(6) The insulin utilization theory (Books, Books/insulin_resistance, Amazon, LifeExtension/insulin_and_aging, LifeExtension/insulin_utilization) - Chromium picolinate can be used to metabolize extra insulin. Treatment with chromium picolinate has been shown to increase the life span of mice 15%. There are some reports that chromium picolinate may be harmful to DNA, and is primarily useful in losing weight. Perhaps some other source of the chromium ion should be used to impact insulin metabolism and help with the weight loss factor related to the caloric restriction theory (3). See also insulin and insulin resistance, Insulin and Aging, Dr. Lam's Insulin and Aging, and Life Extension magazine on Metabolic Syndrome and insulin resistance. It is desirable to avoid or deemphasize sugary foods and consume foods with a low glycemic index (*) to avoid obesity, metabolic syndrome (syndrome X), and insulin resistance problems. Metformin makes cells less insulin resistant, and testosterone from bodybuilding, injections, or stick-on patches prevents and treats insulin resistance in men. "Hyperinsulinemia (excess insulin in the blood) has been implicated as a major risk factor" in numerous age-related diseases, such as Alzheimer's disease, heart attack, and stroke. (See Fantastic Voyage by Ray Kurzweil and Terry Grossman). Alpha lipoic acid has been shown to improve insulin-stimulated glucose disposal at 100-300 mg twice a day, and drugs used to treat metabolic syndrome include chromium 200 mcg x 2 or 3/day, alpha lipoic acid, EPA/DHA (fish oil) 1000 mg/day, co-enzyme Q 60-100mg x 2, Carnosine 500 mg x 2, magnesium 200-400 mg/day, CLA 500-1,500 mg x 2/day, 500-1,500 mg x 2, L-carnitine 600 mg x 2 or 3 per day, vitamin E 400-800 IU/day, vitamin C 2000 mg/day, biotin, arginine 3 grams x 3, glutamine 500-1000 mg, DHEA 25 mg x 2, and N-acetyl-cysteine (NAC) 500 mg x 2/day. Otherwise, the glycemic index of food may be effectively lowered by Precose and Glyset prescription medicines, which slow down absorption of carbohydrates from the digestive tract.
The more sugar insulin transports into cells [Books], the more vulnerable the cell to glycation reactions [Books] producing carbonylated proteins [Books] that may clog up proteasomes (14). Glycation reactions with DNA [Books] may also take place. This is probably the reason that genes like daf-16 [Links, Books] in C. Elegans involved in insulin management are deemed "longevity genes" [Books].

