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José Viña - Envejecimiento a nivel celular y orgánico. Envejecer es normal
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José Viña - Envejecimiento a nivel celular y orgánico. Envejecer es normal

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Entre el 20 de marzo y el 13 de mayo de 2014, la Fundación Ramón Areces organizó el ciclo de conferencias 'Envejecimiento, Sociedad y Salud' en colaboración con el Centro de Estudios del …

Entre el 20 de marzo y el 13 de mayo de 2014, la Fundación Ramón Areces organizó el ciclo de conferencias 'Envejecimiento, Sociedad y Salud' en colaboración con el Centro de Estudios del Envejecimiento. Diferentes expertos abordaron esta importante cuestión social desde distintos puntos de vista.

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  • In which we have looked for which genes are modulated in extreme longevity
  • And finally I want to thank specially prof. Viña for directing all of this work, and for transmiting us his enthusiasm for science

Transcript

  • 1. JOSE VIÑA Facultad de Medicina. UNIVERSIDAD DE VALENCIA FUNDACION RAMON ARECES. MADRID El ENVEJECIMIENTO A NIVEL CELULAR Y ORGÁNICO: ENVEJECER ES NORMAL
  • 2. NVEJECIMIENTO FISIOLOGICO ¿ENVEJECIMIENTO COMO PROBLEMA ARACTERISTICAS DEL ENVEJECIMIENTO: NTENARIANOS: ENVEJECIMIENTO EXCEP ODULACION DEL ENVEJECIMIENTO ¿POD OROLLARIO : ENVEJECIMIENTO SATISFAC MENSAJE: CUIDESE HOY
  • 3. 1988- 2013
  • 4. Aging as a problem:THAÏS Ah ! tais-toi, voix  impitoyable, Voix que  me dis: Thaïs, tu vieilliras! Un jour,  ainsi,  Thaïs ne serait plus  Thaïs! Non! Non! je  n'y puis croire
  • 5. Time October 2005 National Geographic November 2005 Scientific American March 2006 Social impact of aging studies
  • 6. TIME: sept 10, 2013
  • 7. NVEJECIMIENTO FISIOLOGICO ¿ENVEJECIMIENTO COMO PROBLEMA ARACTERISTICAS DEL ENVEJECIMIENTO: NTENARIANOS: ENVEJECIMIENTO EXCEP ODULACION DEL ENVEJECIMIENTO ¿POD OROLLARIO : ENVEJECIMIENTO SATISFAC MENSAJE: CUIDESE HOY
  • 8. UNIVERSAL INTRINSIC PROGRESSIVE DELETERIOUS AGEING Characteristics of aging Vina et al (2007) IUBMB Life, according to Strehler, B. L. (1977)
  • 9. Aging is not a disease: AGE  ASSOCIATED CHANGES Biological Aging Is No Longer an Unsolved Problem LEONARD HAYFLICK
  • 10. Aging is not a disease: AGE  ASSOCIATED CHANGES (1) occur in every multicellular animal  that reaches a fixed size at  reproductive maturity (2) cross virtually all species barriers (3) occur in all members of a species  only after the age of reproductive  maturation
  • 11. Aging is not a disease: AGE  ASSOCIATED CHANGES (4) occur in all animals removed from the wild  and protected by humans even when that  species probably has not experienced aging for  thousands or even millions of years (5) occur in virtually all animate and inanimate  matter (6) have the same universal molecular etiology,  that is, thermodynamic instability. Unlike aging, there is no disease or  pathology that shares these six qualities.
  • 12. The role of mitochondria in aging
  • 13. Role of mitochondria in aging
  • 14. LA BUSQUEDA DE GENES DE LONGEVIDAD
  • 15. The search for longevity genes: p53 0 25 50 75 100 survival(%) time (months) WT Super/Super 0 5 10 15 20 25 30 35 40 spontaneous survival curve WT Super/Super survival(%) time (months) 0 25 50 75 100 0 5 10 15 20 25 30 35 40 survival curve without tumors Logrank test= 0.01 (*) Logrank test= 0.02 (*) 0 25 50 75 100 0 25 50 75 100 survival(%) time (months) WT Super/Super WT Super/Super 0 5 10 15 20 25 30 35 400 5 10 15 20 25 30 35 40 spontaneous survival curve WT Super/Super WT Super/Super survival(%) time (months) 0 25 50 75 100 0 25 50 75 100 0 5 10 15 20 25 30 35 400 5 10 15 20 25 30 35 40 survival curve without tumors Logrank test= 0.01 (*) Logrank test= 0.02 (*) 0 25 50 75 100 survival(%) time (months) WT Super/Super 0 5 10 15 20 25 30 35 40 spontaneous survival curve WT Super/Super survival(%) time (months) 0 25 50 75 100 0 5 10 15 20 25 30 35 40 survival curve without tumors Logrank test= 0.01 (*) Logrank test= 0.02 (*) 0 25 50 75 100 0 25 50 75 100 survival(%) time (months) WT Super/Super WT Super/Super 0 5 10 15 20 25 30 35 400 5 10 15 20 25 30 35 40 spontaneous survival curve WT Super/Super WT Super/Super survival(%) time (months) 0 25 50 75 100 0 25 50 75 100 0 5 10 15 20 25 30 35 400 5 10 15 20 25 30 35 40 survival curve without tumors Logrank test= 0.01 (*) Logrank test= 0.02 (*)
