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Improving Longevity with Metadichol ® by Inhibiting the BCAT1 Gene

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Metadichol ® [1] is a Nanoemulsion of long-chain alcohols found in many foods. It is commonly called Policosanol and is present in foods such as rice, sugar cane, wheat, peanuts Metadichol acts as an inverse agonist on Nuclear Vitamin D receptors (VDR) that are present in cells throughout the body to stimulate the immune system and affects many biologIcal processes to modulate many diseases. Branched-chain amino acid transferase (BCAT1) catalyzes the reversible transamination of leucine, isoleucine, and valine branched-chain amino acids (BCAA) to their respective alpha-keto acids, liberating L-glutamate. When this gene is inhibited, the amino acid chains accumulated in the tissue triggering longevity in the nematodes. The health and longevity of the nematodes improved when BCAT1 was inhibited. Gabapentin has been shown to inhibit BCAT1, but IC50 is 10000 uM. Metadichol® inhibits BCAT1 with an IC50 of 3.3 um, 3000 times more potent than Gabapentin.
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Improving Longevity with Metadichol® by Inhibiting the BCAT1 Gene
PR Raghavan
Nanorx Inc, PO Box 131, Chappaqua, NY 10514, USA
*Corresponding author: PR Raghavan, Nanorx Inc, PO Box 131, Chappaqua, NY 10514, USA, E-mail: raghavan@nanorxinc.com
Received date: February 10, 2017; Accepted date: March 10, 2017; Published date: March 13, 2017
Copyright: © 2017 Raghavan. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Metadichol® [1] is a Nanoemulsion of long-chain alcohols found in many foods. It is commonly called Policosanol
and is present in foods such as rice, sugar cane, wheat, peanuts Metadichol acts as an inverse agonist on Nuclear
Vitamin D receptors (VDR) that are present in cells throughout the body to stimulate the immune system and affects
many biologIcal processes to modulate many diseases.
Branched-chain amino acid transferase (BCAT1) catalyzes the reversible transamination of leucine, isoleucine,
and valine branched-chain amino acids (BCAA) to their respective alpha-keto acids, liberating L-glutamate. When
this gene is inhibited, the amino acid chains accumulated in the tissue triggering longevity in the nematodes. The
health and longevity of the nematodes improved when BCAT1 was inhibited. Gabapentin has been shown to inhibit
BCAT1, but IC50 is 10000 uM. Metadichol® inhibits BCAT1 with an IC50 of 3.3 um, 3000 times more potent than
Gabapentin.
Keywords: Aging; BCAT1; Metadichol; VDR; Nuclear receptors;
Inverse agonists; Protean agonists; Urothelial carcinomas; Ovarian
cancer; Hepatocellular carcinoma; Nasopharyngeal carcinoma;
Hyperglycemia
Introduction
BCAA catabolism and specically increased activity of the
corresponding enzyme, BCAT1 has been linked to various diseases
(Table 1) in aging [2,3] and pathological states [4], including
accelerated growth of malignant gliomas [5], decreased sepsis survival
[6] and increased accumulation of liver fat [7], the latter being linked
to a number of metabolic diseases [8,9]. Consistently, systemic
disruption of one BCAT iso-form [10], namely BCATm, in mice
increases energy expenditure and reduces body weight [11] and cancer
[12,13].
BCAT1 related diseases
Astrocytoma Colitis
Glioblastoma Crohn Disease
Glioma Inflammatory Bowel Diseases
Malignant neoplasm of brain Leukemia
Neoplasms, Ductal, Lobular, And
Medullary Acute leukemia
Ductal Carcinoma Myeloid Leukemia
Carcinoma, Large Cell Muscular Dystrophy, Duchenne
Melanoma Muscular Dystrophy
Skin Neoplasms
Duchenne And Becker Muscular
Dystrophy
Neuroendocrine Tumors Amyotrophic Lateral Sclerosis
Nevi and Melanomas Motor Neuron Disease
Lymphoma Anterior Horn Cell Disease
Lymphoproliferative Disorders TDP 43 Proteinopathies
Hematopoietic Neoplasms Adenocarcinoma
Myeloid Leukemia, Chronic Cystadenocarcinoma
Myeloproliferative disease
Neoplasms, Cystic, Mucinous, And
Serous
Malignant neoplasm of skin Hyperglycemia
Table 1: BCAT1 related diseases.
