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Telomeros, envejecimiento y prevencion Dr.A.Fernandez-Cruz - Barcelona - april 2014

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La medicina de las 4 Ps
•PREDICTIVA
•PREVENTIVA
•PERSONALIZADA
•PARTICIPATORIA

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Telomeros, envejecimiento y prevencion Dr.A.Fernandez-Cruz - Barcelona - april 2014

  1. 1. Telomerós, Envejecimiento y Prevención Dr. Arturo Fernández- Cruz
  2. 2. Health demographic change and wellbeing
  3. 3. The economic crisis
  4. 4. Incidencia de IAM en población de 25 a 74 años por sexos
  5. 5. 1200 millones OMS
  6. 6. PREVEND 8074 JIM Nov 2013
  7. 7. La medicina de las 4 Ps •PREDICTIVA •PREVENTIVA •PERSONALIZADA •PARTICIPATORIA La detección temprana 90% de supervivencia La detección tardía 10% de supervivencia NEJM Modelo matemático 1980-2000 Reducción de los FRs Nuevos tratamientos Solo el 7% debido CABG o STENTs NEJM enero 2013
  8. 8. Progress in science depends on new techniques, new discoveries, and new ideas probably in that order Sydney Brenner
  9. 9. Tecnologías que crecen exponencialmente Test genéticos a bajo coste Test de medición de Telomeros Computadores-Bio-informática, Historia y archivos electrónicos Técnicas de imagen TAC, RM (Colonoscopia virtual), “IPad” Conexión por Internet, medicina on-line (visitas virtuales) Redes Sociales Mi tecnología favorita es el iPhone “digital medicine” NUEVAS TECNOLOGÍAS
  10. 10. “senescent” cells healthy cell 50-70 divisions healthy cells are MORTAL cancer cell cancer cells are IMMORTAL unlimited divisions Henrietta Lacks
  11. 11. telomeretelomere Chromosome (parent cell) Telomeres are lost everytime that a cell divides “the end-replication problem” DNA is lost from the ends Chromosome (daughter cell #1) Chromosome (daughter cell #2)
  12. 12. An embryonary gene known as telomerase is able to elongate telomeres to compensate excessive telomere loss during embryo development. This gene, telomerase, is silenced after birth … however … Cancer cells manage to reactivate telomerase, thus escaping the mortal fate of adult cells and becoming immortal. TTAGGG TTAGGG AATCCC AATCCC genes telomeres TTAGGG TTAGGG AATCCC AATCCC TTAGGG TTAGGG AATCCC AATCCC cell death cell senescence aging TTAGGG TTAGGG AATCCC AATCCC genes telomeres cancer TTAGGG TTAGGG AATCCC AATCCC TTAGGG TTAGGG AATCCC AATCCC TTAGGG TTAGGG AATCCC AATCCC TTAGGG TTAGGG AATCCC AATCCC TTAGGG TTAGGG AATCCC AATCCC
  13. 13. Telomere length as a biomarker of biological age & health status Canela et al., PNAS (2007) Telomere length predicts age & cognitive impairmentTelomere length decreases with age HTQFISH
  14. 14. cancer (> 95% of cancers activate telomerase) high Telomerelength disease health age Telomeres, telomerase and aging Human pathologies due to telomerase defects dysqueratosis congenita (DKC1, Terc) aplastic anemia (Terc, Tert) idiophatic pulmonary fibrosis (Terc, Tert) loss of the regenerative capacity of the skin lungs, bone marrow… Telomere length=Biomarker of aging? Lower percentiles of telomere length= higher risk of diseases (cardiovascular, neurodegenerative, death by infections)
  15. 15. Telomere length measurements for individuals Life Length´s partnership with:
  16. 16. Page 20© 2014 Life Length. All rights reserved. Reproduction of this document or any portion thereof without prior written consent is prohibited. Telomere Measurements for individuals Your median telomere length is estimated to be normal compared to Life Length´s database population. 1. Your telomere length Median Telomere Length: 9.2 Kb < 7.8 78 – 8.5 8.2 – 13.7 13.7 – 15.3 > 15.3 VERY SHORT SHORT NORMAL LONG VERY LONG Median Telomere Length (MTL) = 9.2 ± 0.3 Kb You: 9.2 Kb The adjacent graph shows a comparative analysis of the median telomere length in your sample compared with the control database. Each line represents a specific percentage of our database. For example, falling in the 75th percentile means that 25% of people of your age have a longer median telomere length than you. It is therefore best if your sample falls into one of the higher bands. 2. Median telomere length – Comparison by age band and percentiles 20 30 40 50 60 70 80 90 Chronological age (years) Mediantelomere length(Kb) 16 15 14 13 12 11 9 8 95 90 75 50 25 10 05 % 3. Your estimated biological age Estimated Biological Age: 55 years old Chronological Age: 50 years old Value ± SD Biological age based on chronological age and telomere length Comparison of MTL per age group Comparison of MTL against entire database (to find severe outliers) Extract from actual evaluation