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(7) The advanced Hayflick cell division limit theory based on telomeres (Fortune/Youth Pills, Books, Amazon, LifeExtension, LifeExtension/telomere_therapy, Mechanisms of Aging/telomeres, Innovita, End Replication Problem, Shay & Wright Article, Historical Claims, telomeres & mortality, Mouse, the Unbeliever: SenescenceInfo/Telomeres & Telomerase, and Geraldine Aubert and Peter M. Lansdorp, Telomeres and Aging, Physiol. Rev. 88: 557-579, 2008.) - Revolutionary advanced methods based on telomerase technology or alternate technology for allowing mitotic cell division to continue indefinitely [Geron] following gene therapy or alternative treatment to re-extend telomeres [81s]. In vertebrates, telomeres at chromosome tip-ends [Books] consist of long tandem arrays of minisatellite [5'-TTAGGG-3']_n repeats. "Normal human cells stably expressing transfected telomerase can maintain the length of their telomeres, and exceed their maximum lifespan by more than fivefold." Furthermore, normal cells immortalized with telomerase do not become cancerous [article], although 85% of known cancer cells express telomerase to enable them to keep dividing. In fact, it is believed that cellular telomeric crisis [Links, Books, Papers, Amazon] due to shortening of cellular telomeres causes carcinomas [article, in breast cancer, Books]. Cytological observations of broken chromosome ends [Links, Books, Papers, Amazon] by McClintock in maize in the 1940s [Books] led to the suggestion that telomeres functioned to prevent chromosomal end-point fusions, which have been recently shown to sometimes lead to cancer. Sperm cells and oocytes (germ cells) manifest high telomerase levels without showing cancer problems. When telomerase is applied exogenously to mitotic human cell cultures, they become immortal. I note that the catalytic component of telomerase is generated by the hTERT gene [Links, Books, Papers, Amazon], consisting of 16 exons and 15 introns spanning ~37 kb of genomic sequence (Wick et al., 1999) near the distal end of chromosome 5p at 5p15.33, probably the most distal gene on the chromosome, which contains 609 genes. The half-life of the associated molecule is up to 4 weeks. The hTR sequence for the RNA part of telomerase is located on chromosome 3 (1,436 genes) at 3q26.3, and the associated RNA exhibits a half-life of about 5 days. In adult tissues, hTR is present and most highly expressed in the spermatocytes and Sertoli cells of the testis, moderate expression is observed in germinal center lymphoid follicles, and weak expression is present in regenerative cellular epithelia, but is not seen in the nervous system and mesenchymal derived tissues including connective tissue, bone, cartilage, and the circulatory and lymphatic systems cells. Expression of hTR in adult tissues is predominantly limited to dividing cells, although certain differentiated postmitotic cells express hTR. [Yashima K, Wright WE, Shay JW, et al., 1998, Papers/hTR activation, Papers/small molecule hTR activators, J. Zhao, et al, 2003, Links/telomerase RNA gene activation, Links/hTR plasmids, Links/hTR transfection]. The hTR or hTERC promotor is silenced via methylation [Papers, Links]. The lengths of different chromosomes correlate directly with telomere length, and the telomeres are shorter the closer they are to the centromere; p-arm telomeres are shorter than q-arm telomeres. The lengths of telomeres may vary between alleles at the same telomere in a diploid cell. The shortest telomere in human cells is at 17p [Books, Wikipedia/Chromosome 17, Ornl, Genes & Disease]. The catalytic component of telomerase available is the limiting factor in telomerase expression, and transcriptional regulation of hTERT gene expression rather than of hTR for the RNA component of telomerase is central in replicative senescence and immortalization. Replicative senescence is pro-inflammatory and pro-carcinogenic, although it limits uncontrolled tumor growth. Mammalian telomeres of maximum reported length 30,000 base pairs shorten by 50-200 base pairs with each S phase of the cell cycle, starting with typically 15,000 to 20,000 base pairs in the germ line with typically 7,000-10,000 base pairs in human adults, and counting down to 4,000-7000 base pairs in senescent cells at the M1 senescent cell checkpoint preceding a conditionally triggered countdown to the M2 crisis state before apoptosis, end-point fusions, and other phenomena associated with cell death or cancer set in. Telomeric t-loops thousands of base pairs long are uncapped to reach the M1 senescence checkpoint, when the length of telomere has shrunk so that the loop tries to close at a spot where non-canonical subtelomeric repeats are encountered differing from the tandem telomeric hexanuceotide repeats TTAGGG, so that the TRF2 t-loop formation protein closing the loop cannot find a proper binding site. In experiments, fibroblasts with telomeres shortening up to 200 base pairs per cell division were found to loose only 5-20 bp per cell division when the cell was equipped with the most effective antioxidant defense. Cells of the healthy colon mucosa typically loose 44 base pairs per cell division. On the other hand, patients 77.5 years old were shown to have white blood cells that lost 71 telomeric base pairs per year [Nazmul Huda, et.al, 2007], perhaps showing some old-age acceleration in telomere erosion. The same paper showed that telomere lengths nearly matched between elderly twins. Note that replicative senescence does not apply in quite the same way to non-mitotic cells such as muscle cells [Links], muscle satellite cells [Links], cardiac myocytes [Links], and most nerve cells, which appear to age via other mechanisms involving the cell membrane, cell membrane permeability changes from hydroxyl radical reactions, membrane damage from ROS, accelerated ROS from AGEs, and internal waste accumulation. (Sometimes such cells are renewed by stem cells from bone marrow, as in the the case brain microglial cells [77s], so that the telomeric state of mitotic stem cells may be behind the continued health of non-mitotic tissue.) However, Geron claims that in vitro cultures of non-mitotic nerve and muscle cells as well as mitotic cells are functionally benefited by telomerase activation, listing 20 cellular types [81s]. "In many cases, introduction of active telomerase also increases the capacity of cells to withstand stress due to high or low levels of oxygen, toxic molecules, or abnormal growth conditions." Experiments in 2007 have succeeded in immortalizing muscle cells in in vitro culture using a combination of hTERT and cyclin-dependent kinase 4. When grown in in vitro cultures, human (73-78 year lifespan) embryonic cells divide about 50 times before reaching their telomere-imposed cell division limit, mouse (3 year life span) cells divide 15 times, and the cells of Galapagos tortoises (175 year life span) divide 90 times. Cells from human adults, on the other hand, were observed to typically divide 20 times, or 50 times from the embryonic stage of development. Telomerase activation by small molecule telomerase activators [81s/TA] such as epithalon peptide (Ala-Glu-Asp-Gly), Tricostatin A, CGK1026, astragalus root extract, cycloastragenol (RevGenetics Astral Fruit-C), or astragaloside IV, however, can confer an immortal phenotype on cells by bypassing the usual cellular senescence pathway, and can restore a youthful phenotype to aging cells with short telomeres.
"In 1999, Australian researchers confirmed that carnosine increases the longevity of human fibroblast cells in the laboratory. Carnosine extended the Hayflick limit (the maximum number of times a cell can divide), from a "normal" 50 by up to an additional 10 times!" [69] See Life Extension on Carnosine and Cellular Senescence and The Barron Report. Note that von Zglinicki et al. showed that cells grown in a high oxygen atmosphere experience increased telomere loss and increased single-stranded telomere breaks, then prematurely senesce. So any drug protecting telomeres against oxidative stress should help, including the "super antioxidant" carnosine [69]. Reducing oxygen in a cell culturing system sometimes yielded cells capable of 3x as many cell divisions [Zs. Nagy, The Membrane Hypothesis of Aging, p.8.]. Also, note that the fibroblasts of the mouselike dunnart double 170 times, but the animal only lives 3 years, no doubt because the other mechanisms of cellular senescence kill it before replicative senescence does [Zs. Nagy, p.8]. Similarly, it is surprising that the mouse has telomeres > 25,000 base pairs long; typically dying not of replicative senescence, but of mitochondrial failure. Mice with the hTR RNA component of telomerase knocked out show no old-age effects due to telomere shortening until the 6th generation. Coincidentally, the mouse is more prone to cancer than humans; mouse telomeres are so long that they rarely catch runaway cell division. Telomeres sometimes stop the runaway cell division associated with cancer unless the cancer causes the gene to express telomerase. Syrian hamster embryo cells express telomerase to keep their cellular telomeres long for 20-30 population doublings until they senesce by another mechanism. "Normal somatic cells are generally telomerase negative, except for bone marrow stem cells." Note that germ cells express the most telomerase, maintaining their telomere length constant, while stem cells senesce more slowly than normal somatic cells because they intermittantly express telomerase [M.Fossel, Cells, Aging, and Human Disease, p.54]. Another Hayflick limit extender is the RNA and B-vitamin complex Neygeront [79], which may boost the number of possible cell divisions by 20%. Kinetin (N6-furfuryladenine), in carefully controlled doses, may be another Hayflick limit extender. Kinetin, a cytokinin pioneered in anti-aging research by Dr. Suresh Rattan, (also a student of zeatin) is presently being used on skin cells. Mind you, we are sometimes up against the problem: "The senescent phenotype was not prevented... although telomerase activity was induced...", the solution to which we must seek in other sections of this and similar essays. For instance, activating telomerase to lengthen telomeres saves fibroblasts, but not pancreatic islet cells, from senescence. I note that another method of increasing telomerase levels in the cell is via heat shock proteins, which mediate the assembly of telomerase (GB Morin, DO Toft, JW Shay, WE Wright, MA White, et al., (1999)). Note hsp90 levels may be elevated for transport of nuclear transcription factors into the nucleus via the action of interleukin 6 produced by exercise. A technique described by Vasa, et. al., used nitric oxide to activate telomerase and delay senescence in endothelial cells. See Nitric Oxide Activates Telomerase and Delays Endothelial Cell Senescence and Hayashi, et.al, 2006. 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. Bodybuilding exercises promote nitric oxide synthase production, and in the presence of arginine this leads to NO generation [Books/nitric oxide] suitable for telomerase activation and promotion of mitochondrial biogenesis [Books]. NO generation is also promoted by broccoli sprouts, genistein, and resveratrol [Links, the release of NO in endothelial tissues is promoted by acetylcholine, which may be boosted with Ashwagandha, Huperzine A, or Acetyl L-Carnitine. Nitric oxide release for purposes of telomerase activation might be best promoted in the vascular endothelium by bodybuilding workouts in presence of arginine and Ashwagandha, Huperzine A, or Acetyl L-Carnitine as supplements, to which we might add broccoli sprouts, genistein, or resveratrol with gamma tocopherol to neutralize peroxynitrite.