Humanity has always been searching for immortality, and it has
been a timeless quest. Manseld and-and his co-workers at ETH
Zurich [3] systematically researched the genomes of three dierent
organisms and found genes present in all three were associated with
the aging process. ese are also present in humans. ey followed the
developing sequences of each organism with age and studied the
manner of the expression along each stage. By comparing the amount
of messenger RNA found in the cells of the animals, this allowed them
to measure gene activity. rough this data, they found that the three
organisms have 30 genes in common, which signicantly impact the
aging process.
By blocking the mRNA to the corresponding genes only increased
the lifespan by 5%. But one gene, called BCAT1 gene, when blocked
increased the lifespan by nearly 25%. When this gene is blocked, the
amino acid chains accumulated in the tissue triggering longevity in the
nematodes.
Chang et al. [14] showed that overexpression of BCAT1
overexpression is associated with advanced tumor status, and implies
adverse clinical outcomes of Urothelial carcinomas, suggesting that its
Journal of Aging Science Raghavan, J Aging Sci 2017, 5:1
DOI: 10.4172/2329-8847.1000174
Research Article OMICS International
J Aging Sci, an open access journal
2329-8847
Volume 5 • Issue 1 • 1000174
role in tumor progression could serve as a prognostic biomarker and a
novel therapeutic target in urothelial carcinomas.
Wang et al. [15] BCAT1 suppression led to signicantly prolonged
survival time in the xenogra model of advanced peritoneal epithelial
ovarian cancer. And suggesting that BCAT1 is a novel therapeutic
target. Work on Hepatocellular carcinoma by Xu et al. [16], who
showed that BCAT1 expression was upregulated in these patients and
that BCAT1 may serve as a potential molecular target for the diagnosis
and treatment.
Panosyan et al. [17], showed that Glutamine, glutamate, asparagine,
and aspartate are involved in an enzyme network that controls
nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1
and clinical aggressiveness of malignant gliomas were linked to
augmented metabolism of amino acids.
A study by Zhou and coworkers [18] showed that gene amplication
and c-Myc up-regulation are responsible for BCAT1 overexpression in
primary NPC, and overexpression of BCAT1 induces cell proliferation,
migration, and invasion. e results suggest that BCAT1 may be a
novel molecular target for the diagnosis and treatment of
nasopharyngeal carcinoma.
Given the increasing importance of BCAT1 in human diseases,
Metadichol®, standard Gabapentin, and policosanol (an active
ingredient in Metadichol®) a nonnano form, the same one used in the
preparation of Metadichol®, was tested for its inhibitory activity using
cell lines U87MG and Hs 683 cell lines. e choice of the cell lines is
because they express BCAT1 and also it could be compared with the
standard Gabapentin that was tested using these cell lines.
Experimental
e procedure followed is described on page 6 of European Patent
application [3]. e work was outsourced and performed under by
Shakti BioResearch Labs Woodbridge, CT. e experiment was
duplicated.
Cell Lines and Culture Conditions: Hs683 (Catalog No. HTB-138)
and U87MG (Catalog No. HTB-14) were obtained from American
Type Culture Collection (ATCC). ey were grown in T75 asks in
DMEM (GIBCO, Catalog No. 11965-092) and MEM (GIBCO, Catalog
No. 11905-080) media, respectively, at 37°C in a humidied, 5% CO2
incubator. Both DMEM and MEM media were supplemented with
10% fetal bovine serum (ATCC, Catalog No. 30-2020) and penicillin-
streptomycin (ATCC, Catalog No. 30-2300).
Proliferation Assay
Proliferation is done for 72 hours where you allow the cells for 2-3
doubling time.
Cells (2,000-3,000 cells/well) were seeded in 100 uL of specied
media in a 96-well plate and incubated overnight at 37°C in a
humidied, 5% CO2 incubator. Media replaced with new 100µL of
fresh media containing various concentrations of the compounds.
Aer 72 h incubation with the compounds at 37°C in a humidied, 5%
CO2 incubator, cell viability was measured in a luminometer aer the
addition of 100 µL/well Cell Titer Glo reagent (Promega). IC50s were
calculated using SoMax soware.
Metadichol® (size below 60 nm) used was a 0.5% (5 mg per ml)
solution in water and Vehicle was diluted 10-fold in specied media
followed by 3-fold serial dilutions.
Gabapentin (Selleckchem Catalog No. S1338) (was in a phosphate
buer) was dissolved in PBS at a concentration of 0.2 M; a 10-fold
dilution made in the specied media followed by 3-fold serial dilutions.
