The New Nuclear Atom As We See It: Green's Fantastic 4 in the transition from Classical General Relativity to Unified Quantum field Theory, 
in the Cornerstone of Galaxy M51, and in a real-time MRI heartbeat.
Jim Green's Home Page. The background photo shows Jim Green at age 51 in the year 2000.

Music[2]. 4 [Videos]Suzanne64 Gar
James A. Green the 3rd. Main Essay Revision: July 23, 2014, Index Revision: July 23, 2014 Engineering Negligible Senescence___________
Quick Summary and Do List. Notes and Theses. Started: June, 2000. Email Jim at, or post at Introduction Blog.

"If I knew I would live as long as I have, I'd have taken better care of myself." - George Burns at 101: 85 years in 40 seconds [with frame age] As Time Goes By

_Proud Mary M51
_Your Wildest Dreams
_A Summer Song
_Rocket Man
Anti-Aging Medicine: Life Extension in Review || 1 | 2 | 3 | 4 || Index Change Log

Longevity 1 | 2 | 3 | 4 | Bibliography | Labs 1 | 2 | 3 | Foots | Refs | Sup Notes 1 | 2 | 3a | 3b1 | 3b2 | 3b4 | 3b5 | 3b6 | 4 | 5 | Vendors | Change Log | Index Change Log | Age Transformation | Special: Restoring Senescent Cells
Topics | Am | An | B | Ca | Cb | D | E | F | G | Hs | Ht | I | J | K | L | Mc | Md | N | O | Pq | Pr | Q | R | Sl | Sm | Te | Tf | U | V | W | X | Y | Z | Topics | More Topics | Health Topics || Home | Dental
Anti-Aging Firewalls | Fighting Aging | Biology of Aging/Blogs | MethusFoundationBlog | Biosingularity | @aging Blog | LifeExtension Blog | William Faloon | Dr. Jerry Shay | Dr. Woodring E. Wright
Videos : Immortality & Anti-Aging Medicine & Telomeres & Telomerase & Longevity & Medicine & Stem Cells & DNA Science & Gerontology & DNA Damage || Dr. William Andrews | Dr. Titia de Lange
& DNA Repair & Telomeres & Telomerase & E. Blackburn & Cellular Senescence & Replicative Senescence & M.Fossel & Nutraceuticals (HPlan) & Neuro & Aubrey de Grey: SENS Therapies || SENS | Henry Stewart Talks
& Cells & Skin & Detox & Heart & Cancer & Stroke & Neck Rejuvenation [Exercises] & Facial Exercises || Senior Journal || Solaray | Herbal Remedies | QC | Ray | AC-11 | Barron/End of Old Age & Dr. Carol Greider
Mechanisms of Aging | INNOVITA | SENS | Fight Aging | Methusalah Foundation || Essential Evidence Plus | MIT | Molecular Biology of Aging Refs 2 | Hayflick Limit Papers | Longevity Genes
PubChem | PubMed | Labome |[ Wikipedia | Wikigenes | iHOP | SA Biosciences ]| Geron/Telomerase A || Cycloastragenol+: TA Sciences | Iron-Dragon | King Tiger | Genescient | Dr. Al Sears
AGE inhibitors | Alzheimers | Anti-Inflammatory | Cardiology | Antioxidants || Anticancer || Telomerase Inhibitors || Telomerase Activators | Sierra Sciences | IsAGenix | Product B | Terraternal | RevGenetics
Search: Journals | Basic Calc | Sci Calc | PubMed | NIH | MedLine | WebMD | HealthLine | Access Medicine | Wiki/Medicine | Medical Diagnosis | Truth In Aging || Clinical Trials | BioMedSearch | Discovery Medicine/Telomere
Google |[ Patents | Patent Lens ][ Books | LibCong | Amazon | Powells ][ Google Scholar | Wikipedia ][MedLib | LibWeb] | Merriam-Webster | Cope | HUGO | U.S. National Library of Medicine | Discovery Medicine

| LEF | Aging Cell | Rejuvenation Research | IAAS | A4M | ARC | ImmInst | SWL | Groups/LEF | Guide | MF | Immortal Humans

Table of Contents [Main Essay: 1, 2, 3, 4, Anti-Aging Drugs and Therapy, Supporting Material; Cyclic Telomerase Activation, Program 2013].
Introduction - Dosages - Telomere Remodeling with Cyclic Telomerase Activation [2013] - Mortality Charts - Life Expectancies - Age Transformation
___i.1. Theories of Aging and Avenues of Treatment
___i.2. Animals of Short and Long Life Span
___i.3. The Biology of Senescent Cells
___i.4. Anti-Aging Treatment Drugs and - Dosages
(0) The Genetic Theory of Aging
___0.1 The Supercentenarian Way of Exercise and Diet: Olive Oil, Red Wine, Resveratrol, Tea, and Chocolate
___0.2 Longevity Genes.
___0.3 Breeding for Longevity.
___0.4 Gene Therapy for Longevity.
(1) The Free Radical Theory of Aging
___Damage from Alkylation due to Aldehydes produced by Lipid Peroxidation
(2) The Hormone Replacement Theory
___Sex Hormones
(3) The Caloric Restriction Theory
(4) The Cell Membrane and Lipofuscin Wastes Theory
(5) The Glycation Theory of Aging

(6) The Insulin Utilization Theory
(7) The Advanced Hayflick Cell Division Limit Theory Based on Telomeres
___The Structure and Location of hTERT and hTR telomerase components.
___The hTERT component.
___The hTR component.
___Fractionation of Telomerase.
___Molecular Densities of Telomerase.
___Telomere Lengths.
___Replicative Senscence, Stress-Induced Senescence, and Disease.
___Telomere Shortening.
___Telomerase and Aging in Non-Mitotic Cells and Mitochondria.
___Carnosine and Antioxidant Telomere Defense.
___Aging without Telomere Shortening.
___Neygeront and Kinetin.
___P16INK4A and the Reversibility of Senescence.
___Heat Shock Proteins Increase Telomerase Levels.
___Telomerase Activation by Nitric Oxide in Endothelial Progenitor Cells.
___Small Molecule Telomerase Activators [List/Telomerase Activators, Alphabetic List, Index, Select Table]
______Geron Telomerase Activators.
______Astragalus Preparations from Vendors.
______Combinations of Telomerase Activators.
______Cut-Rate Telomere Therapy with Fenugreek, Black Cohosh, and Exercise.
______Telomolecular Nanotechnologies.
______DNA Rolling Nanocircle Encoding.
______Direct hTERT Delivery to Cells.
______hTERT mRNA Delivery to Cells.
______Sierra Sciences Identifies 858 Telomerase Inducers.
______Endogenous and Exercise-Induced Telomerase Activators.
______HDAC Inhibitor Telomerase Activators.
______Interleukin 2.
______Epithalon Peptide.
______HGH and IGF-1 as Telomerase Activators.
______Cyclic Telomerase Activation with Readily Available Nutraceuticals.
______Breast Cancer, Cell Division, and Astragalus Root.
___The Telomere Positioning Effect and Youthful Patterns of Gene Expression
___Telomere Capping Proteins [Shelterin, Mammalian Telomere Protein Factors]
________Blackburn: Telomerase Does Not Act on Capped Telomeres
________Atorvastatin (Lipitor), Simvastatin (Zocor), TRF2, T-Loop Closure, and Rejuvenation
________Telomere Enlongation with Replication Protein A and hEST1A
________The Telomere DNA Helicases and Co-Factor Magnesium
___The Time Machine Effect
___Rejuvenation Rates
___Rejuvenation Times Δt to Final Model Age tFM = 25 from Initial Age t0.
___Rejuvenation Times Δt to Final Model Ages tFM from Initial Age t0 = 60.
___Anti-Aging Flight Plan for Rejuvenation.
___Fast Acting Techniques.
___Recovery from Cellular Senescence.
___Therapy for recovering from cellular senescence [Restoring Senescent Cells].
_____Skin Creams for Rejuvenating Senescent Dermal Fibroblasts
_____Caveolin-1 is downregulated by c-Myc.
_____Survivin and Cellular Senescence Recovery.
_____N-[2-(Cyclohexy-Loxyl)-4-Nitrophenyl]-Methanesulfonamide for Recovering from Senescence.
_____Forskolin down-regulates levels of caveolin-1 with cyclic AMP to Rejuvenate Senescent Cells.
_____Experimental siRNA restoration of senescent cells.
_____Arginylglycylaspartic acid for Senescent Cell Morphology Restoration
SIRT1 Deacetylates and activates Ku when Young Extracellular Matrix rejuvenates Senescent Cells.
Tocotrienol-rich fraction can reverse senescence in human diploid fibroblasts.
___Posting Results.

(8) Stem Cell Technology
____The Role of Increasing DNA strand separation temperature in aging and cloning
(9) Age Comes Through Lack of Exercise Theory
___Muscle Regeneration.
___Heat-Shock Proteins and Hormesis.
___Damage from Exercise in the presence of Arterioscleriosis.
(10) The DNA Repair Theory of Aging
_____Introduction: DNA Repair and Species Life Span.
_____Telomere Erosion, hTERT Activation improves DNA Repair, Chromosomal Instability, and Homocysteine.
_____Genomic Instability, DNA Helicases, and Magnesium as a Cofactor.
_____Epigenetic Regulation and Undesirable DNA Demethylation in Aging.
_____Mitochondrial DNA Damage and Repair.
_____Deuterium Theory of Aging via Damage to DNA.
_____Preventing DNA Damage.
(11) The Immunological Theory of Aging
(12) The Metallic Wastes extension to the Mitochondrial Theory of Aging
(13) The Membrane Theory of Aging of Zs-Nagy
(14) The Proteasome in Aging
(15) Inflammation and Aging
(16) Other Mechanisms for Aging
____History of Infections.
____Wear and Tear - Dental.
____Solubility Changes in Proteins and Protein Aggregation with Aging.

