IL-1 induction of the inflammatory mediators cyclooxygenase-2 and IL-6, at least in part, by the regulation of the stability of their mRNAs "

Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.[Lithium phosphorylates GSK-3Beta]

"cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. This growth defect [is] a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. glycogen synthase kinase-3beta (GSK-3beta; encoded by Gsk3b) [is] a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3beta was associated with enhanced hypertrophic differentiation{cGKII inhibits GSK-3beta which results in enhanced hypertrophic differentiation i.e. enhanced height growth}. cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3beta. Analyses of mice with compound deficiencies in both protein kinases (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. Beta-catenin levels decreased in Prkg2(-/-) mice, while overexpression of cGKII increased the accumulation and transactivation function of beta-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3beta. hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII."

Remember that cGKII has been found to increase height growth and is closely related to CNPs and Nitric Oxide.  Lithium inhibits GSK-3beta just like cGKII does, could Lithium have similar benefits on height growth?


Lithium treatment and thyroid abnormalities.

"The main findings from this review included: a) lithium definitely affects thyroid function as repeatedly shown by studies on cell cultures, experimental animals, volunteers, and patients; b) inhibition of thyroid hormone release is the critical mechanism in the development of hypothyroidism, goitre, and, perhaps, changes in the texture of the gland which are detected by ultrasonic scanning; c) compensatory mechanisms operate and prevent the development of hypothyroidism in the majority of patients; d) when additional risk factors are present, either environmental (such as iodine deficiency) or intrinsic (immunogenetic background), compensatory potential may be reduced and clinically relevant consequences may derive; e) hypothyroidism may develop in particular during the first years of lithium treatment, in middle-aged women, and in the presence of thyroid autoimmunity; f) thyroid autoimmunity is found in excess among patients suffering from affective disorders, irrespective of lithium exposure; g) in patients who have been on lithium for several years, the outcome of hypothyroidism, goitre, and thyroid autoimmunity do not much differ from those observed in the general population; h) hyperthyroidism and thyroid cancer are observed rarely during lithium treatment."

Lithium seems to have similar effects to thyroid hormone which is probably why supplementing with Lithium inhibits thyroid hormone production.

Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/beta-catenin signalling.

"Lithium is well known to induce thyroid growth.  Thyroid proliferation depends on the thyroid-stimulating hormone (TSH)/cAMP/cAMP response element binding protein (CREB) pathway, [and] Wnt/beta-catenin signalling may be of critical importance{Wnt and beta-catenin are critical for bone growth as well}. In other cell types lithium activates canonical Wnt signalling by GSK-3beta inhibition, which in turn stabilizes cytosolic free beta-catenin. Here we investigated the potential modulation of Wnt/beta-catenin signalling under lithium treatment in primary and neoplastic human thyrocytes.
Primary (S18) and neoplastic (NPA, FTC133) thyrocytes treated with and without LiCl were analysed.
LiCl dose-dependently inhibited GSK-3beta, stabilized free beta-catenin and inhibited beta-catenin degradation. LiCl altered the assembly of adherens junction by upregulating the E-cad-herin repressor, Snail, and downregulated E-cadherin expression. At a dose of 5 mM, LiCl significantly increased the proliferative potency of thyrocytes, which appeared to be mediated by beta-catenin, since nuclear beta-catenin stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF)-mediated transcription and upregulated downstream targets like cyclin D1. To characterize the specificity of Wnt/beta-catenin-driven thyrocyte proliferation, we transfected primary thyrocytes and FTC133 cells with dominant negative TCF4 to block Wnt-dependent pathways or with dominant negative CREB to inhibit the TSH/cAMP cascade. In cells transfected with dominant negative CREB lithium-stimulated proliferation was unchanged whereas blocking Wnt/beta-catenin by dominant negative TCF4 reduced proliferation by approx. 50%.
Wnt/beta-catenin signalling is of major importance in the control of lithium-dependent thyrocyte proliferation."

Lithium serves similar functions as Thryoid hormone.

Lithium is a GSK-3beta inhibitor which it accomplishes by adding a phosphate group to it. Other things that have been found to increases height like cGK II also operate by inhibiting GSK-3beta. Lithium in turn inhibits TNF-alpha which can cause chondrocyte apoptosis. However, Lithium inhibits gPAPP which is critical for height growth due to it adding phosphate groups to GAGs like chondroitin during key stages of endochondral ossification.  Lithium but not too much should increase height during development.

According to [Calcitonin and parathyroid hormone secretion and calcium metabolism in patients with diffuse toxic goiter during treatment with lithium carbonate], lithium induces an increase in interstitial calcium absorption.  According to Influence of lithium and exercise on serum levels of copper and zinc in rats., exercise decreases lithium concentration and lithium increases serum levels of zinc and copper.

Erythrocyte sodium-lithium countertransport activity is inversely correlated to adiponectin, retinol binding protein 4 and body height.