Small Molecule Telomerase Activators [Wikipedia/Telomerase, Books/Histone Deacetylase Inhibitors and Small Molecule Telomerase Activators, Links, Papers, Books/telomere homeostasis, Books/telomerase activators, Books/Small Molecule Telomerase Activators]. Geron [SEC filings, Investor Guide] and a subsidiary TA Therapeutics have announced a small molecule telomerase-activator TAT2002, orally bioavailable, presently used in AIDS therapy that may become useful in life extension work, say on T-lymphocytes and on on the skin [article], now to involve telomerase activation therapies or telomerase transcription-activation methods. Geron has also determined that its telomerase activators promote wound healing. [Geron/telomerase activators] Concentrations of astragalosides at 1 μg/ml are typical for topical applications or in testing for telomerase activation effectiveness using a telomerase TRAP assay [Books]. Telomerase activity has a half-life of about 24 hours. One of Geron's formulas [See also A' alternate-source version Compositions and Methods for Increasing Telomerase Activity, A'', Hong Kong Univ. formulas and Patent Lens] for a small-molecule telomerase activator is Astragaloside IV (molecular diagram, vendors RevGenetics), Terraternal), which the firm claims is associated with an optimal dosage of 50 mg to 100 mg per day (p.39-40). This looks like an overdose by a factor of 10 or 20, but that may be due to reduced bioavailability of astragaloside IV by itself. 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, vendors RevGenetics, Terraternal], can also be increased by chitosan [Wiki/chitosan, Links/chitosan] or sodium deoxycholate [Links, Books]. The small-molecule telomerase activator TA-65, a product of TA Sciences, most likely to be cycloastragenol [81s/6b, Books, Links, Papers] has also been announced by Geron along with several other formulas based on astragalus root extract molecules [Geron European Patent and Hong Kong University European Patent]. TA-65 is prescribed at 5 mg/day, the same dose recommended by Geron for cycloastragenol in their European patent (p.39-40). (See page 65 for the molecule, and note that " cycloastragenol is the common genuine aglycone of the astragalosides", the smallest of astragaloside-related telomerase activator molecules, resembling astragaloside IV with its two lower ball-like carbon rings off, as does likewise small astragenol. "One-nut" versions of astragaloside IV are described on page 66, cycloastragenol 6-β-D-glycopyranoside and cycloastragenol 3-β-D-xylopyranoside.) Since TA Sciences claims TA-65 is "one single, potent molecule" from astragalus extract, it is probably cycloastragenol, and not astragaloside IV, which requires 50 to 100 mg per day doses to be effective without excipients to improve bioavailability. TA-65 might be astragenol, the dosage of which was unspecified in the Geron European patent. However, Geron singles out cycloastragenol as having very low toxicity and excellent bioavailability on page 40 of Compositions and Methods for Increasing Telomerase Activity (or see A' alternate-source version Compositions and Methods for Increasing Telomerase Activity, or A''), and emphasizes a procedure for converting astragaloside IV chemically to cycloastragenol. TA-65 is applied by TA Sciences in staggered fashion 3 months on, three months off, and again three months on during a period of one year. After 3 months, they see 230 base pairs of telomere growth [81s/6d]. About 50-200 telomere base pairs are lost per cell division, a number than can be reduced by taking antioxidants. Note that humans typically have about 50 cell divisions available at the embryonic stage, so that such a program of treatment might go on for years. Geron's preferred embodiments for a small molecule telomerase activator are based on astragaloside IV, cycloastragenol, astragenol, and astragaloside IV 16-one, although they have named several other effective compounds also obtained from astragalus root extract, including cycloastragenol 6-β-D-glucopyranoside and cycloastragenol 3-β-D-xylopyranoside. Relatively highly bioavailable cycloastragenol may be obtained from astragaloside IV [RevGenetics] or by other methods from astragalus membranaceus. Geron has also described a "formula III" telomerase activator embodiment, ginsenoside RH1 [Links, Papers, Links/ratios, Papers/ratios]. Solaray Korean Ginseng Extract is probably a good source of ginsenoside RH1 [molecule], and recently I think the best and safest commonly available medicine for telomerase activation was GAIA Astragalus Root Extract featuring 30 drops/mg of astragalosides, given at 5 mg of astragalosides/day during 2-week activation time cells alternating with 2 week periods of telomerase inhibition with telomerase inhibitors like garlic, curcumin, resveratrol, quercetin, silymarin, melatonin, vitamin E, green tea EGCG, and fish oil EPA. Telomerase inhibitors and telomerase activators are not to be taken at the same time. Since GAIA Herbs Astragalus Root Extract is no longer available at 1 mg astragalosides per 30 drops, 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. Note that Ginsenoside RH2, a telomerase inhibitor, may also be present in Ginseng Extracts, in addition to telomerase activator ginsenoside RH1. Note that the ginsenosides [Links, Books] are distinct from the astagalosides, being triterpene saponins [Books] from ginseng [Links, Books, in circulation]. One starting material from ginseng is panaxatriol. Geron also names astragalosides A, 1, 2, 7, and astraverrucins I and II, which can be obtained from Astragalus Verrucosis, as telomerase activators. TA-65 "is a naturally occurring molecule extracted from the well known Traditional Chinese herb Astragalus membranaceus [LifeExtension, Solaray, GAIA Astragalus extract, 1 mg of astrogalosides per 30 drops]", also called Milk Vetch Root, or Huang-qi (Yellow Leader) [81s/6b]. Geron seems to have tested materials known to boost the immune system in its search for small molecule telomerase activators, as both astralagus root and ginseng root had been used in traditional medicine for the immune system. Both contain saponins. Perkins Coie has recently filed a patent application on behalf of Geron's Chief Scientific Officer Calvin B. Harley [Forbes/Calvin B. Harley, Papers/Calvin B. Harley, Books, Portrait] for anti-aging skin creams using astragalosides. Liposomal delivery systems [68] in connection with small molecule telomerase activator delivery look quite interesting. Another firm, (now-defunct) Telomolecular Nanotechnologies [SEC data 11/7/06], also developed therapeutic products based on telomerase activation [case studies], and was developing products including rejuvenating skin creams based on telomerase activation. According to Telomolecular Nanotechnologies (Corporate Video), youthful "telomerized cells" seem immune to free radical damage and glycation, due partly to the telomerase position effect described in subsequent section. "...Cells with sufficiently elongated telomeres energetically produce, in high levels, proteins like catalase, superoxide dismutase, glutathione, Ku, collagen, elastin and many other proteins important in tissue formation, cell repair, and antioxidation, that become scarce as telomeres shorten." (See Overexpression of Telomerase... by Armstrong, G. Saretzki, and Peters, et. al.) Telomolecular Nanotechnologies proposed DNA nanocircles for telomere re-extension [Telomolecular Nanotechnolgies/nanocircles, Amazon, Links, Books, Papers]. Produced by a DNA synthesizer, DNA rolling nanocircle encoding for telomere rejuvenation was invented by Dr. Eric Kool (article) of Stanford University. See Dr. Kool's patent. However, DNA nanocircles for telomere extension are not ready for internal use at this time, but only used for special applications and in the study of ALT mechanisms in cancer. "Telomolecular believes that nanocircles might work efficiently in living animals." Another firm, Phoenix Biomolecular, has specified a cell penetrating peptide scheme to deliver the enzyme telomerase directly to cells. Sierra Sciences [Wikipedia] is also working to develop telomerase activation techiques [Patent Ap]. More than one small-molecule telomerase activator [Links] has been found. I list 61 substances under investigation as telomerase activators. Sierra Sciences has specified hundreds. The relative speed with which these agents can be used to achieve rejuvenation is being measured by TA Sciences and other firms. See papers on telomerase activation, for instance by histone deacetylase inhibitors [Video, Links, Books]. "Treatment with tricostatin A (TSA) [Wikipedia, Books, Links, Epigenetic Protocols, chap.8, Future_Medicine/article, article2, anti-cancer, elevates Hsp22 level with life extending effect] induced significant activation of hTERT mRNA expression and telomerase activity in normal cells, but not in cancer cells." Histone deacetylase inhibitor trichostatin A "activates the hTERT promoter in normal cells", thus enabling telomerase synthesis. I stated above that resveratrol is an activator for SIRT1, a histone deacetylase enzyme [Links, Books, LifeExtension], the activation of which results in gene silencing that keeps DNA more tightly wound on histone cores, preventing eccDNA formation. Perhaps resveratrol can be used as a SIRT1 gene silencer to shut down telomerase transcription following treatment with a small-molecule telomerase activator like tricostatin A, a histone deacetylase inhibitor which is genotoxic at some dosages, however. CGK 1026 [Links, Papers, ChemBank/CGK 1026 molecule], discovered in 2004, is said to "derepress" hTERT expression, and has been used as a substitute for Tricostatin A. CGK1026 is thought to inhibit the recruitment of HDAC [?] into E2F-pocket protein complexes assembled on the hTERT promoter. It is described by several sources: Linscott's Directory of Immunological and Biological Reagents, as catalog # 565730, Merck CGK 1026 - Order # 565730-5MG, and EMC Biosciences CGK1026. A more detailed look at the situation shows that some commonly available foods contain histone deacetylase inhibitors that may prove valuable in life extension via telomere extension by telomerase activation. For instance, diallyl sulphide (garlic) and sulphoraphane (broccoli) are zinc-activated (meats, seafood, oysters) class I histone deacetylase inhibitors (HDACs). Another allyl compound from garlic or deodorized garlic [Wikipedia/garlic, Links, LifeExtension] that is more active as a histone deacetylase inhibitor than allyl sulphide [Links] is allyl disulphide [Links], and a still stronger one is allyl mercaptan [Links]. I note that allicin from garlic has the opposite effect and inhibits telomerase expression, also often inducing apoptosis in cancer cells. Note that overdoses of garlic and allyl compounds have toxic effect; consuming 5 garlic cloves in a tomato soup with chopped onions can induce severe diarrhea. Butyrate [Links] is also a histone deaceylase inhibitor (10) or chromatin-remodeling factor that may lengthen telomeres by enabling telomerase transcription and is known to extend the life span of Drosophila 40%. "FR901228" is a typical concealed-identity histone deacetylase inhibitor [Links, LifeExtension] being investigated by Japanese scientists that is known to activate telomerase transcription. Resveratrol (red grapes, Japanese Knotweed root) is a class III histone deacetylase activator via its ability to turn on SIRT1 deacetylase enzyme. (I note that resveratrol is sometimes described as a deacetylation activator, although resveratrol, possibly via specific properties as a histone deacetylase inhibitor, activates the gene SIRT1, yielding the corresponding NAD-dependent SIRT1 deacetylase enzyme for gene silencing, which itself probably silences the SIRT1 gene). NAD, incidentally, is found in tuna. Perhaps using histone deacetylase inhibitor transcription activators butyrate, sulphoraphane, diallyl sulphide, and allyl mercaptan properly, or tricostatin A, or TA Sciences TA-65, would cover our telomere elongation requirements with feedback from telomere length testing [Links, Books, Papers, LifeExtension]. Then resveratrol or allicin from garlic could be applied to decisively halt transcription of telomerase, perhaps after a telomere length measurement. The histone deacetylase inhibitors prepare chromatin DNA for transcription with RNA polymerase, dissociating the histones from DNA prior to transcription. However, there are 4 types of covalent modifications of histone proteins - acetylation, phosphorylation, ADP-ribosylation, and methylation. Histone deacetylation inhibitors allow chromatin to expand and become transcriptionally active, sometimes activating telomerase. Histone deacetylation causes compaction of chromatin, silencing genes. Histone acetylation expands chromatin, while histone deacetylation compacts it. It sometimes happens that modification of chromatin to a decondensed, transcriptionally active structure induces the senescent phenotype, which resveratrol prevents by compacting it and inducing gene silencing. HDACs may activate p53, while activation of SIRT1 (human SIR2) with resveratrol prevents p53 activation with chromatin compaction and gene silencing, causing extended life span. Telomere shorting itself finally induces a p53-dependant DNA damage detection pathway leading to the senescent state of the cell. What we need are telomerase activators that make the correct sections of chromatin transcriptionally active, such as astragaloside IV (see RevGenetics Astragaloside IV (Astral Fruit)) or cycloastragenol (RevGenetics Astral Fruit-C). For a tested, surefire approach to telomerase activation, see sources, books, papers and links on treatment with trichostatin A, which is experimentally promising in published studies on stimulating hTERT expression for telomerase synthesis and telomere enlongation. A larger molecule of about 15,500 Daltons (still capable of passing through the nuclear pore) worth exploring in this connection is the cytokine IL-2 or interleukin 2, a "lymphokine" which augments the expression of mRNA for human telomerase in T-cell lymphocytes. IL-2 "has been approved by the Food and Drug Administration (FDA) for the treatment of cancers (malignant melanoma, renal cell cancer), and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines." - [Wikipedia]. Interleukin 2's telomerase-enhancing role in T-lymphocytes has been noted by other investigators. [See IL-2 source BD, IL-2 Links]. There is evidence that DHEA acts as a physiological regulator of interleukin-2 biosynthesis (Yu, 1995, citing in Arking, The Biology of Aging, p.233.), so supplementation with DHEA may help interleukin-2 maintain T-lymphocyte telomeres. Furthermore, Princeton University researchers have identified a small protein telomere capping activator Est1 [Links, Papers]. Preliminary data suggest estrogen activates telomerase in T-lymphocytes [Handbook of Models for Human Aging, p.37]. Furthermore, "estrogen and its receptor activate telomerase in estrogen-responsive