  • 16. The search for longevity genes: telomerase
  • 17. The search for longevity genes: Ras
  • 18. CALORIC RESTRICTION MICE (NEJM) AGING : THE PROBLEM WITH MODELS
  • 19. CALORIC RESTRICTION MICE (NEJM) MONKEYS (Science vs Nature) AGING : THE PROBLEM WITH MODELS
  • 20. CALORIC RESTRICTION MICE (NEJM) MONKEYS (Science vs Nature) HUMANS (JAMA) AGING : THE PROBLEM WITH MODELS
  • 21. Caloric restriction increases life span in mice Weindruch and Sohal (1997) N Engl J Med
  • 22. BMI and mortality
  • 23. Letter to the Editor JAMA Title: Overweight is not overweight : comment on “Association of all-cause mortality with overweight and obesity” . Authors: Jose Viña, Consuelo Borras, and Mari Carmen Gomez- Cabrera JAMA13-0598 Decision Letter Dear Prof. Vina: We have completed our review of your Letter to the Editor and are pleased to accept it for publication in JAMA. Your manuscript is accepted with the understanding that its contents, all or in part, have not been published elsewhere and will not be published elsewhere in print or electronic format except in abstract form or by the consent of the editor.
  • 24. . Thus, direct estimates of total fat mass will provide a more accurate body assessment. It has been shown that, for the general population, in addition to BMI, waist circumference and waist to hip ratio are of importance for assessing mortality risk 7 . Consequently, even though it is widely accepted, classifications of obesity based on BMI are inadequate. Indeed, if overweight decreases all-cause mortality, then it is not overweight. Viña et al JAMA, 2013 JAMA 2013
  • 25. Overweight and life span
  • 26. NVEJECIMIENTO FISIOLOGICO ¿ENVEJECIMIENTO COMO PROBLEMA ARACTERISTICAS DEL ENVEJECIMIENTO: NTENARIANOS: ENVEJECIMIENTO EXCEP ODULACION DEL ENVEJECIMIENTO ¿POD OROLLARIO : ENVEJECIMIENTO SATISFAC MENSAJE: CUIDESE HOY
  • 27. The Spanish centenarian study Unpublished results Which genes are modulated in extreme longevity?
  • 28. Strategy CHARACTERISTIC miRNAs AND mRNAs OF CENTENARIANS
  • 29. miRNAs in centenarians Young Octogenarian Centenarian miRNAs are similar in young and centenarians!!!!!
  • 30. Centenarians up-regulate miRNAs
  • 31. Functional transcriptomic analysis www.nature.com/scientific reports
  • 32. Strategy
  • 33. Functional transcriptomic analysis Genechip Human Gene 1.0ST Array Estimated number of genes: 28.869 200ng de RNAtotal Hibridación a 45o C 60rpm durante 18h
  • 34. mRNAs in centenarians Young Octogenarian Centenarian mRNAs are different between octogenarians and centenarians!!!!
  • 35. Comparison of mRNAs C vs Y C vs O
  • 36. The subnetworks... A “sub- network” is a group of genes connected structurally or functionally to one common gene A “sub- network” is identified when there are known realtionships between the genes involved in the Ariadne data base,
  • 37. Subnetwork analysis • All- 1721 genes that change in centenarians • Combine- 51 genes regulated by the 3 miRNAs specific for centenarians (from 1721 genes that change in centenarians) 3 miRNAs 1721 mRNAs 51 mRNA s
  • 38. T Cell Receptor OvsJCvsJ Arrows indicate genes that are in the “combine” list
  • 39. Subnetworks : summary BCLxL, FAS, FASLG, CCL5 TCR TGFB 1 CYTO KINE SP1 TNF IFNG
  • 40. The four critical genes converge in... 2.38 * Young Octogenarian Centenarian
  • 41. Bcl-xL Mitochondrial protein!!!!!!
  • 42. Bcl2 lowers H2O2 levels in cells
  • 43. Bcl2 lowers protein oxidation in cells
  • 44. NVEJECIMIENTO FISIOLOGICO ¿ENVEJECIMIENTO COMO PROBLEMA ARACTERISTICAS DEL ENVEJECIMIENTO: NTENARIANOS: ENVEJECIMIENTO EXCEP ODULACION DEL ENVEJECIMIENTO ¿POD OROLLARIO : ENVEJECIMIENTO SATISFAC MENSAJE: CUIDESE HOY
  • 45. HEALTH SPAN AND LIFESPAN LIFESPAN IS INCREASING SIGNIFICANTLY HEALTH SPAN IS NOT IMPROVING Increases in life span have led to more age associated disaseaes Osteoporosis Alzheimer Degeneración macular Problemas de audición Accidentes cerebrovasculares Elderly people
  • 46. AGING CAN BE MODULATED Moderate exercise Four helpings of fruit Two wine glasses Do not smoke Increases life 14 years Khaw et al Plos Med (2008)
