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hTERT activation [Wikipedia, Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension, Biocarta Pathways]. See Telomerase Activation Therapies, Telomerase induction, Small Molecule Telomerase Activators, [List, 81s, 81s/TELOMERASEACTIVATE], (7). The topic "hTERT activation" arises most frequently in the discussion of cancer, although it is also mentioned occasionally in connection with aging or anti-aging treatment. It may refer to the upregulation of hTERT mRNA transcription (ultimately producing more copies of the hTERT catalytic component of telomerase), or to the phosphorylation of cytoplasmic hTERT protein (the catalytic component of telomerase), which causes hTERT protein to be transported into the cellular nucleus from the cytoplasm. We see more telomerase activity in both cases. In the former case, transcription factors acting on the hTERT promoter upregulate hTERT mRNA transcription, and/or an HDAC inhibitor expands chromatin to enable transcription. If hTERT protein phosphorylation activates telomerase, kinases phosphorylate the hTERT protein in the cytoplasm for translocation into the nucleus. A third case exists: elevation of HSP90 heat shock protein levels can accelerate hTERT production and assembly by more effectively handling protein folding of fresh hTERT. Cancers frequently up-regulate telomerase as part of their program for undesirable cellular proliferation. On the other hand, hTERT is not an oncogene and up-regulation of telomerase does not induce cancer. For instance, the germ line cells are permanently telomerase up-regulated. As a matter of fact, telomerase up-regulation tends to prevent cancer where it occurs as a consequence of telomere shortening, as in carcinomas and adenocarcinomas based on the behavior of epithelial tissues. However, some compounds which activate telomerase are carcinogens. See Yu Sheng-Kong, Woodring E. Wright and Jerry W. Shay (2002), Human Telomerase and its Regulation, Microbiology and Molecular Biology Reviews, Sept. 2002, pp. 407-425, and associated papers. Also see Links/genes with enhancers. See hTERT activation pathways, Biocarta/Overview of telomerase protein component gene hTert Transcriptional Regulation, hTERT activation via the PI3K/Akt pathway and hTERT activation via the MAP Kinase pathway. I note that telomerase activators are sometimes billed as "(weakly) tumor promoters", because they somewhat counteract telomerase inhibitors that induce cancer cell apoptosis. In practice, I advocate applying telomerase activators in quadrature with telomerase inhibitors in cycles of telomerase activation followed by telomerase inhibition and treatment with anticancer drugs and nutraceuticals.
hTERT enhancer [Links, Images, Video, Papers, Patents, Books; Books/transcription enhancers, Patents/hTERT enhancer, Amazon/hTERT enhancer]. Gene transcription enhancers upstream or far downstream from the promoter of a gene and on the other side of the gene can sometimes enhance transcription very markedly via distant application of transcription factors acting on enhancers typically associated with gene looping promoting transcription. See activating hTERT transcription enhancers [Images, Papers, Patents, Books].
hTERT immortalization of cells [Links/the immortalization of cells by hTERT, Images, Video, Papers, Patents, Books, Amazon; Links/the immortalization of cancer cells by hTERT, Images, Video, Papers, Patents, Books, Amazon]. Normal cells or cancer cells may be immortalized by telomerase activity from improving hTERT mRNA transcriptional expression, by improving phosphorylation of cytoplasmic hTERT, or by improving levels of the hTERT assembly chaparone HSP90 with p23. Woodring E. Wright published his landmark paper in 1989 on cellular immortalization or reversible senescence [Images, Video, Papers, Patents] with O M Pereira-Smith and Jerry W. Shay. Dr. Wright was on the team that first demonstrated cell division limit extension in human cells using hTERT transfection with a viral vector published by Andrea G. Bodnar, Michel Ouellette, Maria Frolkis, Shawn E. Holt, Choy-Pik Chiu, Gregg B. Morin, Calvin B. Harley, Jerry W. Shay, Serge Lichtsteiner, and Woodring E. Wright (1998), Extension of life-span by introduction of telomerase into normal human cells, Science 16 January 1998, pp. 349 - 352. See Hayflick, His Limit, and Cellular Aging, which contains a time table for discovery and development in the field.
hTERT insulator [The hTERT gene is embedded within a Nuclease-resistant Chromatin Domain, Links, Images, Papers, Patents, Books] Usually, DNA methylation [Links] works to silence a gene, but in cases in which the gene is flanked by an insulator [Links, Patents, Books] and an enhancer [Links, Patents, Books], the enhancer is only turned on when the insulator is methylated at 5-cytosine in a CG-microsequence and covered with a silencing protein. Usually, a silencing protein binds to a similarly methylated promoter to silence a gene. I note that DNA methylation is primarily evident in placental mammals. In the mouse, gene silencing manages development from the embryonic stage, but only modifies about 100 genes.
hTERT methylation [Index/hTERT promoter methylation, Links/hTERT gene methylation, Images, Video, Papers, Patents, Books; Links/hTERT gene hypomethylation, Images, Video, Papers, Patents, Books; Links/methylation and transcription from hTERT, Images, Video, Papers, Patents, Books; Links/methylation and gene silencing, Images, Video, Papers, Patents, Books; Links/CpG methylation, Images, Video, Papers, Patents, Books; Index/Telomeric Chromatin; Index/Folic acid]. Hypermethylation of CpG islands in gene promoters is associated with gene silencing. Methylation of genes usually tends to silence them, with hTERT being the apparent exception, hTERT being densely methylated 600 bp upstream of the transcription start site. However, the region -150 bp to +150 bp around the transcription start site is unmethylated when the hTERT promoter is active, and transcription from hTERT is controlled by this region. We continue to regard methylation as being associated with gene silencing, including hTERT. (Zinn, Pruitt, Eguchi, Baylin, and Herman, 2007). According to telomere epigenetics (7.5, Index/Telomeric Chromatin), a high degree of DNA methylation tends to prevent telomere lengthening, while a low degree of DNA methylation tends to enhance telomere lengthening. However, this applies to subtelomeric and telomeric heterochomatin marks that are difficult to modify with conventional supplements. Modifying these repressive heterochromatin marks usually leads to aberrant telomere lengthening observed in tumors. "Loss of either DNA methylation or histone trimethylation marks at mammalian telomeres results in increased telomere recombination and aberrant telomere elongation." (Roberta Benetti, et al., 2008).
To keep methylation high is the approach usually recommended for good health by nutrionists. "Folate plays an essential role in one-carbon transfer involving remethylation of homocysteine to methionine, thereby insuring the provision of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions." - (Young-In Kim, 2005).
