Anti-Aging Medicine: Sup Notes 3a | 3b1 | 3b2 | 3b4 | 3b5 | Product B Explorer | 3b6
One, Two, Three,...Infinity: A Lucky Strike.
Telomerase is a 123 Kilodalton enzyme.
Rejuvenation via Cyclic Telomerase Activation (7)

Phase I: For 0 < t < 57.967123 = t0, B = 1,
Model Age = Bt.
Phase II: For 57.967123 < t < 64.3, B = - 5.2 years/yr,
Model_Age = B(delta_t) + t0 = (B/12)N + 57.967123,
N = 1, 2, 3,...,76 months, using astragalus extracts.
Phase III: For 64.3 < t < infinity, B = 0,
Model Age = 25.
Press for Age Transformation's FLIGHT PLAN.

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Highlight Links 3a
[74s] Hair Loss, TERT, Saw Palmetto with Beta-sitosterol, Finasteride, Dutasteride, & PABA.
[75s] Carbonylation of Proteins.
[76s] Nanomedicine.
[77s] Microglia in the Aging Brain are telomere-limited, subject to replicative senescence.
[78s] Jekyll-Hyde Formulas for Life Extension, including Turmeric with Pepper, Cocoa powder drinks, Wasabi, and Astragalus.
[79s] Rejuvenation to produce anti-aging transformations.
[80s] Notes on The Anti-Aging Solution by Giampappa, Pero, and Zimmerman.

Highlight Links 3b1 - Cells Responding to Telomerase Activation & Telomerase Inhibitors
[81s] Life Extension via Telomere Extension in Vivo, with Cells that Respond to Telomerase Gene Transduction.
____Telomerase Inhibitors (1)-(73) with hyperlinked numeric and alphabetic selection guides.

Highlight Links 3b2 - Telomerase Activators
____Telomerase Activators (1)-(185), with hyperlinked numeric and alphabetic selection guides.
[81s/6b] Astragalalus-based small-molecule telomerase activators and others.
[81s/6d] 230 base pairs of telomere growth per 3 months of treatment with TA-65. - TA Sciences, Greta Blackburn letter.
____More Telomerase Activators (7)-(22).

Highlight Links 3b4 - Telomerase Activators
____Still More Telomerase Activators (23)-(64).

Highlight Links 3b5 - Telomerase Activators
____Still More Telomerase Activators (65)-(132).
____Telomere Measurement.
____Telomerase Expression Measurement.
[81bs] Senile purpura.

Product B Explorer - Telomerase Inducers
____Product B Telomerase Inducers (133)-(153).

Highlight Links 3b6 - Telomerase Activators
____Further Telomerase Activators (154) - (185).

Still More Telomerase Activators (65)-(132).

(65) E6/E6AP, something from virology and cancer not to be used. "The human papillomavirus E6 oncoprotein activates telomerase. This effect is cell-type specific, observed in mammary epithelial cells or keratinocytes but not in fibroblasts." [1].
[Links/E6/E6AP, Images/E6/E6AP; toxicity]. E6/E6AP is a ubiquitin ligase obtained from human papillomavirus type 16 (HPV16) and is associated with "Angelman Complex", and is too dangerous to be used, most likely. It seems to attack the p53 tumor-suppressor protein with ubiquination, destroying cancer defenses. Probably materials derived from drugs used for centuries will be more popular than medicines distilled from disease-associated viral proteins in any case. The papilloma virus may be associated with cervical cancer and genital warts. I note that vaccines against this class of viruses have recently been developed.
References
[1] Satoru Kyo and Masaki Inoue (2002),
Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy?,
Oncogene, 21 January 2002, Section (7) Oncogenes, Vol. 21, No. 4, Pages 688-697.
[2] Scheffner M, Huibregtse JM, Vierstra RD, Howley PM, (1993),
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53,
1: Cell, 1993 Nov 5;75(3):495-505.
[3] See Xu M, Luo W, Elzi DJ, Grandori C, Galloway DA, (2008),
NFX1 interacts with mSin3A/histone deacetylase to repress hTERT transcription in keratinocytes,
Mol. Cell. Biol. (2008).

(66) Bmi-1 protein. [Links/Bmi-1 protein, Images, Papers, Patents, Books; toxicity]. Although the the Bmi-1 oncogene is connected with breast cancer, it might be safe enough for males to be used some of the time for therapeutic purposes in lengthening telomeres [1], [2], [3]. "The recent observation that Bmi1, a Polycomb group repressor, is essential for the self-renewal of adult murine hematopoietic stem cells (HSCs) and neuronal stem cells, in part via repression of genes involved in senescence, suggests that stem cells have evolved specific mechanisms to repress senescence and to prolong their capacity to proliferate." [2].
Bmi1 and Ezh2 bind to the p16INK4a promoter (Bracken et al. 2007, Kotake et al. 2007) to decrease p16INK4a expression in senescence, and decreased occupation of the p16INK4a promoter [Papers, Patents, Books] by polycomb group proteins (Bmi1, Cbx7, Cbx8, and Me118) corresponded to increased p16INK4a levels. High levels of P16INK4a can induce senescence, so control of P16INK4a accumulation is of considerable interest in life extension medicine. See P16INK4a and senescence [Links, Images, Papers, Patents, Books]. P16INK4a may be controlled by Id-1 helix-loop-helix protein, which can be promoted using Nerve Growth Factor produced from off-the-shelf supplements including acetyl L-carnitine, Huperzine A, carnosic acid, and rosemary extract.
Supplements promoting Bmi1 protein [Papers, Patents, Books] may also be useful for controlling p16INK4a concentrations in old cells.
Is Bmi1 upregulated by exercise? [Papers, Patents, Books].
References
[1] See Dimri GP, Martinez JL, Jacobs JJ, Keblusek P, Itahana K, Van Lohuizen M, Campisi J, Wazer DE, Band V (2002),
The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells, Cancer Research, 2002.
[2] In-Kyung Park, Sean J. Morrison, and Michael F. Clarke (2004),
Bmi1, stem cells, and senescence regulation, Journal of Clinical Investigation, vol.113, issue 2, Jan.15,2004.
[3] Itahana K et al. (2003),
Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1,
Molecular and Cellular Biology 23: 389-401.
[4] Dietrich N, Bracken AP, Trinh E, et al. (2007),
Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus,
EMBO Journal 26:1637-48.

(67) Terminalia chebula [Links, Images, Papers, Patents, Books; WikiGenes/Terminalia Chebula] (Combretaceae) [Links], Haritaki [Links, Images, Papers, Books; toxicity], The ethanolic extract from the fruit of Terminalia chebula (Combretaceae), or Haritaki is an antioxidant. Also termed chebulic myrobalan [Links, Images, Papers, Patents, Books; toxicity]. By 2012 believed to reduce telomere shortening via antioxidant effect only [1]. This one is popular in Ayurvedic Medicine and is sold! See also [Links/Terminalia chebula fruit extract, Images/Terminalia chebula fruit extract]. Also known as Haritaki [Links]. See Haritaki Extract [Images, Links]. Chebuloside II, a pentacyclic triterpene glycoside also described as a triterpenoid glycoside, [Links/Chebuloside II, Article including the molecular structure of chebuloside II (p.113)] is used as a marker for the quality of the ethanolic extract. This particular molecule reminds me of astragaloside IV in its structure. "Terminalia chebula is a tree with a rounded crown and spreading branches. Its principle constituents contain chebulagic acid [Links, Images/chebulagic acid molecule], chebulinic acid [Links, Images/chebulinic acid molecule], and corilagin [Links, Images/corilagin molecule]. Its fruits have laxative, stomachic, tonic and alterative properties. It is also known as an adaptogen and hepatoprotective drug." - PharmacyEscrow.com. Note that "Haritaki" is described as "alterative" by PharmacyEscrow.com, suggestive, perhaps, of Matahari side-effects. Triphala (available from Solaray Ayurvedic Herbs), includes Chebulic Myrobalan (Haritaki) as a major component, along with Belleric Myrobalan and Amla. (It is shelved next to Shatavari.) (Music: Time After Time by Cyndi Lauper.) See Ritu Haritaki Rejuvenative Use Of T. Chebula for its preparation of Haritaki as a cold infusion, hot infusion, tea, powder, extract tab or capsule. See also Banyan Botanicals: Haritaki. Haritaki is a component of the multi-pathway telomerase activator Astral Fruit NF sold by RevGenetics, which also includes cycloastragenol, astragalus extract, and aqueous extract of Purslane. By April 27, 2012, Terraternal reported that Haritaki (Terminalia Chebula) merely conserves telomere length without actually lengthening telomeres in their section on Terraternal Telomere Guard. Terraternal now sells Terminalia Chebula and claims that it reduces telomere shortening via antioxidant effect. "It was observed that in the case of the cells administered to the T. chebula extract, the telomere length had shortened by an average of 192 bp/PDL, which was slower than the 342 bp/PDL observed in the control group." [1]. Harada Fruit Extract (142) (Terminalia Chebula, Haritaki) is also a telomere-lengthening component of Product B for dermal fibroblasts.
See the hTERT activation pathway for Haritaki or the Terminalia Chebula hTERT activation pathway.
References
[1] See MinKyun Na, KiHwan Bae, Sam Sik Kang, Byung Sun Min, Jae Kuk Yoo, Yuko Kamiryo, Yu-ichiro Senoo, Seiichi Yokoo, Nobuhiko Miwa (2004), Cytoprotective effect on oxidative stress and inhibitory effect on cellular aging of Terminalia chebula fruit,
Phytotherapy Research, Volume 18 Issue 9, Pages 737 - 741, Published Online: 11 Oct 2004.

(68) Colostrum [Index/Colostrum, Wikipedia, WikiGenes/Colostrum, Links, Images, Video, Papers, Books; Links, Biocarta Pathways; toxicity; Colostrum Cream; Links/Colostrum skin creams, Images, Video, Papers, Patents, Books; Index/Growth Factor Skin Creams; Links/Transdermal application of colostrum]. Colostrum is obtained from the milk of mothers of newborn during the first day after birth. Note that colostrum solution rots like milk, so that it must be kept in the fridge or mixed with a preservative. It includes includes several growth factor telomerase activators in an early mother's milk. Colostrum transcribes hTERT mRNA, Phosphorylates hTERT, uses the MAPK pathway, and contains the the telomerase activators IGF-1, IGF-2, EGF, TNF-alpha, FGF (FGF-2 and FGF-4), PDGF, VEGF, and TGF-alpha. It also contains the telomerase inhibitor TGF-beta, which restores the extracellular matrix. Colostrum contains both FGF-2 and VEGF, which upregulate survivin, which can reverse replicative senescence. It seems that mixing colostrum with cream in a blender, then in an ultrasonic cleaner, improves both its transdermal and internal bioavailability by creating milk lipid liposomes for the colostrum.
Music: You're Sixteen by Ringo Star.
Skin Cream TypeBrandGrowth Factor LinksCost
Colostrum skin creams [Images]Nature's Gift Colostrum Renewal Skin CreamEGF (Epithelial Growth Factor)$19.95
Colostrum skin cream [Images]SequelRich in growth factors:
TGF-beta; TGF-alpha, EGF, IGF-1,
IGF-2, VEGF, FGF, PDGF.
$27.95
EGF skin cream [Images]Pursue Epidermal Growth Factor CreamEGF (Epidermal Growth Factor)$85.00
EGF skin cream [Images]Lux Life EGF CreamEGF (Epidermal Growth Factor)$89.00
EGF skin cream [Images]ReVive Skin Care CreamsEGF (Epidermal Growth Factor)$165.00
Growth factors skin cream [Images]RegeniskinEGF, PDGF, TGF, FGF$29.95
"Because of the increased risk of cancer by EGF, inhibiting it decreases cancer risk." - Wikipedia/EGF. Bovine colostrum is available as a supplement. See Links/Bovine Epidermal Growth Factor. Bcl-2 from astragaloside activation and together with simultaneous EGF activation increases the likelihood of lymphoma. Formerly, I suspected Astragalosides and colostrum don't mix. Presently, I am inclined to believe that Bcl-2 and C-myc may both be elevated without much risk in a cyclic program of treatment, so that now I am less concerned about this. Indeed, astragalus extract, which upregulates c-Myc via the MAP kinase pathway, also upregulates IL-2, which upregulates Bcl-2. Astragalus extract also activates the MAP kinase pathway (Index), which upregulates c-Myc, as does EGF. So C-myc and Bcl-2 are both upregulated by astragalus extract, which is quite safe. Therefore I am now less worried about simultaneously upregulating c-Myc and Bcl-2 in a cyclic treatment with 2 weeks of telomerase activator application followed by 2 weeks of telomerase inhibitors.
March 14, 2010 Today I acquired some Colostrum (with Epidermal Growth Factor EGF) for telomerase activation from GreenAcres, which now sells brands of Colostrum, including LifeTIME (500 mg/cap x 120 caps, $22.99). It was the bigger of two bottles the manager Matt offered me, both of which were billed as Colostrum. The 2nd bottle looked more like the pure, accurate Colostrum. So what do I select? LimuZ Nei from Total Body Research Labs contains a 6.1 gram mixture of Acetyl L-Carnitine, Colostrum, Limu (Laminaria japonica) 40:1 Fucoidan Extract standardized to 85% N-acetyl-Glucosamine, and Stevia. At the time I felt astragalosides and colostrum don't mix, so I saved it for later before consuming it. It could probably best be substituted for astragalosides for two 15-day periods in two months, although vitamin D and pomegranate extract should probably also be taken, as they are for IGF-1, which also has the potential to activate cellular proliferation. Note that Biocarta Pathways suggests that both IGF-1 and EGF are useful for life extension, although Jerry Brainum indicates that Vitamin D and Pomegranate Extract both reduce the likelihood of cancer. By 2012 I fearlessly take colostrum with astragalus products, boost IGF-1, and save the vitamin D for the telomerase inhibitor phase of monthly cyclic treatment.

(69) ? Gotu Kola ? [Wikipedia/Gotu Kola, Index/Gotu Kola, WikiGenes/Gotu Kola, Links/Gotu Kola, Images, Video, Papers, Patents, Books; Links/Gotu Kola and telomerase activation; toxicity]. VIDA Institute recommends taking astragalus root extract with ginkgo biloba (to improve circulation) and gotu kola (to improve vision and fine circulation). Ginkgo Biloba and gotu kola are thought to make astragalus root extract telomerase activators more available to tissue fine structure via circulation improvements. "Centella Asiatica (gotu kola) has been shown clinically to improve circulation in the fine capillary vessels of human tissue." Gotu Kola might turn out to be a telomerase activator, although I have not seen this reported yet. It has properties that suggest this may be true. (Check). "Gotu Kola is a minor feature in the longevity myth of the Tai Chi Chuan master Li Ching-Yuen. He purportedly lived to be 256, due in part to his usage of traditional Chinese herbs including Gotu Kola. A popular folklore tale from Sri Lanka speaks of a prominent king from the 10th century AD named Aruna who claimed that Gotu Kola provided him with energy and stamina to satisfy his 50-woman harem." - Wikipedia/Gotu Kola. However, "Excessive consumption of Gotu Kola can cause cancer (due to the Asiaticoside content of Gotu Kola)." Note that telomerase activators, because they somewhat disable tumor inhibition mechanisms based on telomerase inhibition, may be described as (weakly) tumor promoters. Therefore the observation that excessive Gotu Kola consumption can cause cancer is about what one expects for a strong telomerase activator. Using telomerase inhibitors and anticancer nutraceuticals for two weeks after two weeks on telomerase activators seems to be effective in preventing cancer from application of telomerase activators, however. See also
Asiaticosides [Links, Papers, Patents, Books, Links/Asiaticosides and telomerase activation; Images/Asiaticoside molecules].

