We have uncovered a novel genetic pathway that determines adult lifespan in the nematode Caenorhabditis elegans. This pathway encodes components of DNA damage/cell cycle checkpoints, which are known to prevent inappropriate cell division. However, because non-dividing cells comprise the C. elegans adult soma, it appears that these checkpoint proteins also control the survival of cells in a postmitotic state. Down-regulation of checkpoint functions in adult C. elegans renders them very stress resistant and extends their lifespan. Through a whole genome RNA interference screen, we determined that many novel genes encode checkpoint functions and influence lifespan. We now propose to determine the mechanism(s) by which these genes act during aging and survival, and whether their functions are conserved in mammals. We will determine the role of lifespan-modulating checkpoint proteins in the survival of nematode neurons, which are crucial regulators of nematode lifespan, mouse cortical neurons, and dopaminergic neurons derived from human embryonic stem cells. We will modulate checkpoint functions in these post-mitotic cells and determine their resistance genotoxic and cytotoxic insults. We will identify chemical compounds that modulate survival through checkpoints, with a view to developing novel interventions into aging and neurological disease. This interdisciplinary project requires expertise in invertebrate aging, mammalian neuroscience, high throughout screening, chemical biology, molecular genetics and stem cell biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Linked Research project Grant (RL1)
Project #
5RL1ES016655-05
Application #
8102159
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Balshaw, David M
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$373,054
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
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Alavez, Silvestre; Lithgow, Gordon J (2012) Pharmacological maintenance of protein homeostasis could postpone age-related disease. Aging Cell 11:187-91
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McColl, Gawain; Rogers, Aric N; Alavez, Silvestre et al. (2010) Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans. Cell Metab 12:260-72
Bhaumik, Dipa; Scott, Gary K; Schokrpur, Shiruyeh et al. (2009) MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY) 1:402-11