Green-1

Boosting Telomerase Activity and Telomere Lengthening

Confine methylating folic acid (5 mg/day) to the morning for general good health and methylation of homocysteine before starting telomere treatment in the evening, which might begin with Vitamin C for DNA demethylation to promote gene transcription and telomere lengthening, along with acetylation to promote transcription by expanding chromatin.

Perhaps the HDAC inhibitor sulphoraphane is unsuitable for this application, since in inhibits hTERT in breast cancer cells and telomerase activity in liver cancer cells, for instance. It may have the desired effect in normal cells, but this is uncertain for now.

Another HDAC inhibitor to promote chomatin acetylation might be effective in accelerating hTERT transcription, such as diallyl sulphide from oysters, sodium butyrate, sodium 4-phenylbutyrate, and more certainly the orally bioavailable CGK1026.

Use 1.5 grams of L-arginine plus 1.5 grams of L-lysine to boost HGH levels and provide L-arginine and L-lysine for nuclear transport signals, then take a workout with weights to maximize heat shock proteins such as HSP90 that transport transcription factors into the nucleus that activate transcription from the hTERT gene by interacting with the hTERT promoter.

HSP90 also improves telomerase production by improving protein folding during telomerase construction (White). It may be beneficial to take heat-shock protein supplements to boost HSP90.

Alpha lipoic acid boosts heat shock protein expression and HSP90 expression, while gamma tocopherol (from peanuts) blocks heat shock proteins (HSPs).

Carnosine and zinc also boost HSP expression. TEXOE boosts HSP70 and HSP27. HSP70 is important for translocation of proteins into the nucleus.

A half an hour before the workout, move to demethylate the hTERT promoter with Vitamin C, and acetylate DNA to expand chromatin and improve transcription with sulforaphane from broccoli sprouts [Wikipedia]. Using broccoli sprouts also provides anticancer protection without using a telomerase inhibitor. Chromatin can also be expanded by acetylating it for transcription from the hTERT gene with HDAC inhibitors such as sodium 4-phenylbutyrate, sodium butyrate, (or possibly the telomerase activators Tricostatin A, or orally bioavailable CGK 1026, which are known telomerase activators). At the same time, take telomerase activators that improve transcription of hTERT mRNA, such as the MAP kinase pathway telomerase activators including astragalus root, astragalus extract, the astragalosides, cycloastragenol, and (possibly feminizing) progesterone, and add the androgenic telomerase activators such as testosterone from forskolin or tribulus, the HIF-1 transcription factor telomerase activators (feminizing-in-overdose Diosgenin from Fenugreek, Ginkgo Biloba, and Ginkgolides) at suitably conservative dosages, EGF from colostrum, HGH secretagogues, and Nitric Oxide boosters such as L-arginine (5-10 grams/day) and L-citrulline (200 mg/day - 1000 mg/day).

Nerve Growth Factor (NGF) boosters such as aceytl-L-carnitine plus alpha lipoic acid, carnosic acid, Huperzine A, PQQ, and rosemary tea promote Id-1 helix-loop-helix transcription factor to activate hTERT mRNA transcription.

There are other telomerase activators such IGF-1 and resveratrol that phosphorylate cytoplasmic hTERT for import into the nucleus. IGF-1 may be taken during the telomerase activation phase of cyclic treatment or prepared from HGH by the liver, but resveratrol should only be used during the final 2-week telomerase inhibitor phase of treatment, because resveratrol is involved in chromatin compaction and gene silencing.

After the workout and before bedtime, take Fenugreek extract (50% extract, 50% seed) at 1-1.5 grams (< 3 grams) to open telomere t-loops for access by the telomerase holoenzyme with Fenugreek's 4-hydroxyisoleucine, which boosts insulin, phosphorylating tankyrase 1 and stripping the t-loop closure protein TRF1. Bear in mind that 3 grams of Fenugreek seed per day for 12 weeks typically endows one with large, pendulous breasts. The high insulin makes one tired and hungry after 0.5-1.0 hours, so plan to sleep through the tired feeling and the munchies. Other telomerase activators exist and might be used in parallel in a "telomerase activator stack" for two weeks, including Haritaki, Purslane extract, and other medicines. The 2nd half of the month should feature telomerase inhibitors and cancer screen medicines and nutraceuticals.
Vitamin C demethylation at CpG sites to promote telomere lengthening
A half hour before bed during the 2-week telomerase activator phase of cyclic treatment, but after taking Fenugreek, it may be useful to take an additional large dose of vitamin C in time-release capsules just before bedtime to promote telomere lengthening.

This may demethylate telomeric and subtelomeric DNA at CpG sites to improve telomere lengthening after building up a high level of fresh telomerase from the hTERT promoter, which will be demethylated for gene activity in the region -150 to +150 base pairs from the transcription start site, although it may or may not be heavily methylated in the region 600 bp upstream of the transcription start site.

However, I could only confirm that vitamin C demethyates DNA at CpG sites in embryonic stem cells. This is to be done for two weeks before applying telomerase inhibitors for two weeks in a monthly cyclic protocol of telomease activation followed by telomerase inhibition.

May 1, 2011 - The 4th Anniversary of my Telomerase Activation Experiments.
See Visionary Sky 75 for satellite weather visions on the threshold of May Day,
with The History and Future of Telomerase Activator Research and observations at
the Vida Institute in Cambodia and in Telomerase Activation Blogs, TA-65 Blogs,
Longevity Blogs, and Life Extension Blogs. See also fenugreek telomerase activator preparations,
a factor in she male longevity.
April 23-25, 2011 - Easter Treats
Fenugreek seeds and Fenugreek Extract (105) [Index] are probably the most cost-effective telomerase activators available, activating telomerase directly via Fenugreek's diosgenin, which upregulates HIF-1 transcription factor to promote transcription of hTERT mRNA, which produces more of the hTERT catalytic component of telomerase. Furthermore, Fenugreek's 4-hydroxyisoleucine [Images] phosphorylates tankyrase 1 by increasing insulin secretions, allowing tankyrase 1 to act as telomeric PARP on telomere t-loops to remove telomere closure protein TRF1, opening the t-loops to allow access by the telomerase molecule.
Niacinamide (Nicotinamide) is also useful in promoting tankyrase 1 expression, and Gymnema Sylvestre may also be used to phosphorylate tankyrase 1 by increasing insulin secretions. Thus Fenugreek, Gymnema Sylvestre, 4-hydroxyisoleucine [Images] and Niacinamide (nicotinamide, a form of Vitamin B3) may be used as t-loop opening, Tankyrase-activating adjuvants for other telomerase activators [List, Index].










L-isoleucine in the Sky with Diamonds:
A scene from the Knee of Orion.
April 22, 2011 - Isoleucine as a highly bioavailable telomerase activator component:
lifexnotes3b3.html ((100.4) C3-(L)-isoleucyl-cycloastragenol was the most bioavailable of the enhanced-bioavailability telomerase activators tested by Geron by Nov.18, 2010, being more bioavailable than cycloastragenol). Note that L-valine, L-leucine, and L-isoleucine are branched-chain amino acids that turn on muscle synthesis.
April 21, 2011 - L-Valine as a highly bioavailable telomerase activator component:
2-(L)-Amino-3-methyl-butyric acid [Images, Papers, Patents, Books; molecule, sources, toxicity; Wikipedia/Valine, Links/L-Valine, Images, Papers, Patents, Books; molecule, supplements, sources]. L-Valine is a branched-chain amino acid that must be ingested, as it is not produced by the body. L-Valine promotes muscle growth and tissue repair, stimulating protein synthesis and boosting the immune system. It appears by Nov 18, 2010 as a Geron exemplary telomerase activator component molecule, a component for a more bioavailable set of telomerase activators like 4 C3-(L)-valyl-cycloastragenol [Images, Papers, Patents, Books; molecule, sources, toxicity], which is, however, no more bioavailable than cycloastragenol.

Cycloastragenol
4 C3-(L)-valyl-cycloastragenol refers to an L-Valine attatched by an ester bond to carbon 3 of the usual cycloastragenol structure in the lower left hexagonal ring, numbering 1,2,3 counterclockwise from carbon 1 at the topmost vertex of that hexagonal ring left of the triangular cyclopropane ring. One wonders about the benefits of taking a mix of L-Valine and cycloastragenol together, as separate molecules. Combining them into one molecule may have largely the same result, if the ester bond is metabolized. However, the bioavailability may be improved by the bound molecule.


April 15, 2011
We now have Terraternal Cycloastragenol at 60 caps x 25 mg/cap for $400.00. This is about the same dose as the most recent papers recommend for TA-65.

Iron Dragon cycloastragenol

Iron Dragon cycloastragenol as a creamy
viscous dark blue, navy, or indigo fluid.
April 7-9, 2011 & April 13, 2011
Preliminary testing shows Iron Dragon cycloastragenol seems to be formulated as a skin cream for transdermal administration of cycloastragenol. However, company literature suggests that Iron Dragon cycloastragenol is not for human use, but is intended for experiments on in vitro cell cultures. It comes as a dark blue, navy, or indigo fluid in a transparent skin cream dispenser marked "Cycloastragenol 5 mg/ml, 60 ml". A correspondent volunteered that "it tastes like heck". According to the fine print: "This product is for laboratory research purposes only. Can be harmful if ingested. Not for human use. Keep out of reach of children." After the seventh day of application to a patch of skin, it seems to burn somewhat. As the Iron Dragon's red eyeballs suggest, the cycloastragenol cream immediately burns one's eyes, just as it seems to cause some irritation in the skin. I once suggested cycloastragenol eye drops, and perhaps Iron Dragon's red eyes are a friendly retort by an experimenter who saw the consequences for himself, as I did. The world is as it is, and not necessarily as Jim Green suggests it may be. Perhaps astragaloside IV eye drops and astragaloside IV skin cream from Terraternal will be superior to corresponding cycloastragenol formulations. Presently carnosine eye drops are used (carnosine-related compounds such as N-acetylcarnosine [IAAS/cataracts]) to extend the lifetimes of cells in the cornea. On the other hand, the Iron Dragon cycloastragenol cream may contain an alcohol or some other ingredient responsible for its irritant property, which takes 7 days to manifest itself. Perhaps it can be conveniently used by applying it in round-robin fashion to different patches of skin in a sequence to get the cycloastragenol into the blood stream via the transdermal route of administration.
February 16, 2011
Should vitamin D be taken together with astragaloside IV? Maximum Telomere Support from Medicinal Nutraceutics offers Astragaloside IV with Vitamin D. Vitamin D conserves telomere length by inhibiting inflammation (J. Brent Richards, et. al., 2007). However, vitamin D3 inhibits telomerase in cancer cells, for instance in hematoloical malignancies, and probably also in normal cells (Satoru Kyo and Masaki Inoue, 2002). Vitamin D3 and retinoic acids are naturally applied together in anticancer treatment. Vitamin D3 and retinoic acid receptors form a heterodimer which interacts with DR3 and DR3' regions in the hTERT promoter to inhibit telomerase. "DR3 consists of two directly repeated pairs of AGGTGA motifs spaced by three nucleotides (DR3), and modulates the expression of Vitamin_D3-responsive genes as a cis-element. Notably, the sequence 5'-AGTTCATGGAGTTCA-3' (named DR3') located at -2530 on the hTERT promoter is similar to DR3." Thus it may be better not to use high-level Vitamin D3 treatment during a telomerase activation phase of telomere enlongation, but to save it for the telomerase inhibition phase of a (monthly) cyclic treatment period.
February 12, 2011
In the future, the substructure of a telomerase activator molecule interacting with DNA may be identified, such that other molecules can be synthesized featuring this substructure. This may lead to the synthesis of more inexpensive telomerase activators with superior bioavailability characteristics.
February 12, 2011 - 10 grams of Vasodilator Arginine for Telomerase Activation Stacks
I suspect that a good parallel combination of telomerase activators [List] is 100 mg of Terraternal Astragaloside IV and 10 mg of arginine with whey protein. After 1-30 minutes, the vasodilation from Nitric Oxide (NO) due to arginine is quite evident in the skin, scalp, and elsewhere, enabling the transport of astragaloside IV metabolites such as cycloastragenol, or telomerase activators TAT2, TA-65, and Astral Fruit NF deep into tissues where they might not otherwise reach. Nitric oxide activates telomerase in endothelial progenitor cells. It also promotes HGH, as does the whey protein. HGH promotes the transcription of the catalytic component of telomerase from the hTERT gene. Then IGF-1 from digestion of HGH in the liver phosphorylates hTERT, enabling its transport from the cytoplasm into the nucleus. This goes best with exercise to promote more Nitric Oxide and HGH generation. I recall that every cell in the body has a receptor for IGF-1. At 10 grams, arginine has a clarifying effect due to improved circulation in the brain that probably improves preparation for college exams and makes driving safer, although it promotes mild euphoria.
I suppose Arginine at 10 grams should be useful for promoting transport of cycloastragenol and other telomerase activators deeper into tissue structure associated with small capillaries enlarged by vasodilation. It may be useful to take gamma tocopherol (perhaps from peanuts) to minimize the negative effects of high nitric oxide tending to produce lipid peroxidation, however. In other words, a telomerase activation stack had better include 10 grams of arginine to activate telomerase in the linings of all veins and arteries to promote telomerase activator transport via vasodilation of capillaries. I can't feel the vasodilation at 5 grams of arginine, while 10 grams makes every fiber tingle pleasantly. This should also rejuvenate the thymus gland, allowing further production of T-cells, for which 5-10 grams of arginine/day is conventionally prescribed. I propose to use this instead of Alpha GPC in the future for the first 15 days of the month, although Alpha GPC (alpha glycerylphosphorylcholine) is a fine addition to this stack to promote HGH and combat old age cognitive decline. Fifteen days of 10 grams of arginine/day is more inexpensive than 15 days of Alpha GPC, costing perhaps $30.00 using Wal-Mart Spring Valley Arginine.
January 23, 2011 Hi-O Silver!
lifexnotes3b2.html (List), lifexnotes3b3.html ((101) Silver), Silver upregulates telomerase in immune cells. "However, the ability of CD8+ lymphocytes to up-regulate telomerase is lost after repeated encounters with Ag (silver) and continued chronic stimulation ultimately leads to critically shorter telomeres and other changes associated with replicative senescence." - after Steven Russell Fauce, Beth D. Jamieson, Allison C. Chin, Ronald T. Mitsuyasu, Stan T. Parish, Hwee L. Ng, Christina M. Ramirez Kitchen, Otto O. Yang, Calvin B. Harley and Rita B. Effros (2008), Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ Lymphocytes, Journal of Immunology, 2008, November 15; 181(10): 7400-7406. Thus, silver can only be used on a temporary basis to upregulate telomerase in immune system cells.
Company Proposals, Papers and Patents for Mixing Up the Medicine. Galaxy M100.

