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T: Ta - Te
T cells (T-Lymphocytes) [Links/T cells, Images, Video, Papers, Books, Patents, Amazon, LifeExtension; Links/T-Lymphocytes, Images, Video, Papers, Patents, Books, Amazon, LifeExtension; Links/senescent cytotoxic (CD8+/CD28-) T cells, Images, Video, Papers, Patents, Books; HIV, Virology]. During chronic HIV-1 infection [Images, Video] CD8+ T-cells (Killer T-cells, or Wiki/Cytotoxic T-cells, Links, Images, Video) exhaust their ability to up-regulate telomerase, leading to critically short telomeres and other changes associated with replicative senescence and reducing their antiviral activity. Stimulation of CD8+ T-cells [Images, Papers] with TAT2 (cycloastragenol [CAS Registry no. 84605-18-5, RevGenetics ref]) upregulates telomerase activity in these cells, eliminating their senescent phenotype and restoring antiviral capacity. See Steven Russell Fauce, Beth D. Jamieson, et al., Antiaging Therapy with TAT2: Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes, The Journal of Immunology, Nov 2008, 181: 7400-7406. See also Rita Effros, Telomerase-based approaches to enhance immunity to viruses during ageing, August 29, 2007.
L-Cysteine supports T-cell production, improving immune function and NAC (N-acetyl cysteine) levels while supporting expression of glutathione and taurine [Images]. 5-10 grams of L-arginine per day is sometimes prescribed to restore the function of the thymus gland and its production of T-cells. Alpha Lipoic Acid elevates cAMP in T-cells to reduce caveolin-1 (gene CAV1) and oppose T-cell senescence.
TA-65 [Links, Images, Video, Papers, Patents, Books, LifeExtension].
TA-65 is a telomerase activator, also termed Geron GRN-665, now a product of TA Sciences [TA Sciences back pages], obtained from an extract of Astragalus Membranaceus Root [81s/6b]. TA-65 is primarily cycloastragenol [TAT2, Links, Video], to be taken 5 mg/day 3 months on, 3 months off for a year, which may be obtained chemically from telomerase activator astragaloside IV [Links, Video] by treatment with a hydrolyzing acid, or otherwise from astragalosides or extracts of Astragalus Membranaceus (7, Links, Video). (Some sources wrote that TA-65 was NOT cycloastragenol, but an astragalus extract. A 1/08/2011 email source quotes a chemical analysis showing that TA-65 is:
5.47 mg cycloastragenol + 0.27 mg astragaloside IV + < 0.01 mg astragenol per serving.) Recent research shows that TA-65 works better at 20-30 mg/day (Calvin B. Harley, Weimin Liu, Maria Blasco, Elsa Vera, William H. Andrews, Laura A. Briggs, and Josheph Raffaele (2011), A Natural Product Telomerase Activator As Part of a Health Maintenance Program, Rejuvenation Research, 14(1), 2011). However, it does not increase mean telomere length (like astragalus root extract does at 11 to 33 grams/day), and by June 2012 I would say TA-65 and cycloastragenol were comparatively poor performers in situ. So was Astragaloside IV. See VIDA Institute/Astragalus Formulations, our tests at Greenwood Research, and Community Measurements. See the Geron Patent Compositions and Methods for Increasing Telomerase Activity (or the A' alternate-source version Compositions and Methods for Increasing Telomerase Activity, or A'') and Formulations Containing Astragalus Extracts and Uses Thereof. Also see Recharge Biomedical/tables of Expression Profiles of Genes Involved in hTERT Promoter Regulation, which include data for Sierra Sciences C0057684 and TA Sciences TA-65. The same file has tables of genes upregulated and downregulated by TA-65. TA-65 therapy may be managed through Recharge Biomedical, via Telomerase Activation managed by Al Sears, MD, or from TA Sciences. Geron's TAT2, which might be TA-65, has been identified as Cycloastragenol, CAS Registry no. 84605-18-5. "TA-65 alone will reduce the percentage of cells with short telomeres ( < 4 kbp) with minimal effects on mean telomere length..." - Calvin B. Harley, et.al, 2010. Note that retinal pigment epithelial cells transfected with hTERT plasmids show telomeres lengthening at 115-255 bp per population doubling, and that BJ foreskin fibroblasts similarly transfected show a telomere length increase of 340-370 bp per population doubling, the same order of magnitude (400-460 bp/year telomere growth, corresponding to roughly 1 cell division per year) originally observed at TA Sciences in 2007 using TA-41 by Bob Waskom and Greta Blackburn. - From 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, vol. 279, 16 January 1998. Tests of TA-65 were also done on prepared mice. See Bruno Bernardes de Jesus, Kerstin Schneeberger, Elsa Vera, Agueda Tejera, Calvin B. Harley, and Maria A. Blasco (2011), The telomerase activator TA-65 enlongates short telomeres and increases health span of adult/old mice without increasing cancer incidence (Full Text PDF), Aging Cell, 22 March 2011.
According to the VIDA Institute (quote), the most effective astragalus formulation for the human body is astragalus extract, perhaps in combination with raw astragalus root, although it works best for Natural Killer (NK) cells. See http://vidainstitute.org/index.php/astragalus-formulations (quote). Astragaloside IV was determined by the VIDA Institute (quote) as failing to lenthen telomeres, and cycloastragenol was determined to be quite marginally effective. Astragalus extract is pictured by the VIDA Institute (quote) to most effectively lengthen telomeres in Natural Killer cells, but to also lengthen telomeres in other blood cell types, including granulocytes, native T-cells, and memory T-cells, while holding B-cell telomere lengths constant. A higher dose might have lengthened B-cell telomeres. Video: Jim Green at Age 63.
TA-65 Physicians [Links, Images, Video] include Al Sears, MD of Telomerase Activation and Recharge Biomedical Clinic (Dr Edward Park). See also TA Sciences in New York City. Note that by February 2012, TA-65 was available as an option from RevGenetics.
Targeted Genome Editing [Links, Images, Video, Papers, Patents, Books, Amazon; Zinc Finger Nucleases; HUGO's Human Genome; Model Organism Genomes]. See also Gene, and Gene Therapy. Targeted genome editing with Zinc Finger Nucleases (ZFN technology) will allow many repairs for Single Nucleotide Polymorphisms (SNPs) responsible for diseases like sickle-cell anemia and cystic fibrosis. In addition, extra genes for hTERT and other factors such as SOD or certain endogenous antioxidants can be added to the genome at suitable sites. Furthermore, genes required for enhanced immunity to specific diseases [Papers] or to environmental factors [Papers] may be installed. Genes may be temporarily installed in the genome to enhance or accelerate recovery from accidents or disease. See Longevity Genes, Mammalian Telomere Protein Factors, Telomere Loop Control Proteins, and Gene. Other technologies for genome editing include:
CRISPR [Links, Papers, Patents, Books] (clustered regularly interspaced short palindromic repeats),
CRISPR/Cas [Links, Papers, Patents, Books], and
TALENS [Links, Papers, Patents, Books] (transcription activator-like effector nucleases).
TA Sciences [Links, Images, Video; TA Sciences Site, TA Sciences back pages]. TA Sciences markets telomerase activation via TA-65, a molecule obtained from astragalus extract, probably cycloastragenol [TAT2, Index/Cycloastragenol] [81s/6b]. Geron's preferred embodiments for a small molecule telomerase activators are based on astragaloside IV, cycloastragenol, astragenol [Links], and astragaloside IV 16-one [Links], although they have named several other effective compounds also obtained from astragalus root extract [Links, Video], including cycloastragenol 6-β-D-glucopyranoside and cycloastragenol 3-β-D-xylopyranoside. Geron also names astragalosides A, 1, 2, 7, and astraverrucins I and II, which can be obtained from Astragalus Verrucosis, as telomerase activators. Geron has also described a "formula III" telomerase activator embodiment, ginsenoside RH1, obtained from ginseng. (7), [81s/6b]. Geron also describes black cohosh as a telomerase activator.
Tatoo Removal [Links, Images, Video, Papers, Patents, Books, Amazon].
TAT2 [Index/TAT0002, cycloastragenol, Links/TAT2, Images, Papers, Patents, Books, LifeExtension]. "...TAT2 (cycloastragenol, CAS Registry no. 84605-18-5) was prepared by purification of acid hydrolyzed Astragaloside IV and is available from TA Therapeutics (email charley@geron.com)." Furthermore, "Our initial investigations into the mechanism of action of TAT2 suggest that telomerase activation, which typically peaks 24-48 h after TAT2 treatment, is preceded by early activation of the MAPK/ERK pathway (within minutes of TAT2 exposure), followed by increased production (or reduced turnover) of hTERT mRNA transcripts (peaking around 12 h). Interestingly, the main nuclear effectors of the MAPK pathway include the ETS transcription factors (37), which are known to play a major role in the transcriptional regulation of telomerase activity (38). The MAPK pathway has also been implicated in posttranslational up-regulation of telomerase activity through phosphorylation of hTERT (14), but the effects of TAT2 on this pathway have not been investigated. Thus, although the direct binding partner of TAT2 is not known, our data suggest that TAT2 up-regulates telomerase activity via activation of the MAPK pathway and subsequent increase in hTERT mRNA and/or active phosphorylated forms of hTERT protein." - from Steven Russell Fauce, Beth D. Jamieson, Allison C. Chin, Ronald T. Mitsuyasu, Stan T. Parish, Hwee L. Ng, Christina M. Ramirez Kitchen, Otto O. Yang, Calvin B. Harley, and Rita B. Effros, (2008), Antiaging Therapy with TAT2: Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes, The Journal of Immunology, Nov 2008, 181: 7400-7406.
TAT0002 [Index/TAT2, Bionity News/TAT0002, Links/TAT0002, Images, Papers, Patents, Books], a small-molecule telomerase activator from Geron (probably cycloastragenol, or TA Sciences TA-65), announced by Geron and a subsidiary TA Therapeutics. TAT0002 is presently used in AIDS therapy. It may become useful in life extension work, say on the skin [Index/Skin], now to involve telomerase activation therapies.
According to a source at the Immortality Institute, "Telomerase induction (was) tested originally using a 10:1 95% ethanolic extract of Astralagus root (this extract was called GRN925, the preparation of which is described in the 2005 Hong Kong patent Formulations Containing Astragalus Extracts and the Uses Thereof on page 37 as "Example 1".). The most potent compound in the extract seems to be astragaloside IV (probably TAT0001) or cycloastragenol [Links], one of which which may be the GRN-665 (TA-65) TAT0002 molecule." Search for the CAS Registry number of TAT2, which identifies it as cycloastragenol. Geron's TAT2, which might be TA-65, has been identified as Cycloastragenol, CAS Registry no. 84605-18-5. One may take cycloastragenol with chitosan to enhance bioavailability as Astral Fruit-C from RevGenetics.
Activation pathway for TAT2: "...our data suggest that TAT2 up-regulates telomerase activity via activation of the MAPK pathway and subsequent increase in hTERT mRNA and/or active phosphorylated forms of hTERT protein...", Steven Russell Fauce, Beth D. Jamieson, et al, (2008), Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes, The Journal of Immunology, 2008, 181, 7400-7406.
TAT153 [Telomerase Activators/(119) TAT153, Links/TAT153, Images, Video, Papers, Patents, Books]. TAT153 is a new small molecule telomerase activator from Geron announced in 2010. It may be associated with TAT153 cDNA.
