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Buck Institute for Age Research

                                    20 November, 2012
                                  Health extension salon #3




       Living healthier and (maybe) longer




                                  Lawrence Berkeley National Laboratory
Population structures are changing
          1950                          2030
  Males        Females          Males         Females




                          AGE




                                                         AGE
 Population (thousands)         Population (thousands)
Good news …. we (homo sapiens)
        are living longer
Bad news …..we can’t afford it
Why are we living longer?

And why is that triumph draining our
            resources?
Medicine became pretty good at
  treating individual diseases

But, alas, very poor at treating
    basic aging processes
Aging = susceptibility to (chronic)
            disease
  Neurodegeneration,                 Osteoporosis
     memory loss
                        Macular degeneration,
                            hearing loss
                    Heart disease
                                    Vascular disease
                     Sarcopenia,
                        frailty     Diabetes,
                                metabolic syndrome
        Decreased
 lung, kidney, etc function             CANCER
Age-related diseases rise exponentially
               with age

        INCIDENCE




                     AGE
    Age is the largest single risk factor
What are these basic aging processes?

          Can they be altered
    (without waiting for evolution)?
Age-related diseases are
     (mostly) degenerative
 Neurodegeneration,                 Osteoporosis
    memory loss
                       Macular degeneration,
                           hearing loss
                   Heart disease
                                   Vascular disease
                    Sarcopenia,
                       frailty     Diabetes,
                               metabolic syndrome
       Decreased
lung, kidney, etc function             CANCER
Is there a common biology that links
cancer, degenerative disease and aging?


   (a working hypothesis …. and model)
Suppressing cancer costs -- aging
   Tumor Suppressor                           Aging
     mechanisms                             Phenotypes


                                                   Late life
                                                phenotypes,
                                              including cancer
                                                (antagonistic
                                                 pleiotropy)
    Care-          Gate-               Apoptosis
   takers         keepers            Deplete proliferating/
 prevent/repair   eliminate/          stem cell pools --->
 DNA damage,        arrest
                                 Tissue atrophy/degeneration
   mutations      damaged/
                   mutant
                     cells
                                      Senescence
                               Deplete proliferating/stem pools
Longevity assurance              Cell dysfunction ---> loss of
                                tissue function/homeostasis
What is cellular senescence?
 GROWTH ARREST
                             SASP
           SA-Bgal

         lamin B1
           loss                       p16INK4a


Persistent DNA damage foci   Heterochromatin
    (DNA-SCARS/TIF)            foci (SAHF) Campisi, Curr Opin Genet, 2010
                                                  Rodier & Campisi, J Cell Biol, 2011
Senescent Cells Accumulate In Vivo
                           With Increasing Age
                       Human, rodent and primate
              skin, retina, liver, spleen, aorta, kidney, etc.

           At Sites of Age-Related Pathology
  Venous ulcers, atherosclerotic plaques, arthritic joints
   Benign prostatic hyperplasia, pre-neoplastic lesions

    growth arrest   SASP

    SA-Bgal

                        p16INK4a


 DNA damage foci    Heterochromatin
(DNA-SCARS/TIF)       foci (SAHF)                                     Dimri et al.,
                                 Campisi, Curr Opin Genet, 2010
                                                                      PNAS, 1995
                                Rodier & Campisi, J Cell Biol, 2011
aged tissue         degenerating tissue




young tissue
                         senescent      dysfunctional
                            cell             cell       SASP

                     aged tissue          neoplastic tissue




               premalignant senescent
                   cell        cell                     SASP
Are you depressed yet?
We can now – genetically – selectively
   kill senescent cells (in a mouse)!

What happens to age-related pathology?
Clearing senescent cells in mice
                   Prematurely aged mice:
                 cataracts, sarcopenia, fat loss,
                        cardiomyopathy
  senescent                                                senescent
  s cells                                                     cells
 accumulate                                                eliminated
                                                         (no cataracts,
                                                          sarcopenia,
                                                            fat loss)




DJ Baker, T Wijshake, T Tchkonia, NK LeBrasseur, B G Childs, B van de Sluis,
                 JL Kirkland, JM van Deursen, Nature, 2011
p16-3MR (tri-modal reporter) mice
   BAC containing murine INK4a locus inserted into mouse genome
                       (location not yet known)
3MR knock-in: downstream of p16INK4a promoter + inactivation of p14ARF
       Mice have normal (diploid) copies of p16 and p14 genes

          p16 Promoter         renLuc mRFP HSV-tk
                               3MR: renilla luciferase; modified
                                red fluorescent protein; herpes
                                simplex virus thymidine kinase




                                        P
   GCV = gancyclovir                                        P
                                            HSV-Tk
Low affinity for cellular TK
 High affinity for viral TK    GCV                        GCV
                                        phosphorylation
                                                       DNA CHAIN
                                                      TERMINATOR
IR/chemo-induced senescent cells fuel metastases

    1                 2                        3




control            IR/Doxo          irradiated + GCV
              = senescent cells




                              15 days post tail vein injection
Can we find drugs to do in humans
   what we can do genetically
             in mice?

