Exercise to stimulate androgen (testosterone) and hTERT transcriptional activator HGH release, with consequent elevation of hTERT protein phosphorylating IGF-1
Cyclic telomerase activation treatments. hTERT protein phosphorylation is required to transport the hTERT catalytic component of telomerase from the cytosol into the cellular nucleus.
Telomerase-activating growth factor skin cream based on colostrum that reconstructs both collagen and elastin in the extracellular matrix by including TGF-beta. Happily, TGF-beta is a telomerase inhibitor, so that purely TGF-beta skin creams exist for a telomerase inhibition phase of treatment following a telomerase activator phase of treatment.
This way, collagen and elastin may be reconstructed all the time in the extracellular matrix, while lengthening skin cell telomeres in the usual manner with cyclic treatment based on the application of growth factors featuring endogenous telomerase activators. Otherwise, I tried and rejected melatonin, a telomerase inhibitor, for daytime use, finally confining it to 1 hour before bedtime [1,2]. Melatonin has been shown to extend the life span of mice up to 20%, although it may promote cancer at some dosage levels, and so I use it with anticancer curcumin (another telomerase inhibitor), red grapes, and broccoli sprouts. I use Centrum Performance, which includes Ginko Biloba for improving cerebral circulation & HGH release, and take plenty of vitamin C, as favored by Linus Pauling [27, 28, 29, 30, 31], who extended his lifetime. (Dr. Pauling took between 12,000 and 18,000 mg of vitamin C every day for years and lived to 93.) Recently (2005) it has become clear that vitamin E and perhaps alpha lipoic acid should also be taken to cover free radicals dissolved in lipids, since vitamin C only dissolves in water, while alpha lipoic acid is soluble in both lipids and water. Alpha lipoic acid and acetyl L-carnitine are taken together, perhaps also with PQQ and ubiquinol, to combat mitochondrial aging and old age cognitive decline. This should result in superior protection for mitochondrial DNA. Neuroprotective, anticancer, cardioprotective curcumin (found in curry powder and turmeric) should be taken (with black pepper, bioperine, or piperine to improve bioavailability) to chelate iron catalyzing destructive Fenton reactions and prevent lipid peroxidation runaway chain reactions (see Aubrey de Grey, The Mitochondrial Free Radical Theory of Aging) in which peroxidized lipids dramatically accelerate free radical cell damage. Excess iron in the diet catalyzing runaway Fenton reactions peroxidizing lipid membranes can induce neural inflammation and dementia in experimental animals quite independently of caloric intake. Societies with low iron input (Japanese) or well-chelated iron (India, due to curry in the diet and little sacred cow consumed) have much lower rates of Alzheimer's Disease from iron-related inflammation than America and many other western nations, and show fewer glowing iron deposits in PET scans of their brains. I take a tablespoon of turmeric (with pepper including piperine to improve curcumin bioavailability) in water frequently during periods in which telomerase is not to be activated, and curcumin or turmeric pills are becoming widely available. Olives may be taken like pills for antioxidant hydroxytyrosol (a phytochemical, Links/hydroxytyrosol), oleic acid, squalene, oleuropein, and oleocanthol, and anticancer red grapes like pills may be taken for quercetin and trace resveratrol. It is a good idea to take more folic acid and B-vitamins than the RDA amounts to fix methylation, homocysteine problems, and glucose toxicity leading to carbonylation of proteins with glycation and consequent problems with Advanced Glycation End products (AGEs) [62s]. Finally, I am on a low-calorie diet now that emphasizes whey protein, low-mercury chunk light tuna or mackerel fish, egg whites, fiber, and vegetables rich in phytochemicals, vitamins, and the TNF-alpha inhibitor Luteolin. Note that mammal flesh heavy with saturated fats promotes HDL cholesterol and might defeat you with heart attack or stroke. The Revenge of the Pets could sink you with cancer; colon cancer is due to secondary bile products originating in meat fat. The high methionine levels in red meat or eggs may result in high homocysteine levels when methylation is degraded by aging [69s], leading to atherosclerosis. Furthermore, meat, poultry, and eggs contain arachidonic acid that can increase inflammation, increase the stickiness of blood platelets, and gum up the proteasomes, organelles that digest used-up proteins tagged with ubiquitin [2s], although arachidonic acid is vital to developing youngsters. Tend to eat foods low in saturated fats and cholesterol [62, 62c]. Boiled fish or fish canned under heat and pressure and packed in water, on the other hand, contains the omega-3 fatty acids good for the fatty sheath around brain cells. Mackerel fish is rich in CoQ10. Perhaps we should be like the star man of NGC 7000: follow the Pelican in the matter of appropriate protein by eating fish. However, mercury in canned fish, especially in shark, swordfish, king mackerel and tilefish, may be dangerous to human infants. Chunk-light tuna has less mercury than many other varieties of tuna. I now try to eat low-sugar, low-glycemic load foods to minimize low-grade inflammation [70s]. I might add that bodybuilding [Index] exercises (see books on bodybuilding physiology) increase your androgen levels as well as the HGH levels, especially in the presence of the amino acid arginine. There is evidence that treating gum disease and exercising can both ward off Alzheimer's Disease. At 53 (2002), I was still doing pull-ups with 100 lb. chained on, and did 100 push-ups at 52 [26]. According to Larry Scott, it takes 20-40 min. of pumping up to adequately increase HGH levels, so I use a split routine about 40 min to an hour each day, taking several days to cover my whole body. Incidentally, I also used alpha-hydroxy in Pond's Age Defying Complex to grow new skin cells, but am switching to a CoQ10 skin cream that will clean out cellular wastes, antioxidize cells, remove wrinkles, and not reduce the number of cell divisions available to my skin cells. Perhaps a future L-Carnosine skin cream (such as Resilience Rescue) could even extend the number of cell divisions available [54]. This might also be accomplished with a skin cream containing TA-65 [Index] or astragalus extract in glycerin or liposomes applied in a month-on, month-off periodic manner for a year.