Mixing Up
The Medicine
Subterranean Homesick Blues - Bob Dylan.

January 22, 2011 New Pack: Company Proposals, Papers, and Patents
Strange telomerase-activating flying saucer "9-legged Web spider" tri-phenyl compound molecules from Ben Gurion University on the Negev and new "Enhanced bioavailability" telomerase activators from Geron have surfaced on Internet:
(99)Triphenyl Compound Telomerase Activators developed at Ben Gurion University [Links, Images, Papers, Books]. See Aviv Gazit et al, TELOMERASE ACTIVATING COMPOUNDS AND METHODS OF USE THEREOF, US Patent. (See PDF version.)

(100) Geron 2010 Enhanced-bioavailability telomerase activators.
See (WO/2010/135247) COMPOSITIONS AND METHODS FOR INCREASING TELOMERASE ACTIVITY [Links, Images, Papers, Patents, Books]. Exemplary compounds from the new Geron patent for more bioavailable telomerase activators include:
(1) 2-(L)-amino-3-methyl-butyric acid 6-alpha,
(2) 2-(L)-Amino-3-methyl-butyric acid,
(3) 4 C3-(L)-valyl-cycloastragenol.
and many related chemicals and pharmaceutically acceptable salts including simple hydrochloride salts.
To improve bioavailability, some of the former star compounds, such as astragaloside IV, were modified. For instance, astragaloside IV was converted to 17-[5-(l -Hydroxy- 1 -methyl-ethyl)-2- methyl-tetrahydi'O-furan-2-yl]-4,4J3J4-tetramethyl-tetradecahydro- cyclopropar9, 1 Olcvclopentaraiphenanthrene-3 ß,6a, 16ß-triol f cycloastragenol]. See flash chromatography. Music: Blue Suede Shoes, Granddaddy.
January 15, 2011
Telomerase Activators [List] (95), (96), and (97) were excavated and are being explored:
(95) E1A [Links/transcription factor E1A, Images, Papers, Books]. E1A increased luciferase assay reports of hTERT promoter and hTR promoter activity by up to a factor of 3, and exon 2 of E1A alone was sufficient to introduce a 2-fold increase. E1A was shown to interact with Sp1 sites on the hTR promoter to produce transcriptional activation, (and no doubt similarly on the hTERT promoter). - after (C.J. Cairney and W.N. Keith, 2007).
(96) Ets [Links/transcription factor Ets, Images, Papers, Books] is an hTERT transcriptional activator (C.J. Cairney and W.N. Keith, 2007).
(97) Glucocorticoids [Links/Glucocorticoids; Links/glucocorticoid activation of hTERT, Images, Papers, Books]. Several "putative" binding sites for the glucocorticoid, progesterone, and androgen steroid hormones have been found in the 5' flanking region of the hTR gene and may also be present in the hTERT gene (C.J. Cairney and W.N. Keith, 2007).
January 6-7, 2011
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis.
Perhaps Zinc Finger Nuclease technology for targeted genome editing, antisense RNA technique, engineered targeted migration to lysosomes, engineered targeted migration to the cell membrane, or engineered targeted ubiquination can be used to neutralize senescence problems originating in the accumulation of p16INK4a protein. Perhaps it will be possible to modify a well-understood viral vector such as the adenovirus or AAV virus serotypes to readily insert DNA code for antisense p16INK4a RNA into the genome at a known location. See also tagging proteins for targeted organelle migration and p16INK4a in cancer. P16INK4a is a tumor-suppressor protein from p16 that can become too concentrated in the cell to avoid cellular senescence, so that methods for controlling its concentration are being sought after. I note that carcinogens exist which produce ubiquitination of tumor suppressor gene proteins like p53 and Rb. Note that p16INK4a is built from just 168 amino acids, so that antisense RNA for it may be compactly coded. Note also that Id-1 helix-loop-helix protein downregulates p16INK4a production (Zheng et al. 2004, Ohani et al. 2001), and that Id-1 may be upregulated with Nerve Growth Factor promoted by acetyl L-carnitine, carnosic acid, Huperzine A, rosemary extract, Platelet Activating Factor, and other available supplements. Perhaps p16INK4a can be conveniently regulated with off-the-shelf supplements. Note that Platelet Activating Factor is associated with asthma and is not actually used to elevate Nerve Growth Factor in practice. "At a concentration of 10-12 mol/L, Platelet Activating Factor causes life threatening inflammation of the airways to induce asthma like symptoms." - Wikipedia.
December 29, 2010
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 250–400 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 year x 20 = 2500 bp.
December 13, 2010
Genistein is a telomerase inhibitor. This means soy milk or soy products containing genistein should not be taken while attempting to activate telomerase transcription.
November 30, 2010
"We found through increasing telomerase activity in human cells over a wide range that telomerase association with telomeres as measured by chromatin immunoprecipitation depends on telomerase concentration. Overexpression of telomerase increased its association with telomeric DNA and this was sufficient to elongate telomeres in primary or cancer cells in a length-independent manner far beyond physiological size. Thus, even long telomeres are extendible, indicating that the non-extendible state is not adopted permanently." - Joachim Lingner, Telomerase and chromosome end replication, ISREC. Thus, by achieving high telomerase densities, we expect to be able to lengthen average telomere length in cells, not just shortest telomere length.
November 12, 2010
Recently, I get the impression that one finally gets short telomeres (about 4 kbp) using astragalosides anyway in some cells (see November 11 entry), but the cells are immortal if you keep using it, because the shortest telomere always gets lengthened enough to close, preventing cellular senescence. This means that after several hundred years, you may need to keep taking astragalosides regularly for 15 days every month to keep those telomere t-loops sealed and preserve a youthful appearance. Departure from astragalosides could then result in an accelerated aging phenomenon familiar from movies like Lost Horizon, where immigrants from Shangri-la became suddenly very old after they left the city where their Chinese astragalus root astragalosides were available. In fact, this may actually already have been observed in reality before entering the realm of story-telling literature and music.
November 4-11, 2010
Note that the Anti-Aging Flight Plan chart may be similar if the observed approximate B = -5 years per year rejuvenation rate is due to a reduction in the number of short telomere ( < 4 kbp) cells, rather than to an increase in average telomere length. That this may be true is indicated by recent research on TA-65. (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.) Average telomere length growth may require hEST1A and Replication Protein A to open telomere t-loops when the length is greater than 4 kbp. However, 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 using the TA-65 Patton Protocol. - 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 250–400 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 Michel M. Ouellette, Martha Lia, Brittney-Shea Herbert, Mari Johnson, Shawn E. Holt, Heidi S. Liss, Jerry W. Shay and Woodring E. Wright (2000), Subsenescent Telomere Lengths in Fibroblasts Immortalized by Limiting Amounts of Telomerase, The Journal of Biological Chemistry, April 7, 2000, vol. 275, 10072-10076. October 22, 2010 AKT protein kinase [Links, Images] phosphorylates hTERT in the cytoplasm for import into the nucleus, promoting telomerase activity. This is also true for Protein Kinase C [Index, Links, Images], C-Abl tyrosine kinase [Images], and Protein Phosphatase 2A [Images]. (after Mouldy Sioud, Methods in Molecular Biology, Vol.2, Vol. 361, p.241.) Resveratrol, for instance, phosphorylates the hTERT catalytic component of telomerase via AKT (Index/AKT). Also see Laura J. Mauro and Douglas N. Foster (2002), Regulators of Telomerase Activity, (article), American Journal of Respiratory Cell and Molecular Biology, 26(5): 521 (2002), according to which both Protein Kinase Cα and Akt Kinase phosphorylate hTERT protein, equipping it for return from the cytosol to the nucleus. I note that antioxidants such as glutathione and N-acetylcysteine are believed to keep hTERT protein inside the nucleus. October 10, 2010 (90) ER81 Transcription Factor promotes telomerase activity. September 16, 2010 Activator Enhancer-binding Protein-2 (AP-2) was identified in 2007 as a transcriptional activator of the hTERT promoter. September 13, 2010 VEGFA activates telomerase, according to some reports. August 22, 2010 Fibroblast Growth Factor (88) is a new telomerase activator on our list, although FGF2 (53) appeared earlier. FGF1 through FGF23 are known to exist. FGF1 (aFGF) is acidic Fibroblast Growth Factor, and is used in cosmetics along with Epidermal Growth Factor (EGF) (30), which activates telomerase in epidermal keratinocytes. New illustrations of related products and videos on these developments have been reviewed and included. August 18, 2010 lifexnotes3b2.html (pathway search added to list of telomerase activators). August 16, 2010 Portulaca Oleracea (Purslane) , is now our telomerase activator #87. [Links/Portulaca Oleracea, Images, Papers, Books; Links/Portulaca Oleracea activates telomerase, Images, Papers, Books]. According to Ray Sahelian, MD, "Purslane extract [Links, Images] ... could up-regulate telomere lengths and telomerase activity in PHAS-fed groups." PHAS stands for "Purslane Herb Aqueous Extracts." Incidentally, Astral Fruit-NF, the 3rd generation Astral Fruit product, was described to me in a communication from RevGenetics leadership Anthony Loera as containing "Terminalia Chebula, Portulaca Oleracea, and Astragalus Extract with Cycloastragenol" in a proprietary mix with chitosan and bioperine to improve bioavailability. Anthony refers us to PubMed ID: 15478203 (on Terminalia Chebula), PubMed ID: 17764668 (on Purslane), and PubMed ID: 18981163 (on TAT2, or Cycloastragenol) in his letter. There may be some mistake, as Terminalia Chebula (Haritaki) is described as "alterative" by Pharmacy Escrow. I mean, this could be more for the ladies than for the gentlemen, the 3rd generation "holy ghost" of the Astral Fruit line. Perhaps a 4th generation product is on the way. Perhaps Astral Fruit-NF features faster telomere lengthening by employing parallel pathway activation of hTERT. August 13, 2010 pic2010aug4, pic2010may14, pic2007may modified. August 9, 2010 GAIA Herbs has reintroduced Astragalus Extract in Glycerin at 30 drops per 1 mg of astragalosides, now delivered with a green flag label. This means that we have a superior product on our hands with better-specified content better suiting to our anti-aging therapy experiments. August 4, 2010 Introduced pic2010aug4.html, which contains pictures taken 3.25 years after the start of treatment on May 1, 2007 at Calendar Age = Model Age = 57.961. My model age is 40.1 at calendar age 60.2. The file also contains a list of medicines I am using this month, and is linked to other files in the test series. August 3, 2010 lifexnotes2.html (Time Machine) Nicotine (85) and Ginkgo Biloba (86) were both found to activate telomerase in endothelial progenitor cells. Nicotine and IL-2 both activate telomerase through the Phosphatidylinositol 3'-Kinase/Akt (PI3K/Akt) pathway. In the IL-2 case, Heat Shock Protein 90 (HSP90) acts as a transporter. August 2, 2010 Resveratrol in was included in telomerase activators as (84), as it has been observed to activate telomerase in endothelial progenitor cells via the PI3K/Akt1 pathway. Vince Giuliano thinks that resveratrol inhibits telomerase in cancer cells and activates hTERT in normal cells. We are still checking resveratrol for its telomerase activation characteristics and suitability for cellular rejuvenation therapy. Dosages associated with rejuvenation rates B in years per year are not commonly available. The section on Rejuvenation Rates was modified. August 1, 2010 Introduced improvements in longevity2.html (Rejuvenation Rates), agetransformation.html, and indexlongevity4h.html (HDAC inhibitors). July 24, 2010 Fixed residual recompile errors in 4a.html ,4w.html, 4s.html ,4p.html ,4cf.html, 4an.html , longevity2.html, longevity3.html, longevity4.html, lifexnotes3b1.html, lifexnotes3b2.html, lifexnotes.html, and indexchangelog.html. "He's making a list, and checking it twice..." July 22, 2010 Three files > 256K were split (indexlongevity4a.html, indexlongevity4c.html, and lifexnotes3b.html) into six files and all 40 or so files were recompiled to resolve internal address references to create a new system release with compressed files that will all fit in s5.com.
July 18, 2010
Located hTERT activator candidate (83) Epithelial Growth Factor (EGF) [Links, Images, Papers, Books]. "Growth factors such as epithelial growth factor (EGF) elicit cellular signaling including MAP kinase, Akt and protein kinase C." - Sharyn Baynea and Jun-Ping Liu, (2005) Hormones and growth factors regulate telomerase activity in ageing and cancer, Molecular and Cellular Endocrinology, Volume 240, Issues 1-2, 30 August 2005, Pages 11-22.
July 14-15, 2010
It may be useful to take the histone deaceylase inhibitor (HDAC inhibitor) sodium butyrate [Links, Images, Papers, Books, Wikipedia] during the first 15 days of a cyclic treatment cycle to facilitate transcription of hTERT and hTR while using telomerase activators like astragalus extract. See also sodium 4-phenylbutyrate. The rate of transcription should improve, allowing more rapid telomere reconstruction and faster rejuvenation.
July 12, 2010
Two further telomerase activators, (81) Exercise, and (82) Angiotensin II, were located. Furthermore, Vitamin D3 was pegged as telomerase inhibitor (42).
July 11, 2010
Two new telomerase activators, (79) Shingosine-1-Phosphate (S1P) and (80) Lysophosphatic Acid, were added to my list of telomerase activators under investigation on the hostse system. (79) Shingosine-1-Phosphate (S1P) [Links, Images, Papers, Books]: Shingosine-1-Phosphate activated telomerase in stroke. S1P activates Akt [Links/Akt] and telomerase in brain endothelial cells, suppresses apoptosis, and induces proliferation. (80) Lysophosphatic Acid [Links, Images, Papers, Books]: Lysophosphatic acid activates telomerase in ovarian cancer cells. Uses the PI3K pathway. Most telomerase activators associated with cancer are too dangerous to use for therapeutic activation.
July 8, 2010
Hepatocyte Growth Factor is telomerase activator (78) in my list of telomerase activators now (visible at the hoste site). Also, alpha-glycerylphosphocholine turned out to be excellent in HGH Secretagogues, multiplying HGH by up to a factor of 44 in the presence of exercise. With exercise alone, HGH goes up by a factor of 3. HGH is a telomerase activator, so pumping up with Alpha-glycerylphosphocholine supplements [Images] may be a good strategy for lengthening telomeres. Measurements should be done to confirm this.
June 17-23, 2010
