1 Unlocking the Secrets Of the Telomere The

1 Unlocking the Secrets Of the Telomere: The First Step to Reversing Aging Dr. Al Sears, MD

“Unlocking the telomere is the MOST important event in the history of anti-aging medicine”

True“Age-Reversing Therapy” • My own theory. • The link between telomeres and aging. • Shortened telomeres and age-related loss.

Implications for Anti-Aging Clinicians • Avoidance of factors that accelerate the loss of telomeres. • Currently available therapies that have been shown to slow the loss of the telomere. • Telomerase activators as anti-aging therapy.

The “Tipping Point” that Will Change Life on This Planet Forever • 30 years ago, no one understood WHY we age. . . Most believed that we never would. • As the field of Gerontology advanced, so did the number of theories. • In light of telomere biology, we realize the “causes” of aging are really the “consequences” of aging.

Theories on Why We Age: § § § § Disposable Soma Theory – We just temporarily house our Genes. Oxidative Stress Theory – Free radicals cause damage to cells. Vital Substance Theory – A vital substance is limiting. Genetic Mutation Theory – Accumulation of mutations cause aging. Reproductive Exhaustion Theory – After reproduction we die rapidly. Aging by Design Theory – Aging is programmed. Mitochondrial Dysfunction Theory – Mitochondria become altered. The Neuroendrocrine Theory – Changes in hormone regulation. Wear and Tear Theory – Self explanatory The Rate of Living Theory – Similar to the Vital Substance Theory The Waste Product Accumulation Theory – Self explanatory The Cross-Linking Theory – Proteins such as collagen crosslink. The Immune System Theory – Decreased immune function. Errors and Repairs Theory – Inaccurate repair of damage. The Order to Disorder Theory – Decreased maintenance of entropy. Telomere Theory of Aging – Telomere length controls aging.

The Cause of Aging Cannot Be Environmental • Aging begins at BIRTH. • Aging is inevitable regardless of environmental factors. • You have the potential to replicate EXACT copies of your cells. . . but you don’t. Why? • Aging is a necessary feature of evolution for advanced multi-celled organisms.

What Really Causes Aging? • Leonard Hayflick: �Cell division is a finite biological function and is inexorably tied to the lifespan of a cell line �“Hayflick Limit” describes the number of times a cell can divide �Hayflick was the first to suggest the relationship between cell division and mortality, but did not know the connection to telomeres.

What are Telomeres? • First described in 1975 by Elizabeth Blackburn, who earned the Nobel Prize for medicine in 2009. • Telomeres are found at the end of all eukaryotic chromosomes. • The telomeres protect the chromosome from the replication-related loss of vital genetic information.

Telomeres

Telomere Length as Controlling Mechanism of Aging • There is an age-dependent attrition of telomere length, with losses ranging from 30 to 150 nucleotide pairs per replication, depending on cell type. • Cell division/telomere shortening continues until a critical telomere length is reached, at which point the cell enters senescence and can no longer replicate. • Cellular senescence prevents replication of incomplete or damaged DNA. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345: 458– 460 Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52: 661– 667

Telomeres Tell Cells How Old They Are • Telomeric mediation of gene expression may explain the relationship between telomere length and aging. • Cells with longer telomeres behave like younger cells. • Cells with shorter telomeres behave like older cells.

Aging and Death are NOT The Same Phenomenon • Aging is NOT required for changes to the gene pool. • Aging occurs so individuals may play different roles throughout their lives. • Girl becomes woman, woman becomes mother, mother becomes grandmother • Aging changes an individuals characteristics WITHOUT altering its genome.

The True Role of “Anti-Aging” • If aging ≠ death then Anti-Aging ≠ life extension • What we can achieve by altering the telomere only comes to light when you see aging and death in the right context. • Anti-Aging increases one’s “health span”: The amount of time one can live while still feeling healthy and happy. • Anti-Aging is not about “cheating death. ”

Diseases Affected By Telomere Shortening • • • Cardiovascular Cancer COPD Degenerative Disc Disease Alzheimer’s Osteoarthritis Rheumatoid Arthritis Osteoporosis General Immunity Skin Aging Macular Degeneration Liver Cirrhosis • • • Muscular Dystrophy Cell & Tissue Transplants AIDS Progeria Dyskeratosis Congenita Idiopathic Pulmonary Fibrosis Cri du Chat syndrome Down’s Syndrome Fanconi’s Anemia Tuberous Sclerosis Werner’s Syndrome And, Aging Itself? ? ? ?