         (we think we can)

  Will there be any side effects?

(maybe … we may need to be really
smart about how we use such drugs)

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Judith Campisi at Health Extension Salon #3

  • 1. Buck Institute for Age Research 20 November, 2012 Health extension salon #3 Living healthier and (maybe) longer Lawrence Berkeley National Laboratory
  • 2. Population structures are changing 1950 2030 Males Females Males Females AGE AGE Population (thousands) Population (thousands)
  • 3. Good news …. we (homo sapiens) are living longer
  • 4. Bad news …..we can’t afford it
  • 5. Why are we living longer? And why is that triumph draining our resources?
  • 6. Medicine became pretty good at treating individual diseases But, alas, very poor at treating basic aging processes
  • 7. Aging = susceptibility to (chronic) disease Neurodegeneration, Osteoporosis memory loss Macular degeneration, hearing loss Heart disease Vascular disease Sarcopenia, frailty Diabetes, metabolic syndrome Decreased lung, kidney, etc function CANCER
  • 8. Age-related diseases rise exponentially with age INCIDENCE AGE Age is the largest single risk factor
  • 9. What are these basic aging processes? Can they be altered (without waiting for evolution)?
  • 10. Age-related diseases are (mostly) degenerative Neurodegeneration, Osteoporosis memory loss Macular degeneration, hearing loss Heart disease Vascular disease Sarcopenia, frailty Diabetes, metabolic syndrome Decreased lung, kidney, etc function CANCER
  • 11. Is there a common biology that links cancer, degenerative disease and aging? (a working hypothesis …. and model)
  • 12. Suppressing cancer costs -- aging Tumor Suppressor Aging mechanisms Phenotypes Late life phenotypes, including cancer (antagonistic pleiotropy) Care- Gate- Apoptosis takers keepers Deplete proliferating/ prevent/repair eliminate/ stem cell pools ---> DNA damage, arrest Tissue atrophy/degeneration mutations damaged/ mutant cells Senescence Deplete proliferating/stem pools Longevity assurance Cell dysfunction ---> loss of tissue function/homeostasis
  • 13. What is cellular senescence? GROWTH ARREST SASP SA-Bgal lamin B1 loss p16INK4a Persistent DNA damage foci Heterochromatin (DNA-SCARS/TIF) foci (SAHF) Campisi, Curr Opin Genet, 2010 Rodier & Campisi, J Cell Biol, 2011
  • 14. Senescent Cells Accumulate In Vivo With Increasing Age Human, rodent and primate skin, retina, liver, spleen, aorta, kidney, etc. At Sites of Age-Related Pathology Venous ulcers, atherosclerotic plaques, arthritic joints Benign prostatic hyperplasia, pre-neoplastic lesions growth arrest SASP SA-Bgal p16INK4a DNA damage foci Heterochromatin (DNA-SCARS/TIF) foci (SAHF) Dimri et al., Campisi, Curr Opin Genet, 2010 PNAS, 1995 Rodier & Campisi, J Cell Biol, 2011
  • 15. aged tissue degenerating tissue young tissue senescent dysfunctional cell cell SASP aged tissue neoplastic tissue premalignant senescent cell cell SASP
  • 17. We can now – genetically – selectively kill senescent cells (in a mouse)! What happens to age-related pathology?
  • 18. Clearing senescent cells in mice Prematurely aged mice: cataracts, sarcopenia, fat loss, cardiomyopathy senescent senescent s cells cells accumulate eliminated (no cataracts, sarcopenia, fat loss) DJ Baker, T Wijshake, T Tchkonia, NK LeBrasseur, B G Childs, B van de Sluis, JL Kirkland, JM van Deursen, Nature, 2011
  • 19. p16-3MR (tri-modal reporter) mice BAC containing murine INK4a locus inserted into mouse genome (location not yet known) 3MR knock-in: downstream of p16INK4a promoter + inactivation of p14ARF Mice have normal (diploid) copies of p16 and p14 genes p16 Promoter renLuc mRFP HSV-tk 3MR: renilla luciferase; modified red fluorescent protein; herpes simplex virus thymidine kinase P GCV = gancyclovir P HSV-Tk Low affinity for cellular TK High affinity for viral TK GCV GCV phosphorylation DNA CHAIN TERMINATOR
  • 20. IR/chemo-induced senescent cells fuel metastases 1 2 3 control IR/Doxo irradiated + GCV = senescent cells 15 days post tail vein injection
  • 21. Can we find drugs to do in humans what we can do genetically in mice? (we think we can) Will there be any side effects? (maybe … we may need to be really smart about how we use such drugs)