Methylating chemicals and their foodstuffs include:
Boosting Telomerase Activity and Telomere Lengthening
Confine methylating folic acid (5 mg/day) to the morning for general good health and methylation of homocysteine before starting telomere treatment in the evening, which might begin with Vitamin C for DNA demethylation to promote gene transcription and telomere lengthening, along with acetylation from an HDAC inhibitor, to promote transcription by expanding chromatin with acetylation of histones. The HDAC inhibitor sulforaphane inhibits telomerase in liver cancer cells and breast cancer cells, and may or may not be useful for this application. Use 1.5 grams of L-arginine plus 1.5 grams of L-lysine to boost HGH levels and provide L-arginine and L-lysine for nuclear transport signals, then take a workout with weights to maximize heat shock proteins such as HSP90 that transport transcription factors into the nucleus that activate transcription from the hTERT gene by interacting with the hTERT promoter. HSP90 also improves telomerase production by improving protein folding during telomerase construction (White). It may be beneficial to take heat-shock protein supplements to boost HSP90. Alpha lipoic acid boosts heat shock protein expression and HSP90 expression, while gamma tocopherol (from peanuts) inhibits the expression of heat shock proteins (HSPs). Carnosine and zinc also boost HSP expression. TEXOE boosts HSP70 and HSP27. HSP70 is important for translocation of proteins into the nucleus. A half an hour before the workout, move to demethylate the hTERT promoter with Vitamin C, and acetylate DNA to expand chromatin and improve transcription with a suitable HDAC inhibitor. Chromatin can be expanded by acetylating it for transcription from the hTERT gene with HDAC inhibitors such as diallyl disulfide or allyl mercaptan from allicin in crushed garlic, sodium 4-phenylbutyrate, sodium butyrate, L-carnitine, (or possibly the telomerase activators Tricostatin A, or orally bioavailable CGK 1026, which are known telomerase activators). At the same time, take telomerase activators that improve transcription of hTERT mRNA, such as the MAP kinase pathway telomerase activators including astragalus root, astragalus extract, the astragalosides, cycloastragenol, and (possibly feminizing) progesterone, and add the androgenic telomerase activators such as testosterone from forskolin or tribulus, the HIF-1 transcription factor telomerase activators (feminizing-in-overdose Diosgenin from Fenugreek, Ginkgo Biloba, and Ginkgolides) at suitably conservative dosages, EGF from colostrum, HGH secretagogues, and Nitric Oxide boosters such as L-arginine (5-10 grams/day) and L-citrulline (200 mg/day - 1000 mg/day). Nerve Growth Factor (NGF) boosters such as aceytl-L-carnitine plus alpha lipoic acid, carnosic acid, Huperzine A, PQQ, and rosemary tea promote Id-1 helix-loop-helix transcription factor to activate hTERT mRNA transcription. There are other telomerase activators such IGF-1 [Index] and resveratrol [Index] that phosphorylate cytoplasmic hTERT for import into the nucleus. IGF-1 may be taken during the telomerase activation phase of cyclic treatment or prepared from HGH by the liver, but resveratrol should only be used during the final 2-week telomerase inhibitor phase of treatment, because resveratrol is involved in chromatin compaction and gene silencing. After the workout and before bedtime, take Fenugreek extract (50% extract, 50% seed) at 1-1.5 grams (< 3 grams) to open telomere t-loops for access by the telomerase holoenzyme with Fenugreek's 4-hydroxyisoleucine, which boosts insulin, phosphorylating tankyrase 1 [Index] and stripping the t-loop closure protein TRF1. Bear in mind that 3 grams of Fenugreek seed per day for 12 weeks typically endows one with large, pendulous breasts. The high insulin makes one tired and hungry after 0.5-1.0 hours, so plan to sleep through the tired feeling and the munchies. Other telomerase activators exist and might be used in parallel in a "telomerase activator stack" for two weeks, including Haritaki, Purslane extract, and other medicines. The 2nd half of the month should feature telomerase inhibitors and cancer screen medicines and nutraceuticals.
Vitamin C demethylation at CpG shores of CpG islands to promote telomere lengthening
A half hour before bed during the 2-week telomerase activator phase of cyclic treatment, but after taking Fenugreek, it may be useful to take an additional large dose of vitamin C in time-release capsules just before bedtime to promote telomere lengthening. This may demethylate telomeric and subtelomeric DNA at CpG shores of CpG islands to improve telomere lengthening after building up a high level of fresh telomerase from the hTERT promoter, which will be demethylated for gene activity in the region -150 to +150 base pairs from the transcription start site, although it may or may not be heavily methylated in the region 600 bp upstream of the transcription start site. However, I could only confirm that vitamin C demethyates DNA at the CpG shores of CpG islands in embryonic stem cells and in fibroblasts, where it acts to accelerate the reprogramming of fibroblasts into induced pluripotent stem cells. This is to be done for two weeks before applying telomerase inhibitors for two weeks in a monthly cyclic protocol of telomease activation followed by telomerase inhibition.
Supplemental Remarks and Contradictory Signals
Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity in tumor cells. (Isabelle Guilleret and Pu Yan, 2002). According to Guilleret and Pu Yan, hTERT is the first gene discovered in which methylation correlates positively with gene expression. That is, methylation is usually a repressor for genes, but not for hTERT. (Theodora R. Devereux, et. al, 1999) checked hTERT promoter methylation many different tissues, including normal fibroblasts, fetal fibroblasts, and breast epithelial cells, which were much less methylated at 72 internal hTERT promoter CpG sites than in immortalized fibroblasts and cancer cells. See Isabelle Guillereta and Jean Benhattar (2003), Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres, Experimental Cell Research 289, Issue 2, 1 October 2003, 326-334. Also see (Kiyoaki Nomoto, et al, 2002) who found hTERT expression correlated with hTERT gene methylation, and (Widschwendter A, et al, 2004), who found no such correlation in normal ovarian cells, ovarian cancer cells, or cervical cancer cells. "No correlation was detected between hypermethylation of hTERT and hTERT mRNA expression." - (Widschwendter A, et al, 2004). See also Theodora R. Devereux, et al, (1999), DNA Methylation Analysis of the Promoter Region of the Human Telomerase Reverse Transcriptase (hTERT) Gene, Cancer Research 59, 6087-6090, December 1, 1999. "Most of the hTERT-negative normal cells and about one-third of the hTERT-expressing cell lines had the unmethylated/hypomethylated promoter, whereas the other hTERT-expressing cell lines showed partial or total methylation of the promoter. The promoter of one hTERT-negative fibroblast cell line, SUSM-1, was methylated at all sites examined."
See also Guido Krupp and Reza Parwaresh, Telomerases, telomeres, and cancer, "It has been suggested that DNA methylation recuits histone deacetylase causing histone deacetylation and gene transcription repression. Pharmacological inhibition of histone deacetylation by inhibiting histone deacetylases with Trichostatin A (TSA) induces an increase in hTERT promoter activity and activation of telomerase in telomerase negative cells. In telomerase-positive cells, however, TSA induces telomerase inhibition." The hTERT gene promoter is GC-rich and forms a dense CpG island (of 72 CpG sites), providing sequences that are targets of cytosine methylation to provide transcriptional control. Methylation of cytosine sites in CpG island sequences is a mechanism for transcriptional repression of Rb and p16INK4A. (op.cit.). "In many tumors...the CpG island (sites) of the hTERT gene are often methylated. DNA de-methylation induced by 5-azacytidine results in increased hTERT expression..." (op.cit.).
Histone Modifications of the Epigenome (Encyclopedia)
hTERT mRNA [(7) Telomerase/hTERT component, Links/hTERT mRNA, Images, Video, Papers, Patents, Books; Fast Telomere Extension]. The half-life of hTERT mRNA is 1-3 hours, the half-life of the active telomerase complex is 24 hours, the half-life of hTERT protein is 4 weeks, and the half-life of hTR RNA is 5 days. Thus, dosing with astragalus every few hours may allow hTERT mRNA levels to gradually increase over time, at least maintaining hTERT mRNA for translation into hTERT protein. The common adult dosage [Links, Papers, Books] is 2 to 6 g per day of the powdered root, taken in divided doses 3-5 times a day, according to many Chinese specialists. 33 grams/day is the usual maximum, conveniently taken in 4 doses of 8 or 9 grams/dose, which is what I use. Rejuvenating results seem to be observed in elderly Chinese specimens (70 looks 40) after a number of years with this approach, as if higher telomerase levels could be built up gradually and sustained with small doses of astragalus taken every few hours. This suggests that hTERT mRNA levels are gradually improved or sustained after an interval if frequent dosing every 3 hours or so is used to boost declining hTERT mRNA with a half-life of 1-3 hours. The half-life of mRNAs in mammalian cells varies from less than 30 minutes to about 20 hours. The most rapidly degrading mRNAs are transcription factor mRNAs, which contain AU-rich sequences near their 3' ends signaling for rapid degradation. Fast Telomere Extension may be implemented with liposomal transfection of nucleoside-modified hTERT mRNA evading the innate immune system that incorporates structural modifications for a longer mRNA half-life.
hTERT Nuclear Transport [Links, Images, Video, Papers, Patents, Books].
hTERT Nuclear Export [Links, Images, Papers, Patents, Books].