cells through the estrogen response element sites in the hTERT promoter". Another group in Russia at the St. Petersburg Institute of Bioregulation and Gerontology announced in 2003 that Epithalon Peptide [see also epitalon, aka epitalon], a small 4-peptide protein made from the sequence alanine, glutamine, aspartic acid, and glycine, (Ala-Glu-Asp-Gly), activates telomerase and extends telomeres [Links, Papers, Original Paper, Biogerontology article 1, article 2, epithalamin articles, sources, sources2, sources and costs]. Epithalon peptide has been injected 5 times weekly into mice, resulting in 34.2% prolongation of life span in mice without cancers. Sublingual (under the tongue) administration is probably possible with such short peptide molecules, and perhaps it can be topically applied like a skin cream, taken sublingually under the tongue, in buccal fashion in the pouch of the cheek, or if need be as a suppository. Perhaps resveratrol could be used like a brake after a telomerase activation treatment period to silence transcription and halt the telomere extension process, reducing risks. Mice overexpressing IGF-1 showed higher levels of phospho-Akt [Books, Links] leading to increased telomerase activity and more effective cardiac stem cells, creating a better supply of new myocytes for the heart. (Torella et.al., 2004, cited by Arking). Perhaps telomerase activity can be stimulated by improving our levels of IGF-1 by direct input of the hormone or by stimulating it via exercise in the presence of amino acid stacks [Human IGF-1 stimulator, Links/IGF-1, Books/IGF-1]. I note that Growth Hormone (GH or HGH) has been shown to upregulate telomerase in hamster ovaries and in rat liver cells (hepatocytes). [Links, Books]. On the other hand, an antagonist of growth hormone-releasing hormone has dramatically decreased telomerase activity [Books, Books2, Links, Papers] in experimental xenografted transplants [article]. Telomerase activation has been achieved in cord blood using IGF-1 in the presence of PHA (phytohaemagglutinin; 1 μg/ml, Sigma, St Louis, Mo., U.S.A.). Note that while attempting telomere extension via a growth hormone strategy for telomerase activation, one should avoid ingesting telomerase inhibitors such as garlic allicin or resveratrol. Evidently, there has also been some progress in hTERT activation using the insect hormone ecdysone (muristerone) to induce telomerase transcription and cellular immortalization in human fibroblasts [article]. Finally, I note that US Patent 6787133 has been granted to Geron for a procedure to purify telomerase for the purpose of identifying telomerase activators and inhibitors.
Increased telomere length, more telomerase activity, and active meristematic stem cell presence have been identified as important factors in the long life spans of 2000-5000 year old bristlecone pine trees [106]. Furthermore, inducing more telomerase activity in embryonic stem cells seems to improve their defenses. Although telomerase expression is up-regulated in cancer,and used to detect cancer, the gene for telomerase is not an oncogene and its activation does not induce cancerous growth deregulation by itself. Inhibition of telomerase in human tissues helps suppress run-away cancer cells by killing them with enforced replicative senescence, so telomerase activation treatments to lengthen our telomeres for life extension purposes should be periodic and short-term, or done ex vivo prior to an adult stem cell transplant, and not continuously in vivo. TA Sciences proposes using their TA-65 telomerase activator 3 months on, 3 months off, and 3 months on again for a year. In the future we may need to use carefully measured doses of TA-65, trichostatin A or Epithalon Peptide to lengthen our telomeres. Hilariously, no mouse has ever died from telemere shortening, or suffered from a shortage of telomerase, however. In mice the dominant aging mechanism seems to be mitochondrial aging via lipid peroxidation. On the other hand, relatively cancer resistant humans can die from telomere shortening; as telomere length goes to zero once-mitotic bone marrow, human skin, liver, colon mucosa and lymphocyte cells become senescent and chromosomally unstable. Lymphocytes then suffer irreversible cell cycle arrest. Cell death follows, sometimes after a lengthy delay. Progress on small molecules for telomerase activation is also proceeding from research on plants. Recently it has been shown that telomere shortening is aggravated in each cell division of mitotic cells by high homocysteine levels, so that a homocysteine blocker [Links] featuring TMG (trimethyglycine) 500 Mg - 720 mg, folic acid 400 Mcg, vitamin B6 perhaps 25 Mg, and vitamin B12 250 Mcg is effective at preserving telomere length, in addition to preserving the epithelial cell linings of the veins and arteries of the heart and the brain and fending off artherosclerosis. [See Dr. Phillip Lee Miller, Life Extension Revolution.] Both antioxidant treatment preventing free-radical-induced single-strand DNA breaks (repaired by Cat's Claw extract (AC-11) along with double-strand breaks and photochemical DNA damage) and homocysteine treatment featuring a homocysteine protection formula preventing more telomere loss per cell division tend to preserve telomere length, so that some centenarians seem to have rather long telomeres. Another possibility for lengthening telomeres, Alternative Telomere Lengthing [Best], may be implemented with DNA nanocircles, which seem to be generated in cancer cells from long telomeres via recombination of long telomeres. Researchers suspect that the small telomeric circles form through the resolution of an intratelomeric strand invasion resembling a t-loop. Two recent papers demonstrated that human alternative lengthening of telomere (ALT) cells have abundant t-circles similar to Telomolecular Corporation's (Corporate Video) DNA nanocircles, pointing to their potential role in promoting telomere replication in the absence of telomerase. "Analysis of telomere restriction fragments from human cells that rely on ALT for telomere maintenance revealed that they possess telomeric tracts that are extremely heterogeneous in length, ranging from undetectable to abnormally long (Bryan et al., 1995), which would also point towards a recombinational origin (see also Henson et al., 2002)." Intense interest in the ALT pathway exists partly because it is a stumbling block to the application of telomerase inhibition as cancer therapy. Without telomere extension via small molecule telomerase activators or synthetic nanocircle ALT, however, it seems death is finally certain, as telomeres will be consumed eventually otherwise, destroying T-lymphocytes in the immune system, microglial cellsin the brain associated with clean-up operations, the skin, the lining of the internal organs, and all other mitotic cells including the lining of the colon. I might add that the consequence of cloning an animal from a mature specimen with shorter-than-embryonic telomeres is that the clone dies young, as in the case of Dolly the sheep, the first cloned mammal to make headlines. To successfully clone an adult requires pre-extension of telomeres prior to nuclear transfer, otherwise, the cloned offspring may die ahead of time [Books]. In practice, cattle are cloned from embryonic or fetal cells to avoid the short-telomere early death syndrome. It is also noteworthy that people having a longer telomere length (upper half of the population) live longer than those in the lower half of the population, who have 1.86 times the mortality rate, with 3.2 times the heart disease and 8.5 times the infectious disease of the long telomere upper half. [Cawthon, et.al., 2003, cited in The Biology of Aging by Robert Arking, p.442.]
Breast Cancer, Cell Division, and Astragalus Root
The average age for breast cancer in males is 67, and in women 62, afflicting 1 in 8 women over a lifetime. During each menstrual cycle, estrogen together with other ovarian hormones signals cells in the breast to divide and multiply. Breast enlargement involving estrogens and other ovarian hormones in males or females may result in cell divisions sufficient to drive cells closer to the Hayflick limit, when they become senescent and genomically unstable after telomeres become uncapped, thus cancer-prone. Thus anti-senescence drugs like the small-molecule telomerase activators in astragalus root extracts may be useful in preventing breast cancer arising from genomic instabilities in breast cells that have divided many times and eventually become senescent ahead of other cells as a consequence of estrogen and ovarian hormone signaling. Aging busty "ass trap gal-us" soulmates might take astragalus root extract to ward off breast cancer before it is observed, it seems. We wonder if the term "astragalus" itself did not signify originally this set of patients that could benefit from the use of the herb. "Recent studies show that more than 90% of all cancer is caused by critical telomere shortening [Books, Links, Papers; Books/cancer due to critical telomere shortening, Links], for example, in 97% of premalignant epithelial lesions [Images] critical telomere shortening is observed (Meeker, John Hopkins University 2005, Papers)." - Telomolecular Corporation SEC statement. 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. [Links/breast cancer, Books, Wikipedia]. Chromosome 17 has short telomeres [Links] implicated in breast cancer. Perhaps astragalus extract in glycerin or in liposomes would be useful if applied topically to the breast, in addition to astragalosides or other small molecule telomerase activators taken orally to apply telomerase activation in a cyclic manner for improving stem cell and tissue genomic stability against malignant transformations.
The Telomere Positioning Effect & Youthful Patterns of Gene Expression
Also see the telomere positioning effect [Books, Links, LifeExtension]. Long telomeres silence genes close to the telomere, and as the telomere shrinks genes proximate to the telomere are more expressed. Therefore to obtain youthful patterns of gene expression in mitotic, dividing cells, it is desirable to maintain long telomeres [Books]. A good deal of work is now going on to identify telomere-shortening-sensitive-genes (TSSG) [Links, Papers]. I note that the shortest telomere on human chromosome 17p [Books, Wikipedia/Chromosome 17, Ornl, Genes & Disease; GeneCards/P53] at 17p13.1 seems to be fairly close (within 7,512,445 bp out of 80 million bp) to the gene for the tumor suppressor gene p53, so that more tumor suppressor p53 protein should produced when this telomere gets sufficiently short. This way shorter telomeres would work together with the tumor-suppression system and apparatus for stopping the cell cycle and to induce the senescent state of the cell when telomeres shorten. See Links/the telomere position effect and tumor suppressor gene p53. "The level of p53 protein increases in near senescent cultures" of cells [Vaziri and Benchimol, 1996]. It turns out that subtelomeric DNA contains genes for zinc fingers [Links, Wikipedia, ZFC, Books] and olfactory receptors [Books] that should be more actively transcribed when telomeres are short. Zinc fingers [Books, Books/zinc fingers in cellular senescence] may be transcribed in clusters that activate or deactivate promotors for genes like fingers applied to a piano keyboard. Their telomere position effect activation in subtelomeric DNA when telomeres become short may directly impact gene expression to produce some of the observed aging effects. Perhaps RNA interference [Books], or RNAi, may be applied to oppose undesirable effects caused by the expression of mRNA controlled by zinc fingers in subtelomeric DNA someday. Genes involved in the wrinkled skin, graying hair, and healing abilities may be involved, as Geron has shown that these are improved by lengthening telomeres [Wikipedia/Telomerase]. "Cells with sufficiently elongated telomeres energetically produce, in high levels, proteins like catalase, superoxide dismutase, glutathione, Ku, collagen, elastin and many other proteins important in tissue formation, cell repair, and antioxidation, that become scarce as telomeres shorten." [From Telomolecular Corp/case studies, see also LifeExtension/Telomere Control and Cellular Aging, the papers of Dr. Woodring Wright and Dr. Jerry Shay.] "As the hTERT gene is only a few hundred kilobases from the end of chromosome 5p [Books], one could speculate that TPE (silencing) of hTERT limits the maximal length of human telomeres during embryogenesis." [JW Shay & WE Wright, 2005.]. (In earlier 2002 work [Cong, Shay, and Wright, 2002], the hTERT gene was stated to be most distal gene on 5p, but 2 million base pairs from the telomere, so that the telomere position effect would have little effect on hTERT.) Evidently, the telomere position effect should cause the body to automatically resist aging by more strongly activating telomerase as we age, a tendency we must supplement to achieve a longer-than-usual lifespan. Perhaps proteins mediating telomerase assembly such as p23 and Hsp90 are less available as time goes on. The location of the hTERT gene in other species with different lifespans becomes an interesting question. Species may be engineered in the future with extra distal hTERT genes on other chromosomes to extend their life spans. Perhaps the telomere position effect is also involved in thymic recovery and the withering of the thymus gland, which is involved in T-lymphocyte production and connected to the immunological theory of aging (11). On the other hand, as we shall see according to the Membrane Hypothesis of Aging (13), to obtain youthful patterns of gene expression may also require modifying the cell membrane permeabilities (modified by cross-linking of membrane-imbedded proteins) to ionic species such as potassium that modify the dehydration, colloidal properties, and density of cellular material, factors which should apply to both mitotic and non-mitotic cells. In dense, dehydrated cells enzyme reactions are inhibited, so that protein turnover and protein synthesis are retarded, tending to produce more ceroid wastes and lipofuscin that choke the cell and increase free radical production, eventually leading to inflammation and processes involving cytokines that are ultimately poisonous to the cell. Also, deproteinization of chromatin restores its youthful low DNA strand separation temperature, so that restoring youthful patterns of gene expression [Books] may be assisted by undoing protein cross-links or other protein properties in chromatin that inhibit DNA strand separation [Books] and gene expression [Books, Books/chromatin and gene expression].
