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TA 65 - Telomeres and Telomerase - Los Angeles 2015

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TA 65 - Telomeres and Telomerase - Los Angeles 2015

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TA 65 - Telomeres and Telomerase - Los Angeles 2015

  1. 1. Telomeres and Telomerase Activation Workshop Los Angeles 2015
  2. 2. Telomeres and Telomerase Activation Workshop Ron Rothenberg MD The following potential conflict of interest relationships are germane to my presentation. Equipment: NA Speakers Bureau: TA Sciences Stock Shareholder: NA Grant/Research Support: NA Consultant: NA Status of FDA devices used for the material being presented NA Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation NA
  3. 3. Ron Rothenberg MD Medical Director Encinitas, California
  4. 4. Telomeres and Telomerase • Telomere and telomerase biology • Impact of telomere shortening • Improving telomere shortening – Lifestyle – Telomerase activation with TA-65MD ® • Literature review TA-65MD ® • How TA-65MD ® can improve immune function
  5. 5. • Telomerase activation and cancer • Safety of TA-65MD ® • Non-telomeric actions of telomerase • Inflammation and telomerase • How is Is TA-65MD ® different from Cycloastragenol? • Patient comments • Testing • Should you and your patients take TA- 65MD ®
  6. 6. T.A. Sciences® - Telomerase Activation Sciences • Geron performed empirical screen on Chinese herbal medicines and discovered TA-65 in 2000 • Incorporated 2002 and selling TA-65 ® since 2007 • June 2013- estimated 7000 person-years of TA-65 exposure at an average BID dose of TA-65. • No cases of adverse events being attributed to TA-65 or TA-65MD by the subjects’ physicians • TA-65 ® for Skin (Telomerase Complex) released March 2014 • Harley CB et al., A natural product telomerase activator as part of a health maintenance program: metabolic and cardiovascular response. Rejuvenation Res. 16, 386-95 (2013).
  7. 7. Astragalus Membranaceous • Chinese medicine for more than 2,000 years for healing and diabetes • Primary chemical constituent is cycloastragenol (CAG) (TAT2) • Used as a tonic to improve the functioning of - • Lungs • Adrenal glands • Gastrointestinal tract • Increase metabolism and sweating • Promote healing • Reduce fatigue
  8. 8. Cycloastragenol Activates hTERT gene
  9. 9. Hayflick Limit Population Doublings Time Time Hayflick L et al. The serial cultivation of human diploid cell strains. Exp Cell Res. (1961).25(3):585– 621.
  10. 10. Hayflick limit • The Hayflick limit: The number of times a normal cell population will divide until cell division stops. • The telomeres associated with each cell's DNA will get slightly shorter with each new cell division until they shorten to a critical length and cellular death or mutation result
  11. 11. Telomeres • Region of repetitive nucleotide sequences (TTAGGG) at each end of the chromatid • Protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes • Telomeres act as the cellular aging clock. • Telomere loss is a Major Cause of Cellular Aging
  12. 12. Telomeres: • Telomere length is dynamic and results from balance between factors. – Erosion (Blackburn, 1991) – Oxidative stress (Von Zglinicki, 2000) – Restoration through telomerase activity, (Greider and Blackburn, 1985) • Telomere length remains a key feature that indicates the viability of a cell (Blackburn, 2000).
  13. 13. Telomere Function • Serve as chromosome end caps to protect genomic integrity • Prevent fusion • Prevent genomic instability • Necessary for cellular replication • Protection from cellular senescence • Protection from DNA mutations that can lead to cancer • Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010 Mar 25;464(7288):520-8.
  14. 14. Telomere Biology • 24,382 citations in Pub Med on February 27, 2015 regarding telomeres & telomerase. – Telomere shortening is a root cause of cellular aging and mitochondrial degradation. – Age related decline, dysfunction, and a shortened lifespan are all related to telomere shortening. • Jaskelioff M et al., Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 6, 102-106 (2011)
  15. 15. Telomerase Activation • Reverses some aspects of aging in old mice – Brain, spleen and reproductive organs were rejuvenated – Resulting in increased neurons and new viable sperm cells. – Sense of smell returned. – None of the mice developed cancer. • Jaskelioff M et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011 Jan 6;469(7328):102-6.
  16. 16. Telomere Length Determines Cellular Age • Somatic cells – Make up > 99% of the cells in the adult body – Have little or no telomerase and telomeres shorten as we get older. • Telomere Length Shortening: – Conception: Telomeres start out 15,000 base pairs (bp) long. – By Birth the embryo has divided so many times that telomere length is down to 10,000 bp. – Over the rest of our lifetime we lose another 5,000 to 7,000 bp. – When telomere length gets to 3-5,000 bp, the genome is no longer protected from mutations, the cell can no longer divide, becomes senescent, metabolism slows down, and the cell dies. – Senescence-Associated Secretory Phenotype - inflammation
  17. 17. Estriol in Utero Entringer S et al. Maternal estriol concentrations in early gestation predict infant telomere length. J Clin Endocrinol Metab. 2015 Jan;100(1):267-73.