Length of the Telomere as Controlling Mechanism of Aging Hundreds of published, peer-reviewed studies show the relationship between telomere length and markers of disease, life span and quality of life.

Telomere Length and All-Cause Mortality • Telomere length was assessed in 143 healthy men and women >60 years of age • Individuals with the shortest telomeres had significantly decreased survival rates: � 3. 18 -fold higher mortality rate from heart disease � 8. 54 -fold higher mortality rate from infectious disease Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003 Feb 1; 361(9355): 393 -5.

Relationship Between Telomere Length and Age-Related Conditions * * * = p<. 05 T/S ratio * Atzmon G, Cho M, Cawthon RM, Budagov T, et al. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26; 107 Suppl 1: 1710 -7.

Telomere Length & Dementia – Nurses’ Health Study ▫ Controlled for: age, education, smoking history, cardiovascular disease, hypertension, cholesterol levels, and diabetes ▫ telomere length below the median: � 12 -times greater risk of being diagnosed with dementia � 9. 6 -times greater risk of being diagnosed with mild cognitive impairment. Relative telomere/single gene ratio ▫ 62 women, > 70 years of age Grodstein F, van Oijen M, Irizarry MC, Rosas HD, Hyman BT, Growdon JH, De Vivo I. Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses' health study. PLo. S One. 2008 Feb 13; 3(2): e 1590.

Telomere Length & Cardiovascular Disease • Measured mean telomere repeat copy number to single gene copy number (T/S ratio) • Found that decreased T/S ratio was significantly associated with risk of MI loge-transformed T/S ratios • 674 Caucasian males M/I No M/I Zee RY, Michaud SE, Germer S, Ridker PM. Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach. Clin Chim Acta. 2009 May; 403(1 -2): 139 -41.

Telomere Length: A Crucial Indicator of Health and Longevity • Telomere length is: �A marker for cell age �A predictor of longevity �A predictor of age-related disease

Telomerase Activity Has Positive Impact On Adult Stem Cells • “The real targets for [Telomerase Activators] are the adult stem cells scattered throughout our body, which are required for regenerating and repairing our organs and tissues. • Activating telomerase in populations of adult stem cells can extend their function and help promote organ repair and regeneration. ”

Telomerase Activity Predicts Longevity in Humans • Multi-generational study of Ashkenazi Jews with exceptional longevity �Parent group (n = 86; average of 97 years) �Offspring group (n = 175) �Control group (n = 93) • Found that the population exhibited abnormally high telomerase activity, mediated by a mutation of h. TERT – a catalytic subunit of telomerase. • Results link human longevity with telomerase activity Atzmon G, Cho M, Cawthon RM, Budagov T, et al. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26; 107 Suppl 1: 1710 -7.

Telomerase Activity Has Positive Impact On Adult Stem Cells “The real targets for [Telomerase Activators] are the adult stem cells scattered throughout our body, which are required for regenerating and repairing our organs and tissues. Activating telomerase in populations of adult stem cells can extend their function and help promote organ repair and regeneration. ” • --Bryant Villeponteau, Ph. D. [ex-Geron Corporation, ex-Sierra Sciences] on-line post to Dr. Stephen Coles and the Gerontology Research Group 1/16/11

The Paradigm-Shifting Story of Telomerase • Telomerase is the enzyme responsible for rebuilding telomeres by adding nucleotide repeats (TTAGGG). • Telomerase activity is observed in fetal tissue, adult germ cells, and tumor cells. • Activity is nearly undetectable in somatic cells.

Activation of Telomerase Has Been Shown To: 1. Immortalize cells 2. Reverse the age of tissue 3. Reverse aging in whole organisms

Telomerase Can “Immortalize” Cells Study published in the journal Science: • Human retinal pigment epithelial cells were transfected with vectors encoding the human telomerase catalytic subunit (h. TERT). • Control cells showed telomere shortening, as well as normal levels of β-galactosidase, a marker of cellular senescence. • Telomerase+ transfected cells exhibited longer telomeres. • By the time the study was published, the telomerase+ cells had exceeded their expected lifespan by 20+ replications. Bodnar AG, Ouellette M, Frolkis M, Holt SE, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998 Jan 16; 279(5349): 349 -52.