An Optimum Anti-Aging Program Dosages: [62s] and Medicines and Dosages 2011
Free Radical Defense for Cell Membranes and DNA with Antioxidants, Anti-Glycating Drugs, and Diet
See my medicine program for February, 2011 with photos. I am beginning to suspect that the ideal anti-aging program uses Vitamin C with bioflavonoids [LifeExtension], perhaps from 1000 mg C per day up to the Linus Pauling maximum dose of 18000 mg per day, in which case bioflavonoids reduce any overdose effects of Vitamin C on white blood cells. Dr. Al Sears claims that 500-1500 mg of vitamin C, taken twice a day, helps to preserve telomere length in mitotic cells, which is accelerated by free radical damage. However, it is clear that cyclic telomerase activation is required to implement telomere rejuvenation resembling time travel backwards in time. Grape seed extract [LifeExtension, Links] helps Vitamin C penetrate cell membranes better. I get my grape seed extract now in a fancy SolarRay brand of resveratrol including grape seed extract and red wine extract and take 2500 mg of vitamin C every day. Resveratrol (a telomerase inhibitor and SIRT1 activator) should be taken with a source of quercetin [113] like onions, apple slices, or red grapes to improve bioavailability and probably with chunk light tuna to provide NAD [Wikipedia/NAD+, Links/Niacin], which enables its sirtuin-activating properties. This will retard the shortening of the genetic clock telomeres in the nucleus that cause nuclear DNA aging [30]. High-gamma Vitamin E (gamma tocopherol to ensure peroxynitrite quenching) and perhaps R-dihydro lipoic acid or alpha lipoic acid should also be taken to cover free radicals dissolved in lipids, since vitamin C only dissolves in water, whereas alpha lipoic acid is soluble in both lipids and water. This should result in superior protection for mitochondrial DNA and cellular aging due to mtDNA aging [Books]. These days I get about 1000 mg of alpha lipoic acid daily, which also effectively opposes the formation of Advanced Glycation End products [Books] that accelerate the formation of free radicals. Acetyl L-Carnitine [Index] 500mg with 200mg Alpha Lipoic Acid [Index] three times a day fights cell sugar damage (glycation of proteins), improves neurite growth, stimulates mitochondrial metabolism, and improves mental energy, vigilance, and perceptual focus. Antioxidant and iron-chelating curcumin is a "Sirius" anticancer star, but today I also get plenty of anticancer odorless garlic (a telomerase inhibitor) and garlic oil, and am worrying about how garlic may be taken otherwise. Heavy metals like mercury from fish or your fillings should be chelated with N-acetyl-cysteine (NAC), curcumin, or perhaps with carnosine. The antioxidant preservative BHT (butylated hydroxytoluene, LifeExtension/BHT) recommended by Dr. Denham Harman helps mice to live 45% longer, so perhaps we should consider using it [Links, Patents, Books; Papers/antioxidant BHT, Patents, Books].
In addition, one should also take broccoli sprouts to combat cancer and tumor formation with sulphoraphane [Index, Links, Books]. I get lots of broccoli with indole-3-carbinol in salads and broccoli sprouts rich in sulphoraphane at least once a month. One should take a multivitamin pill like CENTRUM Performance daily to supply essential vitamins and trace elements like selenium shown to be effective in cancer suppression. It takes one atom of selenium to form the cytoplasmic kind of superoxide dismutase (SOD) antioxidant. Selenium is also found in the endogenous antioxidant glutathione, and is of course required for its synthesis in the body. Another cytoplasmic kind of superoxide dismutase, CuZnSOD, is formed by an atom of copper and an atom of zinc. The mitochondrial type, MnSOD, is formed by an atom of manganese. Supplements featuring bioavailable SOD [52] such as wheat sprouts [64s], SODzyme, and GliSODin may be taken with mind-sharpening SOD-boosters such as nootropic Huperzine A [65s], Ashwagandha [63s], or Deprenyl [92]. Furthermore, calories should be restricted by the reduction of saturated fats, high-sugar foods and high-glycemic load foods [70s]. Try celery for breakfast, or celery with cooked tomato paste to get plenty of lycopene in to guard against colon cancer, and avoid the meat fats giving rise to the carcinogenic secondary bile products that cause it by nourishing carcinogen-producing bacteria. Omega-3 fatty acids from fish and fish oils good for your heart should be substituted for omega-6 fatty acids. DHA is brain food, and it is best to get it in pure form, since the EPA in ordinary fish oil raises your triglyceride levels. The sulforaphane in broccoli, the selenium in CENTRUM, the resveratrol and quercetin in red grapes, and the capsaicin in red chili peppers will help prevent cancer complications involving cells with telomeres that we want to preserve at robust length. Greater-than-RDA levels of folic acid and B-vitamins such as B12 and B6 should help deflect methylation problems and glucose toxicity in glycation [62s]. Lipid-soluble benfotiamine [Books], the lipid soluble-form of vitamin B1, is found in trace amounts onions, so I wolf down an onion sandwich every day. (Be sure to mind your breath spray while you're at it.) Using a benfotiamine pill for a dose of 100 mg or more is preferable to taking trace quantities of it found in onions, garlic, shallots, or leeks. Also, pumping up via weight lifting every day using a 3-day split routine to cover the entire body increases the HGH human growth hormone level, and stimulates the pituitary gland or the pineal gland into behaving as if you are a useful specimen that ought to be preserved. It improves your carnosine reservoir, if that is actually a factor. It's best to take whey protein to enhance your HGH levels, and to get micronized creatine monohydrate for quality muscle contractions. Include an amino stack to optimize HGH, which opposes cortisol, an aging accelerator we must foil with HGH and DHEA (dehydroepiandrosterone). To this you may add other antioxidants such as vitamins A and vitamin E, blueberries with other dopamine enhancers like Deprenyl for your brain, and other phytochemicals described below [25] including curcumin (from turmeric, and with black pepper added to improve curcumin