Telomere Capping Proteins [Telomere Extension by Telomerase, Telomerase Components in Cell Signaling, Links, Books, Papers, Links/capping supplements].
Uncapped telomeres [Papers, Books, Links] terminate in a single-stranded overhang 100-300 nucleotides in length. Dr. Yie Liu's lab at the National Laboratory of Molecular Gerontology has illustrated that the proteins PARP1 [Links, Papers, Books] and MSH2 [Links, Papers], a DNA mismatch repair protein, play a role in maintaining telomere capping function [Books, Links, Papers] in which a t-loop configuration many thousands of base pairs long is believed to protect chromosome ends from being recognized as broken DNA. As I note in section 10 on DNA Repair, the maximum life span of 13 species is directly correlated to the activity of poly (ADP-ribose) polymerase (PARP) in mononuclear leukocytes. Disruption of the telomere loop [Books, Papers] and subsequent exposure of the 3' overhang represents the uncapped state of telomeres. The ability to mask telomeres from being recognized as damaged DNA is crucial to maintaining normal cellular function, as uncapped telomeres directly associate with many DNA damage response proteins [Links, Books] in telomere-initiated cellular senescence. Telomere integrity depends on the ability to maintain telomere length and/or the ability to mask telomeres from being recognized as damaged DNA via telomere capping [Books, Links]. Statins [Links, Books] have been observed to provide an enhancement of the associated telomere protection biology [Paper, Books], but are often avoided due to certain hazards. In certain experiments atorvastatin (0.1 mol/L) and mevastatin (1.0 mol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein TRF2 (telomere repeat-binding factor), as shown by immunoblotting. Today atorvastatin is available by prescription, but mevastatin is not used due to multiple side effects. Uncapping of telomeres may be detected by the loss of TRF2, and the effect of the statins has been produced by application of exogenous TRF2 [Books, Papers], which protects human telomeres from end-to-end fusions. PARP1 interacts with TRF2 and is involved in repairing damaged telomeres. "As the length of telomeres in leukocytes shortened the risk of coronary heart disease increased... the risk was substantially attenuated by pravastatin [Links, Books]. Since statins have been shown to increase the production of a protein-telomere capping protein that prevents telomeres from shortening it is a potential hypothesis that statins bring about their benefit by this mechanism. This is very early research but it implies that statins could well have the ability to slow certain aging processes." - ErinPharm Gazette, Jan. 2007. I note that my friends have warned me not to meddle with statin drugs due to side effects [article, Books, Links] such as lowering the body's level of CoQ10. Effective treatment to improve levels of telomere-capping associated proteins is, however, definitely on the horizon. Overexpression of TRF2, which stabilizes the telomeric loop, shifts the telomere length threshold for senescence towards shorter telomeres. Also, expression of telomerase protects the telomere cap, so that small-molecule telomerase activators such as astragalus extract, astragaloside IV, or cycloastragenol defend telomere capping. Telomere uncapping induces the state of cellular growth arrest termed senescence, or mortality state M1. [Senescence and Immortalization: The Role of Telomeres and Telomerase, Jerry W. Shay and Woodring E. Wright, from Carcinogenesis, 2005]. If the genes maintaining the senescence checkpoint M1 are blocked, say by a viral oncogene, the cells continue to divide and proceed to the crisis state M2, typically followed by cellular apoptosis. Both M1 and M2 can be prevented by introducing telomerase. [Telomere Regulation in Eucaryotic Cells, from Chromosomal Instability and Aging: Basic Science and Clinical Implications By Fuki M. Hisama, Sherman M. Weissman, George M. Martin, Informa Health Care, 2003.] The telomere t-loop closes closer to non-canonical sequences differing from TTAGGG repeat (subtelomeric repeats) as cell divisions proceed and the telomere shortens. The telomeres are reduced by 50-200 bp per division until the telomere tail fails to close into a t-loop (bound with a small d-loop) when TRF2 cannot find a proper binding site due to the non-canonical nature of the repeat there, for instance and typically TGAGGG. See also Carol W. Greider's Telomeres Do D-Loop T-Loop Minireview, IMGENEX on telomere-associated factors, Jerry Shay's turn-of-the-century article in Nature on on telomeric t-loops and d-loops, Dr. Connie Nugent's lab, and Joao Pedro de Magalhaes on telomeres and telomerase. Recent work shows that telomere-protection protein POT1 is involved in binding the single-stranded overhang at the tip end of the telomere to close the t-loop and is required for telomere length regulation and chromosomal end protection [Yang, et.al, 2007]. Humans have one POT gene, mice have two. Telomeres are bound to a set of numerous interacting proteins grouped in 6 subunits, including POT1, TRF1, TRF2, TIN2, TPP1, and Rap1, which insure proper maintenance of telomeres. It has been described as the telomere binding complex [Papers, Books, Links], the telosome [Books, Links, Papers], or more recently shelterin [Links, Papers]. Note that telomeric protein complexes are also being investigated by Dr. Zhou Songyang [Papers, Papers/telomeres and Dr. Zhou Songyang]. Jesse Fender and other investigators including Wright and Shay have been exploring the interaction of the protein Ku and telomerase. Ku, which is involved in localizing telomeres to the nuclear membrane, is also important in assisting telomerase function, lack of Ku leading to telomere-telomere fusions and cellular dysfunction. Incidentally, according to a model propounded by E. Blackburn in Switching and Signaling at the Telomere (2001), telomerase does not act on capped telomeres, but only on telomeres that have become short enough to become uncapped. Telomere enlongation via telomerase then provides telomeres long enough to cap themselves. See telomerase artist's conceptions [telomerase & proteins database, telomere image]. Note that telomerase inhibitor RHPS4 [article] acts through stabilization of four-stranded G-quadruplex structures formed by single-stranded telomeric DNA found at the end of the t-loop structure, so that telomerase does not act on the closed loop. I get the impression that it is only necessary to close the 92 t-loops of human cellular chromosomes for human cells to function as the immortal phenotype, and that the percentage of senescent cells in a tissue determines how old it looks, so that the macroscale human phenotype can be rejuvenated by merely making telomeres long enough to close the t-loops, as far as mitotic cells are concerned. In time, the rejuvenated cells secrete collagen, elastin, and endogenous antioxidants in a way that restores a youthful look, although ceroid or lipofuscin deposits may have to be removed with CoQ10, alpha lipoic acid, or other drugs to completely finish the job. There may be no milage in unlocking closed telomeric loops for telomerase activation, then resealing them, to achieve even longer telomeres for a still more youthful patterns of gene expression associated with longer telomeres. Can telomeres be made as long as desired by the continued application of telomerase activation? Or does everything stop when the t-loop closes and the cell assumes the immortal phenotype? Today it seems that opinion favors the later point of view, but this must be fairly easily determined by experiment, and is perhaps very securely known.
The WRNp helicase protein (associated with Werner Syndrome) that unwinds DNA turns out to be complexed on the telomere [Image] with other t-loop proteins. The proper function of WRNp requires Mg²⁺⁺ as a cofactor, so that telomere maintenance may be improved by taking magnesium supplements. Cells lacking WRN helicase activity show defective telomere lagging strand synthesis [Crabbe, et al, 2004]. Life Extension magazine has noted that low magnesium levels common in the population lead to high rates of hypertension and sudden death. This is perhaps partially due to premature endothelial senescence linked to WRNp helicase malfunction from Mg²⁺⁺ cofactor shortfall and associated with high monocyte adhesion and consequent formation of atherosclerotic plaques. Magnesium supplementation may also be used to decrease high blood pressure in non-senescent cases, however.
The Time Machine Effect
Cosmic Humor and Pursuit of the Aquarian Soul: Moonwalking Scattered Backwards in Time
Keratinocytes of the epidermis live about as long as the period of the moon by transiently expressing telomerase, showing perhaps 1000 stem cell divisions over a lifetime, and coincidentally the synced-up moon projects the mythos of shedding one's "skin". The book of Proclus on the moon-god's spine is thus a "telomere" at the end of the line on the moon, a haunting "God Particle" or "M.Fossel". Furthermore, the Hayflick and Moorhead revolution of 1961 may be mirrored at the summit of NGC 2264 as our hero makes his way to eternal glory as Orion amid his amazing Winter Crescent flying saucer of stars, shining on the smile of Andromeda in Perseus, the Pleiades, and Aries above like the first light of the Sun on the bottom of the New Moon.
Rejuvenation Rates
Note that TA Sciences, using 5 mg/day TA-65 (cycloastragenol?) on a 3-month-on, 3-month-off cycle for a year measures 460 bp/year telomere growth in blood granulocytes, while aging normally subtracts about 50 bp/year, so that on TA-65 the telomere biotimer moves backwards in time about 9 times as fast as it goes forwards when "aging", after normal aging base pair losses are accounted for. That is, we observe a rejuvenation rate of about 9 years per year, or 0.75 years/month. A telomerase activator base pair acquisition rate of about 50 bp per year is required just to hold the line for zero aging, so TA-65 must actually provide about 510 bp/year, 50 bp of which are consumed by normal aging. Adults may experience 1 to 2 cell divisions per year, since approximately 50 cell divisions take place from the embryonic stage of development in mitotically active human somatic tissues excepting stem cells and germ cells. Persistence is required in de-aging using telomerase activators, as the process takes place gradually, somewhat like aging itself. However, instead of merely slowing the aging process, telomere remodeling with cyclic telomerase activation is expected to carry its practitioners all the way back to the young adult state, if telomeres measure longer year by year. Bear in mind that antioxidants and antiglycating drugs, DNA repair acceleration, homocysteine screens, cell membrane treatments, and vitamin C should help ensure a successful outcome with a minimum population of senescent cells to threaten cancer or susceptibility to diseases of old age. Note that there are 10 bp/turn in Watson-Crick B-DNA, with 33.2 Angstrom units per turn, or 3.32 nm/turn, so that in one year when 50 bp are lost, we typically lose 16.6 nm of telomere length. On the other hand, using TA-65 according to the Patton Protocol, we should see 9 x 16.6 nm = 149.4 nm of telomere growth per year, amounting to 1494/33.2 = 45 turns of the Watson-Crick DNA double helix at each end of every chromosome, about 76.67 telomeric TTAGGG satellite DNA repeats/year. 149.4 nm is in the EUV extreme ulraviolet range of wavelengths, and more than 2 years of growth are required for the telomere growth length to approach the wavelength of violet light, 380-450 nm. I note TA Sciences TA-65 user Bob Waskom, aged 69, observed a rejuvenation rate of 8 years per year, or 400 bp per year, which amounts a to 2/3 years/month rejuvenation scenario. See TA Sciences testamonials. Of all animals, only Leach's Storm Petrel [Wikipedia, Links, Images] has telomeres which lengthen with age. The animal lives from 20 to 35 years and is black with a white mark on the tail resembling a load of salt.