(70) IRF4 (Interferon Regulatory Factor 4) [Wikipedia/IRF4, WikiGenes/IRF4, Links, Images, Video, Papers, Patents, Books; Links/the IRF4 promoter, Images, Video, Papers, Patents, Books; Images/IRF4 molecule; toxicity; Links/Interferon Regulatory Factors; Links/Interferon]. Interferon Regulatory Factor 4 (IRF4 and, to a lesser extent, IRF8) upregulate telomerase in immune cells during immune system activation. See also IRF8 [Wikipedia/IRF8, WikiGenes/IRF8, Gene Cards/IFR8 Links, Images, Papers, Books; Images/IRF8 molecule]. Perhaps IRF4 and IRF8 are suitable for liposomal sprays or creams. IRF-4 expression is upregulated during lymphocyte activation [Links, Images, Video, Papers, Patents, Books]. "The induction of telomerase by IRF-4 and IRF-8 correlates with the activation of the TERT promoter. IRF-4 binds the interferon response-stimulated element and the gamma interferon-activated sequence composite binding site in the TERT core promoter region in vivo. Additionally, the binding of Sp1, Sp3, USF-1, USF-2, and c-Myc to the TERT promoter is elevated in cells expressing IRF-4. IRF-4, but not IRF-8, synergistically cooperates with Sp1 and Sp3 in the activation of the TERT promoter. Collectively, these results indicate that IRF-4 and IRF-8, two lymphoid cell-specific transcription factors, increase telomerase activity by activating TERT transcription in immune cells." [1]. See the hTERT activation pathway for IRF4 or the IRF4 hTERT activation pathway.
References
[1] Radmila Hrdlikova, Jii Nehyba, and Henry R. Bose Jr. (2009),
Regulation of Telomerase Activity by Interferon Regulatory Factors 4 and 8 in Immune Cells,
Molecular and Cellular Biology, February 2009, p. 929-941, Vol. 29, No. 3.

(71) DHEA [Index, WikiGenes/DHEA, Gene Cards/DHEA Links/DHEA; Links/DHEA as a telomerase activator, Biocarta Pathways; Images/DHEA molecule; toxicity]. DHEA raises levels of IGF-1 [List], that it must be indirectly a telomerase activator, too. However, I am presently uncertain whether it raises IGF-1 enough to be useful for this application. See Links/DHEA elevates IGF-1 levels, and Links/DHEA promotes the expression of IGF-1. DHEA typically elevates serum IGF-1 levels by 10% according to DHEA by James South. See also Links/DHEA in bodybuilding. Note that IGF-1 activates telomerase by phosphorylating hTERT catalytic component of telomerase in the cytoplasm, enabling its import into the cell nucleus. There it can act in telomerase to extend the telomere. Thus IGF-1 from DHEA creates no fresh hTERT mRNA transcripts, and applying it does not improve the number of hTERT catalytic component of telomerase molecules. Note also that DHEA is a precursor of testosterone, an androgen associated with telomerase activation. DHEA can be used after testicle removal to elevate testosterone, unlike many other testosterone expression boosters which act on the gland of Leydig in the testicles. Testosterone from DHEA is capable of improving hTERT mRNA levels in many tissues.

(72) Pregnenolone [WikiGenes/Pregnenolone, Index, Links/Pregnenolone, Links/Pregnenolone as a telomerase activator, Biocarta Pathways; Images/Pregnenolone molecule; Images/Pregnenolone skin creams; toxicity]. Pregnenolone elevates expression of DHEA (TA/DHEA), which elevates the expression of telomerase activator
IGF-1 (TA/IGF-1), so that pregnenolone is a telomerase activator via the IGF-1 pathway, that is, via the Pregnenolone/DHEA/IGF1/PI3K/AKT1 pathway. See the PI3K/Akt Pathway and AKT. How well pregnenolone works in telomerase activation therapy is still in question. Since the mechanism is to phosphorylate hTERT, no fresh hTERT mRNA transcripts are produced, although the telomere is lengthened. However, there are papers which claim that the PI3K pathway can directly increase hTERT mRNA levels.

(73) Id-1 Helix-Loop-Helix Protein [Index, Links, Images, Video, Papers, Patents, Books; Links/the Id-1 promoter, Images, Papers, Patents, Books; WikiGenes/Id-1 helix-loop-helix protein; Images/Id-1 helix-loop-helix protein molecule; toxicity]. Id-1 helix-loop-helix protein activates telomerase [Links, Images, Papers, Books] in human keratinocytes [1]. See The Helix-Loop-Helix Family of Transcription Factors and Activating expression of Id1 helix-loop-helix protein.
Nerve Growth Factor, Rosemary Extract, and Carnosic Acid
Id-1 is activated, for instance, by Nerve Growth Factor [Index], which can be activated with carnosic acid from Rosemary [Links; toxicity] in Essential Oil of Rosemary or Rosemary leaves. Sage is also a rich source of carnosic acid. So perhaps carnosic acid can be used as a telomerase activator via its indirect activation of Id-1 helix-loop-helix protein, which normally acts to suppress cellular differentiation. Nerve Growth Factor may be boosted up to 100x by Acetyl L-Carnitine, or by Acetyl L-Carnitine Arginate. Platelet-Activating Factor also enhances the expression [Links; toxicity] of Nerve Growth Factor, as does Huperzine A [Images, toxicity]. See drugs and supplements enhancing expression of Platelet-Activating Factor. See Papers/the hTERT activation pathway for Id-1 helix-loop-helix protein or Papers/the Id-1 helix-loop-helix hTERT activation pathway.
Id-1 helix-loop-helix protein also helps down-regulate p16INK4a. [P16, P16 inhibitors: Retinoic Acid, Other]
See (Zheng et al. 2004, Ohani et al. 2001). High levels of p16INK4a can induce senescence, and it is desirable to limit p16INK4a levels to avoid cellular senescence. "Most senescent cells seem to express P16INK4A, a cyclin-dependent kinase inhibitor and tumour suppressor that enforces growth arrest by activating Rb." (Darren J. Baker, et al, (2011)). Since Id-1 may be upregulated with Nerve Growth Factor from acetyl L-carnitine, carnosic acid, Huperzine A, and rosemary extract, p16INK4a can be regulated with induced Id-1. Although p16INK4a is valuable as a tumor suppressor, increasing p16INK4a expression decreases forebrain progenitors [Images] and neurogenesis [Images, Papers, Patents, Books]. Furthermore, the gradually ubiquitinated tumor-suppressor P16INK4a can become too concentrated in the cell to avoid cellular senescence, so that methods for controlling P16INK4A concentration based on reducing its expression are being developed. Resveratrol and exercise both reduce P16INK4A, and the expression of P16INK4A is aggravated by smoking [2].
References
[1] See Rhoda M. Alani, Jens Hasskarl, Miranda Grace, Maria-Clementia Hernandez, Mark A. Israel, and Karl Münger, (1999),
Immortalization of primary human keratinocytes by the helix–loop–helix protein, Id-1,
PNAS, August 17, 1999 vol. 96 no. 17 9637-9641.
[2] See Wenjie Zheng, Heyao Wang, Lixiang Xue, Zongyu Zhang, and Tajun Tong (2004),
Regulation of Cellular Senescence and P16INK4A Expression by Id1 and E47 Proteins in Human Diploid Fibroblast,
The Journal of Biological Chemistry, vol.279, No.30, July 23, pp. 31524-31532.

(74) Stem Cell Factor (Kitl) [Links/Stem Cell Factor, Images, Video, Papers, Patents, Books; Links/the Stem Cell Factor Promoter, Images, Video, Papers, Patents, Books; Links/Kitl stem cell factor, Images, Video, Papers, Patents, Books; WikiGenes/Stem Cell Factor; Images/Stem Cell Factor molecule; toxicity]. Stem Cell Factor (Kitl) has been observed to activate telomerase [1]. See MD Ultimate Stem Cell Factor [Links/MD Ultimate Stem Cell Factor, Images, Video, Papers, Patents, Books], a product used to regenerate skin. See drugs or supplements to upregulate Stem Cell Factor. See the hTERT activation pathway for Stem Cell Factor or the Stem Cell Factor hTERT activation pathway.
References
[1] Susanna Dolci, Lauretta Levati, Manuela Pellegrini, Isabella Faraoni, Grazia Graziani, Anna Di Carlo and Raffaele Geremia (2002),
Stem cell factor activates telomerase in mouse mitotic spermatogonia and in primordial germ cells,
Journal of Cell Science 115, 1643-1649 (2002).

(75) Bcl-2 [Links, WikiGenes/Bcl-2; Images/Bcl-2 molecule; toxicity]. Bcl-2 activates telomerase and inhibits apoptosis [1]. Note that Bcl-2 is upregulated by IL-2, which is upregulated by astragalus membranaceus extract and astragaloside IV. See drugs or supplements to upregulate Bcl-2 and IL-2. Zinc also upregulates Bcl-2. Nuclear Factor Kappa Beta can also mediate Bcl-2 upregulation.
Simvastatin, clozapine, olanzapine, lithium, and zinc supplements upregulate Bcl-2, although they may not all be suitable for our application. Interleukin 2 is available for treatment by injection. As I recall from on-line research (check), Sustained Bcl-2 upregulation tends to promote lymphoma when C-myc levels are high, so that simultaneous upregulation of C-myc and Bcl-2 may be a cancer hazard. However, both C-myc (via the MAP kinase pathway) and Bcl-2 (via IL-2) are believed to be upregulated by astragalus extract, which is quite safe. It will probably suffice to use telomerase activators for 2 weeks, then telomerase inhibitors and anticancer nutraceuticals for two weeks in a program of cyclic treatment to avoid problems imposed by sustained application of telomerase activators. If telomeres become dysfunctional and p53-dependent apoptosis is the main driver for tumor suppression, then the elimination of p53-dependent apoptosis by Bcl-2 overexpression can lead to the rapid development of lymphoma. See (Yibin Deng, Suzanne S. Chan, and Sandy Cheng, 2008). See the hTERT activation pathway for Bcl-2 or the Bcl-2 hTERT activation pathway.
References
[1] See M Mandal, R Kumar, (1997),
Bcl-2 modulates telomerase activity, Journal of Biological Chemistry, 272, May 30, 1997, 14183-14187.

(76) Replication Protein A [Index, WikiGenes/Replication Protein A, Links, Images, Video, Papers, Books; Links/the Replication Protein A promoter, Images, Papers, Books; GeneCards/RPA1, (YeastGenome/RPA1, YeastGenome/Telomere Maintenance); Images/Replication Protein A molecule; toxicity]. Replication Protein A on human Chromosome 17, which is present in all Eucaryotic cells, has been observed to activate telomerase in yeast [1]. Note that the shortest telomere is on chromosome 17. Estp1 [YeastGenome/Est1] has been conserved in evolution and is present in humans as hEST1A [Index, List, Links]. "Overproduction of hEST1A cooperated with hTERT to lengthen telomeres." [2]. hEST1A recruits telomerase holoenzyme by binding to hTERT. (See Diagram). hSMG6 [Links/hSMG6, Links/SMG6] is identical to hEST1A [List]. (See Joachim Lingner, Senior scientist, Telomerase and chromosome end replication, ISREC.) According to Gene Cards, overexpression of SMG6 (in humans hEST1A) results in telomere uncapping. Therefore perhaps hSMG6 or hEST1A can be used to extend t-loop capped telomeres, opening them so that they can be extended by telomerase. Telomerase does not act on telomeres unless the telomere is uncapped (7). Thus large telomere t-loops corresponding to very youthful cells may be prepared by using hEST1A (hSMG6) together with telomerase, probably by stopping SMG6 towards the end of a treatment period to reseal telomere t-loops. Such cells may have superior staying power, lasting for more cell divisions before uncapping, generating a DNA damage signal, and entering the state of replicative senescence. HEST1A and RPA may be upregulated by histone deacetylase inhibitors that expand chromatin to upregulate transcription in general. Sodium butyrate (upregulates SP1), sodium 4-phenylbutyrate, sulforaphane, and L-carnitine are candidate HDAC inhibitors for the upregulation of Replication Protein A and HEST1A. (check) "We show that E2F-1 [Images, Papers, Patents, Books] up-regulates the expression of a number of genes coding for components of the DNA replication machinery. Among them is the gene coding for the 32 Kd subunit of Replication Protein A (RPA2)." [3]. "One helix of the three helix RPA bundle is contributed by each RPA subunit, with this structure responsible for supporting heterotrimerization of the RPA complex (Bochkareva et al., 2002)." - Atlas of Genetics and Cytogenetics in Oncology and Haematology, RPA2. The 3 helix subunits are sometimes characterized as RPA70, RPA32, and RPA14 (70, 32, and 14 kDa subunits). "RPA binds directly to single-stranded DNA (ssDNA) where it organized and protects ssDNA during replication." - See Assays for RPA. Also see drugs and supplements upregulating Replication Protein A.
References
[1] Vera Schramke, Pierre Luciano, Vanessa Brevet, Sylvine Guillot, Yves Corda, Maria Pia Longhese, Eric Gilson & Vincent Géli, (2003),
RPA regulates telomerase action by providing Est1p access to chromosome ends,
Nature Genetics 36, 46 - 54 (2004) Published online: 21 December 2003.
[2] Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L., (2003),
Functional conservation of the telomerase protein Est1p in humans, Curr Biol. 2003 Apr 15;13(8):698-704.
[3] Yael Kalma, Lea Marash, Yocheved Lamed and Doron Ginsberg (2001),
Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2, Oncogene, 15 March 2001, Volume 20, Number 11, Pages 1379-1387.

(77) Uncaria sinensis Havil [WikiGenes/Uncaria Sinensis Havil, Links, Images, Papers, Books; toxicity]. Uncaria sinensis Havil signficantly inhibits telomere shortening and might be a telomerase activator [1]. "The life-span of the HEK-N/F cells was elongated by 201% as a result of the continuous administration of 3 µg/ml of the Uncaria sinensis extract compared to that of the control." Perhaps this was due to an antioxidant effect inhibiting telomere degradation.
References
[1] MinKyun Naa, Young Ho Kima, Byung Sun Minc, KiHwan Baea, Yuko Kamiryod, Yu-ichiro Senood, Seiichi Yokood, Nobuhiko Miwad, Kyung Sik Songe and Yeon Hee Seongf (2006), Cytoprotective effect on oxidative stress and inhibitory effect on cellular aging of Uncaria sinensis Havil, Journal of Ethnopharmacology, Vol 95, Issues 2-3, Dec 2004, pp 127-132.

