Monday, January 7, 2013

Grow Taller with Folinic Acid

For the first time, there is evidence that Folinic Acid treatment may increase length in developing individuals see (*NEW*).  Considering that Folinic Acid should not be harmful to length development, if an individual has active growth plates it's definitely a supplement one should add to their regime.

Hypermethylation of the growth plate chondrocytes may be a way to induce supranatural height growth.  DNA Methyltransferase stopping the addition of methyl groups to stem cell chondrocytes in the resting zone may be an indication to cease height growth.  High levels of HGH may also cause hypermethylation explaining gigantism(but why Gigantism is not inducible in all with HGH is unclear).  Folinic Acid is available as a supplement:Folinic Acid 800 mcg.

Are there any other ways of inducing DNA Hypermethylation(Bare in mind that DNA Hypermethylation increases the spread of cancer as DNA Methylation is one of the negative feedback mechanisms on cell growth)?  And since hypermethylation may not be possible to induce in growth plates general methods of increasing DNA synthesis like Folinic Acid may have similar effects.

Damaging effects of chronic low-dose methotrexate usage on primary bone formation in young rats and potential protective effects of folinic acid supplementary treatment.

"Methotrexate (MTX) is a most commonly used anti-metabolite in cancer treatment and as an anti-rheumatic drug. MTX chemotherapy at a high dose is known to cause bone growth defects in growing bones. We examined effects on bone growth of long-term MTX chemotherapy at a low dose in young rats, and potential protective effects of supplementary treatment with antidote folinic acid (given ip at 1 mg/kg 6 h after MTX). After two cycles of 5 once-daily MTX injections (at 0.75 mg/kg, 5 days on/9 days off/5 days on), MTX at this dose caused significant reduction in heights of growth plate and primary spongiosa bone on day 22 compared to controls. In contrast, a similar dosing regimen but at a lower dose (0.4 mg/kg) caused only slight or no reduction in heights of both regions. However, after the induction phase at this 0.4 mg/kg dosing, continued use of MTX at a low dose (once weekly at 0.2 mg/kg) caused a reduction in primary spongiosa height and bone volume on weeks 9 and 14, which was associated with an increased osteoclast formation and their bone surface density as well as a decreased osteoblast bone surface density in the primary spongiosa. Folinic acid supplementation was shown able to prevent the MTX effects in the primary spongiosa. Acute use of MTX can damage growth plate and primary bone at a high dose, but not at a low dose. However, long-term use of MTX at a low dose can reduce primary bone formation probably due to decreased osteoblastic function but increased osteoclastic formation and function, and supplementary treatment with folinic acid may be potentially useful in protecting bone growth during long-term low-dose MTX chemotherapy."

Folinic Acid(leucovorin) prevents damage to the bone marrow.  It may help by reducing the number of micronuclei.

"Low-dose MTX is able to inhibit other folate-dependent enzymes such as thymidylate synthase, which further blocks the de novo purine synthesis by directly inhibiting the activity of 5-aminooimidazole-4-carboxamide ribonucleotide transformylase, causing an increase in both intracellular and extracellular adenosine (an potent anti-inflammatory mediator), and an increase in cAMP"

No data was taken on Folinic Acid treatment alone.

A comparison of vitamin A and leucovorin for the prevention of methotrexate-induced micronuclei production in rat bone marrow.

"Methotrexate [is] a folate antagonist. In rats, methotrexate is known to induce micronuclei formation, leading to genetic damage, while vitamin A is known to protect against such methotrexate-induced genetic damage. Leucovorin (folinic acid) is generally administered with methotrexate to decrease methotrexate-induced toxicity.
We aimed to determine whether vitamin A and leucovorin differed in their capacity to prevent formation of methotrexate-induced micronuclei in rat bone marrow erythrocytes. The present study also aimed to evaluate the effect of combined treatment with vitamin A and leucovorin on the formation of methotrexate-induced micronuclei.
Male and female Wistar rats were injected with 20 mg/kg methotrexate (single i.p. dose). The control group received an equal volume of distilled water. The third and fourth groups of rats received vitamin A (5000 IU daily dose for 4 successive days) and leucovorin (0.5 mg/kg i.p. dose for 4 successive days), respectively. The fifth and sixth groups of rats received a combination of vitamin A and a single dose of methotrexate and a combination of leucovorin and methotrexate, respectively. The last group of rats received a combination of leucovorin, vitamin A and single dose of methotrexate. Samples were collected at 24 hours after the last dose of the treatment into 5% bovine albumin. Smears were obtained and stained with May-Grunwald and Giemsa. One thousand polychromatic erythrocytes were counted per animal for the presence of micronuclei and the percentage of polychromatic erythrocyte was determined.
Comparison of methotrexate-treated rats with the control group showed a significant increase in the percentage of cells with micronuclei and a significant decrease polychromatic erythrocyte percentage. Combined methotrexate and vitamin A therapy and combined methotrexate and leucovorin therapy led to significant decreases in the micronuclei percentage and an increase in polychromatic erythrocyte percentage when compared to rats treated with methotrexate alone. Leucovorin was found to be more effective than vitamin A against the formation of methotrexate-induced micronuclei."

