Transcription factors regulating lifespan of Caenorhabditis elegans

Aging is a gradual decline of physiologic function, that affects nearly all living organisms. An extensive body of research aims to unravel and understand the underlying processes and influences on aging. This research shows that aging is a complex process integrating numerous molecular pathways and biochemical interactions. Over the last decades, scientists have found conserved molecular pathways, as well as exogenous and endogenous stressors and small molecules, which regulate life span. Diet, single-gene mutations and tissues play interconnected roles in this process. The reproductive system is best known for sexual reproduction, but strongly impacts metabolism and longevity. Inhibition of germ line stem cell proliferation extends the lifespan of an organism, termed gonadal longevity. This interaction is extensively described in Caenorhabditis elegans, but may be conserved up to humans. Several mediators and pathways are identified and proposed to work in an integrated network enhancing homeostasis and prolonging life. Yet the map of this network is incomplete and many other factors remain to be elucidated. A comprehensive knowledge of this network could lead new approaches to attenuate the process of aging. In this study, we use Caenorhabditis elegans to study gonadal longevity. Gonadal longevity can be induced by different modes, including temperature sensitive single-gene mutations that disrupt germline proliferation, such as glp-1/Notch, mes-1/tyrosine kinase or laser micro-surgical removal of the germline. This study unravels the impact of two transcription factors on gonadal longevity. On the one hand, NHR-91, a homolog of NR6A, regulates GLP-1/NOTCH longevity, but not other modes of gonadal longevity. We show that loss of NHR-91 leads to a misregulation of fatty-acid desaturases and their products in glp-1 mutants. On the other hand, ATF-5, a homolog of mammalian ATF4, is a transcriptional regulator of multiple modes of gonadal longevity. These findings indicate that the different modes of gonadal longevity can impact Caenorhabditis elegans through pathways or mediators that are not always congruent. Through functional genomic screens of the ATF-5 transcriptome, we identify the ER-chaperone HSP-4 as a downstream target of ATF-5, required for lifespan extension. We further find that heat shock factor HSF-1 is an upstream regulator of ATF-5. Surprisingly, two kinases known to regulate ATF-5 expression, namely GCN-2 and PEK-1, play no obvious role in regulating gonadal longevity. These studies indicate that gonadal longevity is governed by multiple transcription factors, with multiple modalities