CELLULAR AGING AND LONGEVITY Lawrence Berkeley National Laboratory Buck Institute for Age Research

What IS Aging?

Aging is a biological process Aging 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 SPAN ORGANISMS Single-celled Min/hrs Multi-cellular, Post-mitotic Days/wks Years Multi-cellular, Post-mitotic + Renewable tissues No 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 Cellular aging

A closer look …… Cellular senescence (cellular aging)

'Young' Presenescent 'Aged' Senescent Senescent human fibroblasts

Short/dysfunctional telomeres DNA Damage Oncogenes Chromatin Instability Stress/damage Signals Cellular Senescence: Arrests Cell Growth In response to Potential Cancer-Causing Events Irreversible arrest of cell growth

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 epithelial cell Nucleus Basement membrane Mammary alveoli (in culture and in vivo) + lactogenic hormones Milk proteins Mammary fibroblast

 -casein DAPI Young fibroblasts  -casein E-cadherin Mammary alveoli: effect of senescent/'aged' fibrobasts 'Aged" fibroblasts

Mammary epithelial cell Collagen stroma Mammary branching Mammary fibroblast

Mammary branching: effect of senescent/'aged' fibrobasts Primary duct Secondary duct Core Young fibroblasts'Aged" fibroblasts

Senescent cells and normal tissue function and structure Cancer protection Aging tissues Bad news!

Good news! We can identify many of the molecules produced by senescent cells ….and…. We can inhibit some of them!

Core Area Number PRIMARY SECONDARYTERTIARY Mammary branching: effect of senescent/'aged' fibrobasts Young fibroblasts'Aged" fibroblasts

Mammary branching -- undoing the effect of senescent/'aged' fibroblasts Young Aged Total branching 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 and Friends -- including CREA NIH/NIA, DOD, DOE