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

Cellular Senescence What is it? Response of normal cells to potentially cancer-causing events

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

REPLICATIVE SENESCENCE Irreversible arrest of cell proliferation (universal) Resistance to apoptosis (stem cells) Altered function (universal but cell type specific) SENESCENT PHENOTYPE

Cellular Senescence What causes it? (what causes the senescent phenotype?) Cell proliferation (replicative senescence) = TELOMERE SHORTENING DNA damage Oncogene expression Supermitogenic signals What do inducers of the senescent phenotype have in common?

Inducers of cellular senescence Cell proliferation (short telomeres) DNA damage Oncogenes Strong mitogens Potentially Cancer Causing Normal cells (mortal) Immortal cells (precancerous) Inducers of senescence Cell senescence TransformationApoptosis Tumor suppressor mechanisms

Cellular Senescence An important tumor suppressor mechanism Induced by potentially oncogenic events Most tumor cells are immortal Many oncogenes act by allowing 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

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

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

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

Cellular Senescence An important tumor suppressor mechanism What does cellular senescence have to do with aging? The senescent phenotype entails changes in cell function Aging is a consequence of the decling force of natural selection with age

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 deleterious effects in old organisms (what's good for you when you're young may be bad for you when you're old)

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 e.g., senescent fibroblasts secrete proteases, growth factors, inflammatory cytokines

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