  • 47. AGING CAN BE MODULATED Moderate exercise Four helpings of fruit Two wine glasses Do not smoke Increases life 14 years Khaw et al Plos Med (2008)
  • 48. AGING CAN BE MODULATED Moderate exercise Four helpings of fruit Two wine glasses Do not smoke Increases life 14 years Khaw et al Plos Med (2008)
  • 49. •Exercise is beneficial for your health •The dosing of exercise •Exhaustive exercise and longevity •Systemic adaptations to exercise •Exercise, a psychoactive drug •Contraindications of exercise EXERCISE ACTS AS A DRUGEXERCISE ACTS AS A DRUG (BJP, 2012)(BJP, 2012)
  • 50. Participation in the Tour de France significantly enhances longevity. TDF participants General population Polynomial regression curve for TDF participants Polynomial regression curve for general population TDF participants General population Polynomial regression curve for TDF participants Polynomial regression curve for general population TDF participants General population Polynomial regression curve for TDF participants Polynomial regression curve for general population Int J Sport Med (2011)
  • 51. Effect of moderate wine consumption on longevity gene expression in humans THE VALENCIA NUN STUDY
  • 52. Favorable effects of wine…
  • 53. Gene Pathway AKT1, CDKN2A, FOXO3, IRS1, FRAP1 Insulin TERF1, TERF2, TERT Telomerase SESN2,CAT, SOD2, P53 Oxidative stress SIRT1 Caloric restriction IL1A Inflamation Effect of wine (moderate) on gene expression in catholic nuns Blood sampling: Before the study Blood sampling : after 14 days of wine
  • 54. Red wine increases catalase expression - 100 200 300 400 500 600 0 1 2 3 4 5 6 7 8 9 10 Before After Population1 n=4 Population2 n=5 Catalase %
  • 55. Red wine increases Mn-SOD expression - 50 100 150 200 250 300 350 0 1 2 3 4 5 6 7 8 9 10 Before After Population1 n=4 Population2 n=5 Mn-SOD %
  • 56. Red wine increases p53 expression - 50 100 150 200 250 300 350 400 0 1 2 3 4 5 6 7 8 9 10 Before After Population1 n=4 Population2 n=5 p53 %
  • 57. Red wine increases sirtuin expression - 50 100 150 200 250 300 350 400 450 500 0 1 2 3 4 5 6 7 8 9 10 Before After Population1 n=4 Population2 n=5 Sirtuin1 %
  • 58. NVEJECIMIENTO FISIOLOGICO ¿ENVEJECIMIENTO COMO PROBLEMA ARACTERISTICAS DEL ENVEJECIMIENTO: NTENARIANOS: ENVEJECIMIENTO EXCEP ODULACION DEL ENVEJECIMIENTO ¿POD OROLLARIO : ENVEJECIMIENTO SATISFAC MENSAJE: CUIDESE HOY
  • 59. SUCCESSFUL AGING Aims: Adapt to changes that are going to occur Compress morbidity Prevent frailty and dependency Feel that you are useful
  • 60. La respuesta social….. Grandma and granchid Retired Ferrero people help Foundation Painting, carving etc late sold in “mercatino” Comprometidos con el progreso, la investigación, la educación y la cultura
  • 61. Successful aging People like you and I, though mortal, of course, do not grow old no matter how long we live. What I mean is that we never cease to stand like curious children before the great Mistery into which we were born AE. to Otto Juliusberger, close friend and doctor
  • 62. Successful aging
  • 63. NVEJECIMIENTO FISIOLOGICO ¿ENVEJECIMIENTO COMO PROBLEMA ARACTERISTICAS DEL ENVEJECIMIENTO: NTENARIANOS: ENVEJECIMIENTO EXCEP ODULACION DEL ENVEJECIMIENTO ¿POD OROLLARIO : ENVEJECIMIENTO SATISFAC MENSAJE: CUIDESE HOY
  • 64. CUÍDESE AHORA CUIDARSE NO ES SER EGOISTA SINO ALTRUISTA [www.cuidesehoy.es]
  • 65. CUIDESE HOY PARA QUE NO LE CUIDEMOS MAÑANA
  • 66. Conclusiones (1) • Prepararnos para la vejez es una responsabilidad nuestra • La medicina antienvejecimiento es una especialidad nueva que pretende aplicar conocimientos actuales al objetivo de llegar a la vejez de la mejor manera posible
  • 67. Conclusiones (2) Las maniobras antiaging se basan en • Moderación dietética (restr. Calórica) • Aumentar el aporte de productos vegetales • Ejercicio fisico moderado • Control del estrés • Dejar de fumar • PREVENCION de enfermedades degenerativas (cuanto antes mejor! )
  • 68. EPILOGO • La madurez puede ser un periodo de gran felicidad porque las personas mayores saben su sitio en el mundo(L. Pauling). • Para disfrutar de ese periodo hace falta cuidarse para llegar bien al mismo www.cuidesehoy.es
  • 69. VIÑA’s LAB
  • 70. ¡GRACIAS!