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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
- 16. Are you depressed yet?
- 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)