  18. 18. Without the protection from telomeres, our cells age and eventually die and are susceptible to mutations, and turn on inflammation (SASP) Telomeres
  19. 19. Same Genes, Why the Difference?
  20. 20. Telomeres are the Biological Clock of Aging • Organs deteriorate as more and more of their cells die off or enter cellular senescence. • Shortened telomeres impair immune function that might also increase cancer susceptibility • Telomere length represents biological age as opposed to chronological age – Eisenberg DT. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Am J Hum Biol.2011. 2, 149-67
  21. 21. The Impact of Telomere Shortening • "Short telomeres appear to be associated with increased risks for human bladder, head, neck, lung, and renal cell cancers” • Fraternal twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements • Wu X et al. Telomere Dysfunction: A Potential Cancer Predisposition Factor (2003) J National Cancer Inst. 2003 Aug 20;95(16)1211-18. • Johansson, S et al. Telomere length predicts survival independent of genetic influences (2007) Aging Cell, 2007.
  22. 22. SASP
  23. 23. The Telomere Syndromes • Short telomeres are involved with almost all the diseases associated with aging • Few specialists are aware of the root cause of the diseases they are treating • Calado RT et al. Telomere diseases N Engl J Med. 2009 Dec 10;361(24):2353-65. .
  24. 24. SHORTER Telomere Associations • Earlier death Farzaneh-Fal 2008, Willeit 2010; • Older age Cawthon 2003, Bakaysa 2007; • Genetic Polymorphisms (Codd 2010; Gu 2011); • Stressors (Environmental, physiological, and psychological) O’Donovan 2012, Epel 2009, Lin 2012, Entringer 2013; • PTSD Ladwig 2013; • Stress (cortisol) Wikgren 2012, Kroenke 2011, Epel 2005; • Employment and work schedule (women) Parks 2011; • Childhood Institution Drury 2011 or trauma O’Donovan 2011; • Depression Wikgren 2012, Elvsashagen 2011, Hartmann 2010, Wolkowitz 2011; • Pessimism (women) O'Donovan 2009; • Phobic anxiety (women) Okereke 2012; • Hostility (men) Brydon 2012;
  25. 25. SHORTER Telomere Associations • Poor Sleep Quality (women) Prather 2011; • Sleep Apnea (adult) Barcelo 2010, Savolainen 2014; • Migraine (women) Ren 2010; • Low physical activity level Ludlow 2011, Krauss 2011; • Smoking cigarettes Valdes 2005, McGrath 2007 • Alcohol consumption Strandberg 2012, Pavanello 2011; • Polycyclic Aromatic Hydrocarbon Exposure Bin 2011, Pavanello 2010; • Lead (in vitro) Pottier 2013;
  26. 26. What Can Be Done To Keep Telomeres Long? • Lifestyle - – Nutrition, Exercise, stress reduction, meditation – Nutraceuticals • Omega 3’s, resveratrol, Vitamin D • Liu AJEpid, 2013, Liu HumaReprod 2013 – Limit inflammation – Limit free radial damage – Limit toxic environmental exposure • Restore Youthful hormone levels • Activate Telomerase
  27. 27. • Prostate cancer patients – Active Surveillance • Whole grains, low fat, fruits and veggies, plant based protein • Moderate aerobic exercise • Stress reduction: yoga, meditation, social support • Compared relative telomere length and telomerase enzymatic activity • Raised stress hormones associated with short relative telomere length - epinephrine, norepinephrine, and cortisol • After 5 years, relative telomere length had increased in the lifestyle intervention group and decreased in the control group; significant. • Ornish, D et al. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncology. 2013 Oct;14(11):1112-20. Telomere Length – Lifestyle vs. control
  28. 28. Mindfulness-based cancer recovery – Telomere Length • MBCR: Mindfulness training, Hatha Yoga, Group support • Telomere Length in the intervention group was maintained whereas it was found to decrease for control participants • Carlson L et al. Mindfulness-based cancer recovery and supportive-expressive therapy maintain telomere length relative to controls in distressed breast cancer survivors. Cancer. 2014 Nov 3
  29. 29. Telomere length and Breast Cancer Recurrence and all cause Mortality • Short telomeres are associated with increased cancer risk • Stage I to stage IIIA breast cancer survivors • Followed 11 years • Telomere shortening between baseline and 30 months was statistically significant for increased risk of breast cancer-specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39 • Change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) was statistically significant for all-cause mortality • Duggan C et al. Change in peripheral blood leukocyte telomere length and mortality in breast cancer survivors. J Natl Cancer Inst. 2014 Apr;106(4)
  30. 30. Survival in percent as a function of years after incident cancer by quartiles of telomere length • Weischer M et al. JNCI J Natl Cancer Inst 2013;105:459-468
  31. 31. More Mediterranean diet = longer telomeres, • Conclusion In this large study, greater adherence to the Mediterranean diet was associated with longer telomeres. P <.004 • Marta Crous-Bou et al. Mediterranean diet and telomere length in Nurses’ Health Study: population based cohort study BMJ 2014; 349
  32. 32. Telomeres and Exercise • VO2 max associated with telomere length • Exercise (3x a week) associated with greater telomere length. P < .01 • Østhus IB et al. Telomere length and long-term endurance exercise: does exercise training affect biological age? A pilot study. PLoS One. 2012;7(12). • Kim JH et al. Habitual physical exercise has beneficial effects on telomere length in postmenopausal women. Menopause. 2012 Oct;19(10):1109-15.
