Anti-Aging Medicine: Sup Notes 3a | 3b1 | 3b2 | 3b4 | 3b5 | The 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)-(179), 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 or TA-41. - 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.

Highlight Links 3b6 - Telomerase Activators
____Further Telomerase Activators (154) - (179).


Telomerase Activators (including list pointers and an alphabetical index) [Links, Books, Papers; Links/small molecule telomerase activators, Books, Patents, Index/Telomerase Activate] - Many of these are experimental or available only as "chemicals" or experimental drugs and not yet widely available for phamaceutical applications. Some are dangerous, others are safe enough to use.
Small molecule telomerase activators [Links] include:

List Pointers for Telomerase Activators under Investigation [> Telomerase Inhibitors]

(1) Epithalon peptide, (Ala-Glu-Asp-Gly). Injectable. Discovered in 2003. 2003
(2) Tricostatin A. Injectable. Discovered as telomerase activator in 2000. 2000
(3) Interleukin 2. Injectable 2005
(4) TAT0002 (Geron). (TAT2 = cycloastragenol, Geron 2005, main TA-65 ingredient). 2005
(5) GRN139951 (Geron). (Probably astragaloside IV.) 2005
(6) GRN140665 (Geron). (Mostly cycloastragenol, or Geron TAT0002 or TA-65). 2005
__(6b) TA-65 (TA Sciences). (GRN-665, mostly cycloastragenol, or Geron TAT0002). 2007
__(6_) Astragalus Root [Index], 2005
__ (6_)Astragalus Root Extract [Index], 2005
__(6c) astragaloside IV. Orally bioavailable, announced in 2005. 2005
__(6d) cycloastragenol. Orally biovailable, TAT2, the primary TA-65 ingredient. 2005
__(6e) astragenol. Orally bioavilable, announced in 2005. 2005
__(6e) astragaloside IV 16-one. Orally bioavailable, announced in 2005. 2005
__(6f) 2OR,25S-epoxy-3β,16β,25-trihydroxy-9β-methyl-19-norlanost-1,5-diene 2005
__(6g) cycloastragenol 6-β-D-glucopyranoside 2005
__(6h) cycloastragenol 3-β-D-xylopyranoside 2005
__(6e) Ginsenoside RH1. Orally bioavailable. Announced in 2005. 2005
(7) EST1, for yeast, including EST1p and its homologue hEST1A in humans 2003
(8) HGH, Human Growth Hormone, via HGH secretagogues (8a)-(8j). 2005
____(8a) Dopamine HGH secretagogue __
____(8b) Mucuna Pruriens HGH secretagogue __
____(8c) CDP-choline HGH secretagogue __
____(8d) Alpha-GPC HGH secretagogue __
____(8e) L-Arginine HGH secretagogue __
____(8f) Ornithine HGH secretagogue __
____(8g) Arginine (1500 mg) plus Lysine (1500 mg) HGH secretagogue __
____(8h) Exercise HGH secretagogue __
____(8i) DHA HGH secretagogue by boosting dopamine __
____(8j) Melatonin HGH secretagogue __
____(8k) GABA HGH secretagogue __
(9) IGF-1.2001
(10) Estrogen and Telomerase Activators via Strong Estrogen Bioactivity 1999
(10b) Estrogen Receptors (1318).1999
(11) Bisphenol A (BPA).2004
(12) Other histone deacetylase inhibitor possibilities..
(13) TAC1 with auxin.2003
(14) STAT3.2005
(15) Raloxifine. (orally bioavailable Evista from Eli Lilly). 2006
(16) Ecdysone. An insect hormone. 2006
(17) Saquinavir. (Invirase [Roche Invirase]) an anti-HIV drug and protease inhibitor. 2001
(18) Cimicifuga Extracts. C. racemosa (black cohosh) extracts (26-deoxyacetein).2005
(18b) 26-deoxyacetin a C. racemosa (black cohosh) extract.2005
(19) CGK 1026. CGK 1026 derepresses hTERT expression. 2004
(20) Heat shock proteins. Heat shock proteins like Hsp90 mediate telomerase assembly.1999
(21) Nitric Oxide. (Vasa, 2000, Hayashi 2007) 2000
(22) 5-azacytidine. (DANGER: may promote prostate carcinomas). 2002
(23) CGK733. Revives senescent cells, but not a true telomerase activator. October 19, 2007
(24) HIF-1. Hypoxia-inducible factor 1, promoted by diosgenin, ginkgo biloba, and exercise.2006
(25) Mre11. Mre11 protein. 2002
(26) Ependymin Peptide. From goldfish brains: sequence ESCKKETLQFRKHL.2005
(27) Protein kinase C. 2002
(28) Retinoic acid. [Telomerase Inhibitors/Retinoic Acid]. Limits p16INK4A.2000
(29) DMSO (Dimethyl Sulfoxide). [Telomerase Inhibitors/Dimethyl Sulfoxide (DMSO)]..
(30) Epidermal growth factor EGF. 2002
(31) Surface Ig. 1997
(32) IL-7, Interleukin-7, appears to stimulate expression of telomerase within T-cells. 1998
(33) IL-15, Interleukin-15 stimulates telomerase in T-cells. 2005
(34) Okadaic acid. Poisonous. 2002
(35) Tankyrase. A telomeric PARP phosphorylated by insulin and promoted by Niacinamide. 2004
(35b) Doxycyclin. Can stain teeth. Telomere growth can depend on the presence of doxycyclin. .
(36) hRAP1. 2004
(37) C0057684 from Sierra Sciences. 2007
(37b) C0313741 from Sierra Sciences (announced February 2010, noted here Feb 2013). 2010
(38) Platelet Derived Growth Factor (PDGF). 2004
(39) FR901228. (Romidepsin) Japanese research at Okayama University. 1998
(40) NF-kappaB. [Transcription factor, for inflammatory cytokines.] 2000
(41) TNF-alpha. [Inflammatory] 2004
(42) ?Shark Liver Oil? [Not known to be a telomerase activator.].
(43) Sp1 is upregulated by sodium butyrate, and down-regulated by low insulin. 2000
(44) Cocoa. [Not known to be a telomerase activator.] .
(45) Ginsenoside Rg1. 2011
(46) Novel Telomerase Activators developed at Ben Gurion University on the Negev. 2008
(47) C0057684. From Sierra Sciences. 2002
(48) Antigenic stimulation activates telomerase in T-cells. 2002
(49) Juve Tea. 2007
(50) Anti-CD3 monoclonal antibody (mAb). 1996
(51) Ca ionophore. 1996
(52) Phorbol 12, 13-dibutyrate. 1996
(53) FGF-2, Fibroblast Growth Factor 2 . 2003
(54) beta ecdysterone (20-hydroxyecdysone). [Not known to be telomerase activator.] .
(55) VEGF2 & VEGFA. 2009
(56) G-CSF: granulocyte colony-stimulating factor. 2003
(57) Phosphatidylinositol 3'-kinase. 2005
(58) Akt protein kinase, phosphorylates hTERT protein. 1999
(58b) Resveratrol. Phosphorylates hTERT protein via (58) Akt Protein Kinase. See also (84) 2009
(59) c-Myc is upregulated by EGF, colostrum, estradiol, and PDGF. 1999
(60) Progesterone and Ligands of the Progesterone Receptor (60.1 - 60.7). 2002
(61) Antisense oligode-oxyribonucleotides (ODNs) against Bcr-Abl/c-Abl mRNA. 2004
(62) Survivin. 2005
(63) Arsenic, a poisonous tumor promoter, also elevates hTERT levels. Inhibits telomerase. .
(64) Androgens can activate telomerase, perhaps after conversion into estrogens [Forskolin]. 2003
(64a) Testosterone, an Androgen. 2003
(64b) Forskolin [Index], for the heart, muscles, and melanocytes. 2003
(65) E6/E6AP viral protein, a ubiquitin ligase from human papilloma virus. Poisonous. .
(66) Bmi-1 protein (66). (Dangerously associated with the breast cancer Bmi-1 oncogene.) 2002
(67) Terminalia chebula (Combretaceae, Haritaki), ethanol extract. (Antioxidant.) 2012
(68) Colostrum (Contains EGF (30)). 2002
(69) ? Gotu Kola ?. Taken with astragalus extract to improve circulation. .
(70) IRF4 - Interferon Regulatory Factor 4 (and to a lesser degree IRF8). 2009
(71) DHEA (Dihydroepiandrosterone). 2003
(72) Pregnenolone. 2003
(73) Id-1 helix-loop-helix protein, upregulated by Nerve Growth Factor. 1999
(74) Stem Cell Factor (Kitl). 2002
(75) Bcl-2. 1997
(76) Replication Protein A. 2003
(77) Uncaria sinensis Havil Just retards telomere shortening. 2006
(78) Hepatocyte Growth Factor. 2005
(79) Sphingosine-1-Phosphate (S1P). 2007
(80) Lysophosphatic Acid. 2007
(81) Exercise. 2001
(82) Angiotensin II. 2006
(83) Epithelial Growth Factor (EGF). 2002
(84) Resveratrol. (See also (58) Akt with (58b) Resveratrol). 2009
(85) Nicotine. 2009
(86) Ginkgo Biloba, by promoting the expression of HIF-1. 2007
(87) Purslane (Portulaca Oleracea). (Antioxidant). 2007
(88) Fibroblast Growth Factor (FGF): FGF-1, FGF-2, FGF-7, other FGF growth factors. 2003
(89) AP-2 (Activating Enhancer-binding Protein-2). 2007
(90) ER81 Transcription Factor. 2004
(91) C-Abl tyrosine kinase, phosphorylates hTERT. 2002
(92) Protein Phosphatase 2A, phosphorylates hTERT. Telomerase Inhibitor. .
(93) hALP - Histone acetyltransferase hALP, activates hTERT transcription. December 2010.
(94) IL-3 upregulates telomerase in hematopoietic stem cell in vitro cultures. January 2011.
(95) E1A upregulates hTERT transcription by binding to Sp1 sites. 2007
(96) Ets transcription factor upregulates hTERT transcription. 2007
(97) Glucocorticoid "putative" sites upregulate hTERT transcription. 2007
(98) New Symmetrical Bis-Substituted Derivatives of the Anthraquinone. 2003
(99) Tri-Phenyl Compound Telomerase Activators developed at Ben Gurion University. 2008
(100) Enhanced-bioavailability telomerase activators from Geron (2010). 2010
(101) Silver (Ag) upregulates telomerase in immune system cells. 1997
(102) Silymarin activates telomerase. 2010
(103) Sodium Butyrate upregulates Sp1, which upregulates hTERT. .
(104) Trapoxin HDAC inhibitor like Tricostatin A, may upregulate hTERT. .
(105) Fenugreek Seeds & Fenugreek Extract, via Tankyrase, HIF-1 and Diosgenin. 2004, 2006
(106) Folic acid, by phosphorylating cytoplasmic hTERT with AKT. 2009
(107) Epiregulin, an Epidermal Growth Factor family member. 2003
(108) TGF-alpha, (Transforming Growth Factor Alpha) - candidate telomerase activator. 2003
(109) Acetyl L-Carnitine (via NGF production of Id-1). 2002
(110) Cottage Cheese (casein) by upregulating IGF-1 [Index]..
(111) IGF-2, by upregulating progesterone [Index]. 2002
(112) Amphiregulin, EGF family member, via MAP Kinase pathway, candidate. October 27, 2011
(113) HP-EGF (Heparin-binding EGF), EGF family member, via MAP Kinase pathway, candidate. 2002
(114) Betacellulin, EGF family, via MAP Kinase pathway. 2002
(115) Heregulins, EGF family, via MAP Kinase pathway. 2002
(116) Rapamycin rejuvenates progeria cells, extends mouse lifetimes. .
(117) FBX4 overexpression lengthens telomeres. 2006
(118) Nucleostemin lengthens telomeres by degrading TRF1. 2006
(119) TAT153, announced by Geron in 2010. 2010
(120) UP1 Works in UB1=UAGGGU-expressing cells, may be applied exogenously. 1998
(121) Product B from IsAGenix. December 2011.
(122) GRN510 - A new Geron telomerase activator based on a Chinese medicinal herb. April 2012.
(123) Gamma Tocotrienol - A Terraternal report. April 2012.
(124) Bacopa. (136) Bacopa Extract (Product B, List) July 2012
(125) AP-1 transcription factor activator protein. 2005
(126) Astraverrucins. 2005
(127) NAC (N-acetyl-cysteine) activates telomerase in endothelial cells. 2008
(128) Lithium, by upregulating Bcl-2 (75). .
(129) Zinc, by upregulating Bcl-2 (75)..
(130) Arginine, by upregulating Nitric Oxide and HGH..
(131) Citrulline, by upregulating Nitric Oxide and HGH..
(132) Omega-6 < Omega-3 balance can lengthen telomeres in leukocytes.2012
(133) Acacia Bark Extract (Product B, List) lengthens fibroblast telomeres. Antioxidant. 2012
(134) DL-Alpha Lipoic Acid (Product B, List) lengthens fibroblast telomeres. Antioxidant.2012
(135) Asian Ginseng Root Extract (Product B, List) (Panax Ginseng) lengthens fibroblast telomeres.2012
(136) Bacopa Extract (Product B, List) lengthens fibrobast telomeres. See also Bacopa (124).2012
(137) Berberine Rhizome Extract (Coptis Chinensis) (Product B, List) lengthens fibrobast telomeres.2012
(138) Black Tea Extract (Camellia sinensis) (Product B, List) lengthens fibrobast telomeres.2012
(139) Boswellia Fruit Extract (Boswellia serrata) (Product B, List) lengthens fibrobast telomeres.2012
(140) Grape Seed Extract (Vitis vinifera) (Product B, List) lengthens fibrobast telomeres.2012
(141) Green Tea Extract (Camellia sinensis) (Product B, List) lengthens fibrobast telomeres.2012
(142) Harada Fruit Extract (Terminalia Chebula) (Product B, List) lengthens fibrobast telomeres.2012
(143) Hawthorn Fruit Extract (Crataegus pinnatifida) (Product B, List) lengthens fibrobast telomeres.2012
(144) Horny Goat Weed (Epimedium saggittatum) (Product B, List) lengthens fibrobast telomeres.2012
(145) Maca Root Extract (Lepidium Meyenii) (Product B, List) lengthens fibrobast telomeres.2012
(146) Milk Thistle Extract (Product B, List) lengthens fibrobast telomeres.2012
(147) Plantain Leaf Extract, (Product B, List) lengthens fibrobast telomeres.2012
(148) Pomegranate Fruit Extract (Punica granatum) (Product B, List) lengthens fibrobast telomeres.2012
(149) Quercetin (Product B, List) lengthens fibrobast telomeres.2012
(150) Resveratrol (Product B, List) lengthens fibrobast telomeres.2012
(151) Turmeric Root Extract (Curcuma longa) (Product B, List) lengthens fibrobast telomeres.2012
(152) Velvet Bean Extract (Mucuna Pruriens) (Product B, List) lengthens fibrobast telomeres.2012
(153) White Tea Extract (Camellia sinensis) (Product B, List) lengthens fibrobast telomeres. 2012
(154) Thymus Gland Extracts 2010
(155) R1881 (an androgen) 2009
(156) Nucleoside-modified hTERT mRNA (Fast Telomere Extension) 2013
(157) NFAT1 transcription factor 2009
(158) Leptin 2010
(159) Alpha Lipoic Acid (upregulates HSP90) ?
(160) IL-6 growth factor activating STAT3 2005
(161) Echinacoside retards senescence. Candidate. _
(162) Oregano Ligand of Progesterone Receptor. _
(163) Verbena Ligand of Progesterone Receptor. _
(164) Tumeric (Turmeric) Ligand of Progesterone Receptor. _
(165) Thyme Ligand of Progesterone Receptor. _
(166) Red Clover Ligand of Progesterone Receptor. _
(167) Damiana Ligand of Progesterone Receptor. _
(168) Fo-Ti via Strong Estrogen Bioactivity. _
(169) Soy via Strong Estrogen Bioactivity. _
(170) Clover via Strong Estrogen Bioactivity. _
(171) Licorice via Strong Estrogen Bioactivity. _
(172) Hops via Strong Estrogen Bioactivity. _
(173) Tocotrienol-rich fraction (from palm oil, rice bran, oats, or barley). 2011
(174) 5 HTP (weakly via side effects) ?
(175) Stem Cell 100 ?
(176) Teprenone (geranylgeranylacetone) ?
(177) Myocardin A 2007
(178) Garlic (crushed) (for non-cancerous cells, via diallyl disulfide) 1994
(179) TAM-818 best of nearly 300,000. 2014
See also Anticancer Telomerase Activators,
Telomerase Activators Promoting Transcription of hTERT mRNA.


