Index to Anti-Aging Medicine
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R
R-Dihydro-Lipoic Acid [LEF/R-Dihydro-Lipoic Acid, Links, Images, Video, Papers, Patents, LifeExtension; Links/R-Lipoic Acid, Images, Video, Papers, Patents, LifeExtension]. See above Alpha Lipoic Acid [Index, Links, Images, Video, Papers, Patents, Books, LibCong/alpha lipoic acid, LifeExtension], (1). Recently, sodium-R-lipoic acid [Links, Images, Video, Papers, Patents, LEF] has been shown to be more bioavailable than lipoic acid (half active R-lipoic acid, half inactive S-lipoic acid) or pure R-lipoic acid, capable of achieving 10-30 times higher levels in the blood than R-lipoic acid, reaching peak plasma concentrations in just 10-20 minutes. See the Life Extension Foundation's Super R-lipoic Acid, a brand of sodium-R-lipoic acid.
Radix Astragali [Links, Images, Video, Papers, Patents, Books, LifeExtension, LibCong, Amazon]. Astragalus root/Milk Vetch root, Astragalus membranaceus/Astragalus mongholicus, a name used in traditional Chinese medicine. Elements of Radix Astragali are thought to improve the bioavailability of astragalosides in astragalus extract. Radix astragali (astragalus root) is taken at up to 33 grams/day to induce telomere growth, where as astragalus root extract may be taken at up to 11 grams/day. Radix astragali is usually taken in smaller doses throughout the day, say 9 grams + 8 grams + 8 grams + 8 grams, perhaps as NOW Astragalus Root, which is offered in 500 mg capsules. Telomere growth varies between cell types. See VIDA Institute. Chitosan, sodium deoxycholate, and radix astragali may all three be used to improve the bioavailability of astragalosides such as Astragaloside IV that are the active principles in astragalus root. It is probably true that superior results are obtained by using astragalus root with a histone deacetylase inhibitor like sodium butyrate or L-carnitine to expand chromatin for transcription by hyperacetylating histones. An HDAC inhibitor is required to get the best telomere-lengthening results from mesenchymal-derived tissues such as connective tissues, cartilage, and bone when a telomerase activator is applied. Otherwise, transcription of the hTR component of telomerase may be inadequate. Note that Radix = root, or the base of a number system in mathematics.
RAGE Receptor [Wikipedia, Links/RAGE receptor, Images, Video, Papers, Patents, Books, LifeExtension, Amazon; Alzheimers Disease, Amyloid Beta]. RAGE receptor is a 35kD transmembrane receptor of the immunoglobulin superfamily for advanced glycation endproducts (AGEs), a pattern-recognition receptor. Protein ligands which bind to the RAGE receptor include AGE protein, HMGB1 protein (Amphoterin), S100b, Amyloid-beta-protein, and Mac-1. After ligand binding, RAGE signals activation of the transcription factor NF-kappaB, which controls several genes involved in inflammation.
Rapamycin [Links, Images, Video, Papers, Patents, Books, LifeExtension; Index/TOR, Index/mTOR]. A number of drugs with Caloric Restriction-mimetic effect are being investigated, such as rapamycin, which extends the lifespan of mice and rats, but has inhibitory effect on the immune system. More familiar CR-mimetics include resveratrol and metformin.
References
[1] Van Meter M, Seluanov A, Gorbunova V (2012),
Forever young? Exploring the link between rapamycin, longevity and cancer,
Cell Cycle 2012 Dec 1;11(23):4296-7.
RAS [Index/Cancer-critical genes, Wikipedia, Links/oncogenic Ras, Images, Video, Papers, Patents, Books, LifeExtension Amazon/oncogenic Ras]. "Telomerase does not prevent human fibroblasts from undergoing a senescence response to oncogenic RAS...", Judith Campisi, Cellular Senescence, in Chromosomal Instability and Aging, p.31. See Index/Gene (Human Genome), Oncogenes, Senescence response to Oncogenes, Premature Stress-Induced Senescence and the index entries for Senescence, Cellular Senescence, and Replicative Senescence.
Reactive Nitrogen Species (RNS) [Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension, Wikipedia]. The two most important RNS include:
(1) nitric oxide (NO, but most correctly given with the free radical description: NO.) [Links, Images, Papers, Patents, Books] and the
(2) peroxynitrite (ONOO-). The peroxynitrite (ONOO-) [Links, Images, Papers, Patents, Books] is important in lipid peroxidation.
Nitric oxide is a telomerase activator [List] and vasodilator often intentionally boosted with arginine.
Reactive Oxygen Species (ROS) [Kimball/Biology_Pages/Reactive Oxygen Species by Ben Best, LibCong, Links/Reactive oxygen species, Images, Video, Papers, Patents, Books, Amazon, LifeExtension, Wikipedia], (1), Red Wine [25d]. See Free Radical Theory of Aging (Wikipedia, LifeExtension), antioxidants, endogenous antioxidants, ROS scavengers like melatonin, catalase, glutathione peroxidase, SOD, and SOD-mimetics such as wasabi and MnTBAP. Caloric restriction reduces ROS levels. ROS include oxygen free radicals that often take a free electron away from a molecule to pair with their single free electron, "oxidizing" the molecule. Common ROS include hydrogen peroxide (H2O2), ozone (O3), the superoxide ion (O2.-), and the hydroxyl radical (.OH). Hydrogen peroxide, superoxide, and nitric oxide react with a restricted class of biological molecules, while the hydroxyl radical will quickly react with almost any molecule. A free radical has an unpaired electron produced by oxidation/reduction reactions in which only one electron is transferred at a time, or produced by a broken covalent bond when only one electron from each pair remains with an atom. When free radicals react with non-radicals, a chain reaction is propagated until two free radicals react, finishing with a two-electon bond in which each radical has contributed its free electron. ROS are said to include oxygen free radicals and oxygen-containing molecules that are not strictly free radicals, such as singlet oxygen and hydrogen peroxide (H2O2), that are strong oxidants. The role in aging of endogenously generated ROS was proposed as the "free radical theory of aging" by Denham Harman in 1956, who in 1972 noted that mitochondria accumulate damage caused by free radical reactions and also produce free radicals, playing the role of a mitochondrial clock in the aging process. ROS levels are higher in senescent fibroblasts.
ROS are formed
(1) In the brain from autooxidation of norepinephrine,
(2) In the brain from autoxidation of dopamine, and
(3) in secretions from activated leukocytes,
(4) in mitochondria, (the major souce of oxidative lesions)
____from the mitochondrial electron transport system,
____via the inner mitochondrial membrane oxidative phosphorylation
____pathway
, where 90% of cellular oxygen consumed is processed.
____About 2% of electrons in the transport chain form superoxide radicals.
(5) in peroxisomes, and
(6) in cytosolic enzymatic systems, including
____xanthine oxidase,
____cytochrome P450,
____monoamine oxidase,
____nitric oxide synthase,
____lipoxygenases,
____cyclooxygenases,
____peroxidases, and
____other heme proteins, and
(7) in the autooxidation of catechols to quinones, producing reduced forms of molecular oxygen such as superoxide radicals and hydrogen peroxide, that give rise to free radicals.
(8) in oxidant formation catalyzed by high aging cell levels of redox-active metal ions such as iron, which catalyzes Fenton reactions [Index].
(9) from exogenous sources such as UV-light, ionizing radiation, chemotherapeutics, cytokine inflammation, and environmental toxins.
Damage from ROS occurs when endogenous antioxidant defense is overwhelmed, so that
(1) membranes are damaged by lipid peroxidation,
(2) cytosolic enzymes are functionally compromised,
(3) proteins are functionally compromised, and
(4) DNA is damaged (10).
ROS damage response of the cellular system may include
(1) Repair of damaged DNA (10).
(2) Repair of damaged proteins.
(3) Degradation of toxic products of lipid peroxidation.
(4) Removal of oxidatively modified proteins via proteolysis in proteasomes.