Initial Personal Observations on Life Extension Methods
An Optimum Anti-Aging Program
___Free Radical Defense for Cell Membranes and DNA with Antioxidants, Anti-Glycating Drugs, and Diet
___Protecting Aging Cariomyoctes and Vasculature
___Chromosome Reconstruction with Telomerase Activation and DNA Repair.
___Opening Telomere T-loops for Telomerase Repair and Application of Novel Activators
Future Treatment Possibilities
_____Telomerase Activators
_____Targeted Genome Editing with Adenovirus Transfection
_____Targeted Genome Editing with AAV Adeno-associated Viral Transfection
_____Targeted Genome Editing with Zinc Finger Nucleases
_____Plasmid Transfection Gene Therapy
_____Protein Targeting of Telomerase to Cell Membranes
_____Telomerase Delivery by Nanoparticles
_____Telomerase Activation with Natural Hormones
_____Measuring Telomere Length for Process Control Feedback
_____Telomere Elongation with 5'-TTAGGG-3' Oligonucleotides
_____Telomere Enlongation with Rolling Nanocircles
_____Discovering Telomerase Activators with High-Throughput Screening.
_____Other Mechanisms and Alternatives
The Long-Range Impact & Reproduction

Life Extension Laboratories 1
___Telomere Measurements
___Telomerase Expression Measurements
___Articles on Telomeres
___Cancer and the Gene
___Measuring Cellular Senescence
___Clinical Testing
___Academic Laboratories for Longevity and Geronotology Research
___Lab Equipment Vendors
Life Extension Laboratories 2
___Lab Technique References
___Medical Schools
Longevity Supplement Vendors
___List of Vendors
___Health Food Stores in Wichita, KS
___Sprouted Bread Vendors
___Bodybuilding Supplements and Equipment
___Astragalus, Astragalus Root Extract, and Astragalosides, with Toxicology
___Bibliographical References, Publishers, Theme Book Search
___Introductions to Anti-Aging Medicine
___Supporting Professional Work
___Additional Advanced Material
___Current Textbooks
Footnotes - [25] Functional Foods, [48] Hair Greying [67] TA/Hormones, [75] Causes of Death, [103b] Old Age Diseases.
Supplemental Notes 1 - [1s-56s].
Supplemental Notes 2 - [57s-62s], [62sb] Rejuvenation via Telomere Remodeling with Cyclic Telomerase Activation, [63s-73s].
Supplemental Notes 3 - [74s-80s], [81s] Life Extension via Telomere Extension in Vivo, Telomerase Inhibitors [List], Telomerase Activators [List].
Supplemental Notes 4 - [82s], Molecular Gerontology, [83s], Drug Bioavailability.
Supplemental Notes 5 - [84s], Glossary of Chemical Terms for Astragaloside Papers & Telomerase Papers.
Am | An | B | Ca | Cb | D | E | F | G | Hs | Ht | I | J | K | L | Mc | Md | N | O | Pq | Pr | Q | R | Sl | Sm | Te | Tf | U | V | W | X | Y | Z

Article References | Article References on the Biology of Aging
__i. Introduction.
_____Biological Clocks of the Aging Cell.
__0. Genetic Theory of Aging.
__1. The Free Radical Theory of Aging.
__2. Hormone Replacement Theory and Endocrine Models for Aging.
__3. The Caloric Restriction Theory of Anti-Aging Treatment.
__4. Lipofuscin Wastes and the Aging Cell Membrane.
__5. The Glycation Theory of Aging.
__6. Insulin Utilization and Aging.
__7. Hayflick Limit Theory of Aging Based on Telomeres.
____7.1 Aging Damage to Telomeres
____7.2 Small Molecule Telomerase Activators
________7.2.1 Geron.
________7.2.2 Bioavailablility of Astragalosides and Small-Molecule Telomerase Activators.
________7.2.3 DNA Nanocircles and Telomere Elongation: Eric T. Kool's Work.
________7.2.4 Sierra Sciences: the hTERT Promoter and modulating hTERT expression.
7.2.5 Nitric Oxide as a Telomerase Activator.
________7.2.6 Novel Wistar Institute Telomerase Activators.
________7.2.7 Androgens as Small-Molecule Telomerase Activators.
____7.3 Telomerase Inhibitors.
____7.4 The hTERT Promoter.
____7.5 Telomere Epigenetics - The Role of Methylation
____7.6 The Telomere Position Effect and Youthful Patterns of Gene Expression
____7.7 Telomere T-Loop and D-Loop.
____7.8 Telomere Capping Proteins.
____7.9 Telomerase Functional Environment.
____7.10 Telomerase and Protection of Mitochondrial DNA
____7.11 Measuring Telomere Length
___________7.11.1 with PCR Methods (Cawthon)..
___________7.11.2 with Southern blot analysis of telomere restriction fragments.
___________7.11.3 with Quantitative fluorescence in situ hybridization using digital fluorescence microscopy (Q-FISH).
___________7.11.4 with Quantitative fluorescence in situ hybridization using flow cytometry (flow-FISH).
___________7.11.5 with Quantitative fluorescent in situ hybridization laser scanning cytometry (Q-FISHLSC).
__8. Stem Cell Technology and Anti-Aging Therapy.
___8.1 Introduction to Stem Cells
___8.2 Induced Pluripotent Stem Cells (IPS Cells)
___8.3 Further Stem Cell References.
__9. Aging and Exercise.
__10. Aging and DNA Repair.
__11. The Immune System and Aging.
__12. Aging and Chelation of Metallic Wastes.
__13. The Membrane Theory of Aging (Zs-Nagy).
__14. The Proteasome and Aging.
__15. Other Mechanisms of Aging.
____15.1 Racemization.
____15.2 Smoking.
____15.3 History of Infections
____15.4 Wear and Tear - Dental
____15.5 Non-Oxidative Transformations of DNA and Proteins in Aging.
____15.6 Dysregulation of Transcription and Translation in Aging.
____15.7 RNA Damage and Aging.
__16. Telomerase Inhibitors.
__17. Molecular Biology of Aging References.
__18. Selected references on Astragalosides and Ginsenosides as Telomerase Activators
__19. Selected References on the Characteristics of Telomerase.
__20. Selected References on the biological activity of ginsenosides and astragalosides
__21. Selected References on Enhancement of Antiviral Function using Cycloastragenol (TAT2)
__22. Further References on Telomerase.
__23. References on Zinc Finger Nucleases.
__24. Selected References on Hair Graying
__25. Selected References on Heat Shock Proteins
__26. The Aging Cell.
__27. Restoring Senescent Cells.
__28. FOXO transcription factors and Caveolin control.
__29. Neck Rejuvenation Refs.


i.1. Theories of Aging and Avenues of Treatment
[Refs1.i, Links/Theories of Aging, Images, Video, Papers, Patents, Books, Amazon, LifeExtension;
Links/Anti-Aging Therapies, Images, Video, Papers, Patents, Books, Amazon, LifeExtension; Short Summary].

There are several main avenues of approach to anti-aging therapies based on different theories of aging or model therapies described in on-line journals on biogerontology and gerontology [57], in popular sources on anti-aging medicine [57, Patents], in anti-aging conferences [82] and by life extension experts [4, Labs & Journals]. The life expectancy problem, of course, appears in mortality charts of deaths per thousand [Images]. By May 2013 we have refined techniques for preventing cellular senescence, in which the aging cell undergoes growth arrest and changes its phenotype, including treatment with antioxidants to confine hTERT to the cellular nucleus and to prevent premature stress-induced senescence from ROS. We feature cyclic treatment with telomerase activators [List] such as astragalus root, fenugreek extract, nitric oxide via arginine, testosterone via DHEA, colostrum growth factors, and black cohosh. The telomerase activators lengthen telomeres (7), which generate DNA damage signals stopping the cell cycle with replicative senescence as their length is reduced to 4000 to 5000 base pairs when the telomere t-loop springs open, producing a DNA double-strand break. We also have HDAC inhibitors (such as L-carnitine, sulforaphane from broccoli sprouts, and lactates from pumping up) available to expand chromatin and make telomerase activators work better on connective tissues and other tissues featuring condensed chromatin. Telomerase activators such as growth factor skin creams or colostrum solution also allow us to maintain the extracellular matrix by gradually lengthening dermal fibroblast telomeres to avoid skin wrinkling. Lengthening telomeres improves immune system cell proliferation, allowing us to more readily defeat the pneumonia that often finally closes in on aging specimens in better than average condition. hTERT also improves stem cell proliferation to regenerate tissues. Commonly available antibiotics like garlic and cinnamon are also available to stop bacterial and viral infections from HIV to abcessed teeth. At the same time, we eliminate cellular wastes such as lipofuscin with CoQ10 or ubiquinol and prevent the accumulation of atherosclerotic plaque leading to heart disease by blocking homocysteine, enabling continuing fitness through exercise (9). We apply telomerase inhibitors and anticancer nutraceuticals such as ginger, milk thistle, and garlic during the last phase of each month to prevent cancer. Vitamin K2 supplementation (via MK-7 supplements or Swiss cheese) now allows us to prevent arteriosclerosis from calcification, aortic sclerosis, and the aortic stenosis via calcification that has hardened the hearts of aging bodybuilders like Jack LaLanne who threatened to live forever. For mitochondrial aging we have acetyl L-carnitine with alpha lipoic acid and drugs for improving mitochondrial biogenesis such as PQQ and whey protein. 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 such EGF and PDGF, reversing growth arrest and enabling the complete rejuvenation of the senescent cell. Furthermore, we now have carrots, retinol, retinoic acid, resveratrol, and other methods (including exercise) of limiting the expression of P16INK4a (Chart), which makes recovery from senescence difficult. 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.

i.2. Animals of Short and Long Life Span
[Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension].
A bacterium may survive for a bacterial life span as short as 20 minutes [eHow, Leonard Hayflick, p.216]. Interestingly, it takes E. Coli 20 minutes to produce a cell. The adult mayfly [Links, Images] lives from several hours to one day, although its larval form develops for a year, while the bristlecone pine [Links, Images, Papers, Books] lives up to 5,000 years = 1.825 x 106 days. Among mammals, research suggests that the bowhead whale (Balaena mysticetus, or Greenland Right Whale) may live up to 211 years [>100 years]. The longest-lived animal with the maximum life span, however, was believed to be Arctica islandica, the ocean quahog clam, which may survive more than 400 years. The Hexactinellid sponge [Links, Wiki] is believed to reach ages of up to 15,000 years. Today, however, we find that Turritopsis Nutricula [Links, Images, Papers, Books], which resembles a Cthulhu Plushie [Images], is a biologically immortal lifeform (when not eaten) associated with an expanding terrestrial population. Some fish, like the rainbow trout, show negligible cellular senescence and have high telomerase levels in their tissues. concludes that some animals age, others may not. The hydra, the tiny worm from which we have evolved, whose constellation namesake Hydra appears in the winter beneath the constellation Cancer, might be pictured as the forerunner of evolved eternal life.