(78) Hepatocyte Growth Factor [WikiGenes/Hepatocyte Growth Factor, Links, Images, Papers, Patents, Books; Images/Hepatocyte Growth Factor molecule; toxicity]. All human growth factors seem to be telomerase activators [1]. See links for Hepatocyte growth factor activates telomerase, PI3K/Akt pathway telomerase activation, and growth factors activate telomerase. See the hTERT activation pathway for Hepatocyte Growth Factor or the Hepatocyte Growth Factor hTERT activation pathway.
References
[1] L Gomez-Garcia, FM Sanchez, MT Vallejo-Cremades, IA Gomez de Segura and E De Miguel del Campo (2005),
Direct activation of Telomerase by GH via phosphatidylinositol 3'-kinase, Journal of Endocrinology, 2005, 185, 421-428.

(79) Sphingosine-1-Phosphate (S1P) [WikiGenes/Sphingosine-1-Phosphate, Wikipedia, Links, Images, Video, Papers, Patents, Books; Images/Sphingoshine-1-Phosphate molecule; toxicity]. Sphingosine-1-Phosphate activated telomerase in stroke. S1P activates Akt [Links/Akt] and telomerase in brain endothelial cells, suppresses apoptosis, and induces proliferation. Perhaps S1P could be put into liposomes prepared with a cationic transfection reagent to enter the cell via endocytosis. Note that activation via AKT (Index/AKT) does not create more hTERT mRNA transcripts, but instead phosphorylates the hTERT catalytic component of telomerase in the cytoplasm for import into the nucleus. See also Antonella Riccio (2010), New Endogenous Regulators of Class I Histone Deacetylases, Science Signaling, 5 January 2010, Vol 3, Issue 103. "S1P even activates fibroblast-derived extracellular matrix protein production... (but)...bioavailability of the compound in human skin is a concern. Therefore, a topical formulation based on specific drug carriers has been considered inevitable." - Wikipedia/Sphingosine-1-Phosphate.

"Ceramidase is an enzyme which cleaves fatty acids from ceramide [Images], producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate (S1P)." - Wikipedia/Ceramidase. The ceramidase ACER1 mediates cellular differentiation by controlling the generation of sphingosine (SPH) and sphingosine-1-phosphate (S1P). "ACER1 is highly expressed in epidermis and catalyzes the hydrolysis of very long chain ceramides to generate sphingosine".


(80) Lysophosphatic Acid [WikiGenes/Lysophosphatic Acid, Links, Images, Video, Papers, Patents, Books; Images/Lysophosphatic acid molecule; toxicity]. Lysophosphatic acid activates telomerase in ovarian cancer cells. Uses the PI3K pathway. Telomerase activators associated with cancer are sometimes too dangerous to use for therapeutic activation, and are rarely popular first choices. So far as I can see, lysophosphatic acid has not been eliminated as a practical telomerase activator by systematic testing, however.

(81) Exercise [Bodybuilding]. See Exercise Boosts Telomerase, Reduces Erosion of Telomeres at Fighting Aging. Exercise can elevate telomerase activating HGH growth hormone x 3 on a normal diet, and x 44 if one takes an HGH secrectagogue like alpha-glycerylphosphorylcholine (Alpha-GPC, a component of Secretagogue Gold and Life Extension's Cognitex) before working out. HGH actually improves the number of hTERT mRNA transcripts to activate telomerase, producing more hTERT catalytic component of telomerase molecules. The HGH is finally converted to IGF-1 in the liver, and that is another telomerase activator (via phosphorylation of the hTERT catalytic component of telomerase). So exercise activates hTERT via the HGH/IGF1/PI3K/AKT1 pathway, and probably also directly via HGH/PI3K/. Testosterone is also produced by exercise, which can activatate telomerase via androgenic pathways. Androgens can be converted by aromatases into estrogens, activating the hTERT promoter for hTERT mRNA transcription via the estrogen receptor. See aromatase inhibitors. Additional hTERT activation pathways for exercise exist. Thirty minutes of exercise upregulates PDGF (1.55-fold), and also HIF-1 (hypoxia-inducible factor-I) (2.40-fold). Both are telomerase activators. Epiregulin is also upregulated by 30 minutes of exercise (3.50-fold). Epiregulin is a telomerase activator that is a member of the EGF (epidermal growth factor) family, as is Amphiregulin, which is upregulated 3.4-fold in human neutrophils with 30 minutes of exercise [1], [2].
Telomerase ActivatorNotes on Fifteen Exercise-Induced Telomerase Activators
HGH [Index]HGH is an endocrine hormone upregulating hTERT transcription converted to IGF-1 in the liver. HGH is upregulated by HGH secretagogues including alpha-GPC, CDP-choline, GABA (Gamma-aminobutyric acid), Mucuna Pruriens, glutamine, glycine, ornithine alpha-ketoglutarate, whey protein, 1500 mg arginine + 1500 mg lysine, arginine + ornithine supplements, and by exercise. HGH is a ligand of the Growth Hormone Receptor. See cell types expressing GHR. Transient overexpression of HIF-1A or exposure to the hypoxia mimetic CoCl2 significantly increases GHR mRNA levels and promoter activities. See supplements increasing GHR mRNA levels. Drugs promoting the expression of HIF-1 [Images, Papers, Patents, Books] include ginkgo biloba, ginkgolides, and diosgenin (from fenugreek seed, fenugreek extract, or wild yam).
IGF-1 [Index]Upregulates hTERT phosphorylation for for hTERT protein transport into the nucleus. It may be obtained from conversion of HGH in the liver, and is boosted by creatine monohydrate, colostrum, acetyl L-carnitine plus alpha lipoic acid, cottage cheese, animal protein or soy protein at a gram per pound of bodyweight, essential amino acids at 7.5 grams, and IGF-1 supplements. The expression of IGF-1 is inhibited by cortisol, which may be inhibited with ashwagandha. All cells have IGF-1 receptors.
PDGFTelomerase activator, upregulates c-Myc. PDGF is upregulated 1.55-fold by 30 minutes of exercise and is contained in colostrum and in many growth factor skin creams. PDGF increases the expression of c-Myc, a transcription factor activating the hTERT promoter [NK Banskota, et al., 1989]. PDGF activates the PI3K (Phosphoinositide 3-kinase) pathway.
IL-6Telomerase activator [PDF] and inflammatory cytokine, activates STAT3. IL-6 is upregulated 15-fold by 30 minutes of exercise (and up to 105-fold by 180 minutes of exercise). A IL-6/PI3K/Akt/NFkB cascade may drive hTERT mRNA transcription [PDF ref].
HIF-1Directly upregulates hTERT transcription, upregulated by 30 minutes of exercise 2.4-fold, hypoxia, ginkgo biloba, or diosgenin from fenugreek seeds or wild yam. Upregulates telomerase activity in every cell. HIF-1 levels may be sustained with leucine or its metabolite beta-hydroxy-beta-methylbutyrate. Works on every cell in the body. Explains why high altitude or periodically holding your breath can increase life span.
EpiregulinTelomerase activator, EGF family, probably upregulates c-Myc. Epiregulin is upregulated 3.5-fold by 30 minutes of exercise. Further upregulated by sodium butyrate [Images]. Epiregulin is a ligand of the EGF receptor. Cells expressing EGFR: EGF Receptor Expression in Human Tissues includes epidermal and glandular tissue.
AmphiregulinTelomerase activator, EGF family. Amphiregulin is upregulated 3.4-fold by 30 minutes of exercise in human neutrophils. Amphiregulin is a ligand of the EGF receptor.
Testosterone [Index]Androgenic telomerase activator, converted by aromatases into estrogen. Testosterone may be further upregulated with DHEA, Forskolin, Tribulus, Fenugreek, Longjack (Tongcat Ali), boron citrate, 6-OXO, exercise, and other testosterone boosters [Images, Papers] or supplements. L-carnitine L-tartrate [Images] can be used to boost the number of androgen receptors.
Estrogen [Index]Telomerase activator, obtainable direct or from testosterone by aromatases. See also estriol skin creams.
Strong estrogen bioactivity substances include:
(10.1) Estrogen [Links, Supplements, Images] (10),
(10.2) Fo-Ti (He Shou Wu) [Links, Supplements, Images] (168),
(10.3) Soy [Links, Supplements, Images] (169),
(10.4) Clover [Links, Supplements, Images] (170),
(10.5) Licorice [Links, Supplements, Images] (171) and
(10.6) Hops [Links, Supplements, Images] (172),
HSP90 [Index]Accelerates telomerase synthesis by improving protein folding. Upregulated by Alpha Lipoic Acid, exercise, and stress.
TGF-alpha [List]A telomerase activator upregulated 1.87-fold by 30 minutes of exercise and also found in colostrum. TGF-alpha is a ligand of the Epidermal Growth Factor Receptor. EGF Receptor Expression in Human Tissues includes epidermal and glandular tissue.
IL-2 [Index]A telomerase activator for T-cell lymphocytes upregulated 1.2-fold by 30 minutes of exercise. Phosphorylates hTERT via PI3K/AKT1. Frank Zaldivar, Jessica Wang-Rodriguez, Dan Nemet, Christina Schwindt, Pietro Galassetti, Paul J. Mills, Lori D. Wilson and Dan M. Cooper (2006), Constitutive pro- and anti-inflammatory cytokine and growth factor response to exercise in leukocytes, Journal of Applied Physiology 100:1124-1133, 2006.
TNF-alpha [Index]An inflammatory cytokine with telomerase activation effect. TNF-alpha is upregulated by 1.5-fold by 30 minutes of exercise and is contained in colostrum.
Nitric Oxide [Index]Nitric oxide is upregulated by exercise and telomerase-activating supplements such as L-arginine, L-citrulline, and whey protein, and by telomerase-inhibiting supplements including cocoa and pomegranate. Gamma Tocopherol is used to control lipid peroxidation from NO.
VEGFVEGF is upregulated 1.36 times by 30 minutes of exercise and may be supplemented with colostrum [List]. VEGF is also used in some growth factor skin creams. VEGF and FGF-2 (FGF/FGF-2, or bFGF) upregulate survivin, which can reverse cellular senescence.
The same paper (Connolly, et. al, 2004) shows exercise-stimulated upregulation of HSP90, which improves telomerase synthesis by assisting with hTERT protein folding. Growth factor levels go up with exercise [3].
Another paper shows upregulation of Transforming Growth Factor alpha (1.87 fold), another telomerase activator candidate [4]. In other experiments, exercise elevated expression of telomerase-activating IL-2 (1.43 fold) and TNF-alpha (1.5 fold) [5]. [Note that sodium butyrate boosts the expression of Sp1, which elevates production of epiregulin (an EGF family telomerase activator) by up to 90 times (?) in mammalian ovary cells. Sodium butyrate plus exercise (which elevates epiregulin) might turn out to improve epiregulin expression considerably more than exercise alone. - Do not try this until the proper dosage for favorable effect is determined by experiment on animals.]
Exercise can bring P16INK4A expression down by 2 binary orders of magnitude (factor of 4). Other factors that can decrease P16INK4a expression (P16INK4a makes recovery from cellular senescence difficult) include retinol from carrots, retinoic acid from beta-carotene, resveratrol, and ID-1 transcription factor from nerve growth factor.
See the hTERT activation pathways for exercise or the exercise hTERT activation pathways.
References
[1] Peter H. Connolly, Vincent J. Caiozzo, Frank Zaldivar, Dan Nemet, Jennifer Larson, She-pin Hung, J. Denis Heck, G. Wesley Hatfield and Dan M. Cooper (2004), Effects of exercise on gene expression in human peripheral blood mononuclear cells,
Journal of Applied Physiology, October 2004, vol. 97 no. 4 1461-1469.
[2] Shlomit Radom-Aizik, Frank Zaldivar Jr., Szu-Yun Leu, Pietro Galassetti, and Dan M. Cooper (2008),
Effects of 30 min of aerobic exercise on gene expression in human neutrophils,
Journal of Applied Physiology, January 2008 vol. 104 no.1 236-243.
[3] Rojas Vega S , Knicker A, Hollmann W, Bloch W, Strüder HK (2010),
Effect of resistance exercise on serum levels of growth factors in humans,
Horm Metab Res 2010 Dec;42(13):982-6.
[4] Petra Buttner, Sandy Mosig, Anja Lechtermann, Harald Funke, and Frank C. Mooren (2007),
Exercise affects the gene expression profiles of human white blood cells,
Journal of Applied Physiology 102:26-36, 2007. (First published Sept.2006).
[5] Frank Zaldivar, Jessica Wang-Rodriguez, Dan Nemet, Christina Schwindt, Pietro Galassetti, Paul J. Mills, Lori D. Wilson and Dan M. Cooper (2006), Constitutive pro- and anti-inflammatory cytokine and growth factor response to exercise in leukocytes,
Journal of Applied Physiology 100:1124-1133, 2006.

(82) Antiotensin II [WikiGenes/Angiotensin II, Links, Images, Video, Papers, Patents, Books; Images/Angiotensin II molecule; toxicity]. See Angiotensin II activates telomerase through the MAP Kinase Pathway in Human Endothelial Cells, Science Links, Japan. Angiotensin II is a vasoconstrictor, so that Angiotensin II receptor blockers are used to reduce blood pressure. See also the Map kinase pathway for telomerase activation [Index]. Angiotensin II may elevate blood pressure in a way that often rules out its use for telomerase activation. See activation of telomerase via the MAP kinase pathway and Index/MAP kinase pathway.

(83) Epithelial Growth Factor ((30) EGF) [WikiGenes/Epithelial Growth Factor, Links, Images, Video, Papers, Patents, Books; Images/Epithelial Growth Factor molecule; toxicity]. "Growth factors such as epithelial growth factor (EGF) elicit cellular signaling including MAP kinase [Links], Akt [Links] and protein kinase C [Links]." [1]. "...Transactivation of hTERT by EGF requires a specific hTERT promoter element (TTCCTTTCCG) located at -22, a consensus binding motif for Ets proteins, known to be the major target of EGF signaling. These findings suggest that EGF signals utilize the Ras/MEK/ERK pathway to activate hTERT expression." [2]. See Telomerase activation via MAP kinase [Index], telomerase activation via Akt kinase [Index], and Telomerase activation via protein kinase C [Index].
References
[1] Sharyn Baynea and Jun-Ping Liu (2005),
Hormones and growth factors regulate telomerase activity in ageing and cancer,
Molecular and Cellular Endocrinology, Vol 240, Issues 1-2, 30 August 2005, pp 11-22.
[2] Satoru Kyo and Masaki Inoue (2002),
Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy?,
Section (3) Growth Factors, Oncogene, 21 Jan 2002, Vol 21, No. 4, Pages 688-697.

(84) Resveratrol [Index, WikiGenes/Resveratrol, Links, Images, Papers, Books; Links/Resveratrol activates telomerase, Images, Papers, Books; Images/trans-resveratrol molecule; toxicity]. Resveratrol is known to activate telomerase in endothelial progenitor cells via the PI3K/Akt1 pathway, which phosphorylates hTERT protein in the cytoplasm for import into the cellular nucleus.
References
[1] L Xia, X X Wang, X S Hu, X G Guo, Y P Shang, H J Chen, C L Zeng, F R Zhang andJ Z Chen (2008),
Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms, British Journal of Pharmacology Volume 155, Issue 3, pages 387–394, October 2008.

