title: An age-dependent reversal in the protective capacities of JNK signaling shortens Caenorhabditis elegans lifespan.
abstract: Stress-activated protein kinase (SAPK) pathways are evolutionarily conserved signaling modules that orchestrate protective responses to adverse environmental conditions. However, under certain conditions, their activation can be deleterious. Thus, activation of the c-Jun N-terminal kinase (JNK) SAPK pathway exacerbates a diverse set of pathologies, many of which are typical of old age. The contexts determining whether the outcome of JNK signaling is protective or detrimental are not fully understood. Here, we show that the age of an animal defines such a context. The Caenorhabditis elegans JNK homolog, KGB-1, provides protection from heavy metals and protein folding stress in developing animals. However, we found that with the onset of adulthood, KGB-1 activity becomes detrimental, reducing stress resistance and lifespan. Genetic analyses coupled with fluorescent imaging linked this phenotypic switch to age-dependent antagonistic modulation of DAF-16/FOXO: KGB-1 activation enhanced DAF-16 nuclear localization and transcriptional activity during development but decreased it in adults. Epistasis analyses showed that DAF-16 was necessary and sufficient to explain some of the kgb-1-dependent detrimental phenotypes, but not all. The identification of early adulthood as a point following which the contribution of KGB-1 activity reverses from beneficial to detrimental sheds new light on the involvement of JNK signaling in age-related pathologies. Furthermore, the age-dependent reversal has intriguing implications for our understanding of aging.
authors.affiliation: Graduate Group in Microbiology, University of California at Berkeley, CA 94720-3102, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Twumasi-Boateng
authors.forename: Tim W
authors.initials: TW
authors.lastname: Wang
authors.forename: Linda
authors.initials: L
authors.lastname: Tsai
authors.forename: Kuang-Hui
authors.initials: KH
authors.lastname: Lee
authors.forename: Ali
authors.initials: A
authors.lastname: Salehpour
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Bhat
authors.forename: Man-Wah
authors.initials: MW
authors.lastname: Tan
authors.forename: Michael
authors.initials: M
authors.lastname: Shapira
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D002104:Cadmium / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051858:Forkhead Transcription Factors; D055785:Gene Knockdown Techniques; D017238:Genes, Helminth; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D010641:Phenotype; D034622:RNA Interference; D013312:Stress, Physiological; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D002104:Cadmium; D048031:JNK Mitogen-Activated Protein Kinases; C524496:KGB-1 protein, C elegans; D054637:Dual-Specificity Phosphatases; C501201:VHP-1 protein, C elegans