"rats treated with a combination of methotrexate and vitamin A had a significantly reduced frequency of micronuclei formation when compared to methotrexate (20mg/kg)-treated rats"

Leucovorin helps to prevent genetic damage.  Does it do it in cases not caused by Methotrexate?

Inhibitory effect of folinic acid on radiation-induced micronuclei and chromosomal aberrations in V79 cells.

"Folinic acid (FA), clinically called leucovorin, has been widely used as a nutrient supplement in dietary intake and is capable of inhibiting cytotoxicity and chromosomal damage induced by chemicals. However, data on its antigenotoxic effect on radiation-induced chromosomal damage are limited. The present study was, therefore, performed to investigate the effect of FA on radiation-induced (X-rays and UV radiation) micronuclei (MN) and structural chromosomal aberrations (SCA) concurrently in V79 Chinese hamster lung cells. Exponentially growing cells were exposed to five doses of X-rays (1-12 Gy) and UV radiation (50-800 microJ x 10(2)/cm2) and post-treated with 5 or 50 micrograms FA/ml of culture medium for 16 h. The slides were analyzed for the presence of MN and SCA using standard procedures. X-ray treatment alone produced dose-related cytotoxicity. X-rays produced a clear dose-related clastogenicity as measured by percent of micronucleated binucleated cells (MNBN) (5-79%) and percent of aberrant cells (11-92%). FA at 5 micrograms/ml slightly decreased X-ray induced chromosomal damage in both assays; however, the inhibition was significant (12-46% of MNBN, 14-48% in aberrant cells) only when X-ray-treated cultures were post-treated with 50 micrograms FA/ml. Post-treatment of FA had no effect on X-ray induced cytotoxicity as measured by NDI and MI. A similar a dose-related increase in % MNBN (0.5-10.3%) and percent aberrant cells (6-35%) was produced by UV radiation treatment alone. There were significant percentages of MNBN and aberrant cell inhibitions at both 5 and 50 micrograms/ml in both assays. As in the case of X-ray-treated cells, there was a clear dose-related cytotoxicity in UV-treated cells alone. No reduction in NDI or MI was found when UV-exposed cells were post-treated with 5 or 50 micrograms of FA. FA [decreases] radiation-induced chromosomal damage."

"X-rays produce DNA double-strand breaks (DSBS), DNA single-strand breaks(SSBs), base damages and DNA-protein cross-links and that DSBs are the main lesions responsible for chromosome aberrations"

Folinic Acid protects against many sources of DNA damage(and DNA damage could include damage to DNA Methyltransferase explaining it's growth stunting properties).

Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype.

"The CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues[elevated folate levels may cause hypermethylation]. In the present study, we investigated whether CIMP+ was associated with a specific mRNA expression pattern for folate- and nucleotide-metabolising enzymes. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RT-PCR. CIMP+ was determined by real-time methylation-specific PCR and compared to mRNA expression. Candidate genes showing association with CIMP+ were further investigated in a replication cohort of 150 CRC samples from Japan. In the exploratory study, low expression of gamma-glutamyl hydrolase (GGH) was strongly associated with CIMP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC. Promoter hypermethylation of GGH was observed in only 5.6% (1 out of 18) CIMP+ tumours and could not account for the low expression level of this gene. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype. Further studies of folate metabolism in CIMP+ CRC may help to elucidate the aetiology of these tumours and to predict their response to anti-folates and 5-fluorouracil/leucovorin."

