clinical use of telomere measurement in preventive and personalized medicine dr. dave woynarowski...

Clinical use of telomere measurement in preventive and personalized medicine Dave Woynarowski, M.D.

22nd Annual World Congress on Anti-Aging

May 2014 – Orlando, Florida

Clinical use of telomere measurement in preventive and personalized medicine – Dr. Dave Woynarowski

The following potential conflict of interest relationships are germane to my presentation.

• Equipment: none

• Speakers Bureau: none

• Stock Shareholder: none

• Grant/Research Support: none

• Consultant: Life Length*

• Status of FDA devices used for the material being presented

• Enter Device Name or state NA/Non-Clinical

• Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation

• Enter Device or Drug Name or state NA/Non-Clinical

What is all this fuss about Telomeres and where did it come from?

• Nobel Laureates- telomeres and telomerase

• Pioneers in the field - discovery of the human telomerase gene (Htert) Dr. Bill Andrews at Geron

• Discovery of telomerase activating natural substances Cal Harley at Geron

• Prediction of the whole thing in 1997 by Mike Fossel in the book Reversing Human Aging

• Confluence of information - The Immortality Edge 2010

Nobel Laureates in Medicine

Elizabeth H. Blackburn

Congratulations to the pioneers in Telomere Biology for their 2009 Award!

Jack W. Szostak Carol W. Greider

A Thorn among 2 Roses!

2010 - Predictions came true!

Bill Andrews, Ph.D., CEO at Sierra Sciences

Maria Blasco, Ph.D., Director of Spanish National Cancer Research Center, Madrid, Spain

So what is a telomere and why is it important?

• Correlated with longevity

• Correlated with morbidity

• Correlated with specific “Diseases of Aging”

• A major cause of the Diseases of Aging!

• Potential for predictive value

• Potential for intervention

• A lie detector for interventions!!!!

• Applications for drug testing, supplement testing

• Potential to identify at risk individuals who otherwise might be missed (HT-QFISH)

And what do they look like?

Most commonly seen graphic representation

Functions of the telomere

1. Protect the chromosome and genes from loss of valuable genetic material

2. Protect the chromosome from recombination certain mutations and other aberrations

3. Signal the end of the cells life (via apoptosis, etc.) or replicative senescence

4. Confer longevity to certain cells

Protect the chromosome and genes from loss of valuable genetic material

• The telomere segments were original thought to be junk DNA.

• The end replication problem obligates the loss of DNA because RNA primers are used as templates by at the ends of the replication process. When those primers and their attendant fragments are removed the chromosome is shorter.

• This happens EVERY TIME the cell replicates and leads to the loss of DNA Since the DNA of the telomere does not contain “genes” it can be sacrificed.

• Average base pair (bp) loss is 30 to 250 bp per year and varies from cell line to cell line

Cellular Fate and Telomerase Activation

The Hayflick Limit

Patterns of Gene Expression

The genes stay the same

The pattern alters

There are numerous illnesses associated with aging including but not limited to:

• WBC and tissue telomere length is shortened in:

• Cancer’s of most types – JAMA Dec. 2010 – Typical AMI – CHF* – COPD – Diabetes – Arthritis – Alzheimer’s – Obesity and high stress situations

• Progeriod syndromes with Werner’s syndrome the prototypical telomere dysfunction/shortening results in premature aging phenotype and increased susceptibility to cancer. Sub types of Pulmonary Fibrosis and Aplastic Anemia

Short telomeres and age-related diseases

WEAK IMMUNITY / ASTHMA / ALLERGIES

Senescence & Apoptosis

CANCER

WRINKLES, ARTHRITIS,

OSTEOPOROSIS

REPR

ODUC

TIVE

OR

GAN

S

INFERTILITY, MENOPAUSE

DIABETES CARDIOVASCULAR

DISEASE, HYPERTENSION &

ATHEROSCLEROSIS

DNA Damage

Senescence & Apoptosis

BRAIN

CNS (CENTRAL NERVOUS SYSTEM) DISEASES ALZHEIMER’S, PARKINSONS, DEMENTIA

RETINA

MACULAR DEGENERATION

DISEASE LEVEL

ORGAN LEVEL

CELLULAR LEVEL

STEM CELLS

DNA Damage

Source: Life Length and Recharge Biomedical Clinic

SHORT TELOMERES

Longevity Studies

• Bodnar, Shay et al. Fibroblasts with telomerase + promoter= functional immortality