Alphabetical Index for Telomerase Activators under Investigation [> Telomerase Inhibitors]

2OR,25S-epoxy-3β,16β,25-trihydroxy-9β-methyl-19-norlanost-1,5-diene (6f).
5-azacytidine (22). (DANGER: may promote prostate carcinomas).
26-deoxyactein (key Black Cohosh (18) extract saponin)
5-HTP (174) (weakly via side effects).
Acacia Bark Extract (133) (Product B, List) lengthens fibroblast telomeres.
Acetyl L-Carnitine (via NGF) (109).
Akt protein kinase (58), phosphorylates hTERT protein, upregulated by resveratrol & Sphingosine-1-Phosphate.
Alpha-GPC (8d) HGH secretagogue.
Alpha Lipoic Acid (159), by upregulating HSP90.
Amphiregulin (112), EGF family member, via MAP Kinase pathway, candidate.
Androgens can activate telomerase, perhaps after conversion into estrogens (64) [Forskolin].
Angiotensin II (82).
Anti-CD3 monoclonal antibody (mAb) (50).
Antigenic stimulation activates telomerase in T-cells (48).
Antisense oligode-oxyribonucleotides (ODNs) against Bcr-Abl/c-Abl mRNA (61).
Anthraquinone, New Symmetrical Bis-Substituted Derivatives of, (98).
AP-1 transcription factor activator protein (125).
AP-2 (Activating Enhancer-binding Protein-2) (89).
Arginine (130), by upregulating Nitric Oxide and HGH.
Arginine (8e) HGH secretagogue.
Arginine (1500 mg) plus Lysine (1500 mg) (8g) HGH secretagogue.
Arsenic, a poisonous tumor promoter, also elevates hTERT levels (63) Inhibits telomerase.
Asian Ginseng Root Extract (135) (Product B, List) (Panax Ginseng) lengthens fibroblast telomeres.
Astragalus Root (6_) [Index],
Astragalus Root Extract (6_) [Index],
Astragaloside IV (6c).
Astragaloside IV 16-one (6e).
Astragenol (6e).
Astraverrucins (126).
Bacopa (124). (136) Bacopa Extract (Product B, List) lengthens fibrobast telomeres.
Bcl-2 (75).
Ben Gurion University on the Negev, (99) Novel Telomerase Activators developed at.
Berberine Rhizome Extract (137) (Coptis Chinensis) (Product B, List) lengthens fibrobast telomeres.
Betacellulin (114), EGF family member, via MAP Kinase pathway, candidate.
Beta ecdysterone (20-hydroxyecdysone) (54). [Not known to be telomerase activator.]
Bisphenol A (BPA) (11).
Black Cohosh (18). C. racemosa (black cohosh) extracts (26-deoxyacetein) and other Cimicifuga family extracts.
Black Tea Extract (138) (Camellia sinensis) (Product B, List) lengthens fibrobast telomeres.
Bmi-1 protein (66). (Dangerously associated with the breast cancer Bmi-1 oncogene.)
Boswellia Fruit Extract (139) (Boswellia serrata) (Product B, List) lengthens fibrobast telomeres.
Butyric acid, appropriately encapsulated, and (100) Enhanced-bioavailability variants (check).
C3-(L)-isoleucyl-cycloastragenol (100.4), the most enhanced-bioavailability Geron telomerase activator.
4 C3-(L)-valyl-cycloastragenol (100.3), experimental Geron telomerase activator (Nov 18, 2010).
C-Abl tyrosine kinase (91), phosphorylates hTERT.
Ca ionophore (51) .
Carnosic Acid promotes Nerve Growth Factor to activate Id-1 helix-loop-helix protein transcription (73).
Cimicifuga (18). C. racemosa (black cohosh) extracts (26-deoxyacetein) and other Cimicifuga family extracts.
Citrulline (131), by upregulating Nitric Oxide and HGH.
C0057684 (37), (47) from Sierra Sciences.
C0313741 (37b) from Sierra Sciences.
CD40 [or Surface Ig (31)] activates telomerase in memory B-cells.
CDP-choline (8c) HGH secretagogue.
CGK733 (23). Revives senescent cells, but not a true telomerase activator.
CGK 1026 (19). CGK 1026 derepresses hTERT expression. Used in therapy to replace Tricostatin A.
Clover (170) via Strong Estrogen Bioactivity.
c-Myc (59) is upregulated by EGF, Colostrum, estradiol and PDGF.
Cocoa (44). [Not known to be a telomerase activator.]
Colostrum (68) (Contains EGF (30)).
Cottage Cheese (casein) (110) by upregulating IGF-1 [Index].
Curcumin (151) (turmeric root extract), for normal cells.
Cycloastragenol (6d). Same as Geron TAT2, or TAT0002, the primary TA-65 ingredient.
Cycloastragenol 3-β-D-xylopyranoside (6h).
Cycloastragenol 6-β-D-glucopyranoside (6g).
Damiana (167) Ligand of Progesterone Receptor.
DHA (8i) HGH secretagogue by boosting dopamine.
DHEA (Dihydroepiandrosterone) (71).
Diosgenin promotes HIF-1 (Hypoxia-inducible factor 1) (24).
DL-Alpha Lipoic Acid (134) (Product B, List) lengthens fibroblast telomeres. Antioxidant.
DMSO (Dimethyl Sulfoxide) (29). [Telomerase Inhibitors/Dimethyl Sulfoxide (DMSO) (46)].
Dopamine (8a) HGH secretagogue.
Doxycyclin (35b). Can stain teeth. Presence or absence of telomere growth can depend on the presence of doxycyclin.
E1A (95) upregulates hTERT transcription by binding to Sp1 sites.
E6/E6AP viral protein, a ubiquitin ligase from human papilloma virus (65). Poisonous.
Ecdysone (16). An insect hormone.
Echinacoside (161) retards senescence. (Candidate).
Enhanced-bioavailability telomerase activators (100) from Geron in 2010.
Ependymin Peptide (26). From goldfish brains: sequence ESCKKETLQFRKHL.
Epidermal growth factor EGF (30).
Epithelial Growth Factor (EGF) (83)
Epiregulin (107), an Epidermal Growth Factor family member.
Epithalon peptide (1) (Ala-Glu-Asp-Gly). Injectable. Discovered in 2003.
ER81 Transcription Factor (90).
EST1, for yeast (7).
EST1p, for yeast under (7) including its homologue hEST1A in humans and yeast EST1.
Estrogen (10). and Telomerase Activators via Strong Estrogen Bioactivity.
Estrogen Receptors (1318) - entry (10b)
Ets transcription factor (96) upregulates hTERT transcription.
Exercise (81).
Exercise (8h) HGH secretagogue.
FBX4 (117) overexpression lengthens telomeres.
Fenugreek Seeds & Fenugreek Extract (105) via Tankyrase, HIF-1 and Diosgenin.
FGF-1 (88).
FGF-2 (53).
FGF-7 (88).
Fibroblast Growth Factor (FGF) (88): FGF-1, FGF-2, FGF-7 and other FGF growth factors.
Fibroblast Growth Factor 2 (FGF-2) (53).
Folic acid (106), by phosphorylating cytoplasmic hTERT with AKT.
Forskolin [Index] (Androgens (64), Testosterone) for muscles, heart cells.
Fo-Ti (168) via Strong Estrogen Bioactivity.
FR901228 (39). (Romidepsin) Japanese research at Okayama University.
GABA (8k) [Index], an HGH [List] secretagogue.
Gamma Tocotrienol (123). A Terraternal report.
Garlic, crushed (178) (for non-cancerous cells, via diallyl disulfide).
Geranylgeranylacetone (Teprenone) (176).
Ginkgo Biloba (86), by promoting the expression of HIF-1. Also taken with astragalus extract to improve circulation.
Ginsenoside Rg1 (45).
Ginsenoside RH1 (6e).
Glucocorticoid "putative" sites (97) upregulate hTERT transcription.
? Gotu Kola ? (69). Taken with astragalus extract to improve circulation.
G-CSF: Granulocyte Colony-Stimulating Factor (56).
Grape Seed Extract (140) (Vitis vinifera) (Product B, List) lengthens fibrobast telomeres.
Green Tea Extract (141) (Camellia sinensis) (Product B, List) lengthens fibrobast telomeres.
GRN139951 (Geron) (5). (Probably astragaloside IV.)
GRN510 (122) - A new Geron telomerase activator based on a Chinese medicinal herb.
hALP - Histone acetyltransferase hALP, activates hTERT transcription (93).
Harada Fruit Extract (142) (Terminalia Chebula) (Product B, List) lengthens fibrobast telomeres.
Haritaki (Terminalia chebula, Combretaceae), ethanol extract. (67) (Antioxidants.)
Hawthorn Fruit Extract (143) (Crataegus pinnatifida) (Product B, List) lengthens fibrobast telomeres.
Heat shock proteins (20). Heat shock proteins like Hsp90 mediate telomerase assembly.
hEST1A,the human homologue of yeast EST1p (See also (76)), in (7) with EST1 for yeast.
Hepatocyte Growth Factor (78).
Heregulins (115), EGF family member, via MAP Kinase pathway, candidate.
HP-EGF (113) (Heparin-binding EGF), EGF family member, via MAP Kinase pathway, candidate.
HIF-1 (24). Hypoxia-inducible factor 1 (HIF-1).
Histone deacetylase inhibitor possibilities (12). Other HDAC inhibitor possibilities.
HGH, Human Growth Hormone (8), via HGH secretagogues (8a)-(8i).
Hops (172) via Strong Estrogen Bioactivity.
Horny Goat Weed (144) (Epimedium saggittatum) (Product B, List) lengthens fibrobast telomeres.
hRAP1 (36).
Id-1 helix-loop-helix protein (73), upregulated by Nerve Growth Factor.
IGF-1 (9).
IGF-2 (111), by upregulating progesterone [Index].
IL-2, Interleukin 2 (3). Injectable.
IL-3 (94) upregulates telomerase in hematopoietic stem cell in vitro cultures.
IL-6 (160) growth factor activating STAT3.
IL-7, Interleukin-7 (32), appears to stimulateS expression of telomerase within T-cells.
IL-15, Interleukin-15 (33) stimulates telomerase in T-cells.
Interleukin 2 (3).
IRF4 - Interferon Regulatory Factor 4 (and to a lesser degree IRF8), (70).
Juve Tea (49).
Leptin (158).
Licorice (171) via Strong Estrogen Bioactivity.
Lithium (128), by upregulating Bcl-2 (75).
Lysophosphatic Acid (80).
Maca Root Extract (145) (Lepidium Meyenii) (Product B, List) lengthens fibrobast telomeres.
Melatonin (8j) HGH secretagogue. May be a telomerase inhibitor for cancer cells only.
Milk Thistle Extract (146) (Product B, List) lengthens fibrobast telomeres.
Mre11 (25). Mre11 protein.
Mucuna Pruriens (8b) HGH secretagogue.
Myocardin A (177).
NAC (N-acetyl-cysteine) (127) activates telomerase in endothelial cells.
Nerve Growth Factor activates Id-1 (73). Rosemary, Carnosic Acid, Acetyl L-Carnitine, Huperzine A up NGF.
Resveratrol (58b). Phosphorylates hTERT via Akt Protein Kinase.
NFAT1 transcription factor (157).
NF-kappaB (40). [Transcription factor, for inflammatory cytokines.]
Nicotine (85).
Nitric Oxide (21).
Novel Telomerase Activators developed at Ben Gurion University on the Negev. (46)
Nucleoside-modified hTERT mRNA (156) (Fast Telomere Extension).
Nucleostemin (118) lengthens telomeres by degrading TRF1.
Okadaic acid (34). Poisonous
Omega-6 < Omega-3 balance (132) can lengthen telomeres in leukocytes.
Oregano (162) Ligand of Progesterone Receptor.
Ornithine (8f) HGH secretagogue.
Plantain Leaf Extract (147), (Product B, List) lengthens fibrobast telomeres.
Platelet Derived Growth Factor (PDGF) (38).
Phorbol 12, 13-dibutyrate (52).
Pomegranate Fruit Extract (148) (Punica granatum) (Product B, List) lengthens fibrobast telomeres.
Portulaca Oleracea (Purslane) (87). (Antioxidant.)
Phosphatidylinositol 3'-kinase (57).
Pregnenolone. (72)
Product B (121) from IsAGenix.
Progesterone (60) and Ligands of Progesterone Receptor (60.1 - 60.7).
Protein kinase C (27).
Protein Phosphatase 2A (92), phosphorylates hTERT. Telomerase Inhibitor.
Purslane (Portulaca Oleracea) (87). (Antioxidant.)
Quercetin (149) (Product B, List) lengthens fibrobast telomeres.
Raloxifine (15). (orally bioavailable Evista from Eli Lilly).
Replication Protein A (76) might be upregulated by Sodium Butyrate or Sodium 4-Phenylbutyrate (check).
R1881, (155) (an androgen).
Rapamycin (116) rejuvenates progeria cells, extends mouse lifetimes.
Red Clover (166) Ligand of Progesterone Receptor.
Resveratrol (150) (Product B, List) lengthens fibrobast telomeres.
Resveratrol (84) (See also (58) Akt with (58b) Resveratrol).
Retinoic acid (28). [Telomerase Inhibitors/Retinoic Acid (27)]. Limits p16INK4A.
Romidepsin (39) (FR901228).
Rosemary Extract promotes Nerve Growth Factor to activate Id-1 (73).
Saquinavir (17). (Invirase [Roche Invirase]) an anti-HIV drug and protease inhibitor.
?Shark Liver Oil? (42) [Not known to be a telomerase activator.]
Silver (Ag) (101) upregulates telomerase in immune system cells.
Silymarin (102) activates telomerase.
Simvastatin upregulates Bcl-2 (75), a telomerase activator.
Sodium Butyrate (103) upregulates Sp1, which upregulates hTERT.
Soy (169) via Strong Estrogen Bioactivity.
Sp1 (43) is upregulated by sodium butyrate, and down-regulated by low insulin.
Sphingosine-1-Phosphate (S1P). (79)
STAT3 (14).
Stem Cell 100 (175)
Stem Cell Factor (Kitl) - (74).
Surface Ig (31).
Survivin (62).
TA-65 (TA Sciences) (6b). (Formerly GRN-665, Probably cycloastragenol, or Geron TAT0002.)
TAC1 with auxin (13).
Tankyrase (35). A telomeric PARP phosphorylated by insulin and promoted by Niacinamide.
TAM-818 (179) best of nearly 300,000.
TAT2 (Geron) (4). (TAT2 is cycloastragenol, the common alglycone of the astragalosides).
TAT0002 (Geron) (4). (TAT0002 is cycloastragenol, the common alglycone of the astragalosides).
TAT153 (119), announced by Geron in 2010.
Teprenone (geranylgeranylacetone) (176).
Terminalia chebula (Combretaceae), the ethanol extract (67). (Antioxidant.)
Testosterone (64a), an Androgen.
TGF-alpha (108), (Transforming Growth FActor Alpha) - candidate telomerase activator.
Thyme (165) Ligand of Progesterone Receptor.
Thymus Gland Extracts, (154).
TNF-alpha (41). [Inflammatory]
Tocotrienol-rich fraction (173) (from palm oil, rice bran, oats, or barley).
Trapoxin (104) is an HDAC inhibitor like Tricostatin A, may upregulate hTERT.
Tricostatin A (2). Injectable. Discovered as a telomerase activator in 2000.
Tri-Phenyl Compound Telomerase Activators (99) developed at Ben Gurion University.
Turmeric Root Extract (151) (Curcuma longa) (Product B, List) lengthens fibrobast telomeres.
Tumeric (Turmeric) (164) Ligand of Progesterone Receptor.
UP1 (120) Works in UB1=UAGGGU-expressing cells, may be applied exogenously.
Uncaria sinensis Havil (77) Retards telomere shortening.
VEGF2 & VEGFA (55), Vascular Endothelial Growth Factor (VEGF).
Velvet Bean Extract (152) (Mucuna Pruriens) (Product B, List) lengthens fibrobast telomeres.
Verbena (163) Ligand of Progesterone Receptor.
White Tea Extract (153) (Camellia sinensis) (Product B, List) lengthens fibrobast telomeres.
Wild Yam, via Diosgenin promotion of HIF-1 expression activating hTERT transcription.
Zinc (129), by upregulating Bcl-2 (75).
See also Anticancer Telomerase Activators and
Telomerase Activators Promoting Transcription of hTERT mRNA.