bioavailability), green tea, grape seed extract, garlic, red grape skins, pecans, walnuts, tomatoes, spinach, and red chili peppers. I use a low-fat blueberry yogurt with plenty of whey protein in it that is just 80 calories per cup, delicious, and full of anthocyaninin antioxidants. To this I add a 3-tablespoon chilled cocoa powder in water drink daily for PQQ, chocholate polyphenols, and flavonols, remembering how chocolates were used by super centenarian Madame Jeanne Louise Calment for effective life extension. Like Jeanne, I go over my skin with extra virgin olive oil frequently, and get plenty of cooked tomato paste to up the antioxidant lycopene input. Raspberry seeds and mixed nuts contain anticancer ellagic acid and should be taken. The polyphenol resveratrol found in red grape skins has been shown to increase the lifespan of yeast, worms, flies, and no doubt of 122 year old aging record holder Madame Jeanne Louise Calment, so eat red grapes and supplement your intake of resveratrol. Quercetin (a telomerase inhibitor and SIRT1 activator) improves resveratrol bioavailability [Papers], so take it with quercetin-rich apple slices or red grapes. Madame Jeanne Louise Calment was also fond of her olive oil [76], containing the powerful antioxidant hydroxytyrosol and anticancer compounds squalene and oleic acid, so take more olives and olive oil with antioxidant lycopene or tomato juice. Extra virgin olive oil has fewer toxic impurities than cooked olive oil, and since olive oil lowers LDL and raises HDL cholesterol, it is the optimum component for salad dressings. Just add the spices and hold the vinegar, as it does not help the antioxidant problem by making your pH more basic. The polyphenols found in green tea [25a] may also be responsible for long lives, so take it, but never on an empty stomach. Not eating mammals will reduce the level of cholesterol deposits on the inside of your veins and arteries by reducing toxic homocysteine levels due to incomplete methylation of methionine from red meat [69s]. Trimethylglycine (TMG) might be taken instead to improve methylation without generating a lot of homocysteine. I think tuna fish or mackerel fish with favorable omega-3 fatty acids should be substituted for mammal meat, such as Salmon, Herring, Mackerel, and Bluefish. Remember, your blood pressure goes up as the inverse of the fourth power of the inside radius of your veins and arteries, and we need to prevent strokes and heart attacks from this source, as well as from hypertension due to high salt levels or nervous stress associated with high cortisol levels. Cooking eggs in sesame oil lowers blood pressure partly via its sesame lignans. Some skim milk each day can provide the 9 essential amino acids histidine, lysine, tryptophan, phenylalanine, leucine, isoleucene, threonine, methionine and valine from casein, the principal protein in milk, from which the rest of the 20 or 24 (L.Pauling) important amino acids may be synthesized internally. This also provides calcium to guard against old age shrinkage [102], which also requires vitamin D and HGH. Separate taking skim milk from eating dark chocolate by at least an hour [25], as milk interferes with absorption of dark chocolate polyphenol antioxidants. Soy protein food products and soy isoflavones have many benefits, lowering cholesterol and triglycerides, and tending to prevent cancer, cardiovasular disease, osteoporosis, menopausal syndromes, high blood pressure, metabolic syndrome, and type 2 diabetes. 25 grams of soy protein per day (20-90 mg of soy isoflavones) is an effective dose for lowering cholesterol. Soy milk comes in many flavors and without solid bulk is quite slimming. (However, 1/2 gallon soy milk per day for 2 days can cause constipation and burning urinary tract that would be worrisome to a dog.) Eat the world's healthiest foods and understand their properties and compositions. (See Linus Pauling on Micronutrients.) Melatonin [1], shown to be effective in anti-aging medicine, should be taken before bedtime only. Experimenters found that mice fed extra melatonin lived 20 percent longer than control mice. Curcumin mixed with black pepper to improve bioavailability should also be taken for its excellent neuroprotective and anticancer properties. Otherwise, pre-rinse teeth before brushing with antiplaque mouthwash to prevent build-up of tartar and ward off inflammation associated with Alzheimer's disease [72], brush with an anticavity and whitening fluoride toothpaste like Ultrabrite to prevent tooth decay, spit it out, then use a remineralizing and enamel-hardening mouthwash, which keeps the teeth in an environment with the pH > 5.5, preventing the deminaralization associated with dental caries. Floss at least once a day to clean the proximal surfaces of teeth, and be sure to brush all tooth surfaces. Use an age-defying skin cream with CoQ10, DMAE, carnosine or astragaloside IV to fight wrinkles and cellular wastes in your skin. Grape seed oil also helps with lines around the eyes. Note that Ubiquinone (CoQ10) [39] controls lipofuscin (waste buildup in the cell), a cellular senescence mechanism distinct from telomere shortening. Wastes associated with lipid peroxidation accelerate free radical damage and should be flushed out with CoQ10, DMAE, centrophenoxine, or Piracetam. I find DMAE inexpensive and take 300 mg/day when I can to work on the cellular aging mechanism involving cell membrane penetrability to potassium. Ubiquinone is widely available as the health food store supplement CoQ10 (coenzyme Q) and probably should be taken to cover for lipofuscin cellular senescence, which gradually turns your heart black as time goes on. The new super bioavailable ubiquinol CoQ10 is about 8x better milligram per milligram. As I recall, CoQ10 tags a glycolized protein lipofuscin waste molecule with 3 CoQ10 molecules, so that the waste molecule is excreted by the cell. Acetyl L-carnitine can also be used to undo protein glycolization that results from sugar damage [47] to proteins. Both CoQ10 and Acetyl L-carnitine are substances normally found in the body and both improve your mental energy and perceptual focus. Acetyl L-carnitine plus alpha lipoic acid is sometimes prescribed. Studies showed that old rats behaved like young ones