i.3. The Biology of Senescent Cells
[Refs1b, Index/Replicative Senescence, Links/Cellular Senscence, Images, Video, Papers, Patents, Books, Amazon, LEF].
See also senescent cells [Images, Video, Papers, Books; Wikipedia, Images/microphotographs of senescent cells, Papers, Books]. Cytogerontology [Links, Images, Papers, Books, Aging Cell, Impact Journal on Aging, Journals], the science of cellular aging, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential, a conjecture confirmed by Swim and Parker in 1957 and Hayflick and Moorhead in 1961 (7). The first gerontological journal, Zeitschrift fur Alternsforschung, appeared in 1939, and an early paper on caloric restriction as an anti-aging technique was published in 1917 by Osborne, Mendel, and Ferry. However, some reviewers prefer to cite caloric restriction papers from the 1930s by McCay [article], and the subject is still prized [Methuselah Mouse Award]. See also Biological Gerontology, or Biogerontology [Links, Video, Papers, Patents, Books, Amazon], Molecular Gerontology [Links, Video, Papers, Patents, Books, Amazon] and Rejuvenation Research [Links, Papers, Patents, Books]. Today our goal is life extension with rejuvenation [Links; Links/cellular rejuvenation, Patents, Books] included, to approach physical immortality, which may emerge like powered flight did in the 20th Century, ceasing only when we drop the discipline associated with the Shangri-La science zone where its methods and materials are available. Instead of Wilbur and Orville Wright, we have Woodring E. Wright and Jerry W. Shay for telomere pioneers, now formatted for the high flight of Life Extension as The First Men in the Moon, accompanied, perhaps, by Lasker Award winner and 2009 Nobel Prize in Medicine winner Elizabeth Blackburn to the right, born in Tasmania. Don't miss Jerry W. Shay and Woodring E. Wright's great background piece Hayflick, his limit, and cellular ageing and the Nobel Prize Winner's essay Telomeres and Telomerase: the path from maize, Tetrahymena, and yeast to human cancer and aging by Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak. Some key papers include C.B. Harley, Futcher, and C.W. Greider (1990), Telomeres shorten during aging of human fibroblasts, Nature 345: 458-460 and Andrea G. Bodnar, Michel Ouellette, Maria Frolkis, Shawn E. Holt, Choy-Pik Chiu, Gregg B. Morin, Calvin B. Harley, Jerry W. Shay, Woodring E. Wright (1998), Extension of life-span by introduction of telomerase into normal human cells, Science 16 January 1998, pp. 349 - 352. Lengthening telomeres (7) with telomerase activators while eliminating lipofuscin cellular wastes with CoQ10 and minding other factors should allow us to keep cells functioning indefinitely before they reach senescence. By 2013 we also have technique for reversing cellular senescence by modifying the membrane chemistry of senescent cells, allowing them to respond again to growth factor telomerase activators, restoring their juvenile morphology and youthful characteristics. 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], Journal of Biological Chemistry, 2003 Jul 25;278(30):27789-95, and also Park SC, Cho KA, Jang IS, Kim KT, Ryu SJ.(2004), Functional efficiency of the senescent cells: replace or restore? [Papers, Full Text PDF], Annals of the New York Academy of Sciences, 2004 Jun;1019:309-16, with A. Pieter J. van den Heuvel, Almut Schulze, and Boudewijn M. T. Burgering (2005), Direct control of caveolin-1 expression by FOXO transcription factors, Biochem J. 2005 February 1; 385(Pt 3): 795–802. Today we have good prospects for total recovery from aging with rejuvenation included by managing telomere length, P16INK4a levels, senescent cell membrane chemistry, and other variables.

i.4. Anti-Aging Treatment Drugs and - Dosages [Links, Images, Video, Papers, Patents, Books, Amazon, LEF].
For typical dosages of anti-aging medicines useful in an optimum program, see Dosages [62s], Program 2013, Telomerase Activation Sciences, and telomere remodeling with cyclic telomerase activation using off-the-shelf astragalus root powder (< 33 grams/day), astragalus root extracts (< 11 grams/day) featuring astragalosides and astragalus polysaccharides, or new, chemically pure telomerase activators [List] including somewhat less effective low dose extracts from the astragalus extracts like TA-65 (25 mg/day), cycloastragenol (25 mg/day) in Astral-Fruit NF from RevGenetics, astragaloside IV (100 mg/day) formulations from Terraternal, and astragaloside IV plus vitamin D from Medicinal Nutraceutics as Maximum Telomere Support. By May 2013, it is clear that astragalus root powder (< 33 grams/day) and astragalus root extract (< 11 grams/day) are still perhaps the very best telomerase activators for rejuvenation, lengthening telomeres on the average 460 bp/year in a cyclic application protocol. This corresponds to a rejuvenation rate of about -9 years per year back towards youthful patterns of gene expression. We seem to observe perhaps -5 years per year. A mix of telomerase activators and associated therapies is used with both oral and transdermal admistration of telomerase-activating nutraceuticals to get maximum coverage of different human cell types. This might include Product B, astragalus root (33 g/day), colostrum solution for the skin, hawthorn, bacopa, milk thistle extract, arginine (5-10 g/day), HGH secretagogues, exercise-induced telomerase activators seperately boostable with other supplements, and other selections from our list of telomerase activators, boosted with HDAC inhibitors to expand chromatin for more effective transcription of telomerase components, and alpha lipoic acid for boosting HSP90 for telomerase assembly. See Age Transformation for the expected results of our program for senescent cell recovery to the youthful phenotype via telomerase activation (7) and notes on observed progress. A tremendous amount of relevant material may be searched at Life Extension Magazine, which also provides a fine line of products to support their professional array of educational papers for the public. IAAS (International Anti- Aging Systems) is also very informative with a fine set of European products, and The American Academy of Anti-Aging Medicine (A4M), ARC, and Cambridge University's Immortality Institute (ImmInst) also provide searchable resources and forums for discussion on these topics, as do the many Journals for medical professionals and bioscientists.

(0) The Genetic Theory of Aging
[83] (Refs1.0, Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension, Innovita, NIA).

0.1 The Supercentenarian Way of Exercise and Diet: Olive Oil, Red Wine, Resveratrol, Tea, and Chocolate
Only 153 supercentenarians [Pics, Links, Images, Video, Papers, Books, Amazon, LifeExtension, Wikipedia, Wikipedia/Centenarian, Supercentenarian Counts] over 110 years of age are known to exist in the 18 major developed countries according to Robert & Vaupel, 2001, cited by the biology of aging [Video, Books, Amazon] expert Robert Arking, although gerontologist Robert Young has found 696 claimants worldwide. Note that more than 56,000 Americans are centenarians over 100 years of age. About 1 in 1,000 will become supercentenarians. The highest concentration of people over 100 is found in Blue Zones [Links] where no smoking, legumes, moderate physical activity, and plant-based diets are the norm. The 122 year, 164 day world record holder in aging Jeanne Calment (b.1875-d.1997, "I've been forgotten by God. Wine, I'm in love with that.") Orion's toast to Andromeda with wine-glass Taurus and the high-light star Aldebaran. 
Try red muscadine wines for resveratrol, pomegranate juice for best antioxidant effect. was a daily drinker of red wine, the anti-aging component of which was resveratrol (Index, Books, LifeExtension, Patents) at 160 micrograms per fluid ounce, most abundantly found in red grape skins with a concentration of 50-100 micrograms per gram [25d], in vitis vinifera, labrusca (concord), and muscadine grapes, grape seed extract [36], raisins cured indoors, purple grape juice, eucalyptus, spruce, lily, mulberries, blueberries [25a], cranberries and huckleberries, peanuts, the root of the Japanese knotweed (Polygonum cuspidatum root), and at highest concentration in resveratrol pills, supplements [Images], and capsules. Muscadine wines [100] such as New York state Pinot noir were shown to contain up to 7 times as much resveratrol as regular wines. See the Linus Pauling Institute on resveratrol sources. See also Sardinian Blue Zone wine from Blue Zone Imports. Humorously, the resveratrol molecule resembles a pair of old man's spectacles [Images/trans-resveratrol molecule, Images/cis-resveratrol molecule]. It has remarkable anticancer properties and (like aspirin), prevents red blood cells from sticking together, warding off heart disease. It has also been shown to inhibit lipid peroxidation [Index, Patents, Books, LifeExtension], "the process whereby free radicals steal electrons from the lipids in our cell membranes, resulting in cell damage and increased production of free radicals". Finally, resveratrol limits the expression of the ubiquitinated protein P16INK4A, which makes cellular senescence difficult to reverse.
Press for Jeanne Calment photo album.Press for Jeanne Calment photo album.
Jeanne Calment, age 25; Jeanne Calment, age 60.
Jeanne Calment, record holder in aging at 122.45 yr.
As a Mediterranean type, Madame Jeanne Louise Calment liked her port wine, her olive oil [76], her chocolates, and got plenty of antioxidant lycopene from cooked tomato paste in her Mediterranean diet [25k]. A Mediterranean diet deflecting cardiovascular disease is high-fiber and focused around fruits, vegetables, olive oil, nuts, and fish, with reduced reliance on meat and refined carbohydrates. She could observe that the "grey apes" ate the resveratrol-laden grapes, the fruit of the vine: a sloganeering signal concerning longevity from long ago, and that friends who ate chocolates, which contain .535 mg/gram antioxidant polyphenols and flavonoids [Patents, Endothelial Defense], 4 times as much as in tea, tended to outlive those who did not. Also, Jeanne's chocolate contained pyrroloquinoline quinone (PQQ), which improves mitochondrial biogenesis, tending to prevent aging damage to brain, heart, and muscles, and vasodilating arginine to improve circulation in the brain and thymus gland. (To eliminate wrinkles, Jeanne rubbed extra virgin olive oil over herself, which restores proteasomes.) Resveratrol inhibits the accumulation of amyloid beta peptides (LifeExtension/amyloid_beta) and protects against Alzheimer's disease [72] according to recent research. I note that cocoa promotes nitric oxide generation, which activates telomerase in endothelial cells [Images] of the vascular endothelium [Vasa, et al., 2000, Hayashi, et al., 2006], so that Jeanne Calment's [Index, Links, Images, Photo Gallery] 122.45 year lifetime may be in part due to telomerase activation (7) via nitric oxide generation from ingesting cocoa in chocolate. It must also be true that telomerase activators [Index] and p16INK4A inhibition from her devotion to exercise (9) were an important factor, allowing her cellular telomeres to lengthen for additional cell divisions. Jean rode a bicycle for exercise until she was 100 years old. Chocolate also improves blood supply to the brain for about 2 hours after ingestion, opposing senile dementia. Resveratrol, too, promotes nitric oxide generation. Furthermore, reveratrol phosphorylates the hTERT catalytic component of telomerase in the cytoplasm via AKT kinase, enabling its import into the nucleus, where it enhances telomerase activity, although it does not increase the number of hTERT mRNA transcripts for the catalytic component of telomerase produced by transcription factor interaction with the hTERT promoter. Furthermore, blocking caveolin-1 (gene CAV1) production by inhibiting FOXO transcription factors with AKT kinase works against cellular senescence, tending to reverse it. For other factors, see also [94].