  33. 33. Stress and Telomerase • Correlations between improvements in psychological distress, eating behavior, and metabolic health and increases in telomerase activity. • Telomerase activity may be in part regulated by levels of both psychological and metabolic stress. • Daubenmier J et al. Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study. Psychoneuroendocrinology. 2012 Jul;37(7):917-28.
  34. 34. Meditation and Telomeres • Meditation increased telomerase activity. p<.05 • Jacobs TL, Epel ES, Lin J, Blackburn E, Wolkowitz OM, Bridwell DA, Zanesco AP, Aichele SR, Sahdra BK, MacLean KA, King BG, Shaver PR, Rosenberg EL, Ferrer E, Wallace BA, Saron CD Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology. 2011 Jun;36(5):664-81.
  35. 35. Sleep and Telomeres in Immune Cell • Prather AA et al. Tired telomeres: Poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women. Brain Behav Immun. 2014 Dec 20. pii: S0889-1591(14)00574-1.
  36. 36. Cortisol and Telomeres • Greater cortisol responses to acute stressor associated with shorter telomeres • Long-term consequences of frequent high stress reactivity include accelerated telomere shortening. • Tomiyama AJ et al. Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length. Physiol Behav. 2012 Apr 12;106(1):40-5.
  37. 37. Depression
  38. 38. Telomere Length-Depression • Depression associated with shortened telomeres • Shorter telomeres persist in individuals with lifetime depression • CD8+ cytotoxic T cells and CD20+ B cells are particularly affected in depression. • Alexander Karabatsiakis et al. Telomere shortening in leukocyte subpopulations in depression. BMC Psychiatry 2014, 14:192
  39. 39. Telomerase Neuroscience • CAG Activates Telomerase Activity in neurons • High levels of telomerase expression and activity – In neural stem cells and progenitors – In the prenatal brain – decreases in adults – Are essential for adult neurogenesis • Mice with telomere dysfunction exhibit memory deficits and “depression” • Ip FC et al. Cycloastragenol Is a Potent Telomerase Activator in Neuronal Cells: Implications for Depression Management. Neurosignals. 2014 Jul 31;22(1):52-63.
  40. 40. • CAG induced telomerase activity in cortical neurons • Oral CAG attenuated depression-like behavior in experimental mice • Leucocyte telomere length related to depression, cognitive dysfunction, Alzheimer’s • TERT is neuroprotective and promotes survival in neurons
  41. 41. Dementia and Telomere Length • Shorter TL was a risk for earlier onset of dementia in women (P=.05) • TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging. • Honig LS et al. Association of shorter leukocyte telomere repeat length with dementia and mortality. Arch Neurol. 2012 Oct;69(10):1332-9.
  42. 42. Hormones and Telomerase Activity • Androgen and Estrogen increase telomerase activity on TERT gene • No effect from Cortisol • Tamoxifen decreases telomerase activity • Rodrigo T. Calado et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. Sep 10, 2009; 114(11): 2236–2243.