  17. 17. 0 50 100 150 200 250 300 350 400 450 500 0 5 10 15 20 25 30 35 40 0 50 100 150 200 250 300 350 400 450 500 0 5 10 15 20 25 30 35 40 0 50 100 150 200 250 300 350 400 450 500 0 5 10 15 20 25 30 35 40 0 100 200 300 400 500 600 700 800 0 5 10 15 20 25 30 35 40 0 50 100 150 200 250 300 0 5 10 15 20 25 30 35 40 telomerelength,kb telomere length, kb samples Subject 49- Male 02/02/78 healthy Subject 50- Male 22/09/77 medular aplasia, TERC mut Subject 51- Male 17/05/78 healthy Subject 52- Male 06/06/78 healthy frequency telomere length, kb telomere length, kb telomere length, kb telomere length, kb frequencyfrequencyfrequencyfrequency Subject 49 9.49 ± 2.81 kb n=1951 Subject 50 5.7 ± 2.01 kb n=1685 Subject 51 10.46 ± 3.28 kb n=2796 Subject 52 10.06 ± 3.34 kb n=4811 L5178Y-S 10.06 ± 3.34 kb n=1408 0 5 10 15 20 subject 49 subject 50 subject 51 subject 52 L5178Y-S %telomeres<8kb samples n=1951 n=1685 n=2796 n=4811 n=1408 *** 0 10 20 30 40 50 60 70 80 90 100 subject 49 subject 50 subject 51 subject 52 L5178Y-S *** Telomere length as a diagnosis tool Hospital Vall d´Hebrón Canela et al., unpublished
  18. 18. 0 10 20 30 40 50 60 70 0 5 10 15 20 Meantelomerelength(Kb) Age (years) 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 %shorttelomeres(<3kb) Age (years) Telomere length measurements for individuals % short telomeres detect more differences between individuals than average length % short telomeres show higher dispersion as we age % short telomeres are likely to reflect “way of living” (environment) or biological age
  19. 19. Bioactive food components can influence genetic and epigenetic events associated with a host of disease processes Trujillo E et al. J Am Diet Assoc 2006;106:403-413
  20. 20. Trujillo E et al. J Am Diet Assoc 2006;106:403-413 Dietary factors and the regulation of DNA methylation “CpG sites” 28 millones S Horvad clock-watcher Nature April 2014 Nature 508,22:2014 Methylation status 353 CpG sites algorithm
  21. 21. Genetic tests: genes as risk factors for disease INHERITED Telomere tests: indication of the degree of aging INHERITED ENVIRONMENT MORE POWERFUL PREDICTIONS OF RISKS AND TIME OF ONSET # aging is the highest risk factor for all diseases # telomere length integrates both inheritance & environmental factors EPIGENETICS DEVELOPMENT OF NEW TREATMENTS TO PREVENT DISEASE A NEW ERA in medicine?: Personalized & preventive medicine
  22. 22. Virus Inflamación crónica Factores genéticos Envejecimiento celular – Estrés oxidativo: Integridad del telómero Patogenia del cáncer Inmortalización celular Fallo en los mecanismos de control
  23. 23. Telomere length and Cancer The Association of Telomeres length and Cancer: a Meta-analysis S A Savage et al Cancer Epidemiology Biomarkers Prev 20:1238,2011 Short Telomeres are associated with excess Cancer Incidence and mortality A L Kamaroff JAMA 2010 july 7 P Willet JAMA 304:69, 2010 Fifteen year follow up of association between Telomere length and incidence Cancer and Cancer mortality JAMA 306:42,2011
  24. 24. Breast cancer: Familial breast cancer BRCA1/BRCA2 BRCA1 Age (years) RelativeTelomerelength BRCA2 Age (years) RelativeTelomerelength -0.5 0 0.5 1 1.5 2 2.5 3 3.5 10 20 30 40 50 60 70 80 BRCAX Age (years) RelativeTelomerelength -0.5 0 0.5 1 1.5 2 2.5 3 3.5 10 20 30 40 50 60 70 80 SporadicBC Age (years) RelativeTelomerelength -0.5 0 0.5 1 1.5 2 2.5 3 3.5 10 20 30 40 50 60 70 80 -0.5 0 0.5 1 1.5 2 2.5 3 3.5 10 20 30 40 50 60 70 80 A C B D More powerfull tools to predict risk factors and develop new treatments Javier Benitez (CNIO)
  25. 25. MEDICINA PREDICTIVA • BCR Gail mama BCRAs • BRACAPRO mama ovario • BOADICEA mama, ovario, prostata, melanoma • PREMM colon • PULMON Cancer genograma Diabetes FINDRISK SCORE Cribados Telomeros Genes
  26. 26. Can telomerase delay aging pathologies?