Taurine [Wikipedia/Taurine, Links, Images, Video, Papers, Patents, Books, LibCong, LifeExtension; Atherosclerosis, Index/Cardiovascular Disease, Index/Diabetes, Index/Diabetes/Taurine, Index/Eye Problems of Aging, Index/Heart Attack, Index/Macular Degeneration, Index/Sarcopenia, Index/Smoking, Index/Tinnitis]. Taurine, "an amino acid present in fish, is able to restore normal blood vessel function in smokers." (LEF). "Congestive heart failure responds favorably to taurine therapy." (Life Extension), [36s] (k). In animal studies, taurine reduced mortality due to heart failure by 80% [Ian Macleavy, 2013, LEF]. Taurine is the 2nd most prevalent amino acid in skeletal muscle after glutamine. Taurine helps muscle cells swell with water (an anabolic trigger), and is often given with creatine monohydrate at 3-5 grams 30 minutes before and just after workouts. See Pierno S, De Luca A, Camerino C, Huxtable RJ, Camerino DC (1998), Chronic administration of taurine to aged rats improves the electrical and contractile properties of skeletal muscle fibers, Journal of Pharmacology and Experimental Therapeutics, 1998 Sep,286(3):1183-90, and Goodman CA, Horvath D, Stathis C, et al. (2013), Taurine supplementation increases skeletal muscle force production and protects muscle function during and after high-frequency in vitro stimulation, Journal of Applied Physiology 2009 Jul;107(1):144-54. Taurine is also described as protecting against the formation of AGEs. See Index/Age Inhibitors. Some scholars believe that the exceptionally long life spans of Japanese on Okinawa are due to ingestion of taurine, which is abundant in their fish. On the other hand, vegan diets can lead to taurine deficiencies. Taurine manufacture in the body from cysteine declines with age. Taurine may also be used to treat or prevent type II diabetes. Taurine is useful in treating and preventing fatty liver disease [Index], and helps to control insulin sensitivity. Taurine has lipid-lowering characteristics and is useful at 3 grams/day in treating obesity. Taurine helps prevent hypertension. References
[1] Rahman MM, Park HM, Kim SJ, et al. (2011),
Taurine prevents hypertension and increases exercise capacity in rats with fructose-induced hypertension, American Journal of Hypertension 2011, May;24(5):574-81.
[2] Ian Macleavy (2013),
The Forgotten Longevity Benefits of Taurine, Life Extension Magazine, June 2013.
[3] Yamori Y, Taguchi T, Hamada A, Kunimasa K, Mori H, Mori M (2010),
Taurine in health and diseases: consistent evidence from experimental and epidemiological studies, Journal of Biomedical Science, 2010; 17 Suppl 1:S6.
[4] Laidlaw SA, Grosvenor M, Kopple JD (1990),
The taurine content of common foodstuffs,
JPEN J Parenter Enteral Nutr, 1990 Mar-Apr;14(2):183-8.
Tea Polyphenols [Links, Images, Video, Papers, Patents, Books, LibCong, LifeExtension; Green Tea, Black Tea, White Tea, Theaflavins; Coffee], [25b]. Cancer.gov/Tea Polyphenols, are:
(1) anticarcinogenic [Links/Anticarcinogenic drugs, Images, Video, Index/Anticancer],
(2) cardioprotective [Links/cardioprotective drugs, Images, Video, Papers, Patents], and
(3) neuroprotective [Links/neuroprotective drugs, Images, Video, Papers, Patents, Books].
See Amy R. Cameron, Siobhan Anton, et al., Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a, Aging Cell, Volume 7, Issue 1, Pages 69 - 77, 13 Nov 2007. Also see Kishido, Takahiro; et al., Decline in glutathione peroxidase activity is a reason for brain senescence: consumption of green tea catechin prevents the decline in its activity and protein oxidative damage in ageing mouse brain, Biogerontology, pp. 423-430, Volume 8, Number 4, August 2007. Also see Inami S, Takano M, Yamamoto M, et al. (2007), Tea catechin consumption reduces circulating oxidized low-density lipoprotein, International Heart Journal Nov 2007; 48(6):725-32. [Wikipedia/Green Tea; LibCong, Links/Green Tea Polyphenols, Images, Papers, Patents, Books, LifeExtension]. See the index entries for green tea, black tea, and theaflavins. Compare with coffee. Note that a mixture of green tea or white tea, black tea, coffee, cinnamon, and sweetener has medicinal benefits exceeding any one of the beverages by itself, and inhibits collegenase and elastase.
Teeth Straightening [Links, Images, Video, Papers, Patents, Books, LibCong/orthodontics, Dental].
Telomerase [Patent Lens/Telomerase, LibCong, telomerase database, telomere enlongation by telomerase pathway atlas, Telomeres & Telomerase Lecture Video (Physioage), PatentLens: Telomerase Overview with splice variants; Refs3/Telomerase, Refs4/Telomerase; Wikipedia/Telomerase reverse transcriptase, Links/Telomerase, Images, Video, Papers, Patents, Books, Amazon, LifeExtension]. "Telomerase" is pronounced "tell-Oh-mer-Aze", or "tuh-LAH-mer-ace" (Life Extension magazine, 1998) and "TEE-LOM-ER-ACE" according to the Shay/Wright Laboratory. Elizabeth Blackburn: "Tel-om-er-aze". Links/telomerase, [45], [66], [81s]. - "Extension of life-span by introduction of telomerase into normal human cells", Links, [3]. See Yu-Sheng Cong, Woodring E. Wright, and Jerry W. Shay, Human Telomerase and Its Regulation, Microbiology and Molecular Biology Reviews, September 2002, p. 407-425, Vol. 66, No. 3. This is the 123 kilodalton enzyme composed of hTERT and hTR parts that adds
5'-GGTTAG-3' repeats to telomere tip-ends to prevent replicative senescence from telomere shortening. Recently, it has been shown that the protein dyskerin [Index, Links, Video, Images, Papers, Books] from the gene DKC1 [Links, Video, Images, Papers, Books] is a third component of the telomerase enzyme complex [Images, Video], which is stated to contain two molecules each of hTERT, hTR, and dyskerin. See [Links/telomerase and dyskerin]. See Scott B. Cohen, Mark E. Graham, George O. Lovrecz, Nicolai Bache, Phillip J. Robinson, Roger R. Reddel, (2007) Protein Composition of Catalytically Active Human Telomerase from Immortal Cells, Science, 30 March 2007: Vol. 315. no. 5820, pp. 1850 - 1853. See also Podlevsky, J.D., Bley, C.J., Omana, R.V., Qi, X., Chen, J. (2007), The Telomerase Database, Nucleic Acids Research, 36 D339-D343.
Telomerase Activation Pathways [Telomerase Activators (Alphabetic List), Endogenous Telomerase Activators, Exercise-Induced Telomerase Activators, hTERT Promoter, Biocarta/hTERT_Pathway, Biocarta/Telomeres, Telomerase, Cellular Aging, and Immortality, Links, Images, Video, Papers, Patents, Books, Amazon]. See Index/Telomerase Activators, Telomerase Activators (List), Telomerase Inhibitors (List), hTERT, hTR, hEST1A, Index/Pathway Analysis, Index/Bioinformatics, (7). Many growth factors such as IGF-1 seem to activate telomerase via the Phosphatidylinositol-3-Kinase/AKT1 (PI3K/AKT1), as in IGF-1/PI3K/AKT1. Resveratrol activates telomerase in endothelial progenitor cells via PI3K/AKT1, as do nicotine and ginkgo biloba. Estrogen attenuates endothelial progenitor cell senescence by augmenting hTERT through PI3K/AKT-dependent mechanisms, although the hTERT promoter features a estrogen receptor transcription factor site on the hTERT promoter. See the AKT kinases [Index]. Direct HGH/PI3K activation has been discussed for hTERT, perhaps actually being HGH/PI3K/AKT1. IL-2 was thought to activate telomerase via PI3K/Akt, but some investigators found PI3K-dependent, Akt-independent activation of hTERT via IL-2. TAT2 (cycloastragenol), and probably the rest of the astragalosides, acts via the MAP Kinase pathway, also producing phosphorylated forms of hTERT. Epidermal Growth Factor (EGF), found in Colostrum along with IGF-1, seems to produce its telomerase activation by upregulating C-myc, which has two sites for transcription activation on the hTERT promoter. Id-1 helix-loop-helix protein immortalizes human keratinocytes by activating hTERT and can be produced via nerve growth factor (NGF), which can be generated by application of rosemary (carnosic acid), acteyl-L-carnitine, PQQ, huperzine A, or platelet activating factor. Bcl-2 activates telomerase, and is itself upregulated by IL-2, which is upregulated by astragalus extract and astragalus polysaccharides. Bcl-2 is also upregulated by simvastatin, clozapine, olanzapine, lithium, and zinc supplements. Also 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.
Telomerase Activation Therapies [Links, Images, Video, Papers, Patents, Books, LifeExtension, Amazon, 81s]; Index/Telomerase Activators, List/Telomerase Activators; Endogenous Telomerase Activators, Exercise-Induced Telomerase Activators, Cyclic Telomerase Activation; Telomerase Activators also activating AMPK]. Note that astragalus root contains the molecule used in TA-65 (Geron's GRN-665), a telomerase activator sold by TA Sciences. Small-molecule telomerase activators obtained from astragalus include astragaloside IV [Links, Video/astragaloside IV, Books, Amazon, Links/astragalosides, Video/astragalosides], cycloastragenol [Links, Video], astragenol [Links], and other chemicals [81s/6b]. See also Astragalus & Toxicology of Astragalus, with vendors and Geron's Compositions and methods for increasing telomerase activity (or the A' alternate-source version Compositions and Methods for Increasing Telomerase Activity, or A'') with Formulations Containing Astragalus Extracts and Uses Thereof. Telomolecular Nanotechnologies proposes DNA nanocircles for telomerase activation, and Phoenix Biomolecular proposed a scheme a year or two back to transport telomerase through cell membranes. This may be done, for instance, by embedding the telomerase enzyme in cationic liposomes, and transfecting the hTERT protein and hTR RNA with dyskerin like a gene, or by transfecting the mRNA for hTERT along with hTR mRNA and dyskerin RNA in cationic liposomes that can enter the cell via liposome endocytosis. There are localization sequences of amino acids that can target proteins to cell membrane receptors. Otherwise, electroporation or plasmid transfection technologies based on liposomes formed from cationic transfection reagents can transport the hTERT gene into the cell in a plasmid. However, plasmid numbers are typically reduced as cell division proceeds, and plasmid DNA may have a modest survival time in the cell according to experiments done with fluorescent protein labeling produced by custom plasmid designs. DNA plasmid degradation in human cells [Images, Papers] often seems to proceed much more rapidly than cell division. Therefore plasmid transfections may have to be done repeatedly to be effective. Adenovirus transfection of hTERT and other genes such as hEST1A to support telomerase synthesis always integrates the plasmid into the same spot in the genome, reducing cancer risks associated with lentivirus transfections, which integrate the plasmid DNA into any genome site randomly. The adeno-associated virus (AAV) is smaller and more comfortable for the patient, comes in 12 serotypes, and always integrates to the same site AAVS1 [Wikigenes] on chromosome 19. See Telomere Remodeling with Cyclic Telomerase Activation for telomerase activation with off-the-shelf astragalus extracts. However, Targeted Genome Editing with Zinc Finger Nuclease technology allows larger plasmid inserts into the genome than the Adenovirus (about 7.5 kbp) or Adeno-Associated Virus (AAV) transfection techniques.
Liposome technique can also be used to insert nucleoside-modified hTERT mRNA reprogrammed for long half-life into cells, as is now being explored in Fast Telomere Extension. Telomere extension in 6 days by an amount by which telomeres shorten over 15 years of normal aging has been reported.