(85) Nicotine [WikiGenes/Nicotine, Links, Images, Images/Nicotine gum, Papers, Patents, Books; Links/Nicotine activates telomerase, Images, Papers, Books; Images/Nicotine molecule; toxicity]. Nicotine activates telomerase in endothelial progenitor cells via the PI3K/Akt pathway [1]. Nicotine is also an anti-inflammatory HMGB1 inhibitor.
References
[1] Zhu JunHui; He XiaoJing; Zhou BinQuan; Xie XuDong; Chen JunZhu; Fu GuoSheng (2009),
Nicotine-reduced endothelial progenitor cell senescence through augmentation of telomerase activity via the PI3K/Akt pathway,
Cytotherapy, Vol 11, Issue 4 July 2009 , pp 485 - 491.

(86) Ginkgo Biloba [Index, WikiGenes/Ginkgo Biloba, Links, Images, Papers, Patents, Books; Links/Ginkgo Biloba activates telomerase, Images, Papers, Books; Images/Ginkgo Biloba molecules; toxicity]. VIDA Institute recommends taking astragalus extract with ginkgo biloba (to improve circulation, improving access to cells) and gotu kola (to improve vision and fine circulation). Ginkgo Biloba improves circulation by making platelets less sticky. See Dong, Xie Xu, PhD; et al., (2007), Ginkgo Biloba reduces endothelial progenitor cell senescence through augmentation of Telomerase Activity, Journal of Cardiovascular Pharmacology, Feb 2007, vol.49, issue 2, pp. 111-115. "Ginkgo biloba extract significantly increased telomerase activity and phosphorylation of the serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K). Moreover, pretreatment with PI3K inhibitor, LY294002, significantly attenuated the Ginkgo biloba extract-induced telomerase activity. Taken together, the results indicated that Ginkgo biloba extract delayed the onset of Endothelial Progenitor Cell senescence, which may be related to activation of telomerase through the PI3k/Akt signaling pathway." Note that Ginkgo Biloba [Images] and Ginkgolides upregulate HIF-1 expression (Li Z, Ya K, Xiao-Mei W, et.al, 2008). See the hTERT activation pathway for Ginkgo Biloba or the Ginkgo Biloba hTERT activation pathway.

(87) Portulaca Oleracea (Purslane) [WikiGenes/Purslane, Wikipedia/Portulaca Oleracea, Links, Images, Papers, Patents, Books; Links/Portulaca Oleracea activates telomerase, Images, Papers, Patents, Books; Links/Purslane Extract, Images; Links/Portulaca Oleracea extract, Images; Links/Aqueous extracts of Portulaca Oleracea, Images; Links/Purslane seeds for sale; Links/How to grow purslane indoors; Purslane tincture; toxicity]. According to Ray Sahelian, MD, "Purslane extract ... could up-regulate telomere lengths and telomerase activity in PHAS-fed groups." PHAS stands for "Purslane Herb Aqueous Extracts."
Incidentally, Astral Fruit-NF, the 3rd generation Astral Fruit product, was described to me in a communication from RevGenetics leadership Anthony Loera as containing "Terminalia Chebula, Portulaca Oleracea, and Astragalus Extract with Cycloastragenol" in a proprietary mix with chitosan and bioperine to improve bioavailability. Anthony refers us to
PubMed ID: 15478203 (on Terminalia Chebula),
PubMed ID: 17764668 (on Purslane), and
PubMed ID: 18981163 (on TAT2, or Cycloastragenol) in his letter.
There may be some mistake, as Terminalia Chebula (Haritaki) is described as "alterative" by Pharmacy Escrow. I mean, this could be more for the ladies than for the gentlemen. However, almost all sources of information on Haritaki fail to describe Haritaki's "alterative" side effects, so that they must not be too glaring or obvious. Perhaps a 4th generation product will be on the way. Perhaps Astral Fruit-NF features faster telomere lengthening by employing parallel pathway activation of hTERT. See Zhang Hongxinga, Yu Nancaia, Huang Guofua, Shao Jianboc, Wu Yanxiaa, Huang Hanjub, Liu Qiana, Ma Weia, Yi Yandonga and Huang Haoa, (2007), Neuroprotective effects of purslane herb aqueous extracts against d-galactose induced neurotoxicity, Chemico-Biological Interactions, Volume 170, Issue 3, 15 Dec 2007, pp. 145-152. (See section 1.1. Preparation of aqueous extracts of purslane herb [Links, Images, Patents; toxicity].) See also Imai S, Shiraishi A, Gamo K, Watanabe I, et al, (2007), Removal of phenolic endocrine disrupters by Portulaca oleracea, Journal of Bioscience and Bioengineering, 2007, May; 103(5); 420-6.
Portulaca oleracea contains
oleraceins [toxicity]
___oleracein A [toxicity],
___oleracein B [toxicity],
___oleracein C [toxicity],
___oleracein D [toxicity], and
___oleracein E [toxicity] with
p-coumaric acid [toxicity],
ferulic acid [toxicity], and
adenosine [toxicity].
By April 2012, Terraternal confirmed that Purslane activates telomerase and was selling Terraternal Purslane. See the hTERT activation pathway for Purslane Extract or the Purslane Extract hTERT activation pathway.

(88) Fibroblast Growth Factor (FGF)
[GeneCards/FGF1, Links/FGF1, Images, Papers, Patents, Books, LifeExtension; Links/FGF1 Skin Cream;
GeneCards/FGF2, Links/FGF2, Images, Papers, Patents, Books, LifeExtension; Links/FGF2 Skin Cream;
GeneCards/FGF7; Links/FGF7, Images, Papers, Patents, Books, LifeExtension; Links/FGF7 Scalp Cream;
GeneCards/FGFR2; GeneCards/KGFR; WikiGenes/Fibroblast Growth Factor, Wikipedia, Links, Images, Video, Papers, Patents, Books; Links/Fibroblast Growth Factor activates telomerase, Images, Papers, Patents, Books; Links/the FGF-1 promoter, Images, Papers, Patents, Books; Images/Fibroblast Growth Factor molecules; toxicity]. Twenty-three different Fibroblast growth factors FGF1 through FGF23 exist. FGF1 (aFGF, [toxicity]) is called acidic Fibroblast Growth Factor, and is used in cosmetics along with telomerase activator Epidermal Growth Factor (30). FGF2 is called basic Fibroblast Growth Factor and is a known telomerase activator, promoted by preparations such as Vicco Vanishing Cream from the ladies of India, which contains curcumin as the FGF2-promoting component. (Note that turmeric, which contains curcumin, also contains a ligand of the progesterone receptor that may be responsible for the feminine skin produced by Vicco Vanishing Cream.) In fact, most human growth factors are telomerase-activating. "Fibroblast growth factor, especially FGF1 (aFGF), prevents the DNA damage as well as the senescence of the skin." See FGF1 and Human Growth Factors, from Truth in Aging.com, June 8, 2010.
Skin Cream TypeBrandGrowth Factor LinksCost
Growth factors skin creamRegeniskinEGF, PDGF, TGF, FGF$29.95
FGF2 skin cream (FGF2)VICCO Turmeric Vanishing CreamFGF2 (Basic Fibroblast Growth Factor)$16.04
aFGF skin cream (FGF1)aFGF Skin Softening Essence LotionaFGF (acidic Fibroblast Growth Factor)$69.35
aFGF skin cream (FGF1)E'shee (article)aFGF (acidic Fibroblast Growth Factor).
According to E'shee research, "FGF-1 peptide [Images, Video, Papers, Patents, Books] can transfer different messages to:
* FGFR-2 - rejuvenates fibroblast cells to produce new collagen, hyaluronic acid and elastin;
* KGFR (Keratinocyte Growth Factor Receptor) - rejuvenates the epidermal cells; and
* FGF-7 (Keratinocyte Growth Factor) - rejuvenates hair follicle to produce new hair.
Other growth factors used in skin care products such as EGF (Epidermal Growth Factor) only rejuvenate the epidermis; they do not simulate the production of collagen, hyaluronic acid and elastin like FGF-1 and the aging process will remain or get worse. FGF-1 works as a catalyst and skin cells grow 10 to 20 times faster when compared to other professional skin care products.
" - Send2Press, June 2010.
See the hTERT activation pathway for Fibroblast Growth Factor or the Fibroblast Growth Factor hTERT activation pathway. Note that survivin (which can reverse cellular senescence) is upregulated by VEGF and bFGF (FGF2), both of which are found in colostrum [List]. Salk News Release: FGF-1 governs the expansion and contraction of fat [Links, Images, Video, Papers, Patents, Books].

(89) AP-2 (Activating Enhancer-binding Protein-2) [Wikipedia/Activating Protein 2, hTERT_promoter/AP-2, Links, Images, Video, Papers, Patents, Books; Papers/Activating Enhancer-binding Protein-2 activates telomerase; Images/Activiting Enhancer-binding Protein 2 molecule; [toxicity]]. Activator Enhancer-binding Protein-2 (AP-2) was identified in 2007 as a transcriptional activator of the hTERT promoter [Images, Papers]. See Satoru Kyo, Masahiro Takakura, Toshiyoshi Fujiwara, Masaki Inoue (2008), Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers, Cancer Science, Volume 99, Issue 8, pages 1528–1538, August 2008. The discovery was first noted in Deng WG, Jayachandran G, Wu G, Xu K, Roth JA, Ji L (2007), Tumor-specific activation of human telomerase reverses transcriptase promoter activity by activating enhancer-binding protein-2beta in human lung cancer cells, J Biol Chem, 2007, 282: 26460-70. See
Nutraceuticals promoting expression of AP-2 [Links, Images, Video, Papers, Patents, Books].

(90) ER81 Transcription Factor [Gene Cards/ER81, Links, Images, Video, Papers, Patents, Books; Papers/ER81 activates telomerase; Images/ER81 molecule; toxicity]. Looks dangerous. ER81 might be applied in a liposome delivery system (similar to an IGF-1 lipospray) along with activating cofactors, or in a liposomal skin cream. With inappropriate cofactors the result might be carcinogenic, but with the correct choice this may be a useful activator that can be cultured in E.Coli. The three prominent cofactor oncoproteins [Images, Video, Papers, Patents, Books], HER2/Neu, Ras, and Raf may probably NOT be used with ER81. "...Three oncoproteins, HER2/Neu, Ras, and Raf, stimulate hTERT promoter activity via the ETS transcription factor ER81 and ERK mitogen-activated protein (MAP) kinases." - Basem S. Goueli and Ralf Janknecht (2004), Upregulation of the Catalytic Telomerase Subunit by the Transcription Factor ER81 and Oncogenic HER2/Neu, Ras, or Raf, Molecular and Cellular Biology, January 2004, p. 25-35, Vol. 24, No. 1. See the ERK pathway for telomerase activation [Images, Papers, Patents, Books].

(91) C-Abl tyrosine kinase [Links, Images, Video, Papers, Patents, Books; Papers/C-Abl tyrosine kinase activates telomerase; Images/C-Abl tyrosine kinase molecule]. See supplements upregulating C-Abl tyrosine kinase. AKT protein kinase [Links, Images, Video; toxicity] phosphorylates hTERT in the cytoplasm for import into the nucleus, promoting telomerase activity. This is also true for Protein Kinase C [Index, Links, Images, Video; toxicity], C-Abl tyrosine kinase [Images; toxicity], and Protein Phosphatase 2A [Images; toxicity]. (after Mouldy Sioud, Methods in Molecular Biology, Vol.2, Vol. 361, p.241.) Resveratrol, for instance, phosphorylates the hTERT catalytic component of telomerase via AKT (Index/AKT). Also see Laura J. Mauro and Douglas N. Foster (2002), Regulators of Telomerase Activity, (article), American Journal of Respiratory Cell and Molecular Biology, 26(5): 521 (2002), according to which both Protein Kinase Cα and Akt Kinase phosphorylate hTERT protein, equipping it for return from the cytosol to the nucleus. I note that antioxidants such as glutathione and N-acetylcysteine are believed to keep hTERT protein inside the nucleus.

(92) Protein Phosphatase 2A [Links, Images, Video, Papers, Patents, Books; Papers/Protein Phosphatase 2A activates telomerase; Images/Protein Phosphatase 2A molecule; toxicity]. See above (90) for remarks concerning other telomerase activators [List] that promote telomerase activity by phosphorylating the catalytic component of telomerase, hTERT protein, which causes it to be transported from the cytosol into the cellular nucleus.

(93) hALP - Histone acetyltransferase hALP, activates hTERT transcription. Perhaps we should say that hALP acetylates chromatin, expanding it to make it more available for hTERT transcription.
Histone acetyltransferase hALP [Links/Histone acetyltransferase hALP, Images, Video, Papers, Patents, Books; toxicity; Links/Histone acetyltransferase hALP activates telomerase; Links/Histone acetyltransferase hALP activates hTERT mRNA transcription]. See also Histone acetyltransferases [Links, Images, Video, Papers, Patents, Books]. Histone acetyltransferase hALP was indentified from a screen of a cDNA library of HeLa cells [Images] for transcriptional regulators of hTERT [Images, Papers, Patents, Books]. The screen was performed with an hTERT promoter-based yeast one-hybrid assay. hALP can acetylate free histones in vitro, and contains an N-acetyltransferase domain characteristic of the GNAT family proteins. Its regulation of hTERT transcription seems to depend on its properties as a histone acetyltransferase, reminding us of Tricostatin A, a histone deacetylase inhibitor (HDAC inhibitor), which also promotes histone acetylation to induce hTERT mRNA transcription. It is also thought that perhaps hALP interacts with Sp1. - See Keiko Hiyama, Telomeres and Telomerase in Cancer, (Chapter 3: Regulation of Telomerase through Transcriptional and Posttranslational Mechanisms, by Amy N. Depcrynski, Patrick C. Sachs, Lynne W. Elmore, and Shawn E. Holt), Kluwer, 2009. That hALP was discovered from a cDNA screen of HeLa cancer cells [Images] might indicate that it cannot be used in a program of anti-aging treatment. It is hard to sell the world "cancer milk". However, perhaps in some cases such proteins may have application potential for life extension treatment. Cellular immortalization via activation of hTERT might be conveniently served by this protein. The way that estrogen couples with estrogen receptor and histone acetyl transferase to form the estrogen receptor complex, an hTERT-activating transcription factor, is diagrammed in Geoffrey Cooper and Robert Hausman, The Cell: A Molecular Approach [Site: The Cell], 4th edition, pp. 602-603.