Tables for the rejuvenation times and costs may be deduced by linear analysis.
Let the final model age t_FM be given by t_FM = 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
t_FM = the model age at the end of rejuvenation. In the table below we choose t_FM = 25.
Solving for the rejuvenation time Δt, we find Δt = (t_FM - t₀)/B years.
Then the Actual Age at Final Model Age t_FM is t = t₀ + Δt, and we have Cost = $25.50(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-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
Actual Age at Final Model Age 25,	< 109.4	< 98.13	< 86.88	< 75.69	< 64.38	< 53.13	< 41.88	< 30.63
t = t0 + Δt	> 108.3	> 97.2	> 86.11	> 75.0	> 63.89	> 52.78	> 41.67	> 30.56
Cost at $25.50 per month (dollars)	< 2869	< 2487	< 2104	< 1740	< 1339	< 957	< 574	< 192
= $25.50(12)Δt	> 2550	> 2210	> 1870	> 1530	> 1190	> 849	> 509	> 170

Left: Jeanne Calment, age 25. Right: Jeanne Calment, age 60.
Also see Einstein Greying and Astragalus Extract Program at 2-Year Point.

Rejuvenation Times from 60 to Final Model Ages t_FM in Years with Cost in Dollars

Final Model Age tFM	55	50	45	40	35	30	25	20
Δt-8 Rejuvenation time, B = -8 yrs/yr	0.625	1.25	1.875	2.5	3.125	3.75	4.375	5
Δt-9 Rejuvenation time, B = -9 yrs/yr	0.556	1.111	1.667	2.222	2.778	3.333	3.889	4.444
Actual Age at Final Model Age tFM,	< 60.63	< 61.26	< 61.88	< 62.51	< 63.13	< 63.76	< 64.38	< 65.1
t = t0 + Δt	> 60.55	> 61.11	> 61.66	> 62.22	> 62.77	> 63.33	> 63.88	> 64.4
Cost at $25.50 per month (dollars)	< 191.25	< 382.5	< 573.8	< 765.1	< 956.3	< 1148	< 1339	< 1531
= $25.50(12)Δt	> 170.12	> 339.97	> 510.1	> 679.9	> 850.07	> 1019	> 1190	> 1359

