Transcript Document

Lawrence Berkeley National Laboratory
CELLULAR AGING AND
LONGEVITY
Buck Institute for Age Research
What IS Aging?
Aging is a PROCESS that converts a
healthy, fit organism (for its
environment) into one that is
less healthy and fit
Aging is a biological process
Aging not disease, per se
AGING
Reduced tissue/physiological function
Increased susceptibility to disease
(age-related diseases)
Decreased resistance to stress
(physical and psychological)
Why does aging happen?
If we don't understand this, we can’t
design rational interventions!
What can we do about it?
How can we postpone the
effects of aging?
Aging occurs at multiple levels
• molecules
• cells
• tissues
• organ systems
Cells = molecules + response
-----> tissue, organ system effects
Cellular “aging” = response to
damage or stress
Cell death
(apoptosis)
Arrested cell growth
(cell senescence)
Cellular “aging” responses:
YIN and YANG
Good news!
(prevents cancer)
Bad news!
(promotes aging)
Years
Days/wks
Min/hrs
LIFE SPAN
Evolution of Long-Lived Organisms
Single-celled
No
Cancer
Multi-cellular,
Post-mitotic
Cancer
Multi-cellular, Post-mitotic +
Renewable tissues
ORGANISMS
CELL DIVISION IS RISKY!!
Cancer
The bad news!
Cancer risk rises exponentially with age
Fueled by (somatic) mutations
Mutations caused by DNA damage,
from endogenous and exogenous sources
Cancer
The good news!
Genes evolved to protect from cancer
(tumor suppressor genes)
Tumor suppressor genes cause damaged
cells to die or arrest growth
(undergo apoptosis or senescence)
Ooops! Apoptosis and senescence
= cellular ‘aging’ responses!
Tumor suppression and aging:
An evolutionary balancing act!
Cancer
protection
Cellular
aging
A closer look ……
Cellular senescence
(cellular aging)
Senescent human fibroblasts
'Young'
Presenescent
'Aged'
Senescent
Cellular Senescence: Arrests Cell Growth
In response to Potential Cancer-Causing Events
Chromatin
Instability
Irreversible
arrest of
cell
growth
DNA
Damage
Stress/damage
Signals
Oncogenes
Short/dysfunctional
telomeres
Senescent/'aged' cells:
Many characteristics change
Irreversible
Growth
Arrest
Resistance
to
Apoptosis
Altered
Function/Gene
Expression
Senescent changes in gene expression
Cell division control
Cell structure
Metabolism
Biologically active secreted molecules
Proteinases
Cytokines
Growth factors
What can molecules secreted by
senescent/'aged' cells do?
Disrupt normal tissue differentiation
Example: milk production by
mammary cells
Mammary alveoli (in culture and in vivo)
Mammary
epithelial
cell
+ lactogenic
hormones
Milk
proteins
Basement
membrane
Nucleus
Mammary
fibroblast
Mammary alveoli:
effect of senescent/'aged' fibrobasts
Young fibroblasts
'Aged" fibroblasts
b-casein
E-cadherin
b-casein
DAPI
Mammary branching
Mammary
epithelial
cell
Collagen
stroma
Mammary
fibroblast
Mammary branching:
effect of senescent/'aged' fibrobasts
Young fibroblasts
Primary duct
Secondary duct
Core
'Aged" fibroblasts
Bad news!
Senescent cells and
normal tissue function and structure
Cancer
protection
Aging
tissues
Good news!
We can identify many of the molecules
produced by senescent cells
….and….
We can inhibit some of them!
Number
Core Area
Mammary branching:
effect of senescent/'aged' fibrobasts
PRIMARY
Young fibroblasts
SECONDARY
TERTIARY
'Aged" fibroblasts
Mammary branching -- undoing the effect
of senescent/'aged' fibroblasts
Young Aged
Aged +
HGF Ab
MMPi
Specifically MMP3
Maybe!
(we're working it!)
Cancer
protection
Aging
Acknowledgements
Thanks to:
Many present and past lab members
(Jean-Philippe Coppe, Ana Krtolica,
Simona Parrinello Elliot)
Many colleagues, collaborators and
Friends -- including CREA
NIH/NIA, DOD, DOE