Telomerase Activators [List of Telomerase Activators, Anticancer Telomerase Activators, Endogenous Telomerase Activators; Exercise-Induced Telomerase Activators; Telomerase Activators also activating AMPK; Links/Telomerase Activators, Images, Video, Papers, Patents, Books; SupNotes3/Telomerase Activators, (7), 67; Links/Telomerase Inducers, Images, Video, Papers, Patents, Books; Links/activates telomerase, Images, Papers, Patents, Books; Links/activators of hTERT transcription, Images, Papers, Patents, Books; Links/phytochemical activators of hTERT transcription, Images, Papers, Patents, Books; Links/nutraceutical activators of hTERT transcription, Images, Papers, Patents, Books]. Useful telomerase activators [List] for application to cellular rejuvenation (rejuvenating at B = -5 years per year up to about B = -9 years per year or B= -8 years per year) include astragalus root powder, astragalus root extract, TA Sciences TA-65 and evidently also astragalosides from astragalus membranaceus root extracts such as Solaray Astragalus Root Extract 6 x 200 mg = 1200 mg/day of extract for 5 mg of astragalosides per day or from Nature's Way Astragalus Root Extract available from Herbal Remedies taken at 5 mg of astragalosides per day. Also see GAIA Herbs Astragalus Root Extract in glycerin (green label) at 150 drops per 5 mg of astragalosides. NO (nitric oxide) obtained from L-arginine (5 grams/day to 10 grams/workout) and L-citrulline (200 mg to 1 gram/day) in the presence of exercise (9) may be useful for telomerase-activating and rejuvenating the endothelial cells [Images, Video] of the vascular endothelium [Vasa, et al., 2000, Hayashi, et. al, 2006, Haendeler, 2006, Erusalimsky, 2009]. ([Erusalimsky, 2009] suggests that SIRT1 is activated rather than hTERT by NO in endothelial cells.) A cyclic program of application such as the TA Sciences Patton Protocol (3 months on, 3 months off), or a 2-week on, 2-week off application alternating telomerase activators with telomerase inhibitors, has been used with good results in the case of astragalus root powder, astragalus root extracts, TA-65, or Product B. See also Astragaloside IV and cycloastragenol products from RevGenetics and Terraternal, which have been less successful than 33 grams of astragalus root powder per day for producing gains in average telomere length, according to VIDA Institute (quote), Terraternal, and bioscience researchers. Note that 33 g as 66 x 500 mg capsules/day is hard to choke down in one session, thus the Chinese habit of prescribing astragalus root in divided doses. "Now swallow 66 capsules" led to research on astragalus root extracts (and extracts of extracts) for more convenient and reduced swallowing. However, astragalus root medicinal properties seem to have been discovered after astragalus tea "root beer", a tasty beverage, was used for years based on its appeal to Chinese taste buds. Today this taste may be best rediscovered from astragalus extract in glycerin. The first small molecule telomerase activators Tricostatin A (2000) and Epithalon Peptide (2003) were available by injection only. Prior to their discovery, an additional copy of hTERT had to transfected in an adenovirus vector to impact telomerase activation in the cell. This was done in the first 1998 experiments demonstrating life extension by telomerase activation in cultured cells. The very first small molecule telomerase activator, Trichostatin A, was described in the year 2000 by Yu-Sheng Cong and Silvia Bacchetti. The next one discovered, Epithalon peptide (Ala-Glu-Asp-Gly), found to regulate telomere homeostasis and at first obtained from the epiphysis of the pineal gland, was announced in 2003 by the St. Petersburg Institute for Bioregulation and Gerontology in Russia. CGK 1026, a relatively non-toxic and bioavailable HDAC inhibitor that activates telomerase, was discovered in 2004 in Korea by high-throughput screening. Notable American patents on telomerase activators stem from the Geron research group headed up by Calvin B. Harley and were published in May and June of 2005. In March 2007 TA Sciences announced TA-65, describing it as a molecule like cycloastragenol, the smallest molecule astragaloside derivable by chemical treatment of more structurally involved astragalosides such as astragaloside IV. Chitosan and sodium deoxycholate improve the bioavailability of astragalosides. In 2007 consultants hinted at the existence of hormones that could activate telomerase (Biocarta Pathways). IGF-1 (Notes) turned out to be a telomerase activator, and is a factor in the longer lives of people who exercise systematically. By 2009, IGF-1 was available in Now Foods IGF-1 Liposomal Spray and other IGF-1 liposomal sprays. IGF-1 phosphorylates hTERT in the cytoplasm via AKT to promote telomerase activation. HGH is a telomerase activator that promotes hTERT mRNA transcription that may be boosted with an HGH secretagogue like Alpha-glycerylphosphocholine (Alpha-GPC, 600 mg/dose), a component of the anti-aging Secretagogue Gold product. This can boost HGH by a factor of 44 in a workout, and we realize that HGH may easily be more telomerase activating than IGF-1. Also, it was discovered that epidermal growth factor (EGF) is a telomerase activator available in Colostrum, or initial mother's milk for newborns. It is taken in supplements including Colostrum, although EGF is considered more of a hazard for cancer than IGF-1, and should not be taken together with astragalosides. It may be useful to take a histone deaceylase inhibitor (HDAC inhibitor) like sodium butyrate [Links, Wikipedia] to facilitate transcription of hTERT and hTR. The best time to take a telomerase activator is probably just before bedtime, and an hour or two after taking other evening medication. It is also a good idea to take it just after exercise, because exercise promotes transporters such as HSP90 for conveyance of materials into the cellular nucleus. "TA-65 alone will reduce the percentage of cells with short telomeres ( < 4 kbp) with minimal effects on mean telomere length..." - Calvin B. Harley, et.al, 2010. Perhaps other telomerase activators will turn out to gradually reduce the percentage of short telomeres ( < 4kb) without modifying average telomere length. To improve on average telomere length much with telomerase activation may require activation of hEST1A and Replication Protein A, so that t-loops can open for telomerase access. Product B researchers identified quite a few telomerase inducers that cause fibroblasts to transcribe hTERT mRNA and lengthen their telomeres, considerably expanding our insight.
In the future, the substructure of a telomerase activator molecule interacting with DNA may be identified, such that other molecules can be synthesized featuring this substructure. This may lead to the synthesis of more inexpensive telomerase activators with superior bioavailability characteristics.
See also Anticancer Telomerase Activators and
Telomerase Activators Promoting hTERT mRNA Transcription.
Telomerase Chaparonins [Links, Images, Papers, Patents, Books].
Telomerase Inhibitors [List of Telomerase Inhibitors, Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension]. Telomerase inhibitors inhibit transcription of hTERT mRNA. They are useful in causing cancer cells to become apoptotic, and are often applied as anti-cancer medication along with angiogenesis inhibitors. Resveratrol induces apoptosis in cancer cells as a telomerase inhibitor, and activates telomerase in endothelial progenitor cells as a telomerase activator working through the PI3K/Akt pathway to produce the kinase Akt that phosphorylates hTERT protein in the cytoplasm for import into the nucleus. Recently Rajeev Ragunathan wrote in with the observation that telomerase inhibitors are only active for a few hours, usually. Common telomerase inhibitors [List] include: milk thistle, curcumin, turmeric, green tea, EGCG, tea catechins, melatonin, garlic, ginger extract, fish oil, EPA, DHA, vitamin D3, vitamin E, cocoa, genistein, soy, and quercetin. A high-polyphenol diet tends to generate telomerase inhibitors, so that one usually uses a low-polyphenol diet while attempting to activate telomerase for telomere enlongation. Some telomerase inhibitors only work as such for cancer cells, and are sometimes even telomerase activators for normal human fibroblasts. Milk thistle extract is in this category. See Anticancer Telomerase Activators, which includes many telomerase activators that behave as telomerase inhibitors in cancer cells.
Telomerase Induction [Links, Images, Video, Papers, Patents, Books, Amazon; Anticancer Telomerase Activators; Endogenous Telomerase Activators; Exercise-Induced Telomerase Activators; List/Telomerase Activators, Index].
Telomerase Modulation [Links/Telomerase Modulation, Images, Video, Papers, Patents, Books, Amazon, LibCong, Geron A & B, TA Sciences, Telomolecular Nanotechnologies, Sierra Sciences, Phoenix Biomolecular, GAIA Herbs, Solaray; Endogenous Telomerase Activators; Exercise-Induced Telomerase Activators; List/Telomerase Activators, Index/Telomerase Activators; Index/Telomerase Inhibitors, List/Telomerase Inhibitors].
Telomerase Modulators [81s, Links, Images, Video, Papers, Patents, Books; Endogenous Telomerase Activators; Exercise-Induced Telomerase Activators, List/Telomerase Activators, Index/Telomerase Activators; Index/Telomerase Inhibitors, List/Telomerase Inhibitors].
Telomerase Promoters (hTERT Promoter, hTR Promoter, DKC1 Promoter) [Index/hTERT Promoter, Links/hTERT promoter, Images, Video, Papers, Patents, Book; Index/hTR Promoter, Links/hTR promoter, Images, Video, Papers, Patents, Book; Links/DKC1 promoter, Images, Video, Papers, Patents, Book, Article/DKC1 promoter]. See Yu-Sheng Cong, Woodring E. Wright, and Jerry W. Shay, Human Telomerase and Its Regulation. Also see Endogenous Telomerase Activators and Exercise-Induced Telomerase Activators.
Dyskeratosis Congentia seems to be due to a mutation in an SP1-binding site on the DKC1 promoter. - after Rüdiger Salowskya, Nina S Heissa, Axel Bennerb, Rainer Wittiga, Annemarie Poustka (2002), Basal transcription activity of the dyskeratosis congenita gene is mediated by Sp1 and Sp3 and a patient mutation in a Sp1 binding site is associated with decreased promoter activity, Gene, Vol 293, Issues 1–2, 26 June 2002, pp. 9–19. High Sp1 levels should upregulate dyskerin transcription. The dyskerin gene DKC1 is also upregulated by c-Myc. See Faizan Alawi, Megan N. Lee (2007), DKC1 is a direct and conserved transcriptional target of c-MYC, Biochemical and Biophysical Research Communications, Vol 362, Issue 4, 3 Nov 2007, pp 893–898.
Telomerase Regulation [Anticancer Telomerase Activators; Endogenous Telomerase Activators; Exercise-Induced Telomerase Activators; Telomerase Activators; Telomerase Inhibitors; Links, Images, Video, Papers, Patents, Books, LibCong]. See Yu-Sheng Cong, Woodring E. Wright, and Jerry W. Shay, Human Telomerase and Its Regulation, and the index entry on the hTERT promoter. Novel Telomerase Activators [Links, Images, Video, Papers, Patents, Books] have been proposed in Israel at the WISTAR Institute based on the design of molecules to regulate telomerase. See WISTAR professor Emmanuel Skordalakes PhD [Links, Images, Video, Papers, Patents, Books]. In the body, telomerase is regulated by the epiphysis in the pineal gland via epithalon peptide (Ala-Glu-Asp-Gly), a bioregulator initally discovered in pineal gland extracts in 2003 by the St. Petersburg Institute of Bioregulation and Gerontology. [Links/epithalon peptide, Video, Papers, Patents, Books, see also epitalon (aka epitalon) (Khavinson article preview).] Telomerase regulation [(7), 81s] may be programmed by telomerase activators and telomerase inhibitors [81s]. "Newly synthesized telomeric DNA serves as a platform that recruits DNA-binding proteins that serve to regulate telomerase activity and protect chromosome ends. In human telomeres several well-characterized proteins, called TRF1, TRF2, and POT1, carry out this process. Two proteins, called TIN2 and PIP1, mediate the recruitment and proper assembly of the above telomere-binding proteins on telomeric DNA. Our goal is to understand how TIN2 and PIP1 promote TRF1, TRF2, and POT1 binding to telomeric DNA and how this in turn regulates telomerase activity and protects chromosome ends from being recognized as DNA strand breaks. " - from Emmanuel Skordalakes PhD. Note that the TRF1 and TRF2 proteins bind double-stranded telomeric sequences, and that POT1 binds single-stranded telomeric sequences (from Hahn and Weinberg in Nature Reviews Cancer, May 2002). An analysis of the pathways involved is given in Qiagen/Telomere Extension by Telomerase and in Qiagen/Telomerase Components in Cell Signaling.
Telomere Biology [Labome/Telomeres, Telomere Science, QC/Telomere remarks, Ben Best/Telomeres and Aging; LibCong, Links/Telomere Biology, Images, Video, Papers, Papers, Books, LifeExtension, Amazon, Yahoo Links, (7), Telomeres & Telomerase Lecture Video (Physioage); Ellison Foundation/Telomeres]. See Biocarta Pathways/Telomeres, Telomerase, Cellular Aging, and Immortality, Biocarta/hTERT_Pathway, Qiagen/Telomere Extension by Telomerase, Qiagen/Telomerase Components in Cell Signaling, and Telomerase Activators. See Jose J. Fuster and Vicente Andres (2006), Telomere Biology and Cardiovascular Disease, Circulation Research, 2006; 99:1167-1180 and related papers on telomere biology and disease. Note that human telomeres spring open when they shorten to about 4,000 base pairs, initiating replicative senescence by communicating a DNA damage signal that stops the cell cycle.
