TA 65 - Telomeres and Telomerase - Los Angeles 2015

Telomeres and Telomerase Activation

Workshop

Los Angeles 2015

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

Ron Rothenberg MD Medical Director

Encinitas, California

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

• 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®

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).

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

Cycloastragenol

Activates hTERT gene

Hayflick Limit

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Hayflick L et al. The serial cultivation of human diploid cell strains. Exp Cell Res. (1961).25(3):585–621.

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

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

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).

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.

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)

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.

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

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.

Without the protection from telomeres, our cells age and

eventually die and are susceptible to mutations, and turn on inflammation (SASP)

Telomeres

Same Genes, Why the Difference?

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

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.

SASP

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.

.

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;

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;

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

• 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

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

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)

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

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

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.

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.

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.

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.

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.

Depression

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

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.

• 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

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.

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.

• 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

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

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

Telomerase E Reverse Transciptase Telomerase E RNA Component

T T A G G G

Ready November

Afternoon

A A U C C C

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

Telomere RN

Reproductive Cells Produce Telomerase

The Gene is Repressed in All Other Cells

TA-65® Removes the Repressor

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.

• 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.

Telomerase Extends Cell Life Span and Overcomes the Hayflick Limit

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hTERT -

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Slide courtesy of Woody Wright, Ph.D.

Telomerase reverse transcriptase

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

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.

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

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.

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

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…”

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


• Patton Protocol including TA-65 x 12 months

• No significant change in diet or exercise

• Extensive lab testing • BMD, Dexascan


• 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


• Conclusion: In addition to immune remodeling Patton Protocol-1 (TA-65 + supplements) improves markers of metabolic, bone and Cardiovascular health.

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

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

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

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

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).


• 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

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

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)

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

• Campa D et al. Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev. Aug 7

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

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.


• 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

• 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;

Promoting healthspan in mice using a telomerase gene therapy.

Boccardi V , and Herbig U EMBO Mol Med. 2012;4:685-687

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

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


• 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.


Bioavailability of TA-65MD

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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.

• 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)

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).

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

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

October 13, 2014 TA-65 “Generally Recognized As Safe”

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


• 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;

Inflammatorycytokines

NF Kappa Beta

Inflammatory EnzymesCOX, LOX

InflammatoryCytokines

Arachidonicacid

Bad EicosanoidsTXA2. ASCVD

PGE2, LRC4 - CAPain PGE2, LTB4

Chronic Illness

Acute phaseproteins

CRP, Fibrinogen

EPA

EPA

Control insulin.Less omega 6

Less DietArachadonic

StressInfection

DepressionHigh Glucose and Insulin

Hormone DeclineLack of Exercise

AgingHigh Homocysteine

Trans Fats

EPA

Pro-oxidantsViral Infections

Anti-oxidantsGlutathioneAnti-Inflammatory

Cytokines

Adhesionmolecules

VCAM1, ICAM1,MCP1, MadCAM1

PGI2=prostacyclingood eicosanoids

Coxibs blockvioxx

WellnessEPA, DHAGood

Eicosanoids

DHEA,Testosterone

Melatonin

HighGlucose

NutritionGlucose and Insulin

control

ASCVD

ASCVD

ASCVD

HighHomocysteine

B vits

cancer

cancer

DiabeticRetinopathy

Adipocytes

GH

GH

IBD

SRIFAnti-Inflam

Diet

ASA

aging

E2P4

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

Telomerase and Inflammation

Telomerase Senescent

Cells SASP

Mitochondrial Oxidative Stress

NFKB Cytokines

Red inhibits

TA 65

Anecdotal reports • Skin • Presbyopia • Energy • Aerobic capacity • Immune function

• Less viral infections • Less basal cell skin cancer

“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?

• “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.”

“ 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?

“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

“ 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.”

• “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”

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

• 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.

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

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/telomere-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

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

http://www.tasciences.com/brochure

http://www.tasciences.com/

http://www.telomerescience.com/

Thank you for attending!

Health & Medicine

TA 65 - Telomeres and Telomerase - Los Angeles 2015