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

4. THE SENESCENT PHENOTYPE
What happens when cells exhaust their replicative life span?
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. Supermitogenic/stress signals
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
Strong mitogens/
stress
Cell proliferation
(short telomeres)
DNA damage
Oncogenes
Potential Cancer Causing Events
Normal cells
('mortal')
'Immortal' cells
(precancerous)
Transformation
Cell senescence
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. What does 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 ……
Modern, protected
environment
(very VERY recent)
100%
Natural environment: predators,
infections, external hazards, etc
Survivors
Most of
human
evolution
AGE
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. Cellular senescence: Markers in culture and in vivo
p16 expression
Heterochromatic foci
Telomeric-DNA damage foci
DNA damage foci
Human skin,
stained for SA-Bgal
Dimri et al., Proc Natl Acad Sci USA, 1995

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. Parrinello et al., J Cell Sci, 2005
Senescent fibroblasts disrupt morphological and functional differentiation of epithelial cells
BM + PreS Fb BM + Sen Fb
Pre-S Fb Sen Fb
b-casein
E-cadherin
b-casein DAPI
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. The senescence response is a permanent cell growth
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