0.2 Longevity Genes [Index, Links, Images, Video, Papers, Patents, Books, Amazon, LifeExtension]
It turns out that resveratrol is not only an antioxidant, but also has properties that modify gene expression, activating a longevity gene (SIRT1 in humans, SIR2 in yeast) connected with gene silencing and mimicing caloric restriction that extends the lifespan of yeast by 70%, the lifespan of short-lived fish by 56 to 59%, the life span of the fruit fly Drosophila (about 106 cells) by 35%, and the lifespan of the roundworm C. Elegans (959 cells) 14%. Note, however, that adult Drosophila and C. Elegans are made up entirely of post-mitotic, non-dividing cells not subject to replicative senescence [Index] due to shortening of chromosomal telomeres (7), while you, a human, have many cells subject to telomeric cell division limit control [Ben Best, Links/Model Organisms] managed by hTERT, the gene for the protein catalytic component of the telomeric DNA repair enzyme telomerase (7), which can restore the youthful phenotype of a senescent cell by lengthening telomeres so that their terminal telomere t-loops close, removing a double-strand DNA damage signal that stops the cell cycle and causes cellular senescence. Telomerase is also associated with dyskerin and an RNA component hTR. Note that SIRT1 compacts chromatin via histone deacetylase (HDAC) action, which may silence hTERT and other genes in the telomerase and telomere loop control protein groups, so that SIRT1 is not activated for therapy purposes at the same time hTERT, hTR, dyskerin, and hEST1A in the telomerase group are activated. In fact, hTERT activation may even proceed via a histone deacetylase inhibitor (HDAC inhibitor) like Tricostatin A or CGK 1026 that expands chromatin to encourage transcription from genes. Thus the genes for SIRT1 (silencing to genes and opposed to some other genes useful in therapy at other times), hTERT, hTR, and dyskerin are crucial longevity genes, along with genes for antioxidant-related enzymes (endogenous antioxidant enzymes) such as the glutathione peroxidases GPX1-GPX8 [Index/Glutathione], catalase, and the superoxide dismutase (SOD) genes for SOD1, SOD2, and SOD3:
CuZnSOD (SOD1) - Cytoplasmic SOD [Links/CuZnSOD, Wiki/SOD1, Papers, Patents, Books, LEF].
MnSOD (SOD2) - Mitochondrial SOD [Links/MnSOD, Wiki/SOD2, Papers, Patents, Books, LEF].
SeCuSOD (SOD3) - Extracellular SOD [Links, Wiki/SOD3, Papers, Patents, Books, LEF].
Antioxidants tend to keep hTERT protein inside the cellular nucleus and inhibit damage to DNA, lipid membranes, and cellular organelles from reactive oxygen species (ROS) and other free radicals. There are other longevity genes for telomere loop control proteins in the telosome (shelterin) managing telomere t-loops which may be manipulated. For instance, TRF1 may be removed from the telomere t-loops by phosphorylating tankyrase 1 with insulin stimulation of cell surface insulin receptors, allowing telomere t-loops to open for access by the telomerase holoenzyme (7). This poly(ADP-ribo)sylation reaction requires a NAD+ substrate which can be taken straight at about 2.5 mg/day, or which can be generated from an early morning dose of < 3 grams of nictotinamide (niacinamide), which also increases the expression of tankyrase 1. The gene for hEST1A supports telomerase activity and is another important longevity gene. Recent diligent research has shown that Drosophila has telomeres that must be protected to defend its cells against cell cycle arrest and apoptosis. Drosophila can suffer from telomere-degrading stress-induced premature senescence by giving it too much flying time. Resveratrol is presently available in capsules at 15 mg, 50 mg, 200 mg, 500 mg, and in tablets at 10 mg, and no optimum dose has yet been determined. The bioavailability of sirtuin-activating trans-resveratrol is improved if it is taken with quercetin [113], which is found in apples, pomegranates, onions, and regular red grapes [25d]. Also, resveratrol is protected by quercetin against degradation into cis-resveratrol, an isomer of the molecule. Recently resveratrol (such as Solaray Resveratrol) has been shown to inhibit the formation of eccDNA (Extra Chromosomal Circular DNA) [14s] associated with the aging of yeast cells, and may extend human lifespan 30 to 50 percent. [See Scientific American, Unlocking the Secrets of Longevity Genes, by David A. Sinclair and Lenny Guarante, March 2006, and Secrets of Aging by Sophie L. Rovner.] The inhibition of eccDNA formation is probably the direct result of resveratrol gene silencing via inhibition of histone deacetylase enzymes, which has the effect of keeping DNA tightly wound around histone proteins. The resveratrol-associated increase in SIR2 activity may be amplified by the presence of extra NAD (Nicotinamide Adenine Dinucleotide, Wikipedia, Now NAD, review, found in tuna, milk, tomatoes), which is absolutely required for the enzymatic activity of SIR2 in yeast or its analogous homologue SIRT1 in humans. Another small-molecule sirtuin activator or STAC [Links, Papers] like resveratrol is fisetin, and NAD has also seemed to activate SIR2 or human SIRT1. Also, resveratrol inhibits NFκB [68s], a protein complex that promotes inflammation. See also resveratrol activates Sir2 longevity gene., the article The SIR2 gene: Gene silencing in Aging and programs to find and identify longevity genes. For a more recent article see Maris Kuningas, et al, (2008) Genes encoding longevity: from Model Organisms to Humans, Aging Cell, Vol 7, issue 2, 270-280. I note that UCSF Researchers identified about 200 longevity-impacting genes in 2003 using DNA microarray techniques [Index, Patents]. Humans have perhaps 30,000 genes, 25,000 of which encode proteins, (Human Genome Project, circa 2009) with splicing variants yielding about 100,000 different proteins and enzymes. Also see Longevity Genes and Caloric Restriction from Life Extension magazine, and genetic testing descriptions in Why Do We Age?. DNA microarray studies show more youthful patterns of gene expression when oldsters are on calorie-restricted diets (CR). "Also of note is the fact that identical twins tend to die within 3 years of each other, whereas fraternal twins tend to die within 6 years." [99]. Gene silencing via DNA methylation controls gene expression and might be improved by taking SAMe (S-adenosylmethionine, Patents) supplements, or conventionally folic acid, trimethylglycine, zinc, magnesium, vitamin B2, vitamin B6, and vitamin B12. [25s]. According to Ben Best, "Many cancer-causing chemicals block DNA methylation. Dietary deficiency of nutrients required for methylation (methionine, choline, folate and Vitamin B12) [69s] lowers liver DNA methylation and increases liver cancer in experimental animals." On the other hand, lowering methionine from the average dietary dose to something greater than one fifth of normal for adults, as long as the dose is sufficient to avoid liver cancer, has been shown to extend life span in rodents more than 30%. Thus sometimes doctors prescribe other methylating compounds as replacements for methionine, such as TMG [trimethylglycine]. Most genetic mutations leading to superior longevity in experimental animals are believed to improve the defenses of the organism to environmental stress. However, aging rates are increased by mutations interfering with gene silencing or telomeric silencing. Note that genes for endogenous antioxidants (Index) may be turned on anytime, but gene silencing genes like SIRT1 activated by high-polyphenol quercetin and resveratrol should not be turned on while trying to activate telomerase group genes, because they silence DNA by compacting chromatin, inibiting transcription of hTERT. In fact, high-polyphenol foods like cocoa powder in water (a fine antioxidant) degrade into telomerase inhibitors, so that we try not to consume them while cyclicly attempting to activate telomerase, sticking to a low-polyphenol diet then like grapefuit and tuna packed in water on soda crackers, taken with vitamins, antioxidants and supplements excluding telomerase inhibitors.

0.3 Breeding for Longevity [Links, Images, Papers, Patents, Books, Amazon, LEF].
Finally, I note that it has been shown that siring offspring from the later-life-cycle eggs of females produces longer-lived offspring as time goes on. Breeding for longevity has been demonstrated in rodents and flies with this approach, which might also be applicable to humans. Flies require 15 generations to achieve 30% life extension with this technique. In the lab, we have managed to create 4-year-old-plus mice like Yoda (the equivalent of a 136 year-old human), life span-doubled Methuselah flies, life span-doubled C. Elegans worms, and spade C.Elegans worms with life spans extended by a factor of 6. The experimenter felt that observable results in humans via late breeding might be obtained in 10 generations. Siring children in the years just prior to menopause may produce longer-lived sons and daughters. Many long-lived species [Images] show an increase in reproductive fitness as they grow older [Robert Arking, 2006, p23]. Note, however, that breeding between very elderly specimens may produce a progeric child [Images] showing signs of premature aging.

0.4 Gene Therapy for Longevity [Links, Images, Video, Papers, Patents, Books, Amazon, LEF].
Also note that gene therapy [Index], say to insert extra SOD2 genes, or genes for other endogenous antioxidants, is now feasible. See A4M on Gene Therapy, and Life Extension Foundation articles on Gene Therapy. Gene therapy [Index, Books, Books/and_aging] may be someday performed ex vivo on host adult stem cells or embryonic stem cells created by nuclear transfer that are later cultured and sorted for subsequent implantation. Sometimes today cells are subjected externally to gene therapy, then seeded on a scaffold and reimplanted, say in bone. This may also be accomplished with a hypodermic needle (8). See books on Regenerative Medicine and Gene Therapy. Today gene therapy may be done with targeted genome editing using zinc finger nucleases that can remove Single Nucleotide Polymorphisms (SNPs) in genes and insert new genes that are perfect. For instance, this may be done for sickle-cell anemia. It is also possible to use targeted genome editing to insert entirely new genes or extra copies of desirable genes at specific locations in the human genome. The zinc finger nuclease machine plus supporting components is inserted into the cell via liposome endocytosis in a liposome fashioned from cationic transfection reagents. Simpler techniques are available, including temporary plasmid DNA featuring transfection or transduction that inserts genes in DNA plasmid loops through the cell membrane via liposome endocytosis. On the other hand adenoviruses may be used to insert a gene at a specific site in the genome, and associated adenoviruses may be engineered to insert genes at a specific site on chromosome 19. Stem cells (8) have been subjected to gene therapy [Patents, Books], cultured, and implanted into bone to refresh the vascular endothelium. Another way of refreshing the vascular endothelium is to use bodybuilding exercises to produce nitric oxide synthase while taking a whey protein supplement rich in arginine to produce Nitric Oxide, which activates telomerase in endothelial cells [Vasa, et al., 2000], [Hayashi, et al., 2006]. Other small molecule telomerase activators [81s/TA, List] such as the astragalosides, nitric oxide from arginine, or ginkgo biloba may similarly activate telomerase in endothelial and stem cells to refresh the endothelial cells in the lining of the veins and arteries, warding off heart attack and stroke problems that follow the senescence of endothelial cells that line them. Today it is routine to use orally bioavailable telomerase activators [List] to refresh the vascular endothelium, including ones that specifically promote transcription of hTERT in endothelial progenitor cells or otherwise stimulate telomerase activity in the cellular nucleus, by phosphorylation of hTERT for its import from the cytoplasm into the nucleus, or by providing cofactors such as HSP90. Also see endothelial dysfunction and treatment [Links, Images, Papers, Patents, Books, LifeExtension].