Music[2]: A Day in the Life by the Beatles.
Telomeres [Telomere Science, Ben Best/Telomeres and Aging, LibCong, Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension, LifeExtension/telomere homeostasis, Wikipedia; Ellison Foundation/Telomeres; What are Telomeres?, Images/Telomere Electron Microscopy, Links/Telomere FISH, Images, Papers; Drawings, Images/Telomere Drawings]. See Geraldine Aubert and Peter M. Lansdorp (2008), Telomeres and Aging, Physiol. Rev. 88: 557-579, 2008. Note that "Higher levels of oxidative stress increase the rate of telomere shortening.", [32], [67], (1), (7), (10), [63]. Homocysteine has been found to increase the rate of telomere shortening, so a homocysteine shield with TMG (trimethylglycine), folic acid, vitamin B12 and vitamin B6 helps preserve telomere length. Telomere length can be boosted with telomerase activation therapies (7). [81s]. Human telomeres feature the repeating minisatellite DNA sequence 5'-GGTTAG-3'. The first telomeres to be sequenced by Elizabeth Blackburn in 1978 were from Tetrahymena thermophila and had the sequence TTGGGG. Calvin B. Harley, A. B. Futcher, and Carol W. Greider showed in 1990 [article] that telomeres shorten as cells age. That the life span of cells could be extended with telomerase-induced telomere elongation was shown in 1998 by A. G. Bodnar, Calvin B. Harley, Woodring E. Wright, Jerry W. Shay, et al., in Extension of Life Span by introduction of telomerase into normal human cells [article]. A plasmid vector [Index] was used to transfect a copy of the hTERT gene into the sample DNA to increase telomerase production in this early work. The landmark paper with telomere t-loops shown in electron microscopy [Images], Mammalian Telomeres End in a Long Duplex Loop, was published in 1999. See also Telomeres Do D-Loop-T-Loop Minireview by Carol Greider in Cell, May 14, 1999, which was published the same day. By 2001 we can find a paper by Judith Campisi, Sahn-ho Kim, Chang-Su Lim and Miguel Rubio [article] associating the opening of the telomere t-loop [Links, Images] with the DNA damage signal stopping the cell cycle [Links] and the transition to the senescent state of the cell [Links]. The first drug that was discovered to activate telomerase seems to have been the histone deaceylase inhibitor (HDAC inhibitor) Tricostatin A, as described by Yu-Sheng Cong and Silvia Bacchetti in Histone Deacetylation is Involved in the Transcriptional Repression of hTERT in Normal Human Cells, Journal of Biological Chemistry, Vol. 275, Issue 46, November 17, 2000. Tricostatin A [Links] can stop the cell cycle in early stages of development and is positioned as an antifunqual antibiotic these days, and is usually presented as harmful and not for human consumption as orally bioavailable medicine. Tricostatin A is taken by injection for telomere lengthening. An early telomerase activator [List] for lengthening telomeres, epithalon peptide (Ala-Glu-Asp-Gly) first found in the pineal gland, was announced in 2003 by The Institute for Bioregulation and Biogerontology in St. Petersburg, Russia. Geron announced telomerase activators obtained from astragalus extract in 2005, and subsequently TA Sciences announced TA-65 in 2007. Before 2011, Astragaloside IV products were announced by RevGenetics, Terraternal, and Medicinal Nutraceutics, and RevGenetics introduced cycloastragenol as Astral Fruit-C and subsequently as a component of Astral Fruit NF. Telomeres only become accessible to telomerase during the S phase of the cell cycle.
Telomeres, Telomerase, and Cancer Telomeres, Telomerase, and Cancer, Carol W. Greider, Elizabeth H. Blackburn, Sci.Am., 2/96, [Links, Images, Video, Papers, Patents, Books] (1).
Telomere Forum Bulletin Board Telomere Forum Bulletin Board [Links], [3].
Telomere Binding Proteins [Index/Shelterin, Index/Telosome, Index/Mammalian Telomere Protein Factors, Links/telomere binding proteins, Images, Video, Papers, Patents, Books, LibCong, Amazon/telomere binding protein; Links/telomere proteins, Images, Video, Papers, Patents, Books]. Some of these, such as TRF2, are crucial in closing the telomere t-loop to avoid or cure transition to the senescent phenotype. See (7)/Telomere Capping Proteins. For details of the role of telomere binding proteins of the telosome in telomere maintenance pathways, see Qiagen/Telomere Extension by Telomerase and Qiagen/Telomerase Components in Cell Signaling. See also Telomere Loop Control Proteins, below. The telomere t-loop may be opened by phosphorylating tankyrase 1 with insulin using insulin-boosters such as Gymnema Sylvestre, Fenugreek Extract, Fenugreek seeds, or 4-hydroxyisoleucine. Tankyrase 1 levels may also be boosted with Niacinamide (Nicotinamide, a form of Vitamin B3). Tankyrase 1 opens the telomere t-loop via telomeric PARP activity involving poly(ADP-ribo)sylation of TRF1 using a NAD+ substrate that strips the telomere of the telomere binding protein TRF1. The NAD+ substrate (NADH) can be supplied by < 3 grams of niacinamide (nicotinamide) taken early in the morning, or by NADH supplements [Images] taken at 2.5 mg/day. Note NAD+ + 2e- + H+ <---> NADH . It is safe enough to boost insulin after a workout, although it should not be high all the time. See Diabetes.
Telomere Length Measurement [Links, Images, Video, Papers, Patents, Books, LibCong, Amazon, in Sup Notes 3b5, in LifexLabs/Telomeasures; Biomarkers of Longevity, Biomarkers of Aging, Biomarkers of Cellular Senescence]. Consider telomere length measurement in
blood granulocytes [Links, Images, Video, Papers, Patents, Books].
blood lymphocytes [Links, Images, Video, Papers, Patents, Books].
blood Natural Killer cells [Links, Images, Video, Papers, Patents, Books].
dermal fibroblasts [Links, Images, Video, Papers, Patents, Books].
See Repeat Diagnostics, Spectracell, Telome Health, Life Length, and TA Sciences for associated commercial services [Links, Images]. See Richard M. Cawthon (2009), Telomere length measurement by a novel monochrome multiplex quantitative PCR method, Nucleic Acids Research, 2009 February; 37(3) and Biotechniques.com quantitative real-time PCR method for absolute telomere length, and Marcel E. Gil and Thérèsa L. Coetzer, (2004) Real-time quantitative PCR of telomere length, Molecular Biotechnology, Volume 27, Number 2, June, 2004. Also see the material on associated laboratory techniques at Jerry W. Shay and Woodring E. Wright and the index entry for Metaphase Spread. Sierra Sciences has worked out special telomere measurement methods for fibroblasts in connection with their investigation of telomerase inducers using high-throughput screening assays.
Telomere Loop
Telomere t-Loop [Electron Microscope Image, Links/Telomere T-loop, Images/T-Loop in Electron Microscope, Images, Video, Papers, Patents, Books, Amazon],
Telomere d-Loop [Links, Images, Video, Papers, Patents, Books, Amazon; Shelterin].
The telomere d-loop is formed by the invasion of the 3' single-strand telomeric DNA into double-stranded telomeric DNA. The displaced part of the duplex DNA forms a small D-loop above the site where the single strand binds. The large associated duplex loop is the telomere t-loop. The telomere t-loop at the end of the chromosome can spring open when the telomere becomes too short (< 4000-5000 bp, depending on the cell type, as in lymphocytes vs granulocytes), generating a DNA damage signal [Papers, Books, Video] leading to a cell cycle halt and entry into the M1 senescent state. Human telomere loops as large as 25 kbp and as small as 1 kbp have been observed with electron microscopy. Shorter t-loops with less shelterin are believed to be inherently more accessible to the telomerase holoenzyme than longer t-loops with more shelterin (Titia de Lange, 2005). Nucleosomes have been found in the t-loop [Images, Papers]. Lenthening the telomere with small molecule telomerase activators [List] allows the telomere to cap itself and close the loop, so that the cell can resume cell division and transition back to the immortal phenotype. Overexpression of TRF2 can change the minimum closed length of the telomere t-loop by direct application of exogenous TRF2 or via the action of certain specific statin drugs, such as simvastatin (Zocor), atorvastatin and pravastatin. However, this is not recommended. See (7), and (7)/Telomere Capping Proteins, such as POT1, TRF1, TRF2, TIN2, TPP1, and RAP1. See also Qiagen/Telomere Extension by Telomerase and below for Telomere Loop Control Proteins.
It may be that the telomere t-loop opens during DNA replication in the S phase of the cell cycle, with the replication fork dissociating the single-strand invasion of the double-stranded part of the telomere. (Titia de Lange, 2005). The telomere t-loop may be opened by phosphorylating tankyrase 1 with insulin using insulin-boosters such as gymnema sylvestre, fenugreek extract, fenugreek seeds, or 4-hydroxyisoleucine. Tankyrase 1 levels may also be boosted with niacinamide (nicotinamide, a form of vitamin B3). Tankyrase 1 uses NAD as a substrate in poly(ADP-ribosylation) of TRF1, so NAD supplements [Links] may be useful when applying Tankyrase 1 to encourage hTERT transcription to activate telomerase. Note that nicotinamide elevates NAD substrate levels. Tankyrase 1 opens the telomere t-loop via telomeric PARP activity involving poly(ADP-ribosylation) that strips the telomere of the telomere binding protein TRF1. Later, TRF1 is expressed and reseals the telomere loop. TRF1 changes the loop curvature. It is safe enough to boost insulin after a workout, although it should not be high all the time. See Diabetes.
Telomeric DNA Repair [Links]. Note that telomeric DNA may be damaged and require repair via base excision repair, nucleotide exision repair, or mismatch repair. Non-homologous end-joining or homologous DNA repair could have disasterous consequences, however, and are believed to be blocked by shelterin. Homologous DNA repair of telomeres can result in circular telomeric DNA supporting the rolling-circle replication of the ALT mechanism in cancer cells if certain TRF2 mutants are overexpressed.
Telomere Loop Control Proteins (telomere nucleoprotein complex). See also Genes and Senescence, Refs7.8, Index/Mammalian Telomere Protein Factors and The Telomere Interactome [Figure, Links, Images, Papers, Patents, Books]. According to GeneCards, the shelterin complex [Images, Papers, Patents, Books, Refs7.8], also termed the telosome [Images, Papers, Patents, Books, Refs7.8] is composed of the 6 proteins TRF1, TRF2, TIN2, RAP1, TPP1, and POT1:
TRF1: TRF1 (NCBI/TERF1, Wikipedia, Links, Images/TRF1 gene, Images/TRF1,
___Papers, Patents, Books, Index). TRF1 is the primary telomere loop closure protein.
___TRF1 is a negative regulator of telomere length, inhibiting telomeric association of hTERT.
_____"The TRF1 complex negatively regulates telomerase by loading POT1
_____on the single-stranded part of the telomere." (Ye and de Lange, 2004).
___Stripping TRF1 with tankyrase 1 using a NAD+ substrate opens t-loops for telomerase.
___Overexpression of tankyrase 1 results in telomere enlongation [Images].
___Partial depletion of tankyrase 1 leads to telomere shortening.
___Tankyrase 1 may be phosphorylated for the reaction by stimulation of the cell with insulin.
______Perhaps phosphorylation of tankyrase 1 targets it for import to the nucleus, ala hTERT.
______"Phosphorylation enhances the PARP activity of tankyrase-1.."
_________(Sbodio and Chi, 2002).
___TRF1 protein can be controlled by tankyrase 1, FBX4, or nucleostemin (GenomeBio).
___TRF1 binds to double-stranded telomeric GGTTAG DNA
______and bends the telomere into a loop [Images, Papers]. In fact,
___TRF1 can loop, bend, and pair telomeric repeat arrays in vitro.
___TRF1 and TRF2 bind specifically for 5'-YTAGGGTTR-3'. (Martinez & Blasco, 2011).
___TRF1 dimer DNA gymnastics are enabled via flexibly coupled SANT/Myb domains.
___TRF1 forms homodimers [Images].
___TRF1 interacts strongly with XRCC6/Ku70.
___TRF1 includes a nuclear localization signal; tankyrase 1 does not.
____Tankyrase 1 is found in the cytoplasm & nucleus and is localized to telomeres by TRF1.
____TRF1 can be poly(ADP-ribo)sylated by Tankyrase 2. (Sbodio, Lodish, and Chi, 2002).
____TRF1 promotes efficient replication of GGTTAG repeats and prevents fork stalling
_______during replication of telomeric DNA. Without TRF1, telomeric DNA is fragile.
_______Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient
_______Replication (Agnel Sfeir, et.al, 2009)
____"TRF1 is essential for preventing telomere breakage
_______associated with replication fork stalling
at telomeres
." (Martinez & Blasco, 2011).