  43. 43. • Barbieri, M et al. Higher circulating levels of IGF-1 are associated with longer leukocyte telomere length in healthy subjects. Mech Ageing Dev. 2009 Nov-Dec;130(11-12):771-6. • Kaplan RC et al. Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study. J Gerontol A Biol Sci Med Sci. 2009 Nov;64(11):1103-6 • Movérare-Skrtic S et al. Serum insulin-like growth factor-I concentration is associated with leukocyte telomere length in a population-based cohort of elderly men. J Clin Endocrinol Metab. 2009 Dec;94(12):5078-84. • Rastmanesh, R. Potential of melatonin to treat or prevent age- related macular degeneration through stimulation of telomerase activity. Med Hypotheses. 2011 Jan;76(1):79-85. Optimized Hormones and Telomere length
  44. 44. Telomerase • Maintains the telomere length • Promotes genomic integrity , proliferation, and lifespan • Protects the mitochondria from oxidative stress • Confers resistance to apoptosis • Important for the survival of non-mitotic, highly active cells such as neurons • Grin Y et al. Telomerase activity in the various regions of mouse brain: non-radioactive telomerase repeat amplification protocol (TRAP) assay. J Vis Exp. 2014 Sep 2
  45. 45. To make telomeres longer… • Activate Telomerase – an endogenous enzyme that stabilizes telomere length by adding DNA repeats (TTAGGG ) onto the telomeric ends of the chromosomes, compensating for the erosion of telomeres when cells divide
  46. 46. Telomerase E Reverse Transciptase Telomerase E RNA Component T T AG G G Ready November Afternoon A A UC C C
  47. 47. Telomerase = TERT + TERC Telomerase is a “molecular motor” that adds new DNA bases (TTAGGG) onto the ends of telomeres Telomere hTR = Template = hTERC hTERT Telomerase reverse transcriptase- hTERT T e l o m e r e R
  48. 48. Reproductive Cells Produce Telomerase
  49. 49. The Gene is Repressed in All Other Cells
  50. 50. TA-65® Removes the Repressor
  51. 51. hTERT is “Dual Targeted” • Nucleus -prevents telomere erosion leading to senescence and genomic instability • Terminally differentiated post mitotic cells • Mitochondria – has a different function since mitochondrial DNA does not contain telomeric structures. • Non telomeric activities hTERT in the nucleus: – Cell cycle regulation – Modulation of cellular signaling and gene expression, – Augmentation of proliferative lifespan as well as DNA damage responses • Mitochondrial hTERT – Reduces reactive oxygen species, DNA damage and apoptosis • Ale-Agha N et al.Cellular functions of the dual-targeted catalytic subunit of telomerase, telomerase reverse transcriptase--potential role in senescence and aging. Exp Gerontol.2014 Aug;56:189-93.
  52. 52. • Passos JF et al. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 2007;35(22):7505-13.
  53. 53. Telomerase Extends Cell Life Span and Overcomes the Hayflick Limit 0 50 100 150 200 250 300 40 60 80 100 120 140 160 PopulationDoublings ] ] PopulationDoublings Days hTERT + Cells have Telomerase hTERT - Cells have No Telomerase Slide courtesy of Woody Wright, Ph.D. Telomerase reverse transcriptase
  54. 54. Short Telomeres Long Telomeres  Gray & Thinning Hair  Weakened Immune System  Intestinal Atrophy  Reduced Spleen Size  Decreased Wound Healing  Decreased Lifespan.  Increased cancer • Rudolph KL et al., Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 5, 701-12. (1999). • Samper E et al. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc -/- mice with short telomeres. EMBO Rep. 2, 800-7 (2001). These mice are the same age. Telomerase activity has been inhibited on top and reactivated on the bottom. Findings demonstrate a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism. Slide courtesy of Bill Andrews Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc -/- mice with short telomeres Terc= Telomerase RNA Component, template for telomere replication
  55. 55. Antiviral • Immune cells up-regulate telomerase with activation. • Aging and chronic HIV-1 infection- high proportions of dysfunctional CD8 CTL with short telomeres, suggesting that telomerase is limiting CD8 T lymphocytes from HIV-infected human donors • Small molecule telomerase activator (TAT2) – Activates Telomerase – Retards telomere shortening – Increases proliferative potential – Enhances cytokine/chemokine production and antiviral activity • Fauce SR et al. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol. 2008 Nov 15;181(10):7400-6.
  56. 56. TA-65: Telomeres, HealthSpan, Cancer • Mice treated with TA-65 x 4 months • TA-65 stimulates telomerase activity and elongates short telomeres • Significant decrease of very short telomeres (telomeres < 2, 3 and 4 Kb) at 3 months post-treatment. • Improved – glucose tolerance – Epidermal thickness – Good hair day – Bone density – Higher hemoglobin – No increased cancer incidence • Bernardes de Jesus et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell. 2011,10(4):604-21
  57. 57. TA 65 and immune function • 10-50 mg TA 65 x 12 months • Multivitamin protocol • Human study • Reduction critically short telomeres – (<4 kbp) telomeres (p=0.037) • Positive remodeling of immune system – Greater in CMV+ – Decline in senescent Cytotoxic T cells p< .006 at 12 months – Increase in natural killer cells p < .0001 at 12 months • Harley CB et al. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011 Feb;14(1):45-56.