(1) The free radical theory of aging [50, Refs1.1, Refs2, Index, Links, Images, Video, Papers, Patents, Books, Mechanisms of Aging/radical, on Antioxidants, Amazon, LifeExtension]. The Free Radical Theory of Aging of Dr. Denham Harman featuring treatment with antioxidants [Links, Best] was promoted by Dr. Linus Pauling as treatment with the antioxidant Vitamin C [Index, 27-31], a vitamin that is not synthesized in the body, but that we tolerate well in large doses. Just 800 mg/day of vitamin C improves one's life expectancy by six years, according to Life Extension Magazine. In treatment based on the free radical theory of aging we screen nuclear DNA, mitochondrial lipid membranes, mitochondrial DNA, and the life span limiting telomeres of your genes [3,32,63, 64] that control the Hayflick limit (7) (for cell types, Books) for liver, bone marrow, lymphocyte, skin, blood, microglial [77s], and colon mucosa cell division with antioxidants such as vitamins C, E, A, CoQ10 (ubiquinone or the new, improved ubiquinol variety CoQ10) [Index, 59], green tea polyphenols [25b], inexpensive lycopene from tomato paste [Wikipedia, Links, LifeExtension], dark chocolate polyphenols [25k], grape seed extract [36], the Hull Thornless blackberry [25L], resveratrol, curcumin (from the spice turmeric used to make curry, anticancer, and having many uses) or superoxide dismutase [52] prepared by the body from selenium, copper (intracellular and extracellular SOD) and zinc (cytoplasmic CuZnSOD), or manganese (mitochondrial MnSOD). Sprouts [64s] and wheat grass are a source of SOD, and SOD levels are boosted by Huperzine A [65s], Ashwagandha [63s], Bacopa, and Life Extension Magazine's SODzyme and GlySODin [52]. Wasabi (Japanese horseradish) is a SOD-mimetic and might be used instead of mustard or as a condiment mixed with mustard, although it sometimes endows us with fuming nostrils. New mitochondrial SOD mimetics like MnTBAP [Index] resembling MnSOD are on the way. "Antioxidants such as MnTBAP/MnSOD [Links, Papers, Books, Index molecule image] might inhibit ROS damage to the mtDNA and other macromolecules, thus slowing the progression of mitochondrial energy decline. If so, then such drugs may not only help treat mitochondrial disease patients but also may ameliorate some of the worst ravages of the aging process." (However, MnTBAP itself is only available by injection.) [Innovita, 2.11] Females express more MnSOD [Index/SOD2] and more glutathione peroxidase than males, which may be a factor in why women live longer than men. [Febs Letters, J Vina, 579(12), 254-255, 2005.] Pomegranate [Wikipedia, Images, LifeExtension] is perhaps the best antioxidant for preventing the oxidation of LDL cholesterol and consequent atherosclerosis. Studies have shown that flavonoids (such as the quercetin in apples and pomegranates) prevent the oxidation of low-density lipoprotein thereby reducing the risk for the development of atherosclerosis. Damage done to cells by free radicals may be worst in the case of the telomeres, which are shortened by such damage, lowering the number of times a mitotic cell can divide before it becomes senescent. The telomeres shorten with each cell division, and must be length-maintained to keep up mitotic cells like the skin, the white blood cells, and the lining of the colon [81s]. Vitamin C has been shown to retard telomere shortening [30], and is required to synthesize collagen for tissues and to synthesize carnitine for improved mitrochondrial burning. The oxidized protein content of an old animal [Images, Papers, Books] might represent 30% to 50% of the total protein content [Robert Arking, 2006]. Antioxidants play a major role in defending aging cellular mitochondria against damage in the mitochondrial theory of aging [Mechanisms of Aging/mitochondria]. New synthetic antioxidants (Synthetic Catalytic Scavengers) pioneered by Eukarion were shown to extend the life span of C. Elegans by 50%. Ten percent of adult human bodyweight and 40% of the cell volume is due to mitochondria. Antioxidants may protect mitochondrial components in aging post-mitotic cells, and are effective in cancer prevention [51]. Free radical damage to mitochondrial DNA is thought to impair cellular energy production, leading to organ dysfunction and accelerated aging. The new ubiquinol form of CoQ10 is an important advance in protecting mitochondria from oxidant damage. Gamma tocopherol-rich vitamin E should be used to ensure quenching of the peroxynitrite radicals that particularly threaten mitochondria, noting that too much alpha tocopherol, which does not quench peroxynitrite radicals, can substitute for the gamma tocopherol form, and should be replaced by high-gamma vitamin E. Gamma tocopherol sources include peanuts, peanut oil, walnuts, pecans, corn oil, soybean oil, and sesame oil. Peroxynitrite does most of its damage to the endothelial cells lining the veins and arteries, and may be obtained from rising insulin levels due to the activity of nitric oxide synthase. Powerful Vitamin E tocotrienols and alpha lipoic acid, in addition to gamma tocopherol, may be more useful than is commonly realized in neutralizing peroxynitrites. Mitochondrial decline [Index, Links, Images, Video, Papers, Patents, Books, LEF] can be reversed with alpha lipoic acid and acetyl L-Carnitine [Links, Papers, Patents]. I might add that cooking tomato paste improves antioxidant lycopene bioavailability by a factor of approximately 4. Only telomerase [Index, 3,43,45, 63,66,67, 85], Neygeront [79], and the "super antioxidant" carnosine [69] (which also combats glycation (5) and the formation of AGEs, Advanced Glycation End products) were known to extend the Hayflick cell division limit of about 50 (7) associated with replicative senescence and telomere length in cultured human cells in vitro and for liver, lymphocyte, skin, blood, and colon mucosa cells in vivo, although now new small-molecule telomerase activators [Index, 81s] such as the astragalosides (7) are available to extend the Hayflick limit controllably to more than 400 cell divisions, corresponding to a human lifetime of greater than 600 years. Note that Alpha-lipoic acid [70, Books, LifeExtension, Ray, Ben Best/Lipoic Acid] is soluble in both lipids and water, whereas vitamin C is only soluble in water and vitamin E is the main free radical trap in cellular lipid membranes. However, to avoid side-effects only 200 mg - 500 mg of alpha lipoic acid or its cousins R-dihydro lipoic acid or R-lipoic acid were typically taken daily, although now doses of up to 1200 mg/day are sometimes prescribed. (It might be that alpha lipoic acid protects mitochondrial DNA better than vitamin C.) Timothy J. Smith, M.D., states that fats contribute the most to dangerous free radical concentrations, which largely result from combustion of ATP in the mitochondria and fatty acids in other organelles. Ben Best, in his treatment of Reactive Oxygen Species, notes that antioxidants must not do their job so well that they prevent certain cellular defenses against bacterial infection, but in Mechanisms of Aging [99] that "free radicals act on lipids to produce peroxides (-O-O- bonds) resulting in mutagenic epoxides and insoluble and nondigestible age pigments such as lipofuscin." The body's natural endogenous antioxidant enzymes include SOD [Index, 52], glutathione, and catalase; its sulfur-related antioxidants include lipoic acid [Index, 70], N-acetyl cysteine, and glutathione [Index, 107, 111]. Hydroxytyrosol is the antioxidant rated most highly on the ORAC scale (Oxygen Radical Absorbance Capacity = ORAC) for antioxidant herbs and antioxidant foods, about twice as highly as quercetin [Index]. Vitamin E tocotrienols [Wikipedia, Links, Papers, Patents, Books, LEF] are extremely powerful. Ashwagandha [Index] has been found to elevate endogenous antioxidant levels including SOD, glutathione peroxidase, and catalase. Both glutathione peroxidase and catalase catalyze the conversion of hydrogen peroxide to water. The hydrogen peroxide is produced primarily by the mitochondrial respiratory chain from the action of superoxide dismutase on the superoxide anion. It seems to be hydrogen peroxide that turns your hair grey, and anti-grey cures often promote elevated catalase. See also Shangri-la's Chinese Wolfberry (GoJi Berry) [LifeExtension, Links, Wikipedia], which is also said to "elevate SOD". Li Ching-Yuen [Index], said to have lived to the age of 252 years (1678-1930), consumed Goji berries (wolfberries) daily. Three major areas of oxidative stress exist: LDL peroxidation, protein carbonyls, and isoprostanes [107].
As noted above, recent work on vitamin E (Life Extension, June 2006), indicates that the gamma tocopherol form of vitamin E quenches peroxynitrite, which plays a major role in old age decline, and that taking only the alpha tocopherol form of Vitamin E, which does not quench peroxynitrite, displaces crucial gamma tocopherol in cells. Adding sesame lignans [26s] to the gamma tocopherol form of Vitamin E is thought to increase its beneficial antioxidant effects. As a consequence, sometimes one prescribes cooking in sesame oil and/or taking sesame seeds. The super antioxidant curcumin (from turmeric) is more bioavailable if the piperine in black pepper is added. Melatonin, a hormone and an antioxidant or enzymatic free radical scavenger, is treated in the next section on hormones. Finally, one may drink alkalinated water from a machine or other alkalinated beverages including certain teas that can contribute electrons to neutralize oxygen free radicals [72s], as described by Kurzweil and Grossman in Fantastic Voyage. I note that the free radical theory of aging originated from a 1956 article by Dr. Denham Harman involving cellular radiation damage, "Aging: A Theory Based on Free Radical and Radiation Chemistry" which deduced that aging is due to free radicals liberated by cellular respiration, in a way similar to damage done by free radicals generated by exposure to radiation. UV radiation from the sun causes formation of free radicals in the skin that can damage the mitochondrial genome, and antioxidant sunscreens feature green tea, vitamin C, vitamin E, or other antioxidants to neutralize these radiation-generated free radicals, in addition to UV absorbers or reflectors. In 1968 Dr. Harman published a dietary antioxidant study showing that the synthetic antioxidant and food preservative BHT supplied over a lifetime to mice produced a 45% increase in mouse life span. (See the BHT supply, LifeExtension/BHT.) Note that the transition to the state of cell-cycle arrest leading to cellular senescence can be caused by a double-strand DNA break caused by oxidative damage to DNA [Wikipedia/Senescence]. This is associated with premature stress-induced senescence due to oxidative damage to telomeres. The usual cause of cellular senescence is the double-strand DNA break [Links] caused by the approach of a mitotically dividing cell to its Hayflick Limit (7) of about 50 cell divisions as its terminal telomere t-loop comes open, unshielding a double-stand DNA break preventable with small molecule telomerase activators [Index] such as those contained in astragalus extracts or TA-65 [Index]. In the case of oxidative damage the double-strand DNA break producing cellular senescence may be prevented with antioxidant drugs, or the associated DNA repair (10) may be accelerated with Cat's Claw extract or AC-11.

Damage from Alkylation due to Aldehydes produced by Lipid Peroxidation
Free radicals containing one or more unpaired electrons may ultimately produce [Video, Papers, Patents] aldehydes [Images, Video, Papers, Patents, Books] from lipid peroxidation that are impacting to the process of aging, generating protein and DNA damage. See alkylation and aging [Images, Papers, Patents, Books, LifeExtension]. Also see protein damage due to aldehydes [Images, Papers, Patents, Books] and DNA damage due to aldehydes [Images, Papers, Patents, Books]. For instance MDA (Malondialdehyde) can produce damage to proteins or DNA via alkylation reactions [Links, Papers, Books, LifeExtension]. "Aldehydes such as malondialdehyde (causes DNA adducts) and hydroxynonenal, arising from the free radical degradation of polyunsaturated fatty acids, can cause cross-links in lipids, proteins, and nucleic acids." (L.J.Machlin and Adrianne Bendich, 1987). See defense against alkylation damage [Papers, Patents, Books, LifeExtension] and treatment of alkylation damage [Papers, Patents, Books, LifeExtension]. Note that alcohol produces poisonous aldehydes using endogenous alcohol dehydrogenases, which are converted to harmless carboxylic acids by endogenous aldehyde dehydrogenases and alkylation repair homologs if the load is not too high. Ethanol toxicity (which may be reduced by N-acetylcysteine and vitamin B1) is primarily due to its metabolites acetylaldehyde and acetic acid. Acetylaldehyde binds to proteins to form DNA adducts linked to cancer and organ disease.