Selected Telomerase Activators
(Cycle, 2 weeks telomerase activators, then 2 weeks telomerase inhibitors with anticancer nutraceuticals.)
Telomerase Activator Type Pathway Cells Impacted Supplements for
Astragalus Root
(best, 15-33 grams/day),
Astragalus Root Extract
(2nd best, < 11 grams/day),
Astragaloside IV
[Index, List]
(worst).
cycloartane saponin Transcribes hTERT mRNA,
MAP Kinase Pathway (chk)
Phosphorylates hTERT
via PI3K/AKT pathway.
Stimulates HIF-1 accumulation in hypoxia.
All Cells (check)
Penetrates the cell membrane directly.
Low bioavailability.
Astragalus Extract,
Astragalus Root
(divided doses
of 1-6 grams
every 2-3 hours,
less than 33 grams/day.)
Astragaloside IV
(100 mg/dose,
1 dose per day,
or divided doses
each 2-3 hours.)
Black Cohosh
[List]
C. Racemosa
[L.Nutt]
Phytoestrogen
(26-deoxyactein
(a triterpene glycoside),
fukinolic acid)
estrogenic pathway,
(unknown, check).
Can be feminizing.
Check cells.
Binds in estrogen-responsive cells.
Black Cohosh extract,
Remifemin.
Safer than low-dose estrogen.
CGK1026
[Index, List]
HDAC Inhibitor Transcribes hTERT mRNA, derepresses transcription of hTERT.
All Cells (check).
Penetrates cell
membranes directly.
Orally bioavailable.
Experimental chemical.
Colostrum
[Index, List, Wiki]
Early Mothers Milk Transcribes hTERT mRNA,
Phosphorylates hTERT,
MAPK pathway, contains
the telomerase activators IGF-1, IGF-2, EGF, TNF-alpha, FGF, PDGF, VEGF, and TGF-alpha.
All cells (check) Colostrum supplements.
Cycloastragenol
[Index, List],
Evaluation: nearly
constant telomere lengths.
cycloartane saponin Transcribes hTERT mRNA,
Map Kinase Pathway,
Phosphorylates hTERT.
All Cells (check)
Penetrates cell membrane directly.
Good bioavailability.
Cycloastragenol
(25 mg/dose,
1 dose/day,
or divided doses
each 2-3 hours.)
TAT2,
TA-65.
Cycoastragenol is a component of
Astral Fruit NF.
Ecdysone
[List, Wiki]
Steroid hormone,
(insect)
Transcribes hTERT mRNA In vitro cells, or
transgenic animals.
Review methods for installing a transgene for hTERT than can be switched on or off using ecdysone switching technique based on Cre-mediated inversion.
Experimental.
For lab experiments on cells and transgenic animals.
Epidermal
Growth Factor

(EGF) [List, Wiki]
Growth Factor Transcribes hTERT mRNA,
via the MAP Kinase pathway
c-Myc transcription factor.
Many tissues,
skin
EGF skin creams
[EGF],
Growth Factor Skin Creams
Estrogen
[Index, List]
Sex Hormone
(Steroid Hormone)
Transcribes hTERT mRNA,
via the estrogen receptor, estrogen,
and histone acetyl transferase
transcription factor complex
featuring dimerized estrogen receptor. Can be feminizing.
Many tissues,
skin
Estradiol
(some danger)
Exercise
[Index, List]
Physical Therapy Transcribes hTERT mRNA,
Phosphorylates hTERT
via HGH, IGF-1, HIF-1, PDGF, Epiregulin, TGF-alpha, Testosterone, TNF-alpha, Estrogen, HSP90, IL-2, Nitric Oxide, and TGF-alpha.

Many tissues (check) Physical Therapy,
Bodybuilding,
Anabolic drugs, Alpha GPC,
Arginine,
Citrulline,
Whey Protein,
Testosterone.
Fenugreek
[Index, List]
Seed,
Seed Extract,
Saponins
Transcribes hTERT mRNA
via phytoestrogen diosgenin,
using HIF-1
transcriptional activation.
Phosphorylates Tankyrase
by elevating insulin.
Transcribes hTERT mRNA.
Phosphorylates hTERT.
p38 Map Kinase pathway,
PI3K/Akt pathway.
Can be feminizing.
Many tissues (check) Fenugreek Seed,
Fenugreek Extract
FGF1
[List]
Growth Factor Activates telomerase,
(Pathway obscure)
Many tissues (check),
Skin,
Extracellular Matrix.
FGF1 skin creams,
Growth Factor Skin Creams.
FGF2
[List]
Growth Factor Activates telomerase,
(Pathway obscure)
Many tissues (check),
Skin.
FGF2 skin creams,
Growth Factor Skin Creams,
Curcumin.
FGF7
[List]
Keratinocyte Growth Factor
Growth Factor Activates telomerase,
(Pathway obscure)
Many tissues (check),
Hair Follicles.
FGF7 skin creams,
Growth Factor Skin Creams.
Gamma tocotrienol
[List]
Annatto Lengthens telomeres.
Tissues unknown.
Annatto supplements
Ginkgo Biloba
[Index, List]
Ginkgolides Phosphorylates hTERT
via PI3K/AKT kinase pathway,
Uses HIF-1 activation
to transcribe
hTERT mRNA.
Many tissues (check),
Vascular tissues.
Ginkgo Biloba Extract, Ginkgolides.
HGH
[Index, List]
Growth Hormone,
an endocrine hormone circulating in the blood.
Transcribes hTERT mRNA,
PI3 Kinase Pathway,
direct activation (review).
All Cells (check) Exercise,
Alpha-GPC,
Arginine
HSP90
[Index, List]
Heat Shock Protein Enables hTERT mRNA
transcription.
All Cells (check) Exercise,
Alpha Lipoic Acid.
IGF-1
[Index, List, Wiki]
Growth Factor.
An autocrine/paracrine
hormone made from
HGH in the liver,
not an endocrine hormone circulating in the blood.
Phosphorylates hTERT,
PI3K/AKT pathway.
All Cells (check).
Requires cell surface
IGF-1 receptor.
Exercise,
casein
(cottage cheese).
IL-2
[Index, List]
Inflammatory Cytokine Phosphorylates hTERT Lymphocytes Exercise
Milk Thistle Extract
[Index, List (146)]
(Silymarin [Index, List (102)])
Anti-inflammatory,
anticancer drug,
conserves the endogenous antioxidant glutathione.
Transcribes hTERT mRNA
in healthy human fibroblasts
(empirical).
Human fibroblasts
Silymarin,
Milk Thistle Extract,
Milk Thistle,
Product B.
Nerve Growth Factor
[Index, List]
Growth Factor Transcribes hTERT mRNA
via ID-1 transcription factor.
Nerve cells,
other cells.
Acetyl L-Carnitine,
Rosemary,
Carnosic Acid,
Huperzine A,
Platelet-Activating Factor.
Nitric Oxide
[Index, List]
Vasodilator (obscure) Endothelial cells,
Endothelial progenitors.
Exercise,
Arginine,
Citrulline
PDGF
[List]
Platelet-Derived Growth Factor
Growth Factor Transcribes hTERT mRNA
by elevating c-Myc,
MAP Kinase pathway,
phosphorylates Tankyrase.
(Check tissues)
Exercise
Progesterone
[Index, List]
Sex Hormone
(Steroid Hormone)
Transcribes hTERT mRNA,
MAP Kinase Pathway
Can be feminizing.
Many tissues,
Skin.
Small molecule penetrates cell membrane directly.
Progesterone,
skin creams
Testosterone
[Index, List]
Sex Hormone
(Steroid Hormone)
Transcribes hTERT mRNA via
testosterone, androgen receptor,
and cofactors in the transcription factor complex featuring dimerized androgen receptor. Also via estrogen from aromatase (as crosstalk). Can be defeminizing.
Muscles,
Hair Follicles,
Hematopoietic Stem Cells
Testosterone,
Exercise,
Forskolin
TNF-alpha
[Index, List]
Inflammatory Cytokine Phosphorylates hTERT,
Transcribes hTERT mRNA (check).
Leukocytes,
other tissues (check).
Exercise
Tricostatin A
[Index, List]
HDAC Inhibitor Accelerates hTERT mRNA
transcription by
expanding chromatin.
All cells (check) Tricostatin A
(by injection)
VEGF
[List]
Vascular Endothelial
Growth Factors
VEGFA and VEGF2.
Growth Factor Transcribes hTERT mRNA
All cells (check) VEGF
Growth Factor Skin Creams
See also Anticancer Telomerase Activators and
Telomerase Activators Promoting hTERT mRNA Transcription.
(Provisional, subject to correction.)

(1) Epithalon peptide [(Ala-Glu-Asp-Gly), WikiGenes, Links, Images, Video, Papers, Patents, Books, Khavinson.ru/downloads, Prof. Vladimir Khavinson: Peptide Bioregulation of Ageing, IMMINST/Forum/epitalon (aka epitalon) (Khavinson article preview); Geometric Structure Determination, Images/Epithalon peptide molecule; toxicity; See also Endoluten for premature aging and Peptides Store]. Epithalon peptide has the structure Ala-Glu-Asp-Gly. It is a peptide bioregulator taken by injection or orally in a epitalon aspartame longevity sweetener. An orally bioavailable form is also described by epitalon.net. Epithalon peptide was initally discovered in pineal gland extracts in 2003 by the St. Petersburg Institute of Bioregulation and Gerontology. Incidentally, it has been determined that grafting old pineal glands into mice accelerates their aging [Walter Pierpaoli and Daniele Bulian, 2001]. Perhaps epithalon peptide can be taken in a liposomal spray, like IGF-1. (See liposomal administration of small peptides). The Russian group [Links] announced in 2003 that Epithalon Peptide, a small 4-peptide protein made from alanine, glutamine, aspartic acid, and glycine (Ala-Glu-Asp-Gly) activates telomerase and extends telomeres [Links, Papers, Original Paper, sources, sources2]. See V. Kh. Khavinson, I.E.Bondarev, and A.A.Butyugov (2003), Epitalon Peptide Induces Telomerase Activity and Telomere Elongation in Human Somatic Cells [PDF], Bulletin of Experimental Biology and Medicine, vol. 135, No. 6, June 2003.
Epithalon peptide has been injected 5 times weekly into mice, resulting in 34.2% prolongation of life span in mice without cancers. Sublingual (under the tongue) administration is probably possible with such short peptide molecules. Epithalon peptide may be the safest telomerase activator, since it occurs naturally in the body, and was first isolated from the pineal gland (epiphysis). It is generally geroprotective (mice do not die from telomere shortening), and perhaps telomere homeostasis may be maintained by routine daily use at some specific dosage per kilogram of body weight. On the other hand, we are expecting cyclic treatments of periods on followed by periods off the drug to become standard with this and similar medicines. See Custom Peptide Synthesis [Books, Papers], Peptide Synthesis [Wikipedia, Books], Peptide Sythesizers [Books, Suppliers], Peptide Analyzers [Links]. Vilon [Papers] is a peptide bioregulator (Lys-Glu) that is geroprotective and inhibiting to apoptosis that is sometimes studied together with the geroprotective telomerase activator epithalon peptide (Ala-Glu-Asp-Gly). Epithalon peptide [video] has been offered in a longevity sweetener (epitalon aspartame longevity sweetener) and has been proposed for inclusion into rice (longevity rice) by genetic engineering. See the hTERT activation pathway for epithalon peptide or the epithalon peptide hTERT activation pathway.
(2) Tricostatin A. Tricostatin A (TSA) [WikiGenes/Trichostatin A, Wikipedia, Links, Images, Video, Papers, Patents, Books, Papers/trichostatin A and telomerase activation, Epigenetic Protocols, chap.8, article, article2, anticancer, elevates Hsp22 level with life-extending effect; Images/Tricostatin A molecule; toxicity; sources costs < $100/mg].