  58. 58. TA-65 study results – Harley 2011 • Decreased viral loads in HIV+ patients and CMV infected cells • Improved T cell response and B cell antigen generation • Improved wound healing • Improved bone density • Improved cytokine profile and decreased inflammation
  59. 59. TA-65 and immune function – Harley 2011 • No adverse events • “We conclude that the protocol lengthens critically short telomeres and remodels the relative proportions of circulating leukocytes of immunocompromised subjects toward the more ‘youthful’ profile of non compromised subjects…”
  60. 60. TA-65 and CV function – Harley 2013 • TA 65 and “Patton Protocol supplement” • Human study • Harley, C et al. A Natural Product Telomerase Activator as Part of a Health Maintenance Program: Metabolic and Cardiovascular Response. Rejuvenation Research. Volume 16, Number 5, 2013
  61. 61. TA-65 and CV function – Harley 2013 • Patton Protocol including TA-65 x 12 months • No significant change in diet or exercise • Extensive lab testing • BMD, Dexascan
  62. 62. TA-65 and CV function – Harley 2013 • Fasting glucose and insulin decreased – Decreased 11 years of fasting glucose aging • Total and LDL cholesterol decreased p= .002 • Systolic/Diastolic decreased 17.8/4.2 – Decreased 30 years of aging • Homocysteine decreased significantly • BMD increased in spine
  63. 63. TA-65 and CV function – Harley 2013 • Conclusion: In addition to immune remodeling Patton Protocol-1 (TA-65 + supplements) improves markers of metabolic, bone and Cardiovascular health.
  64. 64. Fly better with TA-65 • Longer Telomeres – increased longevity and healthy aging • TA 65 vs. water treated zebra finches – increase telomere length – faster flight feather renewal- indicating improved function • Reichert, S. et al. Experimental increase in telomere length leads to faster feather regeneration. Exp Gerontol.2014 Apr;52:36-8
  65. 65. Fly better with TA-65 • Conclusions: • TA-65 treated birds had significantly longer telomeres p < .001 • TA-65 treated birds had faster feather renewal rate p<.001 • Greater tissue regeneration and organism health and longevity
  66. 66. SHORTER Telomere Associations – Cardiovascular disease Fyhrquist 2011, Saliques 2010, De Meyer 2011 • Hypertension Bhupatiraju 2012, Insel 2011 • Myocardial Infarction, CHF Brouilette 2003, Yang 2009, Wong 2011 • Atherosclerosis Nzietchueng 2011 • Abdominal aortic aneurysm Yan 2011, Atturu 2010 • With decreased telomerase Dimitroulis 2011 • Carotid Artery Disease Huzen 2011, Nawrot 2010 • Stroke (not all studies) Ding 2012, Martin-Ruiz 2006 • Oxidative Stress Babizhayev 2011, von Zglinicki 2002 Kurz 2004 Oxidized LDL-Cholesterol Nawrot 2010 • Elevated Homocysteine Richards 2008, Bull 2009
  67. 67. Telomere Length and CV • 43,725 participants • Inverse association between leucocyte telomere length and risk of coronary heart disease-independent of conventional vascular risk factors. • Haycock, P et al. Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 2014; 349
  68. 68. Short Telomeres and CAD • Reduced telomere length is associated with all-cause mortality in patients with stable CAD. (adjusted HR 2.1; 95% CI 1.3–3.3) • Lowest quartile of telomere length was also at increased risk of CHF hospitalization. (HR 2.6; CI 1.1–6.0) • Farzaneh-Far R et al. Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study. Arterioscler Thromb Vasc Biol. 28, 1379-84 (2008).