"Sodium/lithium countertransport (SLC) in the erythrocyte cell membrane is closely linked to obesity and insulin resistance. Adiponectin and retinol-binding protein 4 (RBP-4) are believed to affect obesity and insulin resistance. In the present study, we aimed to further characterize the relationship between SLC, inflammatory markers, adiponectin and RBP-4.
We included 93 clinically healthy 58-year-old men selected to display variations in insulin sensitivity. High sensitivity C-reactive protein (hs-CRP), TNF-alpha, soluble TNF-alpha-receptors (sTNFR) 1 and 2, IL-6 and RBP-4 were measured using antibody-based techniques. Adiponectin was determined by a radioimmunoassay kit. The lithium concentration in the special flux medium was measured by atomic absorption spectrophotometry.
In univariate analyses, SLC correlated negatively with RBP-4 (r(s) = -0.256, p = -0.017) and to adiponectin (r(s) = -0.316, p = 0.003) and positively with TNF-alpha (r(s) = 0.346, p = 0.001) and hs-CRP (r(s) = 0.288, p = 0.005). There were no statistically significant correlations with sTNFR 1 or 2 or IL-6. SLC was negatively associated to body height[Sodium Lithium countertransport decreases height?  What does that mean for lithium?} (r(s) = -0.256, p = 0.013).
Adiponectin is anti-inflammatory and anti-diabetic whereas RBP-4 supposedly decreases insulin sensitivity. The positive association of SLC with markers of inflammatory activity such as TNF-alpha and hs-CRP is in line with the proposed link between inflammation and insulin resistance."

"In human red cells, lithium is extruded against its own concentration gradient if the external medium contains sodium as a dominant cation in a process that does not require cellular ATP"<-This SLC.  If SLC is bad how do we affect this?  Do we want Lithium and Sodium levels low or high?

"insulin resistance could be the motor of the increased SLC activity"<-But insulin resistance increases height. Maybe SLC is only correlated with loss of height and not the cause.

"RBP-4 is a 21 kDa protein that binds and transports retinol and is mainly produced in adipose tissue and in the liver."

The study Sodium-Lithium Countertransport Has Low Affinity for Sodium in Hyperinsulinemic Hypertensive Subjects provides insight on how sodium & lithium concentrations affect SLC transport levels.

SLC peaked at around 100 Mm of Sodium for normatensive individuals and 150 Mm for hypertensive individuals. SLC was minimal at around 0 Mm for both. Eat the least amount of salt possible to grow taller. Insulin only affects SLC in hypertensive individuals.

The study did not mention any affects of Lithium levels on SLC.

Wnt/beta-catenin signaling stimulates chondrogenic and inhibits adipogenic differentiation of pericytes: potential relevance to vascular disease?

"Wnt/beta-catenin signaling regulates cell differentiation during embryonic and postnatal development, and there is increasing evidence that it is involved in vascular pathology. Wnt/beta-catenin signaling regulates the chondrogenic and adipogenic differentiation of pericytes[A nerve cell]. We demonstrate that pericytes express several Wnt receptors, including LDL receptor-related proteins 5 and 6, and Frizzled 1 to 4 and 7, 8, and 10, and that Wnt/beta-catenin signaling is stimulated by both Wnt3a and LiCl. Furthermore, induction of Wnt/beta-catenin signaling by LiCl enhances chondrogenesis in pericyte pellet cultures in the presence of transforming growth factor-beta3[LSJL stimulates the WNT pathway], as demonstrated by increased Sox-9 expression and glycosaminoglycan accumulation into the matrix. In contrast, transduction of pericytes with a recombinant adenovirus encoding dominant-negative T-cell factor-4 (RAd/dnTCF), which blocks Wnt/beta-catenin signaling, inhibited chondrogenesis, leading to reduced Sox-9 and type II collagen expression and less glycosaminoglycan accumulation."

"collagen II expression was not induced further by Wnt signaling, suggesting that its expression was already maximal."<-Maybe there's a maximal level for several genes after which height cannot be increased further by more of that gene?

The effect of lithium carbonate administration on growth in the domestic fowl.

"determine the effect of lithium carbonate administration on growth in a domestic fowl model. The results showed that lithium treatment at a therapeutic level (0.2-2.0 mEq/L) did not significantly alter plasma pH levels, food intake, fecal output or body weight gain. Bivariate and multivariate analysis of tibial dimensions revealed that lithium treatment primarily caused increased growth of proximal epiphyseal height. Allometric analyses indicated that lithium administration increased the growth differential between proximal and distal epiphyses."

Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression.

"In 24 euthyroid patients with a major depressive episode who had not responded to antidepressant monotherapy of at least 4 weeks, we measured serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3) and total thyroxine (T4) before (baseline) and during lithium augmentation therapy (follow-up). The time point of the endocrinological follow-up depended on the status of response, which was assessed weekly ). Responders were reassessed immediately after response was determined, and non-responders after 4 weeks of lithium augmentation.