Cellular aging and/or the cell cycle arrest associated with replicative senescence or stress-induced cellular senescence may reduce the production of key antioxidant enzymes SOD1, SOD2, SOD3, catalase, and the glutathione peroxidases GPX1-GPX8, so that longer telomeres and/or hTERT activation may be associated with better endogenous antioxidant defenses.
Our cells are exposed daily to about 1010 superoxide molecules (.O-2, mostly from mitochondria), which react to form other ROS. Superoxide molecules (.O-2) may react with nitric oxide (NO.) to form reactive peroxynitrite (ONOO-) active in the peroxidation of lipids. For this we usually take gamma tocopherol. Mitochondrial MnSOD converts superoxide (.O-2) to hydrogen peroxide (H2O2), which is processed in three competing reactions
(1) H2O2 via glutathione peroxidase (GPX) to water H2O,
(2) H2O2 via catalase to water H2O, and
(3) H2O2 via transition metal catalyzed reactions to reactive hydroxyl radicals (.OH).
The Fenton reactions involving iron (Fe2+) accelerate the Haber-Weiss reactions (3) producing hydroxyl radicals (.OH) and hydroxyl ions (OH-) from hydrogen peroxide (H2O2) and the superoxide anion (.O-2). Iron-catalyzed Fenton reactions may occur, so that it is useful to chelate excess iron with curcumin in turmeric to avoid hydroxyl radicals that modify the permeability of the cell membrane to potassium, as described by Zs-Nagy in The Membrane Theory of Aging.
"Among superoxide radicals, hydrogen peroxide, and hydroxyl radicals, the hydroxyl radicals are the most reactive component. However, hydroxyl radicals have an extremely short half-life, and cannot diffuse from the mitochondria to the nucleus like hydrogen peroxide can to induce nuclear DNA damage. Hydrogen peroxide (and superoxide) can react via the (iron-catalyzed) Fenton reactions to produce hydroxyl radicals in the nucleus. This is prevented by superoxide dismutase that converts superoxide to (hydrogen) peroxide and catalase that converts (hydrogen) peroxide into water. DNA damage is communicated most extensively to mitochondrial DNA, about 10,000 DNA lesions per cell per day." - Erling Seeber, Oxidative DNA Damage and Repair - Implications for Aging, from Aging at the Molecular Level edited by Thomas von Zglinicki, Kluwer, 2003.
Note that the Fenton reaction is the iron-catalyzed Haber-Weiss reaction
H2O2 + .O-2 + Fe2+
hydrogen peroxide + superoxide anion + iron_ion(2+)
producing
.OH + OH- + O2 + Fe3+.
hydroxyl radical + hydroxyl ion + molecular oxygen + iron_ion(3+).
Carnosine protects the brain better against ROS than several other popular antioxidants, including BHT [R. Salganik, A. Dikalova, et al, 2001].
Receptors [Index/Drug Receptors, Links/Drug Receptors, Images, Video, Papers, Patents, Books, Amazon/Drug Receptors, LibCong/drug receptors; Links/Cell Surface Receptors, Images, Video, Papers, Patents, Books, Amazon; Links/Organelle Receptors, Images, Video, Papers, Patents, Books, Amazon; Links/Cell Signaling, Images, Video, Papers, Patents, Books, Amazon]. See Indigo Biosciences for methods for assaying nuclear receptor interactions with drugs. See
(1) Nuclear Receptors for Drugs [Images, Video, Papers, Patents, Books],
(2) Cell Surface Receptors for Drugs [Images, Video, Papers, Patents, Books],
(3) Cytosolic Intermediaries for Drug Receptors [Images, Video, Papers, Patents, Books],
(4) Cytosolic Drug Receptors [Images, Video, Papers, Patents, Books].
(5) Cell Signaling and Drug Receptors [Images, Video, Papers, Patents, Books].
(6) Promoter Sites for Transcription Factors [Images, Video, Papers, Patents, Books].
(7) Protocols for Drug Receptor Assays [Images, Video, Papers, Patents, Books].
See Index/Bioinformatics, Index/Gene (Human Genome), Index/hTERT Promoter, Index/Pathway Analysis, Index/Protocols, List/Telomerase Activators, List/Telomerase Inhibitors, Index/Transcription Factors, Index/Zinc Fingers.
Recipes (Encyclopedia).
Redox Signaling Molecules [Links/redox signaling molecules, Images, Video, Papers, Patents, Books, LifeExtension; Links/redox signaling molecules for anti-aging therapy, Images, Video, Papers, Patents, Books, LifeExtension; Links/ASEA, Images, Video, Papers].
[1] Moo Yeol Lee and Kathy K. Griendling (2008),
Redox Signaling, Vascular Function, and Hypertension [Online],
Antioxid Redox Signal June 2008; 10(6): 1045-1059.
Red Tea [Links/red tea, Images, Video, Papers, Patents, Books, LifeExtension]. Red tea comes from the South African plant Aspalathus linearis (rooibos). Red tea contains the powerful antioxidant polyphenol flavonoid dihydrochalcones:
aspalathin [Links/aspalathin, Images, Video, Papers, Patents, Books, LifeExtension] and
nothofagin [Links/nothofagin, Images, Video, Papers, Patents, Books, LifeExtension].
Aspalathin features more antioxidant power than EGCG. Extracts from black tea (rich in thearubigins and theaflavins), white tea (rich in antioxidant polyphenols), and green tea (rich in the monomeric catechin EGCG) are useful when applied to the skin, as is red tea (rich in aspalathin and nothofagin). See Robert Goldfaden and Gary Goldfaden, M.D. (2011), Topical Resveratrol Combats Skin Aging, Life Extension Magazine, November 2011 [Dr.Robert]. See also McKay DL, Blumberg JB (2007), A review of the bioactivity of South African herbal teas: rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia), Phytotherapy Research, 2007 Jan; 21(1):1-16. Also see Snijman PW, Joubert E, Ferreira D, et al. (2009), Antioxidant activity of the dihydrochalcones Aspalathin and Nothofagin and their corresponding flavones in relation to other Rooibos (Aspalathus linearis) flavonoids, epigallocatechin gallate, and trolox, Journal of Agricultural Food Chemistry, 2009 Aug 12; 57(15):6678-84.
Reflux Extraction [Links/reflux extraction, Images, Video, Papers, Patents, Books; Links/laboratory reflux extraction, Images, Papers, Patents, Books; Links/separation technology, Images, Video, Papers, Patents, Books; Links/thermal reflux extraction, Images, Papers, Patents, Books]. See Instrumental Analysis, Separations, Phytochemical Separations, Analytical Chemistry, and Pharmaceutical Engineering for separation techniques.
Regenerative Medicine [RegMedNet/Regenerative Medicine, Wikipedia/Regenerative_medicine, Links/Regenerative Medicine, Images, Video, Papers, Patents, Books, LibCong, Amazon, LifeExtension, Retinol, Retinoic Acid in Regenerative Medicine, Ben Best, McGowan Institute for Regenerative Medicine, California Institute for Regenerative Medicine, Morphogenesis and Regenerative Medicine Institute, Google's Regenerative Medicine, SpringerLink Advances in Biochemical Engineering/Biotechnology (Links, Images, Papers, Books, Amazon)], [56]. hTERT improves stem cell proliferation to regenerate tissues. DHEA improves the proliferation of neural stem cells. Stem cell therapies have been applied to more than 50 tissues. See Liu S, Li H, Ou Yang J, et al. (2005), Enhanced rat sciatic nerve regeneration through silicon tubes filled with pyrroloquinoline quinone, Microsurgery 2005; 25(4):329-37. Also see DHEA, hTERT, Gene Therapy, Induced Pluripotent Stem Cells (iPS cells), Kidney Disease, Mesenchymal Stem Cells, Nuclear Reprogramming, Plasmids, Pluripotent Stem Cells, Retinoic Acid in Regenerative Medicine, Stem Cell Technology, Telomerase Activators (7), Tissue Engineering, Transfection, and Wound Healing.