  27. 27. Telomerase as an anti-cancer target (Imetelstat) Phase II Clinical trials (breast, lung, prostate etc)
  28. 28. ratones K5-mTert No telomerase Less aging Less cancer More cancer Premature aging La telomerasa se expresa específicamente en células madre telomerase Telomere length Tg telomerase (epithelia) Gonzalez-Suarez et al., Oncogene (2004) Super p53 Super p16 Super p19ARF Cancer suppressors + SUPER-M
  29. 29. Linear regression: WT: Slope=-7.03 ± 1.24 kb/year R2=0.31 (Quadratic: R2=0.34) p<0.0001 TgTERT: Slope=-7.05 ± 1.60 kb/year R2=0.22 (Quadratic: R2=0.30) p<0.0001 0.0 0.5 1.0 1.5 2.0 2.5 0 10 20 30 40 50 60 70 80 Age (years) Meantelomerelength(kb) Vera et al., Cell Reports, 2012 Mouse telomeres shorten 100-times faster than human telomeres Humans: 70 bps/year Mice: 7 Kb/year Increaseinthe%of shorttelomeres(permonth) The increase in the % of short telomeres predicts individual mouse longevity 0 50 100 150 200 -0.5 0.0 0.5 1.0 1.5 Lifespan (weeks) WT: Slope=-0.005022 ± 0.002550 R2=0.2 p=0.06 TgTERT: Slope=-0.01267 ± 0.005604 R2=0.3 p=0.04 WT TgTERT WT TgTERT
  30. 30. telomerase-deficient wild-type Blasco et al., Science (1995) Blasco et al., Cell (1997) Lee, Blasco, et al., Nature (1998) González-Suarez et al., Nat Genet (2000) González-Suarez et al., EMBO J. (2001) Flores et al., Science (2005) Telomerase-deficient mice (Terc-/-): decreased regenerative capacity due to stem cell dysfunction less cancer Super-telomerase mice (K5-Tert): better tissue fitness slightly more cancer The role of telomerase in chromosome stability, cancer & aging
  31. 31. Tomás-Loba et al, Cell (2008) SUPERWild-type Defeating aging with increased telomerase + tumor suppression
  32. 32. Increased “health span” & longevity in SUPER mice Cancer-free survivalOverall survival 0 20 40 60 80 100 0 60 80 100 120 140 160 180 Sp53 (n=25) SUPER (p=0.003; n=6) survival(%) age (weeks) +50% normales (n=25) 0 20 40 60 80 100 0 60 80 100 120 140 160 180 Sp53 (n=49) SUPER (p<0.001; n=12) survival(%) age (weeks) +40% normal (n=49) 0 20 40 60 n=25 n=6 p=0.003 0 20 40 60 n=49 n=12 p<0.001 normal SUPER Survivalat3years(%) normal SUPER Survivalat3years(%) Tomás-Loba et al., Cell (2008) Healthspan
  33. 33. Improved neuromuscular fitness 25000 30000 35000 40000 45000 glucosetolerance(AUC) ** 30-76 weeks Glucosetolerance(AUC) n=5 n=3 wildtype SUPER p=0.02 Improved glucose tolerance 0 25 50 75 100 125 Successrate(%) n=11 n=9 wildtype p=0.02 n=8 n=10 SUPER p=1 young (5-20 weeks) old (116-160 weeks) Improved health late in life in SUPER mice Tomás-Loba et al., Cell (2008)
  34. 34. SUPER-Mwildtype young (5-12 weeks) old (123-165 weeks) wildtype Subcutaneousfatlayer(m) 0 20 40 60 80 100 120 n=19 n=24 SUPER-M n=11 n=61 Less skin aging in SUPER-M mice Subcutaneous fat old (123-165 weeks) Tomás et al., Cell (2008)
  35. 35. Telomere length and ATHEROSCLEROSIS Critical values of replicative senescence the “hayflic limit” vascular age Circ Res 2006 Family History of CHD Heart 2008 European Atherosclerosis Reseach Study II J Mol Med July 2008 White cell telomere lenght and risk of premature AMI Atherosclerosis Thromb Vasc Biol 2003 Lancet 2001 the WOSCOP study Lancet 2007 Tromboembolism RY Zee… P Ridker Int J of Clinical Chemistry 2009; 406:148