"Degraded dietary polyphenols are potent telomerase inhibitors". Telomerase inhibitors include not only EGCG (found in green tea), but also epicatechin and quercetin, myricetin, naringin, naringinen, and biochanin A. Cacao is a telomerase inhibitor according to Terraternal, no doubt because of its abundance of polyphenols, the flavonoids and flavinols including catechins, epicatechins, and procyanidins. See Imad Naasani, Fujiko Oh-hashi, et al., (2003), Blocking Telomerase by Dietary Polyphenols is a Major Mechanism for limiting the growth of Human Cancer Cells in Vivo, Cancer Research, Feb 15, 2003, 63: 824. This is impacting to our telomere lengthening program of 30-day cycles of 15 days telomerase activation ON, 15 days telomerase inhibition ON. Polyphenols including cocoa beverages or chocolate presently taken for antioxidant protection should be dropped during the first 15 days to avoid interference with telomerase activation during the first part of the cycle. Polyphenols should be taken only during the 2nd 15-day period, when telomerase inhibitors are applied. This should result in a faster rate of telomere growth to support rejuvenation. This led to descriptive changes to describe the impact on diet during our telomere-lengthening rejuvenation program for 30-day cycles of 15 days of telomerase activation followed by 15 days of telomerase inhibition. I get the impression that a low polyphenol diet for a cyclic phase of telomerase activation might be devised from skim milk, fish and meat, and from a list of links to high and low polyphenol foods. There must be some plants whose polyphenol degradation products do not include telomerase inhibitors, but these have not yet been identified. On the other hand, milk seems to bind EGCG and tea polyphenols, so that milk should not be taken when polyphenols should be high. See Debora MacKenzie, (2007), Milk Wrecks the Health Benefits of Tea, New Scientist, 01/09/2007. See also GeneSmart/List of High Polyphenol Foods and Low Polyphenol Foods and High and Low Polyphenol Food Links.
June 14, 2010
The rejuvenation tables featuring portraits of Jeanne Calment have been expanded and modified to include B = -5, -8, and -9 years per year rejuvenation rates. Costs and calandar age at target model age have been computed for each value of B. The basic cost per month for telomerase activators ($76.00) has been revised upwards for our present program of therapy, which is also defined.
May 28, 2010
Uncaria sinensis Havil (77), which delays telomere shortening, was added to my list of telomerase activator candidates. Main essay upgraded through (3).
May 26, 2010
New material starting from LEF's June 10, 2010 Inteview with Dr. Michael West on iPS cells (induced Pluripotent Stem cells) and resetting telomere length in section (8) in longevity3.html. Also upgraded index entries on testosterone and acai (hostse only).
May 22, 2010
I upgraded the description of the rejuvenation program in lifexnotes2.html to include extra Solaray Astragalus Membranaceus Root (6x400 mg/day) for astragaloside bioavailability enhancement, early daily pretreatment with 6 sprays of Now Foods IGF-1 liposomal spray for telomerase activation acceleration, and scalp treatment with GAIA Herbs astragalus extract in glycerin to restore hair and hair melanocytes.
March 26, 2010
It may be possible to transport telomerase directly through the cell membrane in cationic liposomes, made with cationic transfection reagents via liposomal endocytosis. This can be done for DNA plasmids, RNA, and various proteins. A number of protein targeting techniques exist for the cell membrane. On the other hand, cationic liposomal transfer of antisense telomerase RNA is used in cancer therapy. Perhaps liposomal transfer of telomerase RNA would be useful in rejuvenation therapy. I note that liposome aerosols have been used for transfection, so that aerosol liposome rejuvenation of the lungs may be done. In old China it was noted that astragalus users sometimes lived until they finally died of whooping cough. (July 2010 - This month I am using Now Foods IGF-1 Liposomal Spray, probably a liposomal aerosol.)
March 16, 2010
Press for Zinc Finger Nuclease videos.Zinc Finger Nuclease Technology for Targeted Genome Editing is ready to go from Sigma Aldrich/Zinc Finger Nuclease Technology. Zinc fingers can be assembled from Sigma Aldrich standard components to fit gene patterns. A pair of zinc finger nucleases making up a catalytically active FokI dimer that functions like scissors at a specific site in the mouse, rat, or human genome can be packaged with a DNA repair template insert (with overlapping hybridizing DNA wings) including a desired gene sequence and delivered to the cell by electroporation or transfection with liposomes made with cationic transfection reagents. This strips the genetic sequence one specifies into the genome where one wants it to go. You just order it up from Sigma Aldrich, and they will send you the package to do the job. They also supply gene knockout packages and other gene-task packages. For instance, they have one that integrates a plasmid from a liposome into the AAVS1 [Wikigenes] site where the AAV adeno associated virus integrates into the human genome on chromosome 19. There are indications that the human genome can be painlessly modified using plasmids in liposomes made from Invitrogen transfection reagents. On the other hand, electroporation may be used to prepare genetically modified cell cultures or modified blood fractions. Using Zinc Finger Nuclease technology you might strip a gene into your own genome for more SOD or MnSOD, or to install an extra copy of hTERT to stay young with, someday soon. ZFN HIV therapy may be available now to be applied by transfection or electroporation with subsequent transfusions or stem cell transplants. Also see Nucleofection and Sangamo Biosciences.
March 13-14, 2010
I noticed that Lipitor (atorvastatin) should be life-extending via its activation of telomere binding protein TRF2. Applying Lipitor at the M1 state with 4000 remaining base pairs should yield about 4000/50 = 80 further cell divisions and lifetimes on the order of 220 years. The additional cell division capacity should strengthen the immune system. The closure of telomere t-loops by TRF2 should remove senescence effects. Zocor (simvastatin) is even more powerfully stimulating for TRF2 expression that Lipitor (atorvastatin), which costs about $65/month. Extra CoQ10 or ubiquinol should be taken, along with a homocysteine shield and antioxidants, including mitochodrially effective antioxidants like alpha lipoic acid and drugs like acetyl L-carnitine. Perhaps the most effective program for antiaging will begin with atorvastatin and end with cycloastragenol/resveratrol cycles. This analysis, however, needs experimental verification and requires more study, including side-effects analysis.
Also, it became clear that AAV adeno-associated virus transfection with artificial genes featuring (say) hTERT promoters with DNA code for peptide bioregulators like epithalon peptide (Ala-Glu-Asp-Gly), Livagen (Lys-Glu-Asp-Ala), or Vilon (Lys-Glu) might be useful in genome redesign for physical immortality. AAV serotypes 1-12 are mild by comparison with adenovirus transfection and always integrate into the genome at the same site AAVS1 [Wikigenes] on Chromosome 19.
March 1-12, 2010
Installed hyperlinked improvements to the Index, and am expanding review of adenovirus, adeno-associated virus, plasmid, and other transfection technologies in gene therapy. Fixed a small class of dead links introduced by the last index recompile.
Feb 25-28, 2010
Information relevant to life extension in an email to my attention was divulged by me to this publically visible file system for < 48 hours. Subsequently, I stripped it out after an email plea not to divulge the information. See Visionary Sky 51, image (51.2) for The Big Picture continental cloud cover mythical mind-mirror of the event, featuring a Big Bad Wolf in a Fedora. I felt like Wiley Coyote feels when Road Runner has Beep-Beeped him. However, I was paid with valuable leading information via the "Pay O tea" method. Feb 12, 2010 The Index was divided into 26 new easily expandable version 4 Index files and recompiled internally with minor expansion. Feb 4-7, 2010 Found telomerase activators [Index] (73), Id1 helix-loop-helix protein (activated by Nerve Growth Factor and Platelet-Activating Factor). Nerve Growth Factor may be expressed by taking carnosic acid. I also added telomerase activator (74) Stem Cell Factor (Kitl) and (75) Bcl-2, which is up-regulated by IL-2 (also listed as a telomerase activator), which is activated by astragalus membranaceus extract or astragaloside IV. Activator (76), Replication Protein A, was also found, which I have described with hEST1A, the human homologue of EST1p in yeast, also a telomerase activator, while including EST1p and hEST1A in (7) under EST1. These entries have been refined in order to better search for associated small-molecule activators enhancing expression of the various new factors now known to activate telomerase. The existence of TERRA telomeric RNA, transcribed from subtelomeric DNA towards the end of the chromosome when telomeres are uncapped and telomeres less effectively mask transcription of nearby genes via the telomere position effect, has been described in connection with possible transcription-active DNA repair of telomeres. Ordinarily, lack of chromosomal DNA repair taking place during gene transcription is associated with Cockayne syndrome. Associated new insights have led to supplemental modificiation of section (7) on telomeres and telomerase. Feb 2010 Started direct application of astragalus extract in glycerin to my scalp. Jan 2010 Life Expectancies was added to supplement Mortality Charts. Dental was upgraded and more hyperlinks added throughout Longevity to improve references. Better references and internal crosslinking were provided all through Lifexnotes3a. Dec 10-14, 2009 Refinements are being added to the footnotes, and more internal links to the index are being worked out. The role of various antiaging factors in the causes of death and the diseases of old age is being more carefully studied, revised and linked to Internet journals, professional sources, and internal material. More evidence has accumulated that DNA repair in general is enhanced by hTERT activation, so we feel on firmer ground with telomerase activation therapy based on TA-65, astragaloside IV, cycloastragenol, astragalus extracts and IGF-1 with Vitamin D than ever. Still more references and material are accumlating on telomerase inhibitors and telomerase activators, of which 72 are now cataloged here, including both medically useful and medically dangerous varieties interesting for their connection to the theory of cancer. Dec 1, 2009 Added a final section in (9) on the dangers of exercise for elderly in the presence of arteriosclerosis, as an elderly reader acquired an anuerysm from doing bench presses. He claimed to be hitting the ice cream too hard. "I had severe hardening of the arteries AND an aneurysm in right subclavian artery [Images], symptoms surfaced suddenly in early November 2005. Large quantities of whole milk products and ice cream consumed for last 50+ years. I was using over 210 pounds resistance in "pec deck" exercise, you can visualise the arterial stress on abnormal structures and reason for aneurysm formation." Today I read he has improved: "However, symptoms were alarming and I regarded them as life threatening. Based on completely normal response to exercise stress, the vascular abnormalities were fully resolved, because symptoms such as I had cannot be cured without some sort of intervention. 92.4% of bodyweight x 4 in strict overhead press and no symptoms, an aneurysm would scream if it were present. If I could have only one healthy substance, I would choose lemons ten times out of nine. DMSO is of interest in some situations. Gotu kola is among the botanicals I take." My advice is not to eat lemons, however, as they attack the enamel of our teeth by unacceptably lowering the pH to a very acidic point. As for arteriosclerosis, I was recommending supplementing vitamin K2, which can cause calcium transport from hardened arteries back to the bone by promoting the formation of osteocalcin. The hardening of the arteries might have been the result of glycation from the sugary ice cream and consequent cross-linking of proteins in the vascular endothelium, which can cause collagen stiffening in the arterial wall. Otherwise, Colostrum (TA/Colostrum), mother's milk for newborns, was added as (68) to my list of telomerase activators, as it contains EGF, Epidermal Growth Factor (TA/EGF), the known telomerase activator (30). Most recent effort has been devoted to upgrading index entries and cross-links. Nov 17, 2009 Added a table: Estimated Rejuvenation Times = T to Target Model Age t1 from Starting Age t0 for a B= -5.2 years/year rejuvenation rate, with Chronological Age After Treatment = t0 + T. The table was appended to Age Transformation and some other files. This one helps aging witnesses look up or compute the estimated time to rejuvenate from a given starting age to some target age using off-the-shelf astragalus extracts. For the cloud cover response to this news, see VisionarySky46/Space Embrace (46.6). Otherwise, some new links are being added to better furnish the index. Nov 13, 2009 Computed a Calvin B. Harley rejuvenation constant of about B = - 5.2 years per year for astragalus extract, based on casual observations, and removed systematic errors from my table of associated computed values in Age Transformation. B = -8 to -9 years per year for TA-65 according to more careful measurements of telomere length done by TA Sciences, where at first Model_Age = Bt, until Model_Age = B'Δt + t0 at some breakpoint t0 downstream. Here B < 0 for rejuvenation, B = 0 for zero aging, B > 1 for accelerated aging, and B = 1 for normal aging. Some day we may find at B(t0) is a function of t0 for very old people, probably slower at older ages. In general, we may modify B(t) by introducing medicines, exercise, and diet therapies at switch points t0, t1, t2,.... Of course, charts of measured telomere lengths and other variables relevant to rejuvenation as a function of time in various tissues such as blood granulocytes and leukocytes would convey a superior physical and realistic representation of the process useful for feedback in treatment.
I think we are about to enter a domain in which longer life could be insured by a Gort-style suit of armour to be worn in an underground shelter during tornadoes, perhaps a padded leather suit lined with kevlar and selectively reinforced with metallic or durable hard plastic components. This would protect against flying debris. Such a garment might also help reduce automobiles to bumpem cars like we rode in amusement parks as children. Components of the suit might be carried in the trunk of a car, or be packed away in a closet. I think of Gort from The Day the Earth Stood Still (1951). Someday soon perhaps most human deaths will be due to storms, accidents, collisions, and disasters, since heart attack, stroke, cancer, and death from old age may be decisively beaten.