• Blasco AAV- virus x 1 injection, 25% extension in middle aged mice 13% extension in old mice

• DePinho et. al.- tamoxifen trigger “reversed the phenotype of aging”

• Gil Aztmon- Increased longevity associated with mutated telomerase

0.25

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Causal relationship between telomere length and aging (in vivo)

Source: Jaskelioff et al., Nature, 2011 (edited)

Testes Spleen Intestinal crypts Vehicle 4-OHT

Terc-/- mice bearing knocked-in ER-Telomerase rejuvenate upon telomerase reactivation with 4-hydroxytamoxifen

Vehicle 4-OHT Vehicle 4-OHT a b c

G0

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d e f

G0 G4 G0 G4

*** *** ** * *** ***

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100

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Vehicle 4-OHT

Vehicle 4-OHT

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Longevity Tied to Genes that Preserve Tips of Chromosomes

• “Telomeres are one piece of the puzzle that accounts for why some people can live so long," says Gil Atzmon, Ph.D., Assistant Professor of Medicine and of Genetics at Einstein, Genetic Core Leader for The Longevity Project at Einstein's Institute for Aging Research, and a lead author of the paper. "Our research was meant to answer two questions: Do people who live long lives tend to have long telomeres? And if so, could variations in their genes that code for telomerase account for their long telomeres?” The answer to both questions was “yes.”

• Genetic Variation in Human Telomerase is Associated with Telomere Length in Ashkenazi Centenarians, appears in the November 9th on-line issue of the Proceedings of the National Academy of Sciences.

Human skin on

a mouse

Young Telomerized

Skin Reconstitution: Old Cells Become Young

Funk et al, Exp Cell Res, 2000

Slide courtesy of Bill Andrews

Old

But what can you do with the number?

• Is mitigation possible?

• Lifestyle

• Diet

• Exercise

• Sleep

• Stress reduction meditation

• Supplements

• Use of Telomere length to follow anti-aging programs and choices

• Drugs and therapies

Issues with measurement

• Populations sizes

• Confounding variables (twin studies and genetically similar populations)

• Test variability and accuracy- the subject of the rest of this talk!

• Tissue vs. PMC’s

• Stem cell aging versus circulating cells

• Telomapping - HT Q-FISH (TAT)

Source: Daniali et al., Nat.Commun., 2013

Telomeres shorten at equivalent rates in somatic tissues of adults

4 6 8 10 12

Leuk

ocyt

e te

lom

ere

leng

th (k

b)

Muscle telomere length (kb)

y = 0.77x + 0.45 R2 = 0.71; P<0.0001

Men Women

4 6 8 10 12 Le

ukoc

yte

telo

mer

e le

ngth

(kb)


y = 0.77x + 0.72 R2 = 0.69; P<0.0001

Men Women

4 6 8 10 12

Leuk

ocyt

e te

lom

ere

leng

th (k

b)


y = 0.79x + 1.27 R2 = 0.69; P<0.0001

Men Women

4 6 8 10 12

12

10

8

6

4

Leuk

ocyt

e te

lom

ere

leng

th (k

b)


y = 0.76x + 1.72 R2 = 0.59; P<0.0001

Men Women

4 6 8 10 12

12

10

8

6

4

Leuk

ocyt

e te

lom

ere

leng

th (k

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y = 0.82x + 0.59 R2 = 0.71; P<0.0001

Men Women

4 6 8 10 12

12

10

8

6

4

Leuk

ocyt

e te

lom

ere

leng

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y = 0.69x + 1.14 R2 = 0.51; P<0.0001

Men Women

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For commercial clinical usage there are 3 basic ways to measure