References
[1] John Ramunas, Eduard Yakubov, Jennifer J. Brady, Stéphane Y. Corbel, Colin Holbrook, Moritz Brandt, Jonathan Stein, Juan G. Santiago, John P. Cooke and Helen M. Blau (2015),
Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells
[PDF, Big Screen PDF], The Faseb Journal, Jan 22, 2015. See Fast Telomere Extension.
Regenerative Therapies for Telomeres [Links, Images, Video, Papers, Patents, Books; (7); Index/Telomerase Activators, List; Telomere Remodeling with Cyclic Telomerase Activation, Life Extension via Telomere Extension in vivo, Fast Telomere Extension].
Rehydration of Cells [Links/Rehydrating cells, Images, Video, Papers, Patents, Books; Links/Cellular dehydration, Images, Video, Papers, Patents, Books; Links/Physiological consequences of dehydration, Images, Video, Papers, Patents, Books]. Cells progressively dehydrate with aging (13). Perhaps it is true that certain motor proteins in cells such as myosin V [Images, Video, Papers, Books], myosin II [Images, Video, Papers, Books], myosin I [Images, Video, Papers, Books], the dyneins [Images, Video, Papers, Books] and the kinesins [Images, Video, Papers, Books] do not function properly when the cell is dehydrated, because they need some room in which to swing their molecular components. These and other molecular machines may seem to call for big glasses of water and other rehydration therapy [Images, Video, Papers, Books] based on altering the permeability of the cell membrane as described in The Membrane Hypothesis of Aging by Zs-Nagy. (13).
Reishi Mushroom (Ganoderma lucidum) [Links, Images, Video, Papers, Patents, Books, LEF; Medicinal mushrooms]. Reishi mushrooms are anticancer, antioxidant, elevate nerve growth factor, and improve the life span of experimental mice. Reishi mushroom inhibits microglial activation, protecting dopaminergic neurons, and can be used to treat neurodegeneration. See Emily Steiner (2013), How Reishi Combats Aging, Life Extension Magazine, Feb 2013. Non-alcoholic fatty liver disease is often associated with toxin-induced liver fibrosis, a condition that may be reversed in animal models by treatment with Reishi mushroom. Anti-inflammatory reishi mushroom is also used to inhibit immunosenescence.
Reishi References
[1] Walter Thompson (2014), Fight Immune Decline With Reishi,
Life Extension Magazine August 2014.
[2] Sanodiya BS, Thakur GS, Baghel RK, Prasad GB, Bisen PS. (2009),
Ganoderma lucidum: a potent pharmacological macrofungus,
Curr Pharm Biotechnol 2009 Dec;10(8):717-42.
[3] Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. (2004),
Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-kappaB signaling, Nutr Cancer 2004;49(2):209-16.
[4] Zheng S, Jia Y, Zhao J, Wei Q, Liu Y. (2012),
Ganoderma lucidum polysaccharides eradicates the blocking effect of fibrinogen on NK cytotoxicity against melanoma cells, Oncol Lett 2012 Mar;3(3):613-6.
[5] Yue GG, Fung KP, Tse GM, Leung PC, Lau CB. (2006),
Comparative studies of various ganoderma species and their different parts with regard to their antitumor and immunomodulating activities in vitro, J Altern Complement Med, 2006 Oct;12 (8):777-89.
[6] Guo L, Xie J, Ruan Y, et al. (2009), Characterization and immunostimulatory activity of a polysaccharide from the spores of Ganoderma lucidum, Int Immunopharmacol 2009 Sep;9(10):1175-82.
[7] Chang SS, Zhou D, Meng GL, et al. (2012),
Effect of Ganoderma lucidum polysaccharides on oxidative stress of hyperlipidemic fatty liver in rats, Zhongguo Zhong Yao Za Zhi 2012 Oct;37(20):3102-6.
[8] Chen WQ, Luo SH, Ll HZ, Yang H. (2005),
Effects of ganoderma lucidum polysaccharides on serum lipids and lipoperoxidation in experimental hyperlipidemic rats, Zhongguo Zhong Yao Za Zhi 2005 Sep;30(17):1358-60.
[9] William Faloon (2015), A Common Virus, Life Extension Magazine, Jan 2015.
"Cistanche is a low-cost nutrient that should be taken daily in the dose of 210 mg, preferably with 1,000 mg of Reishi mushroom extract, to provide broad spectrum protection against the many factors involved in immune senescence."
Rejuvenation Biotechnology [Links, Images, Video, Papers, Patents, Books, LEF; Index/Regenerative Medicine, Index/Stem Cell Technology, Index/Progenitor Cells, Index/Telomerase Activators; Oral phytoceramides]. A descriptor perhaps coined by Aubrey de Grey in Why Aren't More Wealthy People Funding Aging Research?, Life Extension Magazine, September 2011.
Rejuvenation Research [Cambridge/SENS/Rejuvenation Research, Books/anti-aging rejuvenation, Amazon, LibCong/rejuvenation, LifeExtension], ed. Aubrey de Grey [Index/Aubrey de Grey, Wikipedia, Links/Aubrey de Grey, Images, Videos, Papers, Patents, Books, LifeExtension], [40], [79s]. See also Skin Rejuvenation [Links/skin rejuvenation, Images, Papers, Patents, Books, LifeExtension, Amazon/skin rejuvenation, IQ Derma, New Face Solution; Oral phytoceramides]. See also Telomere Remodeling with Cyclic Telomerase Activation, TA Sciences, and Journals.
Rejuvenation of the Hair [74s, Links/hair restoration, Images, Video, Papers, Patents, Books, LifeExtension; Links/hair rejuvenation, Books, LibCong/rejuvenation, LifeExtension; Index/Hair Greying; Index/Hair Loss Treatment]. Hair melanocytes [Images, Video, Papers, Patents, Books] are refreshed by stem cells [Index] that may be rejuvenated with telomerase activation using telomerase activators. See Telomere Remodeling with Cyclic Telomerase Activation and TA Sciences. Melanocyte-stimulating hormone from tribulus may be used to restore hair color, and catalase may prevent internal bleaching from hydrogen peroxide. Onion juice [Video, Papers, Patents, Books], from a juicer or filtered from a blender (Lori Klein, 2013), increases catalase in skin to reduce hydrogen peroxide, stopping hair whitening. Onion juice also increases hair growth. Rinse off before bedtime 1.5 hours after application. Perhaps oral phytoceramides have some application to hair rejuvenation, since they improve the characteristics of the aging scalp.
Rejuvenation of the Neck [Refs11, Index/Neck Rejuvenation, Links/Neck rejuvenation, Images, Video, Papers, Patents, Books, LibCong/rejuvenation, Amazon, LifeExtension; IQ Derma, New Face Solution; Oral phytoceramides]. Colostrum skin cream contains TGF-beta, which reconstructs collagen and elastin in the extracellular matrix. Colostrum skin cream contains other telomerase activators found in growth factor skin creams that restore telomere length in dermal fibroblasts. In addition, exercises for the platysma muscle may be done to tighten the neck. Look up, then bring the chin down to the chest with the tongue pressed tightly to the roof of the mouth, and repeat for 10-15 reps to exercise the platysma muscle and tighten the neck. Repeat for 3 sets. See Revitalize Your Aging Neck with Hexapeptide 10 and Plastic Surgery for Neck Rejuvenation.
Rejuvenation with Young Serum [Links, Images, Papers, Patents, Books]. See Irina M. Conboy, Michael J. Conboy, Amy J. Wagers, Eric R. Girma, Irving L. Weissman & Thomas A. Rando (2005), Rejuvenation of aged progenitor cells by exposure to a young systemic environment, Nature 433, 760-764 (17 February 2005).
Renal Cell Cancer (See Kidney Cancer).