I am also reminded of the movie Forbidden Planet (1956), in which the id-monster of
Dr. Edward Morbius continually renews its molecular structure.
Don't miss Jim Green as Cal Mecham in This Island Earth (1955).
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 off-the-shelf astragalus extracts. Phase III: For 64.3 < t < infinity, B = 0, Model Age = 25. October 22-23, 2009 Developed an index entry on Telomere t-loop control proteins (the shelterin complex, or the telosome) with associated structures and molecules. Also found another telomerase activator (67) that is fairly available, Terminalia chebula [Links, Images, Papers] (Combretaceae) [Links], Haritaki [Links, Images, Papers], to be precise, the ethanolic extract from the fruit of Terminalia chebula (Combretaceae), or Haritaki, also termed chebulic myrobalan [Links, Images, Papers,]. See MinKyun Na, KiHwan Bae, Sam Sik Kang, Byung Sun Min, Jae Kuk Yoo, Yuko Kamiryo, Yu-ichiro Senoo, Seiichi Yokoo, Nobuhiko Miwa, (2004), Cytoprotective effect on oxidative stress and inhibitory effect on cellular aging of Terminalia chebula fruit, Phytotherapy Research, Volume 18 Issue 9, Pages 737 - 741, Published Online: 11 Oct 2004. This one is a popular panacea in Aryurvedic Medicine and is available from specialty pharmacies. See also [Links/Terminalia chebula fruit extract, Images/Terminalia chebula fruit extract]. Also known as Haritaki [Links]. See Haritaki Extract [Images, Links]. Chebuloside II, a pentacyclic triterpene glucoside also described as a triterpenoid glycoside, [Links/Chebuloside II, Article including the molecular structure of chebuloside II (p.113)] is used as a marker for the quality of the ethanolic extract. Note: "Haritaki" is described as "alterative" by PharmacyEscrow.com. Neurobiology of Aging 29(9), 1,404-1,411 - Mice that took creatine monohydrate lived 10% longer than mice that did not take creatine monohydrate. - recently quoted in Muscle & Fitness. Bender, A, et al. Creatine Improves Health and Survival of Mice. Neurobiology of Aging, 2008; 29(9): 1404-1411, quoted in Simply Shredded. "In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species and significantly lower accumulation of the "aging pigment" lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data show that Cr improves health and longevity in mice. Cr may be a promising food supplement to promote healthy human aging. " - from Bender A, et al., 2008. October 13, 2009 - The Day After Columbus Day Discovered the role of zinc in maintaining long telomeres and the associated mysteries, which are now recounted in the Index entry for Z. Most men get about 14 mg/day, women 9 mg, while the optimal dosage is perhaps 45 mg Zinc/day, which is sometimes used to improve the size of a load of semen, which is rich in both zinc and cells with long telomeres. Note that "oysters" are the food richest in zinc. On the other hand, 80 mg/day of Zinc increases hospital admissions in older men, and large doses of several hundred milligrams or more can expose the role of zinc as a neurotoxin and/or unacceptably lower copper levels. October 5-6, 2009 The first edition of the new 2009 release will be on-line today, featuring 5 huge files (4 of them index files) changed into 10 shorter ones, with some search code optimization, expansions, a better index, more search options, and other improvements. The new system is more expandable and should fit into systems that require files < 256 Kb in length, which was getting to be a stumbling block. It may be a week or two before any new internal bugs have been corrected. Off-line code review and optimization may continue for a week or two yet. Oct.6: code-optimized index ab,cd,eh,il. September 29, 2009 The longevity system is being overhauled off-line with redivision into smaller files and recompilation to reset internal pointers. At the same time, some sections are being expanded or rewritten. Expect a new release in mid-October, 2009. September 15, 2009 Added index section on sesame oil and sesame seeds, while investigating the effect of toasting on toasted sesame oil, which is said by some to convert oleic acid into relatively harmful trans fats. I thought perhaps some AGEs might be present in brown toasted sesame oil. Earlier, I added Biocarta Pathway information on telomerase activation via IGF-1 and Epidermal Growth Factor receptors in cell walls. September 4, 2009 Deduced today that beta ecdysterone (20-hydroxyecdysone) may be a telomerase activator like ecdysone, because the molecules closely resemble each other. Beta Ecdysterone is found in spinach and is sold in concentrated from as an anabolic steroid to improve protein synthesis in bodybuilding applications. Beta ecdysterone is now telomerase activator candidate (54), whereas ecdysone is (16). September 2, 2009 Improved the IGF-1 index entry. IGF-1 is a telomerase activator that has anti-aging effect. NOW IGF-1 Liposomal Spray (NOW, about $25.00 at Whole Foods) and NOW IGF-1 Lozenges for Anti-Aging [NOW] are available. Side effects have not been a problem when the products are used as specified by the manufacturer [A1], and anti-aging effects are reported. See IGF-1 from deer antler [Links]. Since IGF-1 increases the risk of prostate cancer by about 4x, a Prostate Specific Antigen (PSA) test is recommended in connection with the use of this class of product [LifeExtension/IGF-1 and Aging]. Vitamin D and pomegranate softgels have been recommended when using IGF-1. August 31, 2009 According to Erusalimsky, 2009, Vascular endothelial senescence: from mechanisms to pathophysiology, nitric oxide (NO) seems not to upregulate telomerase in endothelial cells after all, but to get its benefits by upregulating SIRT1. 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, Exp Gerontol 42: 904–910, 2007. August 27, 2009 RevGenetics now markets the telomerase activator cycloastragenol as Astral Fruit-C, with 5 mg/dose of cycloastragenol and added chitosan to improve bioavailability, now for under $70/month. Cycloastragenol [Links] is the common alglycone of the astragalosides. August 15, 2009 Peanuts are a good source of gamma tocopherol, but sesame seed oil also contains sesamin, a sesame lignan. August 13-14, 2009 Updated longevity3.html (10): Daily grape juice consumption reduces DNA damage and plasma free radical levels. [Mutation Research, 2003.] [Links/DNA age damage reduction, Links/reducing DNA damage]. See Tocotrienols Could Reduce DNA Damage That Leads To Cancer. Folic acid [Links/Folic Acid & DNA repair, Links/Folic Acid, Folic acid supplements could boost DNA repair, says study (1.2 mg folic acid/day used)] and Cat's Claw Extract [AC-11] are also useful as DNA repair supplements. " DNA Repair Adjuvants (article): DNA repair promoters or adjuvants can be divided into three categories: (1) minerals (e.g. selenium and selenomethionine), (2) carboxyl alkyl esters i.e. AC-11 (formerly known as C-MED-100 derived from Cat’s Claw [Uncaria tomentosa]) and (3) Dimericine, a DNA repair enzyme, (T4 endonuclease V) encased in liposomes." Also see Human DNA Repair Genes. Ubiquinol CoQ10 [Links/ubiquinol, LifeExtension/ubiquinol, Biosynergy Ubiquinol, Kaneka QH Ubiquinol] shields nuclear and mitochondrial DNA against free radicals, regenerates vitamin C and vitamin E, and is used to eliminate lipofuscin, eliminating old age spots and lipofuscin from heart muscle. It helps mitochondria process fatty acids, improving neurological energy levels and vitality in general. The anti-aging effect of ubiquinol on experimental rodents and their pelts can be very noticible indeed [LifeExtension/ubiquinol] making ubiquinol a credible mainstay in treatment of mitochondrial factors in aging. August 12, 2009 Improved index entry for Telomerase Regulation. Added WISTAR Instiute to the lifexlabs.html list of Academic Labs and Programs. Novel Telomerase Activators [Links] have been proposed in Israel at the WISTAR Institute based on the design of molecules to regulate telomerase. See WISTAR professor Emmanuel Skordalakes PhD [Links, Papers, Images]. August 11, 2009 Located some new telomerase activators [Index] for T-cells and filed them in lifexnotes3.html under Telomerase Activators as entries (50), (51), and (52): (50) Anti-CD3 monoclonal antibody (mAb) induces telomerase activity in human peripheral T cells. (51) Ca ionophore, a stimulant that bypasses T-cell receptor (TCR) signaling, induces telomerase activity in human peripheral T-cells. (52) Phorbol 12, 13-dibutyrate (PDB) [special hazard: tumor promoter], another stimulant that bypasses nduces telomerase activity in T-cell receptor (TCR) signaling, inducing telomerase activity in human peripheral T-cells. August 10, 2009 Added improvements to Tricostatin A and IGF-1 entries in the index. Added Richard M. Cawthon's Feb 2009 paper in Nucleic Acids on new technique for measuring telomere lengths to lifexlabs.html. August 8, 2009 Ran out of Tripod memory, froze site at August 6, 2009 on Tripod. The longevity.html site continues to develop at AngelCities and S5. Today I discovered Juvetea, which contains ginseng and other components that make it a telomerase activator. It was entered in the index and under telomerase activators/JUVETEA in lifexnotes3b2.html. July 21, 2009 Added index material added on arthritis, a condition that becomes aggravated in old age (roughly mirroring cardiovascular disease, which is related to the progressive senescence of the vascular endothelial cells) as chondrocytes become senescent and joint injuries heal less readily. July 14, 2009 Added a section on cancer prevention via telomerase activation to produce long-telomere cells more resistant to cancer, especially carcinomas, in agetransformation.html, and updated my photo collection of dry and wet age transformation photos. July 12, 2009 Considered higher doses of astragalus extract and alternatives in agetransformation.html, and embellished Reprogramming Height in the same file. July 11, 2009 Upgraded Mortality Charts with more links to relevant charts. July 8-9, 2009 Upper Bound and lower bound estimates with relevant ratios: New calculations estimated 27.44 mg of astragaloside IV per 6 x 200 mg Solaray Astragalus Root Extract pills, using figures from hairy roots of astragalus membranaceus prepared in bioreactors. This upper bound figure must be quite high due to the choice of hairy roots raised in reactors. Earlier calculations based on ethanolic extracts from the big plant roots (radix astragali) of astragalus membranaceus suggested 5 mg of astragalosides per 6 Solaray capsules. July 2, 2009 Added more material and reference links to my somewhat speculative remarks on Reprogramming Height at the conclusion of Age Transformation. June 25, 2009 - June 26, 2009 The S index entries for Senescence and Senescence Pathway were updated to include more material on details of cell cycle arrest at M1, p53 tumor suppressor and p16/Rb cell cyle involvement in the halting of the cell cycle, possible frustration of the M1 cell cycle halt at about 4000 base pairs of telomere length leading to the still shorter-telomere crisis state M2, and cancer. References were included for telomerase activators such as astragalus extracts, TA-65, cycloastragenol (Medicass), Astragaloside IV [RevGenetics, Terraternal, Links] for escaping from the M1 senescent state by lengthening telomeres to close the telomere t-loop to remove the double-strand DNA damage signal leading to the halting of the cell cycle. June 15, 2009 Nicotinamide: [Links/extends replicative lifespan of human cells, Links/nicotinamide, Links/nicotinamide supplements, Amazon, Life Extension/nicotinamide]. With regard to human fibroblast telomere shortening experiments, " Continuous treatment with nicotinamide, which led to lower ROS generation and changes in mitochondrial function, has been reported to extend lifespan (a remarkable 1.6-fold increase) and decelerate telomere shortening (Kang, et al., 2006)", from Telomeres and Telomerase in Ageing, Disease, and Cancer: Molecular Mechanisms of Adult Stem Cell Aging, ed. K. Lenhard Rudolph. See Kang HT, Lee HI, Hwang ES (2006), Nicotinamide extends replicative lifespan of Human Cells, Aging Cell, 5(5): 423-36. June 13, 2009 Added material on the IGF-1 pathway and IGF-1 telomerase activation for anti-aging to the index under IGF-1, including NOW IGF-1 Lozenges for Anti-Aging and NOW IGF-1 Lipospray for sublingual administration. See also the IGF-1 receptor [Wikipedia, Links]. IGF-1 is a risk factor in prostate cancer and breast cancer (Wikipedia). IGF-1 can induce hypertrophy of skeletal muscle and other target tissues. May 16-19, 2009 Refined the newly added Astragalus Extract Program 2 Year Point, added the movies SixtyFortyTwo, YouTube, 51 seconds, Astragalus Extract Treatments, Daily Motion, 2 minutes, 32 seconds, and HairClippings, Daily Motion, 1 minute, 05 seconds. May 8, 2009 Added Einstein Greying (with Physiological Factors of Aging). May 2, 2009 Upgraded agetransformation.html and other files. March 16-26, 2009 GAIA Herbs Astragalus Root Extract was formerly available at 1 mg of astragalosides per 30 drops to support our experimental program for cellular rejuvenation using small molecule telomerase activators to reconstruct chromosomal telomeres featuring 5 mg/day astragalosides for two weeks on, then two weeks off. Since it is no longer available, I have substituted 1200 mg/day of Solaray Astragalus Root Extract to cover the 5 mg of astragalosides, which requires 6 x 200 mg capsules per day in a cyclic protocol featuring 15 days on, then 15 days off. Although this exceeds the recommended dose according to Solaray, I believe from toxicology studies that it is safe enough. Reconstructing cellular telomeres using activation of telomerase closes chromosomal t-loops in senescent cells, restoring the youthful phenotype and patterns of gene expression at a rejuvenation rate approaching 0.75 years per month. Another alternative is Herbal Remedies Astragalus 1.25 mg astragalosides per 250 mg cap, via Nature's Way, ( Standardized 0.5% Astragalosides ), 60 VCapsules per bottle, incuding Astragalus, dried extract 250mg (root) 0.5% astragalosides, with Astragalus (root) 250mg. Four capsules yield 5 mg astragalosides plus 1 gram of astragalus membranaceus root, which improves bioavailability of astragalosides. January 26, 2009 hTERT promoter [Links, Books, Patents/hTERT promoter, Papers, Amazon, Books/human gene promoter and repressor design, Books/transcription promoters]. See Morin, et.al, the Aug. 17, 2004 Geron patent Telomerase promoter driving expression of therapeutic gene sequences. See also M Wick, D Zubov, G Hagen, 1999, Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT), Gene, Volume 232, Issue 1, 17 May 1999, Pages 97-106. Furthermore, don't miss Cong, YS, The Human Telomerase Catalytic Subunit hTERT: organization of the gene and characterization of the promoter, Human Molecular Genetics, 1999, vol.8, no.1, 137-142. See also Yu-Sheng Cong, Woodring E. Wright, and Jerry W. Shay, Human Telomerase and Its Regulation and Izumi Horikawa, P. LouAnn Cable, Cynthia Afshari and J. Carl Barrett, 1999: Cloning and Characterization of the Promoter Region of Human Telomerase Reverse Transcriptase Gene , Cancer Research, 59, 826-830, February 1, 