Tricostatin A
Tricostatin A (C17H22N2O3), the first small molecule telomerase activator discovered circa the year 2000, a histone deacetylase inhibitor (HDAC inhibitor), has FDA approval for use in anticancer therapy. Human deacetylase activity (from HDAC1p, HDAC3 or other human HDAC genes) is inhibited by trichostatin, trapoxin, and butyrate [Index] in vitro. Tricostatin A is expensive and typically taken by injection, whereas butyrate is readily available, inexpensive, and taken as a pill. Again, perhaps a liposomal spray might be a useful method of application, or perhaps a transdermal patch would be an effective. Tricostatin A induced significant activation of hTERT mRNA expression and telomerase activity in normal cells, but not in cancer cells." Histone deacetylase inhibitor trichostatin A "activates the hTERT promoter in normal cells", thus enabling telomerase synthesis. Trichostatin A is genotoxic at some dosages. See sources, books, papers and links on treatment with trichostatin A, which is experimentally promising in published studies on stimulating hTERT expression for telomerase synthesis and telomere enlongation.
"Just read that tricostatin A inhibits telomerase in prostate tumor cells. However, in cells with telomerase inactivated it increased the activity. Tricostatin A can be bought in USA, but I'll need to figure correct dosage and what this costs. See Hau, M., X. Wang, N. Popov, A. Zhang, X. Zhao, R.Zhou, A. Zetterberg, M. Bjorkholm, M. Henricksson, A. Gruber, and D. Xu (2002), The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells, Experimental Cell Research 274: 25-34. See Annamaria Biroccio and Carlo Leonetti, 2004, Telomerase as a new target for the treatment of hormone-refractory prostate cancer, Endocrine-Related Cancer, 2004, 11 (3) 407-421. It has been demonstrated that tricostatin A (TSA), a potent HDAC inhibitor, was able to reduce telomerase activity in liver and prostate cancers by decreasing the levels of the hTERT mRNA (Suenaga et al. 2002). On the contrary, other groups have shown that TSA induced a significant activation of hTERT mRNA and telomerase activity in telomerase-negative cells (Cong & Bacchetti 2000) and attenuated the repression of hTERT during HL60 cell differentiation (Xu et al. 2001)." (Andrew 1/04/08). Trichostatin A [Links] can stop the cell cycle at the beginning of the growth stage and is positioned as an antifunqual antibiotic these days, usually presented as harmful if taken orally and not for human consumption. See also Mashiro Takakura, Satoru Kyo, Yoshihiro Sowa, Zhuo Wang, Noriyuki Yatabe, Yoskiko Maida, Masaaki Tanaka and Masaki Inoue, 2001, Telomerase activation by histone deacetylase inhibitor in normal cells, Nucleic Acids Research, 2001, vol 29, no. 14, 3006-3011. This article reviews application of Tricostatin A. "Transient expression assays revealed that Tricostatin A activates the hTERT promoter. Furthermore, the proximal 181 bp core promoter of hTERT, which contains two c-Myc and five Sp1 sites, was determined to be the responsible element. Overexpression of Sp1 enhanced responsiveness to Tricostatin A, and mutation of Sp1 sites, but not c-Myc sites, of the core promoter of hTERT abrogated this activation. Introduction of the dominant-negative form of the Sp family inhibited Tricostatin A activation. These results indicate that HDAC inhibitor activates the hTERT promoter in normal cells, in which Sp1 plays a key role." See Papers/the hTERT activation pathway for Tricostatin A or Papers/the Tricostatin A hTERT activation pathway.
"Modification of the chromatin landscape can be modulated chemically using the histone deacetylase inhibitor TSA and the DNA methylation inhibitor 5-aza-dC in combination. Expression of hTR and hTERT could be reactivated in telomerase negative cell lines... This was accompanied by increased association of acetylated H3 and H4 (histones), consistent with (elevated) expression levels." (C.J. Cairney and W.N. Keith, 2007). "Alternatively, HDAC inhibitors induce p21WAF1 expression in cancer cells probably through histone-acetylation of the promoter (Sowa et al., 1999; Richon et al., 2000). This may play an important role in the arrest of cell growth or cellular differentiation, leading to indirect inhibition of telomerase activity." - after 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 (5) Histone Deacetylase Inhibitors, Oncogene, 21 January 2002, Volume 21, Number 4, Pages 688-697.

(3) Interleukin 2 [Index, Oxford_Journals/Interleukin 2, Wikipedia, WikiGenes, Links, Images, Video, Papers, Patents, Books; Images/Interleukin-2 molecule; toxicity]. IL-2 is usually described as a proinflammatory/catabolic cytokine like IL-1alpha, IFN-gamma, and TNF-alpha; anti-inflammatory or anabolic cytokines and growth factors include IL-4, IL-10, HGH, and IGF-1. Interleukin 2 acts on lymphocytes. This is a larger molecule of about 15,500 Daltons, a polypeptide of 133 amino acids (still capable of passing through the nuclear pore), the cytokine also termed IL-2 (interleukin 2), a "lymphokine" which augments the expression of mRNA for human telomerase in T-cell lymphocytes. IL-2 "has been approved by the Food and Drug Administration (FDA) for the treatment of cancers (malignant melanoma, renal cell cancer), and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines." - [Wikipedia]. Interleukin 2's telomerase-enhancing role in T-lyphocytes has been noted by other investigators. I think it is only taken by injection. Perhaps it could be applied in liposomes or in a liposomal spray. [Papers/IL-2 and telomerase activation; Papers/interleukin-2 and telomerase activation, Links, Books, article]. See also Yuuki Matsumura-Arioka, Kiyoshi Ohtani, Toshifumi Hara, Ritsuko Iwanaga and Masataka Nakamura, (2005), Identification of two distinct elements mediating activation of telomerase (hTERT) gene expression in association with cell growth in human T cells, International Immunology, 2005, 17(2):207-215. Interleukin 2 seems to activate hTERT via the PI3K/Akt pathway. See K Kawauchi, K Ihjima, O Yamada (2005), IL-2 increases Human Telomerase Reverse Transcriptase Activity transcriptionally and posttranslationally through Phosphatidylinositol 3'-Kinase/Akt, Heat Shock Protein 90, and Mammalian Target of Rapamycin in Transformed NK Cells., The Journal of Immunology, 2005. Activation via AKT protein kinase means that hTERT molecules outside the cell nucleus are phosphorylated for import from the cytoplasm into the nucleus. No new hTERT mRNA transcripts are created, because AKT (Index/AKT) is a kinase on a mission to phosphorylate (Index) hTERT protein, not a transcription factor to bind to the hTERT promoter. Exercise elevated expression of telomerase-activating IL-2 (1.43 fold) and TNF-alpha (1.5 fold) in 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. Melatonin upregulates IL-2 and also HGH, both telomerase activators, although melatonin (List) is on the list of telomerase inhibitors. Perhaps melatonin is only a telomerase inhibitor for cancer cells, and a telomerase activator otherwise, as has been seen many times with other drugs. Since melatonin is a powerful antioxidant, it probably tends to keep hTERT inside the nucleus. See Papers/the hTERT activation pathway for Interleukin-2 or Papers/the Interleukin-2 hTERT activation pathway.

(4) TAT0002 See Index/TAT2 [Links/Geron TAT2, Images, Video, Papers, Patents, Books] and Index/TAT0002 [Links/Geron TAT0002, Images, Video, Papers, Patents, Books]. TAT0002 (orally bioavailable cycloastragenol, Press for more molecular models of cycloastragenol.molecule image), announced by Geron and a subsidiary TA Therapeutics. See the toxicity of cycloastragenol. TAT0002 [Links] is presently used in AIDS therapy. It may become useful in life extension work, say on the skin, now to involve telomerase activation therapies. [Papers/TAT0002].
According to a source at the Immortality Institute, "Telomerase induction (was) tested originally using a 10:1 95% ethanolic extract of Astralagus root (this extract was called GRN925 [from Formulations Containing Astagalus Extracts and Uses Thereof, WIPO DOC], the preparation of which is described in the 2005 Hong Kong patent Formulations Containing Astragalus Extracts and the Uses Thereof, European Patent Office, on page 37 as "Example 1".). See Images/astragalus membranaceus. The most potent compound in the extract seems to be orally bioavailable astragaloside IV (Index, probably TAT0001) or cycloastragenol [Links], one of which which may be the GRN-665 (TA-65) TAT0002 molecule." Note that cycloastragenol is also associated with the names "Astral Fruit-C" from RevGenetics, "astramembrangenin" [Links, Papers, Books, Amazon], "cyclogalegigenin" [Books, Links, Papers, Amazon, molecule], and "cyclosiversigenin" [Links, Books, Papers, Amazon]. See 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, Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes, The Journal of Immunology, 2008, 181: 7400-7406. Test of telomerase activator TAT2. "Enhanced antiviral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation." See also the associated Geron News Release.
Activation pathway for TAT2: "...our data suggest that TAT2 up-regulates telomerase activity via activation of the MAPK pathway [Index] and subsequent increase in hTERT mRNA and/or active phosphorylated forms of hTERT protein [Images]...", Steven Russell Fauce, Beth D. Jamieson, et al, (2008), Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes, The Journal of Immunology, 2008, 181, 7400 -7406. It seems to me that cycloastragenol may be one of the best telomerase activators for skin creams [Index] and for eyedrops [Index], although these were not recently commonly available. See Index/hTERT protein phosphorylation, Papers/the hTERT activation pathway for TAT2 or Papers/the TAT2 hTERT activation pathway.

(5) Geron's GRN139951 (probably orally bioavailable astragaloside IV, Index/Astragaloside IV) [Links, Images, Video, Papers, Patents, Books; toxicity]. "Geron Corporation, in collaboration with the Biotechnology Research Institute, Hong Kong University of Science and Technology, conducted a screen for telomerase activators using human keratinocytes. The source of material for the screen was natural product extracts. In the course of the screen, several extracts were discovered that reproducibly up-regulated the low, basal level of telomerase in human keratinocytes. With analysis of the extract and further testing, one compound in the extract, named GRN139951, was identified as the key telomerase activator in the extract. It was capable of activating telomerase in keratinocytes and other human cell types (e.g. lymphocyte immune cells) at very low concentrations. GRN140665 (probably cycloastragenol), a derivative of GRN139951 also present in the extract but at lower concentrations, was prepared and found to possess similar telomerase activating properties. (I note that cycloastragenol may be chemically derived from Astragaloside IV by a process involving acid hydrolysis described in Geron's patent Compositions and Methods for Increasing Telomerase Activity.) See the toxicity of cycloastragenol. These molecules are under development for the treatment of degenerative diseases by TA Therapeutics, Limited." - BioExchange News See Geron's Compositions and Methods for Increasing Telomerase Activity (or see the A' alternate-source version Compositions and Methods for Increasing Telomerase Activity, or A'') and Hong Kong University's Formulations Containing Astragalus and Uses Thereof. Note that astragalus polysaccharides [Links, Images, Video, Papers, Patents, Books] include the cycloartane glycosides [Links, Images, Video, Papers, Patents, Books], including astragalosides I-IV. I note that the astragaloside molecules are somewhat reminiscent of steroid hormones in their structure, suggesting that perhaps they interact with receptors similar to the steroid receptor superfamily of transcription factors, which bind directly to DNA gene promoters to stimulate transcription. Astragalosides are very likely hydrolyzed by stomach acids into cycloastragenol (TAT2), so that the MAPK pathway [Index] is used by astragaloside IV to activate hTERT in the same manner as for TAT2. Astragaloside IV may be useful for skin cream and eyedrops, as well as for internal consumption as an orally bioavailable telomerease activator. Studies at VIDA Institute suggest that large doses of astragalus root extract are more effective.
Skin Cream TypeBrandTelomerase Activator LinksCost
Astragaloside IV skin creamTerraternal Astragaloside IV skin creamAstragaloside IV$75.00
See Papers/the hTERT activation pathway for Astragaloside IV or Papers/the Astragaloside IV hTERT activation pathway.

(6) Geron's GRN140665 (probably orally bioavailable cycloastragenol, or TAT2). [Links, Images, Video, Papers, Patents, Books; toxicity].

(6b) TA Sciences [TA Sciences back pages] and Geron have announced orally bioavailable TA-65. Advertising seemed initially to suggest that TA-65 would be GRN-665 and probably cycloastragenol, that is, TAT2), "a naturally occurring molecule extracted from the well known Traditional Chinese herb Astragalus," meaning the traditional Chinese medicinal herb Astragalus Membranaceus [Index], also called Huang-qi, or Milk-Vetch Root. However, recent advertising (2010) suggests that TA-65 may be astragaloside IV or astragalus extract. By keeping the identity of TA-65 secret, the company can always improve TA-65. [Monograph/Astragalus, Tech Data/Astragalus, PDRHealth/astragalus, HerbalMed] Astragalus root and Astragalus root extract [Index, Books] are commercially available from Gaia Herbs [product], Solaray, Herb Pharm, and Nutrition Geeks, which do not explain how to use Astragalus Membranaceus for telomere extension. [Links, LifeExtension/Astragalus, Ray Sahelian/Astragalus, Wikipedia/Telomerase and Astragalus, Wikipedia/Astragalus, Univ. of Maryland Medical Center/Astragalus]. See astragalus and telomerase activation [Links, Images, Video, Papers, Books]. "Astragalus deters aging process and facilitates longevity. It delays the natural aging process of diploid blastocyte, prolonging by one third the life span of the cells." TA-65 improves the immune system, the skin, vision, and sexual function. The TA Sciences Patton Protocol "key element is the ingestion of TA-65 nutritional supplement tablets. Taken daily, each tablet contains five milligrams of TA-65. The TA-65 nutraceutical is to be taken for two intervals of three months each over one year."
Today (2011), doses of TA-65 in the range 10-30 mg/day are recommended as part of a cyclic protocol. See the Geron Talk Search Blog on TA-65 Tests. See Recharge Biomedical/tables of Expression Profiles of Genes Involved in hTERT Promoter Regulation, which include data for Sierra Sciences C0057684 and TA Sciences TA-65.
Astragaloside IV, probably the precursor of the TA-65 cycloastagenol molecule. Press to search on Astragaloside IV.
Alternate Molecular Representation, RevGenetics brand.
Another Molecular Representation.
C41H68O14, MW 784.97,
A similar molecular representation.
Astragaloside.
The Key: A Poker-Player's Molecule.
(Patton-protected.)
It now seems likely that both Geron Small Molecule Telomerase Activators GRN139951 (astragaloside IV?) and GRN140665 (TA-65, or GRN-665, cycloastragenol, TAT2), were obtained from astragalus extract. Astragalus membranaceus, a pea family plant from the Leguminosae family native to China [Images, specimen, GreenWeb/Seeds], is usually used for human medicines and is the variety used to produce TA-65, although the company claims to produce its product from a high-potency variety of that species found in a small region of China twice as potent for TA-65 molecule production as regular Astragalus. Many other varieties of astragalus are toxic to livestock and tagged as "locoweed". See [Links/toxicity of astragalus species]. The active principle of Astragalus seems to reside in molecules termed triterpenoid saponins or astragalosides [Links/astragalosides, Books/astragalosides, Papers/astragalosides]. The principle compound, astragaloside IV, is typically found at 0.15 mg/g in astragalus root and now commercially available as RevGenetics Astragaloside IV (Astral Fruit), or as Astragaloside IV from Terraternal. A typical dose of TA-65 is 5 mg, equivalant to 5mg/0.15mg/g = 33.33 grams of Astragalus root if it were astragaloside IV, while the typical maximum dose of Astragalus Membranaceus root used in treatment is 33 grams. However, since Geron prescribes astragaloside IV at 50 mg to 100 mg and cycloastragenol at 5 mg, it is far more likely that TA-65 is cycloastragenol. [See Links/Astragaloside IV, Source Chengdu Cogon Biotech, Chinese sources, Books/Astragaloside IV.] A Geron patent cites astragaloside IV as one embodiment of a formula for a telomerase activator. Geron's European patent (A', A'') describes other telomerase activators from astragalus root extract including cycloastragenol, astragenol, and astragaloside IV 16-one. There are claims that astragalus increases SOD levels [Links, Papers, Books]. The astragalus membranaceus root is typically harvested after 4 or 5 years of growth. See the toxicity of astragalus membranaceus root. Astragalus may derive its telomerase activating property from its ability to increase levels of Interleukin-2 (IL-2) [Vitamin Research], which is used to treat malignant melanoma and renal cell cancer. However, the primary activation pathway is probably the MAPK pathway [Index] used by TAT2, the IL-2 activation pathway being possibly confined primarily to T-lymphocytes. I note that astragaloside VII [Links] is most remarkable for its ability to induce IL-2, although many other saponins also have this property. Note that Astragaloside VII is a very minor fraction in astragalus extract. Perhaps liquid astragalaus extract [Organic Pharmacy/astragalus root extract, Links] can be used in skin treatment to lengthen skin cell telomeres, as TA Sciences proposes for TA-65. I located a liquid GAIA Herbs Astragalus extract in grain alcohol and water at $9.50 to $11.00 per bottle featuring 1 mg of astragalosides per 30 drops, to be taken 3 or 4 times a day for a total of of 3 or 4 mg of astrogalosides per day, very similar to the 5 mg/day TA-65 program. The toxicity of astragalus membranaceus extract is low. [GAIA Astragalus sources with prices.] GAIA also makes Astragalus Root Extract in glycerin. A bottle of astrogaloside extract pills might contain typically 1 mg of triterpene glycosides (astrogalosides) per 225 mg of extract. Liquid astragalus extract is also available in glycerin from Full Spectrum. I note that astragaloside IV is more bioabsorbable from astragalus extract than it is in pure form. Astrogaloside IV may be most efficiently farmed in bioreactors [description, Bioreactors, Books] from the hairy roots of Astragalus Membranaceus. See Wang, Song, and Li, et.al. on astragaloside ratios and their measurement [Links, Books, Papers]. Airlift bioreactors [Links, Images, Papers, CYTOLIFT glass airlift bioreactor] may be the best for farming the root hairs. I note that saponin production in the hairy roots of the related plant Astragalus mongholicus has been remarkably increased in the presence of sitosterol.
TA Sciences wrote in with:
"Dear Jim,
I just wanted to make a quick comment on the point you made about our company being the only one to describe Astragalus in connection with telomerase activation. This is because we are the only ones to have isolated the single molecule (TA-65) in the plant that is a potent telomerase activator. This molecule is found in very small amounts and normal supplements and extracts do not have nearly enough of that molecule to be effective. That is why no one else mentions Astragalus as a telomerase activator, because the plant as normally used is not potent enough. Thank you for your interest in TA Sciences."