CRM/exportin1 (112 kDa) binds to hTERT and transfers it into the cytoplasm. Antioxidants are sometimes used to suppress nuclear export of hTERT. The nuclear export signal at amino acids [Images] 969-981 has the amino acid sequence NMRRKLFGVLRLKC (W.Klapper et al, 2001).
hTERT Nuclear Import [Links, Images, Papers, Patents, Books].
14-3-3 protein (29-33 kDa) binds to hTERT for nuclear transport, and also binds to CRM/exportin1 to suppress the nuclear export signal. The 14-3-3 proteins interact with cellular signaling molecules including Raf-1, Cbl, Bad, and IGF-1, and are molecular chaparones for cellular localization of several proteins. The 14-3-3 proteins also bind with FOXO (when phosphorlated by AKT) to keep FOXO out of the nucleus, preventing transcription of senescence-inducing CAV1 for caveolin-1. Phosphorylation of hTERT by Akt protein kinase or other kinases facilitates its import into the nucleus from the cytoplasm (W.Klapper et al, 2001).
hTERT plasmids [Links/hTERT plasmid design; Links/hTERT plasmids, Images, Video, Papers, Patents, Books, Amazon; addgene, Links/hTERT plasmid vectors, Images, Video, Papers, Patents, Books]. See addgene/hTERT. See also Plasmids, Gene Therapy, Targeted Genome Editing, and zinc finger nucleases.
hTERT plasmids for Gene Therapy [Links/hTERT plasmids for gene therapy; Images, Video, Papers, Patents, Books].
Transfection-Ready hTERT Plasmids [Links/transfection-ready hTERT plasmids; Images, Video, Papers, Patents, Books]. See Origene, Origene NM_198253 with transfection-ready hTERT plasmids.
hTERT promoter [Biocarta/hTERT_Pathway, Biocarta/Telomeres, Telomerase, Cellular Aging, and Immortality, Wikipedia/Promoter; Links/the hTERT promoter sequence, Images, Papers, Patents, Books; Links/hTERT Promoter, Books/hTERT Promoter, Patents/hTERT promoter, Patent Lens/Telomerase, Papers, Amazon, Books/human gene promoter and repressor design, Books/transcription promoters; hTERT promoter (-480 to +1), hTERT & mTERT Promoter Sequences (slide, article.PDF); Wikipedia/Nuclear receptor; hTERT Transcriptional Repressors]. See Morin, et.al, the Aug. 17, 2004 Geron patent Telomerase promoter driving expression of therapeutic gene sequences. See also M Wick, D Zubov, G Hagen, 1999, Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT), Gene, Volume 232, Issue 1, 17 May 1999, Pages 97-106. Furthermore, don't miss Cong, YS, The Human Telomerase Catalytic Subunit hTERT: organization of the gene and characterization of the promoter, Human Molecular Genetics, 1999, vol.8, no.1, 137-142. See also Yu-Sheng Cong, Woodring E. Wright, and Jerry W. Shay, Human Telomerase and Its Regulation and Izumi Horikawa, P. LouAnn Cable, Cynthia Afshari and J. Carl Barrett, 1999: Cloning and Characterization of the Promoter Region of Human Telomerase Reverse Transcriptase Gene , Cancer Research, 59, 826-830, February 1, 1999 [Papers, Books]. See Takakura, M., Kanaya,T., et al, 1999, Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells, Cancer Research, 59, 551-557. See also Telomerase, Aging and Disease (Advances in Cell Aging and Gerontology) by M.P. Mattson, Elsevier, 2001. See also Theodora R. Devereux, Izumi Horikawa, Colleen H. Anna, Lois A. Annab, Cynthia A. Afshari and J. Carl Barrett, 1999. DNA Methylation Analysis of the Promoter Region of the Human Telomerase Reverse Transcriptase (hTERT) Gene, Cancer Research 59, 6087-6090, December 1, 1999; Wick M., Zubov D., and Hagan G. (1999), Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT), Gene 232: 97-106; Wu, K.J., C. Grandori, M. Amacker, N. Simon-Vermot, A. Polack, J. Lingner, and R. Dalla-Favera, (1999), Direct activation of TERT transcription via c-MYC, Nature Genetics. 21: 220-224. See also Joseph C. Poole, Lucy G. Andrews and Trygve O. Tollefsbol (2001), Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT), Gene, Volume 269, Issues 1-2, 16 May 2001, Pages 1-12. See Satoru Kyo, Masahiro Takakura, Toshiyoshi Fujiwara, Masaki Inoue (2008), Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers, Cancer Science, Volume 99, Issue 8, pages 1528–1538, August 2008. Don't miss Ralf Janknecht, ed. Varda Rotter (2004), On the road to immortality: hTERT upregulation in cancer cells, FEBS Letters, Volume 564, Issues 1-2, 23 April 2004, Pages 9-13. Also see Satoru Kyo and Masaki Inoue (2002), Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy?, Oncogene, 21 January 2002, Volume 21, Number 4, Pages 688-697.
The hTERT promoter has relatively high GC content and is lacking both TATA and CAAT boxes, unlike the hTR promoter (C.J. Cairney and W.N. Keith, 2007), which has both TATA and CAAT boxes and is transcribed by RNA polymerase II. Note that "overexpression of tumor suppressor p53 can decrease the expression of hTERT mRNA, as well as directly repress transcriptional activation of the hTERT promoter construct." HDACs (histone deacetylases) that condense chromatin can repress transcriptional activation of hTERT, and conversely sometimes HDAC inhibitors such as Tricostatin A which expand chromatin can activate hTERT mRNA transcription. Transcription factors acting on the hTERT promoter [Images, Papers, Patents, Books] and kinases for hTERT activation via hTERT catalytic component phosphorylation include:
Transcription Factors with Sites on the hTERT Promoter [Links, Images, Papers, Patents, Books; Links/Transcriptional Regulation of the hTERT promoter, Images, Papers, Patents, Books]. "Several transcription factor and repressor binding sites have been identified in the hTERT promoter... Notable among these are two E-boxes for the Myc oncogene, several GC-boxes as Sp1 binding sites, and cis-regulatory elements [definition] that may recruit AP1, AP2, AP4, ATF, CREB, ER, PR, GC, IK2, MYMOD, NF1, T3Ralpha and USF." (Jun-Ping Liu, 2001).
(1) c-Myc enables the hTERT promoter [Notes/(59), Wu, Nature Genetics, 1999, Index/c-Myc, List/c-Myc, Links, Papers, Patents, Books]. The c-Myc protein produced by the c-Myc gene is a transcription factor [Links, Papers, Patents, Books; Wikipedia/C-myc]. Note that the c-Myc (Myc) gene is an oncogene [Links/Oncogene, Wikipedia/Oncogene], which can cause cancer if it is overexpressed, mutated, or translocated. c-Myc is a basic helix–loop–helix leucine zipper protein that dimerizes with Max to bind the DNA sequence 5'-CACGTG-3', known as an E-box, and activates transcription. C-Myc "is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences (E-boxes) and recruiting histone acetyltransferases (HATs)". - Wikipedia/c-Myc. C-myc can be upregulated by EGF, colostrum, estradiol and PDGF, which can be upregulated by exercise. c-Myc is regulated at a more elementary level by its binding proteins including Max, Mad, TFII.1, YY1 and Mitz.
(2) Sp1 [Telomerase Activator List/(43) SP1, Links, Images, Papers, Patents, Books].