1999 [Papers, Books]. See also Telomerase, Aging and Disease (Advances in Cell Aging and Gerontology) by M.P. Mattson, Elsevier, 2001. Note c-Myc activates hTERT promoter [Wu, Nature Genetics, 1999, Links, Links, Books, Papers]. Dr. Michael Fossel suggests using c-Myc plasmids (perhaps with supplemental controls, such as telomerase inhibitors, of course) to activate hTERT in human cells for life extension in Cells, Aging, and Human Disease. "The hTERT promoter lacks TATA and CAAT boxes and is in a CpG island with an E-box (CACGTG) binding site and sites for Sp1 and several for c-Myc... hTERT and c-Myc are expressed in actively dividing cells, but down-regulated in non-dividing cells. ... C-Myc rapidly and directly induces hTERT expression." (M.Fossel, p.286). See also Theodora R. Devereux, Izumi Horikawa, Colleen H. Anna, Lois A. Annab, Cynthia A. Afshari and J. Carl Barrett, 1999. DNA Methylation Analysis of the Promoter Region of the Human Telomerase Reverse Transcriptase (hTERT) Gene, Cancer Research 59, 6087-6090, December 1, 1999. See also Joseph C. Poole, Lucy G. Andrews and Trygve O. Tollefsbol, Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT), Gene, Volume 269, Issues 1-2, 16 May 2001, Pages 1-12. Note that the hTERT promoter for the catalytic component of telomerase contains binding sites for the transcription factor Sp1 [Links, Papers, Books] and for the transcription factor c-Myc [Links, Papers, Books; Wikipedia/C-myc]. Binding sites for the estrogen receptor [Links] and the progesterone receptor [Links] are also found in the hTERT promoter, and it has also been reported that protein kinase C [Links, Books, Books/protein kinase C and telomerase] is involved in the regulation of telomerase activity. It has also been shown that Akt Protein Kinase [Links; Links/Akt Protein Kinase and telomerase, Books] is associated with two receptor sites on the hTERT promoter. See Sang Sun Kang, Taegun Kwon, Do Yoon Kwon, and Su Il Do, Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit, J Biol Chem, Vol. 274, Issue 19, 13085-13090, May 7, 1999. Fixing up this hTERT promoter section seemed to have psychic impact: I woke up on the morning after its preparation with Deck the Halls joyously ringing in my ears as like a distant response from pleased readers, as if from a chapter scene in A Christmas Carol by Charles Dickens. January 6, 2009 Our program for eliminating senescent cells by restoring their youthful phenotype with telomeric DNA repair enzyme activators [Books, Papers, Amazon/telomeric DNA repair] that lengthen the telomere until its terminal t-loop closes, removing the DNA damage signal leading to cellular senescence (such as ethanolic astragalus root extract) seems to work. (It may also be useful to supplement with DNA double-strand break repair acceleration products like AC-11 as well as DNA damage defense products like L-carnosine, vitamin C, and homocysteine shields, although these have mainly foot-dragging effect on aging rather than the backwards-in-time rejuvenation effect associated with telomere reconstruction). However, the rejuvenation rate of 0.667 to 0.75 years/month corresponding to 400 to 460 base pairs of telomere growth per year seems glacially slow, and it seems obvious that in the future deeper knowledge concerning dose dependence, cofactors, alternate drugs, and other factors will accelerate cellular rejuvenation rates. Our present program (7) is conservatively specified for safety. Later, we may find that dose dependence is linear and safe over a wider region. Whether 4x as much extract gets rejuvenation 4x as fast safely is unknown. Relatively large doses of TA-65 or astragaloside IV [RevGenetics] may be effective and safer than astragalus extract. Improving the bioavailability of astragalosides with Chitosan or sodium deoxycholate is a related issue. I presently take my astragalus root extract at 5 mg of astragalosides per day for half of the month, with 4 capsules of Natural Balance Chitosan (250 mg x 4) at each serving. On the other hand, we may find that astragalus root extract rejuvenation is limited by hTR transcription rates for the RNA component of telomerase. It may be useful to accelerate this with HDAC inhibitors that acetylate chromatin DNA and expand the chromatin for transcription like sodium butyrate or Trichostatin A. Finally, it seems that astragalosides are treated like nuclear superfamily transcription factors complexed with the heat shock protein Hsp90 [Links, Wikipedia, Books, Amazon, Papers] before tranfer into the nucleus of the cell. It may accelerate matters to improve Hsp90 expression by some means, perhaps by raising Interleukin 6 levels [Links, Books, Papers, Amazon] via exercise. We might pump up just before taking our astragalus root extract with Chitosan to facilite its march into the nucleus complexed with Hsp90 elevated by the exercise session. Magnesium is a cofactor for the DNA helicase found in telomeric chromatin, so magnesium supplementation may be a factor in getting results more quickly. Availability of inexpensive telomere length measurements should help us determine scientifically what the facts of the matter are, and as results are published to Internet our program for rejuvenation may improve. Incidentally, the telomerase inhibitors used in the 2nd two weeks of the telomere remodeling cycle (when telomerase activators are not used) should include the well-established longevity enhancers resveratrol and melatonin. Of course, a program that fixes the entire problem forever with just one application of a cleverly designed viral vector to modify host DNA may emerge, making all these alternate approaches obsolete and creating new races of physically ageless men. December 30, 2008 Note that Terraternal sells telomerase-activating Astragaloside IV skin cream. I note that lipophilic substances can get through the skin for transdermal drug application [Books] without liposomes, otherwise a liposome cream [Books] is used. Incidentally, I get the impression that orally ingested small molecule telomerase activators also finally get through to dermal fibroblasts, so that application in skin creams may not be absolutely required for skin rejuvenation when using astragalosides or astragalus polysaccharides. The reconstruction of the extracellular matrix controlling skin quality and wrinkles takes somewhat longer than refreshing grey hair melanocytes, since it happens after the number density of senescent cells has declined (due to telomere reconstruction) to the point that substances attacking the extracellular matrix such as collagen and stromelysin are much less abundant in tissue, while collagen and elastin return from newly restored fibroblasts for skin restructuring. At a telomere reconstruction rate of 400 to 460 base pairs per year corresponding to a 8 to 9 years per year rejuvenation rate, results register more slowly in old skin than in hair root melanocyte replacements originating from rejuvenated adult stem cells. December 23, 2008 Activation of telomerase via NO (nitric oxide) activation [Links, Books, Papers] in endothelial cells lining the arteries [Vasa, et al., 2000, Hayashi, et. al, 2006, Haendeler, 2006] can be implemented by taking 3 grams of L-arginine prior to a workout. (Nobelist Louis B. Ignarro recommends 4-6 grams in NO More Heart Disease, together with L-citrulline and 4 antioxidants.) At this dosage, we also often experience thymic gland reactivation [Links], so that the thymus renews its production of T-lymphocytes. The range of telomerase activation with Nitric Oxide produced via nitric oxide synthases is short, because of the short half-life of nitric oxide amounting to just a few seconds [Links], but it seems likely that rejuvenation of the thymus gland may be due to telomerase activation, and that components of the blood such as the primary hematopoietic stem cells [Wikipedia] may also experience telomerase activation via this mechanism. "Endothelial progenitor cells (EPCs)...are considered to derive from hematopoietic stem cells". Perhaps working out twice a day with 3 grams or more of L-arginine prior to each workout will turn out to be a useful rejuvenating strategy for cells derived from hematopoietic stem cells [Links], such as brain microglial cells as well as the endothelial cells. L-Arginine, L-citrulline [Links], and antioxidants (vitamin C and E) have been useful in generating NO for endothelial rejuvenation [Hayashi, et. al, 2006]. L-arginine and L-citrulline may be more useful when taken together, and applicable in skin creams to skin rejuventation applications. Nobel Prize winner Dr. Louis J. Ignarro recommends 4 to 6 grams of L-arginine per day for physiologically effective NO generation, plus L-citrulline to maximize it's effect, together with 4 antioxidants in his book NO More Heart Disease and in his advanced technical books on nitric oxide in physiology and medicine [Books/Louis Ignarro nitric oxide]. The amino acid, L-arginine, is an immune system enhancer that stimulates the thymus gland, boosts white blood cell production and stimulates release of growth hormone. Note: Nitric Oxide, in aging [Patents, Books, LifeExtension], in mitochondrial function [LifeExtension, Books], [112], Nitric Oxide (NO) production stimulated by resveratrol [Books]. NO levels may be raised by taking arginine with whey protein in bodybuilding exercise, which has the effect of activating telomerase [Vasa, et. al, 2000; Hayashi, et.al, 2006] in the endothelial cells of the vascular system, and of promoting mitochondrial biogenesis [Links, Books, Papers]. Nitric oxide may also be stimulated using cocoa [Links]. Thus, Jean Calment's extremely long lifetime of 122 1/3 years may have been due to telomerase activation from nitric oxide activation, reversing the cellular senescence of endothelial cells lining veins and arteries, cutting off atheroscelerosis causing heart attacks and strokes, two of the most common causes of death in aging adults. Nitric Oxide generation is also promoted by pomegranate, an ingredient Life Extension's Endothelial Defense product. See the journal Nitric Oxide [Wikipedia, Links, Books]. November, 2008 - December 16, 2008 For our notes on GAIA Herbs astragalus root extract ratings, comparing the "1 mg astragalosides per 30 drops" version with the approximately 1/13.2 weaker "500 mg crude herb equivalent" version, see longevitysupvendors.html#TOXICOLOGY. October 23-October 29, 2008, Updated December 16, 2008: The Outer Limits The primary thing to take for longevity turned out to be something like a delicious cough syrup, an ethanol and water extract of astragalus made available in glycerin, say GAIA Astragalus root extract in glycerin, rated at 1 mg astragalosides per 30 drops. Basically, less than 1 tablespoon of this stuff per day (150 drops is the actual amount taken of 180 drops per tablespoon), half of the month, repeated every month, will turn a 60 year old man into a 25 year old man in 3.9 to 4.4 years, less than 4.5 years. That is the main thing to remember, really it is, although some weight-lifting is probably also required in many cases. Astragalus extract works by lengthening telomeres via telomerase activation (7) until telomere t-loops in senescent cells close, eliminating senescent cells. This revivifies adult stem cells, so that they can get in there and fix everything. Virtually everything else we had in our antiaging medicine chest was footdragging by comparison with small molecule telomerase activator treatments based on compounds derived from astragalus extracts. The pioneering research in the matter was done by Geron [Geron Patent, A', A''], TA Sciences, Telomolecular Nanotechnologies and other firms including Sierra Sciences. They are still trying to develop faster, more effective telomerase activators that get results quicker. Also see astragaloside IV from RevGenetics or Terraternal. Otherwise, we fine-tune the system against cancer with antioxidants like cocoa powder in water, taken 2 tablespoons at a time from a crystal goblet chilled in the fridge for several hours. However, cocoa is a telomerase inhibitor to be taken during the 2nd 15 days of the month only, due to its dietary polyphenols (catechins) that inhibit telomerase (June, 2010). We fine-tune mitochondrial aging with acetyl L-carnitine taken with alpha lipoic acid. We eliminate lipofuscin with alpha lipoic acid and CoQ10. We exercise daily with 3 grams of arginine in our systems to generate nitric oxide that lengthens the telomeres in the vascular endothelium, warding off heart attack and stroke consequences of atherosclerosis. We are careful to take 2000 mg or more vitamin C daily to have plenty of it to support collagen synthesis and other metabolic reactions. We get our daily multiple vitamins and take a homocysteine blocker featuring vitamins B6, B12, folic acid, and trimethylglycine to further ward off atherosclerosis. However, if you want to see the clock of time turn the other direction, so that you really do seem to get younger, don't forget the astragalus extract. It will cost you perhaps $25.50 per month for two bottles of it to support two weeks of treatment per month, including taxes. You'll be glad you did. The exact rate at which it works for you is less important than the fact that it rejuvenates at something resembling 8 years/year to 9 years/year, that is, 0.667 years/month to 0.750 years per month. This seems glacial at first, but stick to it. After 9 months, you can usually detect some improvement. Tables for the rejuvenation times and costs may be deduced by linear analysis. Let the final model age tFM be given by tFM = t0 + BΔt, where t0 is the Initial Actual Chronological Age, and B is the aging rate. Let B = -8 or -9 years per year aging rate for rejuvenation, so that tFM = the model age at the end of rejuvenation. In the table below we choose tFM = 25. Solving for the rejuvenation time Δt, we find Δt = (tFM - t0)/B years. Then the Actual Age at Final Model Age tFM is t = t0 + Δt, and we have Cost = $76.00(12)(Δt). Note that B=1 corresponds to normal aging, B > 1 represents accelerated aging,