___TRF1 & TRF2 interact with TIN2, which recuits TPP1 & POT1 to chromosome ends.
___TRF1 and TRF2 may suppress nucleotide excision repair (NER) in telomeres.
______(Paula Martinez & Maria A. Blasco, 2011).
TRF2: TRF2 (NCBI/TERF2, Wikipedia, Links, Images/TRF2 gene, Images/TRF2,
___Papers, Patents, Books, Index).
___TRF2 binds to double-stranded GGTTAG DNA, and is a TRF1 paralog.
___TRF1 and TRF2 bind specifically for 5'-YTAGGGTTR-3'. (Martinez & Blasco, 2011).
___TRF2 can remodel a telomeric substrate into loops in vitro,
______but seems to require other factors to do this in vivo.
___TRF2 loss yields ATM kinase activation, p53 phosphorylation,
______and
p21-mediated G1/S cell cycle arrest.
___TRF2 loss may result in double-strand break (DSB) ATM kinase activation,
_____activation of downstream kinase CHK2, p53-phosphorylation, and subsequent apoptosis
_____and/or senescence mediated by p21. (Deng, Chan, and Cheng, 2008)
___Removal of TRF2 from telomeres activates a NHEJ pathway, leading to telomere fusions.
___Telomere repair by NHEJ occurs primarily in cell cycle G1, and is repressed in G2
______by higher CDK activity. (Akimitsu Konishi and Titia de Lange, 2008).
___TRF2 deletion results telomere fusions and deletion of the
_____ 3'-single-strand overhang bound to POT1. (Celli and de Lange, 2005)
___TRF2 forms homodimers [Images].
___TRF2/RAP1 forms a stable heterodimer [Images].
___The TRF2-RAP1 heterodimer localizes near histones H2A, H4, and H1.
___TRF2 interacts strongly with XRCC6/Ku70.
___TRF2 interacting proteins are closely clustered with RAP1 interacting proteins.
___TRF2 & POT1 repress non-homologous end-joining (NHEJ)
_____and homology-directed DNA repair (HDR).
___TRF2 & TRF1 interact with TIN2, which recuits TPP1 & POT1 to chromosome ends.
___TRF2 recruits ORC, inhibiting telomeric circles (eccDNA). (Deng, et.al, 2007).
TIN2: TINF2 (NCBI/TINF2, Wikipedia, Links, Images/TIN2 gene, Images/TIN2,
___Papers, Patents, Books; TRF1-interacting protein 2).
___TIN2 (the shelterin lynchpin), tethers TPP1/POT1 to TRF1 and TRF2,
______connects TRF1 to TRF2, stabilizing TRF2 on telomeres, and
______can enhance some of TRF1's architectural effects on double-stranded telomeric DNA.
___TIN2 is a negative regulator of telomere length (Xin, Liu, & Songyang, 2008).
___Inhibiting TIN2 enlongates telomeres by reducing TIN2 interference with tankyrase 1.
___TIN2 promotes nuclear retention of TPP1 and POT1.
___TIN2-, TPP1- and POT1-interacting proteins are clustered together.
___TIN2 blocks tankyrase 1 from poly(ADP-ribo)sylation of TRF1 and consequent
____TRF1 stripping, contributing to the accumulation of TRF1,
____allowing it to recruit POT1 to single-stranded telomeric DNA. (Ye and de Lange, 2004).
___So knockdown of TIN2 by siRNA derepresses tankyrase 1 at telomeres, removing TRF1,
____allowing the telomerase holoenzyme to access telomeres (Ye and de Lange, 2004).
____Dyskeratosis congenita (a form of bone marrow failure) is associated with mutations in
______exon 6 of TIN2 which often produce short telomeres. (T.Vulliamy, et al, 2011).
____A novel TIN2 variant tethers telomeres to the nuclear matrix.
______(Kaminker PG, Kim SH, Desprez PY, Campisi J., 2009).
___TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres (Abreu, et al, 2010).
___A TIN2 mutation causes Ataxia and pancytopenia. (Tsangarts, et.al, 2008).
RAP1 (NCBI/TERF2IP, Wikipedia, Links, Images/RAP1 gene, Images/RAP1 protein,
___Papers, Patents, Books; Telomerase Activator List/hRAP1).
___TRF2 recruits RAP1 to the telomere, where it regulates telomere length.
_____after (Yibin Deng, Suzanne S. Chan, and Sandy Cheng, 2008).
___RAP1 suppresses Homologous DNA Recombination leading to telomere attrition [Images].
___Homologous DNA Recombination (HDR) can lead to ALT by producing telomeric circles
______(eccDNA).
_____Telomere lengthening via ALT occurs in some cancers. (Titia de Lange, 2005).
___RAP1 interacts with TRF2, targeting RAP1 to chromosome ends for telomere protection.
___RAP1 represses Homology Directed Repair (HDR) of telomeres.
___TRF2 recruits RAP1 to telomeres via van der Waals interactions.
___TRF2 heterodimerizes with RAP1 to mediate its protective function.
___RAP1 is dispensible for inhibiting NHEJ repair of telomeres leading to telomere fusion.
___Loss of RAP1 leads to complete telomere loss via HDR and to end-joining fusions.
___Inhibition of RAP1 leads to enlongated telomeres and loss of telomere heterogeneity.
___RAP1 is involved in subtelomeric gene silencing and transcriptional regulation.
___RAP1 modulates the Nuclear Factor Kappa Beta pathway.
______ - described in (Paula Martinez and Maria A. Blasco, 2011).
___RAP1 ectopic expression induces NFkB activity, RAP1 depletion inhibits NFkB activity.
___RAP1 binds to both telomeric and non-telomeric chromatin. (op.cit.).
___According to Martinez, RAP1 preferentially binds at GGTTAG sites, and binds like the
_____RAP1 head of a Shelterin raccoon to TRF2 dimer forelegs with TRF1 dimer hindlegs,
_____bound at the top by a TIN2 spine tethering a TPP1-POT1 tail. (op.cit.)
___RAP1 also acts as a transcription factor controlling the expression
_____of glycolytic enzymes and ribosomal genes. (op.cit.)
___RAP1 (mammalian) is an orthologue of budding yeast Rap1 [Images, Papers], which
_____binds to telomeric DNA. (Maria A. Blasco, 2007).
TPP1, (NCBI/ACD, Wikipedia, Links, Images/TPP1 gene, Images/TPP1,
___Papers, Patents, Books, Aliases TPP1 = TINT1, PTOP, PIP1, ACD).
___TPP1 is a TIN2-interacting protein,
___TPP1 enhances POT1 single-strand binding activity.
___POT1/TPP1 forms a stable heterodimer [Images].
___The TPP1-POT1 heterodimer may modulate telomerase access to telomeres.
___TPP1's putative OB fold is required for telomerase recruitment.
___Disruption of TPP1 nuclear export can result in telomeric DNA damage
______response and telomere length disregulation. (Xin, Liu, & Songyang, 2008).
___TPP1 nuclear export may regulate the concentration of TPP1-POT1 in the nucleus.
___TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres (Abreu, et al, 2010).
___TPP1 is tethered to TIN2 via its carboxy terminal domain,
_____and binds to POT1 via its central domain. (Martinez & Blasco, 2011).
POT1 (NCBI/POT1, Wikipedia, Links, Images/POT1 gene, Images/POT1,
___Papers, Patents, Books;
___POT1 binds to single-stranded GGTTAG telomeric DNA.
___POT1 binds to the ssDNA sequence 5'-TAGTTAGGG-3'.? (Martinez & Blasco, 2011).
_____Note that 5'-TAGTTAGGG-'3 is not a substring in a repeated GGTTAG sequence
_____5'-GGTTAGGGTTAGGGTTAGGGTTAGGGTTAG...-'3.
___POT1 binds to the G-strand overhang and to the displaced strand in the D-loop.
___POT1 inhibition reduces the number of single-strand GGTTAG repeats by 30% to 50%.
______(Also true of TRF2 inhibition, which can cause all telomeric ssDNA to vanish
______due to the activity of ERCC1/XPF endonuclease cleaving inside neighboring dsDNA.)
___POT1 loose tethering results in heavier POT1 loading on ssDNA in long telomeres
______with more shelterin on them, making telomerase more accessible to short telomeres.
___POT1 mutants not binding ssDNA allow telomeres to grow uncontrollably;
___POT1 caps block telomerase.
___POT1 knockout triggers a DNA damage response pathway initiated by
_____the protein kinase ATR (ataxia telangiectasia related). (Xin, Liu, and Songyang, 2008).
___POT1 represses ATR activity by binding telomere ssDNA and blocking RPA access,
______RPA being the ssDNA binding protein by which ATR is recruited to the telomere.
___POT1 loss may result in single-strand break (SSB) ATR kinase activation,
_____activation of downstream kinase CHK1, p53-phosphorylation, and subsequent apoptosis
_____and/or senescence mediated by p21. (Deng, Chan, and Cheng, 2008)
___POT1 may interact to form a TPP1-POT1 stable heterodimer [Images],
______which binds to the G-strand overhang and to the displaced strand in the D-loop.
___POT1 inhibits the G-quadruplex structure producing telomerase inhibition.
___POT1 & TRF2 repress homology-directed DNA repair (HDR) and
_____non-homologous end-joining (NHEJ). HDR can yeild telomeric circles.
___Links/POT1a (mice), Images, Papers, Patents, Books;
_____POT1a is essential for suppressing DNA damage responses at telomere termini.
___Links/POT1b (mice), Images, Papers, Patents, Books).
_____POT1b regulates the 3' ssDNA overhangs. (Xin, Liu, and Songyang, 2008).

See Titia de Lange (2005), Shelterin: the protein complex that shapes and safeguards human telomeres (Full PDF), Genes and Development 2005, 19: 2100-2110:
Shelterin allows cells to distinguish telomeres from DNA damage sites.
Without shelterin, telomeres are inappropriately processed for DNA damage.
"Within shelterin, TRF2 and POT1 proteins collaborate to repress all DNA damage
response pathways that threaten chromosome ends: DNA damage signaling by the
ATM and ATR kinases and NHEJ and HDR-mediated DSB repair.
"
___(Agnel Sfeir, et.al, 2009)
Multiple shelterin units are bound per telomere.
Shelterin units only accumulate at chromosome ends.
Shelterin recognizes 5 GGTTAG domains (2 with TRF1, 2 with TRF2, and one with POT1).
Only TRF1, TRF2, and POT1 directly recognize GGTTAG repeats. (check)
"Inhibition of any of the proteins that directly bind telomeric DNA (TRF1, TRF2, or POT1) or many of their interacting partners (TPP1, TIN2, or RAP1) in telomerase-positive human cells results in telomere elongation." - after Megan F. Kendellen, Katharine S. Barrientos, and Christopher M. Counter (2009), POT1 Association with TRF2 Regulates Telomere Length, Molecular and Cellular Biology, 2009 October; 29(20): 5611–5619.
TRF1 and TRF2 bind double-stranded telomeric DNA.
TRF1 and TRF2 both feature SANT/Myb-type DNA binding domains [Images]
binding the sequence 5'-YTAGGGTTR-3' in double-stranded telomeric DNA.