There are 5 Sp1 sites on the hTERT promoter. (Cong, Wright, and Shay, 2002). According to some investigators, in normal cells SP1 recruits HDAC to repress transcription, while in cancer cells SP1 promotes transcription from hTERT. (Izumi Horikawa and J. Carl Barrett, 2003). Sp1 has been described as working with C-myc to activate telomerase. Sp1 mutation retards c-Myc stimulated hTERT gene transcriptional activity. SP1 is a zinc finger transcription factor. (C.J. Cairney and W.N. Keith, 2007) pictures Sp1 as a transcriptional activator of hTERT and Sp3 as a transcriptional repressor. According to them, the 5 Sp1 binding sites are used for transcriptional repression of hTERT by transcription factors CtBP, p53, p73, and TGF-beta.
Note that, according to at least one source, the transcription factor Sp1 binds to a GC box with the sequence GGGCGG, and represses transcription by recruiting histone deacetylase, which compacts chromatin. This seems to apply to normal cells, rather than cancer cells. A transcriptional derepressor such as CGK 1026 might work by filling the GC box pocket used by Sp1 for repression, although I find that E2F pocket protein complexes assembled on the hTERT promoter are inhibited by CGK 1026 instead.)
(3) estrogen receptor (ER) [Estrogen receptor pathway, Telomerase Activators/(10) Estrogen, Index, Links, Images, Papers, Patents, Books, Wikipedia/Estrogen Receptor]. See Geoffrey M. Cooper and Robert E. Hausman, The Cell: A Molecular Approach, 4th edition, Chap.15, pp.602-603 on Estrogen Action, which shows the formation of the estrogen receptor complex from estrogen bound to estrogen receptor dimerized and capped by coactivator HAT, or Histone Acetyl Transferase (hALP). The estrogen receptor complex behaves as a transcription factor [Image] upregulating hTERT through interaction with the hTERT promoter. Estrogen (17-beta-estradiol), like many other nuclear receptor superfamily targeting molecules (nuclear receptor superfamily ligands including the steroid hormones, vitamin D3, thryoid hormone, and retinoic acid), can penetrate the cell membrane. Estrogen penetrates to bind with estrogen receptor in the cytosol. Two Estrogen receptors, each coupled with an estrogen molecule, then forms a dimer that penetrates through the nuclear pore into the nucleus and is there capped with HAT (histone acetyltransferase). This is the transcription factor complex that activates target DNA gene promoters in the cell nucleus at the estrogen response element sequence (ERE sequence: article; more than one ERE exists: the vitellogenin Estrogen Response Element (ERE) sequence is: GGTCA CAG TGACC. See the hTERT promoter estrogen receptor binding site). (Until the estrogen receptor is coupled to estrogen from cell membrane penetration, it is coupled with the heat shock protein HSP90.) Note (C.J. Cairney and W.N. Keith, 2007) pictures Estradiol as interacting with the hTERT promoter via the transcription factor ESR-1. "In addition to direct action on the hTERT promoter, estrogen and progesterone also regulate telomerase activity indirectly... E2 (17-beta-estradiol) stimulates c-Myc gene expression and induces an additive c-Myc interaction with the E-box of the hTERT promoter in human breast cancer cells..." (Jun-Ping Liu, 2001).
(4) AP-1 transcription factor activator protein: [Telomerase Activators/AP-1, Wikipedia, Links, Images, Papers, Patents, Books]. "The transcription factor activator protein 1 (AP-1) is involved in cellular proliferation, differentiation, carcinogenesis, and apoptosis and is expressed broadly in both cancer and normal cells. There are several putative AP-1 sites in the hTERT promoter, but their functions are unknown. " (from Masahiro Takakura, Satoru Kyo, Masaki Inoue, Woodring E. Wright, and Jerry W. Shay, (2005), Function of AP-1 in Transcription of the Telomerase Reverse Transcriptase Gene (TERT) in Human and Mouse Cells, Molecular and Cellular Biology, September 2005, p. 8037-8043, Vol. 25, No. 18. AP-1 is sometimes termed "the early response transcription factor", and is formed from a combination of c-Jun and c-Fos. Note that AP-1 [List] is modulated by (137) berberine, a Product B component.
(4b) AP-2 transcription factor activator protein: [Telomerase Activators/AP-2, Wikipedia/Activating protein 2, Links, Images, Papers, Patents, Books].
(5) Id-1 helix-loop-helix protein [Telomerase Activators/ID-1, Links, Images, Papers, Patents, Books]. Id-1 helix-loop-helix protein immortalizes human keratinocytes by activating hTERT and can be produced by nerve growth factor (NGF), which can be generated by application of Rosemary (carnosic acid), acteyl-L-carnitine, or platelet activating factor. Like AP-1 above, Id-1 is a helix-loop-helix transcription factor.
(6) Hypoxia-inducible factor 1 (HIF-1) [Wikipedia/Hypoxia-inducible factors, Telomerase Activators/HIF-1, Links, Images, Video, Papers, Patents, Books, WikiGenes/HIF-1]. HIF-1 (hypoxia-inducible factor 1) activates telomerase [Article, Links]. "Hypoxia activates telomerase via transcriptional activation of hTERT, and HIF-1 plays a critical role as a transcription factor." Ginkgo biloba also promotes transcription of HIF-1. See [Wikipedia/Hypoxia-induced factors, Images/HIF-1, Links/HIF-1 molecule]. HIF-1 activates transcription from hTR. In fact, the hTERT promoter and the hTR promoter both feature Hypoxia Response Element (HRE) sites for binding the transcription factor HIF-1 which overlap the E-boxes for binding c-Myc. "HIF-1 is known to bind to HRE sites in the promoters of a variety of genes where it recruits the basal transcriptional machinery and transcriptional coactivators such as P300/CBP to induce transcription." (C.J. Cairney and W.N. Keith, 2007).
(7) Tankyrase [Telomerase Activators/Tankyrase, Wikipedia/Tankyrase, Links, Images, Papers, Patents, Books, WikiGenes/Tankyrase]. Tankyrase is a poly(ADP-ribose) polymerase associated with an hTERT poly(ADP-ribose) binding site. Tankyrase is a positive regulator of telomere enlongation in vivo, apparently by inhibiting TRF1, which binds the trailing single strand in the telomere loop. The hTERT poly(ADP-ribose) binding site is at amino acids 962-983 and has the amino acid sequence RGFKAGRNMRRKLFGVLRLKCH (W.Klapper et al, 2001).
(8) Ets [Telomerase Activators/Ets, Links/transcription factor Ets, Images, Papers, Patents, Books]. Ets is an hTERT transcriptional activator (C.J. Cairney and W.N. Keith, 2007).
(9) Glucocorticoids [Telomerase Activators/Glucocorticoids, Links/glucocorticoid activation of hTERT, Images, Papers, Patents, Books]. Several "putative" binding sites for the glucocorticoid, progesterone, and androgen steroid hormones have been found in the 5' flanking region of the hTR gene and may also be present in the hTERT gene (C.J. Cairney and W.N. Keith, 2007).
(10) USF2 [Links/transcription factor USF2, Images, Papers, Patents, Books; OMIM/usf2]. USF2, a basic helix-loop-helix leucine zipper transcription factor, excites transcription and is associated with a proximal Ebox (at +44 to +49) and a distal Ebox (-165 to 160) on the hTERT promoter associated with the Ebox sequence CACGTC. Note that c-Myc forms a dimer with Max that binds to these Eboxes to promote transcription, as do the Ebox-binding transcription factors including E2F-1, USF1 (43 kDa), and USF2 (44 kDa), and HIF-1 (HIF-1alpha/ARNT, Hypoxia inducible factor 1-alpha/Aryl hydrocarbon receptor nuclear receptor). See Shoulei Jiang, Maria R. Galindo and Harry W. Jarrett (2010), Purification and identification of a transcription factor, USF-2, binding to E-box element in the promoter of human telomerase reverse transcriptase (hTERT) Proteomics 2010, 10, 203-211. USF2 interacts as a transcription factor with the hTERT promoter as a homodimer or as a heterodimer with USF1 [Links/transcription factor USF1, Images, Papers, Patents, Books, OMIM/usf1]. Both USF1 and USF2 stimulate hTERT transcription as homo- or heterodimers with each other.