Folate is necessary for hypermethylation as Folate is a vitamin essential for DNA synthesis.  Although, excess levels of Folate will likely just be urinated out.

Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis.

"Inappropriate diet may contribute to one third of cancer deaths. Folates, a group of water-soluble B vitamins present in high concentrations in green, leafy vegetables, maintain DNA stability through their ability to donate one-carbon units for cellular metabolism. Folate deficiency has been implicated in the development of several cancers, including cancer of the colorectum, breast, ovary, pancreas, brain, lung and cervix. Generally, data from the majority of human studies suggest that people who habitually consume the highest level of folate, or with the highest blood folate concentrations, have a significantly reduced risk of developing colon polyps or cancer. However, an entirely protective role for folate against carcinogenesis has been questioned, and recent data indicate that an excessive intake of synthetic folic acid (from high-dose supplements or fortified foods) may increase human cancers by accelerating growth of precancerous lesions. Nonetheless, on balance, evidence from the majority of human studies indicates that dietary folate is genoprotective against colon cancer. Suboptimal folate status in humans is widespread. Folate maintains genomic stability by regulating DNA biosynthesis, repair and methylation. Folate deficiency induces and accelerates carcinogenesis by perturbing each of these processes."

Folic Acid (Nature Made Folic Acid Supplement, 400 mcg, 250-Count Tablets (Pack of 3)) as well as Folinic Acid can maximize height growth by protecting against DNA damage.  But excess folic or folinic acid are only necessary but not sufficient conditions for DNA Methylation to occur.  Every child undergoing growth should ensure that they have appropriate quantities of folic and folinic acid to maximize height growth.

DNA Hypermethylation needs something else to occur and one suggested mechanism is S-Adenosyl methionine.


Effect of methotrexate and folinic acid on skeletal growth in mice.

"Four equal groups of Balb/c young male mice (6 animals in each group; mean body weight 11.9 +/- 0.25 g, in their rapid growth phase[3 weeks]) were subjected to the following drug treatment for a period of 3 wk. Group 1 was given intraperitoneal MTX (3.5 mg kg(-1) body weight) every second day. Group 2 received folinic acid (7.0 mg kg(-1) body weight) intraperitoneally every second day. Group 3 was given both drugs (MTX every second day and folinic acid 8 h post-MTX injection). Group 4 was injected with physiological saline every other day to serve as a control group.
Mean lengths of both the tibia and femur of animals were compared in the four treatment groups. A significant decrease in the mean lengths was observed in the group receiving MTX alone. Similarly, there was a significant decrease in the height of the femoral and tibial growth plate in this group when compared with the other groups. The main effect of MTX seemed to be on the hypertrophic proliferative zone of chondrocytes in the growth plate. Furthermore, animals in this MTX-treated group also showed increased levels of MTX in plasma and low levels of erythrocyte folate{thus folate deficiency may play a role in the length decrease}.
Chronic administration of MTX induces suppression of skeletal growth in mice, possibly through the inhibition of the pathway of de novo DNA synthesis{thus other compounds that inhibit new DNA synthesis may also decrease height}. Folinic acid treatment following MTX administration appears to reverse this growth inhibition."

Folinic Acid alone non-significantly increased both femur and tibia length.

A is saline, B is folinic acid, C is MTX, D is MTX + folinic acid.  The growth plate quality seems higher in group B.

Same groups as above.  Again, GP with highest quality is B.  What's interesting to note is that in D the hypertrophic zone seems to be disorganized but the proliferative zone seems expanded.  Therefore, Folinic Acid may revert MTX growth inhibition by more an expansion of the proliferative zone rather than reverting all the effects of MTX.

Growth plate height was non-significantly higher in Folinic Acid group than in the other groups by almost 10% for the femur.  I think why it was shown as non-significant is that the p value chosen was very low p <0.001.

Folinic Acid increased folate levels in erythrocytes by about 40%.

"chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1╬▓ and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1╬▓ in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1╬▓ neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation."

This study did not study Folinic Acid supplementation without MTX.


  1. I've been finding the same conclusion and a few studies that back up this idea just yesterday. XRunner in his notes talks about it.

  2. Xcrunner got all of his information from alkoclar, he copied a lot.