TRF1 and TRF2 can each form homodimers [Images] and higher-order oligomers [Images]
that can bind to an extensive sequence of double-stranded telomeric DNA.
POT1 binds single-stranded telomeric DNA.
Note: Removal of the single-stranded overhang decaps telomeres and opens t-loops.
TIN2, TRF1 and TRF2 are not found in ciliates, but seem to have evolved for telomere
homeostasis in vertebrates, perhaps regulating telomere G-quadruplex formation.
- After (Xin, Liu, and Songyang, 2008).
TIN2, TPP1 and POT1 have been found to localize in both the cytoplasm and the nucleus.
TIN2-TRF2 interaction takes place exclusively in the nucleus (including at telomeres),
but TIN2-TPP1 and TPP1-POT1 interactions occur in both the cytoplasm and nucleus.
That is, telomere protein subcomplex formation is observed in the cytoplasm.
A nuclear export signal (NES) resides next to the POT1-recruitment domain on TPP1, so
interaction and nuclear localization of the TPP1-POT1 complex may be linked.
- After (Xin, Liu, and Songyang, 2008).
TRF2 and POT1 protect chromosome ends by repressing DNA damage signaling
by the ATM kinase and the ATR kinase, respectively. (Denchi and de Lange, 2007).
See also Yong Chen, et al, A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms, Nature Structural and Molecular Biology, vol.18, no.2, February 2011.
Susan J. Hsiao and Susan Smith (2009), Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ, Journal of Cell Biology, Feb 16, 2009.
TRF1, TPP1, and RAP1 show deregulated expression in lymphocytic leukemia.
TRF1, TRF2, TIN2, and POT1 show altered expression in some human tumors.
___(Paula Martinez and Maria A. Blasco, 2011).
Smith, S., I. Giriat, A. Schmitt, and T. de Lange. (1998), Tankyrase, a poly(ADP-ribose) polymerase at human telomeres, Science 282:1484-1487.
See Biocarta Telomeres, Telomerase, Cellular Aging, and Immortality Pathway Analysis, which notes that TRF1 (TERF1) binds the telomere end repeats and prevents telomerase holoenzyme access to the chromosome ends. Also see [Links/telomere t-loop pathway analysis, Links/the telomere nucleoprotein complex, Images, Video, Books, Papers, Patents; Links/the telosome, Images, Video, Papers, Patents, Books; Links/shelterin, Images, Video, Papers, Patents, Books; Links/telomere loop control proteins, Images, Video, Papers, Patents, Books].
Alias Nomenclature for Shelterin/Telosome
TRF1 (TERF1 alias) [Links, Patents, Images/TRF1 gene, Images/TRF1 protein],
TRF2 (TERF2, alias) [Wiki, Links, Images/TRF2 gene, Images/TRF2 protein],
TIN2 (TINF2 alias) [Wiki/TINF2, Links/TIN2, Images/TIN2 gene, Images/TIN2 protein],
PIP1 (ACD alias), [Wiki/PIP1, Links/PIP1, Images/PIP1 gene, Images/PIP1],
Note: The ACD gene is distinct from the TPP1 gene above on chromosome 11, which encodes tripeptidyl-peptidase. ACD - Adrenocortical dysplasia protein homolog, a protein encoded by the ACD gene, is one of six core proteins in the Telosome/Shelterin telomeric complex functioning to maintain telomere length and to protect telomere ends.)
PIP1 (ACD gene alias) [Wiki/PIP1, Links/PIP1, Images/PIP1 gene, Images/PIP1 protein, Papers, Patents, Books].
Rap1 (TERF2IP alias) [Wiki, Links/RAP1 protein, Images/Rap1 gene, Images/Rap1 protein, Papers, Patents, Books],
Ku Protein for double-strand break DNA repair
Ku (See also Links/Ku70, Ku80, Ku86, Ku70/80, and Ku protein complex) [Wiki/Ku_(protein), Links/Ku protein, Images/Ku gene, Images/Ku protein, Papers, Patents, Books, GeneCards/KU gene, GeneCards/XRCC6 gene],
Telomerase Components with Nucleolar Elements
Sometimes 2 molecules of telomerase seem to stick together at the RNA template.
Telomerase itself is now thought to consist of just 3 components:
1 molecule of hTERT protein
[Index, Wiki/hTERT, Links, Images/hTERT gene, Images/hTERT protein, Papers, Patents],
1 molecule of hTR RNA
[Index, Wiki, Links, Images/hTERC gene, Images/hTERC RNA, Papers, Patents], and
1 molecule of Dyskerin
[Wiki, Links, Images/Dyskerin gene, Images/Dyskerin protein, Video, Papers, Patents, Books],
that function in the Cajal bodies
[Wiki/Cajal body, Links/Cajal bodies, Images, Video, Papers, Patents, Books]
of the nucleolus
[Wiki/Nucleolus, Links/Nucleolus, Images, Video, Papers, Patents, Books],
with certain other nucleolar proteins
[Links/Nucleolar proteins, Images, Video, Papers, Patents, Books],
localized to the Cajal bodies that are involved in DNA repair fiber-processing.
Some telomere-processing activities are localized to
PML bodies [Links, Images, Papers, Patents, Books]. See also Tobias Else, (2009), Telomeres and telomerase in adrenocortical tissue maintenance, carcinogenesis, and aging, Journal of Molecular Endocrinology, (2009) 43, 131-141. See also Paula Martinez and Maria A. Blasco (2010), Role of Shelterin in cancer and aging, Aging Cell, 2010, 9:653-666. Also see Index/Longevity Genes.
Telomere Maintenance via ALT, [Links, Images, Papers, Patents, Books; Index/Shelterin, [34s]]. See LibCong/telomere maintenance.
Telomere Repair [Links, Images, Video, Papers, Patents, Books, LibCong, LifeExtension, Amazon, TA Sciences, Telomolecular Nanotechnologies, Sierra Sciences, Telomerase Activators, Exercise-Induced Telomerase Activators, Endogenous Telomerase Activators, Anticancer Telomerase Activators, Product B]. Telomere repair may proceed using telomerase activators, which may include relevant hormones, using HGH, IGF-1, androgens such as testosterone in androgen-sensitive tissues, and estrogen or phytoestrogen estrogen-substitutes such as diosgenin from fenugreek or wild yam or the black cohosh saponin 26-deoxyacetein. [23s]. For a promising experimental program with readily available GAIA astragalus extract and astragalus root, see Telomere Remodeling via Cyclic Telomerase Activation, (7). Telomere repair is fundamental in modern long-range life extension technology, as telomere shortening routinely results in replicative senescence in the human species as telomere t-loops at the ends of chromosomes become undone and generate a DNA damage signal stopping the cell cycle. Note that 14 different exercise-induced telomerase activators exist that can be boosted with supplements. Furthermore, cyclic AMP from exercise downregulates the expression of caveolin-1, tending to reverse cellular senescence and also to prevent it. High LDL cholesterol tending to boost caveolin-1 (CAV1) expression is also lowered by exercise. Furthermore, AKT kinase pathways are activated by exercise that tend to suppress the import FOXO transcription factors into the nucleus, which also induces caveolin-1 expression associated with senescence (Refs 9). Note that recovery from cellular senescence associated with reduced caveolin-1 expression levels can lengthen telomeres substantially. It is suboptimal to dispense with exercise in life extension medicine if arteriosclerosis from glycation and atherosclerotic plaque levels allow hard workouts. Atherosclerotic plaque is low enough if heartbeat and blood pressure are normal.
Note that cells derived from mesenchymal cells such as connective tissues, cartilage, and bone require application of an HDAC inhibitor such as sodium butyrate, lactates from pumping up, or L-carnitine to expand their chromatin before mRNA for the hTERT and hTR components of telomerase can be transcribed to produce telomerase to lengthen their cellular telomeres.
Telomere Shortening [Links, Images, Video, Papers, Patents, Books, LifeExtension, LibCong]. Telomere shortening typically takes place in mitotic, dividing cells at a rate of approximately 50 to 60 base pairs per cell division, so that many mitotic cells in the body have a cell division limit of about 50 cell divisions. Telomere length is between 7000 and 4000 base pairs in most human cells after maturity. Dr. Bill Andrews of Sierra Sciences states in a company movie that telomere length varies between 15,000 bp in embryos to about 9,000 bp at birth, dwindling according to a linear model from about 28 through 60, reaching 5,000 bp in old age. This is approximately confirmed in Evidence for a mitotic clock in human hematopoietic stem cells: Loss of telomeric DNA from Geron's C.B.Harley, et al., in PNAS, Oct 1994. For fetal hematopoetic stem cells the telomere length varies 12 kbp < 14 kbp, while in newborn's cord blood the hematopoietic stem cell telomere length is 11.5 kbp < 13 kbp, and from age 16 to 59 hematopoetic stem cells from bone marrow show a length from 8 kbp < 9 kbp. Note that stem cells express telomerase when they divide and their telomeres degrade less radically than we see in dermal fibroblasts. See Telomere Length as an Indicator of Biological Aging by A.Benetos, et.al, in Hypertension, 2001: 37:381 and also Tim de Meyer, et. al, 2007, Paternal Age at Birth is an important determinant of offspring telomere length, Human Molecular Genetics, Vol. 10, No.24, 3097-3104. For men and women, we see telomere length in kbp between the age of 28 and 60 varying like:
X = Age in years, Y = -0.031*X + 9.219 kbp (Male).
X = Age in years, Y = -0.021*X + 8.907 kbp (Female).
28=Age in years, Y = -0.031*X + 9.219 kbp = 8.351 kbp (Male).
28 = Age in years, Y = -0.021*X + 8.907 kbp = 8.319 kbp (Female).
60 =Age in years, Y = -0.031*X + 9.219 kbp = 7.359 kbp (Male).
60 = Age in years, Y = -0.021*X + 8.907 kbp = 7.647 kbp (Female).
According to this paper, children of older fathers have somewhat longer telomeres at birth. Also see Edwin Chang and Calvin B. Harley, Telomere Length and replicative aging in human vascular tissues and R.C. Alsopp, C.W.Greider, Calvin B. Harley, et. al, Telomere Length Predicts Replicative Capacity of Human Fibroblasts, Nov 1, 1992, PNAS. The M1 senescent state when the telomere t-loop opens features a telomere perhaps 4000 bp long; thus:
(7000 bp - 4000 bp_M1_telomere)/(60 bp lost per cell division) = 3000/60 = 50 cell divisions. The number of base pairs lost per cell division can be reduced from 60 to about 50 by applying antioxidants, homocysteine shields, cortisol inhibitors, caloric restriction, or DNA repair enhancers such as AC-11 (Cat's Claw Extract). Then one gets another 3000/50 - 3000/60 = 60 - 50 = 10 cell divisions before senescence sets in. That is, one gets 60 cell divisions rather than 50 prior to replicative senescence. Suppose that the p53 protein halting the cell cycle when the telomere length = 4000 pairs were to malfunction due to the presence of a carcinogen or p53 mutation. Then one might get an additional 4000/60 = 66 to 4000/50 = 80 cell divisions before running out of telomere length for a total of up to 7000/50 = 140 cell divisions prior to telomore fusion. The finite radius of curvature of the shortening telomere prior to ultimate rupture reduces this maximum number of cell divisions. Since the rate of cell division may be increased by cancer-causing carcinogens like alcohol and estrogens, one may reach the telomere fusion point rapidly. It is also important to keep DNA helicase cofactors like magnesium in sufficient supply. Then up to 60 cell divisions can occur between 7000 and 4000 base pairs up to the M1 senescent state point for a life extension factor of up to 60/50 = 1.2, adding 20% more to a carefully lived human life. Adult stem cells, which express telomerase, can typically divide many more times, say 1000 times in deep epidermal keratinocyte stem cells, which transiently express telomerase when they divide. Furthermore, the germ line is telomerase-immortalized. However, "Chronic inflammation is associated with telomere shortening." - Caleb E. Finch, The Biology of Human Longevity, p.152. Vitamin C and a homocysteine blocker composed of folic acid, vitamin B12, vitamin B6, and trimethylglycine (TMG) both attenuate telomere shortening. Telomere shortening can be reversed using small molecule telomerase activators in a program for rejuvenation via cyclic telomerase activation using astragalosides.