Replication Protein A [Telomerase Activators/RPA, 70 kDa beta-barrel protein, Image (BioInfo Bank/ Biomolecules Gallery), Links, Images, Papers, Patents, Books, GeneCards/RPA1, YeastGenome/RPA1, YeastGenome/Telomere Maintenance; Images/Replication Protein A molecule, Links/Replication Protein A promoter, Images, Papers, Patents, Books; Links/binding sites of the Replication Protein A promoter, Images, Papers; Source: Origene - 20 micrograms for $680.00].
Replication Protein A on human Chromosome 17, which is present in all eucaryotic cells, has been observed to activate telomerase in yeast. See Vera Schramke, Pierre Luciano, Vanessa Brevet, Sylvine Guillot, Yves Corda, Maria Pia Longhese, Eric Gilson & Vincent Géli, (2003, 2004), RPA regulates telomerase action by providing Est1p access to chromosome ends, Nature Genetics 36, 46 - 54 (2004) Published online: 21 December 2003. Est1p [YeastGenome/Est1] has been conserved in evolution and is present in humans as hEST1A [Links]. "Overproduction of hEST1A cooperated with hTERT to lengthen telomeres." - See Snow BE, Erdmann N, Cruickshank J, Goldman H, Gill RM, Robinson MO, Harrington L., (2003), Functional conservation of the telomerase protein Est1p in humans, Current Biology 2003 Apr 15;13(8):698-704. hEST1A recruits telomerase holoenzyme by binding to hTERT. (See Diagram). hSMG6 [Links/hSMG6, Links/SMG6] is identical to hEST1A. (See Joachim Lingner, Senior scientist, Telomerase and chromosome end replication, ISREC.) According to Gene Cards, overexpression of SMG6 (in humans hEST1A) results in telomere uncapping. Therefore perhaps hSMG6 or hEST1A can be used to extend t-loop capped telomeres, opening them so that they can be extended by telomerase. Note, however, that more chromosome end-to-end fusions are seen when SMG6 (hEST1A) is overexpressed. (GeneCards/EST1). Telomerase does not act on telomeres unless the telomere is uncapped (7). Thus large telomere t-loops corresponding to very youthful cells may be prepared by using hEST1A (hSMG6) together with telomerase, probably by stopping SMG6 towards the end of a treatment period to reseal telomere t-loops. Such cells may have superior staying power, lasting for more cell divisions before uncapping, generating a DNA damage signal, and entering the state of replicative senescence. Also see Robert M. Brosh, Jr., David K. Orren, Jan O. Nehlin, Peter H. Ravn, Mark K. Kenny, Amrita Machwe and Vilhelm A. Bohr (1999), Functional and Physical Interaction between WRN Helicase and Human Replication Protein A, Journal of Biological Chemistry, June 25, 1999, 274, 18341-18350.
Replicative Senescence [Wikipedia, Index/Senescence, Index/Cellular Senescence, Links/Replicative Senescence, Images, Video, Papers, Patents, Books, LibCong, Amazon, LifeExtension, Mechanisms of Aging/XII. Telomeres and Aging by Ben Best; Therapy for Recovery from Senescence, Restore or Replace Senescent Cells?]. See Senescence, Senescence Pathways, and Cellular Senescence. Most human cells, for instance dermal fibroblasts [Images], have a cell division limit of about 50, the Hayflick Limit (1961) of Swim and Parker (1957). Exceptions include adult stem cells [Images] that transiently express telomerase to enable more cell divisions, for instance deep dermal keratinocytes, and germ line cells, which express enough telomerase to keep their telomeres at constant length. When the cell division limit is exceeded, the telomere cannot cap itself with a t-loop, and the undone telomere generates a DNA damage signal which stops the cell cycle and precipitates the senescent state of the cell, which has a different pattern of gene expression [Images] than the youthful or immortal phenotype of the cell [Images]. Note that the telomere position effect is involved. When the shortest telomere on chromosome 17p is short enough, the Telomere Position Effect [(7)/TPE, Links, Images, Papers, Patents, Books, LifeExtension] tends to activate the neighboring p53 tumor suppressor gene, which stops the cell cycle [Images]. Senescent fibroblasts increase their expression of caveolin-1 via the gene CAV1, swell up to about 3 times their normal size, internalizing cell membrane caveolae containing growth factor receptors for endogenous telomerase activators such as EGF and PDGF, and begin to excrete matrix metalloproteinases [Index] destructive of the extracellular matrix, such as collagenase (MMP-1) and stromelysin (MMP-2). See photos of healthy and senescent dermal fibroblasts from Hayflick, His Limit, and Cellular Aging by Jerry W. Shay & Woodring E. Wright. Senescent fibroblasts also produce lower levels of the matrix metalloproteinase inhibitors protecting the extracellular matrix [Images] from degradation, TIMP1 and TIMP3. In the youthful, immortal phenotype state, the dermal fibroblasts excrete collagen and elastin to maintain the extracellular matrix, preventing wrinkles observed to set in after the senescent state is acquired. Pre-senescent cells also express higher levels of endogenous antioxidants and other factors tending to protect DNA, cell membranes, and the extracellular matrix. Rejuvenation of senescent cells may be sometimes possible with small molecule telomerase activators [Index, List], which can reconstruct telomeres, lengthening them until they can recap themselves with a t-loop structure [Index/Telomere Loop]. Lengthening telomeres tends to produce more youthful patterns of gene expression, even when cells are not senescent. Recovery from cellular senescence with considerable gain in telomere length may be managed otherwise, by reducing expression of the cell membrane gatekeeper protein caveolin-1 (gene CAV1), which is elevated in senescent cells. Many diseases of old age have their origin in replicative senescence [81s]: See Michael Fossel, Cells, Aging, and Human Disease. Note that most cells never become senescent in aging specimens and that our procedure for lengthening telomeres with telomerase activators prevents, but does not reverse, cellular senescence. See Christian M. Beausejour, Judith Campisi, et.al, (2003), Reversal of Human Cellular Senescence: roles of p53 and p16 pathways, The EMBO Journal, 2003, 4212-4222. Growth arrest in replicative senescence is established by p53 (TP53 gene) and pRb (retinoblastoma) tumor suppressor proteins. Replicative senescence is reversible or not depending on the expression of pRb regulator p16. Cells with low levels of p16 resumed growth when p53 was inactivated, but cells with high levels of p16 at senescence failed to recover and proliferate after p53 inactivation, re-entering the cell cycle without growth after pRb inactivation. Thus the senescence response to telomere dysfunction is reversible and maintained mainly by p53, although p16 provides a 2nd barrier to the unlimited growth of human cells after they have entered the state of replicative senescence. P16INK4A is ubiquitinated, however, and the expression of p16INK4A can be reduced with retinoic acid obtained by taking retinol, retinal, or beta-carotene, or by Id-1 helix-loop-helix transcription factor obtained after treatment with nerve growth factor from taking acetyl L-carnitine, huperzine A, rosemary, or carnosic acid. Exercise can reduce P16INK4A by a factor of 4. Colostrum [List] contains FGF-2 and VEGF, which upregulate survivin, which can reverse replicative senescence.
See Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999), Microarray Analysis of Replicative Senescence [Links, Images, Video, Papers, Books], Curr Biol, 9:939-45. See also Thomas Kuilman, Chrysiis Michaloglou, Wolter J. Mooi and Daniel S. Peeper (2010), The essence of senescence, Genes and Development, 2010, 24: 2463-2479.
"In contrast to cycling fibroblasts, those that have entered senescence do not express hTERT. This phenomenon is also consistent with the regulatory model based on the E2F–pocket protein–HDAC complex. It is well known that expression of cyclin-dependent kinase inhibitors (e.g., p16INK4A and p21Waf1/Cip1) progressively increases with cumulative population doublings and telomere shortening, resulting in the accumulation of hypophosphorylated pocket proteins in senescent cells. These activated pocket proteins stably suppress E2F target genes by facilitating heterochromatin formation during cellular senescence. Our results suggest that this potentiated pRB pathway [pRB protein] may cause the previously observed senescence-associated constitutive repression of hTERT in normal human cells, which suggests an action of the pRB pathway as a tumor suppressing mechanism; by more stringently repressing hTERT in the course of aging, the pRB pathway may suppress spontaneous immortalization or tumorigenesis. Taken together, our findings revise a well known unidirectional link from telomerase (telomere) to the E2F–pRB pathway in normal human cells (4, 30) as a bidirectional feedback link (Fig. 8B)." - from Won J, Chang C, Oh S, and Kim T (2004), Small-molecule-based identification of dynamic assembly of E2F-pocket protein-histone deacetylase complex for telomerase regulation in human cells, PNAS, 2004, and related articles on CGK1026.