Noel, Noel Thomas Patton, Chairman
TA Sciences, Inc.
E-mail: NTPHK@aol.com
I note that most vendors that manufacture the herbal tincture of Astragalus Membranaceus extract may not have mastered telomerase activation measurements and telomere length measurements like Geron has. Until TA-65 is available, perhaps the best bet for implementing the Patton protocol is to use GAIA Herbs Astragalus Root Extract drops with 1 mg of astragalosides per 30 drops, perhaps at 150 drops per day during each of the two 3-month telomerase turn-on periods in a one year treatment package, to get 5 mg/day of astragalosides containing the TA-65 molecule cycloastragenol (TAT2) and its precursor astragaloside IV along with other astragalosides and bioavailability-improving substances, or the equivalent material from alternate vendors. However, my research above on astragaloside ratios in astragalus extract seems to show that the TA-65 molecule (cycloastragenol?) will be far more abundant in the TA Sciences pill, and the threshold for meaningful physiological activity of the TA-65 molecule is uncertain. Today (2011) we would take 100 mg astragaloside IV/day or 10-30 mg/day of cycloastragenol or 10-30 mg/day of TA-65 as part of a cyclic protocol. By 2013, instead I would take 11 grams/day of condensed astragalus root extract, or 33 grams/day of astragalus root. The astragalus extract TA-41 seemed more effective in early tests than TA-65 later on.
Music: Love Potion #9 - The Searchers.
I note that in several exercises I was doing in early May 2007, the number of reps jumped up about 50% after 2 weeks of using GAIA Herbs astragalus root extract at 5 mg of astragalosides per day, perhaps demonstrating the tonic effect of astragalus membranaceus root extract.
According to a source at the Immortality Institute,
"Telomerase induction (was) tested originally using a 10:1 95% ethanolic extract of Astralagus root (this extract was called GRN925). The most potent compound in the extract seems to be astragaloside IV or cycloastragenol [Links], one of which which may be the GRN-665 (TA-65) TAT0002 molecule.... Here are the Geron use patents for Astragalus and telomerase: http://tinyurl.com/2yypov and http://tinyurl.com/3db889."
According to Geron, the minimum effective concentration (MEC) of astragalosides or related compounds to produce telomerase activation (7) twice that seen in a DMSO control was:
DesignationNameMEC, μM
1astragaloside IV [Books, Papers, molecule, pathway, Index, sources, toxicity]0.01
2cycloastragenol [Books, Papers, molecule, molecule2, molecule3, TAT2, Index, sources, toxicity]0.01
3astragenol [Books, molecule, sources, toxicity]0.03
4astragaloside IV 16-one [sources, toxicity]0.03
52OR,25S-epoxy-3β,16β,25-trihydroxy-9β-methyl-19-norlanost-1,5-diene [sources, toxicity]0.10
6cycloastragenol 6-β-D-glucopyranoside, [sources, toxicity]3.2
7cycloastragenol 3-β-D-xylopyranoside [sources, toxicity]3.2
8ginsenoside RH1 [Links, Books, Papers, molecule, pathway, Index, sources, toxicity]10
This lists the Geron telomerase activators found in astragalus root extract [Notes5/Astragalus Extract Astragalosides Content, Index/Astragalus Extract] and in ginseng extract (or obtained from these) in order by chemical potency. Geron specified that cycloastragenol [Books, Index] is to be administered at 1 mg up to a preferred 5 mg/day, and quoted 50 mg/day to 100 mg/day as optimal dosage for astragaloside IV, which may be high to compensate for bioavailability problems. All of the telomerase activators (7) described above were shown to have excellent bioavailability, although the bioavailability of astragaloside IV is higher in astragalus root extract. Since TA-65 is prescribed at 5 mg/day, and is advertised as a single molecule, it seems likely that TA-65 is cycloastragenol. I note that the relatively bioavailable cycloastragenol can be derived from astragaloside IV, and by other chemical methods from astragalus membranaceus using a hydrolyzing acid. Geron also names astragalosides A, 1, 2, 7, and astraverrucins I and II, which can be obtained from Astragalus Verrucosis [Images, Papers, Patents, Books], as telomerase activators. Perhaps a ginsenoside-oriented telomerase activation procedure could be defined using Solaray Korean Ginseng Extract, featuring 535 mg extract per capsule with 26 mg of ginsensodes (ginsenoside classes) per capsule having Rg1/Rg2 = 0.5. On the other hand, Korean Red Ginseng extract is a net telomerase inhibitor. Ginsenoside RH1 [Index, Links, Papers; Papers/ginsenoside ratios in ginseng, Links] is a telomerase activator specified by Geron. The telomerase-activating ginsenoside Rh1 is a functional ligand of the estrogen receptor (Kar Wah Leung and Alice Sze-Tsai Wong, 2010). However, Astragalus extracts seem to be superior for our purposes with more good effects and low toxicity, and are available in stronger preparations. Furthermore, ginseng extracts may contain ginsenoside RH2, a telomerase inhibitor, and telomerase activator ginsenoside RH1 is also known to activate estrogen receptors, aggravating breast cancer. See also Vendors/Astragalus with Astragalus Toxicology.
[81s/6c]
2005 Anti-Aging Trial of TA-65 at TA Sciences
"The Pivotal 2005 Anti-Aging Trial of TA-65 was a double blind, placebo controlled, 24 week study in which subjects consumed 2 or 4 tablets daily of a placebo control substance (placebo groups) for 12 weeks or 2 or 4 tablets daily of a TA-65 precursor molecule (TA-41 [Links/TA-41]) for 12 weeks (product groups). The product tablets each contained 10 mg of TA-41 (an Astragalus extract) along with other botanical extracts and excipients.
The placebo control tablets were essentially indistinguishable from the product tablets in appearance and taste, even when the tablet was broken. The 12 week placebo or product use period was followed by a further 12 week follow-up period. To ascertain active substance in the blood (for compliance and to better understand the relationship between TA-41 and TA-65), analytical measurements of TA-41 and TA-65 (the presumed major metabolite of TA-41) were conducted at 6 weeks and 12 weeks."

See metabolites of astragalus extract found in the blood [Links, Images, Video, Papers, Patents, Books].
[(11/18/2008 - 08/24/2010) Finally, I get the impression that TA-65 (cycloastragenol, TAT2) is a metabolite of ethanol and water astragalus extracts such as orally bioavailable TA-41, Herb Pharm Astragalus Root Extract, or GAIA Herbs astragalus root extract in glycerin, now available at 1 mg of astragalosides per 30 drops. Cycloastragenol may be produced from astragaloside IV by stomach acids like HCl. This would explain why both 5 mg TA-65 and 5 mg of astragalosides from GAIA Herbs astragalus root extract in glycerin (rated at 5 mg astragalosides per 150 drops) seem to produce rejuvenation rates of B= -5 years per year similar to the B= -8 or B= -9 years per year observed with TA-65 when administered with a cyclic protocol. That is, in 2010 I seem to detect that commercially available astragalus membranaceus root extracts yield rejuvenation rates more like 5 years per year, somewhat worse than the 8-9 years/year rates derived for TA-65. Both schemes seem to produce at best 400 to 460 telomere base pairs per year to repair the telomere t-loops of senescent cells and return the cell to the immortal phenotype.]
Since TA-41 was an astragalus extract, its presumed major metabolite TA-65 would conventionally have been astragaloside IV, which is typically described as the medicinally active component of astragalus extract. Of course, the common alglycone of the astragalosides, cycloastragenol, can be derived from astragaloside IV, and is also found in astragalus extract. Both astragaloside IV and cycloastragenol are rare but natually occurring molecules found in astragalus extract, like TA-65 according to TA Sciences. However, the smaller molecule cycloastragenol is prescribed by Geron at 5 mg/day, whereas pure astragaloside IV is prescribed by Geron at 50 mg to 100 mg/day, and TA-65 is described as pure substance, a single molecule by TA Sciences to be taken 5 mg/day. Therefore it seems TA-65 must be cycloastragenol (TAT2). The similarly small molecule astragenol is described in Geron reports as less active than cycloastragenol. [Links/components of astragalus extract, Papers].
[81s/6d] 230 base pairs of telomere growth per 3 months of treatment with TA-65 or TA-41: A New Hope.
"Dear Friend of T.A. Sciences,
Momentum has been building at T.A. Sciences over the summer. We have gotten 3 month preliminary data for the first group of Patton Protocol clients and we are seeing for the first time in history documented elongation of telomeres in humans. Mean telomere length increased by 230 base pairs in granulocytes (an immune cell that circulates in the blood). Since telomeres normally get shorter with each cell division, if confirmed and validated, this will be highly significant scientific news. Let's just hope this trend continues when data from more people come in over the next few months."

- Greta Blackburn, August 12, 2007, from a letter from TA Sciences to registrants.

This result was probably obtained using an astragalus extract, perhaps TA-41.
TA-65 (mainly cycloastragenol) barely impacts average telomere length in the human body,
although it closes the shortest telomere. According to Terraternal, astragaloside IV
also fails produce such substantial telomere length gains in the body. Astragalus extract does,
as explained in VIDA Institute/Astragalus_formulations. (May 16, 2012)

This scale of telomere growth corresponds to the scale of telomere growth
reported by the VIDA Institute when using astragalus root extract, or astragalus
root extract with astragalus root powder. Since experiments at TA Sciences started
with astragalus extract, perhaps the 230 bp gain corresponds to results
from early TA Sciences experiments with their first astragalus extract formula, TA-41.


Astragalosides: Greenwood Research and Community Measurements, March 2007 to June 2012
Our results here seem to be consistent with VIDA Institute results on astragalus formulations.
When astragaloside IV was used for 6 months and average telomere lengths measured, VIDA Institute found
____Lymphocytes: 7.5-7.0 = reduction of 0.5 kb
____Granulocytes: 9.1-7.4 = reduction of 1.7 kb.
When cycloastragenol was used for 6 months, VIDA Institute found
____Lymphocytes: 7.0-7.0 = No change
____Granulocytes: 7.4-7.3 = reduction of 0.1 kb.
When we used astragaloside IV and (for part of the 6 months) cycloastragenol, we measured
____Lymphocytes 6.3 - 5.9 = reduction of 0.4 kb.
____Granulocytes 8.3 - 7.3 = reduction of 1.0 kb.

Telomeres got shorter. These results are also consistent with Calvin B. Harley, Weimin Liu, Maria Blasco, Elsa Vera, William H. Andrews, Laura A. Briggs, and Josheph Raffaele (2011), A Natural Product Telomerase Activator As Part of a Health Maintenance Program, Rejuvenation Research, 14(1), 2011. This paper finds very little if any average telomere growth from TA-65 per period, but closure of the shortest telomere.

On the other hand, Greta Blackburn's letter to me from TA Sciences early on indicated that average telomere growth in granulocytes on the order of 230 bp in 3 months (460 bp in 6 months).
____Granulocytes = increase of 0.46 kb.

This seems to have been due to the use of astragalus extract (TA-41) at an early stage before TA-65 (mainly cycloastragenol) was available.

When VIDA Institute used astragalus extract for 6 months, they found
____Granulocytes: 7.3-7.6 =Increase of 0.3 kb.

This is consitent with Greta Blackburn's letter, assuming TA Sciences used astragalus extract in their initial trial tests of their Patton Protocol.

So astragalus root extract and astragalus root powder seem to be the products to use to obtain gains in average telomere length, NOT extracts from the extract astragaloside IV and cycloastragenol. There may be missing cofactors involved.

Historically, it seems that astragalus root was used to prepare astragalus tea, a form of astragalus extract investigated by the VIDA Institute, which has the pleasant taste associated with astragalus root extract in glycerin. That is, astragalus root was used to prepare a tasty root beer taken by Chinese natives for its taste. After many years, they noted that their health was markedly better than the health of natives from other regions of China not in the habit of drinking astragalus root extract from water beverages. VIDA Institute says that astragalus root extract made using water leaves virtually nothing behind but cellulose, and that this form of astragalus root extract works fine to lengthen average telomere length, although they recommend some raw astragalus root powder be taken with the extract.

The maximum dose of astragalus root taken in Chinese medicine is 33 grams per day. That is 66 pills x (500 mg/pill). I have tried taking this many astragalus root pills per day from a bottle of 100 pills of 500 mg/pill (NOW astragalus root). It is quite a few pills to choke down, leading to taking it in divided doses throughout the day. I conjecture that this is how divided doses of astragalus root became popular. NOW astragalus root is $5.91 per bottle, so the cost is (66/100) x $5.91 = $3.90 per day. Taken 15 days out of 30, the cost is $3.90 x 15 = $58.51 per month.

Now astragalus root extract, according to the VIDA Institute, boils down to 1/3 as many pills as the root, so that one merely takes 22 pills per day instead of 66. Still, this is a huge number of pills to many people, so that the search for effective extracts of the extract took place to obtain a telomerase activator that could be taken as just 1 or 2 simple pills per day. Most people would pay extra for the convenience of taking just 1 or 2 pills instead of a horse-choking 22 or 66 pills. Thus astragaloside IV, cycloastragenol and TA-65 (astragalus extract extracts) came into being for concentrated application.

However, these medicines don't work as well at contemporary dosages for increasing average telomere length as astragalus root powder at 33 grams/day or 1/3 as much astragalus root extract, though it is certainly more convenient to wolf down just one pill. - June 14, 2012


Revelations of Halloween, 2010
See Calvin B. Harley, Weimin Liu, Maria Blasco, Elsa Vera, William H. Andrews, Laura A. Briggs, and Joseph M. Raffaele (2010), A Natural Product Telomerase Activator As Part of a Health Maintenance Program, Rejuvenation Research, September 7, 2010. A 2011 version of this paper (Calvin B. Harley, et. al., 2011) has been published, claiming better results with 10-30 mg/day of TA-65.