  69. 69. SHORTER Telomere Associations • Diabetes Testa 2011, Kuhlow 2010, Xu 2014, Elks 2014; • Obesity Njajow 2011, Lee 2011, (women ↓ 0.24 KBP) Valdes 2005, Garcia-Calzon ‘14; • Cancers (most but not all types) Willeit 2010/2011, Ma 2011; • Osteoporosis (most studies) Sanders 2009, Valdes 2007; • Avascular Necrosis de la Fuente 2007; • Osteoarthritis Harbo 2012/2013, Zhai 2006; • Rheumatoid arthritis (most studies) Costenbader 2011, Fujii 2009; • Hepatic cirrhosis & progression -TERC/TERT mutations Wiemann 2002, Hartmann 2011, Calado 2011
  70. 70. Cancer • 800 men, women, 45 to 84y, tracked 10 yrs • 92 cases of incidence, 44 of mortality • Shortest v. longest tertile hazard ratio − 3.1 cancer incidence − 11.1 cancer mortality Willeit P et al. Telomere length and risk of incident cancer and cancer mortality. JAMA. 7,69-75 (2010) Telomere Length by Tertiles Shortest Mid Longest Shortest Mid Longest Short Telomeres Predict Cancer Incidence & Death
  71. 71. Will TA-65 Increase risk of Cancer? • TA-65 is a proven telomerase activator (de Jesus, 2011) • Telomerase makes telomeres longer • Medical Literature does not link longer telomeres with cancer • Studies link short telomeres with cancer • Campa D et al. (pancreatic cancer) – Ornish, D et al. (prostate cancer) – Mucciardi G. et al. (bladder cancer) – Qu S et al. Duggan C et al., Carlson, L et al. (breast cancer)
  72. 72. Telomerase and Cancer • Cancer cells express telomerase • Since cancer cells already express telomerase, telomerase activation is not a concern • Cancer cells have other properties not effected by telomerase – loss of contact inhibition – failure of apoptotic pathways
  73. 73. • Campa D et al. Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev. Aug 7
  74. 74. Breast Cancer Risk and Telomere Length • Telomere shortening is associated with increased risk of breast cancer • Qu S et al Association of leukocyte telomere length with breast cancer risk: nested case-control findings from the Shanghai Women's Health Study. Am J Epidemiol. 2013 Apr 1;177(7):617-24
  75. 75. Bladder Cancer and Telomere length • Inverse relationship between Telomere length and Telomerase activity and recurrence. • Mucciardi, G et al. Telomere instability in papillary bladder urothelial carcinomas: Comparison with grading and risk of recurrence. Indian J Urol. 2014 Jul;30(3):245-51.
  76. 76. SHORTER Telomere Associations • GERD Souza 2007 • Inflammatory bowel disease Risques 2008/2011 O’Sullivan 2002 • Chronic obstructive lung disease Amsellem 2011, Savale 2009 • Alzheimer’s disease (not all studies) Movérare-Skrtic 2012, Hochstrasser 2012 (monocytes), Guan 2012, Honig 2012, Mathur 2014 • Parkinson’s disease (not all studies) Guan 2008, Hudson 2011, Eerola 2010, Maeda 2009 • Chronic kidney disease Wills 2011, Perico 2011 • Disability in elderly Risques 2010
  77. 77. • Chronic Infections: • Cytomegalovirus Effros 2011,Dowd 2013, • HIV Effros 2011, • Hepatitis C virus Hoare 2010, Hepatitis B virus Lee 2009, • Epstein-Barr Virus Effros 2011, • Human Herpes Virus-6 Huang 2013; • Ovarian Insufficiency (& Low Telomerase) Liu 2010, miscarriage; • Premature Rupture of Membranes Menon 2012; • Mitochondrial dysfunction Sahin 2011;
  78. 78. Promoting healthspan in mice using a telomerase gene therapy. Boccardi V , and Herbig U EMBO Mol Med. 2012;4:685-687
  79. 79. T cells, Immune, Telomerase • Activation of robust telomerase within T cells is critical, - low telomerase leads to a premature decline of the immune system. • T cell’s telomeres ultimately shorten to a critical length and signal senescence . • Critical role of telomerase in aging • In vitro and in vivo studies have shown that activating telomerase can not only delay aging but also reverse age tissue degeneration • Molgora B et al. Functional assessment of pharmacological telomerase activators in human T cells. Cells. 2013 Jan 14;2(1):57-66
  80. 80. TA-65 vs. HTA • TA-65 vs. HTA vs. control (herbal telomerase activator, astragalus extract) • Activation of telomerase in CD4+ and CD8+ cells (T cells) • Telomerase measured at 72 hrs and 20 days • TA-65 increased telomerase significantly in and HTA did not • Only the T cells treated with the TA-65 extract showed a statistically significant increase in proliferative activity • Molgora B et al. Functional assessment of pharmacological telomerase activators in human T cells. Cells. 2013 Jan 14;2(1):57-66
  81. 81. • CD4 T cells and CD8 T cells experienced greater degrees of proliferation in the presence of TA-65 • Critical during acute viral infection since rapid early vigorous proliferation is essential for effective immune control over the infection • TA-65 may be useful in treating both HIV disease and other clinical situations requiring enhanced T cell telomerase activity. • Molgora B et al. Functional assessment of pharmacological telomerase activators in human T cells. Cells. 2013 Jan 14;2(1):57-66
  82. 82. Bioavailability of TA-65MD 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 1 2 3 4 5 6 7 8 9 10 11 12 PlasmaTA-65activeingredientng/ml Time (hrs) Bioavailability of TA-65 active ingredient from different sources 500 units of TA-65MD (2 Caps) 50 mg of 98% pure CAG 50% pure CAG 10 mg (2 Caps) Astragalus root extract (2 caps) TA-65MD provides more than five times the bioavailability as compared to 98% pure CAG.