The Time Machine.

The rejuvenation technique applied above is telomere remodeling with cyclic telomerase activation, to be supplemented with other antiaging medicine therapies. Here I have assumed that the cost of the ethanol-and-water astragalus extract is the two-bottle price ($11.59 per bottle) of the formerly available GAIA Herbs Astragalus Root Extract in glycerin with taxes included at $25.50. This is the stuff that tastes like a delicious cough syrup and probably makes a wonderful rejuvenating personal lubricant. Since it GAIA Herbs Astragalus Root Extract is no longer available at 1 mg astragaloside per 30 drops, 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. I believe from toxicology studies that this is safe. 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. Obviously, we need more measurements of actual results obtained with off-the-shelf astragalus extracts and similar preparations such as TA Sciences TA-65 and RevGenetics Astragaloside IV or cyclogenol Astral Fruit-C to verify tables like this table for rejuvenation to effective telomeric chromosomal age 25. 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. Measurements of telomere growth in base pairs may be done through Repeat Diagnostics for less than $700 per pass as suggested by RevGenetics, via TA Sciences if one is enrolled in their program, or via kits and software described in our labs section. See the rejuvenation tables for my self-experiment in anti-aging therapy with astragalosides at agetransformation.html, and my video Anti-Aging Therapy with Astragalosides.