then. "ALT-711" (Alagebrium) has also been proposed as a cure for glycolized proteins. Finally, chromium picolinate can supply a chromium molecule essential for the cleaving of insulin, and has been shown to increase the life span of laboratory mice 15%. However, there are fears it can be dangerous to DNA and that it is mainly good for loosing weight. In any case, a low-glycemic load, low-sugar diet is preferred to deflect chronic low-grade inflammation [70s]. Perhaps at least 500 mg per day of carnosine [69], a naturally-occurring substance in fast-twitch muscle fibers present in red meat, poultry, and fish, should be added to this program. High doses of carnosine can be taken, up to 500 mg per kg of body weight in a single serving without toxic effect. Some authors recommend 500mg to 2000 mg per day, and I suspect 500 mg every three hours would be best, although this more than most of us can afford. Additional anti-aging therapies should be considered. A homocysteine screen including TMG (trimethylglycine), vitamin B6, B12, and folic acid will not only protect you against atherosclerosis, but will help preserve telomere length, like the antioxidants on our list. NSAIDS [Links] are neuroprotective against Parkinson's disease and other neurodegenerative disorders, but NSAIDS can also cause ulcer problems, so I am not taking them. Inflammatory COX-2 enzymes can be inhibited with curcumin in turmeric or from gingerols in ginger without hitting the stomach-protective COX-1 enzyme. Tart cherries might also be an effective substitute for NSAIDs, which can cause ulcers if they inhibit COX-1 like aspirin. Old age diseases like macular degeneration [Index] [101] can be guarded against by taking lutein and zeaxanthin, found in orange juice, egg yolks, lettuce, and supplements along with a homocysteine shield to stop associated atherosclerotic plaque. Some curry powder, curcumin, or turmeric should be taken (with black pepper to provide piperine for improved curcumin bioavailability) to chelate copper and iron and head off mitochondrial aging, dementia, heart disease, and cancer (12). Alpha Lipoic Acid may be the best commonly available thing for mitochondrial aging, and I get my inexpensive brand of it from Wal-Mart these days. Another important drug in mitochondrial membrane maintenance is definitely ubiquinol CoQ10, the new "super bioavailable CoQ10" eight times as bioavailable as standard ubiquinone CoQ10. To repair hydroxyl-radical damage to cell membranes, I use DMAE, and am considering Centrophenoxine, which is more expensive and more difficult to obtain in the USA. A phospholipid exchange using phosphatidylcholine (lecithin) is also a promising route to cell membrane repair.
Protecting Aging Cardiomyocytes & Vasculature
Cardiomyocyte aging of heart muscle cells [Links, Books, Books2, LifeExtension] is perhaps best repaired using ubiquinol CoQ10 (Life Extension's super bioavailable CoQ10), pomegranate juice or extract, DMAE, DHEA, resveratrol, carnosine, gamma tocopherol, vitamin E, bilberry extract, and alpha lipoic acid in combination with a low-calorie Mediterranean diet [Books] including a good deal of lycopene, fish, and olive oil together with a program of healthy exercise and plenty of antioxidant cocoa powder. Heart problems (cardiovascular disease) begin to converge toward the end of a lifetime, while the primary earlier cause of death seems to be cancer. Also, I note that Geron lists cardiomyocytes and vasculature as benefiting from pulsed-on-then-off telomerase activation treatments [81s] featuring astragalosides, cycloastragenol, or ginsenoside RH1. Vitamin C to prevent degeneration of collagen, a low-sugar diet with carnosine, vitamin B1, and benfotiamine to oppose glycation, and turmeric with curcumin to prevent free radical Fenton reactions should help prevent degeneration of heart tissue, which should also be protected by avoiding alcohol, which promotes ceroid (lipofuscin) deposits, and by avoiding the smoke of cured tobacco, browned poultry skins, and other food browned by the Maillard reaction, all of which import fully-formed advanced glycation end products into tissue. Bilberry extract strengthens capillary walls, and fortifies the brain against stroke, in addition to protecting vasculature in the heart.
We also take 4-6 grams of L-arginine [Links] per day with 1 gram of L-citrulline [Links] (found in watermelon rind) to generate nitric oxide (NO) from nitric oxide synthase from bodybuilding exercises for maintaining the heart, following Nobelist Dr. Louis B. Ignarro's program outlined in NO More Heart Disease. Gamma tocopherol may be taken to protect the cell membrane against peroxynitrides. In addition, one takes the 4 antioxidants vitamin C, alpha lipoic acid, folic acid, and vitamin E. The L-citrulline helps maintain the NO supply for a longer period of time than results from the use of L-arginine alone,allowing NO to reach more cells. From studies by Vasa and Hayashi [Vasa, et al., 2000, Hayashi, et. al, 2006], we recognize that nitric oxide lengthens telomeres in the vascular endothelium, rejuvenating senescent cells there, tending to deflect heart attack, stroke, and atherosclerosis. This can also rejuvenate the thymus gland, allowing it to produce fresh T-lyphocytes. On the other hand, [Erusalimsky JD, 2009] indicates that NO activates SIRT1, not telomerase, to perform it's life-extending tricks, a contention also supported by [ Hong Y, Quintero M, Frakich NM, Trivier E, Erusalimsky JD, 2007].
Vitamin D [Index, Links/Vitamin D; Links/vitamin D and telomere loss, Books, Papers] attenuates telomere loss rates in leukocytes and many other cells. However, it is a telomerase inhibitor that might interfere with a telomerase activator if taken at the same time. According to William Falloon of Life Extension Magazine, men with low vitamin D levels suffer 2.47 x more heart attacks. He recommends 1000 IU per day, which is inexpensive. A 142% reduction in heart attacks was seen with vitamin D. Women deficient in vitamin D have a 253% increased risk of colon cancer, and women with the lowest level of vitamin D had a 222% increased risk of breast cancer. Men with higher levels of vitamin D have a 52% reduced incidence of prostate cancer. vitamin D also helps prevent strokes.
