Biomedical subjects

Heidi A Tissenbaum

Publications and source records attributed to Heidi A Tissenbaum.

11 recordsLinked to original sources

PubMed2006

Reproduction and longevity: secrets revealed by C. elegans.

What is the relationship between reproduction and longevity? Evolutionary biology suggests that reproduction exacts a cost in somatic maintenance, a cost that reduces longevity. The frequent occurrence of this tradeoff between life span and fecundity, both due to experimental manipulations as well as natural variation, suggest that the mechanism might be conserved during evolution. Until recently, little was known about the mechanistic details of how reproduction might regulate life span. Here we discuss recent advances in our understanding of the regulation of life span by reproductive signaling, focusing on studies using Caenorhabditis elegans.

Aging↗

PubMed2006

C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO.

14-3-3 proteins are evolutionarily conserved and ubiquitous proteins that function in a wide variety of biological processes. Here we define a new role for C. elegans 14-3-3 proteins in life span regulation. We identify two C. elegans 14-3-3 proteins as interacting proteins of a major life span regulator, the C. elegans SIR2 ortholog, SIR-2.1. Similar to sir-2.1, we find that overexpression of either 14-3-3 protein (PAR-5 or FTT-2) extends life span and that this is dependent on DAF-16, a forkhead transcription factor (FOXO), another important life span regulator in the insulin/IGF-1 signaling pathway. Furthermore, we show that both 14-3-3 proteins are co-expressed with DAF-16 and SIR-2.1 in the tissues critical for life span regulation. Finally, we show that DAF-16/FOXO also physically interacts with the 14-3-3 proteins. These results suggest that C. elegans 14-3-3 proteins can regulate longevity by cooperating with both SIR-2.1 and DAF-16/FOXO.

14-3-3 Proteins↗

PubMed2006

Worming pathways to and from DAF-16/FOXO.

In Caenorhabditis elegans, the insulin/IGF-1 signaling pathway controls many biological processes such as life span, fat storage, dauer diapause, reproduction and stress response . This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO). DAF-16 also receives input from several other pathways that regulate life span such as the germline and the JNK pathway [Hsin, H., Kenyon, C., 1999. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362-366; Oh, S.W., Mukhopadhyay, A., Svrzikapa, N., Jiang, F., Davis, R.J., Tissenbaum, H.A., 2005. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. USA 102, 4494-4499]. Therefore, DAF-16 integrates signals from multiple pathways and regulates its downstream target genes to control diverse processes. Here, we discuss the signals to and from DAF-16, with a focus on life span regulation.

Aging↗

PubMed2006

A gene-centered C. elegans protein-DNA interaction network.

Transcription regulatory networks consist of physical and functional interactions between transcription factors (TFs) and their target genes. The systematic mapping of TF-target gene interactions has been pioneered in unicellular systems, using "TF-centered" methods (e.g., chromatin immunoprecipitation). However, metazoan systems are less amenable to such methods. Here, we used "gene-centered" high-throughput yeast one-hybrid (Y1H) assays to identify 283 interactions between 72 C. elegans digestive tract gene promoters and 117 proteins. The resulting protein-DNA interaction (PDI) network is highly connected and enriched for TFs that are expressed in the digestive tract. We provide functional annotations for approximately 10% of all worm TFs, many of which were previously uncharacterized, and find ten novel putative TFs, illustrating the power of a gene-centered approach. We provide additional in vivo evidence for multiple PDIs and illustrate how the PDI network provides insights into metazoan differential gene expression at a systems level.

Animals↗

PubMed2006

Serotonin's SOS signal.

Neurotransmitters relay signals within the brain and to peripheral tissues, allowing communication between nerve cells. New work from in this issue of Cell Metabolism reveals that, in C. elegans, serotonin functions during conditions of stress through the well-characterized insulin/IGF-1 signaling pathway, suggesting a mechanism for the stress response.

Active Transport, Cell Nucleus↗

PubMed2005

Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation.

DAF-16, a forkhead transcription factor, is a key regulator of longevity, metabolism and dauer diapause in Caenorhabditis elegans. The precise mechanism by which DAF-16 regulates multiple functions, however, is poorly understood. Here, we used chromatin immunoprecipitation (ChIP) to identify direct targets of DAF-16. We cloned 103 target sequences containing consensus DAF-16 binding sites and selected 33 targets for further analysis. Expression of most of these genes is regulated in a DAF-16-dependent manner, and inactivation of more than half of these genes significantly altered DAF-16-dependent functions, including life span, fat storage and dauer formation. Our results show that the ChIP-based cloning strategy leads to greater enrichment for DAF-16 target genes than previous screening strategies. We also demonstrate that DAF-16 is recruited to multiple promoters to coordinate regulation of its downstream targets. The large number of target genes discovered provides insight into how DAF-16 controls diverse biological functions.

