This document provides an overview of a workshop on telomeres and telomerase activation held in Los Angeles in 2015. It discusses telomere biology, factors that impact telomere length, lifestyle interventions and supplements that may help maintain telomere length, and clinical evidence on the effects of telomerase activation. Specifically, it summarizes evidence that telomerase activation through supplements like TA-65 has been shown to reverse cellular aging in mice and improve immune function, metabolic health, and psychological outcomes in human studies. It also discusses how stress, lifestyle factors, and diseases like depression are associated with shorter telomere length.
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
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Status of off-label use of devices, drugs or other materials that constitute the subject of this
presentation
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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. • 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. 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. 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
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.
12. 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
13. 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).
14. 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.
15. 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)
16. 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.
17. 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
18. 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.
19. Without the protection from
telomeres, our cells age and
eventually die and are
susceptible to mutations, and
turn on inflammation (SASP)
Telomeres
21. 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
22. 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.
24. 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.
.
27. 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
28. • 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
29. 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
30. 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)
31. 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
32. 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
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
39. 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
40. 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.
41. • 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
42. 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.
43. 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.
44. • 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
45. 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
46. 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
48. 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
52. 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.
53. • 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.
54. 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
55. 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
56. 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.
57. 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
58. 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.
59.
60. 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
61. 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…”
62. 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
63. 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
64. 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
65. 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.
66. 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
67. 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
68. 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
69. 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
70. 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).
71. 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
72. 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
73. 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)
74. 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
75. • Campa D et al. Leukocyte
telomere length in relation to
pancreatic cancer risk: a prospective
study. Cancer Epidemiol Biomarkers Prev.
Aug 7
76. 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
77. 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.
79. • 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;
80. Promoting healthspan in mice using a telomerase
gene therapy.
Boccardi V , and Herbig U EMBO Mol
Med. 2012;4:685-687
81. 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
82. 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
83. • 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
84. 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.
85. • 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)
86. 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).
87. 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
88. 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
90. 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
94. Anecdotal reports
• Skin
• Presbyopia
• Energy
• Aerobic capacity
• Immune function
• Less viral infections
• Less basal cell skin cancer
95. “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?
96. • “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.”
97. “ 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?
98. “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
99. “ 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.”
100. • “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”
101. 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
102. • 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.
103. 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
104. 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
105. 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