Chromosome Reconstruction with Telomerase Activation and DNA Repair
TA-65 (4x8 mg/day), Terraternal cycloastragenol (25 mg/day) or an equivalant telomerase activator [Index] (7) may be used to reconstruct short telomeres with cyclic telomerase activation. RevGenetics Astral Fruit NF contains more than 2.5 mg of cycloastragenol/cap, in addition to supplemental telomerase activators like aqueous extract of Purslane, Haritaki, and astragalus extract. The people's small molecule telomerase activator [81s/6b, List] is GAIA Herbs Astragalus Root Extract in glycerin (1 mg astragalosides/30 drops), taken at greater than 5 mg of astragalosides per day (> 150 drops/day), two weeks on and two weeks off, continuing over the course of a year, with 2 grams of chitosan to improve bioavailability. According to recent Chinese experiments on Beagle dogs that could tolerate 2.85–19.95 g/kg, we suspect that quite large doses of Astragalus Root Extract may be taken. Alternatively, I take at least 6 x 200 mg Solaray Astragalus Root Extract capsules per day for 15 days of the month to get > 5 mg astragalosides per day during the "on" part of the treatment cycle. Another alternative is to take 4 capsules of Nature's Way Astragalus Root Extract, available from Herbal Remedies. Note that smaller doses of astragalus root extract are used to deflect virus infections by activating interferon, while we are trying to activate telomerase with higher doses of the same medicine. During the first two weeks of each month on one must avoid telomerase inhibitors [81s] such as garlic, turmeric (curcumin), resveratrol, quercetin, vitamin E, green tea, melatonin, silymarin, and fish oil EPA, applying them during the next two weeks. Since a high-polyphenol diet can produce telomerase inhibitors, during the first two weeks of each month I recommend a low-polyphenol diet during that period. This keeps the cost at about what it was before using telomerase activators [Index, List] to re-extend your telomeres to repair the tip-ends of your aging chromosomes [Index/Gene]. However, this program is not yet well established. Cycloastragenol at 25 mg/day is probably superior in such a program, and cycloastragenol, the common structural element in the astragalosides, is readily available at this time in TA Sciences TA-65, Terraternal cycloastragenol, Iron Dragon cycloastragenol, and RevGenetics Astral Fruit NF. Note that the astragalosides improve wound healing, and that telomerase activation of stem cells can restore their ability to proliferate. Finally, the DNA repair enhancer Cat's Claw extract is available and some months I can take it for about $10/month in the 2nd part of the month's telomerase activation on-off cycle. I am still doing without the chromatin remodeling factor sodium 4-phenyl butyrate to maybe stretch my telomeres, but I may try it later. Sodium butyrate [Images] is available now in pill form to perhaps accelerate hTERT transcription from the butyrate-expanded chromatin. Sodium 4-Phenylbutyrate, which lengthens the life span of Drosophila, may also be used in this manner. Supplementing magnesium may help telomeric DNA helicases work better to maintain telomeres, and definitely helps lower blood pressure.
Opening Telomere T-loops for Telomerase Repair and Application of Novel Activators
It has become clear that niacinamide (nicotinamide) improves the expression of tankyrase 1, a telomeric PARP which poly(ADP-ribosyates) the telomere t-loop closure protein TRF1, allowing it to detach from the telomere loop, so that the loop can open and provide access to telomerase. Up to 1 gram/kilogram of niacinamide has been given to experimental animals to boost their tankyrase 1 levels, but the recommended human maximum dose is < 3 grams/day, so I am considering trying nicacinamide in that range. It rarely causes side effects. I taking nicinamide in the morning to develop adequate levels of NADH for poly(ADP-ribo)sylation of TRF1 in the evening, and to dimenish niacinamide strength in the evening, because niacinamide itself can interfere with the action of PARP enzymes such as tankyrase 1. Upregulating telomerase expression continuously has been observed to lengthen telomeres. Niacinamide is often taken at 1x or 2x 700 mg/day. Niacinamide-treated dermal fibroblasts at 5 mM niacinamide showed 75 population doublings at 25 mM glucose, and 83 population doublings at 5.5 mM glucose, with excursions to 125 population doublings at normal glucose levels according to Kang, et al., 2006. The canonical Hayflick Limit for such cells is 49 population doublings. The earlier cells were treated with niacinamide, the more their life span was extended. Furthermore, tankyrase 1 may become active for removal of TRF1 by phosphorylating tankyrase 1 with insulin. Therefore, the telomerase activator diosgenin contained in Fenugreek seeds and Fenugreek extract (which activatates production of the HIF-1 transcription factor for hypoxia) becomes attractive, because it also contains 4-hydroxyisoleucine, which increases insulin secretions. Insulin secretion boosting is best limited to after a workout, which also boosts levels of heat shock proteins that transport telomerase activating factors into the cellular nucleus. Therefore, Fenugreek seeds or extract and any other telomerase activators should be taken near the conclusion of an evening workout. Furthermore, arginine should probably be taken at < 10 grams 30 minutes to an hour prior to workout along with L-lysine at 1500 mg to boost HGH levels and dilate blood vessels for transport of these factors to cells. Furthermore, Nitric Oxide (NO) from arginine prior to the workout activates telomerase in vascular endothelial progenitor cells as it assists with transport. Forskolin, which should also be taken prior to the workout, darkens hair and upregulates testosterone, so that androgen-sensitive cells such as heart muscle stem cells and hair follicle melanocytes experience telomerase up-regulation. These measures should be introduced during the first 15 days of the month, when telomerase is to be upregulated to lengthen telomeres, before applying telomerase inhibitors for 15 days to maintain anticancer defenses.