No observed annual change in telomere length, except on the shortest telomere.
Telomeres grew on the average enough to compensate for the annual -55 bp loss due to cell division. By Halloween 2010, it seems TA-65 nets you a little gain on the shortest telomere until the telomere t-loop closes to eliminate the senescent state of the cell. After that, the telomere can't grow any longer until the t-loop pops open after a telomere-reducing cell division, allowing more telomere growth. This fits the Elizabeth Blackburn model of telomerase working only when the telomere is uncapped and the t-loop is open, so that the telomerase enzyme complex can physically access telomeric DNA. Perhaps participant HSP90 levels were low from lack of exercise, so that the telomerase activators were comparatively ineffective. HSP90 is required for effective telomerase activation.

Both cycloastragenol and astragaloside IV are about equally effective on in vitro cell cultures according Geron's May 2005 Patent Compositions and Methods for Increasing Telomerase Activity. However, cycloastragenol is more orally bioavailable. Furthermore, the composition of TA-65 got plasma levels of telomerase activators into a range "moderately activating telomerase", according to the recent September 7, 2010 paper. The paper also confesses that TA-65 was not TAT2 (cycloastragenol), so that by elimination it must have contained astragaloside IV of unspecified purity. I note that Geron recommended administering purified cycloastragenol or purified astragaloside IV at about 100 mg/dose in their May 2005 patent. TA-65 was administered at 10-50 mg/dose. Five milligrams of astragalosides for 15 days might cost me about $50, using GAIA Herbs Astragalus Extract in glycerin (30 drops per milligram of astragalosides), and in addition I would spend $6.00/month on chitosan, 2 grams per dose, to improve bioavailability. Following the original Geron recommendation is quite expensive: (100 mg/5 mg)x($50) = $1000.00 per 15 days of 100 mg of astragalosides per day, or 1000/15 = $66.67 per 100 mg dose per day. This would require 3000 drops of GAIA Herbs Astragalus Extract in glycerin per day. I note that some TA Sciences literature claims TA-65 contains 5 milligrams of their astragaloside molecule.

Was Greta Blackburn's email report of August 12, 2007 mistaken? I note TA Sciences TA-65 testamonial witness Bob Waskom, aged 69, observed 400 bp of measured telomere growth per year. It seems the above paper by Calvin B. Harley, Weimin Liu, Maria Blasco, Elsa Vera, William H. Andrews, Laura A. Briggs, and Joseph M. Raffaele would have us picture these old stories as statistically insignificant, so that only about 55 bp of gain could probably have taken place to cover for the usual attrition due to cell division. Perhaps lack of a low-polyphenol diet during telomerase activation periods, or an alternative source of interfering telomerase inhibitors in the supporting nutraceuticals, or some other factor, may have been a source of systematic error that was not invariably present. Perhaps most experimenters were not in sufficiently good health for TA-65 to be as effective as it was for Bob Waskom (400 bp/year growth) or as described in Greta Blackburn's August 12, 2007 report (460 bp/year). I note that Calvin B. Harley, Weimin Liu, Maria Blasco, Elsa Vera, William H. Andrews, Laura A. Briggs, and Joseph M. Raffaele, (perhaps by ignoring sources of systematic error) seem to unfold a disappointing analysis refuting Greta Blackburn's exciting August 12, 2007 communique, and also tending to refute my rate calculations for rejuvenation rates of up to -9 years per year partly based on her news and the supporting TA-65 testamonial story from Bob Waskom. Better results have been reported in 2011 with 10-30 mg/day of TA-65 (Calvin B. Harley, et. al., 2011). Zero net growth in base pairs per year would tend to invalidate my anti-aging flight plan based on rejuvation rates associated with telomere growth, with its simple model for recovery expectations. I wonder what has been learned about who can take TA-65 and get the best results.

Note that Retinal pigment epithelial cells transfected with hTERT plasmids show telomeres lengthening at 115-255 bp per population doubling, and we find that BJ foreskin fibroblasts similarly transfected show a telomere length increase of 340-370 bp per population doubling, the same order of magnitude (400-460 bp/year telomere growth, corresponding to roughly 1 cell division per year) originally observed at TA Sciences in 2007 by Bob Waskom and Greta Blackburn. - From Andrea G. Bodnar, Michel Ouellette, Maria Frolkis, Shawn E. Holt, Choy-Pik Chiu, Gregg B. Morin, Calvin B. Harley, Jerry W. Shay, Serge Lichtsteiner, and Woodring E. Wright (1998), Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science, vol. 279, 16 January 1998.

One ring to find them, and one ring to bind them, 
in the land of MorWindow where the radiances fly. Press for the lab of Woodring E. Wright and Jerry W. Shay."Human fibroblasts expressing the catalytic component of human telomerase (hTERT) have been followed for 250400 population doublings. As expected, telomerase activity declined in long term culture of stable transfectants. Surprisingly, however, clones with average telomere lengths several kilobases shorter than those of senescent parental cells continued to proliferate. Although the longest telomeres shortened, the size of the shortest telomeres was maintained. Cells with subsenescent telomere lengths proliferated for an additional 20 doublings after inhibiting telomerase activity with a dominant-negative hTERT mutant. These results indicate that, under conditions of limiting telomerase activity, cis-acting signals may recruit telomerase to act on the shortest telomeres..." from Subsenescent Telomere Lengths in Fibroblasts Immortalized by Limiting Amounts of Telomerase Michel M. Ouellette, Martha Lia, Brittney-Shea Herbert, Mari Johnson, Shawn E. Holt, Heidi S. Liss, Jerry W. Shay and Woodring E. Wright (2000), The Journal of Biological Chemistry, April 7, 2000, vol. 275, 10072-10076. By the year 2000, extension of the number fibroblast cell divisions by a factor of 5 to 8 was observed corresponding to new average human life spans of 5x75=375 to 8x75=600 years. Under conditions of limiting telomerase activity, telomerase is recruited to act on and extend the shortest telomeres, although the average telomere length may decline. Thus when telomerase therapy is marginal with inadequate telomerase density in cells to maintain average telomere length growth, we may still observe life extension due to closure of the shortest telomeres. If therapy is discontinued, however, a Shangri-La departure effect resulting in accelerated aging from discontinuing telomerase activation medicine may be observed. This could result in "horror movie" aging acceleration unless we have several kilobases of average telomere length left, in which case an extra 20 population doublings of telomere length would provide about two decades of remaining time to experience aging. This is based on 50 bp loss per year in fibroblasts with an averge telomere length of 2500+4000=6500 bp when 50 bp/cell division per cell division x 20 = 2500 bp.

More New Hopes
(1) Telomeres may be uncapped with hEST1A (SMG6) to allow telomase to physically dock with open telomeres and extend them. Replication Protein A [List] makes the ends of telomeres accessible to hEST1A. Perhaps in the future Replication Protein A and hEST1A protein [Index] will be applied in liposomes to assist us in lengthening telomeres by making them more accessible to telomerase during treatment. The telomerase may be best produced with telomerase activators improving the transcription of hTERT mRNA, since hTERT imported into the nucleus via phosphorylation with Akt kinase or other phosphorylating agents is usually quite limited.

(2) Parallel pathway activation experiments with several telomerase activators may provide superior results in the future. At this time RevGenetics Astral Fruit NF uses 4 telomerase activators: cycloastragenol, Haritaki, Aqueous extract of Purslane, and astragalus extract.

(3) Perhaps it will be possible to get a better price/performance ratio with Aqueous extract of Purslane. Purslane can be grown in one's living room or garden.

(4) Periodic treatment with degradable DNA plasmids generating extra hTERT and administered via liposomes may work better.

(5) Perhaps the hTERT catalytic component of telomerase itself may be administered in a liposome vehicle together with IGF-1 to phosphorylate hTERT (via Akt kinase from the IGF-1 pathway) in the cytoplasm for transport into the nucleus, using an oral liposomal spray (similar to NOW FOODS IGF-1 liposomal spray).

(6) Permanently installing an extra copy of hTERT into the genome with Zinc Finger Nuclease technology may provide a permanent solution allowing us to avoid further expense.
Note that among progeric children, whose dermal fibroblasts exhibit short telomeres, baldness is almost universal. In treatment with telomerase activators [81s], skin constitution is restored to young skin after about 20 population doublings are added. (Fossel, p.156). Note that TA Science's TA-65 (probably cycloastragenol) can add 230 base pairs to blood granulocyte telomeres in vivo in just 3 months. For typical cells on the average, 20 doubling x 50(bp/doubling) = 1000 base pairs, so that about 2.174 years of treatment is required with TA-65 at 460 bp/year (about B = -9 years/year rejuvenation rate), or about 3.76 years of treatment with astragalus extract and chitosan. I would say improvement is visible after 3 years.
"I've been taking astragaloside IV 100 mg daily and believe it is working. I no longer have problem with dry eyes... Getting hold of astragaloside IV was hard as could be and took tons of negotiating. 100 grams 98% $1500 shipped as of last month." - Andrew (correspondent 1/04/08).
Another reader chipped in with a quote for 20 grams of astragaloside IV by HPLC-ELSD purity > 98% for $980.00 from Biopurify, including shipping by Fedex. Write Haifeng Xie(Mr) 2008-04-07 Add: No.99 Xiaojiaheyanjie, Chengdu,Sichuan, China, 610041, Tel: +86-28-66780410, Fax: +86-28-66042638, Web: www.biopurify.com, MSN:biopurify@hotmail.com.
I note that other species of astragalus contain key cycloartane triterpene glycosides [Papers] that activate telomerase or activate IL-2, a telomerase activator (7), including Turkish species [Erdem Yesilada, Erdal Bedir, Yhsan Calyp, Yoshihisa Takaishi and Yasukazu Ohmoto, 2005. Effects of triterpene saponins from Astragalus species on in vitro cytokine release, Journal of Ethnopharmacology, Volume 96, Issues 1-2, 4 January 2005, Pages 71-77.].

(7) hEST1A: [Index] Princeton's Est1, a "telomere capping activator". See Est1 [Links, Images, Video, Papers, Patents, Books/Est1 and telomerase activation; toxicity]. See (76). I believed this one just worked on yeast, but Est1p has been conserved in evolution and is present in humans as hEST1A [WikiGenes/hEST1A, WikiGenes/hEST1A overexpression, Links/hEST1A and telomerase, Images, Video, Papers, Patents, Books; Images/hEST1A molecule; toxicity]. "Overproduction of hEST1A cooperated with hTERT to lengthen telomeres." - See Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L., (2003), Functional conservation of the telomerase protein Est1p in humans, Current Biology, 2003 April 15;13(8):698-704. See methods for promoting the expression of hEST1A [Patents] and supplements promoting the expression of hEST1A [Patents].

(8) HGH [Wikipedia, Links, Index/HGH, WikiGenes/hGH; Images/HGH molecule; toxicity]. Human Growth Hormone upregulates telomerase (article). [Links/HGH and telomerase activation, Images, Video, Papers, Patents, Books]. Note that HGH is partially converted into IGF-1, reviewed as telomerase activator (9) below. HGH is stimulated by whey protein [Links] and HGH secretagogues [Index, Images, Video, Papers, Patents, Books].

(8a) Dopamine (boostable with 2000 mg of Mucuna Pruriens).

(8b) Mucuna Pruriens (from velvet bean) improves HGH levels to activate telomerase. According to Life Extension Magazine (March 2009).

(8c) CDP-choline [Links, LifeExtension] can amplify HGH levels by a factor of 4. Nutrition53 claims better than x2 improvements in HGH levels from alpha-GPC.

(8d) alpha-GPC (Alpha-glycerylphosphocholine) boosts HGH about 60 minutes after exercise. According to another source, Alpha-glycerylphosphocholine [Images; toxicity] can amplify HGH by a factor of 44 in the presence of exercise, where exercise alone would amplify HGH by a factor of 3.

(8e) L-Arginine, an amino acid, boosts Nitric Oxide and HGH.

(8f) Ornithine (Links/HGH secretagogues, Links/Arginine plus Ornithine for HGH) can produce a large increase in growth hormone secretion lasting many hours. I note that fish contain both arginine and ornithine, stimulating HGH, so that coastal people are usually taller than natives that live inland and do without fish.

(8g) 1500 mg of arginine plus 1500 mg of lysine elevates resting levels of HGH.

(8h) Bodybuilding exercise [List] also stimulates HGH [Links].

(8i) DHA improves HGH expression by boosting dopamine levels, although it is a telomerase inhibitor [List] for cancer cells. Thus DHA should be a telomerase activator for cells that are targets of HGH.

(8j) Melatonin [footnotes] is an HGH secretagogue. Melatonin also stimulates the expression IL-2 (List), a telomerase activator. Melatonin may be a telomerase inhibitor for cancer cells only.
(Also see Akbulut KG, Gonul B, Akbulut H. (2009), The role of melatonin on gastric mucosal cell proliferation and telomerase activity in ageing, J Pineal Res 2009 Nov;47(4):308-12. "...Melatonin may delay the ageing of gastric mucosa by inhibiting the replicative cellular senescence via its stimulatory effect on telomerase activity and suppressive effect on cellular proliferation and lipid peroxidation.").

(8k) GABA (gamma-aminobutryic acid) is an HGH secretagogue. Perhaps it is a chromatin-expanding HDAC inhibitor (check) improving transcription of hTERT mRNA, due to the butyric acid [List] component. It causes hTERT mRNA to be transcribed anyway due to its HGH secretagogue properties.

Growth Hormone (GH) may activate telomerase directly through the PI3K signaling pathway [Index] employing phosphatidylinositol 3'-kinase. Note that IGF-1 uses the IGF-1/PI3K/AKT1 pathway, so that we might expect to find a pathway like HGH/PI3K/AKT1 or HGH/IGF1/PI3K/AKT1, since HGH is converted to IGF-1 in the liver. See the article:
L Gomez-Garcia, FM Sanchez, MT Vallejo-Cremades, IA Gomez de Segura and E De Miguel del Campo, Direct activation of Telomerase by GH via phosphatidylinositol 3'-kinase, Journal of Endocrinology, 2005, 185, 421-428. See also Wikipedia/Phosphoinositide 3-kinase, which introduces the family of phosphatidylinositol 3'-kinases. See the hTERT activation pathway for HGH or the HGH hTERT activation pathway.