Policosanol in powder form (supplied by Micro-Sphere S.A
Switzerland) (the same that is used in the preparation of Metadichol®)
was dissolved in DMSO (the nal concentration of DMSO was 0.1%)
to a concentration of 10 µM (with minimal turbidity that did not get
pelleted upon centrifugation), followed by 3-fold dilutions in DMSO. 1
µL of serially diluted policosanol in DMSO was added to 500 L of
media.
Results
A summary of the results is Shown in Table 2. Data and graphs for
cell lines HS683 and U87MG are shown in in Figure 1 and 2
respectively. From the Table, it is seen that Metadichol® is 3000 more
potent (in µM units) than Gabapentin. Policosanol, the active
ingredient of Metadichol in non-nano form, is totally inactive.
Hs683 U87MG Hs683 U87MG
IC50 µM IC50 µg/ml
Metadichol 3.329 5.247 Metadichol 4.661 7.346
Gabapentin 10660 1919 Gabapentin 2214.1 3985.7
Policosanol Inactive Inactive Policosanol Inactive Inactive
Table 2: A summary of the results for cell lines HS683 and U87MG.
e graphs are shown in Figure 1. At higher concentrations, the %
inhibition of Metadichol is over 100, and it could be due to the
formulation which has a pH of 4.5 which is known to aect the cell
lines used.
Discussion
Vitamin D has a role in the down-regulation of BCAT1. A likely
explanation to BCAT1 inhibition lies in the work of Suzuki et al. [19]
using a DNA microarray analyzed 16000 genes for changes in
expression with the dierentiation of human promyelocytic leukemia
HL-60 cells induced by 1,25-dihydroxy D3 (Vit D3), and their work
showed that BCAT1 was downregulated. Metadichol has a particle size
of less than 60 nm. We have demonstrated that it binds to the vitamin
D receptor (VDR) as an inverse agonist. It is the only known inverse
agonist of VDR known in the medical literature, and so it is not
surprising that there is inhibition of BCAT1.
To further conrm this result we have carried out Metadichol® eect
on expression and dierentiation on THP-1 cell line which is a human
leukemia monocyte cell line, which has been extensively used to study
monocyte/macrophage functions, mechanisms, signaling pathways,
and nutrient and drug transport. is cell line has become a familiar
model to estimate modulation of monocyte and macrophage activities.
Over 6300 genes were expressed and ltered to a set of 754 signicant
genes that were signicant. BCAT1 is seen to be down-regulated [20].
Calcitriol (1,25-Dihydroxy Vitamin D) is the natural ligand for the
VDR and acts as an agonist. Metadichol likely behaves more like a
Protean agonist which act as both positive and negative agonists on the
same receptor, depending on the degree of constitutive activity that is
present. If there is no constitutive activity, the agonist would be an
Citation: Raghavan PR (2017) Improving Longevity with Metadichol® by Inhibiting the BCAT1 Gene. J Aging Sci 5: 174. doi:
10.4172/2329-8847.1000174
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J Aging Sci, an open access journal
2329-8847
Volume 5 • Issue 1 • 1000174
active agonist. When constitutive activity is present, the Protean
agonist would be an inverse agonist [21].
Metadichol is a product made from agricultural waste and is a
renewable resource. It has the potential to serve as an anti-aging
molecule with a broad spectrum of activity, particularly given that its
constituents (long-chain lipid alcohols are classied as GRAS). Given
that they are present in foods commonly consumed on a daily basis
and has demonstrated no toxicity at doses of up to 5000 mg/kg
[22-24]. Given this safety record, Metadichol is ready for large scale
clinical testing to prove its ecacy in BCAT1 related diseases and
saving years of work in bringing a potential drug to market.
Figure 1: . Data and graphs for HS 683 cell line.
Citation: Raghavan PR (2017) Improving Longevity with Metadichol® by Inhibiting the BCAT1 Gene. J Aging Sci 5: 174. doi:
10.4172/2329-8847.1000174
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Volume 5 • Issue 1 • 1000174
Figure 2: Data and graphs for U87 MG Cell Line.
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Citation: Raghavan PR (2017) Improving Longevity with Metadichol® by Inhibiting the BCAT1 Gene. J Aging Sci 5: 174. doi:
10.4172/2329-8847.1000174
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Volume 5 • Issue 1 • 1000174
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Citation: Raghavan PR (2017) Improving Longevity with Metadichol® by Inhibiting the BCAT1 Gene. J Aging Sci 5: 174. doi:
10.4172/2329-8847.1000174
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Volume 5 • Issue 1 • 1000174
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... Metformin has been shown to inhibit expression of mitochondrial branched-chain aminotransferase (BCAT) [14]. We have recently shown that Metadichol is a potent inhibitor of BCAT1 [15]. ...
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