Telomeres stained purple for FISH,
Fluorescent In Situ Hybridization.
QFISH technique measures the brightness of
the purple dots to measure telomere length.
Looking Out for Number One.
Future Treatment Possibilities
Telomerase Activators
Just how future treatment for aging might work using the enzyme telomerase to controllably lengthen telomeres in dividing, mitotic cells has become clearer lately. One at first envisions Dr. Jekyll downing a test tube full of it, or injecting it into the body, but such a large molecule will not cross the blood-brain barrier, nor pentrate directly into cells, except perhaps in liposomes fashioned from cationic transfection reagents and taken into the cell by endocytosis. This a method for inserting DNA plasmids into cells. However, Geron has announced small-molecule telomerase activators [Index] and the St. Petersburg Institute of Bioregulation and Gerontology revealed that Epithalon Peptide, a small 4-amino acid peptide chain protein made from alanine, glutamine, aspartic acid, and glycine (Ala-Glu-Asp-Gly), activates telomerase and extends telomeres, so that telomerase need not be taken and transported across cellular membranes. Instead, one will swallow, inject, or sublingually ingest telomerase activators under the tongue. At this time the best candidates seem to be astragalosides obtained from astragalus extract, such as astragaloside IV or cycloastragenol, the common alglycone of the astragalosides, the core around which the astragalosides are built. These are less likely to be associated with cancer than alternatives that activate telomerase (7) but also promote cellular proliferation. In particular, IGF-1 (Insulin-like Growth Factor 1) and EGF (Epidermal Growth Factor) may be used, but to inhibit cancer one may take extra Vitamin D and pomegranate extract at a disjoint time when using IGF-1. Bear in mind that vitamin D3 [Index] is a telomerase inhibitor that should not be taken together at the same time with telomerase activators.
Targeted Genome Editing with Adenovirus Transfection
Most older proposals [66] featured injection of a nucleic acid complex or a plasmid into the cell, or using a "viral vector" mechanism to permanently promote the expression of telomerase in cells to lengthen telomeres. For this gene therapy to work, the viral vector had to integrate the hTERT gene for the catalytic component of telomerase like a provirus into the host cell DNA at some point. This is gene therapy technique [Links, Papers, Patents, Books, Wikipedia, LifeExtension], possibly using adenovirus transfection, which always integrates the adenovirus code into the genome at the same place. On the other hand, lentiviruses integrate DNA into random locations in the genome, and are more likely to cause cancer. It so happens that hTERT or other genes such as C-Myc for hTERT activation may be transfected using adenovirus vectors. [See QbioGene/Adenovirus for gene therapy applications, Books/adenoviral transfections, Links/Adenoviral Transfections, Invitrogen/adenoviral transfections, Amaxa Biosystems, Amazon/adenoviral transfections]. Targeted introns may improve control of gene expression [Links, Books]. Sendai viral techniques may also be useful for our life extension application [Links, Papers, Books], as well as other viral vector methods [Papers, Books]. Dr. Michael 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 [Links, Images, Video, Papers, Books, Amazon].
Targeted Genome Editing with AAV Adeno-associated Viral Transfection
Also, it seems 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 human genome at the same site AAVS1 [Wikigenes] on Chromosome 19.
Targeted Genome Editing with Zinc Finger Nucleases [Refs23]
Press For Zinc Finger Nuclease VideosAnother emerging possibility in gene therapy is targeted genome editing with zinc finger nucleases to allow insertion of DNA code into the genome at a wider variety of sites. 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. The advantage of using a transfection technology such as zinc finger nuclease technique that permanently impacts the genome to obtain anti-aging effect may include reduced expense over the course of treatment.
Plasmid Transfection Gene Therapy
Alternative methods, such as a liposome transfection mechanism for plasmid transfection gene therapy, have been specified. Today plasmids to be transfected are transported in liposomes fashioned from cationic transfection reagents available from a variety of firms, including Invitrogen. Michael Fossel suggested using C-myc plasmids for activating hTERT, since there are several sites for C-myc on the hTERT promoter. For other possibilities (such as hEST1A, also called EST1p) based on plasmids including genes improving hTERT performance in telomerase synthesis, see TA/Telomerase Activators. Note that "Intracellular plasmid copy number increases during exposure to a liposomal vector and decreases after the vector removal. In one case, HeLa cells were incubated with a cationic liposomal vector for 24 h. Fluorescent EMA-pGL1 plasmid entry was detected by flow cytometry. At first we see increasing fluorescence intensity distribution during exposure to the liposomal vector. Later we see decreasing fluorescence intensity distribution after removal of the liposomal vector at 24 h, presumably due to EMA fluorescent label dilution resulting from cell division." - Wen-Chi Tseng, Frederick. R. Haselton and Todd D. Giorgio, 1997, Transfection by Cationic Liposomes Using Simultaneous Single Cell Measurements of Plasmid Delivery and Transgene Expression, Journal of Biological Chemistry, 1997. This means that plasmids transfected via cationic liposome technology may typically decrease in number as cell division continues, so that repeated application synchronized to cell division frequency may be useful in medical treatment featuring plasmid-in-liposome gene therapy. See Srinivasan C, Siddiqui S, Silbart LK, Papadimitrakopoulos F, Burgess DJ., 2009, Dual Fluorescent labeling method to visualize plasmid DNA degradation, Bioconjug Chem., 2009 Jan;20(1):163-9. For another relevant paper, see Liu Lei, Li Xinyu, Zhu Xuefei and Li Guigang, 2008, Cationic liposome-mediated bcl-xl gene transfection into human keratocytes, Journal of Huazhong University of Science and Technology, Volume 25, Number 3, June, 2005. Plasmid transfection schemes may fail to permanently impact the genome and require many repeat runs to be effective, so that the total cost of therapy with telomerase activators or targeted genome editing with zinc finger nucleases may be less.