Factors Influencing Telomerase Activity
[List Activators, List Inhibitors; Links, Images, Papers, Patents, Books].
(11) E1A [Telomerase Activator/E1A, Links/E1A protein, Images, Papers, Patents, Books]. E1A increased luciferase assay reports of hTERT promoter activity and hTR promoter activity by up to a factor of 3, and exon 2 of E1A alone was sufficient to introduce a 2-fold increase. E1A was shown to interact with Sp1 sites on the hTR promoter to produce transcriptional activation, (and no doubt similarly on the hTERT promoter). - after (C.J. Cairney and W.N. Keith, 2007).
(12) NF-kappa-B: [Index, Telomerase Activator/NF-kappa-B, Wikipedia, Links, Images, Papers, Patents, Books; Links/NF-kappa-B as a telomerase activator, Links/NF-kappa-B hTERT activation pathway]. See M Natarajan, S Mohan, R Konopinski, R A Otto, and T S Herman (2008), Induced telomerase activity in primary aortic endothelial cells by low-LET gamma-radiation is mediated through NF-kappa-B activation, British Journal of Radiology, (2008) 81, 711-720.
(13) Progesterone [Telomerase Activators/(60) Progesterone, Index, Links, Images, Papers, Patents, Books, Wikipedia/Progesterone receptor]. It is believed by some experimenters that progesterone, which is antagonistic to estrogen, acts primarily through the Map Kinase pathway to activate hTERT mRNA transcription, although some crosstalk may enable it to act through the estrogen receptor. See human progesterone receptor (hPR), a member of the steroid-receptor superfamily of nuclear receptors. Note that "the hTERT promoter lacks a canonical progesterone-responsive element." "Progesterone significantly induced hTERT mRNA expression within 3 hours after exposure. This transient effect peaked at 12 hours and then decreased." - Zhuo Wang, Satoru Kyo, et al, (2000), Progesterone Regulates Human Telomerase Reverse Transcriptase Gene Expression via Activation of Mitogen-activated Protein Kinase Signaling Pathway, Cancer Research, Oct 1, 2000, 60, 5376. That is, progesterone modulates hTERT gene expression by activating the Mitogen-Activated Protein Kinase (MAPK) pathway. "Progesterone usually antagonizes estrogen action and inhibits estrogen-induced cell proliferation in reproductive tissue such as the endometrium. Consequenty, progesterone is therapeutically applied to inhibit estrogen-dependent cancers." Progesterone-stimulated hTERT mRNA expression rises after 3 hours and is inhibited after 12 hours by a mechanism involving p21WAF1/Cip1, a cyclin-dependent kinase inhibitor.
Phosphorylating Kinases Influencing hTERT Location and Telomerase Activity
[Links, Images, Papers, Books; hTERT Protein Phosphorylation].
(14) Protein kinase C [Telomerase Activators/(27) Protein Kinase C, Links, Images, Papers, Patents, Books, Books/protein kinase C and telomerase]. Protein Kinase C is involved in the regulation of telomerase activity. Note that kinases phosphorylate proteins, so that Protein Kinase Cα phosphorylates the hTERT catalytic component of telomerase, enabling its transport into the nucleus from the cytoplasm.
(15) Akt Protein Kinase [Telomerase Activators/(58) AKT Kinase, Index, Links; Links/Akt Protein Kinase and telomerase, Books] is associated with two sites for phosphorylation on hTERT protein. See Sang Sun Kang, Taegun Kwon, Do Yoon Kwon, and Su Il Do, Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit, J Biol Chem, Vol. 274, Issue 19, 13085-13090, May 7, 1999. Note that resveratrol activates telomerase by phosphorylating cytoplasmic hTERT with Akt1 kinase, although it also activates SIRT1, which deacetylates DNA with HDAC effect, compacting chromatin and generally repressing transcription with gene silencing. Ordinarily, this represses transcription of hTERT. Conversely, HDAC inhibitors like Tricostatin A often activate hTERT transcription by expanding chromatin. It seems that several growth factors such IGF-1 activate telomerase via Akt1. See also the index entry for Promoters (Gene Promoters and Transcription Factors). See hTERT activation via the PI3K/Akt pathway. By now we realize that phosphorylation of the hTERT catalytic component of telomerase can "activate" existing hTERT molecules (so that they can migrate from cytoplasm into the nucleus) without supplying a transcription factor that increases the number of hTERT mRNA transcripts. Usually "telomerase activators" increase the number of hTERT mRNA transcripts. It will be useful to keep this difference in mind while analyzing "telomerase activators". The AKT protein kinase phosphorylates hTERT in the cytoplasm to enable its import into the nucleus. AKT is not a transcription factor, but a kinase with a mission to phosphorylate.
(16) The MAP Kinase pathway: hTERT activation via the MAP Kinase pathway. EGF activates hTERT via the MAP Kinase pathway. See Yoshiko Maida, Satoru Kyo, et.al, (2002), Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway, Oncogene, 13 June 2002, Vol 21, No.26, Pages 4071-4079. TAT2 (cycloastragenol) has been identified as hTERT activating via the MAP Kinase pathway, so that the astragalosides probably probably primarily activate hTERT via the MAP Kinase pathway. "...investigation showed that TAT2 enhances telomerase activity by activation of the ERK/MAPK pathway", from Fauce, Steven Russell, PhD, Univ.Calif., LA, (2007), Telomerase modulation and its effect on antiviral activity of CD8+ T lymphocytes, PhD thesis dissertation, advisor, Rita B. Effros. See Wikipedia/MAPK/ERK pathway. MAPK signaling cascades can influence transcription via direct phosphorylation of Sp1, and via the transcription factors c-Myc, AP-1, and Ets in the core promoter region of the hTERT gene [Links]. See Davis, R.J. (1993), The mitogen-activated protein kinase signal transduction pathway, Journal of Biological Chemistry 268, 14553-14556.
See also hTERT Transcriptional Repressors. "The minimum sequence of promoter activity is contained within 330 bp upstream of the ATG (the translation start site)... The GC-rich region forms a large CpG island arund the ATG, suggesting methylation may be involved in the regulation of hTERT expression." - Yu Sheng-Kong, Woodring E. Wright and Jerry W. Shay (2002), Human Telomerase and its Regulation, Microbiology and Molecular Biology Reviews, Sept. 2002, pp. 407-425, and associated papers. See also Analysis of the hTERT promoter occupancy in vivo using chromatin immunoprecipitation assays, chromatin immunoprecipitation assays, Wikipedia/Chromatin Immunoprecipitation (ChIP) [Links, Images, Video, Books], and Wikipedia/ChIP-on-chip [Links, Images, Video, Books, Publications].