(9) IGF-1 [Index, Wikipedia, Links/IGF-1, Images, Video, Papers, Patents, Books, WikiGenes/IGF-1]. IGF-1 upregulates telomerase (2001 article). [Links/IGF-1 and telomerase activation, Images, Video, Papers, Patents, Books, IGF-1 & HGH upregulating amino stack supplement, Links/IGF-1 supplements, Biocarta Pathways; Images/IGF-1 molecule; toxicity]. See Biosynergy IGF-1, Sytropin HGH, IGF-1 Plus, Vespro IGF-1 Max, and other IGF-1 supplements. See IGF-1 hormone level testing. Probably some exercise should be done when using IGF-1 with HGH for telomere extension, to keep everything moving in the direction of physiologically useful growth. Otherwise, I suspect growth-promoting hormones are more likely to produce cancer, and in fact prostate cancer occurs more frequently when IGF-1 is high. According to Jerry Brainum (Iron Man, March 2010), pomegranate prevents IGF-1 from inducing prostate cancer. IGF-1 receptor inhibitors are sold as anticancer drugs and inhibiting IGF-1 receptors is similar to inhibiting DAF-2 in C Elegans, which lengthens its life span. [article]. IGF-1 is a telomerase activator that may be somewhat risky, especially when one is not exercising (9) and in fairly good health on an anticancer diet. Supplemental vitamin D is recommended when using IGF-1 as a telomerase activator to defend against cancer, as described below. However, IGF-1 supplementation should probably not be dampened by telomerase inhibitors during the 2 weeks of telomerase activation in a monthLy cycle of telomerase activation and inhibition when one is exercising and does not suffer from cancer or atherosclerosis.
The above 9 compounds are the most promising and best-tested as small molecule telomerase activators. However, IGF-1 is opposed by cortisol, and usually does have favorable anabolic impact on healthy people. IGF-1 seems to work against victims of both artherosclerosis and cancer, when its positive effect on cellular proliferation is harmful. Treatment for both diseases may feature IGF-1 blockers or interference with IGF-1 receptors. Liposomal IGF-1 Spray and Anti-Aging IGF-1 Lozenges have been developed by NOW Foods. "IGF-1 rescues human intervertebral annulus cells from in vitro stress-induced premature senescence." - Books/how to manage senescent chondrocyes - from ISpine: Evidence-Based Interventional Spine Care. See the Index Entry on IGF-1, which contains many more details. As Dr. Jerry Brainum recently pointed out in Iron Man, DHEA boosts IGF-1 levels [Links, Papers], as does bodybuilding exercise. Creatine monohydrate boosts IGF-1 levels and is associated with lower lipofuscin levels and 10% increased lifespans in rodents. Furthermore, vitamin D can be used to eliminate prostate cancer risk from IGF-1 [Links]. Lycopene is synergistic with vitamin D in reducing cancer risks [LifeExtension], and vitamin E is another useful chemopreventive element for eliminating prostate cancer. See Herbal Powers/antiaging for vendor notes on IGF-1. For IGF-1 antiaging, see americannutrition/store/anti-aging-hgh.html. See also MaxLife's IGF-1 Plus - Revolationary Anti-Aging Formula and Nature's Healthy People IGF-1 liposome spray. Review HGH secretagogues. HGH converts to IGF-1 in the liver, so boosting HGH with exercise, secretagogues (such as Arginine plus Ornithine, found in fish), CDP-choline, or whey protein (say from protein powder or skim milk) should boost IGF-1. Since HGH emerges from the pituitary in several spurts throughout the day, it may be useful to pump up 3 or 4 times a day to get maximum HGH. Note that IGF-1 expression is boosted by creatine monohydrate, colostrum, cottage cheese, DHEA, exercise, IGF-1 supplements, and indirectly by whey protein (via HGH conversion in the liver). Ashwagandha can prevent cortisol from reducing IGF-1 levels.
Activation Pathway for IGF-1: (see IGF-1) seems to be the IGF-1/PI3K/AKT1 pathway. See the hTERT activation pathway for IGF-1 or the IGF-1 hTERT activation pathway.

(10) Estrogen [Index, Links/Estrogen, WikiGenes/Estrogen, WikiGenes/Estrogen and telomerase, Links, Images, Video, Papers, Patents, Books; Images/17-beta-estradiol molecule; toxicity]. The sex hormone estrogen causes cells with estrogen receptors to express telomerase, but its suitability for our application must be somewhat hazardous, since it is associated with colon cancer, prostate cancer, ovarian cancer, and endometrial cancer. However, estrogen therapy is used, for instance in transsexual applications and in other medical applications. Current recommendations for estrogen dosing in transgender applications range from starting doses of 0.625 to 2.5 mg/day. Search for Estrogen treatments for telomere extension [Papers, Patents, Books]. See the application of estrogen (17[beta]-Estradiol) to the blocking of senescence in endothelial progenitor cells. "The estrogen receptor α is found in endometrium, breast cancer cells, ovarian stroma cells and the hypothalamus; estrogen receptor β has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells." - Wikipedia.
Search [Links/estrogen and telomerase activation, Images, Video, Papers, Patents, Books]. I note that estrogen is a steroid hormone that binds to a steroid superfamily receptor that attaches itself to DNA to activate transcription. While estrogen causes the cell to express telomerase and lengthen telomeres during transsexual restructuring involving breast and hip tissue proliferation, progesterone can cause the same effects. Evidently tissue acquired by cellular proliferation involving the application of progesterone alone is more likely to become genomically unstable in old age than tissue enhanced or restructured by estrogen, which may be dangerous when treatment is continued, although in many cases subjects submit to 10 years of continuing treatment. The skeleton takes about 10 years to replace itself, and with estrogen available, hips broaden. [Wikipedia, Papers/transsexual restructuring with hormones; Papers/transsexual hormones, Links/transsexual hormones, Books, Amazon]. Perhaps tissue restructured with progesterone should be treated with astragalosides or other small molecule telomerase activators to render it more genomically stable and resistant to breast cancer. Of course, the phase of she-male transformation may take place spontaneously as a consequence of high-hormone honeymoon travels, as mythically imaged in the surface of the moon. See Erotic Hots Study Guide for more on this theme. "Estrogen attenuates endothelial progenitor cell senescence by augmenting hTERT through PI3K/Akt-dependant mechanisms (Papers, Links, Imanishi, et al, 2005)." - Caleb E. Finch, The Biology of Human Longevity, p.167. In this case, another activation pathway seems to be directly via estrogen receptor transcription factor. See Papers/the hTERT activation pathway for estrogen or Papers/the estrogen hTERT activation pathway. Note that progesterone uses the MAP Kinase pathway to activate transcription of hTERT, while estrogen is capable of interacting with the hTERT promoter via the estrogen receptor transcription factor, as described in The Cell: A Molecular Approach by Geoffrey M. Cooper and Robert E. Hausman, Chap 15, pp 602-603 on Estrogen Action, which shows the formation of the estrogen transcription factor complex from estrogen bound to estrogen receptor dimerized and capped by coactivator HAT, or Histone Acetyl Transferase (hALP). The estrogen transcription factor complex behaves as a transcription factor upregulating hTERT through interaction with the hTERT promoter. Note that Fo-ti (He Shou Wu) from the sexually suggestive Polygonum multiflorum root boosts estrogen levels. See Karen Oerter Klein, Mona Janfaza, Jeffrey A. Wong and R. Jeffrey Chang (2003), Estrogen Bioactivity in Fo-Ti and Other Herbs Used for Their Estrogen-Like Effects as Determined by a Recombinant Cell Bioassay, The Journal of Clinical Endocrinology and Metabolism Vol. 88, No. 9 4077-4079. "Soy, clover, licorice, and hops have a large amount of measurable estrogen bioactivity."
Telomerase Activators via Strong Estrogen Bioactivity
(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),
are telomerase activators via strong estrogen bioactivity. For the hips (which contain beta receptors for estrogen) bone restructuring may require such estrogenic substances for certain she male transformation applications. See telomerase activators that are ligands of progesterone receptor also associated with she male restructuring. Note that progesterone is safer than estrogen, which may be associated with endometrial cancer above some threshold dosage.

(10b) Estrogen Receptors (1318) [Links/estrogen receptor 13, Links/estrogen receptor 14, Links/estrogen receptor 15, Links/estrogen receptor 16, Links/estrogen receptor 17, Links/estrogen receptor 18; toxicity]. These are known to activate telomerase in healthy cells. See the article Shuwen Wang and Jiyue Zhu (2004), The hTERT Gene Is Embedded in a Nuclease-resistant Chromatin Domain, The Journal of Biological Chemistry, Dec. 31, 2004, 279, 55401-55410. See drugs and nutraceuticals increasing the expression of estrogen receptors and increasing the expression of estrogen receptors.

(11b) Bisphenol A (BPA), an estrogen disrupter with estrogen-like bioactivity, up-regulates telomerase expression. It is released from certain dental polycarbonate crowns, and may be associated with cancer, like estrogen. [Papers/Bisphenol A and Telomerase Activation, Links; toxicity].

(12) Other histone deacetylase inhibitors [Index/HDAC Inhibitors, Links, Books, LifeExtension; toxicity]: Telomerase activation may perhaps be achieved with histone deacetylase inhibitors (similar to tricostatin A) that are available to us now, but are as yet untested or unreported for telomerase activation activity. Perhaps histone deacetylase inhibitors, which expand chromatin for transcription, may work effectively together with astragalosides or other small-molecule telomerase activators functioning through nuclear transcription factors much as steroid hormones interact by binding with the steroid receptor transcription factors [Links/nuclear receptor superfamily] attaching directly to the gene promoter. See the hTERT promoter. Broccoli sprouts for sulforaphane, plus its zinc cofactor, might work more effectively with astragalosides to promote hTERT transcription after chromatin expansion via the HDAC inhibitor and antioxidant sulforaphane plus zinc. Such hypotheses will require testing. Histone deacetylase inhibitors that turn out to be useful include:
(12.1) CGK 1026,
(12.2) Tricostatin A,
(12.3) Sodium butyrate,
(12.4) Sodium 4-phenylbutyrate,
(12.5) Phenylbutyric acid, and perhaps also
____(A) Diallyl sulphide [Books, Links; toxicity] (found in garlic), a zinc-activated (meats, seafood, oysters) class I histone deacetylase inhibitor (HDAC inhibitor). Note that garlic's allicin is a telomerase inhibitor, however. Diallyl sulphide may be obtained from the breakdown of allicin. Furthermore, it induces apoptosis in cancer cells, as a telomerase inhibitor does. Nevertheless, acetylation of chromatin due to diallyl sulphide is expected to improve the transcription of hTERT mRNA when telomerase activators that activate hTERT mRNA transcription are used. This is not now certain. "Diallyl disulfide (DADS), one of the major components of garlic (Allium sativum), is well known to have chemopreventative activity against human cancer such as colon, lung and skin", and also against bladder cancer. (H.F Lua, C.C Sueb, C.S Yuc, et al, 2004).
____(B) Sulforaphane [WikiGenes/Sulforaphane Books, clinical reports, Papers/clinical reports, toxicology, Books/toxicology of sulforaphane; toxicity] (found in broccoli & brocolli sprouts), another zinc-activated (meats, seafood, oysters) class I histone deacetylase inhibitor (HDAC inhibitor). Sulforaphane is found at high concentration in broccoli sprouts, and is the most powerful natural inducer of anti-carcinogenic chemoprotective phase 2 enzymes known. Sulphoraphane acetylates chromatin, expanding it to enable transcription, and is expected to improve the performance of many telomerase activators that work by improving the transcription of hTERT mRNA. Sulphoraphane inhibits telomerase in breast cancer cells, but has negligible effect on telomerase activity in normal breast cells. See Syed M. Meeran, Shweta N. Patel, Trygve O. Tollefsbol (2010), Sulforaphane Causes Epigenetic Repression of hTERT Expression in Human Breast Cancer Cell Lines, July 2010,5(7), e11457.
____(C) Butyrate [Links, WikiGenes/Butyrate]. See sodium butyrate [Images, WikiGenes/Sodium Butyrate; toxicity], which may accelerate transcription of hTERT in the presence of a telomerase activator by expanding chromatin.
____(D) Phenylbutyrate (PhB) [WikiGenes/Phenylbutyrate; toxicity], Trichostatin A better-tolerated in long-term treatment.
____(E) Valproic Acid [Wikipedia; toxicity](VPA), Trichostatin A better-tolerated in long-term treatment.
(12b) Hayflick limit extenders [Books] -
____(A) Carnosine [LifeExtension/Carnosine; toxicity], [69].
____(B) Vitamin C,
____(C) Neygeront [79], an RNA and B-vitamin complex.
____(D) Kinetin (N6-furfuryladenine; toxicity), a cytokinin pioneered in anti-aging research by Dr. Suresh Rattan, (also a student of zeatin) is presently being used on skin cells.
These drugs (12) have been used to extend the Hayflick limit associated with replicative senescence to some degree, but the mechanisms seem to have nothing to do with telomerase activation, and more to do with antioxidant effect or anti-glycation effects, perhaps. Telomerase activation should be checked in these cases.
Dietary Sources of HDAC inhibitors may include:
(1) butyrate [Images],
(2) biotin [Images],
(3) lipoic acid [Images],
(4) garlic organosulfur compounds [Images]
____4.1 allyl mercaptan [Images, Article]
____4.2 diallyl disulfide [Images] and
(5) metabolites of vitamin E [Images/Metabolites, List, Images/Supplements].
Endogenous HDAC Inhibitors [Links, Images, Papers, Patents, Books].
__[1] L-carnitine (Vitamin C with Methionine (perhaps from fish) + Lysine -> Carnitine)
_____is an endogenous HDAC inhibitor [Ref].
__[2] D-beta-hydroxybutyrate (Beta-OHB) is an endogenous inhibitor
_____of class I histone deacetylases (HDACs).

__[3] Valproic acid [Ref].
__[4] beta-hydroxybutyrate [Images, Article (Ketogenic Diets)].

(13) TAC1 with auxin activates telomerase in plant cells. See the associated PhD thesis by Shuxin Ren. [Links/TAC1 with Auxin Activates Telomerase, TAC1, Auxin]. See telomerase activation in plant cells [Images, Papers, Patents, Books; toxicity].

(14) STAT3 [Wikipedia/STAT3, Links/STAT3, Images, Video, Papers, Patents, Books; Links/STAT3 and telomerase expression, Images, Video, Papers, Books; WikiGenes/STAT3, WikiGenes/STAT3 and telomerase; Images/STAT3 molecule; toxicity]. STAT3 is a key regulator of telomerase expression in normal and cancer cells (Papers). Liza Konnikova, Marina C. Simeone, Matthew M. Kruger, Maciej Kotecki, and Brent H. Cochran (2005), Signal Transducer and Activator of Transcription 3 (STAT3) Regulates Human Telomerase Reverse Transcriptase (hTERT) Expression in Human Cancer and Primary Cells [PDF], Cancer Research August 1, 2005 65; 6516. "Growth factors, such as platelet-derived growth factor (PDGF) and interleukin-6 (IL-6) that activate STAT3, were found to rapidly up-regulate hTERT in primary fibroblasts (HS27) and primary HASMC (Human Aortic Smooth Muscle Cells) at both the protein and mRNA levels..." EGF also activates STAT3. See Cytokine Signaling by the JAK STAT Pathway [Links, Images Video, Papers, Patents, Books]. Check growth factors activating STAT3 [Papers, Patents, Books] and nutraceuticals activating STAT3 [Papers, Patents, Books].

(15) Raloxifene [Wikipedia/Raloxifene, Links/Raloxifene, Images, Video, Papers, Patents, Books; Images/Raloxifene molecule; toxicity]. Raloxifene is available as orally bioavailable Evista [Links, Images, Video] from Eli Lilly. See (2006) Raloxifene Increases Proliferation and Up-regulates Telomerase Activity in Human Umbilical Vein Endothelial Cells. Raloxifene reduces incidence of breast cancer, and is used as an adjuvant in breast cancer treatment. Raloxifine also prevents osteoporosis in premenopausal women. For application to osteoporosis treatment or prevention in women, supplemental calcium and/or vitamin D should be added if daily intake is inadequate. Works through estrogen receptors. Side effects of Raloxifene might include strokes or blood clots, however, as it increases the risk of venous thromboembolism.