(2) The hormone replacement theory [Refs1.2, Links, Images, Papers, Patents, Books, Amazon, LifeExtension, A4M, Mechanisms of Aging/hormones] - Increase your levels of heart muscle protective testosterone, cortisol-opposing DHEA, HGH (human growth hormone, produced by the pituitary gland), and/or melatonin [1], taken at night. HGH improves the transcription of hTERT mRNA to activate telomerase. Melatonin [Wikipedia, Books, LifeExtension, Ben Best] effectively scavenges free radicals and has been shown to increase the life span of laboratory mice 20% and the maximum life span of fruit flies 30%. Melatonin (25 mg/day before bedtime) is a telomerase inhibitor. Therefore melatonin's effect is understood to derive from the free radical theory of aging: it may preserve telomere length via antioxidant-equivalent action. Melatonin also promotes higher levels of the endogenous antioxidant glutathione peroxidase enzymes. Attenuated decline in DHEA-S and melatonin both predict increased life span in rhesus monkeys [Robert Arking, 2006, p.87]. "Serum bioavailable testosterone (T) and estradiol (E2), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), and growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations all decrease during aging in men" [Ref]. Sometimes I felt groggy the next day after evening melatonin, but 1-25 mg of melatonin 1 hour before bedtime produces no objectionable hangover. However, melatonin-induced hormonal carcinogenesis has been noted in laboratory animals at some dosages. Your androgen and HGH levels can be beefed up via bodybuilding exercises with weights. There are also HGH-boosting amino acid supplements or "secretagogue" formulas such as alpha-GPC, arginine (2000-3000 mg), lysine (250-600 mg), L-ornithine (2000-6000 mg), L-glutamine (500-1000 mg), glycine (2000-6000 mg), niacin (250-500 mg) whose effectiveness can be boosted by choline (2000-3000 mg) and pantothenic acid (1000-2000 mg) that help with the generation of HGH and androgens, which falls off with age. "Stacking" amino acid preparations like these before a bodybuilding workout enhances the HGH surge promoted by exercise. [Phillip Lee Miller, Life Extension Revolution, 2005, p.123-125]. According to Miller, fasting enhances HGH generation [Index] and bodybuilding HGH release is more effective if one does not eat for 2 hours prior to a workout. However, bodybuilders are often presented as getting superior results by taking whey protein [Index] just prior to a workout during or before which creatine monohydrate [Index] for improving muscle contraction quality is consumed, and micronized creatine is optimal for fast entry into the bloodstream. Myostatin inhibition by whey protein [Index] is superior if taken prior to a workout, rather after one. Whey protein [Index, Links, Books, LifeExtension] boosts HGH levels [Links, Papers]. DHEA (see Ben Best on DHEA supplementation, Index) is useful at 50 to 100 mg/day for men. DHEA (produced by the adrenals) modulates the release of interleukins, interferons, TNF-alpha and other immune system factors, and inhibits cortisol [Index, LifeExtension, Links, Books, Wikipedia], which can harden your arteries, up your blood pressure, increase cholesterol and triglycerides, suppress the body' ability to fight off cancer, poison your brain cells, afflict you with memory loss, attack your immune response, up your blood sugar and insulin, thin your bones, pad your waistline, put your immune system to sleep, and possibly whiten your hair when cortisol levels increase due to stress, "the great aging accelerator", which can give you the hormone profile of someone twice your age. The DHEA/cortisol ratio is about 15 in healthy people, but declines to as low as 3 in aging or stressed people. Miller notes that DHEA-opposed high cortisol levels from stress can cause IGF-1 Insulin-like Growth Factor levels to go up, causing GHIH Growth Inhibiting Hormone levels rise, inhibiting the release of HGH, so that stress can inappropriately interfere with HGH release. DHEA [LifeExtension, Books, Wikipedia], which is converted into testosterone or estrogen, also increases the levels of neurotransmitters important for short- and long-term memory and learning, thus protecting the brain from old age cognitive decline [Index], and is required for a robust immune response boosting the number of immune cells. [See Phillip Lee Miller, Life Extension Revolution, 2005, p22-43.] DHEA is naturally increased by good exercise (9) and sleep habits. Overdoses of DHEA are associated with oily skin, sweating, acne, hair growth, restlessness, overstimulation, and aggression. On the whole, trifling with your hormones by ingesting or injecting hormones is more dangerous than taking antioxidants: sometimes hormone imbalances can result in cancer. Finally, I note that pregnenolone [Links], a precursor of DHEA, lengthens C. Elegans lifespan 15 to 20 percent. Endocrinology institutes look into the hormone angle in anti-aging medicine. See The Neuroendocrine Theory of Aging in International Anti-Aging Systems on Theories of Aging. High cortisol levels due to stress accelerate aging, and may be treated with ashwagandha [Index] [63s], or with DHEA. Surprisingly, the dopamine availability improver (MAO-B inhibitor) Deprenyl (Selegiline) [92] was shown to extend the maximum life spans of laboratory animals, perhaps doubling remaining life spans, but it may regionally require a prescription from a doctor that favors its use, or from an anti-aging clinic. Prozac may not be taken at the same as deprenyl, thus prompting the requirement for a medical interview prior to deprenyl use. The liquid Deprenyl Citrate is considered superior. Other dopamine-enhancers include blueberries, St. John's Wort, bromocriptine [Links], and other compounds [97]. Recent research showed Deprenyl also increased SOD levels in substantia nigra, striatum and cerebral cortex brain cells. Peptide bioregulators isolated from the neuroendocrine system with application to life extension and administered intravenously have been investigated and promoted by The St. Petersburg Institute for Biogregulation and Gerontology [Postings]. They point out that thymalin [Links, Papers, Books, SPIFBG, L-Glu-L-Trp peptide chain note] and epithalamin [Index/Epithalon Peptide, Links, Papers, Books, LifeExtension, SPIFBG, increase melatonin secretion, L-Ala-L-Glu-L-Asp-Gly geroprotective tetrapeptide structure] are geroprotective and restore neuroendocrine system and immune system functions. See Peptides and Aging, by Vladimir Kh. Khavinson. It is perhaps true that small peptide bioregulators can be applied in liposomal sprays instead of in injections, like we presently take IGF-1 in Now Foods IGF-1 Liposomal Spray.

Sex Hormones modified by menopause and male andropause can be tuned for anti-aging effect. In women, progesterone stimulates bone-building osteoblasts to preserve bone density. This is also true in men, who by 65 loose bone mass as fast as women, and by 75 suffer from osteoporosis as much as women. In women progesterone also reduces fibrous breast lumps, reducing the risk of breast cancer. In men, declining testosterone levels can lead to depression, loss of muscle, increased body fat, and loss of libido. Testosterone protects heart muscle from damage and keeps cholesterol and blood pressure down. Also, estrogens can get high in males, leading to increased risk of heart attack or stroke, BPH (benign prostatic hyperplasia), and suppress testosterone production in the testes. This leads to a consideration of prostate disorders, as BPH induced by factors stirred up in the prostate gland increases the risk of prostate cancer and leads to difficulties in urination. High estrogen levels probably cause cancer of the prostate via proliferation of prostate cells by the same mechanism used by estrogen to proliferate cells in breast cancer. According to Dr. Phillip Lee Miller, testosterone/estrogen ratios are between 80 and 120 for men at their physical and mental peak, and estradiol/free testosterone ratios are less than one. Medicines used to treat prostate disorders due to estrogen include saw palmetto, nettle root extract (120-250 mg/day), boswellia extract, Pygeum Africanum extract (50-100 mg/day), flax lignans, Norway spruce lignans, lycopene (10-20 mg/day), cernitin, zinc (keep less than 50 mg/day), boron, and selenium (200 mcg/day). Green tea inhibits DHT (dihydrotestosterone), a factor in both prostate disorders and hair loss [74s]. Also, the enzyme aromatase acts on testosterone to produce estrogens, a problem which worsens as testosterone levels decline. Aromatase inhibitors [Patents, Books, LifeExtension] include Arimidex and Aromasin. Careful hormone tuning requires measurements of hormone levels and ratios usually performed by a medical doctor. Dr. Miller describes thyroxine adjustments and many hormone homeostasis details similarly described by Dr. Vladimir Dillman in Hypothalamus Pituitary and Aging by Everitt and Burgess.

(3) The caloric restriction theory [Refs1.3, Index, Links, Images, Papers, Patents, Books, Amazon, LifeExtension, Mechanisms of Aging/CRAN] - Caloric restriction for life extension dates from Osborne and Mendel (1915). Lab animals taking 30% to 50% fewer calories live perhaps 40% to 50% longer - so take fewer calories, settle for fiber at breakfast, have carrots, onions, broccoli, chopped green peppers, celery, and lettuce and do not break your fast with a big early banquet. Every other day no food is nearly as effective, and CR or Caloric Restriction is often described (perhaps erroneously) as the most effective presently known method for life span prolongation. Recent studies using cDNA microarrays [Index] show more youthful patterns of gene expression when Caloric Restriction is used, vs. aged patterns of gene expression. The drugs Metformin [Index, 65] or Acarbose [Index, 91] are sometimes used to mimic the effect of a low-calorie diet, but require a doctor's prescription because treatment options for problems with these drugs may involve a transfusion or some other injectable or prescription-only option. Other nutraceuticals inducing CR-mimetic gene expression (CR-mimetics) include resveratrol, pterostilbene, quercetin, black tea polyphenols, and grape seed (LEF). A high level of carbohydrates can result in high blood glucose (hyperglycemia) leading to type 2 diabetes and high risk factors for vascular disease such as high triglycerides and high C-reactive protein. According to William Falloon of Life Extension Magazine (Feb 2010), inhibiting three carbohydrate digestive enzymes with glucoregulatory agents has CR-mimetic effect:
Life Extension Magazine recommends combating carbohydrate overload [Links] by driving fasting glucose levels below 86 mg/dL. See glucoregulatory agents for caloric restriction. Green tea or green tea extract may be used to the raise basal metabolic rate to help burn off excess calories. Green tea also inhibits the enzyme lipase, which breaks down fats before they are digested. The caloric restriction with adequate nutrition (CRAN) approach probably works by reducing Reactive Oxygen Species (ROS) and glycation damage to proteins, lipids, and DNA due to the presence or combustion of sugars. There are about 220 cell types [AltRef] in the human body. This approach should also limit sugar damage (5) resulting in glycation of cell proteins [See crosslinking], elevated insulin levels, and silent or systemic inflammation [70s]. There is evidence that caloric restriction [Index] works principally by activating SIRT1, like resveratrol, which can be used to activate SIRT1 independently, without caloric restriction, which is sometimes associated with infertility. The SIRT1 enzyme seems to be largely responsible for the health- and longevity-enhancing effects of caloric restriction in mammals, boosts the manufacture of signaling molecules such as insulin, and regulates other key cellular proteins such as p53, FoxO, and KU70 involved in setting a threshold for cell death by apoptosis or in prompting cellular repairs. Recently Pere Puigserver of Johns Hopkins has shown that fasting raises NAD levels in liver cells, prompting increased SIRT1 activity. "Caloric restriction has been shown to reduce the age-dependent accumulation of AGEs in both red blood cells (see the glycation of hemoglobin) and skin collagen [Index] (Cefalu, 1995)... In addition, a higher level of SOD is seen in some tissues with caloric restriction (CR) and a lower level of superoxide or hydroxide radicals is seen throughout the life span." (Arking, p.208)
Pinolenic acid supplements [Images, Index] derived from pine nuts stimulate hunger suppression hormones including cholecystokinin and GLP-1 (Glucagon-Like Peptide 1) making caloric restriction easier to bear. The appetite suppressant pinolenic acid is useful in implementing a program of caloric restriction, and is thereby also useful for suppressing the dangers of insulin overload associated with obesity's chronic low-grade inflammation and leading to atherosclerosis, heart attack, stroke, cancer, Alzheimer's, and other old age disorders [75, 103, 103b].