Telomerase Restores Youthful Markers in Live Tissue • Normal human dermal fibroblasts were transfected with h. TERT and then grafted onto mouse skin. • Mice grafted with telomerase-negative control cells exhibited phenotypic signs of senescence (increased fragility, reduced levels of collagen I and III, and subepidermal blistering). • Mice grafted with telomerase+ cells exhibited a youthful phenotype, despite the same number of replications. Funk WD, Wang CK, Shelton DN, Harley CB, Pagon GD, Hoeffler WK. Telomerase expression restores dermal integrity to in vitro-aged fibroblasts in a reconstituted skin model. Exp Cell Res. 2000 Aug 1; 258(2): 270 -8.

“The results were strikingly unequivocal. The telomeres in cells with h. TRT lengthened, and the cells themselves kept on multiplying, through the Hayflick limit and well beyond. “At the time the papers were submitted they had made 20 or more extra divisions, yet they looked young, vigorous and essentially normal. ” Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998 Jan 16; 279(5349): 349 -52.

Now- The Final Piece of Proof! Harvard Researchers Demonstrate How Telomerase can Reverse Aging In a Whole Organism

Harvard Researchers Demonstrate How Telomerase can Reverse Aging In a Whole Organism

A Groundbreaking Study. . . • Harvard Medical School Professor, Ronald De. Pinho, used the TERT-ER mouse to demonstrate the profound effect of telomerase activation on age management. • TERT-ER mice have short dysfunctional telomeres and are deficient in telomerase. • 4 -hydroxytamoxifen (4 -OTH) is used to induce telomerase in TERT-ER mice. Jaskelioff M, Muller FL, Paik JH, Thomas E, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2010 Nov 28

TERT-ER Mice: Aged and Atrophied • Decreased survival �TERT-ER mice: 43. 5 versus �Telomere-intact mice: 86. 8 weeks • Widespread tissue atrophy �Decreased brain weight/hypomyelination �Testicular atrophy/decreased testicular size �Splenic atrophy �Intestinal crypt depletion/villous atrophy • Decreased fertility • Decreased olfactory discrimination (common aging marker in mice)

Testes weight (g) Testicular Atrophy is Reversed and Fertility is Restored P=0. 0001 TERT-ER Telomerase activated

Other Organs Were Also Restored • Similar results were seen in the spleen and the intestines. • Performance on olfactory discrimination tasks was restored to youthful levels. • “When we flipped the telomerase switch on and looked a month later, the brains had largely returned to normal. ” -- Dr. Ronald De. Pinho commenting on his groundbreaking Harvard study

Aging Brain Restored to Normal Size • Reversed cerebral atrophy • Restored white matter structures • Elongated telomeres in the corpus callosum Brain weight (mg) • Reversed hypomyelination P=0. 02 • Neural progenitor cells were reactivated TERT-ER Telomerase activated

How Do We Slow the Loss of the Telomere? • Factors that accelerate telomere shortening �Homocysteine �Inflammation �Oxidation �Depression �Emotional Stress �Physical Trauma • Factors that slow telomere shortening • Telomerase activators

Stop Accelerated Telomere Loss by Lowering Homocysteine • Multiple studies have shown that elevated homocysteine levels are associated with short telomeres. • In one study, elevated homocysteine tripled the rate of shortening. Bull CF, O'Callaghan NJ, Mayrhofer G, Fenech MF. Telomere length in lymphocytes of older South Australian men may be inversely associated with plasma homocysteine. Rejuvenation Res. 2009 Oct; 12(5): 341 -9. Richards JB, Valdes AM, Gardner JP, Kato BS, et al. Homocysteine levels and leukocyte telomere length. Atherosclerosis. 2008 Oct; 200(2): 271 -7.

Nutrient Protocol for Lowering Homocysteine • Vitamin B 12: 500 mcg • Folic Acid: 800 mcg • Vitamin B 6: 25 mg • Riboflavin (B 2): 25 mg • Trimethylglycine (TMG): 500 mg

Preservation of Telomeres with Vitamin C: In Vitro Evidence • In 1998, researchers at the Hiroshima Prefectural University in Japan added Vitamin C in the form of Asc-2 -O-phosphate (Asc 2 P) to human vascular endothelial cells. • They measured a slowdown of age-dependent telomere shortening of 52 -62%. • Telomerase activity underwent an age-dependent decline which was significantly slowed by Asc 2 P. • Researchers concluded that age-dependent telomere-shortening was decelerated by both suppression of intracellular oxidative stress and by telomerase retention Furumoto K, Inoue E, Nagao N, Hiyama E, Miwa N. Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress. Life Sci. 1998; 63(11): 935 -48.