Note that the hTERT C-site repressor region was discovered by Sierra Sciences, which has developed an inhibitor for the C-site repressor inside the hTERT promoter that can highly activate telomerase. See Sierra Sciences (WO/2002/101010) and METHODS AND COMPOSITIONS FOR MODULATING TELOMERASE REVERSE TRANSCRIPTASE (TERT) EXPRESSION, which explain the location of the repressor regions and the inhibitor for promoting telomerase activation. Also see the Sierra Sciences patent 7795416, Telomerase expression repressor proteins and methods of using the same. The Sierra Sciences telomerase activator would probably work better in a short telomerase activation/telomerase inhibition cycle than in the six-month long cycle of the Patton Protocol. High doses may be dangerous, as it can massively activate telomerase, in which case it may seem to behave like a tumor promoter.
hTERT Promoter methylation [Index/hTERT methylation, Links, Images, Papers, Patents, Books; Index/Folic Acid, Index/Telomeric Chromatin]. The hTERT promoter is in a CpG island regulated in part by DNA methylation. CpG islands [Images, Papers, Patents, Books] are often found in the vicinity of gene promoters functioning as potential targets for gene repression via DNA methylation. ..."In telomerase-positive samples, a methylation of all the CpG sites was observed for the hTERT promoter region (-500 to +1), whereas the exonic part (+1 to +450) revealed an unstable methylation pattern. Incomplete methylation of the proximal exon region could be necessary for, at least, a low level of hTERT transcription." See Isabelle Guilleret1, a and Jean Benhatta (2004), Unusual distribution of DNA methylation within the hTERT CpG island in tissues and cell lines, Biochemical and Biophysical Research Communications, Volume 325, Issue 3, 17 December 2004, Pages 1037-1043. Demethylation of DNA could contribute to aging by interfering with the hTERT promoter. See Cheng Liu, Xiaolei Fang, Zheng Ge, Marit Jalink1, Satoru Kyo, Magnus Björkholm, Astrid Gruber, Jan Sjöberg, and Dawei Xu (2007), The Telomerase Reverse Transcriptase (hTERT) Gene Is a Direct Target of the Histone Methyltransferase SMYD3, Cancer Research, March 15, 2007 67; 2626. Writers vary somewhat in their descriptions of CpG island methylation in hTERT: "The data show that the hTERT CpG island is not methylated in primary tissues and cultured cells, suggesting that CpG island methylation is not responsible for hTERT repression in telomerase-negative cells." In some tumors, however, demethylation of methylated CpG islands with 5-azacytidine upregulated hTERT expression. In normal human cells, histone deacetylation is primary in silencing hTERT transcription, as shown by upregulation of hTERT after application of Tricostatin A, a histone deaceylase inhibitor. - (Jun-Ping Liu, 2001). At this time I use 1.6 mg/day to 5 mg/day of folic acid to preserve essential methylation from super B-vitamin pills that function as a homocysteine blocker. Nutritionists frequently recommend preserving essential DNA methylation with 0.4 mg/day - 1 mg/day folic acid to avoid obesity and diseases stemming from defective methylation.
hTERT protein phosphorylation [Nutraceuticals and Telomerase Activators Phosphorylating hTERT, Links/hTERT protein phosphorylation, Images, Papers, Patents, Books; Links/the role of hTERT phosphorylation in the regulation of telomerase activity, Images, Papers, Patents, Books]. The phosphorylation of hTERT protein (the catalytic component of telomerase) is associated with translocation of hTERT from the cytoplasm to the nucleus during CD4+ T-cell activation [Images]. Telomerase activity in resting T-cells [Images] is not dependent on net hTERT protein increase [Images], but on hTERT protein phosphorylation associated with its import into the nucleus from the cytoplasm [Images]. See Kebin Liu, Richard J. Hodes and Nan-ping Weng (2001), Cutting Edge: Telomerase Actiation in Human T-Lymphocytes Does not Require increase in Telomerase Reverse Transcriptase (hTERT) Protein but is Associated with hTERT phosphorylation and Nuclear Translocation, Journal of Immunology, 2001; 166; 4826-4830. Sang Sun Kang, Taegun Kwon, Do Yoon Kwon and Su I Do (1999), Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit, The Journal of Biological Chemistry, May 7, 1999, 274, 13085-13090. Kinases phosphorylate proteins.
hTERT repressor [Links/hTERT repressor, Images, Papers, Patents, Books, Amazon, LifeExtension1, LifeExtension2, Biocarta Pathways]. See also William H. Andrews, C.A.Foster, S. Fraser, Hamid Mohammedpour, of Sierra Sciences, 2004: Methods and Compositions for Modulating Telomerase Reverse Transcriptase (TERT) Expression, United States Patent No. 6,686,159 B2, Andrews, et al., Feb 3, 2004. Explains the hTERT repressor part of the hTERT promotor and means of interfering with hTERT repression. "In 2001, Sierra Sciences discovered a repressor binding site (dubbed "Site C") that blocks the expression of telomerase reverse transcriptase ("TERT"). For this discovery, Sierra Sciences was issued U.S. patent #6,686,159 in 2004. Sierra Sciences discovered another repressor binding site, "GC-Box 5," in 2004, for which it was issued patent #7,279,328 in 2007." - Wikipedia/Sierra Sciences. See US Patent 7,279,328 (2007) Methods and Compositions for Modulating Reverse Transcriptase (TERT) Expression (2007), which refers the reader to (Nozawa K., et al., 2001, Horikawa et al., 2005, Oh, S., et al., 1991, and Oh, S., et al., 2000). See also (Won, Yim and Kim, 2002, Won, Chang, Oh, and Kim, 2004). Transcriptional repressors of hTERT include Sp3, AP-1, MZF, WT1 and E2F (C.J. Cairney and W.N. Keith, 2007).
hTERT Transcriptional Repression [Telomerase inhibitors, Links/hTERT transcriptional repression, Images, Papers, Patents, Books]. Notes (Cong, Wright, and Shay, 2002): hTERT is repressed in most tissues prior to birth. P53 transcriptionally represses hTERT. This takes place within hours, before cell cycle arrest or apoptosis takes place. Histone deacetylases (HDACs) are involved in hTERT transcriptional repression. Interferon-alpha represses hTERT activity within 4 hours in malignant and non-malignant human hematopoietic stem cell lines, primary leukemic cells and normal T-lymphocytes. The hTERT gene is thought to be a direct transcriptional target of the interferon-alpha signaling pathway. The new vitamin D3 analog 5,6-trans-16-ene-vitamin D3 represses hTERT transcription. Retinoic acid [List] and dimethyl sulfoxide [List] repress hTERT transcription. Treatment with the DNA methylation inhibitor 5-azacytidine induced hTERT transcription in 2 telomerase-negative ALT cell lines. (Showing methylation is an important factor in hTERT transcriptional repression.) Transcriptionally repressed genes tend to be associated with hypoacetylated histones, whereas transcriptionally active genes tend to be associated with hyperacetylated histones. (Acetylation expands chromatin, making it available for transcription.) Accumulating evidence exists that telomerase activity can be regulated by hTERT phosphorylation [Encyclopedia]. (Won, Chang, Oh, and Kim, 2004). Transcriptional repressors of hTERT include Sp3, AP-1, MZF, WT1 and E2F (C.J. Cairney and W.N. Keith, 2007).
hTERT Transcriptional Repressors
[Links, Images, Papers, Patents, Books; Telomerase Inhibitors: (61) Transcriptional Repressors of hTERT]. hTERT transcriptional repressors exist in several chromosomes. MAD/MAX heterodimers bound to E-boxes repress hTERT transcription. Repressors of hTERT transcription include factors from 3 lists:
hTERT transfection [Links, Images, Papers, Patents, Books, Amazon, LifeExtension2].
hTERT vectors [Links/hTERT vectors, Images, Papers, Patents, Books, Amazon, LibCong/DNA viral vectors LifeExtension2]. See Mogfield JE, Liu WR, Reid R, 2006: Adenoviral human telomerase reverse transcriptase dramatically improves ischemic wound healing without detrimental immune response in aged rabbit model., Human Gene Therapy, 2006; 17(6): 651-660. This shows how telomerase may be activated via gene therapy using a viral vector. See Origene, Genetiq or Vector Biolabs for hTERT vectors [Links/hTERT viral vectors, Images; Links/hTERT vectors, Images]. See also [Links/targeted insertion of the hTERT gene, Images, Papers, Patents, Books, Amazon], targeted gene insertion [Links, Images, Papers, Patents, Books, Amazon] and gene insertion [Links, Images, Papers, Patents, Books, Amazon]. Also see Anti-Aging Insertion of the hTERT gene [Links, Papers, Patents, Books] with anti-aging gene insertion [Links, Papers, Patents, Books, Amazon]. See also targeted genome editing with zinc finger nucleases.
hTR (hTERC, TERC) [Biocarta/Overview of telomerase RNA component gene hTerc Transcriptional Regulation, Wikipedia/Telomerase RNA component, Links/the hTR gene, Images, Papers, Patents, Books; Links/the hTR promoter, Images, Papers, Patents, Books; Links/hTR plasmids, Images, Papers, Patents, Books; Links/hTR transfection, Images, Papers, Patents, Books]. hTR (hTERC) - The gene encoding the RNA component of human telomerase corresponding to the telomeric DNA 5'-GGTTAG-3' minisatellite tandem repeat. "The template region of TERC is 3'-CAAUCCCAAUC-5'. This way, telomerase can bind the first few nucleotides of the template to the last telomere sequence on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go, realign the new 3'-end of telomere to the template, and repeat the process." - Wikipedia/Telomerase [Books].
