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Young Blood and Brain Aging




             Saul Villeda, PhD
   University of California San Francisco
    Eli and Edythe Stem Cell Institute
Aging is a process affecting every individual
Aging is associated with a decline in
         cognitive functions




                          Hedden and Gabriel Nat. Rev. Neurosci 2004
Aging is associated with a decline in
         cognitive functions




                 Aging




Young                             Old
Question: Can the effects of aging on cognitive
            function be reversed?




                     Aging




    Young                             Old
Stem cells and tissue regeneration
Stem cells and tissue regeneration
Stem cells and tissue regeneration
Stem cells and tissue regeneration
Stem cells and tissue regeneration
Palmer et al. J Comp. Neurol. 2000
Mirzadeh et al. Cell Stem Cell 2008
Reviewed by Zhao et al. Cell 2008
Reviewed by Zhao et al. Cell 2008
Reviewed by Zhao et al. Cell 2008
Aging impairs neural stem cells and associated
              cognitive function




                                      Reviewed by Lazarov et al.
                                        Trends Neurosci 2010
Aging impairs neural stem cells and associated
              cognitive function




                                      Reviewed by Lazarov et al.
                                        Trends Neurosci 2010
Systemic perturbations in old animals enhances
    neural stem cell and cognitive functions




                                    Van Praag et al. J. Neurosci. 2005
Systemic perturbations in old animals enhances
    neural stem cell and cognitive functions




                                    Van Praag et al. J. Neurosci. 2005
Hypothesis
   Changes naturally occuring in the aging
systemic milieu (blood) impair neural stem cell
           and cognitive functions
Using parabiosis surgery to investigate changes in
            the young and old brain




                     Old-Young

                                  Pioneered by Rando Conboy et al. Nature 2005
Using parabiosis surgery to investigate changes in
            the young and old brain




   Young-Young       Old-Young                 Old-Old

                                  Pioneered by Rando Conboy et al. Nature 2005
Exposure to old blood impairs neural stem cell
           function in young mice




                    Old Blood




       Parabiosis
                                     Villeda et al. Nature 2011
Villeda et al. Nature 2011
Old = Young




Villeda et al. Nature 2011
Exposure to old blood impairs cognitive
       function in young mice




                 Old Blood




                                Cognitive
                               Impairments



    Parabiosis
                                 Villeda et al. Nature 2011
Exposure to young blood enhances neural stem
      Stem cells and tissue regeneration
          cell function in old animals




                                   Villeda et al. Nature 2011
Systemic exposure to young blood enhances
     neural stem cell function in old mice
                                           Old = Young




                                    Villeda et al. Nature 2011
Systemic exposure to young blood enhances
     neural stem cell function in old mice
                                           Old = Young




                                    Villeda et al. Nature 2011
Exposure to young blood rejuvenates stem cell
     Stem cells and tissue regeneration
            function in old animals

                                                                                      Muscle Cells




                                          Young Blood


                                                                                                    Neurons


                                                             Tissue Specific
                                                               Stem Cells


                                                                                      Blood Cells



  Conboy et al. Nature 2005, Brack et al. Science 2007, Villeda et al. Nature 2011, Ruckh et al. Cell Stem Cell 2012
Question: Can the beneficial effects of young
 blood extend beyond stem cell function?




                  Rejuvenation

                                 ?
Exposure to young blood improves
communication between neurons in the old brain



                                 Old-Old   Old-Young


                  Rejuvenation
Exposure to young blood improves learning
       and memory in old animals




                Rejuvenation




                                 Cognitive
                               Improvements
Testing hippocampal-dependent spatial
               learning and memory


Radial Arm Water Maze    DAY 1: Training Phase




                         DAY 1: Training Phase




                                                 Villeda et al. Nature 2011
Exposure to young blood improves learning
       and memory in old animals
Direction of the Lab
Understanding how administration of young blood
        late in life improves the old brain



                  Rejuvenation

   Function                            Genes




  Cognition                            Cells
Acknowledgements
Villeda Lab:              Collaborators:
   Lucas Smith              Thomas Rando
   Kristopher Plambeck       (Stanford/VA Palo Alto)
   Jill Bouchard            Xinmen Xie (AfaSci)
   Liz Wheatley             Bende Zou (AfaSci)
                             Marion Buckwalter (Stanford)
Wyss-Coray Lab:              Theo Palmer (Stanford)
                             Ge Li (VA Seattle)
   Tony Wyss-Coray          Elaine R. Peskind (VA Seattle)
   Jeong-Soo Park           Jeffrey A. Kaye
   Yingbo He                 (Oregon Health Sciences)
   Greg Bieri               Joseph F. Quinn
   Jian Luo                  (Oregon Health Sciences)
   Kira Irving              Douglas R. Galasko (UCSD)
   Rafael Wabhl
   Markus Britschgi
   Alex Eggel            Funding:
   Ching Ding
   Trisha Stan              UCSF Fellows (Sandler
   Eva Czirr                 Foundation)
   Kurt Lucin               NIH Director’s
   Jinte Middledorp          Independence Award
   Daniella Birdnik         CIRM Award
   Joseph Castellano        NIA
The Villeda Lab at UCSF
                     COGNITION