Upregulating UCP3
I might add that advances in the mitochondrial theory of aging [Index, Mechanisms of Aging/mitochondria] show that dieting-resistant, obese patients have lower levels of UCP3 [Links, Images, Papers, Patents, Books], an uncoupling protein [Diabetes 53:S130-S135, 2004] found in muscle mitochondria that is upregulated by thyroid hormone T3. Thyroid hormone T3 to upregulate UCP3 may be obtained by taking tyrosine (promotes thyroid hormones), 7-keto DHEA (promotes thyroid hormone T3), Bauhinia Purpurea L (converts thyroid hormone T4 to thyroid hormone T3), or Bauhinia Purpurea L with Bacopa (promotes thyroid hormone T4). Mice with higher UCP3 show higher metabolic intensity (17% greater oxygen consumption), and 36% longer life span according to Ben Best. [Aging Cell; Speakman, J.R. 3(3):87-95 (2004)]. Furthermore, decreased body weight, decreased fat mass, improved glucoregulatory function, decreased blood pressure, and decreased blood lipids predict increased life span in rhesus monkeys [Arking].

Recently, there are signs that caloric restriction works by activating SIRT1 [Index, Books], which activates KU70 by deacetylating Ku70, so that SIRT1 and KU70 regulate the localization of Bax [Books/Bax and aging], which then determines the susceptibility of a cell to programmed cell death. This technique sequesters Bax away from mitochondria. Thus SIRT1 [Index, sequence] interacts with KU70 to improve DNA repair and prevent cellular apoptosis [article, Cohen paper, 2004, Books/KU70 and aging]. Note that Bax, often described as a "death protein" was the first pro-apoptotic target of the tumor suppressor gene p53 [Index, Books] discovered. It was noted early that resveratrol diminished Bax-induced apoptosis. Also see small molecule activators of sirtuins (STACs) [Links, Papers, Patents, Books], such as resveratrol. Other drugs with CR-mimetic effect are being investigated, such as rapamycin, which extends the lifespan of mice and rats, but has inhibitory effect on the immune system.

(4) The cell membrane and lipofuscin wastes theory [Refs1.4, Refs2, Papers, Patents, Books, Amazon, LifeExtension/Lipofuscin, LifeExtension/cell_membrane_aging, Mechanisms of Aging/toxins] - Coenzyme Q, or CoQ10, [Index, 59] also known as ubiquinone CoQ10, or the new and more effectively bioabsorbed uniquinol CoQ10 may be used to clean up lipofuscin wastes (Books) that build up in non-mitotic (postmitotic) cells and turn the heart black as time goes on [Papers/lipofuscin microphotographs, Papers/lipofuscin in heart cells]. In general, lipofuscin accumulation is a robust marker of aging in human muscle tissues [Links]. Coenzyme Q has been shown to extend the mean life span of lab rats 11.7% and the maximum life span of rats by 24%. "Chemically speaking, the lipofuscin is a strongly altered, extensively cross-linked, mainly insoluble, auto fluorescing lipoprotein mass, localized in the lysosomes, where it is formed. It is not a toxic substance in itself, and it was assumed that it may inhibit the cell functions simply by occupying a great part of the useful cell volume. However, eventually lipofuscin accumulation may inhibit autophagy, leading to protein turnover problems, activation of apoptotic mechanisms, and cell death. In the formation of lipofuscin, a great significance has been attributed to the lipid peroxidation, initiated by oxygen free radicals..." Three CoQ10 molecules attach themselves to a lipofuscin waste molecule in order to tag it as waste to be excreted by the cell. Ubiquinone is naturally present in cells, but may be taken to clean up wastes before surgery seems to reveal the heart to the surgeon as a black object. Old age spots may benefit from treatment with ubiquinone or ubiquinol CoQ10. Lipofuscin is also reduced in aging neurons by alpha lipoic acid [Index]. Aging specimens have about 50% less CoQ10 in their cells than youngsters. I note that CoQ10 increases the cellular energy level in the brain at the mitochondrial level, improving perceptual focus. Other drugs useful in removing lipofuscin include centrophenoxine (lucidril, perhaps the most efficient substance currently available), piracetam, DMAE, and the amino-acids acetyl-L-carnitine [Index] and carnosine [69], which may extend the Hayflick limit somewhat. Carnosine doses of 50 mg-100 mg/day show no side effects, but higher doses of 1000 mg to 1500 mg a day sometimes report histamine-related allergic reactions. (See allergic reactions to drugs.) Also see idebenone (CoQ10) [59]. Another drug useful in removing lipofuscin deposits from the brain is hydergine [Index, Books, 110]. "The real eyeopener is a study by Imre Zs.-Nagy, M.D., of the Hungarian-Italian Verzar Laboratory for Experimental Gerontology, in which centrophenoxine (DMAE + auxin) extended life span in lab rats by as much as 33 percent." [60] Studies suggest that lack of garbage collection in post-mitotic (non-dividing) cells is a key cause of cellular death and aging with Advanced Glycation End product AGEs in cellular garbage accelerating the rate of free radical formation leading to chronic inflammation associated with many diseases of old age, including Alheimer's Disease, stroke, and atherosclerosis. Lipofuscin-loaded human fibroblasts display decreased autophagy of wastes into lysosomes and shortened survival time when exposed to amino acid starvation, so it probably helps with lipofuscin problems to get a glass of skim milk every day, or bodybuilding whey protein powder highly enriched in amino acids.
Another name for lipofuscin originating in disease or drink is ceroid [Links, Images, Papers, Patents, Books, LifeExtension]. Lipofuscin or ceroid formation is aggravated by the overconsumption of alcohol, which may be opposed by grape seed extract, centrophenoxine, DMAE, and other medications.
Our program for fighting lipofuscin garbarge collection problems in aging postmitotic cells will include minimal alcohol consumption, lipofuscin removal drugs described above such as ubiquinol CoQ10 or hydergine, plus antioxidants, antiglycating drugs, amino acid sufficiency, and iron-chelating drugs for opposing lipofuscin formation, and finally conditionally immortalized stem cells, fibroblasts, and epithelial cells obtained with small molecule telomerase activators to replace postmitotic muscle and nerve cells [Links, Books] that have died. In some tissues, stem cell transplants may be required. Astragalus root (at 25-33 grams/day) and other medicines can be used to increase the number of available stem cells and to conditionally rejuvenate and immortalize mitotic cells including the mononuclear leukocytes of the immune system. Thus a program featuring age transformation for approaching physical immortality with rejuvenation included might be simply based on diet, pills, externally applied creams, exercise [List], telomere remodeling with cyclic telomerase activation, and probably only rarely with cellular transplants of externally cultured patient-cloned stem cells, embryonic stem cells, cells cloned from the patient and obtained with fine needle biopsy technique, or induced stem cells such as iPS cells obtained by transformation from other kinds of cells, by application of the relevant transcription factors (8).