The hTR (hTERC) Promoter
[Links/The hTR Promoter, Images, Papers, Patents, Books; Links/The hTERC Promoter, Images, Papers, Patents, Books]. The hTR promoter contains a TATA box-like element and a consensus CCAAT box, so that it is probably transcribed by RNA polymerase II. Deletion of the CAAT box eliminates hTR transcription in luciferase assays. See (C.J. Cairney and W.N. Keith, 2007). Binding of the transcriptional activator NF-Y to the CCAAT box is essential for activation of transcription from hTR. See the transcriptional activator NF-Y [Images, Papers, Patents, Books; Links/the NF-Y Promoter, Images, Papers, Patents, Books].
Human Cell Types [Links/Human Cell Types, Images, Papers, Books; Links/Telomerase-Positive Human Cell Types, Images, Papers, Books, (includes some stem cell types and germline cells); Links/Telomerase-Negative Human Cell Types, Images, Papers, Books, (includes most human somatic tissues)]. Lack of cancer in telomerase-positive stem cells and germline cells means that telomerase itself is not oncogenic. - from Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science, 1998.
Human Embryonic Stem Cells [Human Embryonic Stem Cells: A Primer; Links, Images, Papers, Patents, Books, LibCong/Embryonic Stem Cells, LibCong/Adult Stem Cells, LifeExtension].
Human Genome [Index/Gene (Human Chromosomes and Genes), HUGO Gene Families, GHR/Gene Family Browser, NCBI/Human Genome Resources, OMIM, Books, LibCong/The Human Genome, Wikigenes, Wikipedia/Human Genome, Nature/Human Genome, Amazon, Links, LifeExtension, Links/The Human Genome and aging, Books/the human genome and aging], Stillman & Stewart, The Genome of Homo Sapiens, CSHL Press, 2004. [OMIM, Searching OMIM, Human Chromosomes 1-23, Index/Gene for Human Chromosomes]. [Also see Human Epigenome Project - Methylation Patterns, (Beck & Olek, The Epigenome), Animal Genome Size Database].
Human Growth Factors [Index/Growth Hormones and Growth Factors, Links, Images, Video, Papers, Patents, Books, LifeExtension; Wikipedia/Growth Factor, Links/Growth Factors, Images, Video, Papers, Patents, Books, LifeExtension; Index/Skin]. According to Mexican researchers Gomez and Garcia, most growth factors are telomerase activators. HGH and IGF-1 activate telomerase by increasing the number of hTERT mRNA transcripts (HGH), or by phosphorylating the hTERT catalytic component of telomerase for import from the cytoplasm to the nucleus (IGF-1). Many growth factors are found in skin creams [Index], including Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF, aFGF = FGF1, bFGF = FGF2, and Fibroblast Growth Factors FGF1-FGF23), Platelet Derived Growth Factor (PDGF), Tissue Growth Factor (TGF), Keratinocyte Growth Factor (KGF), Vascular Endothelial Growth Factor (VEGF), and IGF-1. See Qiagen's SABiosciences Growth Factor PCR array. Note that Colostrum Skin Creams [Images] are rich in telomerase-activating growth factors and in telomerase-inhibiting TGF-beta, which reconstructs collagen and elastin in the extracellular matrix. Colostrum transcribes hTERT mRNA, Phosphorylates hTERT, uses the MAPK pathway, and contains the the telomerase activators IGF-1, IGF-2, EGF, TNF-alpha, FGF (FGF-2 and FGF-4), PDGF, VEGF, and TGF-alpha. See Growth Factor Skin Creams. See Rojas Vega S , Knicker A, Hollmann W, Bloch W, Strüder HK (2010), Effect of resistance exercise on serum levels of growth factors in humans, Horm Metab Res 2010 Dec;42(13):982-6. Growth factor telomerase activators include:
Protein Production Methods [Index]
These proteins are often produced in small quantities using recombinant DNA technology from E. Coli transfected with appropriate plasmids, perhaps from cell-free extracts featuring cell-free in vitro extraction. For large-scale methods, see commercial large-scale recombinant protein production [Images]. OriGene now offers >5,000 full length human proteins expressed in HEK293 cells and purified with affinity column. GeneArt produces proteins from from transient transfected HEK293 or CHO cells with protein purification by affinity tag chromatography, Protein G/A chromatography, or ion exchange chromatography, using SDS PAGE or general gel filtration for quality control. Eucaryotic proteins can usually not be folded correctly in procaryotic bacterial cells, so that eucaryotic HEK293 and CHO cells are used. Several transfection techniques may be used. Plasmids are engineered with an EBNA1 expression vector (5- to 8-fold increase) to increase the protein production. Using the promoter from a cytomegalovirus DNA (a cytomegalovirus expression cassette) can drive the protein production up by a factor of 10. See pPK-CMV Expression Vectors and Vectors for High-Level Gene Expression. The epi-CHO cell line was developed to increase protein production by adding peptones such as GPN3 and TN1 (Tryptone N1, a casein peptones). See Industrial choices for protein production by large-scale cell culture [Images, Papers, Books]. See Chris Wenstrom (2006), Advances in large-scale recombinant protein production, Basic Biotechnology eJournal, 2006 2:20-25.
Human Growth Hormone (HGH) See Index/HGH.
Human Heat Shock Protein Hsp22 [Hytest/Human Heat Shock Protein Hsp22, Links, Images, Video, Papers, Patents, Books, LifeExtension]. Hsp22 extends the life span of Drosophila 30%. (Ben Best, also FASEB Journal, Genevive Morrow, Milanie Samson, et.al.) Also see elevating Hsp22 with Trichostatin A, [Index/Heat Shock Proteins, Links, Images, Papers, Patents, Books, Wikipedia, LibCong/Heat Shock Proteins, LifeExtension] [24s]. See supplements boosting HSP22 [Images, Papers, Patents, Books].
Human Lifecycle [Academic.Sun/Human Lifecycle, Links, Images, Video, Papers, Books, LifeExtension; Index/Age Progression, Age Progression Studies].
Huperzine A [Links/Huperzine A, Images, Video, Papers, Patents, SOD-booster, Books, Amazon, LifeExtension] [65s]. In addition to improving the expression of SOD, Huperzine A also enhances the expression of Nerve Growth Factor, which stimulates the production of Id-1 helix-loop-helix protein, a telomerase activator [Index] that also inhibits the expression of tumor suppressor protein p16INK4a (Zheng et al. 2004, Ohani et al. 2001), which can induce senescence after accumulating to high levels. High levels of P16INK4A can make replicative senescence apparently irrecoverable, until P16INK4A levels are reduced. Huperzine A also blocks enzymes decreasing acetylcholine levels, which is used to improve focus in bodybuilding workouts.