(94) Interleukin 3 [Gene Cards/Interleukin-3, Links/Interleukin 3, Images, Video, Papers, Patents, Books; Links/Interleukin 3 upregulates telomerase, Images, Papers, Patents, Books; toxicity]. "Initial basal telomerase levels in hemopoietic stem cells can be transiently upregulated in the course of in vitro cultures upon stimulation with cytokines including interleukin 3 (IL-3)." - S. Zimmerman and U.M.Martins, Senescence Signatures of Human Hematopoietic Stem Cells, from K.Lenhard Rudolf, Telomeres and Telomerase in Aging, Disease, and Cancer, Molecular Mechanisms of Adult Stem Cell Aging, Springer, 2008, p142. See also (Engelhardt et al. 1997, Yui et al. 1998, Zimmerman et al. 2004).

(95) E1A [Links/E1A protein, Images, Video, Papers, Patents, Books; sources; toxicity]. E1A protein increased luciferase assay reports of hTERT promoter and hTR promoter activity by up to a factor of 3, and exon 2 of E1A alone was sufficient to introduce a 2-fold increase. E1A was shown to interact with Sp1 sites on the hTR promoter to produce transcriptional activation, (and no doubt similarly on the hTERT promoter). - after (C.J. Cairney and W.N. Keith, 2007).

(96) Ets [hTERT promoter/Ets, Links/transcription factor Ets, Images, Video, Papers, Patents, Books; sources; toxicity] is an hTERT transcriptional activator (C.J. Cairney and W.N. Keith, 2007).

(97) Glucocorticoids [Links/Glucocorticoids, Images, Video, Papers, Patents, Books; Links/glucocorticoid activation of hTERT, Images, Papers, Patents, Books; toxicity]. Several "putative" binding sites for the glucocorticoid, progesterone, and androgen steroid hormones have been found in the 5' flanking region of the hTR gene and may also be present in the hTERT gene (C.J. Cairney and W.N. Keith, 2007).

(98) New Symmetrical Bis-Substituted Derivatives of the Anthraquinone [Links/Anthraquinone; Links/Symmetrical Bis-Substituted Derivatives of the Anthraquinone; toxicity]. Lipid Peroxidation side-effects. See Hsu-Shan Huang, Jeng-Fong Chiou, Yaou Fong, Ching-Cheng Hou, Yu-Cheng Lu, Jen-Yi Wang, Jing-Wen Shih, Yen-Ru Pan, and Jing-Jer Lin (2003), Activation of Human Telomerase Reverse Transcriptase Expression by Some New Symmetrical Bis-Substituted Derivatives of the Anthraquinone, Journal of Medicinal Chemistry, 2003, 46, 3300-3307. "Anthraquinone-based compounds currently occupy a prominent position in cancer chemotherapy, and the anthraquinone mitoxantrone is an important compound used clinically as an anticancer agent. op.cit." 1,5-bis acetyloxy anthraquinones [Links/1,5-bis acetyloxy anthraquinones, Images, Papers, Patents, Books] that are related to the antitumor agent mitoxantrone [Links/mitoxantrone, Images, Papers, Patents, Books] behave like small molecule telomerase activators. See [Links/1,5-bis acetyloxy anthraquinones for telomerase activation, Images, Papers, Patents, Books]. These compounds do exhibit lipid peroxidation side-effects, however. See lipid peroxidation side-effects of the 1,5-bis acetyloxy anthraquinones [Images, Papers, Patents, Books]. "The synthesis of 1,5-bisacyloxyanthraquinones... was based on simple acetylation involving 1,5-dihydroxyanthraquinone (anthrarufin) with an excess of the appropriate acyl chlorides in the presence of pyridine and dichloromethane at room temperature for 1-2 h or in the presence of NaH and THF at room temperature or after refluxing for 1-2 h. All final products were characterized by NMR, IR, UV, and mass spectrometry. op.cit."
Anthraquinone constituents of Fo-ti: Chrysophanic acid, chrysophanol, emodin. The anthraquinones chrysophanic acid, chrysophanol, and emodin all exhibit anticancer properties (S. Mohammad Abu-Darwish and A. Mazen Ateyyat, 2008). There are some indications that as fo-ti (from Polygonum multiflorum roots) turns your hair black, it also turns the other end black, inflicting Melanosis Coli observed due to chronic use of herbal laxatives containing anthraquinones. Perhaps this is the secret of "Fool-T".

(99) Tri-Phenyl Compound Telomerase Activators developed at Ben Gurion University on the Negev [Links, Images, Video, Papers, Books; toxicity]. See Aviv Gazit et al, TELOMERASE ACTIVATING COMPOUNDS AND METHODS OF USE THEREOF, US Patent, US Patent App. 12/602,956, 2008, WO Patent WO/2008/149, 353, 2008. (See PDF version.) Many of these molecules resemble 9-legged web spiders.

(100) Enhanced-bioavailability telomerase activators from Geron (2010).
See (WO/2010/135247) COMPOSITIONS AND METHODS FOR INCREASING TELOMERASE ACTIVITY [Links, Images, Papers, Patents, Books]. Exemplary compounds from the new Geron patent for more bioavailable telomerase activators include
(1) 2-(L)-amino-3-methyl-butyric acid 6-alpha... [Images, Papers, Patents, Books; molecule, sources, toxicity],
(2) 2-(L)-Amino-3-methyl-butyric acid... [Images, Papers, Patents, Books; molecule, sources, toxicity;
____Wikipedia/Valine, Links/L-Valine, Images, Papers, Patents, Books; molecule, supplements, sources].
____L-Valine is a branched-chain amino acid that must be ingested, as it is not produced by the body.
____L-Valine promotes muscle growth and tissue repair, stimulating protein synthesis and
____boosting the immune system. It appears by Nov 18, 2010 as a component molecule of a class of
____Geron exemplary telomerase activators. L-Valine = 2-(L)-Amino-3-methyl-butyric acid.
(3) 4 C3-(L)-valyl-cycloastragenol [Images, Papers, Patents, Books; molecule, sources, toxicity].
____4 C3-(L)-valyl-cycloastragenol refers to an L-Valine attatched by an ester bond to carbon 3 of the usual ____cycloastragenol structure in the lower left hexagonal ring, numbering 1,2,3 counterclockwise
____from carbon 1 at the topmost vertex of that hexagonal ring left of the triangular cyclopropane ring.
____One wonders about the benefits of taking a mix of L-Valine and cycloastragenol together,
____as separate molecules. Combining them into one molecule may have largely the same result,
____if the ester bond is metabolized.
____However, the bioavailability may be improved by the bound molecule.
(4) C3-(L)-isoleucyl-cycloastragenol was the most bioavailable compound tested, and more bioavailable than cycloastragenol. Note that L-valine, L-leucine, and L-isoleucine are branched-chain amino acids that turn on muscle synthesis. See lifexnotes5.html for other enhanced-bioavailability telomerase activators and relevant synonyms.

Cycloastragenol
The invention includes many related chemicals and pharmaceutically acceptable salts including simple hydrochloride salts. To improve bioavailability, some of the former star compounds, such as astragaloside IV, were modified. For instance, astragaloside IV was converted to 17-[5-(l -Hydroxy- 1 -methyl-ethyl)-2- methyl-tetrahydi'O-furan-2-yl]-4,4J3J4-tetramethyl-tetradecahydro- cyclopropar9, 1 Olcvclopentaraiphenanthrene-3 ß,6a, 16ß-triol f cycloastragenol]. I note that recent work (Calvin B. Harley, et al. 2010, In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol, a potent small molecule telomerase activator) shows that cycloastragenol is highly bioavailable orally, much more so than astragaloside IV. Thus TA-65 shows < 6 mg cycloastragenol in chemical analyses prepared by industrial investigators, commercial vendors of cycloastragenol (Iron-Dragon, Biologix Peptide) offer cycloastragenol in 10 mg/dose formulations, while astragaloside IV may be taken 50 mg per tablet or 2x50 = 100 mg per dose per day from vendors such as Terraternal. Most recently in the Spring of 2011 Terraternal has offered Terraternal cycloastragenol at 25 mg/cap, following a paper by Calvin B. Harley, et. al, 2011 that recommends 20-30 mg as the optimal dose for TA-65, which is primarily cycloastragenol according to independent lab analysis. See also US Patent 7,846,904 B2, Dec.7,2010., Compositions and Methods for Increasing Telomerase Activity, Geron Corporation. See also Compositions and Methods for Increasing Telomerase Activity by Calvin B. Harley, et al., US Patent 2010/0292197, Nov.18, 2010. According to the VIDA Institute, we are measuring more telomere growth in granulocytes, leukocytes, and NK cells from 30 grams/day of astragalus root (or 10 grams per day of astragalus root extract) than we are measuring from the above-mentioned smaller doses of astragaloside IV or cycloastragenol. See also flash chromatography (Silica Prep LC).

Butyric acid [Wikipedia, Links, Papers, Patents, Books; dosage, toxicity; PubChem]. Butyric acid is a fatty acid and an HDAC inhibitor (like sodium buyrate) that expands chomatin for transcription, improving transcription of hTERT. Butyric acid smells like vomit and must be taken in a capsule with an enteric coating, and is rated by the United States Environmental Protection Agency as a toxic substance. Abdominal pain, shock, and collapse can occur as a result of ingestion of butyric acid. In human therapy butyric acid is usually given as sodium salts of butyric acid [Links, Papers, Patents, Books] or as arginine salts of butyric acid [Links, Papers, Patents, Books]. See
Sodium butyrate [Index, Links, Papers, Patents, Books] and
Arginine butyrate [Links, Papers, Patents, Books; National Cancer Institute/Arginine Butyrate, Pronunciation].
Arginine butyrate combines nitric oxide activation with HDAC inhibitor action. See Vianello S1, Yu H, Voisin V, Haddad H, He X, Foutz AS, Sebrié C, Gillet B, Roulot M, Fougerousse F, Perronnet C, Vaillend C, Matecki S, Escolar D, Bossi L, Israël M, de la Porte S. (2013), Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy, The FASEB Journal, 2013 Jun;27(6):2256-69.

(101) Silver (Ag) upregulates telomerase in immune system cells. [Links, Images, Papers, Books; toxicity]. Colloidal silver [Images, toxicity] is sold as an antibiotic, and probably works by upregulating the functions of immune system cells. This is probably associated with upregulation of telomerase. See Weng, NP, et al. (1997), "Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation and aging", Immunology Reveiw. 1997, 160:43-54. Note that too much silver colloid can produce silver poisoning (argyria) [Images], which can stain men blue. Note that Arsenic (63) may similarly upregulate telomerase by stimulating immune cells, and that it is also somewhat poisonous. However, recent reports indicate that arsenic treatment leads to genetic instability and may inhibit hTERT transcription. Immune cells also upregulate telomerase in response to mitogenic stimulation and to TAT2 (cycloastragenol). "However, the ability of CD8+ lymphocytes to up-regulate telomerase is lost after repeated encounters with Ag (silver) and continued chronic stimulation ultimately leads to critically shorter telomeres and other changes associated with replicative senescence." - after 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), Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ Lymphocytes, Journal of Immunology, 2008, November 15; 181(10): 7400-7406. Thus, silver can only be used on a temporary basis to upregulate telomerase in immune system cells.
Music[2]: Bye, Bye Life (All That Jazz (1979)).

(102) Silymarin activates telomerase. [The Product B Explorer/(146) Milk Thistle Extract, Index/Silymarin, Index/Milk Thistle, Wikipedia/Milk Thistle, Wikipedia/Silbinin Links/Silymarin activates telomerase, Images, Papers, Patents, Books; toxicity; Images/Silymarin supplements, Links/Silymarin; Images/Silymarin molecule]. In reality, it seemed that silymarin rarely behaves like a telomerase activator. It does so, for instance, when a patient has an iron-overload disease called beta-thalassemia. Then the iron accelerates free radical reactions (probably via Fenton reactions), damaging telomeres, so that T-lymphocytes can be saved by silymarin, which is a superantioxidant that interferes with the damage to telomeres from free radicals. In fact, silibinin, the primary active constituent of silymarin, is a telomerase inhibitor when applied to cancer cells that works well as an anticancer agent against human prostate adenocarcinoma cells, breast carcinoma cells, ectocervical cancer cells, colon cancer cells, and both small and large lung carcinoma cells. Silymarin was identified as a telomerase activator in B. Bagherpour, et. al. (2006), Effects of Silymarin, Telomerase Activity and Proliferation of Peripheral Blood T-Lymphocytes in β-Thalassemia Patents, 2010 in the 11th Congress of the European Hematology Association, Amsterdam, the Netherlands, 2006 (direct link).

That silibinin, the primary active component of silymarin, behaves like a telomerase inhibitor for cancer cells, was given by P. Thelen, et al., (2003), Inhibition of telomerase activity and secretion of prostate specific antigen by Silibinin in prostate cancer cells, The Journal of Urology, 171(5);1934-1938.

The case for using silymarin as a telomerase activator for non-cancerous normal cells has been getting stronger. See the pivotal paper Parzonko A, Naruszewicz M., Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, Warsaw, Poland (2010), Silymarin inhibits endothelial progenitor cells senescence and protects against the antiproliferative activity of rapamycin: preliminary study, Journal of Cardiovascular Pharmacology, December 2010 56(6), 610-618. "We examined whether silymarin, a complex of flavonolignans with hepatoprotective and antioxidative properties, can protect EPCs against rapamycin-induced senescence.... Silymarin increased telomerase activity 3-fold, reduced the number of senescent cells, and increased EPC proliferative activity (up to 64%) in comparison with cells cultured with rapamycin alone. Moreover, silymarin partially prevented impairment of tubular-like structure formation in Matrigel by rapamycin."

Note that Product B's (146) Milk Thistle Extract (Silymarin) seems to have been identified as a telomerase activator for human fibroblasts at Sierra Sciences in their tests to find telomerase inducers, as described in Product B PatentScope.pdf. According to Product B PatentScope.pdf, Milk Thistle Extract activates transcription of hTERT in human fibroblasts, and may be taken at 10 mg to 5 grams twice daily to lengthen telomeres.

Silymarin from Milk Thistle prevents glutathione depletion. Endogenous antioxidants and antioxidants in general tend to confine hTERT to the nucleus, tending to elevate telomerase activity. "Maximum levels of glutathione coincide with a peak of telomerase activity in proliferating 3T3 fibroblasts; glutathione depletion decreases by 60% telomerase activity, and restitution of glutathione levels restores telomerase activity..." - from Maria Dolores Edo and Vicente Andres, 2005, "Aging, Telomeres, and Atherosclerosis", Cariovascular Research, 66 (2005), 213-221. The usual method of upregulating glutathione is to take alpha lipoic acid. Other glutathione boosters include N-Acetyl-Cysteine (NAC), SAMe, whey protein, asparagus, broccoli, avocado and spinach. N-Acetyl-cysteine is an amino acid precursor of glutathione. "Raw eggs, garlic and fresh unprocessed meats contain high levels of sulphur-containing amino acids and help to maintain optimal glutathione levels." Note that glutathione incorporates selenium, which may be obtained from popular multivitamin pills such as Centrum, for instance, to promote glutathione synthesis.

A correspondent [Josh Mitteldorf, How to Live a Long Time, Blog] remarked in a letter (January 2014) that milk thistle extract (silymarin), a component of Product B, is 20x as effective in lenthening telomeres as cycloastragenol according to Dr. Bill Andrews. "According to Andrews, Silymarin is the best herbal telomerase enhancer, some 20x more powerful than cyclo-A in vitro."