  83. 83. • Fyhrquist F et al. The roles of senescence and telomere shortening in cardiovascular disease. Nat Rev Cardiol. 2013 May;10(5):274-83. Senescence-associated secretory phenotype (SASP)
  84. 84. TA-65: The Only Telomerase Activation Product documented in peer reviewed medical literature • TA-65 is a small-molecule activator of telomerase purified from a common medicinal plant, astragalus membranaceous • TA-65 activated telomerase in human keratinocytes, fibroblasts, and immune cells in culture. • Harley CB. et al. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 14, 45-56 (2011).
  85. 85. Telomerase Activation with TA-65 • SUMMARY OF HUMAN FINDINGS (Harley 2011, 2013) • Short Telomeres lengthened • Senescent CD28- T Cells reduced • Naive Cytotoxic T Cells (CD95-) increased • Bone density Improved • Cardiovascular Improvements LDL-C, Systolic BP, Blood Glucose, Insulin • Metabolic Marker Improvements • Better Skin Elasticity
  86. 86. TA-65® Published Safety Conclusions • Safety findings: No adverse events occurred among the subjects taking the telomerase activator • The Telomerase Activator elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence • As of June 2013, there are now an estimated 7000 person-years of TA-65 exposure at an average BID dose of TA-65. Disease and mortality was not formally tracked, but TA Sciences reports few if any adverse events, and no cases of adverse events being attributed to TA-65 or TA-65MD by the subjects’ doctors. Harley CB et al. Rejuvenation Research (2011 & 2013) Bernardes de Jesus et al. Aging Cell. 2011,10(4):604-21
  87. 87. October 13, 2014 TA-65 “Generally Recognized As Safe”
  88. 88. Is Telomerase Activation the “Fountain of Youth”? • TA-65 works in selected biological systems • Multiple mechanisms of aging still continue but • Mechanisms are interconnected • Inflammation – Telomere dysfunction • Telomere loss – senescence – senescence associated secretory phenotype (SASP) – cytokines - inflammation • But, people who have transiently activated the telomerase enzyme, have seen statistically significant improvements in their immune system, cardiovascular and metabolic bio- markers, bone density, skin elasticity and Quality of Life Jurk D et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun. 2014 Jun 24
  89. 89. SHORTER Telomere Associations • Cataracts Sanders 2011, Pendergrass 2001 (rat); • Periodontitis (blood leukocytes) yes Masi 2011 no Takahashi 2004; • Atopic dermatitis Wu 2000; • Psoriasis Wu 2000; • Telomere mutations Calado 2009; • Inflammation O’Donovan 2011;
  90. 90. Inflammatory cytokines NF Kappa Beta Inflammatory Enzymes COX, LOX Inflammatory Cytokines Arachidonic acid Bad Eicosanoids TXA2. ASCVD PGE2, LRC4 - CA Pain PGE2, LTB4 Chronic Illness Acute phase proteins CRP, Fibrinogen EPA EPA Control insulin. Less omega 6 Less Diet Arachadonic Stress Infection Depression High Glucose and Insulin Hormone Decline Lack of Exercise Aging High Homocysteine Trans Fats EPA Pro-oxidants Viral Infections Anti-oxidants GlutathioneAnti-Inflammatory Cytokines Adhesion molecules VCAM1, ICAM1, MCP1, MadCAM1 PGI2=prostacyclin good eicosanoids Coxibs block vioxx WellnessEPA, DHA Good Eicosanoids DHEA, Testosterone Melatonin High Glucose Nutrition Glucose and Insulin control ASCVD ASCVD ASCVD High Homocysteine B vits cancer cancer Diabetic Retinopathy Adipocytes GH GH IBD SRIF Anti-Inflam Diet ASA aging E2 P4 Resveratrol Red inhibits Unified Theory of Wellness Chronic Inflammation Is the Cause and the Effect of the Diseases of Aging Pain © Ron Rothenberg 2014 PGE2: Pain Cancer Skin aging Angiotensin II p53 CRP ResveratrolEPC’s Vitamin D TXA2 Athero- sclerosis PTH Phosphate Magnesium RANKL Immune IGF1 Catecholamines
  91. 91. Telomerase and Inflammation Telomerase Senescent Cells SASP Mitochondrial Oxidative Stress NFKB Cytokines Red inhibits TA 65
  92. 92. Anecdotal reports • Skin • Presbyopia • Energy • Aerobic capacity • Immune function • Less viral infections • Less basal cell skin cancer
  93. 93. “THE TA 65 FOR MYSELF IS GREAT. I AM NEVER WINDED WHEN I DO SPORTS (HORSE BACK RIDING, SNOW SKIING) I NEVER FEEL THE NEED TO CATCH MY BREATH. IT IS EXPENSIVE, BUT I WILL CONTINUE TO USE IT.” “ I just pop out of bed. Before, I would kind of think that it would be a minor task and think about the steps are required to launch myself out of bed.” CHI emailed question: Your observations on TA-65?