0 < B < 1 represents decelerated aging, and B < 0 corresponds to rejuvenation. Rejuvenation Times to Model Age 25 from Initial Age in Years with Cost in Dollars Initial Actual Chronological Age t0 100 90 80 70 60 50 40 30 Δt-5 Rejuvenation time, B = -5 yrs/yr 15.0. 13.0. 11.0 9.0 7.0 5.0 3.0 1.0 Δt-8 Rejuvenation time, B = -8 yrs/yr 9.375 8.125 6.875 5.685 4.375 3.125 1.875 0.625 Δt-9 Rejuvenation time, B = -9 yrs/yr 8.333 7.222 6.111 5.000 3.888 2.777 1.666 0.556 t = t0 + Δt-5 = Actual Age-5 at Final Model Age 25 115.0 103.0 91.0 79.0 67.0 55.0 43.0 31.0 t = t0 + Δt-8 = Actual Age-8 at Final Model Age 25 109.375 98.125 86.875 75.685 64.375 53.125 41.875 30.625 t = t0 + Δt-9 = Actual Age-9 at Final Model Age 25 108.333 97.272 86.111 75.0 63.888 52.777 41.666 30.556 Cost-5 = $76.00(12)Δt-5 13,680 11,856 10,032 8,208 6,384 4,560 2,736 912 Cost-8 = $76.00(12)Δt-8 8,550 7,410 6,270 5,185 3,990 2,850 1,710 570 Cost-9 = $76.00(12)Δt-9 7,597 6,586 5,573 4,560 3,546 2,533 1,519 507 Press for Jeanne Calment photo album.Press for Jeanne Calment photo album. Left: Jeanne Calment, age 25. Right: Jeanne Calment, age 60. Also see Einstein Greying and Astragalus Extract Program at 2-Year Point. "...and bending down beside the glowing bars, murmer a little sadly how love fled, and paced the mountains overhead, and hid his face amid a cloud of stars." - When You Are Old, by William Butler Yeats. Rejuvenation Times from 60 to Final Model Ages tFM in Years with Cost in Dollars Final Model Age tFM 55 50 45 40 35 30 25 20 Δt-5 Rejuvenation time, B = -5 yrs/yr 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 Δt-8 Rejuvenation time, B = -8 yrs/yr 0.625 1.25 1.875 2.5 3.125 3.75 4.375 5.0 Δt-9 Rejuvenation time, B = -9 yrs/yr 0.556 1.111 1.667 2.222 2.778 3.333 3.889 4.444 t = t0 + Δt-5 = Actual Age-5 at Final Model Age 61.0 62.0 63.0 64.0 65.0 66.0 67.0 68.0 t = t0 + Δt-8 = Actual Age-8 at Final Model Age 60.625 61.25 61.875 62.5 63.125 63.75 64.375 65.0 t = t0 + Δt-9 = Actual Age-9 at Final Model Age 60.556 61.111 61.667 62.222 62.778 63.333 63.889 64.44 Cost-5 = $76.00(12)Δt-5 912 1,824 2,736 3,648 4,560 5,472 6,384 7,296 Cost-8 = $76.00(12)Δt-8 570 1,140 1,710 2,280 2,850 3,420 3,990 4,560 Cost-9 = $76.00(12)Δt-9 507 1,013 1,520 2,027 2,534 3,040 3,547 4,053 from 'The Time Machine'. The Time Machine. Also consider the age transformation table associated with my personal program for rejuventation with astragalus extract. As you can appreciate, we need more measurements of telomere growth via telomerase activation therapy done with off-the-shelf, inexpensive astragalus extracts to get better oriented. My measurements using grey hair counts might also be compatible with a 7 years/year rejuvenation rate, or 0.583 years per month. It's really a life or death issue for millions of people [See old Outer Limits TV show intros and The Twilight Zone]. I theorize that formerly astragalus extracts were not widely recognized for their rejuvenating properties because results seem glacial at first, and because the medicine is fairly expensive, so that few experiments were done. If you want the most deluxe treatment associated with this technique, see TA Sciences. There you have the opportunity to make a contribution to science and use the astragalus-derived TA-65, which seems to probably be cycloastragenol obtained from astragaloside IV [Geron Patent, A', A'']. Making measurements via Repeat Diagnostics for about $650.00 each might also help you contribute to the calibration of the astragalus extract telomerase activation effect and to the history of science in this domain. Otherwise, I recommend keeping a file of undyed hair clippings from all over your head, taken every several months, so you can have a record of the rejuvenation process. Don't forget to include photos and movies. Life extension on the order of 8 times the normal human lifetime seems feasible with this technique, since telomerase activation can easily extend mitotic cell division potential by a factor of 8, and with all we now know, we might be able to extend human life indefinitely. Music: Love Potion Number 9. Also may make a wonderful rejuvenating personal lubricant. October 17, 2008 Cocoa Polyphenols may have been the primary factor behind Jeanne Calment, the 122 1/3 year-old aging record holder [Links, Images, Photo Gallery], who seems to have gotten some life extension milage from her consumption of 5 lb. of chocholate per week, although perhaps absorption of antioxidant hydroxytyrosol from olive oil rubbed into her skin was similarly impacting. However, cocoa is a telomerase inhibitor, so she was not getting herself longer telomeres (June 2010). See Life Extension's Endothelial Defense with "CocoaGold". Cocoa inhibits undesirable platelet aggregation leading to atherosclerosis associated with heart attack and stroke and promotes blood flow for 8 hours after ingestion. Since cocoa promotes nitric oxide generation, cocoa may turn out to activate telomerase in endothelial cells via NO (nitric oxide) activation [Vasa, et al., 2000, Hayashi, et. al, 2006], although this is so far unconfirmed. Thus Jeanne Calment's long life span may be due in part to telomerase activation in the vascular endothelium due to ingestion of cocoa in chocolate. I myself take two tablespoons of cocoa powder (chilled in a wine goblet of water for two hours or more) 4 times a day. Finally, note that Jeanne Calment's resveratrol from red wine is also nitric oxide activating and therefore also probably contributes to telomerase activation in endothelial cells. Pomegranate, also found in endothelial defense preparations, is another nitric oxide activator. It is remarkable how sharply the cut-off in human aging seems to be focused at 110, so that Jeanne Calment's barrier-penetrating extra 12 1/3 years beyond it as a supercentenarian seems to deserve special scrutinty. Chocolate boosts the blood supply in the brain, according to Life Extension Magazine, reducing the risk of dementia, another good reason for aging record holder Jeanne Calment to take 5 lb. per week of it. Increased chocolate consumption improves blood flow to the brain for 2 to 3 hours. Dark chocolate is superior to milk chocolate because it contains more cocoa flavonols per gram. September 30, 2008 Upgraded astragaloside IV vendors list in index and in supplement vendors file. Telomolecular demonstrates Bimene, a new product using nanotechnology to restore collagen to aging skin. Reviewed telomerase inhibition for anticancer treatment using resveratrol. September 11, 2008 Jim Green at 51. Press for Jim Green's home page. I noted in longevity2.html that a telomeric chromosomal rejuvenation rate of 9 years per year (460 telomere base pairs per year) amounts to 0.75 years/month, and that 8 years per year (400 bp/year) amounts to 2/3 years/month. Both of these rejuvenation rates have been measured for TA-65 on different TA Sciences customers, according to communications from TA Sciences. Rejuvenation may be continued cyclicly for as long as required to produce a young adult pattern of gene expression and the corresponding immortal phenotype for most specimens, although it doesn't restore your teeth. My impression from relatively crude experiments here is that ethanol-and-water astragalus extracts such as GAIA astragalus extract taken at 5 mg/astragalosides per day during the activation part of telomerase-activation-deactivation cycles produce roughly the same result. See also TA-41 (a TA Sciences ethanol and water astragalus extract) test results. Note that TA Sciences makes precise telomere measurements available from 2 university labs along with their TA-65 rejuvenation pill molecule, no doubt the smallest-molecule astagaloside, the metabolite found in the blood after ingestion of TA-41. TA-65 is probably cycloastragenol, which Geron can produce from astragaloside IV (RevGenetics, Terraternal) by removal of 2 ring structures. Astragaloside IV is a larger molecule exhibiting the rejuvenation effect based on telomerase activation. The bioavailability of Astragaloside IV can be improved with chitosan. Note that some additional supplements, careful diet, and exercise are beneficial to the rejuvenation process, and that telomerase activators and telomerase inhibitors should not be taken at the same time for optimal telomere remodeling. Acetyl L-Carnitine with alpha lipoic acid should probably be taken concurrently for mitochondrial rejuvenation and lipofuscin reduction, together with 2000 mg/day or more of Vitamin C (at 500 mg/dose) and a homocysteine blocker including vitamin B6, vitamin B12, and folic acid. Arginine at 3 grams/day with exercise produces Nitric Oxide that refreshes the vascular endothelium by lengthening endothelial telomeres, also restoring thymic function, allowing the body to create fresh T-lymphocytes and maintain youthful thymic hormone levels. See Repeat Diagnostics and the How Long are My Telomeres article from RevGenetics, a manufacturer of Astragaloside IV, to measure your telomere length from a commercial lab for less than $700. July 14, 2008 Section 15 on other aging processes now includes wear and tear on the teeth and a strategy for defeating dental caries that also reconstructs and remineralizes tooth enamel. See also my dental files. Astragaloside IV. Press for RevGenetics Astragaloside IV Astral Fruit. June 19, 2008 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. Broccoli sprouts for sulforaphane, plus its zinc cofactor, might work more effectively with astragalosides to promote hTERT transcription after chromatin expansion via HDAC inhibitor sulphoraphane plus zinc. Such hypotheses will require testing. June 12, 2008 DNA repair enhancement [Links, Books, Papers, Patents, Amazon, LifeExtension, AC-11, Links/AC-11]. Telomere Repair [Links, Books, Papers, Patents, LifeExtension, Amazon, TA Sciences, Telomolecular Nanotechnologies, Sierra Sciences, Geron's Compositions and Methods for Increasing Telomerase Activity (A', A'') and Formulations Containing Astragalus Extracts and Uses Thereof], and via relevant hormone introduction, [23s]. For a promising experimental program with readily available GAIA astragalus extract, see Telomere Remodeling via Cyclic Telomerase Activation, (7). Telomere repair is fundamental in modern long-range life extension technology, as telomere shortening routinely results in replicative cellular senescence in the human species. June 10, 2008 SNPs - Single Nucleotide Polymorphisms [Wikipedia, Links, Books] in the human genome can create different scenarios for anti-aging nutritional supplementation and medical treatment. See GeneLink, used by Solgar NutrigenomX, which provides a report on about 12 SNPs, together with tailored supplements from Solgar. See also Gene Essence, which prepares a personalized genetic information "Gene Essence Report" on about 90 medically important disease association SNPs through Biomarker Pharmaceuticals, using a DNA chip equipped with 1.8 million DNA probes to detect over 1 million SNPs. See the April 2008 article Genetic Polymorphisms and Human Aging: Association Studies Deliver [Links/Genetic Polymorphism and Human Aging, Books, Papers, Patents, LifeExtension, Amazon]. See also DNA microarrays [Wikipedia, Links, Books; Affymetrix]. By now (June 17, 2010), we realize that SNPs can be fixed with targeted genome editing using zinc finger nucleases. June 6, 2008 Improvements to the index: corpora amylacea, treatment of microglial activation, improvements to curcumin, oleocanthal, ect. May 31, 2008 Testosterone enables reverse cholesterol transport [Links, Books, Papers, LifeExtension, Amazon], removing excess cholesterol from tissues and carrying it to the liver, thereby reducing the likelihood of atherosclerosis, heart attack, and stroke. Reverse cholesterol transport works by augmenting scavenger receptor B1 [Links] in the liver, which acts to stimulate cholesterol uptake, and by increasing the activity of hepatic lipase [Links], which removes phospholipids from the surface of HDL cholesterol, enhancing the uptake by scavenger receptor B1. May 30, 2008 Alpha Lipoic Acid with Acetyl L Carnitine [LifeExtension, Links, Books, Papers] has been shown to restore mitochondria to a youthful state, and is thought to be the answer to the mitochondrial theory of aging. Recently, sodium-R-lipoic acid [Links] has been shown to be more bioavailable than lipoic acid (half active R-lipoic acid, half inactive S-lipoic acid) or pure R-lipoic acid, capable of achieving 10-30 times higher levels in the blood than R-lipoic acid, reaching peak plasma concentrations in just 10-20 minutes. See Life Extension's Super R-lipoic Acid, a brand of sodium-R-lipoic acid. May 10, 2008 Among mammals, research suggests that the bowhead whale (Balaena mysticetus, or Greenland Right Whale) may live up to 211 years. Measurements on the nuclei of the whale eye done with racemization techniques often show ages close to 100. When this whale dives, I am reminded by his tail of Orion's battleaxe resume Gemini sinking in the West, crowned with his soaring story of resurrection as a phoenix in the East. Also upgraded bibliography. May 6, 2008 Added material on hTR or hTERC, the gene for the RNA component of telomerase coding for TTAGGG tandem repeats, including links to hTR plasmids and hTR transfection. Some tissues may require hTR plasmids or hTR transfection if they cannot be served by adult stem cells for rejuvenation, because in some mesenchymal-derived tissues the hTR promoter is methylated at CpG islands and plated over with a silencing protein. May 4, 2008 May the Fourth be with you. YouTube: Telomolecular Nanotechnologies Corporate Video on Telomeres and Telomerase in Life Extension, Eucaryotic Cells, Molecular Biology, Molecular Medicine, Medical Nanotechnologies, Visualization of DNA, DNA Sequencing, DNA Repair, RNA, RNA Sequencing, The Cell Membrane, The Nuclear Pore, Viral Transfection, DNA Plasmids, The Human Genome, Genome Design, Drug Design, Proteins, Molecular Machines, Gel Electrophoresis, DNA Lab, Polymerase Chain Reaction (PCR). April 30, 2008 Epigenetic Regulation and Undesirable DNA Demethylation in Aging [Links, Books, Papers, Amazon, LifeExtension; Links/Epigenetic Dysregulation in Aging, Books, Papers, Amazon; Links/DNA methylation, Books/DNA Demethylation, Links, Books, Books/epigenetic regulation in senescent cells, Links/causes of DNA demethylation, LifeExtension/DNA demethylation]. Methylation of genes is used in the development of placental mammals to silence gene promoters after their developmental role is over, or to switch on genes controlled by an insulator in charge of an enhancer. Life Extension Magazine promotes SAMe [Links] as a cure for undesirable DNA demethylation, noting that "Cellular aging is partially caused by de-methylation". (Added to the index and section (10) on DNA repair in aging.) April 28, 2008 Added hTERT transcription factors [Links, Books, Papers, Patents] down-regulating hTERT, including E2F-1, Mad1, TGF-β, and Menin to the list of telomerase inhibitors in lifexnotes3b1.html. Also added hTERT transcription factors active in hTERT activation including c-Myc, Sp1, and Ets family protein ER81, and estrogen receptors to telomerase activators in lifexnotes3b2.html. See Shuwen Wang and Jiyue Zhu, 2004: The hTERT Gene is Embedded in a Nuclease-resistant Chromatin Domain, Journal of Biological Chemistry, vol 279, No.53, Dec.31, 2004, pp 55401-55410. In addition, I added material on the "hTERT insulator" topic to indexlongevity2.html. April 27, 2008 There are 5 RecQ DNA helicase genes [Books/DNA helicases, Books/RecQ DNA helicase genes] used to unwind DNA, some or all requiring Mg+2 as a cofactor [Hu & Ellis, Bloom Syndrome, in Chromosomal Instabilty and Aging, by Hisama, et al, 2003]. Therefore, it may be that deficiencies in dietary magnesium are connected with genomic instabilities in aging cells via the malfunctioning of DNA helicases. The WRNp helicase [Books, Books/cofactors] associated with Werner Syndrome, for instance, is localized to the telomere, and may malfunction if sufficient magnesium is not available as a cofactor [Links, Papers]. According to Life Extension magazine, low levels of magnesium are chronic in the US population, and magnesium should be supplemented. YouTube Video: Helicase in Action in DNA Replication Process. April 26, 2008 Homocysteine blockers reduce the formation of micronuclei in aging