Reproduction [Wikipedia, Wikipedia/Reproductive System, Wikipedia/Sexual Reproduction, Wikipedia/Ovaries, Wikipedia/Ovum, Wikipedia/Oogenesis, Links/Human Oogenesis, Images, Papers, Patents, Books, Amazon/Human Oogenesis; Erotic Hots Study Guide]. 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 and nutraceuticals 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. 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 reproduction to cover any requirement in a natural way as we approach physical immortality with rejuvenation included. Individuals will maintain a minimum population of senescent cells to preserve the immortal phenotype as fertile young adults, so that reproduction will be possible whenever it is convenient or necessary for recovery.
Resilience Rescue L-Carnosine skin cream, [54].
Resveratrol: [Wikipedia/Resveratrol, Links/Resveratrol, Images, Video, Papers, Patents, LibCong, Amazon; LifeExtension, Terraternal/Resveratrol, Links/Resveratrol dosage, Books, Benefits of Resveratrol; Telomerase_Activators/Resveratrol; Plant Sources: Itadori Tea; Telomerase Activators/Product B/Resveratrol (150)], (0). Resveratrol enhances AMPK signaling to stimulate autophagy that consumes cellular junk and reduces triglycerides and glucose in the blood. Furthermore, resveratrol activates telomerase in normal cells by phosphorylating the hTERT catalytic component of telomerase via the Akt kinase, and is a small-molecule SIRT1 activator. This promotes the import of hTERT protein from the cytoplasm into the nucleus without generating new hTERT mRNA, however. "Resveratrol delays the onset of Endothelial Progenitor Cell senescence and this effect is accompanied by activation of telomerase through the PI3K-Akt signaling pathway." [Ref]. Note that niacinamide inhibits SIRT1, so that it should not be taken while using resveratrol. Instead, NAD+ (Niacinamide Adenine Dinucleotide) should be supplemented directly at about 2.5 mg every other day. Resveratrol's heightened SIRT1 expression downregulates P16INK4A expression, retarding the onset of irreversible replicative senescence, which sets in when P16INK4A levels are too high. Also, resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP-degrading phosphodiesterases. Resveratrol increases cAMP levels and promotes mitochondrial biogenesis by competitively inhibiting PDEs. (Park, et al. 2012). It also inhibits COX-2 enzymes and has anti-inflammatory properties. Resveratrol down-regulates telomerase in cancer cells, and may be used to treat breast cancer. Recently Vince Giuliano pointed out that resveratrol seems to be a telomerase activator [List] for normal cells (via the phosphorylating the Akt1 kinase pathway) and a telomerase inhibitor for cancer cells (Ref), so perhaps it will be useful to take resveratrol all of the time. However, since high-polyphenol resveratrol activates SIRT1 to inhibit transcription from genes like a histone deaceylase by condensing chromatin, I would advise regarding it as an hTERT mRNA transcription inhibitor. That is, resveratrol can serve as a spoiler for drugs which improve the transcription of hTERT mRNA by condensing chromatin to oppose transcription. The phosphorylation of hTERT protein in the cytosol merely transports existing hTERT catalytic component of telomerase into the nucleus, without providing for the preparation of more hTERT catalytic component of telomerase from hTERT mRNA. Thus resveratrol is merely weakly telomerase activating by enabling transport into the nucleus of existing hTERT protein. See Resveratrol by Ray Sahelian, Effect of Resveratrol on Telomerase Gene Regulation in Cancer Cells, and Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms. Note that Akt1 phosphorylates hTERT in the cytoplasm for import into the nucleus. Resveratrol is a natural polyphenol, is neuroprotective, opposes macular degeneration, decreases the expression of beta-amyloid plaque leading to Alzheimer's Disease, is anticancer, uses gene regulation to oppose cancer, stimulates Nitric Oxide, is an antioxidant, generates antioxidants, stimulates apoptosis of cancer cells (like curcumin), and is anti-inflammatory (like quercetin). See also Resveratrol & Quercetin by James South, with [Links/Resveratrol, LibCong/resveratrol, LibCong/Quercetin, Quercetin] and Wang XB, Zhu L, Huang J, Yin YG, Kong XQ, Rong QF, Shi AW, and Cao KJ (2011), Resveratrol-induced augmentation of telomerase activity delays senescence in endothelial progenitor cells, Chin Med J (Engl) 2011 Dec;124(24):4310-5. According to Life Extension Magazine, Resveratrol embodies a cutting-edge technology. Resveratrol increases the life span of Drosophila by 35% and decreases hydrogen peroxide levels to protect mitochondria. Furthermore, resveratrol increases life span of round worms and fruit flies somewhat, and lengthens the life span of yeast cells by 70% to 80%. Resveratrol is found in wines, grapes, berries, and roots, peanuts, and Polygonum Cuspidatum (Japanese Knotweed, the Itadori Plant) [100]. On the other hand, Resveratrol is not found in sun-dried raisins. Notable Resveratrol sources [Links/Resveratrol supplements] include resveratrol capsules from Life Extension Foundation, Terraternal, and RevGenetics. For an inexpensive source of resveratrol, see the index entries on Polygonum Cuspidatum (Japanense Knotweed), the resveratrol source that grows easily in your backyard and makes pie that has been compared to rheubarb pie. Other good sources of resveratrol include mulberries, blueberries, < bilberries, and muscadine grapes. "Red grapes generally yield about 0.24 and 1.25mg per cup."
FoodWeight/CupResveratrol Weight/Cup
Red grapes1 c (160 g)0.24 – 1.25 mg
Cocoa powder1 c (200 g)0.28 – 0.46 mg
Boiled Peanuts1 c (180g)0.32 - 1.28 mg
Resveratrol supplements [Links, Images, Video, Papers, Patents, Books, LifeExtension] make far higher concentrations of resveratrol available.
Resveratrol Supplement [Images, Video]transresveratrol mg/capCost Dec 1,2012
Biorganic Life Grape Glow Resveratrol100 mg/oz$27.99/64 oz
Country Life Resveratrol Plus100 mg/cap$9.89/60 caps
Doctor's Best Trans-Resveratrol100 mg/cap$13.55/60 caps
Enzymatic Therapy Resveratrol Forte125 mg/cap$10.97/60 caps
Life Extension Optimized Resveratrol250 mg/cap$34.50/60 caps
Finest Natural Resveratrol100 mg/cap$19.99/60 caps
Nature's Way Resveratrol Synergistic Formula37.5 mg/cap$9.99/60 caps
Now Foods Natural Resveratrol200 mg/cap$24.99/120 caps
Swanson
$49.99/120 caps
Retail
Perfect ResGrape Resveratrol200 mg/serving$41.95/30 servings
Piping Rock Resveratrol250 mg/cap$14.28/90 caps
Puritan's Pride Resveratrol250 mg/cap$22.49/120 caps
ReserveAge Organics Resveratrol250 mg/cap$29.99/60 caps
RevGenetics R250 Resveratrol250 mg/cap$13.99/30 caps
RevGenetics X500 Resveratrol500 mg/cap$23.99/30 caps
Tropical Oasis Trans-Resveratrol300 mg/oz$24.19/32 oz
Vinomis Laboratories Vindure 900400 mg/cap$39.95/30 caps
Vitacost Trans-Resveratrol250 mg/cap$19.99/60 caps
Vitamin Shoppe Trans-Resveratrol250 mg/cap$28.79/60 caps
Peanuts have about half as much resveratrol as red wine. See [Links/Resveratrol content of foods, Links/Resveratrol content of plants]. See also [Allvita/Resveratrol is anticancer, Wizard of Vitamins/Resveratrol, Resveratrol from Longevinex and/or Red wine, Links/Resveratrol from Longevinex]. Resveratrol may be substituted for caloric restriction (CR) with fair results. Resveratrol chelates copper, helping it to oppose the spread of cancer. Resveratrol also inhibits the histamine release of inflammatory mast cells triggering asthma and allergic reactions. - (Julius Goepp, MD, Activate Your Longevity Genes via Caloric Restriction, Life Extension Magazine, Feb. 2010).