Preserve Telomere Length with Vitamin C: In Vivo Evidence • Analysis controlled for age, overall health, BMI, smoking, stress level, cardiovascular disease, and diabetes. • Women in the 4 th quartile of vitamin C intake had significantly longer telomeres relative to women in the 1 st quartile. Mean Telomere Length (BP) • Vitamin levels were assessed in 586 women aged 35 -74 1 st Quartile 4 th Quartile Xu Q, Parks CG, De. Roo LA, Cawthon RM, Sandler DP, Chen H. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009 Jun; 89(6): 1857 -63.

Stress in the Workplace Causes Shortening of the Telomere 1 st Quartile Damjanovic, et al. , J Immunol. 2007 Sep 15; 179(6): 4249 -54 4 th Quartile

Depression Causes Shortening of the Telomere Simon, et al. , Biol Psychiatry. 2006 Sep 1; 60(5): 432 -5.

Reducing Stress Slows the Loss of the Telomere • After adjusting for age and various health/behavioral factors, women with the highest stress levels had the shortest telomeres. • The degree of telomere shortening correlated to a minimum of a full decade of again Average T/S Ratio • Chronic stress has been shown to accelerate telomere shortening. High Stress Low Stress Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004 Dec 7; 101(49): 17312 -5.

Superoxide Dismutase (SOD) Slows Telomere Shortening • Superoxide dismutase is a naturally occurring cellular antioxidant that aids the immune system cells in killing or deactivating invading microorganisms. • In human fibroblasts with low antioxidant capacity, increasing cellular superoxide dismutase activity slowed telomere shortening and increased the life span of the cells. Serra V, von Zglinicki T, Lorenz M, Saretzki G. Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. J Biol Chem. 2003 Feb 28; 278(9): 6824 -30.

Maintain Telomere Length with Omega 3 Fatty Acids Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010 Jan 20; 303(3): 250 -7.

The Right Exercise Increases Telomerase Activity • Murine model �Voluntary running for 3 weeks �Exercise induced: ▫ A 2. 9 -fold increase in aortic telomerase activity ▫ A 3. 3 -fold increase in telomerase activity in circulating mononuclear cells in the spleen • Human model �Compared to controls, professional athletes exhibited a: ▫ 2. 5 -fold increase in telomerase activity in young athletes ▫ 1. 8 -fold increase in telomerase activity in middle-aged athletes Werner C, Fürster T, Widmann T, Pöss J, et al. Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation. 2009 Dec 15; 120(24): 2438 -47.

Keeping Telomeres Long § Right Exercise § Anti-Oxidants § Omega 3’s § Vitamin D 3 § Don’t Smoke § Weight Management § Reduce Stress § Reduce Depression § Reduce Pessimism § Be Happy!

How to Activate Telomerase Now. . .

Assessment of Telomere Length Repeat Diagnostics: First and only CLIA Certified laboratory in the world to provide cell type specific telomere length measurements. www. repeatdiagnostics. com Spectracell: Uses “whole blood” sample. Does not differentiate between lymphocytes and granulocytes. www. spectracell. com Life Length: Founded by Dr. Maria Blasco, Director of the Spanish National Cancer Institute. First to measure percentage of critically short telomeres. www. lifelength. com

Telomerase Activators On the Market • TA-65 from TA Sciences • Product B from Isagenix • T-ACTIVATOR 100 from Telomere Biosciences

Geron Corporation • Discovered a process to extract a very rare molecule that is found in tiny amounts in the Chinese herb Astragalus and they named the molecule TA-65. • Patented the sequence of the telomerase genome and granted license to TA-Sciences to sell TA-65. • Dr. Bill Andrews: As Director of Molecular Biology at the Geron Corporation from 1992 to 1997, he was one of the principal discoverers of the gene of human telomerase.