• Q-PCR- quantitative signal amplification

• FLO-FISH -cytometry

• HT Q-FISH-confocal microscopy

Q-PCR Pro’s

1. Longstanding usage (decades) and data base- familiar technology.

2. Least costly of all technologies.

3. Not labor or knowledge intensive.

4. Fast turn around.

5. Has been “gold standard” of telomere measurements in the past

Q-PCR Con’s

1. Better suited to smaller non repetitive gene sequences- telomeres are relatively large (5-10Kb)

2. Subject to errors of “DNA Quality”

3. Accuracy and Reproducibility of telomere measurements

4. Gives only Average telomere length- cannot supply median or short telomere percentages

DNA is a double helix composed by two antisense strands. The strands have a direction (5´ to 3´ given by the succesion of sugars and phospates). Never mind the details, the point is that a new DNA synthesis can only occur in the 5´ to 3´ direction as depicted in the cartoon. To amplify DNA, you need DNA polymerase, nucleotides and a short piece of DNA called a “primer” to initiate the DNA polymerization. By cycling between heating (to separate the DNA strands) and cooling (to allow the join of the DNA and primers) it is possible to duplicate the original DNA material. Theoretically at least, in every cycle you duplicate the number of molecules present in the previous one. Therefore, the amplification is exponential.

5´ 3´

5´

3´

5´

3´

5´ 3´

5´

3´

5´

3´

Original DNA molecule

Heat, strands separation. Then, cool down and primer annealing.

DNA synthesis in the presence of DNA polymerase

DNA duplication

Cycling around 30 times

Primer

Primer

How does PCR work?

How does PCR work? Below is a typical curve of amplification in a real-time PCR equipment. At the begining, and although there is amplification, the detector cannot detect any meaninful increase of DNA. However, after some cycles (10 in the example) there is an exponential increase in the amount of DNA. Later on, the reaction reaches a plateau due to the lack of reagents and saturation of the detector. So scientists compare the reaction at the region pointed by the arrow.

If you have two samples, one with more DNA target than the other, the first one will get into the exponential phase sooner. This allows the quantitative comparison of samples (look at the picture to the right).

http://www.google.es/url?sa=i&source=images&cd=&cad=rja&uact=8&docid=SpXWTIchVstMMM&tbnid=F6M0tcMtKlzLZM:&ved=0CAgQjRw4rwE&url=http://www.rpgroup.caltech.edu/courses/PBL/dna0907.htm&ei=M7s1U_PYCKPI0AXTxoHoBA&psig=AFQjCNHALiNiAJqyL6g9iepmgT0o-cG1mg&ust=1396116659219535

chromosome telomere

single copy gene

break

The whole DNA target cannot be amplified and so there is no exponential duplication of the entire sequence.

How does PCR work? Now, to correctly quantify the copy number of a certain DNA sequence (such as a telomere) you also need to quantify an internal control (which is single copy to assure the normalization).

Because the single copy gene has a unique sequence (no repetitive sequence) any damage to the sequence target inhibits PCR amplification:

TTAGGG repetitions

There is still exponential amplification! Although now you amplify two pieces instead of one. However, what matters is the total amplification not the length.

CONCLUSION: Telomere sequence amplification is more robust than the internal control sequence. That means that telomere sequences will amplify regardless of the DNA quality. However, you need a the ratio between the quantification of both telomere and control. Thus, the quantification is not reliable.

How does PCR work? In contrast, telomere sequence is highly repetitive. Therefore, even if the DNA sequence is damaged, there is always chances to still amplify full pieces of telomeres

FLO-FISH Pro’s

• Long standing use and reasonable data base size specifically for telomere use.

• Primarily designed to cater to institutions

• More costly than QPCR but less costly than HT-QFISH

• Allows differentiation between granulocytes and lymphocytes (may have some importance in viral infections)

• Reports Median Telomere Length instead of average

FLO-FISH Con’s

• Still rather costly

• Does not report short telomere data

• Accuracy and reproducibility are defined and probably better than QPCR and similar to HT-QFISH

• FACS technology is well defined and automated

HT Q-FISH Pro’s

1. Accurate reproducible scalable

2. Allows visualization of individual chromosomes

3. Defining feature: Allows determination of critically important short telomeres and of “signal free ends”

4. Expanding data base and increasing scientific usage

5. Ideal for individual clinical evaluations and repeated determinations

6. Telomapping possible

HT Q-FISH Con’s

• Expensive* and proprietary

• Logistics: Longer turn around time and live cell requirement

• Recent technology so less familiarity in scientific community

• Requires higher levels of expertise

* Expected cost reductions in the near future demand for latest technology replaces obsolete methods

