cellular senescence what is it? what causes it? why is it important (cancer and aging)?

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