  36. 36. Telomere length and preclinical ATHEROSCLEROSIS Framingham Heart Study Arterioesclerosis Thromb Vac Biol May 2011 ASKLEPIOS STUDY European Heart Journal 2009 Obese man Heart 2008 Carotid Atherosclerosis Hypertension 2004:43;182 Coronary Artery Disease Arterioesclerosis Thromb Vasc Biol 2004:24, 546 Calcium Score Atherosclerosis 2009 Vascular thrombosis RY Zee ..P Ridker 2013
  37. 37. Leukocyte and plaque telomere length in cases and controls. Huzen J et al. Arterioscler Thromb Vasc Biol. 2011;31:1219-1225 Copyright © American Heart Association, Inc. All rights reserved.
  38. 38. X LAD ligation Aging is not a disease…but there are many aging-associated diseases preclinical model for cardiovascular disease Normal heart Failing heart Failing heartNormal heart PET – FDG uptake Histopathology AAV9-TERT AAV9-empty
  39. 39. AAV9-TERT treatment protects 20% of the mice from death by infact Bruno Bernardes de Jesus Christian Bär 0 10 20 30 40 40 60 80 100 AAV9-empty AAV9-mTERT: 2x1012vg/m No virus Percentsurvival Heartinfarct Days after myocardial infarction n=35 n=37 n=21 p=0,07 74% 57% FVB/N 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 Longitudinalthickness (mm) Transversalthickness (mm) 1 week p=0.02 p=0.01 p=0.5 n=4 n=13 n=5 n=4 n=13 n=5 p=0.03 p=0.01 p=0.7 1 week AAV9-empty AAV9-mTERT: 2x1012vg/m Sham (no myocardial infarction) Echocardiography
  40. 40. Myocardial Infaction AAV9-empty SHAM AAV9-mTERT: 2x1012vg/m An AAV9-TERT treatment reduces scar formation upon infaction Bruno Bernardes de Jesus Christian Bär Masson trichrome Scar size/LV size, % Numberofmice 0 5 10 15 20 Mild Severe Extremely severe AAV9- eGFP AAV9- mTERT 0 10 20 30 40 %ofarea AAV9- eGFP AAV9- mTERT n=10 n=7 p=0.14 MI AAV9-empty AAV9-mTERT: 2x1012vg/m
  41. 41. 0 50 100 150 200 meanspotintensity/ nucleus(a.u.) mean 52.33 a.u. (1850 nuclei) mean 64.98 a.u. (1968 nuclei) 124% of AAV9 empty p<0.0001 0 50 100 150 meanspotintensity/ nucleus(a.u.) mean 40.08 a.u. (2455 nuclei) mean 44.85 a.u. (3096 nuclei) 112% of AAV9 empty p<0.0001 AAV9-empty (n=4) AAV9-mTERT (n=4) (2x1012vg/m) cardiomyocytes fibroblasts (infarct area) AAV9-TERT treated mice show longer telomeres in heart after infaction Bruno Bernardes de Jesus Christian Bär
  42. 42. Telomere length and Diabetes Association of Telomere shortening with IGT and DM2 macroangiopathy Atherosclerosis Nov 2007 Accelerated senescence in the kidneys of patients with DM2 nephropathy American J of Physiology 2008 DM2 Microalbuminuria Diabetes Care 2007;30:2909 Diabetologia 2006 Leukocyte Telomere shortening in elderly type 2 DM with previous AMI Atherosclñerosis 2009 Association of Telomere length with type 2 DM oxidative stress and UCP2 gene variation Atherosclerosis 2010 DNA damage. Diabetes Care 2006
  43. 43. Challenge: Individualized Risk Assessment in Low- and Intermediate Risk Individuals Algorithms Neural Network MSCT, MRT, PET Telomeres And Genes of clinical relevance Lp(a) PLA2 CRP, BNP Apo A-, HDL 2b ApoB Phytosterols Metabolic syndrome Other
  44. 44. CONFIDENTIAL Rupture-Prone Plaques may not be Severely Stenosed but are Inflamed with Thin Fibrous Caps Early Plaque with Lipid Pool Thick Cap with Small Necrotic Lipid Core “Stable Plaque” Thin Cap “Rupture-Prone” Plaque Ruptured Plaque with Thrombus in Lumen Adapted from Kolodgie F, et al. Arterioscler Thromb Vasc Biol 2006.
