Endocrine signaling in Caenorhabditis elegans controls stress response and longevity.

Modulation of insulin/IGF signaling in the nematode Caenorhabditis elegans is the central determinant of the endocrine control of stress response, diapause, and aging. Mutations in many genes that interfere with, or are controlled by, insulin signaling have been identified in the last decade by genetic analyses in the worm. Most of these genes have orthologs in vertebrate genomes, and their functional characterization has provided multiple hints about conserved mechanisms for the genetic influence on aging. The emerging picture is that insulin-like molecules, through the activity of the DAF-2/insulin/ IGF-I-like receptor, and the DAF-16/FKHRL1/FOXO transcription factor, control the ability of the organism to deal with oxidative stress, and interfere with metabolic programs that help to determine lifespan.

Recent aging research in Caenorhabditis elegans.

Evidence gathered over the past 15 years shows that the nematode Caenorhabditis elegans is excellently suited as a model to study aging processes in the entire organism. Genetic approaches have been used to identify and elucidate multiple mechanisms and their corresponding genes that limit the life span of C. elegans. These highly conserved pathways include the well-studied insulin/IGF-1 receptor-like signaling pathway, which is thought to be a central determinant of life span, since several other mechanisms depend or converge on the insulin/IGF-1 pathway transcription factor DAF-16/FoxO. In this review we focus on new insights into the molecular mechanisms of aging in C. elegans, including new genes acting in the insulin/IGF-1 pathway and germline signaling. In addition, stress response pathways and mitochondrial mechanisms, dietary restriction, SIR2 deacetylase activity, TOR and TUBBY signaling, as well as telomere length contribution are discussed in relation to recent developments in C. elegans aging research.

Aging at the interface of stem cell renewal, apoptosis, senescence, and cancer.

The aging-related research field has focused on the detection of genetic factors that affect the aging process, but more recently scientists have started to shift their attention to novel and more integrative ways of studying cellular and organismal function. Such approaches allow them to uncover and explore unexpected patterns and themes, resulting in a more comprehensive knowledge of the complex regulatory pathways and networks involved in aging and age-related diseases. Eventually, this knowledge will lead to a systems-level understanding of aging. The third "Functional Genomics of Aging" conference held in Palermo, Italy, in March/April 2006 highlighted some of the more exciting work in this area.

Trigger Factor and DnaK possess overlapping substrate pools and binding specificities.

Ribosome-associated Trigger Factor (TF) and the DnaK chaperone system assist the folding of newly synthesized proteins in Escherichia coli. Here, we show that DnaK and TF share a common substrate pool in vivo. In TF-deficient cells, deltatig, depleted for DnaK and DnaJ the amount of aggregated proteins increases with increasing temperature, amounting to 10% of total soluble protein (approximately 340 protein species) at 37 degrees C. A similar population of proteins aggregated in DnaK depleted tig+ cells, albeit to a much lower extent. Ninety-four aggregated proteins isolated from DnaK- and DnaJ-depleted deltatig cells were identified by mass spectrometry and found to include essential cytosolic proteins. Four potential in vivo substrates were screened for chaperone binding sites using peptide libraries. Although TF and DnaK recognize different binding motifs, 77% of TF binding peptides also associated with DnaK. In the case of the nascent polypeptides TF and DnaK competed for binding, however, with competitive advantage for TF. In vivo, the loss of TF is compensated by the induction of the heat shock response and thus enhanced levels of DnaK. In summary, our results demonstrate that the co-operation of the two mechanistically distinct chaperones in protein folding is based on their overlap in substrate specificities.