Telomere-Telomere Fusion (Telomere Fusion, or Telomeric Fusion) [Links/Telomere Fusion, Images, Video, Papers, Patents, Books; Index/Shelterin]. Telomere fusion appears to have taken place in karyotype evolution, for instance in the formation of human chromosome 2 [Paper: Wells, et al., 1990, Links, Papers, Video, Image, YouTube Video, LibCong/Telomere Fusion] from the fusion of great ape chromosomes a few million years ago, and in Arabidopsis thaliana, near a centromere. The Great Apes have 24 chromosome pairs per ape vs. the human 23 chromosome pairs per human. The internal (GGTTAG)n array found inside human chromosome 2 is very degenerate in sequence, with only half of the repeats being GGTTAG. (After David Kipling, The Telomere, p.39.) Note that twins may be of the same or opposite sexes, suggesting that the human species started out something like the twins Romulus and Remus suckling at the breasts of a she-wolf at the foundation of Rome [Images, Wikipedia]. The 23-chromosome pair fusion may have produced twins that copulated with each other to continue the human race after it formed from a 24-chromosome pair ape similar to a chimpanzee, quite possibly an aged, genomically unstable specimen. [Wikipedia/Chimpanzee genome project.] Mammals have widely varying numbers of chromosome pairs in their karyotypes [ref, Links]. Dogs have 39 chromosome pairs, very different from great ape 24 or human 23. Telomeric fusion often results in dicentric chromosomes with 2 centromeres and subsequent apoptosis, unless one centromere is deactivated. According to Wikipedia, the longest-living chimpanzee in captivity was 75, and according to another article, the animal is Cheetah from the Tarzan movies, now 76. In the wild, chimpanzees are said by All About Chimpanzees to live 35-40 years, and in captivity, they live about 60 years. It looks like chimps are doing almost as well as man did around the turn of the century. "From 1900 to 2000, man's life expectancy grew from 45 to 75.". I guess this makes a common ancestor for chimps and man very credible. Many other primates have a much shorter lifespan.
End-to-end fusions can arise from the activation of either the classic (C-NHEJ) or the alternative (A-NHEJ)..." non-homologous end joining pathways. "...Fusions arising on TRF2-depletion are mediated by the C-NHEJ pathway, and fusions induced by TPP1-POT1 depletion are mediated by the A-NHEJ pathway..." See Ral, R. et. al. (2010), The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres, EMBO Journal 29, 2598-2610. (Paula Martinez and Maria A. Blasco, 2011). Breakage-fusion-bridge cycles [Images, Papers, Patents, Books] may ensue leading to polyploid cells associated with cancer. Telomere uncapping leads to end-to-end fusions via non-homologous end joining (NHEJ), and to telomere length loss and possible creation of telomeric circles via homologous recombination (HR). Critical shortening or deprotection of telomeres due to shelterin defects leads to a DNA Damage Response (DDR) activating ATM kinase or ATR kinase signaling pathways and subsequent p53 phosphorylation leading to replicative senescence mediated by p21, or to p53-mediated apoptosis. Breakage-fusion-bridge cycles characteristic of genomic instability start when sister chromatids fuse, forming a bridge during anaphase that is broken when fused sister chromatids forming a dicentric chromosome are pulled apart by their two centromeres. "Successive B-F-B cycles will lead to further terminal deletions and amplifications, generating arrays of inverted repeats typical of the amplified regions found in human cancer.... This leads to many of the chromosome rearrangements observed in cancer cells, namely dicentrics, rings, translocations, large duplications, double-minute chromosomes, amplifications, and terminal deletions." Breakage-Fusion-Bridge cycles continue until telomere healing endows the chromosome with a new telomere. Murnane, J.P., (2010), Telomere loss as a mechanism for chromosome instability in human cancer, Cancer Research 70, 4244-4259.
Telomere Therapies [Links, Images, Video, Papers, Patents, Books, LibCong, Amazon; Telomerase Activator List, Telomerase Inhibitor List, Anticancer Supplements]. See Telomere Remodeling with Cyclic Telomerase Activation, TA Sciences, Telomolecular Nanotechnologies, Sierra Sciences, Geron's Compositions and Methods for Increasing Telomerase Activity, and Geron & Hong Kong University's Formulations Containing Astragalus Extracts and Uses Thereof. See also the papers on telomere therapies in the references on lifexrefs/Small Molecule Telomerase Activators and sections (7) and [81s]. Also see telomere therapies from Terraternal and RevGenetics.
Telomere Transcription [Links, Images, Video, Papers, Patents, Books]. Telomeres are transcribed to produce TERRA telomeric RNA [Images, Video, Papers, Patents, Books], starting from subtelomeric DNA and moving toward the end of the chromosome, when telomeres become uncapped. This has some impact on the telomere position effect, and may improve telomeric DNA repair, since some DNA repair is only done during transcription. TERRAs, or telomere-repeat-containing RNAs transcribed from telomeres [Images, Video, Papers, Patents, Books], inhibit telomerase and are negative regulators of telomere length.
Telomeric Chromatin [Links, Images, Video, Papers, Patents, Books, Amazon; Index/hTERT methylation, Index/Folic Acid; Index/Shelterin]. Human telomeric chromatin typically consists (say, in human fibrolasts) of 7000 to 4000 base pairs of 5'-GGTTAG-3' minisatellite hex repeats shortening with each division of the cell until the M1 state is reached at which chromosomal telomere t-loops open and a DNA double strand damage signal is processed leading to cell cycle arrest and the senescent state of the cell. The 5'-GGTTAG-3' sequence specified from the hTR template is often described in the early literature as 5'-TTAGGG-3'. Chromatin in short human telomeres contains a different nucleosomal structure than chromatin in long telomeres. [H Tommerup, A Dousmanis and T de Lange, 1994. "Unusual chromatin in human telomeres", Molecular and Cellular Biology, 1994 September; 14(9): 5777-5785.] Yeast telomeres contain no nucleosomes [Images, Video], but human telomeric chromatin is wound on nucleosomes built from histones. (It seems that telomeric chromatin can be expanded or condensed by acetylating or deacetylyating telomeric histones H3 and H4 in the nucleosome.) See (Paula Martinez and Maria A. Blasco, 2011) on telomeric chromatin regulation by epigenetic factors [Images, Papers, Patents, Books]. Telomeric and subtelomeric domains are rich in histone marks characteristic of repressed heterochromatin. When these histone marks characteristic of chomatin repression [Patents, Books] are removed, telomeres lengthen. "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). The histone marks characteristic of repression include the tri-methylation of histone H3 at lysine 9 (H3K9m3) and the tri-methylation of histone H4 at lysine 20 (H4K20m3). Also, three heterochromatin proteins characteristic of chromatin repression are bound: HP1α, HP1β, and HP1γ, also known as CBX5, CBX1, and CBX3, respectively. Note that subtelomeric DNA is heavily methylated in the repressed phase. Excessive telomere enlongation is associated with removal of these 2 histone H3 and H4 tri-methylations and removal of the 3 Heterochomatin Proteins. Repression of the two histone lysine N-methyltransferases SUV39H1 and SUV420H1 results in the loss of the two H3K9m3 and H4K20m3 heterochromatic trimethylation marks and the production of long telomeres. In addition, repressive subtelomeric DNA methylation must be eliminated by reducing the expression of DICER1 or the three DNA (cytosine 5) methyltransferases DNMT1, DNMT3A, and DNMT3B. (op.cit.) Thus telomeric histones can be methylated, but telomeric GGTTAG sequences cannot be, because they lack the CpG sequences required as a substrate by the DNA methyltransferases. However, subtelomeric chromatin can be DNA methyltransferase methylated. Note that the retinoblastoma (RB) protein family (RB1, RBL1, and RBL2) interacts with the SUV4-20H Histone Methyltransferases to efficiently tri-methylate H4 at lysine 20. Human telomeres and subtelomeres are enriched in Heterochromatin Protein 1 (HP1) important for chromatin compaction. HP1 molecules are recruited to chromatin via their affinity for trimethylated histone H4 lysine 9 residues. The mammalian telomeres and subtelomeres show low levels of acetylated H3 and acetylated H4. (High levels of acetylated H3 and acetylated H4 tend to expand chromatin and defeat gene silencing, allowing the hTERT gene to function in improving telomere enlongation.) Cells show (aberrant) telomere enlongation when they lack SUV39H1 and SUV49H2 histone methylatransferases that provide telomeric histone trimethylation at histone H4 lysine 9 residues. Similar aberrant enlongation of telomeres is seen when cells lack RB1, RBL1, and RBL2 retinoblastoma proteins all three. (Maria A. Blasco, 2007).
References
[1] Schoeftner, S. and Blasco, M.A. (2009),
A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs,
EMBO Journal 28, 2323-2336.
[2] Benetti, R. et al. (2007),
SUV4-20h deficiency results in telomere enlongation and derepression of telomere recombination,
Journal of Cell Biology 178, 925-936.
[3] Garcia-Cao, M., O'Sullivan, R., Peters, A.H., Jenuwein, T., and Blasco, M.A. (2004),
Epigenetic regulation of telomere length in mammalian cells by SUV39h1 and SUV39h2 histone methyltransferases, Nature Genetics 36, 94-99.
[4] Gonzalo, S. et al. (2006),
DNA methylases control telomere length and telomere recombination in mammalian cells,
Nature Cell Biology 8, 416-424.
[5] Benetti, R., et al. (2008),
A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rb12-dependent regulation of DNA methyltransferases, Nature Structural Molecular Biology 15, 268-279.
Methylation and Acetylation in Telomere Enlongation Therapy
Decreasing global and subtelomeric DNA methylation causes telomeres to enlongate. Increasing global and subtelomeric DNA methylation tends to reduce telomere enlongation. However, this applies primarily to heterochromatin marks difficult to modify with conventional supplements. It leads to the questionable conclusion that telomere enlongation therapy should seek to reduce global and telomeric DNA methylation while using telomerase activators, and to enhance global and telomeric DNA methylation while using telomerase inhibitors in a monthly cyclic protocol.
Note that Nutrition and the Epigenome describes folic acid as methyl-donating and supportive of DNA methylation. The usual approach recommended by nutrionists is to keep methylation high. DNA methylation defects are responsible for a number of diseases. Furthermore, hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity. (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. 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. See Index/hTERT methylation. The methyl donor folic acid seems to be a telomerase activator, supports the synthesis of telomeric DNA, and should be higher than median when attempting to improve hTERT mRNA transcription. However, it should not be maintained continuously at high levels (5 mg/day) to minimize cancer risks, so that it should return to normal levels (0.4 mg/day to 1.6 mg/day) during periods of telomerase inhibition in cyclic treatment. See Paul L, Cattaneo M, D'Angelo A, Sampietro F, Fermo I, Razzari C, Fontana G, Eugene N, Jacques PF, Selhub J. (2009), Telomere length in peripheral blood mononuclear cells is associated with folate status in men, Journal of Nutrition 2009 Jul;139(7):1273-8. Also 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.
Clearly, histone acetylation is to be promoted while trying expand chromatin for transcription of hTERT when attempting lengthen telomeres with telomerase activators, and deacetylation for chromatin compaction discouraging transcription of hTERT is to be used while emphasizing telomerase inhibitors in a cyclic rejuvenation protocol. Acetylation is done with histone deacetylation inhibitors such as Tricostatin A, CGK 1026, and perhaps also with sodium butyrate, sodium 4-phenylbutyrate, lactates from pumping up, L-carnitine or other HDAC inhibitors. Improved conditions that are optimum for increasing telomere length vs. stabilizing telomere length may be designed with a conservative choice of readily available supplements specifically modifying methylation and acetylation.