Alleles↗

PubMed2005

Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO.

The conserved SIR2 protein regulates life span in both yeast and worms: in both organisms overexpression of SIR2 can extend life span and in Caenorhabditis elegans this life span extension is dependent on the forkhead transcription factor, DAF-16. Here, we have done extensive genetic analysis with sir-2.1(ok434), a null mutant of C. elegans sir-2.1, the closest homolog to yeast Sir2p and human SIRT1 to further elucidate its function in life span regulation. sir-2.1(ok434) mutants show a slight decrease in life span as well as sensitivity to various stresses. Our genetic analysis suggests that sir-2.1 is required for life span extension by caloric restriction, independent of the insulin/IGF-1 signaling pathway. Importantly, analysis with unc-13 mutants indicates that sir-2.1 and daf-16 have overlapping and distinct roles in life span regulation. Our expression analysis shows that sir-2.1 has overlapping and distinct expression pattern compared with daf-16, consistent with the results from our genetic data. Our data defines a central role for C. elegans SIR2 in regulation of life span by caloric restriction and demonstrates that sir-2.1 and daf-16 have both overlapping and distinct functions in regulation of C. elegans life span.

Aging↗

PubMed2005

Bloom syndrome ortholog HIM-6 maintains genomic stability in C. elegans.

Bloom syndrome is caused by mutation of the Bloom helicase (BLM), a member of the RecQ helicase family. Loss of BLM function results in genomic instability that causes a high incidence of cancer. It has been demonstrated that BLM is important for maintaining genomic stability by playing a role in DNA recombination and repair; however, the exact function of BLM is not clearly understood. To determine the mechanism by which BLM controls genomic stability in vivo, we examined the phenotypes caused by mutation of the C. elegans BLM helicase ortholog, HIM-6. We find that the loss of HIM-6 leads to genomic instability as evidenced by an increased number of genomic insertions and deletions, which results in visible random mutant phenotypes. In addition to the mutator phenotype, him-6 mutants have a low brood size, a high incidence of males, a shortened life span, and an increased amount of germ line apoptosis. Upon exposure to high temperature, him-6 mutants that are serially passed become sterile demonstrating a mortal germ line phenotype. Our data suggest a model in which loss of HIM-6 results in genomic instability due to an increased number of DNA lesions, which either cannot be repaired and/or are introduced by low fidelity recombination events. The increased level of genomic instability that leads to him-6(ok412) mutants having a shortened life span.

Animals↗

PubMed2005

JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16.

DAF-16/forkhead transcription factor, the downstream target of the insulin-like signaling in Caenorhabditis elegans, is indispensable for both lifespan regulation and stress resistance. Here, we demonstrate that c-Jun N-terminal kinase (JNK) is a positive regulator of DAF-16 in both processes. Our genetic analysis suggests that the JNK pathway acts in parallel with the insulin-like signaling pathway to regulate lifespan and both pathways converge onto DAF-16. We also show that JNK-1 directly interacts with and phosphorylates DAF-16. Moreover, in response to heat stress, JNK-1 promotes the translocation of DAF-16 into the nucleus. Our findings define an interaction between two well conserved proteins, JNK-1 and DAF-16, and provide a mechanism by which JNK regulates longevity and stress resistance.

Active Transport, Cell Nucleus↗

PubMed2005

C. elegans tubby regulates life span and fat storage by two independent mechanisms.

In C. elegans, similar to in mammals, mutations in the tubby homolog, tub-1, promote increased fat deposition. Here, we show that mutation in tub-1 also leads to life span extension dependent on daf-16/FOXO. Interestingly, function of tub-1 in fat storage is independent of daf-16. A yeast two-hybrid screen identified a novel TUB-1 interaction partner (RBG-3); a RabGTPase-activating protein. Both TUB-1 and RBG-3 localize to overlapping neurons. Importantly, RNAi of rbg-3 decreases fat deposition in tub-1 mutants but does not affect life span. We demonstrate that TUB-1 is expressed in ciliated neurons and undergoes both dendritic and ciliary transport. Additionally, tub-1 mutants are chemotaxis defective. Thus, tub-1 may regulate fat storage either by modulating transport, sensing, or responding to signals in ciliated neurons. Taken together, we define a role for tub-1 in regulation of life span and show that tub-1 regulates life span and fat storage by two independent mechanisms.

Adipose Tissue↗

PubMed2002

Model organisms as a guide to mammalian aging.

Recent studies on aging in model systems such as yeast and roundworms have revealed conserved regulation of the process in response to nutrient availability and specific genes that appear to mediate this regulation. Here we review these findings with a focus on the nematode Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae and highlight general features of the regulation of aging that may have implications for mammals.

Aging↗