Stem Cell Transplants with Transfected Cells
Invitrogen and other firms have worked out procedures for transfecting cell lines using liposomes containing plasmids fashioned from transfection reagents. For instance, see the Invitrogen NEON transfection system, which is applied to the electroporation of liposomes bearing plasmids into various in vitro cultures of cells such as dermal fibroblasts or T-cells. This method might be used to prepare rejuvenated adult stem cells for stem cell transplant operations. See hTERT plasmid sources.
Protein Targeting Telomerase to Cell Membranes
However, Phoenix Biomolecular has specified a cell penetrating peptide scheme to deliver the enzyme telomerase directly to cells. This may be done using the transport tagging mechanism that the cell uses in targeting proteins to organelles, which is also used in some cases to target proteins to the exterior cell membrane. It is also possible to transport proteins into cells though the cell membrane inside liposomes fashioned from cationic transfection reagents (Debs et al. 1990). Furthermore, RNA may be transfected into the cell by this technique (Malone et al. 1989; Wilson et al. 1979). See liposome endocytocis [Images, Papers, Patents, Books]. On the other hand, cationic liposomal transfer of antisense telomerase RNA is used in cancer therapy. Perhaps liposomal transfer of hTERT mRNA 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. Also, Christopher M. Counter and Blaine N. Armbruster specified a telomere elongation scheme published in 2007 that identifies a hPot1-hTERT fusion protein deliverable in liposomes and otherwise to rapidly enlongate telomeres. See POT1-hTERT fusion proteins [Links, Images, Papers, Patents, Books] and liposome delivery of POT1-hTERT fusion proteins [Links, Images, Papers, Patents, Books].
I note that a reverse transcriptase is used to reprogram DNA, that the enzyme telomerase is such a reverse transcriptase, and that gene therapy applies them at random sensitive points in the host DNA using techniques involving viral vectors, plasmids, or liposome transfection [68], which is always less safe and straightforward than applying a small molecule telomerase activator like epithalon peptide, tricostatin A (TSA), Astragaloside IV, Cycloastragenol or TA Sciences new TA-65 from Astragalus [Index], or Interleukin 2 to promote transcription from the existing hTERT gene.
Telomerase Delivery by Nanoparticles [Links, Images, Papers, Patents, Books].
There is also the patent Telomerase Delivery by Biodegradable Nanoparticle, that was developed by Telomolecular Corporation in 2008. The patent describes nanoparticle design for slipping hTERT through cell membranes, and moieties for targeting nanoparticles to different tissues. Note that it may be necessary to phosphorylate hTERT conveyed into the cellular cytoplasm by this method, so that it can be transported into the nucleus. This may be done using AKT1 kinase via application of resveratrol or IGF-1, which can be provided by increasing HGH levels using HGH secretagogues, since IGF-1 is produced from HGH in the liver.
Telomerase Activation with Natural Hormones
Dr. Don Kleinsek indicates that a hormone may be used to induce telomere lengthening [67], and growth hormone activates hTERT transcription in hamster ovaries and rat liver cells [article], improving the number of hTERT mRNA transcripts and indicating that Growth Hormone may be used to lengthen telomeres. Note that 17-beta-estradiol (estrogen) and progesterone are hormones that activate hTERT transcription, although they are associated with feministic transformations. Most growth factors turn out to activate hTERT transcription in certain target tissues. (IGF-1, produced from HGH in the liver, activates telomerase activity by phosphorylating hTERT in the cytoplasm for return to the cellular nucleus and may be the Kleinsek-specified hormone.) Conversely, an antagonist of growth hormone-releasing hormone was observed to dramatically decrease telomerase activity [article]. Perhaps in the future one will consume whey protein [Index, Links, Books, LifeExtension], which boosts HGH, prior to a bodybuilding workout also supplemented by HGH-boosting amino acid stacks or HGH secretagoges [Links/amino acid HGH Boosters, Links, Books, Papers, LifeExtension], in order to lengthen one's telomeres using readily available medicine, equipment, and procedures. I am still struggling to fully research these and other advanced techniques.
Measuring Telomere Length for Process Control Feedback
Whatever is done, it seems clear that effective telomere lengthening treatment or therapy to retard telomere shrinkage will require methods for measuring the telomere length using fluorescence microscopy [85] or some other advanced technique, such as endonuclease cutting of telomeres with subsequent polymerase chain reaction (PCR) gene fragment amplification of the telomere tails and then gene sequencing to obtain telomere length with single nucleotide resolution, rather than the Southern analysis method using electrophoresis on a gel prepared with telomere fragments obtained by the use of an enzyme on a larger quantity of tissue. Methods using Fluorescent in Situ Hybridization (FISH), Flow-FISH, and telomere-centromere FISH are popular. Repeat Diagnostics, Spectracell Laboratory, and TA Sciences now offer measurements of telomere length for feedback supporting programs to activate telomerase with astragalosides.
Telomere Elongation with 5'-TTAGGG-3' Oligonucleotides
It has been discovered that strings of [5'-TTAGGG-3']n sequences may patched on to telomeres to lengthen them just by supplying them in the environment. Researchers are working at synthesizing such telomere strings now. Perhaps it would do to merely supply [5'-TTAGGG-3']n sections in solution or inject them into the cell inside liposomes absorbed via liposomal endocytosis. Something similar was proposed by Michael D. West, Jerry Shay, and Woodring E. Wright in 1997 in their US Patent Methods and Reagents for Lengthening Telomeres. Their patent prescribes making available to the cell oligonucleotides as nucleic acids typically including at least 2 to 3 telomeric repeat sequences, which in humans is 5'-TTAGGG-3'. Perhaps telomere enlongation by orally bioavailable oligotide liposomal spays or liposomal skin creams will furnish suitably rapid rejuvenations. The oligotides themselves may be prepared by PCR from samples isolated from our own DNA or prepared by DNA synthesizers, or isolated from engineered plasmids grown in E. Coli using methods familiar from recombinant DNA technology [Books, Amazon] and genetic engineering [Books, Amazon].