Also, note that resveratrol is renoprotective, preserving kidney structure and function by preventing ishcemia/reperfusion injury, observed perhaps as a consequence of sepsis (massive bacterial infection) following surgical operations. Resveratrol is effective against nephrotoxic drugs such as cisplatin (a chemotherapy drug), cyclosporin A (another chemotherapy drug) and gentamicin (an antibiotic). The caloric restriction mimetic properties and glucose toxicity control of resveratrol are useful in treating diabetic kidney damage. See Julius Goepp, MD, "Innovative Strategies to Combat Kidney Disease", Life Extension Magazine, May 2010, p.28. Resveratrol has been effective in restoring motor control in artificially-induced Parkinson's Disease in experimental animals.
See Robert Goldfaden and Gary Goldfaden, MD (2011), Topical Resveratrol Prevents Skin Aging, Life Extension Magazine, November 2011 [Dr.Robert] and Baxter RA, Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation, Journal of Cosmetic Dermatology, 2008 March; 7(1):2-7.
Resveratrol increases NAD+ levels. NAD+ (NADH, Nicotinamide adenine dinucleotide) enhances SIRT1 activity. Also, supplemental NAD+ seems to enhance resveratrol SIRT1 activation. Both resveratrol and NAD+ reduce neural degeneration and extend neuron lifespan. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. It is suspected that adequate intracellular NAD+ levels are essential for neuronal survival. There is a 1:1 stoichiometry between intracellular NAD+ content and sirtuin-mediated deacetylation. This fact bears on determining optimal dosages of NAD+. Ray Sahelian promotes 2.5 mg of NADH every other day, or perhaps as much as 5 mg every other day. At higher levels, stomach upset is sometimes observed.
Bioavailability: "Additionally, lecithin [Images, phosphatidylcholine] has been found to enhance the oral absorption of polyphenols like quercetin and resveratrol. [Journal of Agriculture and Food Chemistry 13; 50:1706-12, 2002]". Note that quercetin improves the bioavailability of resveratrol. Ethanol in red wine is thought to improve the bioavailability of quercetin and resveratrol in red wine, partially explaining the French Paradox that although ethanol is not too good for you, red wine is good for you after all. Muscadine wines [Images] have the highest concentrations of resveratrol. A Pinot Noir from New York State is a source, although red grapes, Muscadine wines, and resveratrol supplements are better. Fisetin is a rare flavonoid that augments reveratrol effects.
Dosage: Most sources recommend 200-400 mg/day of transresveratrol. RevGenetics offers up to 1000 mg/day of transresveratrol (cis-resveratrol does not have transresveratrol's benefits) in 1000 mg capsules. Megadoses of resveratrol have been reported as associated with resveratrol side-effects including anxiety and blood abnormalities including anemia and over-thinning of the blood.
Caution: Resveratrol thins the blood, so if you are using a blood-thinning agent, it may be best to visit with your doctor before taking resveratrol. See Links/resveratrol and blood thinning.
Resveratrol Extraction Technique: [Links, Images, Video, Papers, Patents, Books]. Extraction goes well with ethanol and water, 80 parts ethanol to 20 parts water at 60 degrees centigrade for 30 minutes if preparing extractions from grapes. This may be separated further by chromatography. See Ana I. Romero-Pérez, Rosa M. Lamuela-Raventós, et al., (2001) Method for the Quantitative Extraction of Resveratrol and Piceid Isomers in Grape Berry Skins. Effect of Powdery Mildew on the Stilbene Content, Journal of Agriculture and Food Chemistry, 2001, 49 (1), pp 210–215. See also resveratrol extraction technique from Japanese knotweed and resveratrol extraction technique from Polygonum Cuspidatum. Check Itadori tea as a resveratrol source.
Retinol [Wikipedia, Links, Images, Papers, Patents, Books, LifeExtension; Wikipedia/Retinoic acid, Links/Retinoic acid, Images, Papers, Patents, Books, LifeExtension; Telomerase Inhibitors/retinoic acid; Telomerase Activators/retinoic acid; Vitamin A; Regenerative Medicine, cAMP]. Retinol from carrots is converted to retinoic acid inside the cell. Retinoic acid inhibits telomerase in cancer cells and inhibits p16INK4A generally. P16INK4A makes recovery from cellular senescence difficult, and limiting its expression extends the time a normal cell can express telomerase before senescence. Retinol is a popular ingredient in skin creams.
Retinoic Acid in Regenerative Medicine [Links, Papers, Patents, Books, LEF; McGowan Institute].
Retinoic acid from retinol has recently been identified as playing a key role in tissue regeneration in mammals (including humans), as well as in Mexican salamanders. Perhaps one should try eating a lot of carrots and using a retinol skin cream [Images, Papers, Patents, Books, LifeExtension]. See Malcolm Maden (2013), Regeneration in the adult organism - a cure for aging? [1], as described in Ben Best (2014), The 2013 Sens Foundation Conference, Life Extension Magazine, June 2014. Also see Malcolm Maden in the SENS Video. " Dr. Maden (UF faculty) has demonstrated regeneration of major portions of injured brain in axolotls. He has determined that retinoic acid, the vitamin-A (or retinol) metabolite that facilitates growth and development, plays a key role in regeneration. He commented that a human child has an ability to regrow amputated fingertips, and that retinoic acid contributes to this process. Dr. Maden has shown that applying retinoic acid to the spinal cord of a rodent causes nerve fibers to regrow. He explained that depriving rats of vitamin A (retinoic acid) results in symptoms of Alzheimer’s disease. Restoring the retinoic acid reversed the symptoms. Dr. Maden hopes that understanding the process of regeneration in axolotls will lead to the ability to induce wound-healing and tissue regeneration in people without scar formation." See Retinoic acid as a cure for aging [Papers, Patents, Books, LEF].
References
[1] Malcolm Maden (2007), Retinoic acid in the development, regeneration and maintenance of the nervous system, Nature Reviews Neuroscience 8, 755-765 (October 2007).
"Retinoic acid (RA) is involved in the induction of neural differentiation, motor axon outgrowth and neural patterning... RA continues to play a role after development has been completed. Elevated RA signaling in the adult triggers axon outgrowth and, consequently, nerve regeneration. RA is also involved in the maintenance of the differentiated state of adult neurons, and disruption of RA signalling in the adult leads to the degeneration of motor neurons (motor neuron disease), the development of Alzheimer's disease and, possibly, the development of Parkinson's disease. The data... strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration [Patents] and the treatment of neurodegeneration [Patents]."
[2] Malcolm Maden and Matthew Hind (2003), Retinoic acid, a regeneration-inducing molecule [PDF], Developmental Dynamics Regeneration Special Issue, Vol 226, Issue 2, pp 237–244, February 2003.
[3] Eguchi G, Eguchi Y, Nakamura K, Yadav MC, Millán JL, Tsonis PA (2011), Regenerative capacity in newts is not altered by repeated regeneration and ageing, Nat Commun 2011 Jul 12;2:384.
[4] Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857354/.
[5] Kragl M, Knapp D, Nacu E, Khattak S, Maden M, Epperlein HH, Tanaka EM (2009), Cells keep a memory of their tissue origin during axolotl limb regeneration, Nature 2009 Jul 2;460(7251):60-5.