  94. 94. • “Several years ago, I started wearing tennis shoes or sandals around the house even after putting on pajamas - because my feet were just a little tender walking around on hardwood floors. Now, without even thinking about it, I realize that I do not bother to wear shoes around the house after putting on pajamas. My feet are not sensitive to hard floors any more.”
  95. 95. “ I am stronger overall. I can see markedly better muscle definition in my arms and shoulders. Tennis players may know what I mean when I say that am now able to project markedly more power on the tennis court. I am quite sensitive to this as I take a couple lessons a week and play a lot of tennis. .” “My overall sense of well being and physical confidence and strength almost seem weird at first as if I am transitioning to a different person. Definitely a little strange. Of course, it is all good.” CHI emailed question: Your observations on TA-65?
  96. 96. “Thanks for your email concerning TA 65 and one thing I have noticed is that I’m not getting as many sinus infections as I have in the past which is huge. My Lymphedema seems to be improving and that could also be because of the supplements I’m taking along with a healthy diet including more protein.” “For me, it seems like there is greater sense of energy, AND a sense of dietary control. I have watched my morning fasting glucose fall steadily since taking TA-65. Is it TA-65, finally getting control of exercise and food, the workouts, or the Placebo effect? Who knows? I can only say that at 70 I continue to come in 1st, 2nd or 3rd in my running….and I do not train.. Does it cost too much? Of course?” AB, physician and researcher
  97. 97. “ I believe the TA65 gives me more energy and sometimes I only take one because it is so expensive.” “In the past, my right leg was not as strong as my left in going up the stairs to my porch, especially if I was carrying groceries or whatever and I would have to kind of plan the step. Now I no longer even think about it because the issue has disappeared. “ “I notice it will interfere with my sleep if I take it at night so I take one in the morning and one mid afternoon.. In conclusion I would say it gives me more energy.”
  98. 98. • “I was getting basal cell skin cancers removed every year for the past 5 or 6 years but have not had any found since I started TA-65” • “People have commented on how good my skin looks” • “My swimming speed has improved in short triathlons” • “Memory seems better with no other changes in program other than adding TA-65”
  99. 99. Why use TA-65? • In preventive/regenerative medicine we want to optimize health and fitness for our patients and ourselves • We want to use multiple modalities: Lifestyle, neutraceuticals, hormone optimization. • Telomere optimization through TA-65 is a powerful addition of another approach to health and fitness. • We have adequate data that TA-65 works to increase telomerase and lengthen telomeres and that it is safe. • We have adequate data that TA-65 improves immune function in T cells • Telomerase also protects us against inflammation, protects mitochondria and is necessary for optimal brain function
  100. 100. • We could wait 20 years for a prospective double blind controlled study but…. • We could use the information we have now to prevent the constant erosion of our telomeres, our DNA and our lives.
  101. 101. Helpful Tools • Telomere length measurement options – Plasma: LifeLength, Repeat Diagnostic, SpectraCell • Marketing Materials from T.A. Sciences® – Video Loop, Patient & Doctor Brochures & Media Articles • Clinical Study Results – Past & Future
  102. 102. How are the results reported? The Patient Telomere Score is calculated based on the patient’s average telomere length in peripheral whole blood cells. This average is then compared to telomere lengths from a population sample in the same age range as the patient to determine the patient’s percentile score. SpectraCell's Telomere Test analyzes: Lysis of Cells DNA Extraction Amplification Helpful links: http://www.spectracell.com/clinicians/products/te lomere-testing/ REPEAT DIAGNOSTICS TELOMERE LENGTH ANALYSIS How are the results reported? (2 Ways) -The 2-Panel assay provides measurements of telomere length for total lymphocyte and granulocyte populations. - The 6-Panel assay, telomere lengths are measured for lymphocytes and granulocytes as well as B-cells, naïve and memory T-cells and NK cells. Sample report info: http://repeatdiagnostics.com/testinfo.html Procedure: Telomere length analysis utilizing multicolor flow- FISH can be performed on subsets of human leukocytes from peripheral blood collected from individuals. Helpful links: http://repeatdiagnostics.com/index.html How are the results reported? • Mean telomere length • • Percentage of short telomeres • Procedure: HT Q-FISH, same as Q-FISH (determination of telomere length on chromosomes from blood samples by hybridization of specific probes using fluorescent microscopy) with high throughput, multiple simultaneous samples. Helpful links: http://www.lifelength.com/index-eng.html
  103. 103. Additional Materials from TA Sciences • Waiting Room Video • Media Articles • Patient and Physician Brochures – www.tasciences.com/brochure • Websites – www.tasciences.com – www.telomerescience.com
  104. 104. Thank you for attending!

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