Telomerase Activation: TA-65® • Naturally-occurring, highly purified single molecule derived from the Chinese herb Astragalus • Activates the h. TERT gene • In vitro: moderately activated telomerase in keratinocytes, fibroblasts, and immune cells • In vivo: orally administered in doses of 10 -50 mg/day for 12 -months Astragalus tragacantha (ssp. Vicentinus) Kingdom: Plantae Division: Magnoliophyta Class: Magnoliopsida Order: Fabales Family: Fabaceae Subfamily: Faboideae Tribe: Galegeae Genus: Astragalus Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011 Feb; 14(1): 45 -56.

Results of TA-65® Following 1 -year on TA-65 ®, we observed a significant decrease in the percent of criticallyshort telomeres.

TA-65® Reduces Number of Damaged Immune Cells • A study published in the September 7, 2010 issue of the journal Rejuvenation Research, showed TA-65 significantly reduced. . . • Senescent cytotoxic T cells and natural killer cells. . . • With a significant reduction in the percent of short (<4 kbp) telomeres (p = 0. 037). Harley, C. , Weimin L. , et al, “A Natural Product Telomerase Activator As Part of a Health Maintenance Program, ” Rejuvenation Research 2010

TA-65® in My Own Practice • First doctor licensed to administer TA-65. • Patients following TA-65 protocol since August 2008.

Case Study: Michael • Michael recently turned 60 but has the clinically documented “pulmonary age” of a 24 -year old. • Michael’s “neurological age, ” is only 44, a sign he has the brainpower of a much younger man. • Michael had other remarkable changes including better eyesight, lower cholesterol and dramatically higher testosterone.

Case Study: Michael • All that extra energy helped him win at the recent North American Grappling Association Championship. In the space of one hour, Michael won two first place titles against men who were twenty years his junior. • In Michael’s own words: “With TA-65 I lost 20 pounds, increased my muscle mass and flexibility, eliminated joint pain I’ve had for years and miraculously made the inside of my body younger. ”

Telomerase Activation: Product B Clinical Study 30 Random Subjects Double Blind, Placebo Controlled Baseline, 3 months, 6 months, 12 months Adverse events will be tracked

Telomerase Activation: Product B Clinical Study § § § Faces, Hands, etc. , Photographed Short telomeres measured Waist circumference Body Mass Index (BMI) Total Body Water (TBW) Total Body Fat (TBF) § Oxidative Stress Panel § Routine Urinalysis

Telomerase Activation: Product B Clinical Study § § § § CBC w/Diff Thyroid panel including a Free T 3 HSCRP (Highly sensitive C Reactive Protein) Total and free Testosterone Total Estrogen Chem 20 including a lipid profile IGF-1

Telomerase Activation: T-Activator 100 Statistically Significant Improvement in Several Major Age-Related Biomarkers that Normally Decline with Age, including: • Reduction in the Percentage of Cells with Short Telomeres, and Lengthening of Critically- Short Telomeres • Improvement in T-cell Count and Immune System Function • – “Representing a drop of 20% in [senescent] CD 8+/CD 28 -cells, an apparent age reversal of 5 -20 years in this biomarker of immune aging” • Increase in Bone Density [measured by GE DEXA] • Improved Cardiovascular Age [measured as ‘Arterial Elasticity’] • Improvement in Blood Glucose Levels

Partial Study Results: T-Activator 100 • Oxidative Stress: A 51 -68% reduction in TA vs. control • Inhibition of TNF-Alpha: A 1. 25 -1. 78 -fold increase in TA vs. control • Homocysteine: Up to a 50% decrease in TA vs. control • Cortisol: Up to a 50% decrease in TA vs. control [at levels comparable to in vivo psychological stress] • Telomerase Activators: “Low nanomolar levels of TA-65 moderately activated telomerase. ” [Drs. Calvin Harley, Bill Andrews, et. al. ]

Additional Telomerase Activators are in Development Sierra Sciences �Founded by Dr. Bill Andrews in 1999 �Screened 254, 593 compounds �Identified 858 telomerase inducers http: //www. sierrasci. com/

Sierra Sciences Team • Sierra Sciences �Founded by Dr. Bill Andrews �Screened 254, 593 compounds �Identified 858 telomerase inducers http: //www. sierrasci. com/

Dr. Al Sears, MD Wellness Research Foundation 11903 Southern Blvd. , Ste. 208 Royal Palm Beach, FL 33411 866 -792 -1035 www. alsearsmd. com