CELLULAR AGING AND LONGEVITY Lawrence Berkeley National Laboratory Buck Institute for Age Research.
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Transcript of CELLULAR AGING AND LONGEVITY Lawrence Berkeley National Laboratory Buck Institute for Age Research.
CELLULAR AGING ANDLONGEVITY
Lawrence Berkeley National Laboratory
Buck Institute for Age Research
What IS Aging?
Aging is a biological processAging not disease, per se
Aging is a PROCESS that converts a healthy, fit organism (for its
environment) into one that is less healthy and fit
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)
Evolution of Long-Lived Organisms
LIFE
SPA
N
ORGANISMS
Single-celled
Min
/hrs
Multi-cellular, Post-mitotic
Day
s/w
ks
Year
s
Multi-cellular, Post-mitotic +Renewable tissues
No Cancer
Cancer
CELL DIVISION IS RISKY!!
Cancer
Cancer risk rises exponentially with age
Fueled by (somatic) mutations
The bad news!
Mutations caused by DNA damage, from endogenous and exogenous sources
Cancer
Genes evolved to protect from cancer(tumor suppressor genes)
Tumor suppressor genes cause damaged cells to die or arrest growth
(undergo apoptosis or senescence)
The good news!
Ooops! Apoptosis and senescence= cellular ‘aging’ responses!
Tumor suppression and aging:An evolutionary balancing act!
Cancer protection
Cellularaging
A closer look ……
Cellular senescence(cellular aging)
'Young'Presenescent
'Aged'Senescent
Senescent human fibroblasts
Short/dysfunctionaltelomeres
DNADamage Oncogenes
ChromatinInstability
Stress/damage Signals
Cellular Senescence: Arrests Cell Growth In response to Potential Cancer-Causing Events
Irreversiblearrest of
cell growth
Senescent/'aged' cells:Many characteristics change
IrreversibleGrowth Arrest
Resistanceto
Apoptosis
AlteredFunction/Gene
Expression
Senescent changes in gene expression
Cell division control
Cell structure
Metabolism
Biologically active secreted moleculesProteinasesCytokines
Growth factors
What can molecules secreted bysenescent/'aged' cells do?
Disrupt normal tissue differentiation
Example: milk production by mammary cells
Mammaryepithelial
cell
NucleusBasementmembrane
Mammary alveoli (in culture and in vivo)
+ lactogenichormones
Milk proteins
Mammaryfibroblast
-casein DAPI
Young fibroblasts
-casein
E-cadherin
Mammary alveoli: effect of senescent/'aged' fibrobasts
'Aged" fibroblasts
Mammaryepithelial
cell
Collagenstroma
Mammary branching
Mammaryfibroblast
Mammary branching: effect of senescent/'aged' fibrobasts
Primary ductSecondary duct
Core
Young fibroblasts 'Aged" fibroblasts
Senescent cells andnormal tissue function and structure
Cancer protection
Agingtissues
Bad news!
Good news!
We can identify many of the molecules produced by senescent cells
….and….
We can inhibit some of them!
Cor
e A
rea
Num
ber
PRIMARY SECONDARY TERTIARY
Mammary branching: effect of senescent/'aged' fibrobasts
Young fibroblasts 'Aged" fibroblasts
Mammary branching -- undoing the effectof senescent/'aged' fibroblasts
Young Aged
Tota
l br a
n chi
ng
Specifically MMP3
Aged + HGF Ab MMPi
Cancer protection
Aging
Maybe!(we're working it!)
Acknowledgements
Thanks to:
Many present and past lab members
(Jean-Philippe Coppe, Ana Krtolica,Simona Parrinello Elliot)
Many colleagues, collaborators andFriends -- including CREA
NIH/NIA, DOD, DOE