Methods of identifying longevity modulators and therapeutic methods of use thereof
The present invention is based at least in part on the discovery of a role for the JNK signaling pathway in longevity. In particular, the present inventors have shown that modulation of the c-jun N-terminal kinase (JNK) signaling pathway in an organism, optionally in combination with modulation of the insulin receptor (IR) signaling pathway, can enhance longevity in an organism. Accordingly, the present invention features methods of identifying modulators of longevity in assays featuring organisms and/or cells having either a functional or deregulated JNK signaling pathway and, optionally, a functional or deregulated IR signaling pathway. Also featured is an in vitro method of identifying an agent capable of enhancing longevity featuring an assay composition having a JNK signaling pathway molecule and insulin signaling pathway molecule. Further featured are therapeutic methods for the use of JNK signaling pathway modulators to enhance longevity.
1. A method for identifying an agent capable of increasing lifespan, comprising:
contacting an organism selected from the group consisting of nematodes, yeast and Drosophila with a test agent;
assaying for the ability of the test agent to increase the activity of c-jun N-terminal kinase-1 (JNK-1) and localization of DAF-16 to the nucleus when compared to a suitable control to which no agent is added; and
selecting an agent that increases JNK-1 activity and nuclear localization of DAF-16;
to thereby identify an agent capable of increasing lifespan.
2. The method of claim 1 , wherein the organism is a nematode.
3. The method of claim 2 , wherein the nematode is C. elegans.
4. The method of claim 2 , wherein the nematode is a parasitic nematode.
5. The method of claim 1 , further comprising assaying for the ability of the test agent to affect a detectable phenotype selected from the group consisting of lifespan and stress resistance in said organisms as compared to a suitable control.
6. The method of claim 5 , wherein said stress is selected from the group consisting of oxidative stress, ultraviolet (UV) stress, hypoxic stress, heavy metal stress and heat stress.
7. The method of claim 1 , wherein the organism has decreased JNK-1 activity.
8. The method of claim 1 , wherein the organism has a deregulated insulin signaling pathway molecule selected from the group consisting of DAF-2, AAP-1, IRS, AGE-1, PDK-1, AKT-1, AKT-2 and DAF-18, or orthologue thereof.
9. The method of claim 1 , wherein JNK-1 activity is determined by measuring the phosphorylation of JNK-1.
10. The method of claim 1 , wherein JNK-1 activity is determined by measuring the kinase activity of JNK-1.