Telomere Enlongation with Rolling Nanocircles
Similarly, nanocircles of AATCCC repeats complementary to telomere 5'-TTAGGG-3' repeats may be used, as proposed by Telomolecular Corporation. See Links/DNA nanocircles for telomere repair and Papers/DNA nanocircles.
Discovering Telomerase Activators with High-Throughput Screening
Telomolecular Corporation (defunct) investigated natural proteins known to enlongate telomeres [Links, Papers]. Sierra Sciences is also investigating antiaging telomerase activation technologies, and claims to have discovered hundreds of telomerase activators using high-throughput testing techniques. The problem then is to measure the associated rates of telomere reconstruction in base pairs per year (say 460 bp/year = 9 years/year rejuvenation rate), the safety of the medicines, and to determine side-effects.
Other Mechanisms and Alternatives
Other mechanisms exist to lengthen telomeres without telomerase. One writer has proposed using a viral vector procedure to turn off telomerase expression entirely, then replace worn-out cells with stem cells featuring telomeres lengthened by exogenous telomerase. Without the stem cells, however, this would lead to damaged tissues and/or premature aging. It seems clear that excellent feedback on telomere length will benefit research into methods for lengthening the telomeres, and may be required in the course of cyclic anti-aging treatments. The muscle cells and neural cells do not divide, although they have stem cell progenitors [Links] that do go through stem cell mitosis. The telomere-lengthening procedures are most important for the mitotic cells of the body, including the skin cells, the white blood cells, and also for the cells of the lining of the colon that finally stopped Dr. Linus Pauling at 93 and that will stop us if we don't fix them by lengthening their telomeres. It is like a fuse burning down to a ball. These cells can divide 50-100 times before using up their telomeres, which are typically from 4,000 to 15,000 base pairs long, about 1/10,000 the total DNA in the gene. Typically 20-50 telomere base pairs (bp) are used up per cell division, depending on the cell type [63]. However, recent studies have shown shortened telomeres in rat brains, and studies using telomerase to restore youthfulness to old neural tissue in culture are in the works. Thus some sort of telomerase treatment or telomere-lengthening procedure may be applied to a wider range of cells than the skin, the white blood cells, and the colon in the struggle to overcome cell senescence, be it premature stress-induced senescence or replicative senescence. Indeed, the problem of obtaining post-mitotic cell life extension by preventing cellular garbage formation (lipofuscin, ceroid) by free radical action catalyzed by iron or by cleaning cellular garbage out of the cell is a major focus of development. To live 5000 years may require applying something like meristematic stem cells, however, as in bristlecone pine, or at least rejuvenating our internal supply of stem cells with hTERT transcriptional activators and supplements promoting kinases for hTERT phosphorylation. We may take medicine to propel adult stem cells from the bone marrow out into circulating blood, extract the blood, then externally telomere-extend them with telomerase activation, sort them from the blood, freeze them, and eventually treat them to have properties more resembling embryonic stem cells, as has been done with mice before they are re-implanted as desired. Since telomerase activation enables stem cell proliferation, we may improve the proliferative abilities of our stem cells by taking small molecule activators such as the astragalosides, equipping ourselves with continually rejuvenated stem cells rivaling the meristematic stem cells of the bristlecone pine.
It should be generally useful to monitor crucial biomarkers [77] in a systematic program to treat aging. For more on the medicines used to treat aging symptoms, see the Cross-Reference List of Anti-Aging Medicines, International Anti-Aging Systems, and the Life Extension Foundation. Also see the research programs to find and identify previously unknown longevity genes. [83]
The Long-Range Impact & Reproduction [Wikipedia, Wikipedia/Reproductive System, Wikipedia/Sexual Reproduction, Wikipedia/Ovaries, Wikipedia/Ovum, Wikipedia/Oogenesis, Links/Human Oogenesis, Images, Video, Papers, Patents, Books, Amazon]. Our advanced programs for cyclic telomerase activation and cellular therapy including cell membrane rejuvenation, elimination of cellular lipofuscin and ceroid deposits, antioxidant DNA screening, accelerated DNA repair, and antiglycation drugs will probably result in youthful patterns of gene expression maintained for many decades, or even centuries, so that women will not go through menopause until much later than they now do. Women past menopause will probably experience rejuvenation effects including reactivation of their pre-menopausal state as a consequence of using the above drugs and medicines like fenugreek extract or black cohosh. It is commonly believed that when oocytogenesis is completed, no additional primary oocytes are created to make human ova, so that oocytes reach their maximum at about 20 weeks of gestational age, when there are approximately seven million of them. Recently, this has been challenged by new observations A, B. This should make it possible to maintain a pool of fertile men and women for any required substantial recovery in a natural way as we approach physical immortality with rejuvenation included. Our goal will be to maintain youthful cellular condition as fertile young adults, a strategy which also provides the best protection against diseases of old age due to cellular senescence. In other words, we will work to minimize our population of senescent cells and we shall now proceed to construct the immortal phenotype.
Accidents will continue to remove individuals from the population, and the program of evolution of the human phenotype may be continued on a different time scale. Evolution, our old ace in the hole for confronting difficulties requiring physical adaptation, has been increasingly proceeding outside of our physical bodies as we have developed vehicular instrumentalities instead of longer, faster limbs and books and computers with worldwide data networks instead of bigger, better brains. It is no longer necessary to develop specializations for hunting in new terrestrial environments now that special clothing, sunscreens, and sunglasses are available, so that physical evolution of the mortal body is relatively outmoded. Programmable machines and robots will become increasingly available to perform most dangerous or potentially damaging work. Chromosome-targeted and cell-targeted therapies will have evolution and its partner death working on a much longer time-scale than heretofore. O Death, where would we be without you?
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