Hyaluronic Acid (Hyaluronan) [Links/Hyaluronic Acid, Images, Video, Papers, Patents, Books, Amazon, LifeExtension; Links/Hyaluronan, Images, Video, Papers, Patents, Books, Amazon, LifeExtension; Transdermal administration enhancers for hyaluronic acid; Hyaluronic Acid plus Vitamin C (Before and After)]. Pronounced "High-AL-u-ronic Acid". "Hyaluronic acid (or hyaluronan) is a carbohydrate polymer that is one of the major components of the skin’s extracellular matrix. With its ability to attract and retain water, hyaluronic acid adds volume to the gel-like matrix surrounding the network of collagen fibers that support the skin. This function adds vital moisture and structural integrity to the dermis. In addition, new studies have shown that hyaluronic acid’s capacity to bind to a cell-surface receptor called CD44 allows it to play a vital role in stratum corneum barrier function and hydration through its ability to aid in keratinocyte differentiation and extracellular lipid formation." - (Gary Goldfaden, MD and Robert Goldfaden (2010), Novel Compounds from the Sea Promote Younger-Looking Skin, Life Extension Magazine, Nov 2010.) Also see the role of ceramides in stratum corneum barrier function and hydration. Hyaluronic acid, found throughout our body in synovial fluid, connective tissue and various other tissues, may be taken orally as a supplement to smooth skin and repair joint function, or applied transdermally to remove wrinkles quickly. Note that hyaluronic acid inhibits the cartilage-dissolving matrix metalloprotienase MMP-13 to protect joints in therapy for arthritis, and is best given with pain-relieving krill oil (300 mg/day), fish oil (2400 mg/day), and astaxanthin, which also inhibits MMP-13.
Hyaluronic acid is produced by hyaluronan synthases (HAS1, HAS2, and HAS3), membrane-bound enzymes which use UDP-alpha-N-acetyl-D-glucosamine and UDP-alpha-D-glucuronate as substrates to produce glycosaminoglycan hyaluronan at the cell surface and extrude it through the membrane into the extracellular matrix. The HAS1, HAS2 and HAS3 isoforms reside at different chromosome locations and have been cloned. Key differences between the isoforms are the chain length of the associated hyaluronan molecules and the ease with which they can be released from the cell surface. (After Wikipedia/Hyaluronan_synthetase.) Some "Instant Face Lift" formulations [Links/Instant Face Lift, Images, Video, Papers, Patents, Books, Amazon, LifeExtension; Links/DMAE instant face lift, Images, Video, Papers, Patents, Books, LEF] use DMAE, DMAE with hyaluronic acid, or hyaluronic acid with retinol and DMAE to restore hyaluronan as a component of the extracellular matrix for up to 12 hours, after which it slowly vanishes over the next 12 hours. More elaborate Instant Face Lift compositions also exist. See Neck Rejuvenation. Hyaluronic acid is available as a serum for cosmetic applications. Hyaluronic acid may also be taken orally, then restoring hyaluronan in joints and elsewhere for a time. Permeation enhancing substances for transdermal administration include aliphatic alcohols (such as ethyl alcohol and isopropyl alcohol) or glycerol (glycerine, glycerin). See transdermal administration enhancers for hyaluronic acid. Note that growth factor skin creams lengthen telomeres slowly to obtain more youthful patterns of gene expression that restore components of the extracellular matrix. Colostrum skin creams also contain TGF-beta, which restores both collagen and elastin in the extracellular matrix. Hyaluronic acid may be used in the treatment of arthritis. Krill oil is superior to fish oil for arthritis relief, and krill oil plus astaxanthin with hyaluronic acid is better yet. Note that hyaluronic acid inhibits the cartilage-dissolving enzyme MMP-13 to protect joints. (Jason Ramirez, 2011). Recently, I have been experimenting with hyaluronic acid solution encapsulated in milk lipid liposomes made with heavy whipping cream and a spray bottle. An ultrasonic cleaner may be used more effectively to produce milk lipid liposomes from mixtures. Milk lipid liposomes are known to be relatively effective for transdermal application of medicines.
 Papakonstantinou E, Roth M, Karakiulakis G (2012),
Hyaluronic acid: a key molecule in skin aging, Dermatoendocrinol 2012 Jul;4(3): 253-258.
 Allemann I B, Baumann L (2008),
Hyaluronic acid gel (Juvéderm) preparations in the treatment of facial wrinkles and folds,
Clin Interv Aging 2008 Dec;3(4):629-34.
 Sakai S, Yasuda R, Sayo T, Ishikawa O, Inoue S (2000),
Hyaluronan exists in the normal stratum corneum, J Invest Dermatol 2000 Jun;114(6):1184-7.
 Bourguignon LY, Ramez M, Gilad E, et al. (2006),
Hyaluronan-CD44 interaction stimulates keratinocytes differentiation, lamellar body formation/secretion, and permeability barrier homeostasis,
J Invest Dermatol 2006 Jun;126(6):1356-65.
Hydergine [Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension, IAAS/Hydergine, IAAS/Hydergine(2)], , (4). Hydergine, see mitochondrial theory of aging, (4). Hydergine is an ergoloid mesylate (derived from rye) developed by Dr. Albert Hofmann of Sandoz, who derived LSD from ergots of rye. It is one of the world's most useful and popular "smart drugs", known to have the following effects when taken 2.25 mg to 9 mg daily:
Hydroxycitric Acid [Links, Images, Video, Papers, Patents, Books, LifeExtension]. Hydroxycitric Acid (HCA) is extracted from the rind of the garcinia cambogia plant of Indonesia [Images]. Taken before exercise, it makes fat from fat cells available for combustion during exercise. Hydroxycitric acid is taken 500 mg to 1000 mg per dose 2 or 3 times per day, with one dose 30 minutes prior to a workout. - (after Muscle and Fitness Magazine, 2010). Hydroxycitric acid is suspected of elevating norepinephrine "fat breakdown hormone" to achieve its fat loss thermogenic effects [Images]. Check hydroxycitric acid elevates norepinephrine.
Hydroxytyrosol [Links/High-ORAC Herbs; Links/hydroxytyrosol, Images, Video, Papers, Patents, Books, LifeExtension]. Hydroxytyrosol, found in olives and olive oil, is the highest-ORAC antioxidant.
Hyperglycemia [Links/Hyperglycemia, Images, Video, Papers, Patents, Books, LifeExtension].
Hyperglycemia (high blood sugar) may result in glycation damage and may be associated with diabetes. Cinnamon may be used to lower blood sugar, and caloric restriction may also be useful.
 Aronson D, Rayfield EJ (2002),
How hyperglycemia promotes atherosclerosis: molecular mechanisms,
Cardiovasc Diabetol 2002 Apr 8;1:1.
Hyperimmune Eggs [HyperimmuneEgg.org, Links, Images, Video, Papers, Patents, Books, LifeExtension; Images/sources of hyperimmune eggs, Images/sources of hyperimmune egg powder].
Hyperimmune eggs may be used to improve the immune system to combat immunoscenescence. In addition, they lower levels of lipid deposits and cholesterol levels. "Of note also are the dramatic differences seen in athletic performance, endurance, recovery and strength in individuals consuming hyperimmune egg (20, 21). [These results may be due to down-regulation of proinflammatory cytokines, which have been shown to result in fatigue (22)]." - HyperimmuneEgg.org
Hyperoxia Equipment (Encyclopedia).
Hypertension (High Blood Pressure) (Encylopedia)
Hypoperfusion (Encyclopedia Entry).
Hypoxia [Wikipedia/Hypoxia, Links/Hypoxia, Video, Images, Papers, Patents, Books, LifeExtension]. Hypoxia (oxygen shortage in tissue) may be due to arteriosclerosis or arterial blockage and is correlated to mtDNA4977 deletions, Alzheimer's Disease, and other diseases of neurological aging. See LibCong/Hypoxia, Ch.6 Deletions of Mitochondrial Genome and Neurodegenerative Diseases in Principles of Neural Aging, ed. Dani, Hori, and Walter, [53s], [59s]. Hypoxia is associated with the telomerase-activating HIF-1 transcription factor, which is expressed during exercise [List] or when diosgenin, Fenugreek extract, or Ginkgo Biloba is taken. HIF-1 transcription factor interacts directly with the hTERT promoter to induce the expression of more hTERT mRNA. It is believed have this property in every cell in the body.
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