cells, a symptom of chromosomal instability. Folic acid and vitamin B12 alone reduce micronucleus formation, as does a general reduction in homocysteine levels, obtained perhaps by consuming less red meat rich in methionine. [Maurer, et al., Chromosomal Instability in Normative Aging, from Chromosomal Instability and Aging, 2003, p.138.] Werner Syndrome cells thrive in vitro when hTERT is activated [Junko Oshima, Werner Syndrome, in Chromosomal Instability and Aging, 2003, p.176], suggesting that perhaps small molecule telomerase activators such as TA-65 and astragalus extract may be used to cure Werner Syndrome patients or alleviate their symptoms. April 18, 2008 Index improvements. C-myc [Wikipedia, Links, Books, Papers, Patents, Amazon, LifeExtension] is a gene producing the c-myc protein, a transcription factor that upregulates hTERT, which produces the catalytic component of the DNA repair enzyme telomerase, the reverse transcriptase that extends telomeres. Dr. Michael Fossel has pointed out in Cells, Aging, and Human Disease that c-myc, or c-myc activators, may be useful in life extension applications for re-extending telomeres in order to escape from replicative senescence. Ordinarily, we have no problems with c-myc, which is located towards the q-end of chromosome 8. C-myc is normally expressed as a transcription factor in response to growth factors such as EGF, Epidermal Growth Factor, which excites the proliferation of many types of cells, and which is also a telomerase activator. However, c-myc is an oncogene in Burkitt's lymphoma. This happens when c-myc is translocated to an immunoglobin location toward the q-end of chromosome 14, in which case its expression becomes unregulated. There are also Burkitt's lymphomas associated with c-myc translocation to immunoglobin sites on chromosomes 2 and 22, in which c-myc becomes similarly unregulated. The translocation leading to Burkitt's lymphoma usually occurs as a consequence of a Herpes virus infection, or from infection with Epstein-Barr virus, and sometimes as a consequence of infection with HIV. [Geoffrey M. Cooper, Ch.15, Cancer, The Cell, 1997, p.608, pp. 618-619.] April 16, 2008 Realized that acetylcholine helps make nitric oxide available to endothelial cells, so that acetylcholine boosters Ashwagandha and Huperzine A may be useful in connection with telomerase activation using NO generated by nitric oxide synthase from arginine during bodybuilding exercise. Also, the acetylated form of L-carnitine (acetyl-l-carnitine) facilitates the release and synthesis of acetylcholine by donating its acetyl group towards the production of acetylcholine. NO generation is also promoted by broccoli sprouts, genistein, and resveratrol. Since NO reacts with the superoxide anion to form peroxynitrite, which produces hydroxyl radicals, it is probably a good idea to use the peroxynitrite inhibitor gamma-tocopherol when using NO to promote telomerase activation. (After or during.) See Vasa, et al., 2000, Hayashi, et al., 2006. March 24, 2008 Located Mogfield JE, Liu WR, Reid R, 2006: Adenoviral human telomerase reverse transcriptase dramatically improves ischemic wound healing without detrimental immune response in aged rabbit model., Human Gene Therapy, 2006; 17(6): 651-660. This shows how telomerase may be activated via gene therapy using a viral vector. March 22, 2008 Introduced 4-page structure into the main essay and the index, also dividing the bibliography and the labs section into two pages. This makes individual pages storable on S5, and leaves room for expansion. Requested an update for the local Pico Search index. Coincidentally, the forsythia bloomed today, two days after the Spring Equinox, and tomorrow is Easter Sunday. March 21, 2008 - Deuterium Theory of Aging [article, Links, Books, Papers]. Deuterium in water is thought to contribute to DNA damage, and deuterium-depleted water [Links, Papers], or Dd-water, may be taken to reduce damage to DNA from deuterium [Wikipedia]. Deuterium water is toxic, and the associated problems seem to stem from the effect of deuterium on the hydrogen bond. Deuterium bonds are stronger and shorter than normal hydrogen bonds, sometimes modifying the shape of an enzyme. Deuterium-depleted water has contributed to the survival time of breast cancer patients after metastases have been observed. Dd-water may be obtained from glaciers at high altitude, as for instance Hunza water [Links]. Natives from this region report living extended lifespans on the order of 120-140 years. Plants can be constructed to produce deuterium-depleted water on a large scale [article], and it is available in liter bottles like a soda beverage. March 15, 2008 Noticed that PDGF, Platelet Derived Growth Factor [Links], is a telomerase activator. Upgraded lifexnotes5.html and other files. March 2, 2008 Refinements to the index. February 12, 2008 Astragaloside IV is more bioavailable when taken in astragalus root extract, which is typically used to boost the immune system. The bioavailability of astragaloside IV [Article, Papers], can also be increased by chitosan [Wiki/chitosan, Links/chitosan] or sodium deoxycholate [Links, Books]. The astragalosides are the safest and most readily available small-molecule telomerase activators for telomere remodeling with cyclic telomerase activation that I know of. Telomerase inhibitors including silymarin, curcumin, resveratrol, quercetin, green tea, garlic, fish oil, and vitamin E should not be taken while trying to turn on hTERT with astragalosides for telomerase activation, but may be taken in the next two weeks of a cyclic treament cycle. Otherwise, NO from arginine works with nitric oxide synthase from exercise to lengthen telomeres in endothelial cells and to promote mitochondrial biogenesis. Drug bioavailability [Links, Wikipedia, Books] of orally taken compounds is worst when the molecular weight is > 500, the calculated octanol/water partion is > 5, the number of H-bond donors is > 5, and the number of H-bond acceptors is > 10. (See van de Waterbeemd, Drug Bioavailability.) Hence, we concentrate on small-molecule telomerase activators, and for the conjugate part of a telomere remodeling cycle, on small-molecule sirtuin activators with a molecular weight < 500 such as resveratrol and quercetin, when small-molecule telomerase inhibitors like silymarin, garlic, and curcumin may also be taken.
February 8, 2008
Added a terminal section on the impact of extreme life extension with rejuvenation included on reproduction and evolution in the future. A new entry on telomere-telomere fusion in the index envisions human evolution from the great ape genome.
Jan 25, 2007
Aging muscle regeneration via stem cells, young serum, signalling proteins, NO, mechanisms for improving mitochondrial biogenesis in section (9). See new telomerase activators or telomere-growth methodologies for that list in lifexnotes3b2.html. Also introduced improvements in mortality charts.
Dec. 11-12, 2007
Greying hair [Wikipedia/hair color, Wikipedia/Grey Hair] is sometimes described as due to stem cell failure that no longer renews a melanocyte hair coloring cell in the hair follicle, so that the melanocyte dies and the hair turns white. This was a news story in 2004. I am not sure yet whether stem cell renewal via telomerase activation can restore the melanocyte to the hair follicle after the transition has taken place. (By November 2008 I am sure it can.) I note that Geron and Telomolecular Nanotechnologies seem to believe that white hair can be restored to normal dark hair using telomerase activation [Links/hair restoration with telomerase, article]. (I have verified this by November 2008.). There are products on the market now that claim to restore hair and hair color with telomerase activation, such as iGrowHair Telomerase [Links/telomerase excreting acidophilus, Wikipedia/Lactobacillus Acidophilus: improves immune function]. I sometimes imagine that my hair is getting darker as I experiment with telomerase activation, but then my hair looks dark after a shower when it is wet, and greyer later... perhaps explaining ancient popular belief in baptism. Just plunking a handful of water on the top of my head makes me look 5-10 years younger - it must help! (By November 2008 there can be no doubt, although I still look younger after a shower.)
See Lactobacillus Acidophilus improves immune function: [Links, Papers, Books, Links/Genome of Lactobacillus Acidophilus]. The Lactobacillus Acidophilus genome consists of 1,993,564 bp on one DNA molecule with no plasmids and shows 1864 genes.
Dec. 9-10, 2007
Gene Therapy sections expanded. [Books, Links, Papers, Wikipedia, LifeExtension], Adenovirus transfection - hTERT or other genes such as c-MYC for hTERT activation may be transfected using adenovirus vectors or retroviral vectors. [LifeExtension, QbioGene/Adenovirus for gene therapy applications, Books/adenoviral transfections, Links/Adenoviral Transfections, Invitrogen/adenoviral transfections, Amaxa Biosystems, Amazon/adenoviral transfections]. See also retroviral vectors in gene therapy [Links, Books, Amazon, LifeExtension]. Targeted introns may improve control of gene expression [Links, Books, LifeExtension]. Sendai viral techniques may also be useful for our life extension application [Books], as well as other viral vector methods [Books, LifeExtension]. Micheal Fossel also mentions possible dendrimer [Books] and transcatheter application techniques [Books] in his 2004 textbook Cells, Aging, and Human Disease, and points out that high-pressure commercial gene guns [Wikipedia, Books] may be employed on the skin [Books]. See also plasmid delivery in gene therapy [Books, Links, Amazon, LifeExtension].
Dr.Michael Fossel, MD & PhD in neurobiology. Press for Interview.
Dr. Michael Fossel.
CD28 & The Immortal Phenotype.
Dr., Dr., Give Me the News.
Dec 6, 2007
Toxicology studies and experiments in progress seem to indicate that GAIA astragalaus extract in glycerin may be applied directly to the skin and scalp at 1 mg of astragalosides/30 drops for telomerase activation in the skin and hair follicles. A superior solution may become available as astragalus extract in liposomes. I note readings in Michael Fossel's Cells, Aging, and Human Disease make telomerase activation seem quite primary in anti-aging medicine, most other preventative treatments rather palative by comparison. For instance, heart attack and stroke are primarily due to endothelial cell senescence [Links], and elderly cancer not due to carcinogens such as cigarette smoke is primarily due to genomic instability originating in short telomeres, according to Fossel [Links] and other researchers. The extended lifetime telomerase activation gives to the immune system and to adult stem cells is seen as crucial in the long-range maintenance of neural and muscle tissue, too, so that both mitotic and primarily non-mitotic tissues are benefited by telomerase activation of cells in the body. Otherwise, Fossel reports on indications that Alzheimer's Disease may be primarily due to the replicative senescence of epithelial and microglial cells, so that the primary causes of death can be traced to replicative senescence preventable with telomerase activation. Using a cyclic activation scheme (TA Sciences) allows the telomeres to catch runaway cellular proliferation in cancer during down-subperiods of the telomerase activation treatment cycle. Fossel's book envisions boosting telomerase activation via hTERT gene therapy using viral vector transfection, or via c-MYC plasmid activation of telomerase [Nature, 1999, Papers], and presents many stimulating new ideas and observations. More than 10x the usual 50 allowable human cell divisions has been obtained in in vitro experiments when telomerase activation was employed, according to Fossel. Perhaps Methuselah's legendary 969 year record will be broken hereafter. Note that extra copies of transfected hTERT in the human genome can still have telomerase inhibited with standard telomerase inhibitors if this is indicated in cancer treatment.
Dec 4, 2007
Conflicting data on retinoic acid as a telomerase inhibitor or activator, new index entries on matrix metalloproteinases, skin solutions. (Retinoic acid is a telomerase inhibitor.) See Retinoic Acid [Links; Links/retinoic acid telomerase].
Nov 20 & 24, 2007
Embryonic stem cells have recently been created by nuclear reprogramming of skin cells, so that embryonic stem cells can be obtained without taking embryos apart [article1, article2, Links/embryonic stem cells via nuclear reprogramming, Books, Papers]. The results were seperately published by Dr. Shinya Yamanaka of Kyoto University in Cell [Papers, Links, images] and James Thomson of the University of Wisconsin in Science [Papers, Links, images].
Nov 19, 2007
It may be useful to take whey protein, which ups HGH, and arginine, which ups NO levels, while using astragalosides or astragalosides + chitosan to activate telomerase. Nitric Oxide from arginine supplements causes anabolic effects, including telomerase activation in epithelial tissue according to Vasa. HGH from whey protein intake ups IGF-1, also an anabolic stimulant associated with telomerase activation, although it subsequently lowers HGH. Chitosan improves telomerase activator astragaloside IV bioavailability. [62s].
Searching uncovered more telomerase activators: Mre11 protein [Links, Books, Papers] has been noted to lengthen telomeres in plant and human cells. (Bundock and Hooykaas, 2002.) Also, Ependymin Peptide Mimetics work: a 14-amino acid ependymin peptide was effective. Ependymin [Links, Books, Papers] is a secretory protein found in the cerobrospinal fluid and extracellular fluid of goldfish brains. Ceremedix, Inc. makes the 14-amino-acid ependymin peptide, which has the sequence ESCKKETLQFRKHL, or Glu-Ser-Cys-Lys-Lys-Glu-Thr-Leu-Gln-Phe-Arg-Lys-His-Leu. See (Hirsch, Erica, 2005. Telomerase Activity and Telomere Lengths in Fibroblast Cells Treated with Ependymin Peptide Mimetics). [Telomerase Activators].
Nov 13, 2007
Nitric Oxide from arginine is typically used in NO bodybuilding preparations to improve blood supply and boost anabolic effects. Vasa's work on telomerase activation via NO in epithelial tissues might apply to Nitric Oxide preparations used in bodybuilding based on the preparation of NO from arginine by nitric oxide synthases in the body. I note that NO has also been reported to activate mitochondrial genesis.
Nov 11, 2007
Added more refinements to section (14) on the proteasome and aging, and to the corresponding references.
Nov 8, 2007
Oleuropein, a major constituent of olive oil and olive fruit, was shown to be effective in stimulating and reviving proteasome activity, resulting in anti-senescence effects and 15% life extension. [article] Of course, this helps explain good results that Jean Calment got with olive oil. Also, ginsenoside Rh2 was shown to be a telomerase inhibitor, although Geron has shown ginsenoside Rh1 to be a telomerase activator. Thus the effectiveness of anticancer ginseng extracts in activating telomerase is in question. Another telomerase inhibitor recently uncovered is green marine algae extract. [article]
Oct 22, 2007