                        AGING

               REJUVENATION
Dr. Saul Villeda at Health Extension Salon #6

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Dr. Saul Villeda at Health Extension Salon #6

  • 1. Young Blood and Brain Aging Saul Villeda, PhD University of California San Francisco Eli and Edythe Stem Cell Institute
  • 2. Aging is a process affecting every individual
  • 3. Aging is associated with a decline in cognitive functions Hedden and Gabriel Nat. Rev. Neurosci 2004
  • 4. Aging is associated with a decline in cognitive functions Aging Young Old
  • 5. Question: Can the effects of aging on cognitive function be reversed? Aging Young Old
  • 6.
  • 7.
  • 8.
  • 9. Stem cells and tissue regeneration
  • 10. Stem cells and tissue regeneration
  • 11. Stem cells and tissue regeneration
  • 12. Stem cells and tissue regeneration
  • 13. Stem cells and tissue regeneration
  • 14. Palmer et al. J Comp. Neurol. 2000 Mirzadeh et al. Cell Stem Cell 2008
  • 15. Reviewed by Zhao et al. Cell 2008
  • 16. Reviewed by Zhao et al. Cell 2008
  • 17. Reviewed by Zhao et al. Cell 2008
  • 18. Aging impairs neural stem cells and associated cognitive function Reviewed by Lazarov et al. Trends Neurosci 2010
  • 19. Aging impairs neural stem cells and associated cognitive function Reviewed by Lazarov et al. Trends Neurosci 2010
  • 20. Systemic perturbations in old animals enhances neural stem cell and cognitive functions Van Praag et al. J. Neurosci. 2005
  • 21. Systemic perturbations in old animals enhances neural stem cell and cognitive functions Van Praag et al. J. Neurosci. 2005
  • 22. Hypothesis Changes naturally occuring in the aging systemic milieu (blood) impair neural stem cell and cognitive functions
  • 23. Using parabiosis surgery to investigate changes in the young and old brain Old-Young Pioneered by Rando Conboy et al. Nature 2005
  • 24. Using parabiosis surgery to investigate changes in the young and old brain Young-Young Old-Young Old-Old Pioneered by Rando Conboy et al. Nature 2005
  • 25. Exposure to old blood impairs neural stem cell function in young mice Old Blood Parabiosis Villeda et al. Nature 2011
  • 26. Villeda et al. Nature 2011
  • 27. Old = Young Villeda et al. Nature 2011
  • 28. Exposure to old blood impairs cognitive function in young mice Old Blood Cognitive Impairments Parabiosis Villeda et al. Nature 2011
  • 29. Exposure to young blood enhances neural stem Stem cells and tissue regeneration cell function in old animals Villeda et al. Nature 2011
  • 30. Systemic exposure to young blood enhances neural stem cell function in old mice Old = Young Villeda et al. Nature 2011
  • 31. Systemic exposure to young blood enhances neural stem cell function in old mice Old = Young Villeda et al. Nature 2011
  • 32. Exposure to young blood rejuvenates stem cell Stem cells and tissue regeneration function in old animals Muscle Cells Young Blood Neurons Tissue Specific Stem Cells Blood Cells Conboy et al. Nature 2005, Brack et al. Science 2007, Villeda et al. Nature 2011, Ruckh et al. Cell Stem Cell 2012
  • 33. Question: Can the beneficial effects of young blood extend beyond stem cell function? Rejuvenation ?
  • 34. Exposure to young blood improves communication between neurons in the old brain Old-Old Old-Young Rejuvenation
  • 35. Exposure to young blood improves learning and memory in old animals Rejuvenation Cognitive Improvements
  • 36. Testing hippocampal-dependent spatial learning and memory Radial Arm Water Maze DAY 1: Training Phase DAY 1: Training Phase Villeda et al. Nature 2011
  • 37. Exposure to young blood improves learning and memory in old animals
  • 38. Direction of the Lab Understanding how administration of young blood late in life improves the old brain Rejuvenation Function Genes Cognition Cells
  • 39. Acknowledgements Villeda Lab: Collaborators:  Lucas Smith  Thomas Rando  Kristopher Plambeck (Stanford/VA Palo Alto)  Jill Bouchard  Xinmen Xie (AfaSci)  Liz Wheatley  Bende Zou (AfaSci)  Marion Buckwalter (Stanford) Wyss-Coray Lab:  Theo Palmer (Stanford)  Ge Li (VA Seattle)  Tony Wyss-Coray  Elaine R. Peskind (VA Seattle)  Jeong-Soo Park  Jeffrey A. Kaye  Yingbo He (Oregon Health Sciences)  Greg Bieri  Joseph F. Quinn  Jian Luo (Oregon Health Sciences)  Kira Irving  Douglas R. Galasko (UCSD)  Rafael Wabhl  Markus Britschgi  Alex Eggel Funding:  Ching Ding  Trisha Stan  UCSF Fellows (Sandler  Eva Czirr Foundation)  Kurt Lucin  NIH Director’s  Jinte Middledorp Independence Award  Daniella Birdnik  CIRM Award  Joseph Castellano  NIA
  • 40. The Villeda Lab at UCSF COGNITION AGING REJUVENATION