One might also apply an insulin boost before bedtime to phosphorylate tankyrase 1 in order to open telomere t-loops for telomerase holoenzyme access. Note that as telomere length is lost, H3 and H4 acetylation is increased, so that short telomeres are easier to enlongate than long telomeres.(Maria A. Blasco, 2007). This might be countered by using HDAC inhibitors to acetylate H3 and H4 independently of telomere length, making enlongation of long telemeres possible. However, lengthening long telomeres may lead to more telomeric circle generation. See also Nutrition and the Epigenome and Index/hTERT methylation.
Telomeric RNA TERRAs, or telomere-repeat-containing RNAs transcribed from telomeres, inhibit telomerase and are negative regulators of telomere length. Downregulation of TERRAs takes place as cancer progresses. See Shoeftner, S., and Blasco, M.A. (2008), Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II, Nature Cell Biology 10, 228-236; Schoeftner, S. and Blasco, M.A. (2009), A 'higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs, EMBO Journal 28, 2323-2336; Azzalin, C.M., Reichenbach, P. Khorlauli, L., Glulotto, E., and Lingner, J. (2007), Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends, Science 318, 789-801.
Telomeric Chromosome Stabilization [Links, Images, Papers, Patents, Books, Amazon/Telomere Stabilization].
Telomeric Crisis [article, in breast cancer, Links/telomeric crisis, Images, Video, Papers, Patents, Books, Amazon; Index/Shelterin]. Cellular telomeric crisis due to shortening of cellular telomeres causes carcinomas. See Senescence, p53, Telomere Fusion and Cancer. Many somatic cells (such as the dermal fibroblasts) divide, loosing about 50 bp per cell division from telomeres initally about 7000 bp long, until the senescence checkpoint at M1 = 4000 base pairs, when the telomere t-loop fails to close after cell division and the cell cycle is halted when p53 or pRb detects the open loop as a double-strand DNA break and halts the cell cycle. If p53 or pRb control is damaged, cell division may continue until crisis is reached at M2, when the telomere length is so short that telomeres can fuse, unless this is prevented by telomere t-loop control proteins such as KU or POT1. This typically happens when there is a carcinogen scenario including accelerated cell division fueled by substances like alcohol or estrogens, or when a carcinogen introduces mutations in p53. Mutations induced by carcinogens in oncogenes may lead to cancer. Subsequent cell division [Images] with fused telomeres [Images] leads to anueploidy [Images], multiple nuclei [Images], and other hallmarks of unusual damaged cells that destroy themselves with apoptosis or continue as cancer cells. 90% of human cancers are carcinomas or adenocarcinomas featuring cancer cells originating from telomeric crisis.
Telomeric DNA [Links, Images, Video, Papers, Patents, Images/Electron Microscope Images of Telomeric DNA, Amazon; Index/Shelterin]. Human telomeric DNA typically consists (say, in human fibroblasts) of 7000 to 4000 base pairs of GGTTAG minisatellite hex repeats shortening with each division of the cell until the M1 state is reached at which chromosomal telomere t-loops open and a DNA double strand damage signal is processed leading to cell cycle arrest and the senescent state of the cell. "Due to its high GGG content, telomeric DNA is particularly susceptible to oxidative damage and the generation of single strand breaks. Accordingly, the rate of telomere erosion is also greatly affected by the oxidative burden of the cell." - Jorge D. Erusalimsky, Vascular endothelial senescence: from mechanisms to pathophysiology, Journal of Applied Physiology 106: 326-332, 2009. Also see Von Zglinicki T. Oxidative stress shortens telomeres, Trends in Biochemical Sciences 27: 339–344, 2002.
Telomeric Ends [Links, Images, Papers, Patents, Books, Amazon]. See T-loops and Telomere Loop Control Proteins, such as TRF2 and TRF1.
Telomeric RNA [Links, Images, Papers, Patents, Books]. See Science Daily, New Telomere Discovery Could Help Explain Why Cancer Cells Never Stop Dividing, concerning telomeric RNA, Oct 7, 2007. Telomeres also specify RNA that is transcribed from telomeric DNA, such that telomeric DNA is not silent. See Joachim Lingner, et al., Telomeric Repeat Containing RNA and RNA Surveillance Factors at Mammalian Chromosome Ends, Science Magazine, 2 Nov 2007. Note that transcription from open telomere t-loops should induce DNA repair there. See Telomere Transcription, which produces TERRA telomeric RNA.
Telomolecular Nanotechnologies [Site/Telomolecular Nanotechnologies, Links, Video]. Now out of commission. This firm sold and explained telomerase activation products, DNA nanocircle technology, and therapies. (Corporate Video).
Tenilsetam (3-2-thienyl-2-piperazinone) cross-link inhibitor and nootropic [Links1, Links2, Images, Papers, Patents, Books, LifeExtension]
Teratogens [Links/Teratogens, Video, Papers, Patents, Books, Oxford/Teratogens, LibCong/teratogens, LifeExtension, Amazon]. Teratogens are dangerous to the developing human [49].
Testes Removal [94].
Testicular Cancer [Wikipedia, Links, Images, Video, Papers, Patents, Books, Amazon, LEF; Cancer; Carcinogens; Anticancer Nutraceuticals; Apoptosis; Telomerase Inhibitors; Anticancer Telomerase Activators; Metastasis, NFkB, NFkB Inhibitors, Angiogenesis Inhibitors].
Testosterone [TelomeraseActivators/Androgens, Links/Testosterone, Images, Video, Papers, Patents, Books, LifeExtension; Links/Reverse Cholesterol Transport, Images, Video, Papers, Patents, Books, LibCong, LifeExtension, Amazon]. Testosterone enables reverse cholesterol transport, removing excess cholesterol from tissues and carrying it to the liver, thereby reducing the likelihood of atherosclerosis, heart attack, and stroke. Reverse cholesterol transport works by augmenting scavenger receptor B1 [Links, Images, Papers, Patents] in the liver, which acts to stimulate cholesterol uptake, and by increasing the activity of hepatic lipase [Links], which removes phospholipids from the surface of HDL cholesterol, enhancing the uptake by scavenger receptor B1. See Testosterone supplements [Images, Papers, Patents, Books]. Higher levels of testosterone also help prevent prostate cancer. On the other hand, supplemental testosterone may be dangerous when suffering from prostate cancer. (LEF, As We See It, June 2010) High levels of DHEA, IGF-1 and testosterone were observed to improve the 3-year survival rate in heart disease mortality to 87% fom a low of 27% when DHEA, IGF-1, and testosterone were all low. Low testosterone causes obesity, a problem for patients who have suffered testicle removal. DHEA may be taken in such cases to elevate testosterone. LEF suggests free testosterone in the range 20 to 25 pg/mL of blood are best, although levels as low as 15 pg/mL may be adequate according to some experts. Testosterone levels decrease with age, and levels as low as 8.8 pg/mL are seen in men over 70. Between 30 to 39 years of age, levels of 12.84 pg/mL are typical in the LEF membership. (LEF, June 2010). Testosterone replacement therapy with testosterone gels or patches can reduce LDL cholesterol, reduce blood sugar, reduce glycated hemoglobin, reduce insulin resistance, and prolong life. Blocking aromatization of testosterone (with aromatization inhibitors like chrysin and nettle root) into estrogens eliminates hazards associated with estrogens, such as estrogenic cancers, heart attack, and stroke. On the other hand, testosterone replacement therapy can actually reduce PSA (Prostate Specific Antigen) levels, so that today testosterone seems like less of a prostate cancer threat than formerly. Testosterone boosters include:
(1) Astaxanthin plus saw palmetto berry lipid extract (2000 mg/day, Alphastat Rx-Prostate)
(2) Damiana [Images], an aromatase suppressor that raises testosterone and lowers estrogen, taken at 50-500 mg three times a day. Damiana contains a ligand of the progesterone receptor.
(3) Forskolin, which stimulates the Leydig cells in the testes that secrete testosterone, taken 250 mg per serving twice a day in a 10% forskolin extract. I note that Solaray "FORSKOLII" recommends 1 or 2 x 385 mg/cap per day of a 1% Forskolin extract guaranteed 3.85 mg of Forskolin per cap.
(4) Tribulus (puncturevine) increases testosterone via protodioscin, a furostanolic saponin that causes the brain to release more luteinizing hormone, which acts on the testicles. Tribulus is used to boost muscle and fat loss, taken at 250-750 mg twice a day, cycled 8 weeks on tribulus and 4 weeks off it.
Recent articles in Wikipedia and a video on tribulus from Ray Sahelian claim that testosterone is not elevated by tribulus, but that it enhances sexual behavior by acting on androgenic receptors in the brain, functioning as an aphrodisiac. It is not thought to improve athletic performance by improving testosterone expression by all scholars.
(5) Methoxyisoflavone [Supplements, Images, Papers, Patents, Books] is anti-estrogenic in a way that promotes the release of higher testosterone levels, taken at 500-2000 mg/day with meals. Still fairly new.
(6) Longjack (Tongcat Ali, Longfolia Jack, Eurycoma, Index/Longjack) boosts testosterone levels and decreases cortisol expression when taken 100-300 mg in the morning, 30 minutes before workouts, and before bedtime. Bodybuilding sources suggest 300 mg/day 5 days/week, cycled at 8 weeks on and 2 weeks off. Otherwise aphrodisiac side-effects may become difficult to manage.
(7) Fenugreek elevates testosterone via furostanolic saponins [Links, Images, Papers, Patents, Books, supplements, LifeExtension], which increase the expression of DHEA and LH (Luteinizing Hormone). Fenugreek also promotes insulin secretions via 4-hydroxyisoleucine, while activating telomerase with diosgenin via the HIF-1 transcription factor, which promotes hTERT mRNA transcription to produce telomerase. Insulin phosphorylates tankyrase 1, which allows TRF1 protein-stripping from telomere loops to open the loops and make them accessible to the telomerase holoenzyme. It is safe enough to boost insulin after a workout, although it should not be high all the time. See Diabetes.
(8) L-carnitine L-tartrate [Images] boosts the number of testosterone receptors in muscle, and boosts anabolic hormone release. It may be taken with leucine after a workout to stimulate muscle anabolism as component of a timed supplement stack.
(9) Boron citrate [Images, Papers, Patents, Books] is used to increase free testosterone levels.
(10) DHEA [Links, Images, Papers, Patents, Books] is a precursor of testosterone produced by the adrenal glands.
(11) 6-OXO [Wikipedia/4-Androstene-3,6,17-trione, Images, Papers, Patents, Books]. The aromatase inhibitor 4-Androstene-3,6,17-trione (marketed as 6-OXO) can change the testosterone/estrogen ratio by binding and inactivating aromatase, which converts testosterone into estrogen.
(12) ZMA [Wikipedia/ZMA, Images, Papers, Patents, Books]. Wikipedia claims that ZMA, a supplement containing zinc, magnesium, and vitamin B6, has no significant effects on free testosterone after all.
(13) Pine Pollen [Links, Images, Papers, Patents, Books] improves testosterone levels.
Note that testosterone upregulates FGF2 (FGFb) in the FGF family of fibroblast growth factors, a human growth factor telomerase activator.
Tetrahymena (model organism) [Wikipedia/Tetrahymena, Links, Images, Video, Papers, Books, Genetics; Links/The Genome of Tetrahymena]. The first telomeres to be sequenced by Elizabeth Blackburn in 1978 were from Tetrahymena thermophila and had the sequence TTGGGG, which I thought might be actually associated with the hex repeat 5'-GGTTGG-3'. This happens if the Tetrahymena thermophila telomerase hTR (TERC) RNA template is 3'-CAACCCCAACC-5', which would be very similar to the human TERC template 3'-CAAUCCCAAUC-5' associated with the human telomerase hex repeat 5'-GGTTAG-3'. (check). The classical paper by Blackburn, Greider, and Szostak specifies the template sequence as CAACCCCAA. This is well supported by sequencing data in Greider, C.W. & Blackburn, E.H. (1989), A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis [PDF], Nature 337, 331–337 (1989). The sequencing data here rules out 3'-CAACCCCAACC-5' for 3'-CAACCCCAA-5', so that Tetrahymena telomerase is not as similar to human telomerase as I supposed it might be, and really does feature the hex repeat 5'-TTGGGG-3'.

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