Breast cancer resulting from estrogen or ovarian hormone stimulated cell division driving cells toward the Hayflick limit when cells become senescent and genomically unstable might be warded off by "astragalus" extracts or other small molecule telomerase activators. "Recent studies show that more than 90% of all cancer is caused by critical telomere shortening, for example, in 97% of premalignant endothelial lesions critical telomere shortening is observed (Meeker, John Hopkins University 2005)." - Telomolecular Corporation SEC statement. Note that estrogen affects the receptor levels of a female hormone called progesterone. In the breast, progesterone also acts as a chemical messenger that tells breast cells to divide, hence progesterone and estrogen are applied in female transformations which can become ultimately dangerous when finally cells approach the Hayflick cell division limit.
Oct 21, 2007
Added DNA Synthesizers to Labs page for DNA nanocircle synthesis, ect. with more from Telomolecular Nanotechnolgies. In particular, I address notch signalling and muscle regeneration in (9) on exercise in anti-aging medicine.
Oct 19, 2007
Added CGK733 to the telomerase activator list. It can produce 25% life extension by providing 20 more cell divisions. Its precise mechanism differs from telomerase activation: it revives senescent cells, working "by blocking a protein checkpoint involved in sensing and slowing down cells in response to DNA damage. Although Kim showed that cells whose aging was reversed by CGK733 didn't develop chromosomal abnormalities, the long-term effect of blocking DNA repair mechanisms could lead to cancer." Also Added 5-azacytidine (DANGER: may promote prostate carcinomas) to lifexnotes3b2.html's small molecule telomerase activator list in [81s]. The 5-azacytidine prostate cancer promoting problem is related to its methylating agent property, whereas on the other hand Tricostatin A works around histone acetylation via histone deacetylation inhibition. Added very-potent RHPS4, a Small-Molecule Pentacyclic Acridine, to the corresponding list of telomerase inhibitors. RHPS4 is used in anticancer therapy.
Oct 18, 2007
Upgraded [81s] list of telomerase activators.
Oct 17, 2007
Concluded again after careful inspection that TA-65 is probably cycloastragenol, and added improvements to lifexlabs.html and to the bibliography. Also revealed that chitosan makes astragaloside IV more bioavailable. Added CGK 1026 to the list of telomerase activators.
Oct 16, 2007
Astragalus, which contains small molecule telomerase activating astragalosides, was the first medicine discovered to be effective against lymphoma night sweats caused by the senescence of B-lymphocytes stimulated to divide many times in the presence of an antigen. The astragalosides lengthened B-cell telomeres, preventing B-cell senescence and consequent genomic instability and lymphoma night sweats. Inserted in section (11) on immunosenescence.
Oct.11, 2007
The position of hTERT at the distal end of chromosome 5p has hTERT itself controlled by the telomere position effect TPE. (JW Shay & WE Wright, 2005.)
Oct.10, 2007
Index improvements: teeth problem correction, mole removal, tatoo removal, blemish-removal, better coverage of telomerase activation therapies and astragalus.
October 8, 2007
Added links to Hair Transplants in the Index and in Sup Notes 3.
Sept 20, 2007
Added BioProcess International to journals, biotech firms to Labs.
Sept 12, 2007
TA Sciences gets 230 base pairs of telomere growth per 3 months of Patton protocol treatment during the telomerase-on part of the cycle. Added to (7)/small molecule telomerase activators and to dosages at [62s].
Sept 10, 2007
Spell-corrected first two pages.
Sept 5, 2007
Added reference articles page lifexrefs.html. This under-construction piece will be updated and refined, and allow classical articles to be clicked for reader access to the paper on Internet.
Sept. 1, 2007
Added material in (4) on lipofuscin and ceroid removal.
August 29, 2007
Added liposomal delivery product examples: IQ Derma (rejuvenating), Bodyshape by Hydroderm (for cellulite) to index and footnotes.
August 27, 2007
More historic articles were added to Telomere Articles in the Labs section. Notes from "Telomere Damage in Aging" by von Zglinicki from Aging at the Molecular Level were used to improve (7) on telomere aging theory.
August 23, 2007
Perkins Coie filed a patent application for anti-aging skin creams including astragalosides on behalf of Geron's Chief Scientific Officer Calvin B. Harley [Forbes/Calvin B. Harley, Papers/Calvin B. Harley, Books, Portrait], news which was included in my section on Small Molecule Telomerase Activators.
August 22, 2007
Cosmetic anti-cellulite fat creams and references were added to the index.
August 13, 2007
Improved the toxicology of astragalus and [81s/6b].
August 10, 2007
Improved Vendors file, Jekyll-Hyde longevity beverages.
August 9, 2007
Added toxicology to index, drug dosage info to dosages [62s], and astragalus extract in water to my list of Jekyll-Hyde longevity beverages.
August 8, 2007
Added astragalus section in vendors, added molecular diagram links to [81s/6b].
August 7,2007
Improved Bibliography/Journals and Vendors files.
August 6, 2007
Added Bluebonnet supplements with low-cost ubiquinol, improved Cat's Claw extract discussions in (10) and the index by including material on CAEs (carboxyl alkyl esters) and oxindole alkaloids, which are not used in Dr. Ron Pero's AC-11 Cat's Claw extract. Suggested investigating Solaray Korean Ginseng Extract for telomerase activation as an alternative to astragalus extract oriented telomerase activation. Still inclined toward astragalus.
August 4, 2007
Improvements in mitochondrial DNA repair in (10).
August 3, 2007
Improvements in dosage list for anti-aging program [62s].
July 31, 2007
Telomere T-loop detail added to (7), more refs to dosages [62s].
July 29, 2007
References added to (7) to papers from Dr. Woodring E. Wright and Dr. Jerry Shay, with branching from them to other papers on telomeres and telomerase in cellular aging and the telomere position effect.
July 26, 2007
Improvements in optimum anti-aging program and dosage reference [62s].
July 25, 2007
Improvements in immune theory of aging, section (11), and associated footnote (94).
July 22, 2007
Improvements in Telomere Position Effect in (7), Labs, and in Index M-Z.
July 18-20, 2007
Highlight Links added, organizational enhancements introduced.
July 16, 2007
Added info on telomere capping proteins to section 7, after the discussion of telomerase activators.
July 15, 2007
Added material on varicose veins and horse chestnut to index.
July 11, 2007
Mostly organizational improvements in longevity2.html.
July 9, 2007
Telomerase inhibitors [81s] to avoid while activating telomerase [81s/6b] with astrogalosides from astragalus extract or other telomerase activators include garlic, turmeric (curcumin), resveratrol, vitamin E, green tea, melatonin, and fish oil EPA.
June 30, 2007
Included more book searches on telomerase activators in 81s/6b.
June 26, 2007
Indexed more material on phospholipid exchanges for cell membrane and skin repair, skin clinics, infusion therapies. Bibliography improvements.
June 24, 2007
Added Activar AC-11 Cat's Claw Extract [Links, Books] for DNA repair [Links, Books, Wikipedia], available from Prothera as C-MED-100.
June 23, 2007
The people's small molecule telomerase activator is probably GAIA Astragalus Extract, taken at 5 mg of astragalosides per day, two weeks on and two weeks off, continuing over the course of a year. During the two weeks on one must avoid telomerase inhibitors such as garlic, turmeric (curcumin), resveratrol, vitamin E, green tea, melatonin, and fish oil EPA, applying them during the next two weeks. This keeps the cost at about what it was before using telomerase activation to re-extend your telomeres to repair the tip-ends of your aging chromosomes. However, this program is not yet well established. Cycloastragenol at 5 mg/day is probably superior in such a program, but cycloastragenol, the common structural element in the astragalosides, is not readily available at this time. (Later, GAIA cut the strength of their extract to about 1/13 of its robust strength, abandoning an astragaloside-specific specification for the product at the same time. This made it mandatory to switch to other brands to get 5 mg of astragalosides per serving.)
June 13-16, 2007
Added more links to section (8) subsection on the role in aging and cloning of rising DNA strand separation temperature due to DNA-protein crosslinking, regarding causes and repair.
June 6, 2007
Added links in (7) on Small-Molecule Telomerase Activators to the molecular structure of cycloastragenol (probably TA Sciences TA-65) in the Geron European patent (p.65) (A', A'') and in on-line chemical refs on cycloastragenol [81s/6b, Books, Links, Papers]. "Cycloastragenol is the common genuine aglycone of the astragalosides". See the Geron European Patent, (p.39-40).
June 3, 2007
Added [Books/DNA-protein crosslink repair] to (8).
June 2, 2007
Book and Web links, bibliography links inserted for the previous entry.
June 1, 2007
"Clones of animals with normal life spans are usually prepared via nuclear transfer from embryonic tissues [Books]. Perhaps the steadily increasing cross-linking of aging DNA with proteins [Books], which causes the strand separation temperature of DNA to rise in old DNA, will turn out to be an inhibiting factor in cloning from adults. [See S. Dani, A. Hori and G. Walter, Principles of Neural Aging, Elsevier Press, 1997.] I have not determined whether or not cross-link breakers like Alagebrium (ALT-711, Links) exist that can be used to alleviate this problem, and the role of rising DNA strand separation temperature from DNA-protein cross-linking in aging remains somewhat unclear to me at this time. [See Books/DNA-protein crosslink repair.]" - Added at the end of section (8), after the entry below.
May 31, 2007
It will soon be possible to create and store your own embryonic stem cells for personalized therapies via services available at StemLifeLine in San Francisco [TIME article], starting with spare embryos prepared in an IVF (In Vitro Fertilization) clinic. However, the firm is not promoting this in connection with prior nuclear transfer for human cloning with precise tissue DNA matching or in combination with telomerase activation for chromosomal telomere rejuvenation prior to nuclear transfer, which would be necessary to produce a clone with a normal life span from adult DNA [Wikipedia/human cloning, Books/Human Cloning]. Clones of animals with normal life spans are usually prepared via nuclear transfer from embryonic tissues.
May 1, 2007 - The History of Telomerase Activators [Refs7, Refs7.2, Refs18-21,
Index/History, Index/Telomerase Activators, List; Links, Images, Papers, Patents, Books].
May 1, 2007 I started my personal experiment with telomere remodeling via cyclic telomerase activation initially using GAIA Herbs Astragalus Extract, which was specified in those days at 1 mg of astragalosides per 30 drops. TA Sciences [Index] announced that a chemical found in astralagus extract was being used for TA-65 in March, 2007. Geron announced that astragalus extracts and derivatives were telomerase-activating in a patent Compositions and Methods for Increasing Telomerase Activity (A, A', A'') published June 1, 2005. Hong Kong University of Science and Technology also published on May 19, 2005 on telomerase activation with astragalus extract, in the Hong Kong University/Geron patent Formulations Containing Astragalus Extracts and Uses Thereof (B). These were the first known orally bioavailable telomerase activators [Index, List]. Calvin B. Harley, the chief scientific officer of Geron, has his name on both the Hong Kong University and the Geron patents. That a limit to cell division existed that is responsible for mortal life span was suspected by August Weissman as early as 1888. In 1957 H. Earle Swim and Robert F. Parker reported in Culture Characteristics of Human Fibroblasts Propagated Serially, American Journal of Epidemiology, 1957, Volume 66, Number 2 Pp. 235-243, that they had detected a limit to the division of human fibroblasts in culture, a topic covered again in more depth by Leonard Hayflick and Paul S. Moorhead in 1961. In 1986 an important clue came when Howard J. Cooke and B. A. Smith reported at the Cold Spring Harbor Symposium for Quantitative Biology that telomeres are longer in reproductive haploid cells such as spermatazoa and egg cells but shorten with age in other somatic cells. Calvin B. Harley established with A.B.Futcher and C.W. Greider in 1990 [Nature, 1990] that telomeres grow shorter with each cell division in human fibroblasts, and in 1998 was the leader of the team of Geron scientists including A.G.Bodnar, Jerry W. Shay, and Woodring E. Wright, et.al., that proved hTERT activation could lengthen telomeres and provide additional cell division [Science, 1998], extending life-span by introduction of telomerase into normal human cells. In the early 1998 work, a plasmid vector engineered by William Andrews was used to produce extra copies of the hTERT gene in samples to increase telomerase levels. The first drug that was discovered to activate telomerase seems to have been the histone deaceylase inhibitor (HDAC inhibitor) Trichostatin A, as described by Yu-Sheng Cong and Silvia Bacchetti in Histone Deacetylation Is Involved in the Transcriptional Repression of hTERT in Normal Human Cells, J. Biol. Chem., Vol. 275, Issue 46, 35665-35668, November 17, 2000. Tricostatin A [Links] can stop the cell cycle in early stages of development and is positioned as an antifunqual antibiotic these days, usually presented as harmful and not for human consumption when taken orally. Nitric Oxide was also identified early by Vasa (2000) and Hayashi (2006) in separate papers [Vasa, et al., 2000, Hayashi, et al., 2006]. Telomerase activator epithalon peptide (Ala-Glu-Asp-Gly) was isolated from the pineal gland and announced in 2003 at the St. Petersburg Institute for Biogerontology in Russia. Both Tricostatin A and Epithalon Peptide are taken by injection. For the early time-table of the development of our insight into telomeres, telomerase, and replicative senescence, see Hayflick, His Limit, and Cellular Ageing by Jerry W. Shay and Woodring E. Wright from Nature Reviews Molecular Cell Biology in October, 2000. The orally bioavailable telomerase activator CGK 1026, an HDAC inhibitor, was discovered in 2004 in Korea in the course of high-throughput testing of 20,000 different chemicals. It was preferred to the by-injection-only Tricostatin A in therapy. After the Geron landmark patents in 2005 and associated patents from Geron partner Hong Kong University of Science and Technology in May and June of 2005, Astragalus Membranaceus, Astragalus Extract, Astragaloside IV, and Cycloastragenol (TAT2, or TAT002), and Ginsenoside RH1 and related compounds became visible as telomerase activators. IGF-1 and HGH, which turns into IGF-1 in the liver, were subsequently identified as telomerase activators, and are now sold as antiaging medicine. By late 2011, I have 120 telomerase activators on my big list, and Sierra Sciences has identified hundreds of them using high-throughput testing techniques.