(5) The Glycation Theory of Aging [Refs1.5, Links, Images, Video Papers, Patents, Books, Amazon, LEF, Mechanisms of Aging/glycation], or sugar damage theory [Links, Video, Papers, Books, LEF], or glycation-damaged protein (see carbonylation of proteins, Maillard reaction) leading to Advanced Glycation End products (AGEs) and cross-linking theory and collagen crosslinking [Links, Video, Images, Papers, Patents, Books] theory. Sugar-damage glycation, non-enzymatic glycosylation, aggravated in diabetes and usually originating from nutrient sugars and rapidly-digested white flour, attacks proteins [Links, Video, Books, LifeExtension, carbonylation of proteins] and DNA [Links, Books, LifeExtension] directly. See Annette T. Lee and Anthony Cerami (2006), The Role of Glycation in Aging [PDF], NY Acad Sci, 17 DEC 2006. Enzymatic glycosylation, which may be functional, can also present problems. Glycation damage due to reactions with sugars should be distinguished from glycosylation [Index, Books, Wikipedia], which is an enzyme-directed, site-specific addition of saccharides to proteins and lipids, often for signaling purposes. Advanced Glycation End products, usually formed via a sugar carbonylation reaction with proteins to form Schiff bases that rearrange themselves into Amadori products subsequently irreversibly oxidized by reactions catalyzed by iron into AGEs, accelerate the destruction of lipid membranes and DNA by promoting the formation of destructive free radicals. According to Ben Best, "AGEs in tissues increase the rate of free radical production to 50 times the rate of free radical production by unglycated proteins. AGEs attached to LDL-cholesterol [Images] accelerate oxidation and subsequent atherosclerosis." AGEs are usually tagged as accelerating tissue-stiffening cross-links, but Ben's assertion checks out qualitatively [Links, Papers, Patents, Books, article]. For instance, Breaking the Aging Code: Maximizing Your DNA Function for Optimal Health and Longevity by Vincent C. Giampapa, Miryam Ehrlich Williamson states that AGEs are "free radical factories", Life Extension Magazine backed the "50 times" line in 2001, and Dr. Phillip Lee Miller's Life Extension Revolution cites AGE-induced free radical synthesis at binding sites on membranes. Activation of RAGE (the cellular receptor for advanced glycation end products) by AGEs causes upregulation of the inflammation-associated transcription factor NF-kB and its target genes. AGEs also block nitric oxide activity in the vascular endothelium [Ref]. To fight accelerated aging we not only attack free radical destruction of lipid membranes with antioxidants, but also attack glycation with a low-sugar diet and antiglycating drugs, and we treat Advanced Glycation End products with medicines that clean them out of the cell or modify them. Acetyl L-Carnitine [Index, 58, Best] can be used to clean out glycated proteins associated with sugar damage to the cell. An added benefit is that it improves cellular energy in the brain by facilitating fatty acid transport and oxidation in the cell and (especially in combination with alpha lipoic acid, B-vitamins, and CoQ10) reduces mitochondrial aging. Acetyl L-carnitine may be taken with CoQ10, which also cleans AGEs out of the cell and is in addition a powerful antioxidant. Alteon's ALT-711 (dimethyl-3-phenacyl-thiazolium chloride or Alagebrium), chemically related to glycation inhibitor thiamine, or vitamin B1, may also be used, improving the flexibility of tissues hardened by carbonylated proteins, although studies suggest benfotiamine [Links], the lipid-soluble form of vitamin B1, is more effective. Alpha lipoic acid has also been observed to reduce glycation damage due to glucose and high-fructose diets (Ray). Cross-linked, glycated proteins may be responsible for renal disorders and cardiac enlargement and the hardening of collagen, leading to increased susceptibility to cardiac arrest. Sugar may give rise to chronic inflammation [70s]. Sugars binding to DNA may cause damage and inflammation that leads to malformed cells and cancer. Aminoguanidine is another drug useful in treating these problems, and carnosine is being promoted as a cure for glycation [69]. I note that the amino acid L-lysine and vitamin C together form L-carnitine. The Life Extension Foundation markets acetyl-L-carnitine arginate (acetyl L-carnitine with an extra molecule of arginine) to augment the benefits of acetyl-L-carnitine. "Acetyl-L-Carnitine Arginate is a patented form of carnitine that stimulates the growth of neurites in the brain by increasing Nerve Growth Factor levels. Studies show that acetyl L-carnitine arginate and acetyl L-carnitine stimulate the growth of new neurites by promoting Nerve Growth Factor. Acetyl L-carnitine arginate acts together with acetyl L-carnitine to increase neurite outgrowth." Ordinary acetyl L-carnitine also improves neurite growth to a lesser degree. To improve your memory, you might try Pregnenolone [88], Desmopressin, or nootropic "smart drugs" [article, sources], such as the acetylcholinesterase-blocking and SOD-boosting Huperzine A [65s] or acetylcholinesterase-blocking and SOD-boosting ashwagandha. Mind-sharpening piracetam [Index, Links, Images, Papers, Books, LifeExtension] with extra choline, phosphatidylcholine (lecithin), or quite effectively phosphatidylserine to improve memory may be excellent for final exam preparation. Piracetam is also excellent for lipofuscin removal [Links, Papers, sources].
Chemicals associated with AGEs (Advanced Glycation End products [Index, Links, Papers, Patents, Books, LifeExtension, IAS]) may be partially food-derived, stemming from the heat processing of cooked food, releasing reactive peptides into the blood stream after eating. For instance, recently Ben Best has warned against the AGEs contained in browned poultry skins. I suppose this also applies to anything browned by the Maillard Reaction, including the sugar on cinnamon toast. Curing tobacco causes the formation of glycation end products, which release cross-linking compounds into the blood when cured tobacco is smoked. Reactive peptides of low molecular weight tending to form AGEs are not properly removed from the blood in cases involving renal insufficiency. B-complex vitamins such as thiamine (vitamin B1) [article] and pryidoxamine (a B6 vitamer), vitamin C [27-31] and vitamin E and its variants, and green tea [25b] have been shown to exhibit anti-AGE properties. Vitamin C is anti-glycating for insulin and some other proteins. Vitamin B1, available in water- and fat-soluble forms thiamine and benfotiamine (sources), counteracts glucose toxicity by preventing glucose reactions with proteins. I note that vitamin B1 deficiency causes Wernicke encephalopathy, a serious disorder characterized by loss of short-term memory which may be precipitated in at-risk people (typically alcoholics [Index/Alcohol]) by carbohydrate loading or glucose infusion linked to damage to the mammillary bodies in the brain. Anti-aging experimenters have used up to 1 gram of vitamin B1 per day in experiments to eliminate glycation of proteins by glucose from the chain of AGE-related reactions. Acetyl aldehyde manufactured internally from ethyl alcohol in liquors has been shown to block the formation of AGE compounds from Amadori products produced from glyclamines derived from glycation of proteins by glucose, partially explaining the French paradox. Incidentally, it is glycation that produces cataracts. Note that these cataracts can be removed with carnosine eye drops. Caloric Restriction and CR-mimetic drugs (3) reduce the generation of Advanced Glycation End products. See also glycation in Innovita's article on aging, and Ben Best on the glycation theory of aging. A slow-carbohydrate-to-sugar, low-glycemic index, low-glycemic load diet helps prevent glycation and many diseases, so cook up those onions (benfotiamine), carrots, green beans (vitamin K), lentils, nuts, and peas (vitamin K) steamed, boiled, or lightly heated with extra virgin olive oil and maybe some low mercury fish with high fiber celery (luteolin) or lettuce with Swiss cheese (Vitamin K2) instead of wolfing down another baked potato or goodies heavy with sugar. Add a side dish of apples and some fresh fruit with a glass of skim milk and a cup of green tea. (However, those pats of butter and cubes of red meat, especially burned red meat, had better look suspiciously like cancer, stroke, and heart attack pills, about like cigarettes look like cancer sticks and sugary jelly beans now resemble Reagan-brand Alzheimer's pills unleashed to poison old brains with glycation, AGES, inflammation, and amyloid sheets). I also note that cancer feeds on sugar. Furthermore, sorbitol [Links] is produced by reactions of glucose and fructose with aldol reductase, leading to cataracts and other problems.
" The glycation hypothesis of aging was proposed in 1985 by Anthony Cerami [Links, Home Page]. Collagen cross-linking and collagen transformations were studied earlier by Verzar (1955, 1965). Glycation refers to the nonenzymatic reactions of the carbonyl groups of reducing sugars with amino groups of macromolecules (large molecules) such as protein and DNA." - pg.55 Challenges of Biological Aging by Edward J. Masoro. Carnosine [9s, 69, LifeExtension] prevents the carbonylation of proteins and a consequent knockout of the proteasome system for disposing of used proteins. [75s]. "By inhibiting the proteasome, carbonylated proteins could interfere with cell cycle progression and control.... Protein carbonylation thus becomes a potentially terminal condition." - LifeExtension, 2001.
Note that sugar glycation damage [Links, Images, Papers, Patents, Books] produces cellular garbage in the form of Advanced Glycation End products [Links] that can lead to "silent" or systemic inflammation of tissue when more free radicals are generated by AGEs and consequently by follow-on COX-2 enzymes and other inflammation-oriented cytokines, so that we conceive of glycation damage (carbonylation of proteins and DNA from sugar damage) as a very primary cause of aging that generates escalating levels of free radicals and free radical damage. Other somewhat effective cures, such as inhibiting COX-2 enzymes and other inflammatory enzymes with curcumin or ginger, seem relatively superficial to the whole chain of reactions producing cellular garbage toxins such as lipofuscin (to be cleaned out with CoQ10, acetyl L-carnitine, and alpha lipoic acid) that generate poisonous free radicals that we neutralize with antioxidants. So treatment with a low-sugar, low-glycemic index food diet and with carnosine, vitamin B1, and other drugs that attack glycation's tendency to form AGEs is methodology which gets to the roots of a whole chain of aging effects impacted by many other medication strategies in a less fundamental way. Among the antioxidants and antiglycating compounds, only carnosine is famous for its ability to rejuvenate a senescent cell back to its youthful phenotype, although this may also be done with the small molecule telomerase activators [List] such as astragalus extract (best), cycloastragenol, astragaloside IV, and ginsenoside RH1. Glycation and free-radical damage (coming to some degree unavoidably also by the mitochondrial conversion of fatty acids and sugar to ATP) should both be attacked vigorously, and accompanied by a program featuring R-dihydro-Lipoic acid or plain alpha lipoic acid, acetyl L-carnitine with ubiquinol CoQ10 or ubiquinone CoQ10, Centrophenoxine, or DMAE to clean AGEs out of the cell. Note that the cleaning out of AGEs is done by modifying the penetrability of the cell membrane, so that it becomes more permeable to potassium and the concentration of the potassium ion inside the cell can go down. This causes the cell to be less dehydrated and colloidally condensed, so that genes are more easily transcribed and so internal protein turnover [Books, LifeExtension] can take place. See The Membrane Hypothesis of Aging by Imre Zs.-Nagy (13). Note that AGE structures including cross-linked collagen can be destroyed by macrophages [Books], causing neighboring cells to replace destroyed structures with non-cross-linked molecules. (Arking, p.366) Still, anti-inflammatory COX-2 enzyme inhibitors such as ginger and curcumin are required to fend off many characteristic diseases of old age when saturation of tissues with AGEs and packaging of AGEs into swollen lysosomes has reached an advanced point. Aspirin and other NSAIDs which combat AGEs-stimulated sugar damage inflammation by targeting both COX-1 and COX-2 enzymes can cause stomach ulcers, as COX-1 enzymes are stomach protective. Carnosine is typically prescribed at 2 x 500 mg/day, requiring a substantial dose to become physiologically active, but is known to remain in the blood for only a few hours. Perhaps carnosine should be taken every few hours at 500 mg/dose. Too much carnosine at a time can produce histidine allergic reactions, however. Vitamin B1 (thiamine) is far more inexpensive and may be taken 4 times a day at 250 mg/dose with no undesirable side-effects to combat glycation and AGEs. Anti-aging experiments featuring vitamin B1 at up to 1 gram per a day have been undertaken without mishap. The lipid-soluble benfotiamine form [molecule, Ray, LifeExtension] of vitamin B1 should probably also be taken for best effect, and can be found in onions, garlic, leeks, and shallots that can be mixed up with tomato material rich in lycopene like a dip for celery stalks. Too many onions and garlic cloves, however, can make you sick for a day. (For other such tips, see The Perricone Promise, by Nicholas V. Perricone.) "In a rat study comparing the effects of benfotiamine with water-soluble thiamin, benfotiamine inhibited AGE formation in diabetic rats while completely preventing formation of glycooxidation products, which are toxic by-products of chronic elevated blood glucose. AGE levels were not significantly altered by thiamin. Benfotiamine also normalized nerve function in the animals. After three months of administration, nerve conduction velocity (NCV), a measure of nerve function, was increased by both benfotiamine and thiamin; at six months, NCV was normalized by benfotiamine, whereas thiamin produced no further increases in this parameter." Cinnamon (0.5 - 1 tsp/day) may be used to oppose glycation by lowering blood sugar [Links, Books, LifeExtension]. Some problems like changing your hair color back to normal in hair rejuvenation may require melancor, tyrosine, tyrosine from cottage cheese, or tyrosine kinase inhibitors like Gleevec from a physician - it seems not to be true that everything in aging and rejuvenation [Books2] can be reversed by combating AGEs from glycation and AGEs-stimulated free radicals, although these are impacting therapies for both internal and topical application. However, we may regard typical aging symptoms as due to an inflammatory process [Mechanisms of Aging XX/inflammation] characterized by sugar-damage glycation-activation of molecular sites via AGEs leading to accelerated free radical formation and ultimately to further inflammation involving the activation of cytokines, TNF-alpha, and NF-kappaB; and progressing to cancer, heart attack, stroke, and Alzheimer's disease. The increase in free radicals leads to accelerated telomere shortening, as does the free radical increase due to high homocysteine levels due to defective methylation and treated with TMG (trimethylglycine) [32s], folic acid, vitamin B12, and vitamin B6. In the final analysis, though, the intrinsic telomere shortening process in mitotic cells will infallibly stop the aging clock and kill the organism whether or not toxic glycation and free radicals have been taken care of, unless telomerase activation therapies, senescent cell restoration therapies [Notes, Refs 9, Refs 10], or stem cell therapies are employed to effectively re-extend cellular telomeres. Also, unless corrected with mitochondrial biogenesis, mitochondrial aging is eventually likely to destroy cells via mitochrondrially-induced apoptosis [Index].

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