(103) Sodium Butyrate [Index, Links, Images, Papers, Patents, Books; molecule, supplements, sources, toxicity; Vendors/BODYBIO]. Sodium butyrate, an HDAC inhibitor, is suspected as a telomerase activator, which is exciting because of its extremely small molecular size and low toxicity. It is also believed to upregulate the transcription of the hTR component of telomerase by improving the expression of transcription factor Sp1. This may have application to treatment of old mesenchymal-derived tissues (which exhibit reduced expression of hTR) such as connective tissues in the neck rejuvenation problem. Furthermore, the effect of sodium butyrate on farm animals is to improve their size, eliminate cancer, and improve other characteristics of the animals. It seems that one of the most promising small molecule telomerase activators is a chicken feed that turns out bigger, healthier chickens by accelerating protein construction using an HDAC inhibitor that expands chromatin to enable enhanced-rate production of mRNA transcripts for the proteins. It is sold as a relatively inexpensive supplement in pill form. The proper dose for the telomerase activator application is probably the human dosage recommended by BODYBIO or T.E.Neesly. Note that butyric acid compounds have cropped up before in Geron's enhanced bioavailability telomerase activators (100) announced in 2010. The telomerase activators may include HDAC inhibitor sodium butyrate, which upregulates the Sp1 transcription factor upregulating hTERT. Sodium butyrate may function like HDAC inhibitor Tricostatin A as a telomerase activator [Index]. Note that sodium butyrate may increase hTERT activation by produced by other telomerase activators due to its HDAC inhibitor property of expanding chromatin for transcriptional activity. Sodium Butyrate and/or Sodium 4-Phenylbutyrate might also promote Replication Protein A and HEST1A [Index] transcription. (check). The sodium butyrate-activated Sp1 elevates production of epiregulin (an EGF family telomerase activator). Sodium butyrate plus exercise (which elevates epiregulin) may improve epiregulin expression considerably more than exercise alone. [However, this prescription yields bad dream reports around midnight, so try it out on experimental animals first to determine an appropriate dose.]

(104) Trapoxin [Links/Trapoxin, Images, Papers, Patents, Books; molecule, supplements, sources, toxicity].
Do not use Trapoxin. Trapoxin was suspected as a telomerase activator. However, "Trapoxin...inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle." - (Taunton J, Hassig CA, Schreiber SL, 1996). In other words, it might induce senescence by halting the cell cycle. It was suspected that HDAC inhibitor trapoxin is a telomerase activator via ability to upregulate Sp1, functioning like HDAC inhibitor Tricostatin A. However, "Trichostatin A reversibly inhibits the mammalian histone deacetylase, whereas trapoxin causes inhibition through irreversible binding to the enzyme." - Yoshida M, Horinouchi S, Beppu T. (1995), Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function, Bioessays, 1995 May;17(5):423-30. "Trapoxin A irreversibly inhibits HDAC activity in crude cell lysates, and induces the accumulation of hyperacetylated core histones in a number of mammalian cell lines and tissues. Histone acetylation and methylation have been studied extensively for their anti-tumor activities in carcinogenesis and Trapoxin has been suggested as a potential anticancer agent for pre-clinical trials." - Sigma Aldrich table of DNA-RNA Transcription Regulators.

(105) Fenugreek seeds [Images] and Fenugreek extract [Images], via Tankyrase, HIF-1 and Diosgenin.
Fenugreek treatment to lengthen telomeres may be the most inexpensive method, and have valuable adjuvant properties when other telomerase activators are used, making telomeres more accessible to telomerase via 4-hydroxyisoleucine [Images] amplification of insulin secretions, since insulin phosphorylates tankyrase 1 to remove telomere closure protein TRF1, when the reaction occurs in the presence of a NAD+ substrate (Nicotinamide adenine dinucleotide) to support poly(ADP-ribo)sylation of TRF1. The NAD+ substrate may be supplied from low doses of NAD+ (5 mg every other day), or from < 3 grams of nicotinamide (niacinamide) per day. At the same time, Fenugreek activates the production of hTERT mRNA via the HIF-1 transcription factor, upregulated by diosgenin in Fenugreek. HIF-1 can activate hTERT mRNA transcription in every cell in the body. (IGF-1 also works on every cell in the body, to phosphorylate hTERT for import into the nucleus from the cytoplasm.) Furthermore, Fenugreek promotes testosterone, which produces telomerase activation in muscle tissues, cardiac stem cells, melanocytes, and tissues sensitive to androgens. However, continuous use of Fenugreek seed at 3 grams/day for 8-12 weeks is used for breast enlargement. The high testosterone of Fenugreek produces elevated libido, and so it has been used to produce more libido-enhanced she males than obtained from telomerase activator black cohosh, especially when an alcoholic extract of Fenugreek is rubbed into the chest area. It seems that Fenugreek extract may be used in 2-week telomerase activation/inhibition cycles after evening workouts at 700-1050 mg/serving of 50% Fenugreek seed and 50% Fenugreek extract just before bedtime without producing breast enlargement in exercising males, however. Recently (August, 2011) I've been experimenting with an ethanolic extract of Fenugreek seed rubbed into the scalp for hair restoration, alternating it with telomerase-inhibiting green tea in my monthly cycle of telomerase activation for 2 weeks followed by 2 weeks of telomerase inhibition. This is more inexpensive to prepare than astragalus extract. The high insulin from Fenugreek produces low blood sugar associated with a tired and ready for bed state when taken late in the evening.

(106) Folic Acid [Index, Images]. (See Telomeric Chromatin and hTERT methylation). Folic acid is heavily used in DNA synthesis, and is important in synthesizing telomeric DNA. Note that folic acid supplements stimulate the PI3K/AKT signaling cascade, which is thought to activate telomerase by phosphorylating cytoplasmic hTERT and importing it into the cellular nucleus, where it becomes part of the telomerase holoenzyme and lengthens telomeres like resveratrol, which also phosphorylates cytoplasmic hTERT via AKT kinase for import into the nucleus. See the searches folic acid is a telomerase activator and folic acid accelerates telomerase activity. 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 [OnLine, PDF], Journal of Nutrition, 2009 Jul;139(7):1273-8. Perhaps 5 mg/day during telomerase activation periods with a return to 0.4 mg/day to 2 mg/day during telomerase inhibition periods would improve telomere growth. At this time I merely use 1.6 mg/day to 2 mg/day folic acid to preserve essential methylation and as a component in super B-vitamin pills functioning as homocysteine blocker. High homocysteine levels shorten telomeres.

Note that folic acid is used in DNA synthesis, so that it is heavily consumed by cancer cells, as is sugar. Probably telomere DNA synthesis proceeds generally better in the presence of folic acid, so that it should be taken when attempting to lengthen telomeres to facilitate telomere DNA synthesis. "Damage in telomeric DNA is repaired less efficiently compared with coding regions and can result in short telomeres (22,23). Folate provides precursors for nucleotide synthesis and low folate availability causes nucleotide imbalances and subsequently DNA damage (24,25). Thus, it is possible that folate can influence telomere length by its effect on integrity of telomeric DNA....Folate provides precursors for nucleotide synthesis and low folate availability induces uracil misincorporation and strand breaks in DNA. ...Low folate status is associated with altered telomere length in a nonlinear manner. There is a shortening of telomeres with decreased plasma folate concentration to the median, but telomere length increases with decreased plasma folate concentration below the median (11.6 nmol/L)."
- [(Paul L, Cattaneo M, et al), PDF].

Folic Acid with EGF and PDGF Elevation for Rapid Rejuvenation
Note that folic acid (List, vitamin B9) stimulates the PI3K/AKT pathway to down-regulate caveolin-1 by sequestering FOXO factors away from the nucleus. Thus a large dose of folic acid (1 to 15 mg) along with a bodybuilding workout set up to elevate EGF and PDGF with exercise and supplements such as colostrum might return a man's senescent cells rapidly to a rejuvenated state. This is an experiment for patients without atherosclerotic plaque, arteriosclerosis, or aortic stenosis, however. Repeated application may be required. This may be combined with treatment to simultaneously elevate cyclic AMP.

(107) Epiregulin [Wikipedia/Epiregulin, Links/Epiregulin, Images, Video, Papers, Patents, Books; Links/Epiregulin activates telomerase, Images, Papers, Patents, Books; Links/upregulating epiregulin, Links/supplements upregulating epiregulin; Links/the epiregulin promoter; Wikigenes/EREG, Gene Cards/EREG; Links/the Epidermal Growth Factor Family; Links/the Epidermal Growth Factor Receptor Family (ErbB1 (EGFR), ErbB2 (Her2), ErbB3 (Her3), ErbB4 (Her4))]. Epiregulin is a member of the Epidermal Growth Factor family that can function as a ligand of the Epidermal Growth Factor receptor [Images, Video, Papers, Patents, Books]. The EREG gene, producing proepiregulin [Images, Video, Papers, Patents, Books], gives rise to epiregulin as a cleavage product. There are seven known ligands of the Epidermal Growth Factor Receptor (EGFR) in the EGF family, including
(1) EGF (30) [Images, Video, Papers, Patents, Books, Gene Cards/EGF],
(2) TGF-alpha (108) [Images, Video, Papers, Patents, Books],
(3) Epiregulin (107) [Images, Video, Papers, Patents, Books],
(4) Amphiregulin (AR), (112) [Images, Video, Papers, Patents, Books],
(5) Heparin binding EGF (HP-EGF), (113) [Images, Video, Papers, Patents, Books],
(6) Betacellulin (114) [Images, Video, Papers, Patents, Books], and the
(7) Heregulins (115) [Images, Video, Papers, Patents, Books].
All these (1)-(7) may behave like telomerase activators in specific target tissues. Human epiregulin cDNA describes a single-chain 46 amino acid polypeptide having a 24% to 50% homology with the other EGF family members functioning as ligands of the EGF receptor. Epiregulin induces proliferation of fibroblasts, hepatocytes, smooth muscle cells, and keratinocytes, but inhibits the growth of epithelial tumor cell lines. It shows more activity than any other EGF family growth factor. Like other EGF family members, epiregulin binds to and activates the ErbB1, ErbB2, ErbB3, and ErbB4 tyrosine kinase receptors. Epiregulin stimulates the MAP kinase pathway and promotes the expression of the c-Myc transcription factor upregulating hTERT transcription. See EGF. EGF is a telomerase activator. Epiregulin is a telomerase activator that is upregulated by exercise. Thirty minutes of hard exercise upregulates epiregulin (3.50-fold), platelet-derived growth factor (1.55-fold), and hypoxia-inducible factor-I (2.40-fold) in blood mononuclear cells [Images]. See Peter H. Connolly, Vincent J. Caiozzo, Frank Zaldivar, Dan Nemet, Jennifer Larson, She-pin Hung, J. Denis Heck, G. Wesley Hatfield, and Dan M. Cooper (2004), Effects of exercise on gene expression in human peripheral blood mononuclear cells, Journal of Applied Physiology, October 2004 vol. 97 no. 4 1461-1469. See also Muralidhara Padigaru, Somesh Sharma, Arvind Thankkar, Anaandharajan Rathina Sabapathy, Sapna Hasit Parikh, and Usha Ghosh (Mumbai India), Method of Use of Epiregulin Protein and Nucleic Acid Encoding the Same in Inflammatory Conditions, US Patent 2010/0168008, July 1, 2010. Epiregulin may be used in monitoring and treating inflammatory conditions. Epiregulin may be upregulated in rat ovaries using FSH, and again by a substantial amount if an Sp1 expression plasmid is inserted. Note that Sp1 is upregulated by sodium butyrate. Thus sodium butyrate might upregulate telomerase-activating epiregulin from exercise very appreciably, although this is a hypothesis. See Toshio Sekiguchi, Tetsuya Mizutani, Kazuya Yamada, Takashi Yazawa, Hiroko Kawata, Miki Yoshino, Takashi Kajitani, Takashi Kameda, Takashi Minegishi and Kaoru Miyamoto (2002), Transcriptional Regulation of the Epiregulin Gene in the Rat Ovary, Endocrinology, December 2002, 143(12), 4718-4729. Also see Draper BK, Komurasaki T, Davidson MK, Nanney LB (2003), Epiregulin is more potent than EGF or TGFalpha in promoting in vitro wound closure due to enhanced ERK/MAPK activation, Journal of Cell Biochemistry, 89 (6): 1126–37. "One of the highly expressed genes in the hTERT-immortalized fibroblasts (hTERT-BJ cells) encodes epiregulin, a potent growth factor. Blockade of epiregulin reduced the growth of hTERT-BJ cells and colony formation of hTERT-transformed fibroblasts. Moreover, inhibition of epiregulin function in immortal hTERT-BJ cells triggered a senescence program." - from Lindvall C, Hou M, Komurasaki T, et al. (2003). Molecular characterization of human telomerase reverse transcriptase-immortalized human fibroblasts by gene expression profiling: activation of the epiregulin gene, Cancer Research 63 (8): 1743–7.

(108) TGF-alpha (Transforming Growth Factor alpha). [Cope/TGF-alpha, Links/TGF-alpha, Images, Video, Papers, Patents, Books; Wikigenes/TGFA]. Transforming Growth Factor alpha is a telomerase activator candidate because most human growth factors activate telomerase. The receptor of TGF-alpha is the EGF (Epidermal Growth Factor) receptor. "IGF-1 induced production and secretion of TGF-alpha...." - Wikigenes/TGFA. In white blood cells, exercise upregulates Transforming Growth Factor alpha (1.87 fold observed). See Petra Buttner, Sandy Mosig, Anja Lechtermann, Harald Funke, and Frank C. Mooren (2007), Exercise affects the gene expression profiles of human white blood cells, Journal of Applied Physiology 102:26-36, 2007. (First published Sept.2006).
TGF-beta, however, appears to inhibit telomerase in cancer cells. See Yang H, Kyo S, Takatura M, Sun L. (2001), Autocrine transforming growth factor beta suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells, Cell Growth and Differentiation. 2001 Feb;12(2):119-27. Note that large amounts of TGF-alpha are found in melanoma cell lines. - Wikigenes/TGFA.

(109) Acetyl L-Carnitine (via NGF).
Acetyl L-Carnitine can elevate the expression of Nerve Growth Factor (NGF) by up to 100 times. NGF promotes the expression of Id-1 helix-loop-helix transcription factor, which promotes the transcription of hTERT mRNA. What this propably means is that the use of Acetyl L-Carnitine should be in cycles of telomerase activation and inhibition when the dose is suitably high. The scope of activation still requires clarification. Neural stem cells are quite likely to benefit. Id-1 helix-loop-helix protein activates telomerase in human keratinocytes. Perhaps ocular keratinocytes [Images] could be treated with acetyl L-Carnitine or an NGF cream to activate telomerase in the cornea. Check: Links/Acetyl L-Carnitine activates telomerase, Links/Acetyl L-Carnitine promotes Nerve Growth Factor, Links/Activation pathways triggered by Acetyl L-Carnitine, Links/Acetyl L-Carnitine pathway analysis.