[6] Maden M, Manwell LA, Ormerod BK (2013), Proliferation zones in the axolotl brain and regeneration of the telencephalon, Neural Dev 2013 Jan 17;8(1):1.
[7] Monaghan JR, Maden M (2012), Visualization of retinoic acid signaling in transgenic axolotls during limb development and regeneration, Dev Biol 2012 Aug 1;368(1):63-75.
[8] Corcoran J, So PL, Barber RD, Vincent KJ, Mazarakis ND, Mitrophanous KA, Kingsman SM, Maden M. (2002), Retinoic acid receptor beta2 and neurite outgrowth in the adult mouse spinal cord in vitro, J Cell Sci 2002 Oct 1;115(Pt 19):3779-86.
Retinoblastoma, the pRB gene, and Rb protein [Wikipedia, Links, Images, Papers, Patents, Books, LifeExtension, LibCong; Cancer; Carcinogens; Anticancer Nutraceuticals; Apoptosis, Telomerase Inhibitors; Anticancer Telomerase Activators; Metastasis, NFkB, NFkB Inhibitors, Angiogenesis Inhibitors]. Retinoblastoma is a cancer of the eye that is associated with genetic defects involving the pRB gene, which is a tumor suppressor. It will be useful to use small molecule telomerase activators like astragaloside IV or cycloastragenol on the eyes, to maintain cells in the cornea of the eye. For safety, tests should be done on rabbit eyes and so forth before taking this step. Retinoblastoma side effects haunt developers of medicines to be applied to the eyes. See Links/retinoblastoma and drug eye testing. Also see Eye Problems of Old Age. See also the pRb gene [Images, Papers, Patents, Books] and Rb protein [Images, Papers, Patents, Books]. pRB is regulated by p16.
Reversing Cellular Senescence [Therapy for Recovering from Cellular Senescence, Restoring Senescent Cells (Refs 9), Links, Images, Video, Papers, Patents, Books]. See also my procedure Telomere Remodeling with Cyclic Telomerase Activation, The Patton Protocol for TA-65 developed by Noel Patton by March 2007 at TA Sciences, Longevity Supplement Vendors/Astragalus, and see the index entries on astragalosides, astragaloside IV, and our notes on telomerase activators [Index, List]. Also see section (7) on telomerase activation therapy and in Age Transformation. Mind you, telomerase activation technology prevents replicative senescence by lengthening telomeres. If p16INK4a levels are too high, recovery from senescence itself is difficult, and most textbooks describe the growth arrest associated with cellular senescence as irreversible, although retinoic acid (from retinol, retinal, or beta-carotene), Id-1 helix-loop-helix transcription factor (from nerve growth factor elevated by acetyl L-carnitine, Huperzine A, rosemary, PQQ, or carnosic acid) and resveratrol all three reduce the expression of P16INK4A, a ubiquitinated protein. Exercise also reduces the expression of p16INK4A, which is aggravated by smoking. However, it has been possible by modifying the expression of the cell membrane gatekeeper protein caveolin-1 to restore the phenotype and function of youthful cells. I note that the Patton Protocol gets quick results by using at first 3 months of TA-65 to activate telomerase, then 3 months of guard band time without telomerase activation. On the other hand, my procedure for Telomere Remodeling with Cyclic Telomerase Activation uses 2 weeks of telomerase activators without telomerase inhibitors followed by two weeks of treatment with telomerase inhibitors alone. After 3 months of telomerase activation, the Patton Protocol at first shows roughly twice as much telomere growth, which is good for demonstrating the telomere growth effect associated with TA-65 in a timely manner. On the other hand, by maintaining isolation between telomerase activation and telomerase inhibition phases, I get less interference with telomerase activation during the 2-week activation phase, and I can take some telomerase inhibitors that one prefers to take every month somewhat, such as vitamin E, cocoa powder, and omega-3 fish oil, all of which are telomerase inhibitors. Some telomerase inhibitors for cancer cells behave like telomerase activators when applied to normal cells. I note that ingestion of high-polyphenol foods tends to produce telomerase inhibitors, so that one optimally takes a low-polyphenol diet during the 2-week period when one activates telomerase. However, it would be inconvenient to maintain a (compartively bland) low-polyphenol diet for 3 whole months. Fortunately, the Patton Protocol gets good results anyway, up to 460 base pairs of telomere growth per year for between -8 and -9 years per year of rejuvenation, at least when an astragalus extract such as TA-41 is used.
Modifying Senescent Cell Membrane Chemistry for Rejuvenation
In addition, we now have treatments based on cell membrane chemistry for modifying the expression of the gatekeeper molecule caveolin-1 (gene CAV1) with cyclic AMP [Ref] from forskolin, exercise, and nutraceuticals or by decreasing the expression of FOXO transcription factors with Akt kinase (perhaps via IGF-1 from creatine monohydrate and exercise) to recover from cellular senescence itself and restore sensitivity to growth factor telomerase activators, reversing growth arrest and enabling the complete rejuvenation of the senescent cell. In addition, Folic acid (vitamin B9) may be used to stimulate the PI3K/AKT pathway to down-regulate caveolin-1 by sequestering FOXO factors away from the nucleus. Retinol (say from carrots) may be used to keep p16INK4a low. With caveolin-1 low, growth factors such as EGF or PDGF can then communicate through restored caveolae on the cell membrane to excite telomere growth when p16INK4a is low. Although we are still perfecting life extension details, it seems clear that man is really on the threshold of physiological immortality with rejuvenation included at this time. See Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, Park SC (2003), Senescent phenotype can be reversed by reduction of caveolin status [Papers, Patents, Books], Journal of Biological Chemistry, 2003 Jul 25;278(30):27789-95. A. Pieter J. van den Heuvel, Almut Schulze, and Boudewijn M. T. Burgering (2005), Direct control of caveolin-1 expression by FOXO transcription factors [Links, Images, Papers, Patents, Books], Biochemical Journal, 2005 February 1; 385(Pt 3): 795–802. Caveolin-1 inhibitors such as cyclic AMP [Ref] from forskolin and exercise are being identified and patented for application to anti-senescence therapy. For instance, see Sang Chul Park, Jeong A. Han (2010), US Patent 2010/0152297 A1, June 17, 2010, Composition for Regulating Cellular Senescence Comprising N-[2-(Cyclohexy-Loxyl)-4-Nitrophenyl]-Methanesulfonamide [the orginal patent search; Images, Papers, Books].
Music[2]: Pin Ball Wizard by Elton John.
Reverse Transcriptase Inhibitors [Links, Video, Papers, Patents, Books; Index/HIV, Index/Virology]. Reverse transcriptase inhibitors such as
(1) AZT [List, Links, Images, Video; Papers/as a reverse transcriptase inhibitor, Patents, Books],
(2) Hyssop [Links, Images, Video; Papers/as a reverse transcriptase inhibitor, Patents, Books],
(3) Alpha Lipoic Acid [Index, Links, Images, Video; Papers/as an RTI, Patents, Books], and
(4) Gambogic Acid [List, Links, Images, Video; Papers/as an RTI, Patents, Books].
are useful in treating HIV infections and other viral maladies. I noted elsewhere that Gambogic acid inhibits transcription of telomeric DNA from senescent cells with open telomere t-loops, preventing formation of TERRA telomeric RNA [Images], although this is not an example of reverse transcription, merely of unexpected transcription control.