Median TL % Short telomeres

Blood uptake and PBMC purification PBMC plating and Q-FISH HT confocal microscopy

Capture of individual telomere signals Data processing Data analysis

HT Q-FISH (TAT) technology overview

2 1 3

5 6 4

Advantages of HT Q-FISH histograms

> 20th Percentile < % short telomeres

Sample with high % short telomeres

Sample with low % short telomeres

As there are not many short telomeres, we need

to move toward longer telomeres to cover 20% of

the total

Sample with normal telomere length variability

Why Median Length alone misses the whole picture!

TL dispersion

Mutation in telomerase?

Sample with wide telomere length variability

TL dispersion

How to use the numbers

• Need to repeat testing at intervals no matter what technology you choose (accuracy and reproducibility will now become a huge factor for the individual)

• Patient doctor as allies in the quest for better health span and longer life span

• Review of history and physical including family history for factors that can be modified

• Again follow up!

Walking the walk - Do you?

My telomeres as of November 2013

Results report

Correlation with Flo-FISH

Q-PCR Comparisons sample 1

QPCR comparison sample #2 same time same date

New applications of telomere length as a biomarker

Genotoxic chemotherapy drugs, targeting preferentially on telomeres

(e.g. topoisomerase inhibitors, cisplatin, HU)

Targeting specifically on telomeres(e.g. RHPS4)

Genotoxic chemotherapy (e.g. anthracyclin, oxalipatin)

Source: Lu et al., Front. Med., 2013; Gramatges et al., Clin. Cancer Res., 2013

• Telomere length can be a surrogate marker of chemotherapy sensitivity and toxicity.

• If PBMC telomeres from cancer survivors who underwent chemotherapy are shorter than those from healthy normal persons, these patients may be at high risk for developing secondary cancer disorders.

• In fact, Non-Hodgkin’s Lymphoma patients have a significant risk for developing secondary malignant neoplasms such as solid tumors, melanoma, Hodgkin’s disease, and cancer of the lung, brain, kidney and bladder.

Imetelstat response time is based on telomere length

Source: (Robin Frink, John Minna)

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The question of “dilution” be careful interpreting studies, especially if the accuracy and reproducibility are suspect!

Essential References 1. Deng Y, Chan SS, Chang S. Nat Rev Cancer. 2008 Jun; 8(6):450-8. 8:450-458. 2. Harley CB.Mutat Res. 1991 Mar-Nov;256(2-6):271-82. 3. Bollmann, F. M. (2007) Cancer Treat. Rev., 33, 704-709. 4. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD.Lancet. 2005 Aug 20-

26;366(9486):662-4. 5. Du M, Prescott J, Kraft P, Han J, Giovannucci E, Hankinson SE, De Vivo I. Am J Epidemiol. 2012 Mar 1;175(5):414-22. 6. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Proc Natl Acad Sci U S A. 2004 Dec

7;101(49):17312-5. 7. Drury SS, Theall K, Gleason MM, Smyke AT, De Vivo I, Wong JY, Fox NA, Zeanah CH, Nelson CA.Mol Psychiatry. 2012

Jul;17(7):719-27. 8. Paul L.J Nutr Biochem. 2011 Oct;22(10):895-901. 9. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. JAMA. 2010 Jan 20;303(3):250-7. 10. Song Z, von Figura G, Liu Y, Kraus JM, Torrice C, Dillon P, Rudolph-Watabe M, Ju Z, Kestler HA, Sanoff H, Lenhard

Rudolph. Aging Cell. 2010 Aug;9(4):607-15 11. Vera E, Bernardes de Jesus B, Foronda M, Flores JM, Blasco MA. PLoS One.2013;8(1):e53760. 12. Shin YA, Lee JH, Song W, Jun TW. Mech Ageing Dev. 2008 May;129(5):254-60. 13. Kadi F, Ponsot E, Piehl-Aulin K, Mackey A, Kjaer M, Oskarsson E, Holm L. Med Sci Sports Exerc. 2008 Jan;40(1):82-7. 14. Smith DL Jr, Mattison JA, Desmond RA, Gardner JP, Kimura M, Roth GS, Ingram DK, Allison DB, Aviv A. J Gerontol A Biol

Sci Med Sci. 2011 Nov;66(11):1163-8. 15. Möller P, Mayer S, Mattfeldt T, Müller K, Wiegand P, Brüderlein S. Aging (Albany NY). 2009 Jul 14;1(8):733-9. 16. Canela A, Vera E, Klatt P, Blasco MA.Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5300-5.

