The Salk Institute for Biological Studies

Andrew Dillin

Tony Hunter

Hui Ma

Suzanne C Wolff

Joseph Noel

Thomas J Baiga

Erik Kapernick

Andrea C Carrano

The disclosure provides methods and compositions useful for screening inhibitors of aggregation mediated proteotoxicity. The disclosure provides transgenic animals and cell useful for such screening. Also provided are compounds useful for inhibiting aggregation mediated proteotoxicity in a subject.

Methods for screening and compounds that protect against amyloid diseases

Ubiquitin ligase wwp-1 and ubiquitin conjugating enzyme ubc-18 are identified in nematodes as mediators of dietary restriction induced longevity and therefore as targets for modulation of lifespan in animals. Methods of screening for compounds that modulate longevity by assaying wwp-1 ubiquitination pathway parameters are provided, as are related systems. In addition, methods of using wwp-1 and/or ubc-18 to modulate longevity or delay onset of age-related diseases are described.

Increasing lifespan by modulation of WWP-1 and UBC-18

The Smek (Suppressor of mek null) gene is described and characterized. Smek acts in the stress response pathway of animals by binding to and enhancing the transcription of FOXO, thereby providing the link between the stress response pathway and the insulin/IGF-1 pathway. Given the link between both the stress response pathway and the insulin/IGF-1 pathway and longevity, Smek1 represents an essential target for modulation of life span and the stress response. Methods of increasing life span and stress tolerance by modulation of Smek activity are disclosed, as are screening methods for identifying compounds that modulate Smek activity. In addition, recombinant animals expressing the Smek gene that have a longer life span and enhanced stress tolerance, and methods of using the Smek gene to modulate both longevity and stress tolerance, are described.

Increasing life span by modulation of Smek

The Smek (Suppressor of mek null) gene is described and characterized. Smek acts in the stress response pathway of animals by binding to and enhancing the transcription of FOXO, thereby providing the link between the stress response pathway and the insulin/IGF-1 pathway. Given the link between both the stress response pathway and the insulin/IGF-1 pathway and longevity, Smek1 represents an essential target for modulation of life span and the stress response. Methods of increasing life span and stress tolerance by modulation of Smek activity are disclosed, as are screening methods for identifying compounds that modulate Smek activity. In addition, recombinant animals expressing the Smek gene that have a longer life span and enhanced stress tolerance, and methods of using the Smek genet to modulate both longevity and stress tolerance, are described.

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San Diego, CA, United States of America

Andrew Dillin