Note that decelerated aging with 0 < B < 1 corresponds to the usual program of anti-aging medicine without telomerase activation, a footdragging delay in the aging process. For instance, vitamin C or homocysteine blockers decelerate the aging process, slowing the removal of telomere base pairs from chromosome tip ends. On the other hand, the aging regimes with B < 0 correspond to rejuvenation with telomerase activation. Plotting the final model age t_FM = t₀ + BΔt as a function of t = t₀ + Δt yields charts of aging as controlled by stepwise modification of the aging rate B(t).

Let Δt be the treatment time for a desired age transformation from a certain Chronological Age to a younger Desired Model Age. Then
(Chronological Age - Desired Model Age)/9 < Δt < (Chronological Age - Desired Model Age)/8,
where the ages are given in years and 8 and 9 years per year are the limiting absolute B-factor magnitudes for the age transformation rates.

The video below shows me seemingly dark haired, just out of the shower, with a little olive oil in my hair, which makes me look a little younger. By nightfall I typically look a little greyer, somehow.

Above: SixtyFortyTwo, YouTube, 51 seconds.
Alternate: Astragalus Extract Treatments, Daily Motion, 2 minutes, 32 seconds.
Hair wetted and oiled, Green finds scope for hope in his method.

Sunday May 30, 2009 - With no oil and no water in my hair this afternoon, I see quite a bit of grey in it. On the other hand, with olive oil and/or water in it, it looks quite dark, for instance after a shower. The darkening of brunette grey with such tricks may have something to do with the popularity of baptism and "thou anointest my head with oil" in the Old Testament. I am tempted to try 10 mg of astragalosides per day for a change and see if that works any better than 5 mg on a 15 days on, 15 days off cyclic basis.


Deaging Plot Corresponding to the Above Table
Based on TA Sciences 8 years per year to 9 years per year rejuvenation rate results obtained for TA-65 at 5 mg/day using the Patton Protocol. B = - 5.2 years per year was initially estimated for astragalus extract, and B = - 5.18684 shows that this was close enough for the data quality available. All model ages in the above drawing correspond to May Day, as treatment started on May 1, 2007, whereas my birthday is on May 13, 1949. After 2.5 years at about 60.5 when bone dry I seemed to be 45 to myself, whereas with oiled hair I seemed to restaurant help to be 40 at 60. This led to the B = - 5.2 years per year estimate for the astragalus extract rejuvenation rate.


Deaging Plot Corresponding to Astragalus Extract Observations after about 2.5 years.
(From 58 to Model Age 45 at 60.5 in 2.5 years, projected to Model Age 25 at 64 in 6.33 years.)
The observed rejuvenation rate is computed at B = -5.18684 years per year, approximately B = -5.2, corresponding to the top line on the chart. At the present time, I may seem to be 45, so that at the B = -5.18684 rate I would achieve a 25 year old appearance at about 64.33 years of age in 2013. The dotted lines are for TA-65 at -8 and -9 years per year. Basic cost is about $55/month, including Chitosan, or $660/year, yielding $4,188 for 6.34 years to 25 at 64. Extra money might be spent on CoQ10, alpha lipoic acid with acetyl L-carnitine, magnesium, zinc, vitamin D, multiple vitamins, resveratrol for the off part of the cycle, and other refinements.


Anti-Aging Flight Plan (reminiscent of My World Line by George Gamow).
Here Model_Age = Bt + Starting_Age, B=1 for normal aging, B > 1 for accelerated aging, B=0 for no aging, and B < 0 for rejuvenation, or negative aging. Here initially B= 1 for normal aging, then
B= - 5.2 years/year during the deaging phase, followed by B=0 zero aging until Madame Jean Louise Calment's 122 years, 164 days record is exceeded at 2071.9634 AD, which should be right at the Winter Solstice when shadows are shortest about Dec 22, 2071. About this time the S.Monocerotis skywalker above the Cone Nebula crosses the meridian. Note the "Cross of Years" formed by the 110 and 122.45 barriers. There are thousands of Americans over 100, of whom hardly any will get though the 110 year barrier without medicine. See the associated response of the cloud cover to the inclusion of these charts including the sign of the cross in Visionary Sky 46.5. Note that the B = 0 line in the flight plan can be implemented by using astragalus extract one month out of six, which would lead to a barely discernable jaggle on the B=0 line between 25 and 25 + 5/12 = 25.42 with a five-month rise time and a one-month fall time, since (1/12)(-5.2) = -0.43.
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.

---

Estimated Rejuvenation Times = T to Target Model Age t1
from Starting Age t0 for B= -5.2 years/year
with Chronological Age After Treatment = t0 + T.

Treatment Time T(t0, t1) = (t0 - t1)/5.2 years, T(ray, target) = Treatment Time
Chronological Age after Treatment = t0 + T = t0 + [(t0 - t1)/5.2] years = Final Age. 

Treatment Time (yr), Age after Treatment |  Treatment Time (yr), Age after Treatment (yr)
 Start Target Duration  Target Final Age |  Start Target Duration  Target  Final Age
  t0   t1       T        t1    t0 + T    |   t0   t1       T        t1     t0 + T

T(110, 25) = 16.346, Age(25) = 126.346;    T(105, 25) = 15.385, Age(25) = 120.385,
T(100, 25) = 14.423, Age(25) = 114.423;    T(95,  25) = 13.462, Age(25) = 108.462,
T(90,  25) = 12.500, Age(25) = 102.500;    T(85,  25) = 11.538, Age(25) =  96.538,
T(80,  25) = 10.577, Age(25) =  90.577;    T(75,  25) =  9.615, Age(25) =  84.615,
T(70,  25) =  8.654, Age(25) =  78.654;    T(65,  25) =  7.692, Age(25) =  72.692,
T(60,  25) =  6.731, Age(25) =  66.731;    T(55,  25) =  5.769, Age(25) =  60.769,
T(50,  25) =  4.808, Age(25) =  54.808;    T(45,  25) =  3.846, Age(25) =  48.846,
T(40,  25) =  2.885, Age(25) =  42.885;    T(35, 25)   = 1.923, Age(25) =  36.923,

T(110, 35) = 14.423, Age(35) = 124.423;    T(105, 35) = 13.462, Age(35) = 118.462,
T(100, 35) = 12.500, Age(35) = 112.500;    T(95,  35) = 11.538, Age(35) = 106.538,
T(90,  35) = 10.577, Age(35) = 100.577;    T(85,  35) =  9.615, Age(35) =  94.615,
T(80,  35) =  8.654, Age(35) =  88.654;    T(75,  35) =  7.692, Age(35) =  82.692,
T(70,  35) =  6.731, Age(35) =  76.731;    T(65,  35) =  5.769, Age(35) =  70.769,
T(60,  35) =  4.808, Age(35) =  64.808;    T(55,  35)  = 3.805, Age(35) =  58.805,
T(50,  35) =  2.885, Age(35) =  52.885;    T(45,  35) =  1.923, Age(35) =  46.923,
T(40,  35) =  0.962, Age(35) =  40.962. 

I think perhaps these effects can be reliably mobilized for $1000/year, so for each column of treatment time T,

Approximate Cost = $1000 x T.

Thus we may now have anti-aging medicine and associated technique to survive hundreds of years, although the medicine acts very slowly, like aging itself, to make us young again. Each month the expense of it satisfies

Cost/month > $55, perhaps $55 < Cost/month < $150,

depending on how thoroughly we treat every variable. Of course, still more can be spent by very careful experimenters, especially if they cautiously employ blood testing to measure their age variables and telomere lengths. By the 22nd century, the merit of telomerase activation in connection with anti-aging treatment will be obvious, but for decades to come until decisive demonstrations are readily available from many experimenters, time and expense may veil the solution. A more effective, safe enough, fast-acting anti-aging telomerase activation technique could save many lives merely by subtracting the elements of expense, long suffering, and mystery.