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CELLULAR AGING AND LONGEVITY

Lawrence Berkeley National Laboratory. CELLULAR AGING AND LONGEVITY. Buck Institute for Age Research. What IS Aging?. Aging is a PROCESS that converts a healthy, fit organism (for its environment) into one that is less healthy and fit. Aging is a biological process

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CELLULAR AGING AND LONGEVITY

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  1. Lawrence Berkeley National Laboratory CELLULAR AGING AND LONGEVITY Buck Institute for Age Research

  2. What IS Aging?

  3. Aging is a PROCESS that converts a healthy, fit organism (for its environment) into one that is less healthy and fit Aging is a biological process Aging not disease, per se

  4. AGING Reduced tissue/physiological function Increased susceptibility to disease (age-related diseases) Decreased resistance to stress (physical and psychological)

  5. Why does aging happen? If we don't understand this, we can’t design rational interventions! What can we do about it? How can we postpone the effects of aging?

  6. Aging occurs at multiple levels • molecules • cells • tissues • organ systems Cells = molecules + response -----> tissue, organ system effects

  7. Cell death (apoptosis) Arrested cell growth (cell senescence) Cellular “aging” = response to damage or stress

  8. Bad news! (promotes aging) Good news! (prevents cancer) Cellular “aging” responses: YIN and YANG

  9. Years Days/wks No Cancer Cancer Min/hrs Multi-cellular, Post-mitotic + Renewable tissues Single-celled Multi-cellular, Post-mitotic Evolution of Long-Lived Organisms LIFE SPAN ORGANISMS CELL DIVISION IS RISKY!!

  10. The bad news! Cancer Cancer risk rises exponentially with age Fueled by (somatic) mutations Mutations caused by DNA damage, from endogenous and exogenous sources

  11. The good news! Cancer Genes evolved to protect from cancer (tumor suppressor genes) Tumor suppressor genes cause damaged cells to die or arrest growth (undergo apoptosis or senescence) Ooops! Apoptosis and senescence = cellular ‘aging’ responses!

  12. Tumor suppression and aging: An evolutionary balancing act! Cancer protection Cellular aging

  13. A closer look …… Cellular senescence (cellular aging)

  14. Senescent human fibroblasts 'Young' Presenescent 'Aged' Senescent

  15. Cellular Senescence: Arrests Cell Growth In response to Potential Cancer-Causing Events Stress/damage Signals Chromatin Instability Irreversible arrest of cell growth DNA Damage Oncogenes Short/dysfunctional telomeres

  16. Senescent/'aged' cells: Many characteristics change Irreversible Growth Arrest Altered Function/Gene Expression Resistance to Apoptosis

  17. Senescent changes in gene expression Cell division control Cell structure Metabolism Biologically active secreted molecules Proteinases Cytokines Growth factors

  18. What can molecules secreted by senescent/'aged' cells do?

  19. Disrupt normal tissue differentiation Example: milk production by mammary cells

  20. Mammary alveoli (in culture and in vivo) Mammary epithelial cell + lactogenic hormones Milk proteins Nucleus Basement membrane Mammary fibroblast

  21. Young fibroblasts 'Aged" fibroblasts b-casein E-cadherin Mammary alveoli: effect of senescent/'aged' fibrobasts b-caseinDAPI

  22. Mammary branching Mammary epithelial cell Collagen stroma Mammary fibroblast

  23. Young fibroblasts 'Aged" fibroblasts Secondary duct Primary duct Core Mammary branching: effect of senescent/'aged' fibrobasts

  24. Senescent cells and normal tissue function and structure Cancer protection Aging tissues Bad news!

  25. Good news! We can identify many of the molecules produced by senescent cells ….and…. We can inhibit some of them!

  26. Mammary branching: effect of senescent/'aged' fibrobasts Number Core Area SECONDARY TERTIARY PRIMARY Young fibroblasts 'Aged" fibroblasts

  27. MMPi HGF Ab Specifically MMP3 Mammary branching -- undoing the effect of senescent/'aged' fibroblasts Total branching Young Aged Aged +

  28. Maybe! (we're working it!) Cancer protection Aging

  29. Acknowledgements Thanks to: Many present and past lab members (Jean-Philippe Coppe, Ana Krtolica, Simona Parrinello Elliot) Many colleagues, collaborators and Friends -- including CREA NIH/NIA, DOD, DOE

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