General references

• High-throughput telomere length quantification by FISH and its application to human population studies. Canela, A., et al., Proc Natl Acad Sci, 2007. 104(13): p. 5300-5.

• Telomerase in the human organism. Collins et al. Oncogene 21(4): 564-579

• The longest telomeres: a general signature of adult stem cell compartments. Flores, I., et al., Genes Dev, 2008. 22(5): p. 654-67.

• The shortest telomere, not average telomere length is critical for cell viability and chromosome stability. Hemann et al. Cell 107(1): 67-77

• Obesity, cigarette smoking and telomere length in women. Valdes et al. Lancet 366(9486): 662-664

• Telomere Length predicts replicative capacity of human fibroblasts. Allsopp et al. Proc Natl Acad Sci 89(21) 10114-10118

• Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Blasco, M.A., et al., Cell, 1997. 91(1): p. 25-34.

• Oxidative stress shortens telomeres, von Zglinicki. Trends Biochem Sci 27(7): 339-344

• Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Wiemann et al. FASEB J 16(9): 935-942

• Cellular senescence in cancer and aging. Collado et al. Cell 130(2) 223-233

• Human diseases of telomerase dysfunction: insights into tissue aging. García et al. Nucleic Acid Res. 35(22): 7406-7416

Oncology

• A prospective study of relative telomere length and postmenopausal breast cancer risk. De Vivo et al. Cancer Epidemiol Biomarkers Prev 18(4) 1152-1156

• Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer 8(6):450-458

• Mean leukocyte telomere length and risk of incident colorectal carcinoma in women: a prospective, nested case-control study. Lee et al. Clin Chem Lab Med 48(2): 259-262

• Telomere length, cigarette smoking and bladder cancer risk in men and women. McGrath et al. Cancer Epidemiol Biomarkers Prev 16(4): 815-819

• Telomere length in prospective and retrospective cancer case-control studies. Pooley et al. Cancer Res 70 (8): 3170-3176

• Short telomere length and breast cancer risk: a study in sister sets. Shen et al. Cancer Res 67(11): 5538-5544

• Breast cancer survival is associated with telomere length in peripheral blood cells. Svenson et al. Cancer Res 68(10): 3618-3623

• Absence of a telomere maintenance mechanism as a favourable prognostic factor in patients with osteosarcoma. Ulaner et al. Cancer Res 58(18): 4168-4172

• Telomere dysfunction: a potential cancer predisposition factor. Wu, X., et al., J Natl Cancer Inst, 2003. 95(16): p. 1211-8.

Oncology (cont.)

• Mean telomere length and risk of incident colorectal carcinoma: a prospective, nested case-control approach. Zee et al. Cancer Epidemiol Biomarkers Prev 18(8): 7423-7428

• Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Rudolph KL, Millard M, Bosenberg MW, DePinho RA (2001) Nat Genet 28(2): 155-159

• Telomere length is a prognostic factor in neuroblastoma. Ohali A, Avigad S, Ash S, Goshen Y, Luria D, Feinmesser M, Zaizov R, Yaniv I (2006) Cancer 107(6): 1391-1399

• Telomerase is active in normal gastrointestinal mucosa ns not up-regulated in precancerous lesions. Bachor et al. J Cancer Res Clin Oncol 125(8-9) 453-460

• Telomerase and cancer therapeutics. Harley. Nat Rev Cancer 8(3): 167-179

• Screening for bladder cancer: a perspective. Lotan et al. World J Urol 26(1): 13-18

• Telomerase therapeutics for cancer: challenges and new directions. Shay et al. Nat Rev Drug Discov 5(7):577-584

• Expression of human telomerase subunits and correlation with telomerase activity in cervical cancer. Cancer Res 58(7): 1558-1561

Aging • Telomeres and human disease: ageing, cancer and beyond. Blasco, M.A., Nat Rev Genet, 2005. 6(8): p. 611-22.