There was a statistically significant change in thyroid system activity during lithium augmentation, with an increase of TSH levels and a decrease of peripheral T3 and T4 levels. However, there were no differences in any of the HPT hormones between responders and non-responders at baseline or at follow-up."

High Throughput Transcriptome Profiling of Lithium Stimulated Human Mesenchymal Stem Cells Reveals Priming towards Osteoblastic Lineage.

"Our results show suppression of proliferation and enhancement of alkaline phosphatase (ALP) activity upon lithium treatment of hMSCs under non-osteogenic conditions. Microarray profiling of lithium-stimulated hMSC revealed decreased expression of adipogenic genes (CEBPA, CMKLR1, HSD11B1) and genes involved in lipid biosynthesis. Interestingly, osteoclastogenic factors and immune responsive genes (IL7, IL8, CXCL1{up}, CXCL12, CCL20) were also downregulated. Negative transcriptional regulators of the osteogenic program (TWIST1 and PBX1) were suppressed while genes involved in mineralization like CLEC3B and ATF4 were induced. Gene ontology analysis revealed enrichment of upregulated genes related to mesenchymal cell differentiation and signal transduction. Lithium priming led to enhanced collagen 1 synthesis and osteogenic induction of lithium pretreated MSCs resulted in enhanced expression of Runx2, ALP and bone sialoprotein. However, siRNA-mediated knockdown of RRAD, CLEC3B and ATF4 attenuated lithium-induced osteogenic priming, identifying a role for RRAD, a member of small GTP binding protein family, in osteoblast differentiation."

This is contrary to evidence that Lithium increases MSC proliferation.

"LiCl at 5 mM resulted in more than 20% reduction while at 40 mM it had maximum inhibitory effect with more than 80% reduction in cell proliferation."

"lithium stimulation of hMSC for 7 days in the presence of expansion and osteogenic medium demonstrated highly inhibitory effect of 20 mM LiCl as no ALP staining was observed. However, lower concentration (5 mM) resulted in enhanced ALP staining under both culture conditions."

(Comparison using accession number and not just gene name to be done)
Genes upregulated by Lithium also upregulated by LSJL:
Edn1
A1BG
ALDOB{down}
KIRREL3
FLNC

Downregulated:
PTGS2{up}
CXCL1{up}
Kynu{up}
AREG{up}
RBMS1
NR4A2{up}
GPR115{up}
NR4A1{up}
CFI{up}
RASD1{up}
PACSIN1
COL12A1{up}
LAMA4{up}
WWTR1{up}
ODF4
PPFIBP1

%of Differentially regulated genes: 61.9%

Chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells treated by GSK-3 inhibitors.

"The present study has attempted to evaluate the effects of two well-known glycogen synthase kinase-3 inhibitors, including lithium chloride (LiCl) and SB216763 on a human marrow-derived MSC (hMSC) chondrogenic culture. Passaged-3 MSCs were condensed into small pellets and cultivated in the following groups based on the supplementation of chondrogenic medium: transforming growth factor (TGF)-β1, TGF-β1 + LiCl, TGF-β1 + SB216763, TGF-β3, TGF-β3 + LiCl, and TGF-β3 + SB216763. The cultures were maintained for 21 days and then analyzed for expression of Sox9, aggrecan, collagen II, β-catenin, and axin genes. Deposition of glycosaminoglycan (GAG) in the cartilage matrix was also measured for certain cultures. The presence of both LiCl and SB216763 along with TGF-β in the MSC chondrogenic culture led to the up-regulation of cartilage-specific genes. TGF-β3 appeared much better than TGF-β1. Based on our findings, SB216763 was more effective in up-regulation of cartilage-specific genes. These chondrogenic effects appeared to be mediated through the Wnt signaling pathway since β-catenin and axin tended to be up-regulated and down-regulated, respectively. In the culture with SB216763 + TGF-β3, significantly more GAG was deposited . Addition of either SB216763 or LiCl to hMSC chondrogenic culture up-regulates cartilage-specific gene expression and enhances GAG deposition in the culture."

"inhibition of GSK-3β was responsible for the therapeutic usefulness of lithium salts"

" the pellet cultures treated with LiCl appeared to have zones of hypertrophic chondrocytes "<-So Lithium encouraged more endochondral ossification.

The effects of Lithium on chondrogenic differentiation were not analyzed independently of the TGF-Beta growth factors.

Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: An open-label, nonrandomized chart review

Data for height was collected but not shown which is unfortunate.

Lithium, Bone and Body Weight Studies in Long-Term Lithium-Treated Patients and in the Rat

"Morphometric studies were carried out on radiographs taken on separate occasions, 2 years apart, from patients receiving long-term prophylactic lithium. Similar studies were made of femora of growing rats over a 1-year period. We conclude that lithium dos not affect the size or mineralization of bone from either humans or growing or growing rats, but that it affects whole body growth in growing rats."

Lithium treatment decreased median cortical width of the medicarpal.

There is no trend in any direction of length versus bone length in lithium versus control rates but that means it doesn't affect growth rate and not the length of growth so final growth could be higher.