Rhodiola rosea [LEF/Rhodiola rosea, Wikipedia, 2nd article, Links, Images, Video, Papers, Patents, Books, LibCong, Amazon, LifeExtension; Index/Cortisol; Memory Enhancing Nutraceuticals]. Rhodiola rosea improves measures of mental performance, including associative thinking, short-term memory, calculation, concentration, and speed of audiovisual perception. Recently, Rhodiola has been shown to extend the life span of fruit flies by 10%. [Links, Images, Video, Papers, Patents, Books, Article]. In fact, rhodiola rosea can extend the lives of flies, yeast, and worms (Life Extension Magazine News, Sept. 2013; PLOS ONE article). Furthermore, rhodiola rosea prevents stress-induced cardiac damage, preventing "both stress-induced catecholamine release and higher c-AMP levels in the myocardium". The adaptogen rhodiola rosea (golden root) prevented lower adrenal catecholamine levels during stress, and suggested that the antistressor and cardioprotective effects of Rhodiola rosea derive from limiting adrenergic effects on the heart. Otherwise, tests showed that rhodiola rosea extract has anti-inflammatory effect. - Journal Abstracts, Life Extension Magazine, September 2011. See also Jan Whiticomb (2011), Reducing the Risks of High Cortisol, Life Extension Magazine, September 2011. The primary active component in rhodiola rosea is salidroside [Links, Images, Papers, Patents, Books]. Salidroside extends rodent lifetimes by preventing the accumulation of AGEs. Therefore rhodiola rosea may be regarded as an AGE inhibitor. Also, rhodiola rosea has been shown to protect human cells from aging by inhibiting oxidative stress. According to Jan Whiticomb (2011) rhodiola rosea reduces cortisol levels, reduces stress, protects the heart, prevents cancer, protects against radiation, and modulates the immune system. See Panossian A, Wikman G, Sarris J. (2010), Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy, Phytomedicine, 2010 June; 17(7):481-93.
Ribose [Links, Images, Video, Papers, Patents, Books, LifeExtension; Ribose sources, Ribose supplements]. Ribose is a basic sugar and primary component of DNA and RNA that is recommended for use with creatine monohydrate. It initiates the production of ATP for energy. Doses of 2-5 grams 2-4 times per day are recommended for athletes.
ROS (Reactive Oxygen Species) See Reactive Oxygen Species (ROS), above.
Rosemary [Wikipedia/Rosemary; Links/the herb Rosemary, Images/Rosemary Supplements, Video/Rosemary, Papers, Patents, Books, LifeExtension; Links/rosemary herb medicinal; Links/Rosemary Extract, Images; Papers, Patents, Books, LifeExtension; Links/Essential Oil of Rosemary, Images, Papers, Patents, Books, LifeExtension; Memory Enhancing Nutraceuticals]. Rosemary has "higher antioxidant capacity than vitamin E." "Humans exposed just to the aroma of the essential oil of Rosemary [Links, Images] performed significantly better on overall memory quality compared with controls...and also had increased states of alertness..." - LifeExtension, March 2009. [Links/aromas of rosemary and lavender]. See also rosmarinic acid [Links, Papers, Patents, LifeExtension, Wikipedia], carnosol [Links, Papers, Patents, LifeExtension] and carnosic acid [Links, Papers, Patents, LifeExtension], which are the active antioxidant compounds found in rosemary. Note that carnosic acid also stimulates Nerve Growth Factor (NGF) synthesis, which may be responsible for memory improvements when rosemary is used or when essential oil of rosemary is inhaled through the nose. Nerve Growth Factor stimulates the production of Id-1 helix-loop-helix protein, a telomerase activator [Index] that also inhibits the expression of tumor suppressor protein p16INK4a (Zheng et al. 2004, Ohani et al. 2001), which can induce senescence after accumulating to high levels that can reduce the expression of forebrain progenitors and stunt neurogenesis. In addition, rosemary's carnosic acid is a lipase inhibitor that may be applied to caloric restriction.
Route of Administration (of drugs and medicines) [Wikipedia/Route of Administration, Links/Route of Administration, Images, Papers, Patents, Books, Amazon; LifeExtension].
Royal Jelly [Wikipedia/Royal Jelly, LifeExtension/Royal Jelly; Links/Royal Jelly for anti-aging, Images, Papers, Patents, Books, LifeExtension, LibCong, Amazon]. Aubrey De Grey mentioned it in a table in one of his articles as an anti-aging therapeutic method, along with some other novel approaches, which I have given below with search links on Google: anti-aging hormonal manipulation, Royal Jelly for anti-aging. Claims of the Hive Club. "Royal Jelly is another bee food. It contains components that can smooth the wrinkles in aging skin. Royal jelly is high in B vitamins and beneficial fatty acids. The antioxidant and antimicrobial activity of propolis and royal jelly make them awesome antibiotics. See the antioxidant activities of propolis and of royal jelly, and the antibiotic properties of propolis [Papers, Patents, Books] and of royal jelly [Papers, Patents, Books]. It is so valuable that it is fed exclusively to the queen bee. It is credited with maintaining the queen's larger size and extending her life. Queen bees live four to five years compared to worker bees, who live approximately 40 days." - from Food From Bees to Promote Longevity and Anti-Aging. PDRhealth on royal jelly. [35s].
Rutin [Wikipedia/Rutin, LifeExtension/Rutin; Wikipedia/Rutin, Links/Rutin, Images, Papers, Patents, Books; Sources; Extraction; Bioflavonoid Skin Creams - Rutin Supplements, Rutin Skin Creams; Hesperidin, Hesperidin Supplements, Hesperidin Skin Creams; Quercetin, Quercetin Supplements, Quercetin Skin Creams]. Rutin, a blood-thinning antiplatelet glycoside of quercetin, is an antioxidant, anti-inflammatory supplement useful in treating spider veins [Index]. Rutin "decreases capillary permeability and makes the blood thinner, improving microcirculation so the skin cells receive more oxygen and nutrients". A combination of rutin and quercetin was shown to rejuvenate drying skin cells that refused to replicate, so that they began to reproduce again. (Chondrogianni, Kapeta, Chinou, Vassilatou, and Papassideri, 2010), referenced in Gary Goldfaden MD and Robert Goldfaden (2012), How Bioflavonoids Create Youthful Skin Tone, Life Extension Magazine, November 2012 [Dr.Robert]. See Ghiasi M, Heravi MM (2011), Quantum mechanical study of antioxidative ability and antioxidative mechanism of rutin (vitamin P) in solution, Carbohydrate Research, 2011 May 1; 346(6):739-44. Also see Arjumand W, Seth A, Sultana S. (2011), Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFkappaB, TNF-alpha and caspase-3 expression in wistar rats, Food and Chemical Toxicology 2011 September; 49(9):2013-21. Rutin can regenerate vitamin C after it neutralizes a free radical, defends against damage caused by advanced glycation end-products (AGEs), reduces the breakdown of collagen caused by AGEs, improves circulation, and provides microvascular protection, making rutin useful in the treatment of spider veins. (Gary Goldfaden MD and Robert Goldfaden, 2012). Rutin posseses anti-inflammatory, antiplatelet, antiviral, and antihypertensive properties, suppressing the production of TNF-alpha and the activation of NK-kappaB by lipopolysaccharides, protecting vascular integrity by inhibiting hyperpermeability, by inhibiting expression of CAM cell adhesion molecules, and by inhibiting thereby the adhesion and migration of leukocytes, making rutin useful in treating vascular inflammatory diseases. (LEF Abstracts, Nov 2012).
References
[1] Crampton EW, Lloyd LE (1949),
Effect of rutin on the biological potency of vitamin C, Science, July 1, 1949:18.
[2] Sheu JR, Hsiao G, Chou PH, Shen MY, Chou DS (2004),
Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets, Journal of Agricultural and Food Chemistry, 2004 July 14;52(14):4414-8.
[3] Cervantes-Laurean D, Shramm DD, Jacobson EL, Halweish I, Bruckner GG, Boissonneault GA (2006), Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites, Journal of Nutritional Biochemistry, 2006 Aug;17(8):521-40.
Rye [Links/Rye, Images, Papers, Patents, Books, LifeExtension; Tocotrienols; Telomerase_Activators/Tocotrienol-rich fraction]. Rye is a source of valuable life-extending tocotrienols. Oats, barley, and rice bran oil are also tocotrienol sources. Rye flour has a lower gluten content than wheat flower and contains more soluble fiber. Rye bread includes pumpernickel.

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