• Telomere length, stem cells and aging. Blasco, M.A., Nat Chem Biol, 2007. 3(10): p. 640-9.

• Extension of life-span by introduction of telomerase into normal human cells. Bodnar et al. Science 279 (5349) 349-352

• Association between telomere length in blood and mortality in people aged 60 years or older. Cawthon, R.M., et al., Lancet, 2003. 361(9355): p. 393-5.

• Telomerase induction in T-Cells: a cure for aging and disease? Effros. Exp Gerontol 42(5):416-420

• Accelerated telomere shortening in response to life stress. Epel et al. Proc Natl Acad Sci 101(49):17312-17315

• The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Epel, E.S., et al., Aging 2009. 1(1): p. 81-8.

• The association between telomere length physical health, cognitive aging and mortality in non-demented older people. Harris et al. Neurosci Lett 406(3): 260-264

• The power of exercise: buffering the effect of chronic stress on telomere length. Puterman, E., et al., PLoS One. 5(5): p. e10837.

• Telomeres as biomarkers for ageing and age-related diseases.Von Zglinikci et al. Curr Mol Med 5(2):197-203

• Telomerase reverse transcriptase delays aging in cancer-resistant mice. Tomas-Loba A, Flores I, Fernandez-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borras C, Matheu A, Klatt P, Flores JM, Vina J, Serrano M, Blasco MA (2008) Cell 135(4): 609-622

• Telomeres shorten during ageing of human fibroblasts. Harley CB, Futcher AB, Greider CW (1990). Nature 345(6274): 458-460

• Telomeric Length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. Iwama et al. Hum Genet 102 (4): 397-402

• Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Vulliamy, T., et al., Nat Genet, 2004. 36(5): p. 447-9.

Infertility

• Characterization of telomerase activity in the human oocyte and preimplantation embryo. Wright et al. Mol Hum Reprod 7(10): 947-955

• Telomere length predicts embryo fragmentation after in vitro fertilization in women-toward a telomere theory of reproductive aging in women. Keefe DL, Franco S, Liu L, Trimarchi J, Cao B, Weitzen S, Agarwal S, Blasco MA (2005). Am J Obstet Gynecol 192(4): 1256-1260; discussion 1260-1251

• The telomere theory of reproductive senescence in women. Keefe DL, Marquard K, Liu L (2006) Curr Opin Obstet Gynecol 18(3): 280-285

• Telomere length in the new born. Okuda et al. Pediatr Res 52(3): 377-381

Cardiology • White cell telomere length and risk of premature myocardial infarction. Brouilette, S., et al., Arterioscler Thromb

Vasc Biol, 2003. 23(5): p. 842-6.

• Telomere length inversely correlates with pulse pressure and is highly familiar. Jeanclos et al. Hypertension 36(2): 195-200

• Telomere shortening in human coronary artery diseases. Ogami et al. Arterioscler Thromb Vasc Boil 24(3):546-550

• Telomere shortening in atherosclerosis. Samani, N.J., et al., Lancet, 2001.358(9280): p. 472-3.

• Telomere length as an indicator of biological aging: the gender effect and relations with pulse pressure and pulse wave velocity. Benetos et al. Hypertension 37 (2 part 2): 381-385

Immunology • Genetic Manipulation of telomerase in HIV-specific CD8+ T Cells: enhanced antiviral functions accompany the

increased proliferative potential and telomere length stabilization. Dagarag et al. J Inmmunol 173(10): 6303-6311

• Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. Fauce et al. J Immunol 181(10): 7400-7406

• Natural Product Telomerase Activator As Part of a Health Maintenance Program. Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM A Rejuvenation Res

• Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes.Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST, Ng HL, Kitchen CM, Yang OO, Harley CB, Effros RB (2008) J Immunol 181(10): 7400-7406 stroke mortality, dementia and cognitive decline. Ann Neurol 60(2): 174-180

Neurology • Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Honig et al. Ann

Neurol 60(2):181-187

• Telomere shortening in T cells correlates with Alzheimer´s disease status. Panossian et al. Neurobiol Aging 24(1):77-84

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clinical use of telomere measurement in preventive and personalized medicine dr. dave woynarowski...

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