(16) Ecdysone [Links, Images, Video, Papers, Patents, Books; Papers/ecdysone telomerase activation, Patents/ecdysone telomerase activation, WikiGenes/Ecdysone; Images/Ecdysone molecule; toxicity]. Evidently, there has also been some progress in hTERT activation using the insect hormone ecdysone (muristerone) to induce hTERT mRNA transcription and cellular immortalization in human fibroblasts [article, Links/ecdysone and telomerase activation, Papers/ecdysone and telomerase activation]. See also Mark D Ungrin and Lea Harrington (2006): Strict control of telomerase activation using Cre-mediated inversion (using ecdysone), BMC Biotechnology 2006, 6:10. See Cre recombinase [Wikipedia, Links/Cre recombinase, Images, Video, Papers, Patents, Books; Links/LoxP sites, Images, Video, Papers, Patents, Books; Wikipedia/Cre-Lox recombination]. I note that ecdysone is a steroid hormone like testosterone, estrogen, progesterone, and the corticosteroids including cortisol, all of which may be synthesized from cholesterol. The steroid hormones diffuse across the plasma membrane to bind to intracellular receptors in the steroid receptor superfamily, which pass through the nuclear pore, bind to DNA gene promoter regions, and directly stimulate transcription of their target genes. [Geoffrey M. Cooper, The Cell, Chap.13: Cell Signaling, page 523.] Note that beta ecdysterone (20-Hydroxyecdysone [Wiki, Links]) is an anabolic steroid found in spinach sold for bodybuilding applications that increases muscle protein synthesis. It may be that beta ecdysterone (20-hydroxyecdysone) from spinach activates telomerase like ecdysone. Compare the molecules: Wiki/20-Hydroxyecdysone and Wiki/Ecdysone. See Biocompare's Vectors for Inducible Control of Gene Expression. See Papers/the hTERT activation pathway for ecdysone or Papers/the ecdysone hTERT activation pathway.

(17) Saquinavir (Invirase, Roche Invirase) [Links, Images, Video, Paper, Patents, Books, Wikipedia/Saquinavir, WikiGenes/Saquinavir; Images/saquinavir molecule; toxicity]. Saquinavir is an anti-HIV drug and protease inhibitor, has been shown to increase telomerase expression in peripheral blood mononuclear cells. See the paper by Franzese, et. al: [Links/Saquinavir and telomerase activation, Images, Video, Papers, Patents, Books]. Franzese O, Lombardi A, Comandini A, Cannav E, Testorelli C, Cirello I, Bonmassar E. (2001), Effect of Saquinavir on proliferation and telomerase activity of human peripheral blood mononuclear cells, Life Sci 2001 Aug 17;69(13):1509-20. Saquinavir absorption seems to be improved by omeprazole. This drug has some side effects [Wikipedia]. See Saquinavir interactions with drugs such as digoxin, garlic, methadone, tipranavir/ritonavir, and omeprazole. Coadministration with digoxin results in a significant increase in digoxin levels that should be closely monitored. Garlic induces the metabolism of saquinavir and reduces its concentration, so that it should not be used with saquinavir. Saquinavir inhibits HIV protease. See Papers/the hTERT activation pathway for saquinavir or Papers/the saquinavir hTERT activation pathway.

(18) C. racemosa (black cohosh) extracts. See Cimicifuga extracts [Links, Images, Papers, Patents, Books; Links/black cohosh telomerase activation pathway, Images; Ray Sahelian/Cimicifuga; Images/Cimicifuga; Links/Cimicifuga extracts and telomerase activation, Hong Kong University European Patent, WikiGenes/black cohosh; Images/Black Cohosh molecules; toxicity]. These orally bioavailable drugs were determined to be telomerase activating in Geron patents dating from 2005 such as Compositions and Methods for Increasing Telomerase Activity. Geron specifies Black Cohosh extracts prepared with the Cimicifuga species Cimicifuga racemosa (Wiki/Actae racemosa), Cimicifuga dahurica, Cimicifuga foetida, and Cimicifuga acerina. See also Black cohosh (Cimicifuga racemosa [L.] Nutt.) [Links/Black Cohosh extract; Links/Black Cohosh, Images, Video, Papers, Patents, Books; a species of "buttercup"]. Note that "commercially available preparations of black cohosh [Images, Video] usually contain 1 mg of total triterpene saponins (expressed as

26-deoxyactein, toxicity) in each 20-mg dose of extract." - National Institute of Health/Black Cohosh. See
26-deoxyacetein [Links, Images, Video, Papers, Patents, Books]. Black cohosh (fairy candle) may be the most inexpensive telomerase activator, since a month's supply of black cohosh extract can be gotten at Wal-Mart for four dollars to supply the ladies and post-menopausal women. See Remifemin, which contains black cohosh extract equivalent to 20 mg of root per tablet. See the hTERT activation pathway for black cohosh or the black cohosh hTERT activation pathway. I have read that black cohosh improves tissue stability against breast cancer, and is better for improving femininity than most competing preparations. On the other hand, there are reports that black cohosh is not associated with estrogenic effects and reports to the contrary identifying the fukinolic acid component of black cohosh as estrogenic. Black cohosh is taken in cyclic fashion, typically 3 weeks on and 1 week off, to a maximum of 6 months for the ON part of the cycle, according to reports by herbalists. This minimizes any toxic effect on the liver.

Fukinolic acid [Links, Images, Video, Papers, Patents, Books].
"Fukinolic acid, a compound recently identified in black cohosh, was shown to have estrogenic activity in vitro." (NIH Fact sheet on Black Cohosh).

Other active compounds in black cohosh appear to include:
black cohosh triterpene glycosides [Links, Images, Video, Papers, Patents, Books] (including
actein [Links, Images, Papers, Patents, Books] and
cimicifugoside [Links, Images, Papers, Patents, Books]),
black cohosh resins [Links, Images, Papers, Patents, Books] (including
cimicifugin [Links, Images, Papers, Patents, Books]), and
caffeic acid [Links, Images, Papers, Patents, Books] and
isoferulic acid [Links, Images, Papers, Patents, Books].

There may be telomerase activators in black cohosh that do not have estrogenic side-effects. Perhaps 27-diosgenin (23-epi-26-diosgenin?), which exhibits no estrogenic side-effects, may be in this category. (check).

Also see Shatavari, Fenugreek [Index], Diosgenin, and Progesterone for feminity enhancement.
Music: All Shook Up by Elvis Presley.

(19) CGK 1026 [Index/CGK 1026, WikiGenes/CGK 1026, Links, Images, Video, Papers, Patents, Books, ChemBank/CGK 1026 molecule; Images/CGK1026 molecule; toxicity].

The orally bioavailable CGK 1026 molecule.
The HDAC inhibitor CGK1026 "derepresses hTERT expression". CGK1026 inhibits the recruitment of HDAC [?] into E2F-pocket protein complexes assembled on the hTERT promoter. [2004] Source: Linscott's Directory of Immunological and Biological Reagents, catalog # 565730. Merck CGK 1026 - Order # 565730-5MG. EMC Biosciences CGK1026. CGK1026 binds to E2F binding sites [Images, Papers, Patents, Books] on the hTERT promoter, and inhibits the binding of histone deacetylase 1 [Images, Papers, Patents, Books] and histone deacetylase 2 [Images, Papers, Patents, Books] to derepress hTERT transcription. CGK 1026 has been used to replace Tricostatin A in some medical applications. See Jaejoon Won, Seungwoo Chang, Sangtaek Oh, and Tae Kook Kim, Small-molecule-based identification of dynamic assembly of E2F pocket protein histone deacetylase complex for telomerase regulation in human cells, PNAS, August 3, 2004. CGK1026 has a molecular weight of 326.34651 Daltons, and is an HDAC inhibitor. "The effect of CGK1026 on other promoters is still unclear." - Yi-hsin Hsu, Jing-jer Lin, 2005, Telomere and telomerase as targets for anticancer and regeneration therapies, Acta Pharmacologica Sinica, 2005 May; 26 (5): 513-518.
There are indications that CGK1026 is orally bioavailable, relatively non-toxic, and penetrates the cell membrane directly. Scriptaid 565730 CGK1026; 6-(1,3-Dioxo-1H,3H-benzo[de]isoquinolin- 2-yl)-hexanoic Acid Hydroxyamide. A relatively non-toxic, cell-permeable hydroxamic acid-containing histone deacetylase (HDAC) inhibitor. Facilitates transcriptional activation (TGF/ Smad4) in both stable and transient receptor assays in a concentration-dependent manner. At ~2 g/ ml (6-8 M) concentrations, results in a greater than 100-fold increase in histone acetylation in PANC-1 cells. Reported to derepress hTERT by inhibiting the recruitment of HDAC into E2F-pocket protein complexes assembled on the hTERT promoter. - Calbiochem Brochure.
CGK1026, Tricostatin A, sodium 4-phenylbutyrate, sodium butyrate, and trapoxin (all HDAC inhibitors), may all be useful for increasing telomerase activity. See the hTERT activation pathway for CGK 1026 or the CGK 1026 hTERT activation pathway.

(20) Heat shock proteins [Index; toxicity; heat shock protein transciptional activators] like Hsp90 [Index, Links, WikiGenes/HSP90] to increase telomerase levels in the cell by mediating the assembly of telomerase. See GB Morin, DO Toft, JW Shay, WE Wright, MA White, et al., (1999), Functional requirement of p23 and Hsp90 in telomerase complexes, Genes and Development, Vol. 13, No. 7, pp. 817-826, April 1, 1999. See [Links/HSP90 and telomerase activation, Images, Video, Papers, Patents, Images; Links/HSP90 and p23 in telomerase activation, Links/Upregulation of HSP90]. Note that HSP90 is elevated by exercise. Hsp90 often functions as a transporter for transcription factors to be moved into the nucleus. We also report that hsp90 inhibitors geldanamycin and novobiocin inhibit recombinant telomerase even after telomerase is assembled. - See Keppler BR, Grady AT, Jarstfer MB, 2006, The biochemical role of the heat shock protein 90 chaperone complex in establishing human telomerase activity, J. Biol Chem, 2006. "HSP90 is necessary for telomerase activity, as is p23." - Yu Sheng-Kong, Woodring E. Wright and Jerry W. Shay (2002), Human Telomerase and its Regulation, Microbiology and Molecular Biology Reviews, Sept. 2002, pp. 407-425, and associated papers. Since HSP90 is elevated by exercise and HSP90 is essential for telomerase activity, it is clear that exercise is valuable in telomerase activation therapy. HSP90 is also upregulated by alpha lipoic acid. Thus alpha lipoic acid is also (weakly) a telomerase activator. "Telomerase is a target for hsp90-mediated assembly of the functional enzyme. Therefore, inhibition of hsp90 function by blocking agents would likely inhibit telomerase, but not in a specific manner. Hsp90 blocking agents, such as geldanamycin and its derivatives are touted as anticancer compounds and are currently undergoing clinical trials." after Satoru Kyo and Masaki Inoue (2002), Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy?, Oncogene, 21 January 2002, Volume 21, Number 4, Pages 688-697. That heat shock protein HSP90 is elevated by exercise in blood mononuclear cells is shown in 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. HSP70, which is used in protein transport, is also highly expressed after exercise.
See supplements promoting HSP90 and supplements boosting heat shock proteins. Exercise (Index) or Alpha lipoic acid upregulates heat shock protein expression, as does a combination of lipoic acid, carnosine, and zinc. Furthermore, HSP (Heat Shock Protein) release is stimulated by testosterone and catecholamines (stress hormones) including epinephrine and norepinephrine, which can be released by taking caffeine or by theanine from green tea. Note that gamma tocopherol blocks heat shock proteins, so that gamma tocopherol (found in peanuts and walnuts) should not be taken while trying to activate telomerase activity. See hTERT methylation.

(21) Nitric Oxide [Index, Links/Nitric Oxide and telomerase activation, Images, Video, Papers, Patents, Books, WikiGenes/Nitric Oxide and telomerase activation; Links/Nitric Oxide, Video; toxicity]. Nitric Oxide technique was described by Vasa, et. al, 2000 and Hayashi, et.al, 2006, using nitric oxide to activate telomerase and delay senescence in endothelial cells. See Nitric Oxide Activates Telomerase and Delays Endothelial Cell Senescence. (The telomerase activation effect due to NO was observed and measured.) Since NO reacts with superoxide to form peroxynitrite, which produces hydroxyl radicals, it is probably a good idea to use the peroxynitrite inhibitor gamma-tocopherol if NO is used to promote telomerase activation. I suppose NO may be the smallest of all telomerase activators. It may be true that bodybuilder's nitric oxide preparations, which are anabolic in effect, may be useful in reconstructing telomeres via telomerase activation [Links, Images, Video, Papers, Patents, Books]. Most "nitric oxide" supplements contain the amino acid Arginine-alpha-keto-glutarate, and the production of Nitric Oxide occurs when the amino acid L-arginine is converted into L-citruline through an enzyme group known as Nitric Oxide Synthase (NOS) [Wikipedia/NOS, Links, Images, Video, Papers, Patents, Books; article1, article2]. Note that NO also stimulates mitochondrial biogenesis [Links, Books/Mitochondrial Biogenesis, Books/Exercise Biochemistry]. NO is a major paracrine signaling molecule in the nervous, immune, and circulatory systems, but it only has effect on nearby cells because it is extremely unstable with a half-life of just a few seconds. [Geoffrey M. Cooper, The Cell, Chap.13: Cell Signaling, p.524.] NO can diffuse across the plasma membrane like a steroid hormone, but does not usually act by binding to a receptor that regulates transcription, like a steroid. Instead, NO typically modifies the activity of intracellular target enzymes. According to Erusalimsky, 2009, Vascular endothelial senescence: from mechanisms to pathophysiology, NO is not observed to activate telomerase after all: "...Findings suggest that NO may counteract senescence in the context of cellular stress, including inadvertent cell culture stress, through upregulation of SIRT1. " However, the Erusalimsky concludes that "Nitric oxide bioavailability is critical to normal endothelial function. Advanced age leads to impairment of endothelial NO production and to increased inactivation of NO by superoxide, which contribute to age-related endothelial dysfunction. A number of studies have investigated whether endothelial senescence may be involved in these phenomena. These studies have established that senescent endothelial cells have lower levels of eNOS activity and produce decreased levels of NO." See also Hong Y, Quintero M, Frakich NM, Trivier E, Erusalimsky JD, 2007, Evidence against the involvement of nitric oxide in the modulation of telomerase activity or replicative capacity of human endothelial cells, Experimental Gerontology 42: 904-910, 2007. Conversely, see Farsetti A, Grasselli A, Bacchetti S, Gaetano C, Capogrossi MC (2009), The telomerase tale in vascular aging: regulation by estrogens and nitric oxide signaling, Journal of Applied Physiology 106: 333-337, 2009. Note that 5-10 grams of arginine per day, which produces extra nitric oxide and supplemental HGH, is sometimes used to restore the activity of the thymus gland over the heart that produces T-lymphocytes. Thus nitric oxide therapy has been used for years to rejuvenate the immune system and to prevent heart problems by rejuvenating enthothelial cells. See Papers/the hTERT activation pathway for nitric oxide or Papers/the Nitric Oxide hTERT activation pathway.

(22) 5-azacytidine (DANGER: 5-azacytidine is a demethylating agent that may promote prostate carcinomas) [Wikipedia, Links, Images, Video, Papers, Books, WikiGenes/5-azacytidine; Images/the 5-azacytidine molecule; toxicity]. 5-azacytidine can activate telomerase [Papers]. See Robert F. Newbold (2002), The significance of telomerase activation and cellular immortalization in human cancer, Mutagenesis, Vol. 17, No. 6, 539-550, November 2002. Note that 5-azacytidine is a demethylating agent, unlike the histone deactetylase inhibitor trichostatin A (TSA), which is similarly a small molecule telomerase activator. "Tricostatin A had the opposite effect in prostate carcinoma cell lines in that it inhibited both hTERT mRNA expression and telomerase activity, leading to suppression of cell proliferation."

Consider the searches hTERT mRNA expression inhibitors and hTERT mRNA expression activators. Also see cell proliferation inhibitors and cell proliferation activators.


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