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