(110) Cottage Cheese (casein). Casein (cottage cheese) elevates IGF-1 levels. Note that IGF-1 [Index] activity is limited to cells with IGF-1 cell surface receptors. IGF-1 (Gene Cards/IGF-1) is an autocrine/paracrine hormone manufactured from HGH [Index] in the liver. Note, however, that IGF-1 is not an endocrine hormone distributed in the blood to distant target cells. Autocrine hormones act on the cell producing the hormone, paracrine hormones act on cells surrounding the cell that produces the hormone, and endocrine hormones are transported to distant cells via the bloodstream. However, IGF-1 levels in the blood rise as HGH is processed by the liver.

(111) IGF-2. [Index/IGF-2, Wikipedia/IGF-2, Links, Images, Video, Papers, Patents, Books]. IGF-2 increases the transcription of progesterone [List], a telomerase activator. IGF-2 is found in colostrum [List].

(112) Amphiregulin (AR) [Links/Amphiregulin (AR) Images, Video, Papers, Patents, Books]. See Epiregulin (107) and ligands of the EGF receptor. Amphiregulin is a ligand of EGFR, and is suspected to cause telomerase activation via the MAP Kinase pathway. Amphiregulin is upregulated 3.4 times after 30 minutes of exercise in human neutrophils. - after Shlomit Radom-Aizik, Frank Zaldivar Jr., Szu-Yun Leu, Pietro Galassetti, and Dan M. Cooper (2008), Effects of 30 min of aerobic exercise on gene expression in human neutrophils, Journal of Applied Physiology, Jan. 2008 vol 104, no. 1, 236-243.

(113) Heparin binding EGF (HP-EGF) [Links/Heparin binding EGF, Images, Video, Papers, Patents, Books]. See Epiregulin and ligands of the EGF receptor. HP-EGF (Heparin-binding EGF) is a ligand of EGFR, and is suspected to cause telomerase activation via the MAP Kinase pathway.

(114) Betacellulin [Wikipedia/Betacellulin, Cope/Betacellulin; Links/Betacellulin, Images, Video, Papers, Patents, Books]. See Epiregulin (107) and ligands of the EGF receptor. Betacellulin is a ligand of the Epidermal Growth Factor Receptor (EGFR), and is suspected to cause telomerase activation via the MAP Kinase pathway. Betacellulin is a major peptide growth factor in bovine milk. It is expressed in the goblet cells of the colon, gastric glands, and in the lining of the gastric epithelium. In human cells, betacellulin is expressed primarily in the pancreas and in the small intestine. Betacellulin is a mitogen in the retinal epithelium and vascular smooth muscle cells, stimulating the MAP Kinase pathway there. It may be beneficial to separate betacellulin from bovine milk and offer it as a telomerase-activating supplement, or to culture it from reprogrammed CHO cells.

(115) Heregulins [Cope/Heregulin; Links/Heregulins, Images, Video, Papers, Patents, Books; Links/Neuregulins, Images, Papers, Patents, Books]. See Epiregulin (107) and ligands of the EGF receptor. Heregulins (also called neuregulins) are ligands of EGFR, and suspected to cause telomerase activation via the MAP Kinase pathway. The heregulins include:
HRG-alpha [Images, Papers, Patents, Books],
HRG-beta-1 [Images, Papers, Patents, Books],
HRG-beta-2 [Images, Papers, Patents, Books],
HRG-beta-3 [Images, Papers, Patents, Books], and
HRG-gamma [Images, Papers, Patents, Books].

(116) Rapamycin [Telomerase Inhibitors/(62) Rapamycin, Links/Rapamycin, Images, Video, Papers, Patents, Books; Links/Rapamycin and cellular aging, Images, Papers, Patents, Books; Links/Rapamycin and telomerase activation, Images, Papers, Patents, Books]. Actually, it seems that rapamycin is a telomerase inhibitor. "Milk thistle (List; silymarin) protects telomerase activation from rapamycin in vitro." Rapamycin reverses aging in cells taken from Hutchinson-Gilford progeria patients and extends the lifespan of mice. Rapamycin is an immunosuppressant drug used to prevent rejection of transplanted organs. - Biosingularity, July 2011. Immunosuppressant drugs may not be suitable for our application. Many telomerase activators improve immune system performance, so that immune system enhancing drugs such as astragalus are often targets for telomerase activation testing. See Kan Cao, John J. Graziotto, Cecilia D. Blair, Joseph R. Mazzulli, Michael R. Erdos, Dimitri Krainc, and Francis S. Collins (2011), Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells, Sci Transl Med, 29 June 2011: Vol. 3, Issue 89, p. 89ra58. See also Chunxiao Zhou, Paola A. Gehrig, Young E. Whang and John F. Boggess Rapamycin Inhibits Telomerase Activity by Decreasing the hTERT mRNA Level in Endometrial Cancer Cells, Molecular Cancer Therapeutics, August 2003 2; 789. See also Parzonko A, Naruszewicz M., Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, Warsaw, Poland (2010), Silymarin inhibits endothelial progenitor cells senescence and protects against the antiproliferative activity of rapamycin: preliminary study, Journal of Cardiovascular Pharmacology, December 2010 56(6), 610-618. "Rapamycin, an antiproliferative agent used on drug-eluting stents, induces endothelial progenitor cells (EPCs) senescence through telomerase inactivation and may impair the reendothelization of an injured arterial wall, leading to thrombosis. We examined whether silymarin, a complex of flavonolignans with hepatoprotective and antioxidative properties, can protect EPCs against rapamycin-induced senescence."

(117) Fbx4 [Links, Images, Video, Papers, Patents, Books, Gene Cards/FBXO4]. "...Overexpression of Fbx4 reduces endogenous Pin2/TRF1 protein levels and causes progressive telomere elongation in human cells." Pin2/TRF1 is a telomerase inhibitor, or negative regulator of telomere length. See Tae Ho Lee, Kilian Perrem, J. Wade Harper, Kun Ping Lu, and Xiao Zhen Zhou (2006), The F-box Protein FBX4 targets PIN2/TRF1 for Ubiquitin-mediated Degradation and Regulates Telomere Maintenance, The Journal of Biological Chemistry, Jan 13 2006, 281:759-768. Note that FXB4 has a binding site on the telomerease inhibitor PINX1 gene promoter, where it might function like a repressor. See supplements producing overexpression of FBX4 [Links, Images, Video, Papers, Patents, Books].

(118) Nucleostemin [Links, Images, Video, Papers, Patents, Books]. Nucleostemin lengthens telomeres by degrading TRF1. See Qubo Zhu, Hiroaki Yasumoto and Robert Y.L.Tsai (2006), Nucleostemin Delays Cellular Senescence and Negatively Regulates TRF1 protein stability, Molecular and Cellular Biology, December 2006, 28(24):9279-9290. Note that overexpression of nucleostemin causes cell cycle arrest. See Hanhui Ma and Thoru Pederson (2008), Nucleostemin: a multiplex regulator of cell-cycle progression, Trends in Cell Biology, 24 October 2008, 18(12):575-579.

(119) TAT153 [Links/TAT153, Images, Video, Papers, Patents, Books]. TAT153 is a new small molecule telomerase activator from Geron announced in 2010. TAT153 may be associated with a TAT153 cDNA [Images, Video, Papers, Patents, Books]. Tally-ho, Geron!

(120) UP1 [Links/UP1, Images, Video, Papers, Patents, Books; Links/UP1 enlongates telomeres, Images, Video, Papers, Patents, Books]. hnRNP A1 and a derivative UP1 = UAGGGU enlongate telomerase. See Helene LaBranche, Sophie Dupuis, Yaacov Ben-David, Maria-Rosa Bani, Raymund J. Wellinger and Benoit Chabot (1998), Telomere enlongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase, Nature Genetics volume 19, June 1998. DNA oligonucleotides such as TTAGGG, TTAGGGTTAGGG, and so on have been described in patents captained by Jerry Shay and Woodring E. Wright for application to lengthening telomeres. Perhaps UP1 = UAGGGU is inserted between TT in a telomere like T(UAGGGU)TAGGG and DNA damage enzyme corrected to TTAGGGTTAGGG by carrying out the replacement U -> T. However, the exact mechanism is unknown to me. It seems only to be inserted inside telomeres. UP1 can lengthen telomeres in cell lysates when applied exogenously, according to the authors. Usually UP1 is applied in a retrovirus. Whether or how it can be used for human telomere enlongation in telomere therapy is uncertain. See Bashir Mir, Natalie Tanner, Bhanu P. Chowhary, and Jorge A. Piedrahita (2003), UP1 Extends Life of Primary Porcine Fetal Fibroblasts in Culture, Cloning and Stem Cells August 2003, 5(2): 143-148. The article describes lifespan prolongation in UP1-expressing cells [Images, Papers, Patents, Books]. It is possible that chromosomal abnormalities accumulate using UP1, so that cell lifetimes in culture are extended up to a factor of about 3. (op cit.) See B Chabot (2001), Composition and methods for modulating the length of telomeres, - US Patent App. 20,020/114,797, 2001. Perhaps UP1-expressing cells may be prepared with plasmid transfection technique or with AAV viral transfection technology. Probably UP1 can be put through the cell membrane in liposomes, if UP1 works when applied to cell lysates exogenously. Perhaps we could alternatively use GGUUAG, which would be translated by DNA repair to GGTTAG, the fundamental hex repeat actually installed by telomerase.

(121) Product B from IsAGenix [The Product B Explorer, Product B: Telomere Growth Results, Links, Images, Video, Papers, Patents, Books; PatentScope revelations on Product B components and Product B telomere enlongation]. The Product B patent was associated with master formulator John W Anderson. Now Dr. Bill Andrews also has a site and presentation at IsAgenix. It seems that high-throughput screening tests for telomerase activators must have led to Product B, which contains some interesting new components, telomerase inducers which are specified in the internationally visible Product B PatentScope.pdf. Sierra Sciences: "We have screened 254,593 compounds. We have found 858 telomerase inducers [Images, Papers, Patents, Books]. These represent 38 distinct drug families. Most potent compound=15.89% of goal. We are currently screening natural product extracts [Links/Natural product extracts producing telomerase activity, Images, Papers, Patents, Books]".
Product B seems to be a blend of telomerase activators and telomerase inhibitors, including some compounds that are telomerase inhibitors for cancer cells only. See The Product B Explorer. In my opinion, mixing telomerase activators and telomerase inhibitors like curcumin [List] from turmeric in the same pill might reduce the effectiveness of the pill as a telomerase activator for lengthening telomeres unless curcumin is a telomerase inhibitor for cancer cells only. Otherwise, too much curcumin in this pill might cause it to function primarily as an antioxidant. Note that antioxidants tend to confine hTERT inside the nucleus, perhaps causing curcumin to register a hit as a telomerase inducer. Panax Ginseng in Product B might also function as a telomerase inhibitor in cancer cells, but as a telomerase inducer in normal cells, as required by Product B PatentScope.pdf data. Panax Ginseng seems to be a telomerase inhibitor in cancer cells. (check). Berberine is another Product B component that behaves like a telomerase inhibitor in cancer cells, but like a telomerase activator in normal fibroblasts, according to Product B PatentScope.pdf data. The Product B components Green tea, Black tea, and White tea are all thought to contain EGCG [Index, List], a telomerase inhibitor in cancer cells, although all three are empirically shown to activate telomerase in fibroblasts according to Product B PatentScope.pdf data. The Product B component Milk Thistle extract [Index, List/Silymarin] is an anticancer telomerase inhibitor, but behaves like a telomerase inducer when applied to fibroblasts, according to Product B PatentScope.pdf data. We should clarify when a telomerase inhibitor interferes with a telomerase inducer, since telomerase inhibitors may or may not interfere with all modes of telomerase activity enhancement, including phosphorylation of hTERT to import cytoplasmic hTERT into the nucleus, transcription of hTERT mRNA using transcription factors, provision of required cofactors such as HSP90, phosphorylation of tankyrase 1 to open telomere loops, and provision of ionic cofactors such as Mg(+2). Furthermore, some telomerase inhibitors evidently only inhibit telomerase in cancer cells, and not in normal fibroblasts. Thus certain specific telomerase inhibitors may not interfere with telomerase inducers applied during a program of treatment to lengthen telomeres in normal non-cancerous cells, although others may always block the action of the telomerase holoenzyme. See the Product B patent (WO2012106692) COMPOUND AND METHOD FOR INCREASING TELOMERE LENGTH (WIPO Patentscope, PatentScope.pdf, European Patent Register, Report (John W Anderson Patent, Product B).

(122) GRN510 - A new Geron telomerase activator based on a Chinese medicinal herb.
See [Links, Images, Video, Papers, Patents, Books; Geron/GRN510]. Administration of GRN510 resulted in an increase in telomerase activity in lung tissue samples afficted by Idiopathic Pulmonary Fibrosis (IPF), a chronic, progressive disease of the lung characterized by inflammation and fibrosis. "Treatment with GRN510 at 10 mg/kg/day activated telomerase 2–4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively." [Ref]. Note that hematopoietic stem cells are ordinarily limited to less than 100 divisions in humans [Ref, Lansdorp].

(123) Gamma Tocotrienol [Index, Wikipedia, Links, Images, Video, Papers, Patents, Books, LifeExtension; Links/Sources of Gamma Tocotrienol, Images/Gamma Tocotrienol supplements; Images/Gamma Tocotrienol skin cream; Images/Tocotrienol-rich fraction supplements with alpha-tocopherol from palm oil; Images/Tocotrienol-rich fraction skin cream with alpha-tocopherol from palm oil]. Also see (173) Tocotrienol-rich fraction.
According to Terraternal, gamma tocotrienol activates telomerase in in vitro experiments. See Terraternal Telomere Guard. "In this in vitro study the authors concluded that "gamma-tocotrienol protects against oxidative stress-induced cellular ageing by modulating the telomere length possibly via telomerase". Cells were exposed for 24 hours to gamma-tocotrienol before and/or after 2 hour exposure to hydrogen peroxide (H2O2). At the optimal dose, telomere lengths of treated cells appear to have been roughly 16% longer than controls after only this very short period of exposure." See Annatto [Wikipedia, Links, Images, Papers, Patents, Books, LifeExtension]. Annatto is an excellent source of delta- and gamma tocotrienol without interfering tocopherols. See, for instance, Solaray Annatto Tocotrienols and Annatto Tocotrienol supplements. See Suzana Makpol, Azrina Zainal Abidin, Khalilah Sairin, Musalmah Mazlan, Gapor Md Top, and Wan Zurinah Wan Ngah (2010), Gamma-Tocotrienol prevents oxidative stress-induced telomere shortening in human fibroblasts derived from different aged individuals, Oxidative Medicine and Cellular Longevity, 3(1); Jan-Feb 2010. See their more recent work: Suzana Makpol, Azalina Zainuddin, Kien Hui Chua, Yasmin Anum Mohd Yusof, and Wan Zurinah Wan Ngah (2012), Gamma-tocotrienol modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts [NCBI DOC], Clinics (Sao Paulo) 2012 February; 67(2): 135–143, and also Makpol S, Durani LW, Chua KH, Mohd Yusof YA, Ngah WZ (2011), Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts, [NCBI DOC], Journal of Biomedicine and Biotechnology 2011 Mar 30. Gamma tocotrienol [List] reduces expression of collagenase from senescent fibroblasts, protecting the extracellular matrix, and has favorable impact on gene expression in both senescent and normal fibroblasts, tending to oppose aging. Tocotrienol-rich fraction containing alpha-tocopherol and tocotrienols alpha, beta, gamma, and delta from rice bran, palm oil, oat, or barley, tends to produce telomerase activity in senescent fibroblasts, lengthen telomeres, restore fibroblast morphology, and restart the cell cycle. Tocotrienols have extended animal lifetimes by 18%.

