1. Cellular Senescence What is it? What causes it? Why is it important (cancer and aging)?

2. Cellular Senescence What is it? Response of normal cells to potentially cancer-causing events The senescence response is an anti-cancer mechanisms that prevents the proliferation (growth) of damaged or dysfunctional cells (potential cancer cells)

3. First description: the Hayflick limit Proliferative capacity Number of cell divisions Finite Replicative Life Span "Mortal" Infinite Replicative Life Span "Immortal" EXCEPTIONS Germ line Early embryonic cells (stem cells) Many tumor cells What happens when cells exhaust their replicative life span?

4. REPLICATIVE SENESCENCE Irreversible arrest of cell proliferation (universal) Resistance to apoptosis (lecture on January 31) (certain cell types) Altered function (universal but cell type specific) THE SENESCENT PHENOTYPE

5. Cellular Senescence What causes it? (what causes the senescent phenotype?) Cell proliferation (replicative senescence) = TELOMERE SHORTENING (lecture on February 26th) DNA damage Oncogene expression Supermitogenic/stress signals What do inducers of the senescent phenotype have in common?

6. Inducers of cellular senescence Cell proliferation (short telomeres) DNA damage Oncogenes Strong mitogens/ stress Potential Cancer Causing Events Normal cells ('mortal') 'Immortal' cells (precancerous) Cell senescence Transformation Apoptosis Tumor suppressor mechanisms

7. Cellular Senescence A crucial tumor suppressor mechanism Induced by potentially oncogenic events Most tumor cells are replicatively immortal Many oncogenic mutations allow cells to bypass the senescence response Senescence is controlled by the two most important tumor suppressor genes -- p53 and pRB Mice with cells that do not senesce die young of cancer

8. Cancer Caused by genetic (mutations) and epigenetic (tissue environment) events

9. Cancer: genetic events Activation of oncogenes (continuous "go" signal) Inactivation of tumor suppressor genes (removes "stop" signal) Inactivation of tumor suppressor genes encoding p53 and pRB proteins = most common

10. p53 and pRB proteins Nuclear proteins controlled by complex pathways (upstream regulators and downstream effectors) Control expression of other genes Halt cell proliferation in response to inducers of senescence Crucial for allowing normal cells to sense and respond to senescence signals

11. Cellular Senescence An important tumor suppressor mechanism What does cellular senescence have to do with aging? Senescent cells have altered functions Aging is a consequence of the declining force of natural selection with age The senescence response may be an example of evolutionary antagonistic pleiotropy

12. Aging before cell phones …… 100% Survivors AGE Natural environment: predators, infections, external hazards, etc Most of human evolution Modern, protected environment (very VERY recent) Antagonistic pleiotropy: Some traits selected to optimize fitness in young organisms can have unselected bad effects in old organisms (what's good for you when you're young may be bad for you when you're old)

13. Antagonistic pleiotropy Cellular senescence Selected for tumor suppression (growth arrest) Functional changes unselected, deleterious FUNCTIONAL CHANGES ASSOCIATED WITH CELLULAR SENESCENCE: Secretion of molecules that can be detrimental to tissues if not controlled Senescent fibroblasts secrete proteases, growth factors, inflammatory cytokines

14. Cellular senescence and aging Cells from old donors divide less often than cells from young donors Cells from short-lived species are more sensitive to senescence-inducers, particularly oxidative stress, than cells from long-lived species Cells from donors with premature aging syndromes senesce more readily than cells from normal donors Senescent cells (expressing a senescence marker) accumulate with age and at sites of age-related pathology, including hyperproliferative diseases

15. Human skin, stained for SA-Bgal Dimri et al., Proc Natl Acad Sci USA, 1995 p16 expression Heterochromatic foci Telomeric-DNA damage foci DNA damage foci Cellular senescence: Markers in culture and in vivo

16. 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 Preneoplastic lesions

17. Senescent cells secrete many inflammatory cytokines (e.g., IL6, IL8), growth factors (e.g., PDGF, heregulin), proteases (e.g., MMPs) SENESCENT SECRETORY PHENOTYPE Many similarities among fibroblasts induced to senesce by different stimuli and among fibroblasts from different tissues and donor ages

18. Senescent cells can strongly alter tissue microenvironments May contribute to age-related declines in tissue structure and function, and age related disease

19. Senescent fibroblasts disrupt morphological and functional differentiation of epithelial cells BM + PreS Fb BM + Sen Fb  -casein DAPI Pre-S Fb Sen Fb  -casein E-cadherin Parrinello et al., J Cell Sci, 2005

21. Cellular senescence, aging … and cancer WHAT CAUSES CANCER? Mutations, mutations, mutations …. A permissive tissue** (mutations, including potentially cancer- causing mutations, accumulate with age, starting from early ages)

22. Epithelial Cells Fibroblasts

23. CONCLUSIONS The senescence response is a permanent cell growth arrest that prevents dysfunctional or damaged (potentially cancerous) cells from proliferating = Tumor suppressor mechanism The senescence response may be an example of evolutionary anagonistic pleiotropy -- protecting young organisms from cancer but contributing to aging, age- related disease and (ironically) late life cancer at old ages