Post on 19-Dec-2015
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
Pro
lifer
ativ
e ca
paci
ty
Number of cell divisions
FiniteReplicativeLife Span"Mortal"
InfiniteReplicativeLife Span"Immortal"
EXCEPTIONSGerm line
Early embryonic cells (stem cells)Many tumor cells
What happens when cells exhaust their replicative life span?
What happens when cells exhaust their replicative life span?
REPLICATIVE SENESCENCE
•Irreversible arrest of cell proliferation(universal)
•Resistance to apoptosis (lecture on February 22)
(certain cell types)
•Altered function(universal but cell type specific)
THE SENESCENT PHENOTYPE
Cellular Senescence
What causes it?(what causes the senescent phenotype?)
Cell proliferation (replicative senescence)= TELOMERE SHORTENING
(lecture on February 3rd)
DNA damage
Oncogene expression
Supermitogenic/stress signals
What do inducers of the senescentphenotype have in common?
Inducers of cellular senescenceCell proliferation(short telomeres)
DNA damage OncogenesStrong mitogens/
stress
Potential Cancer Causing Events
Normal cells('mortal')
'Immortal' cells(precancerous)
Cell senescence TransformationApoptosis
Tumor suppressor mechanisms
Cellular SenescenceAn crucial tumor suppressor mechanism
•Induced by potentially oncogenic events
•Most tumor cells are replicatively immortal
•Many oncogenic mutations allow cells to bypassthe senescence response
•Senescence is controlled by the two most importanttumor suppressor genes -- p53 and pRB
•Mice with cells that do not senesce die youngof cancer
Cancer
Caused by genetic (mutations) andepigenetic (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 encodingp53 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 proliferation in response to inducersof senescence
•Crucial for allowing normal cells to sense and respondto senescence signals
Cellular SenescenceAn 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 forceof natural selection with age
The senescence response may be an example ofevolutionary antagonistic pleiotropy
Aging before cell phones ……
100%
Su
rviv
ors
AGE
Natural environment: predators, infections, external hazards, etcMost of
humanevolution
Modern, protectedenvironment
(very VERY recent)
Antagonistic pleiotropy:Some traits selected to optimize fitness in young
organisms can have unselected badeffects in old organisms
(what's good for you when you're young may be bad for you when you're old)
Antagonistic pleiotropyCellular 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
Cellular senescence and aging
•Cells from old donors divide less often thancells 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
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
Senescent Cells Accumulate In Vivo
With Increasing AgeHuman, rodent and primate
skin, retina, liver, spleen, aorta, kidney, etc.
At Sites of Age-Related PathologyVenous ulcers
Atherosclerotic plaquesArthritic joints
Benign prostatic hyperplasiaPreneoplastic lesions
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
Senescent cells can strongly alter tissue microenvironments
May contribute to age-related declines in tissue structure and function, and
age related disease
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
EPITHELIUMBasement Membrane
STROMA
Senescent Epithelial Cell
Senescent Fibroblast
EPITHELIUMBasement Membrane
STROMA
YOUNG TISSUE
OLD TISSUE
Degradative enzymes, Inflammatory cytokines, etc.
AGING ?
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)
EPITHELIUMBasement Membrane
STROMA
Senescent Epithelial Cell
Senescent Fibroblast
EPITHELIUMBasement Membrane
STROMA
YOUNG TISSUE
OLD TISSUE
Degradative enzymes, Inflammatory cytokines, etc.
AGING ?
EpithelialCells
Fibroblasts
EPITHELIUMBasement Membrane
STROMA
Senescent Epithelial Cell
Senescent Fibroblast
OLD TISSUE
Degradative & inflammatory molecules, growth factors, etc
AGING ?
EPITHELIUMBasement Membrane
STROMA
YOUNG TISSUE "Initiated" Cell
Neoplastic Growth