  45. 45. CARE PATHWAY FOR CARDIOVASCULAR RISK CLINIC CardiologyREFERRAL General Practice 0 5 10 15 20 25 30 Ave Patient 10yrCVDrisk Genetic CRF CLINIC VISIT Retest Genetics Telomeros Results RISK SCORE Clinical Chem T-Chol/HDL/TG Lp(a)? etc? Results RISK SCORE + BMI/BP/Smoke Carotid Coronaries ACTION PLAN Blood Pressure Lowering Lipid Lowering Smoking Cessation Weight Loss GPs -Specialist Referral Cardiology Referral Patient Appointment Saliva sample request + Informed consent
  46. 46. Monitoring other effects than LDL: where do we stand ?
  47. 47. Statin may reduce the rate at which Telomeres shorten Lancet 2001 2007 Jan 13 Omega-3 fatty acid supplementation reduces Telomere shortening in the cognitively impaired J of Nutrition October 22 2013 Omega-3 fatty acids, oxidative stress and leukocyte Telomere length- A randomized controlled trial E, Balackburn et al Brain Behavior Immunity Sept 2012 Longitudinal association of Telomere length and Obesity indices in an Intervention Study with Mediterranean Diet the PREDIMED-NAVARRA trial S Garcia-Calzon International Journal of Obesity 2014, 38:177 Paula Martínez, Gonzalo Gómez-López, Fernando García, Evi Mercken, Sarah Mitchell, Juana M. Flores, Rafael de Cabo, Maria A. Blasco. RAP1 Protects from Obesity through Its Extratelomeric Role Regulating Gene Expression. Cell Reports, 2013; DOI: 1- Metabolic Syndrome PREVEND study JIM Nov 2013
  48. 48. The association between Physical Activity in Leisure time and leukocite Telomere lenght LF Cherkas Arch Intern Med 2008;168:154. Lancet oncology Sep 2013 Stress can shorten Telomere in chilhood Nature 17 may2011 Telomere length and Aging related to Depression? Molecular Psychiatry Nov 12 2013 Biol Psychiatry 2012 ;15:294
  49. 49. CORRELATION BETWEEN IMT AND EPC LEVELS IN PATIENTS WITH METABOLIC SYNDROME 0 1 2 3 4 5 6 7 8 9 0,2 0,4 0,6 0,8 1 1,2 GIM EPCsTardías(%)CD34+/VE-cadherina+(%) r = - 0,169 P = 0,017 IMT (mm)
  50. 50. Telomerase activation (with smal molecules)
  51. 51. Telomerase activation with a nutritional supplement
  52. 52. Infancy/youth/adulthood aging cancer cardiovascular diabetes renal disease immunosenescence neurodegeneration etc… telomere loss consequences Interventions (ie, TERT) aging cancer cardiovascular diabetes renal disease immunosenescence neurodegeneration etc… Infancy/youth/adulthood Understanding the molecular basis of aging to prevent disease genetic & environmental
  53. 53. Everything will be alright in the end and if it’s not alright it’s not the END
  54. 54. Muchas Gracias Gastamos mas en armamentos que en la Prevención

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