(124) Bacopa [Product B Telomerase Activators/(136) Bacopa Extract, Index/Bacopa, Links/Bacopa, Images, Papers, Patents, Books, LifeExtension; Links/Bacopa and telomeres, Images, Papers, Patents, Books].
There are 2012 reports that Bacopa activates telomerase [Papers, Patents, Books] and that Bacopa lengthens telomeres [Papers, Patents, Books]. Note that Bacopa extract is a component of the telomere-support formulation (121) Product B from IsAGenix.

According to the patent Product B PatentScope.pdf, Bacopa extract activates transcription of HTERT in human fibroblasts, and may be taken at 1 mg to 500 mg twice daily to lengthen telomeres in human fibroblasts. (It is not unusual for bodybuilders to take 1-2 grams per day of bacopa to improve definition.)

"There are two major substances that have been found to promote replenishment of telomeres: Astragalus from China and Bacopa from India. When combined with ingredients such as Resveratrol, Vitamins D, B-6, and B-12, it is believed Astragalus and Bacopa support a cell's ability to replicate itself vigorously and healthily." - Tammy Colipano (Articles).
There is also a new 2012 supplement for lengthening telomeres including Bacopa's bacopasides:
"Introducing TS-X: a combination of two enormously powerful telomere support ingredients:
1.Astragalosides in approx. 30% greater concentration (considered the “a” grade of telomere support ingredients).
2.Bacopasides in a 50% greater concentration (considered the “b” grade ingredient for telomere support).
3.Fortified with a massive array of complex antioxidants,
designed to protect telomeres from the hotspot degradation caused by free radicals oxidizers.
TS-X will retail for $125 for one bottle & those who purchase 3 bottles will be given a discount to $99.95 per bottle.
" - Daniwalker.com. See TS-X Extreme. See Con K Stough, Matthew P Pase, Vanessa Cropley, Stephen Myers, Karen Nolidin, Rebecca King, David Camfield, Keith Wesnes, Andrew Pipingas, Kevin Croft, Dennis Chang and Andrew B Scholey (2012), A randomized controlled trial investigating the effect of Pycnogenol and Bacopa CDRI08 herbal medicines on cognitive, cardiovascular, and biochemical functioning in cognitively healthy elderly people: the Australian Research Council Longevity Intervention (ARCLI) study protocol (ANZCTR12611000487910), Nutrition Journal 2012, 11:11.

(125) AP-1 transcription factor activator protein: [hTERT Promoter/AP-1, Wikipedia, Links, Images, Papers, Patents, Books]. "The transcription factor activator protein 1 (AP-1) is involved in cellular proliferation, differentiation, carcinogenesis, and apoptosis and is expressed broadly in both cancer and normal cells. There are several putative AP-1 sites in the hTERT promoter, but their functions are unknown. " (from Masahiro Takakura, Satoru Kyo, Masaki Inoue, Woodring E. Wright, and Jerry W. Shay, (2005), Function of AP-1 in Transcription of the Telomerase Reverse Transcriptase Gene (TERT) in Human and Mouse Cells, Molecular and Cellular Biology, September 2005, p. 8037-8043, Vol. 25, No. 18. AP-1 is sometimes termed "the early response transcription factor", and is formed from a combination of c-Jun and c-Fos. AP-1 is modulated by berberine, a component of Product B. Note that AP-2 is also a telomerase activator. See
Nutraceuticals modulating AP-1 transcription activator protein [Links, Images, Papers, Patents, Books].

(126) Astraverrucins activate telomerase [Links/Astraverricins, Images, Papers, Patents, Books;
Links/Astraverricins activate telomerase, Images, Papers, Patents, Books].
Astraverrucins are extracted from Astragalus verrucosus [Links/Astragalus verrucosus, Images, Papers, Patents, Books; sources]. This was briefly described in the Geron patent of 2005 on Compositions and Methods for Increasing Telomerase Activity. Astraverrucin I [Images, suppliers] and astraverrucin II [Images, suppliers] produce an increase in telomerase activity. Astraverrucin I is also termed cycloaraloside A, and is available from suppliers as a chemical, as is Astraverrucin II. See cycloaraloside A suppliers. See also Astragalus verrucosus Moris [Links/Astragalus verrucosus Moris, Images, Papers, Patents, Books; Astragalus verrucosus seeds]. Astragalus verrucosis is found in Sardinia [Images], at just one site with an area of 4 square kilometers, with just 220 individual plants in existence. (See The IUCN Red List of Threatened Species). There is only one population of Astragalus verrucosus in the Arbus municipality of Sardinia.
See Arbus, Sardinia [Wikipedia, Links, Images, Map & Satellite Photos].

The bodybuilder Franco Columbo, who posed with Arnold Schwarzenegger in the movie Pumping Iron [Links], was from Sardinia. Pumping Iron Theme - Everybody wants to live forever (Stereo).

See also Pistelli L, Pardossi S, Flamini G, Bertoli A, Manunta A (1997): Three cycloastragenol glucosides from Astragalus verrucosus, Phytochemistry 45: 585–587, (which describes three cycloartane-triterpene glucosides, astraverrucin I, II and III), and Further Saponins and Flavonoids from Astragalus verrucosus Moris. Note that the cycloastragenol glycosides astraverrucin I and astraverrucin II may be extracted from the stems and aerial parts of the plant Astragalus verrucosus above ground. This would be like having a plant that is easy to harvest with cycloastragenol in its leaves. Perhaps such a plant could be genetically engineered. This would be easier if the genome of Astragalus verrucosus [Papers, Patents, Books] could be sequenced. Also look for the genome of Astragalus membranaceus [Papers, Patents, Books] and other genomes of plants that produce telomerase activators [Papers, Patents, Books].

(127) NAC (N-acetyl-cysteine) [Index]. "Chronic exposure to NAC can delay senescence of diseased endothelial cells via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible." - after Guillaume Voghela, Nathalie Thorin-Trescasesa, Nada Farhata, Aida M. Mamarbachia, et al (2008), Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients, Mechanisms of Ageing and Development, Volume 129, Issue 5, May 2008, Pages 261–270.

(128) Lithium [Links], by upregulating Bcl-2 (75).
See Lithium as a telomerase activator [Links, Images, Papers, Patents, Books].

(129) Zinc [Links], by upregulating Bcl-2 (75).
See Zinc as a telomerase activator [Links, Images, Papers, Patents, Books].

(130) Arginine [Index], by upregulating Nitric Oxide and HGH.

(131) Citrulline [Index], by upregulating Nitric Oxide and HGH.

(132) Omega-3 > Omega-6. [Links, Papers, Patents].
By decreasing omega-6 fatty acid levels while elevating omega-3 fatty acid levels, telomere length may be increased. This thought to be due to the higher level of anti-inflammatory omega-3 fatty acids relative to the pro-inflammatory omega-6 fatty acids. Omega-6 sources to be avoided included corn oil, sunflower oil, and safflower oil, along with arachidonic acid from egg yolks and red meat. Omega-3 sources include fish oil (1,250 mg to 2,500 mg), cold-water fish, walnuts, and flax seed. However, note that the fish oil omega-3 fatty acids DHA and EPA are both telomerase inhibitors. Still, things go better for telomere length if omega-6 to omega-3 fatty acid ratios are smaller. See Michael D. West PhD, How Engineered Stem Cells May Enable Youthful Immortality, Life Extension Magazine, February 2013. See also Kiecolt-Glaser JK, Epel ES, Belury MA, et al. (2012), Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial, Brain Behav Immun 2012 Sept 23.

Telomerase Activators (133) - (153) continued in The Product B Explorer.
Telolmerase Activators (154) - (185) continued in lifexnotes3b6.html.


For more clues, see also Keiko Hiyama, Telomeres and Telomerase in Cancer, (Chapter 3: Regulation of Telomerase through Transcriptional and Posttranslational Mechanisms, by Amy N. Depcrynski, Patrick C. Sachs, Lynne W. Elmore, and Shawn E. Holt), Kluwer, 2009.

Search Links/activate telomerase for more articles and substances that activate telomerase and for investigations of the hTERT promoter [Links/the hTERT promoter, Links/the hTERT promoter sequence, Wikipedia/Promoter]. See also Geron's patent on screening for telomerase activators and inhibitors and books and articles telomeres and replicative senescence: [Books, Amazon, LifeExtension, LifeExtension/telomere_therapy]. See Papers on telomerase activation, and papers on telomerase activation treatment, also papers on therapeutic telomerase activation, and Books/telomere homeostasis [Links, Papers].

Telomere Capping Activators [See Telomere Capping Proteins]
Telomere capping activators include the small molecule telomerase activators, above, because they can be applied to close the telomere t-loop and prevent cellular senescence. However, there are proteins that are not telomerase activators, but which are involved in telomere capping, such as EST1, TRF2, or drugs which may be applied to stimulate telomere capping, such as the statin drugs atorvastatin and pravastatin or exogenous TRF2.

Telomere measurement - Five methods for measuring the length of telomere repeats have been described:
(1) Telomere measurement by quantitative PCR. See also Telomere length measured at nucleotide resolution by gene sequencing after telomere PCR. See Richard M. Cawthon, Telomere length measurement by a novel monochrome multiplex quantitative PCR method, Nucleic Acids Res. 2009 February; 37(3) and Biotechniques.com/A 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.
(2) Southern blot analysis of telomere restriction fragments.
(3) Quantitative fluorescence in situ hybridization with digital fluorescence microscopy (Q-FISH).
(4) Quantitative fluorescence in situ hybridization with flow cytometry (flow-FISH).
(5) Quantitative fluorescent in situ hybridization laser scanning cytometry (Q-FISHLSC) using a fluorescent-labeled peptide nucleic acid probe. For laser scanning cytometry for measuring fluorescent signals from LSC, see CompuCyte, Cambridge, Mass.
Telomere Length Analysis with Multi-Color Flow-FISH [Books, Amazon, Papers, Patents, at Repeat Diagnostics, Wiki/Flow FISH]
Telomere Length Analysis via T/C-Fish (telomere/centromere-FISH) [Links, Papers, Amazon; Links/telomere-centromere FISH].
Quantitative Fluorescence In Situ Hybridization (Q-FISH) [Links, Books, Papers, Patents, Amazon]
See [Books/telomere measurement, Books/telomere length assessment, NCBI Papers].
[Books/Telomeres and Telomerase: Methods and Protocols, Links, Papers].
See Links/restriction endonucleases for telomere length research and Books/Endonucleases.
Links/restriction endonuclease sources. See New England Biolabs
Books/human sub-telomeric sequences [Links].
Google/Telomere Kits
Repeat Diagnostics [See How Long are My Telomeres article from RevGenetics, mfg Astragaloside IV.]

Telomerase Expression Measurements - TRAP - Telomerase Repeat Amplification Protocol (Links) [Books, Papers], TRAP kits [Links, Books, Papers]. TRAP is "the gold standard" in telomerase activation measurements, "but requires fresh or snap frozen samples for enzyme preservation. Alternative measures include RT-PCR for hRT and for hTERT mRNA." See also [Books/Telomerase Expression Measurements, Links, Links/Telomerase Measurements, Books/Telomerase Measurements].
[Books/Telomeres and Telomerase: Methods and Protocols, Links, Papers].
Allied Biotech, Inc. - Telomerase Detection Kits [Links, Books].
Telomerase enzyme activity [Books] requires expression of two genes [Links/GenBank],
hTRT [Books], the protein catalytic component gene, and
hTR [Books], the telomerase RNA component. [Books/measuring telomerase enzyme activity, Books/measuring telomerase activation, Links/telomerase-associated gene sequences].
See Telomerase-associated gene expression measurements via Northern Blot analysis
____[Links, Papers, (Links/Northern Blot analysis, Books)].
Telomerase-associated gene expression measurements via nuclease protection assays
____[Links, Papers, (Links/nuclease protection assays, Books, Papers)]
Telomerase component gene expression measurement via RT-PCR ISH
____[Links, Papers, (Links/RT-PCR ISH, Books, Papers)]
Quantitative Telomerase Detection Kit, US Biomax, Inc.
Google/Telomerase Kits

[81bs] Senile Purpura (ecchymosis) [LifeExtension, Books, Links, Images, Wikipedia]. Since this results from collagen loss, and vitamin C is used in collagen synthesis [Links, nuskin article], perhaps it could be treated with Vitamin C in combination with bioflavonoids, taken orally or also from a vitamin C skin cream. Another approach is to use Bilberry capsules [LifeExtension, Links, Wikipedia]. Bilberry strengthens capillary walls and veinous walls in general, and may be useful for treating senile purpura. A typical cruel prescription these days with senile purpura is "wait and see", and it is often listed as primarily a concern of embalmers.
"Progressive loss of collagen in the dermis and vascular wall may lead to characteristic lesions of old age - senile purpura. The purpura usually occurs on the dorsum side of the hands and the wrists and on the forearms. The lesions may be quite large and are well-demarcated. The skin is very thin, the dorsal veins have fragile walls, and venipuncture may result in rapidly spreading purpura. The lesions resolve slowly. No specific treatment exists..... Purpura due to damage of the vessel wall of the terminal vessels are seen in several metabolic disorders such as diabetes mellitus, vitamin C deficiency (scurvy), Cushing's syndrome following corticosteroid therapy, and uremia. Paraproteinemias and amyloidosis may also lead to purpura." - from Modern Hematology: Biology and Clinical Management by R. Munker, E. Hiller, and R. Paquette.
"Bioflavonoids and ascorbic acid have been shown to increase capillary resistance and to mediate potent antioxidative radical scavenging activities.... We evaluated the clinical effect of oral bioflavonoids and ascorbic acid in patients with chronic progressive pigmented purpura (PPP)... In an open pilot study, oral rutoside (50 mg twice a day) and ascorbic acid (500 mg twice a day) were administered to 3 patients with chronic PPP. RESULTS: At the end of the 4-week treatment period, complete clearance of the skin lesions was achieved in all 3 patients. No adverse reactions were noted. All patients remained free of lesions at the end of 3 months after treatment. CONCLUSION: Our results suggest a beneficial effect of bioflavonoids in combination with ascorbic acid on PPP. " - from Life Extension Magazine, 2000.
Other papers show that treatment of purpura with vitamin C alone, without bioflavonoids, is often disappointing by comparison. Apples, bilberries, blueberries or other fruit might be used to supply the additional bioflavonoids.

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