Laron Z (2008) Hormones (Athens) "The GH-IGF1 axis and longevity. The paradigm of IGF1 deficiency."

Laron Z

[Hormones (Athens), 2008]

Primary or secondary IGF1 deficiency has been implicated in shortening of lifespan. This paper reviews available data on the influence of IGF1 deficiency on lifespan and longevity in animals and man. It has been shown that inactivation of the IGF1 gene or of the GH receptor in both invertebrates (C-elegans, flies-Drosphila) and rodents (mice and rats), leading to IGF1 deficiency, prolong life, particularly in females. In man, evaluation of the 2 largest cohorts of patients with Laron syndrome (inactive GH receptor resulting in IGF1 deficiency) in Israel and Ecuador revealed that despite their dwarfism and marked obesity, patients are alive at the ages of 75-78 years, with some having reached even more advanced ages. It is assumed that a major contributing factor is their protection from cancer, a major cause of death in the general population.

Morgan PG et al. (2007) WormBook "C. elegans and volatile anesthetics."

Sedensky MM, Morgan PG, Kayser EB

[WormBook, 2007]

The mechanism of action of volatile anesthetics remains an enigma, despite their worldwide use. The nematode C. elegans has served as an excellent model to unravel this mystery. Genes and gene sets that control the behavior of the animal in volatile anesthetics have been identified, using multiple endpoints to mimic the phenomenon of anesthesia in man. Some of these studies have clear translational implications in more complicated organisms.

McDonald PW et al. (2006) Cell Mol Neurobiol "Dopamine signaling architecture in Caenorhabditis elegans."

Jessen T, McDonald PW, Blakely RD, Field JR

[Cell Mol Neurobiol, 2006]

1. Aims: In this review, we highlight the identification and analysis of molecules orchestrating dopamine (DA) signaling in the nematode Caenorhabditis elegans, focusing on recent characterizations of DA transporters and receptors.2. Methods: We illustrate the isolation and characterization of molecules important for C. elegans DA synthesis, packaging, reuptake and signaling and examine how mutations in these proteins are being exploited through in vitro and in vivo paradigms to yield novel insights of protein structure, DA signaling pathways and DA-supported behaviors.3. Results: DA signaling in the worm, as in man, arises by synaptic and nonsynaptic release from a small number of cells that exert modulatory control over a larger network underlying C. elegans behavior.4. Conclusions: The C. elegans model system offers unique opportunities to elucidate ill-defined pathways that support DA release, inactivation, and signaling in addition to clarifying mechanisms of DA-mediated behavioral plasticity. Further use of the model offers prospects for the identification of novel genes and proteins whose study may yield benefits for DA-supported neural disorders in man.

Gottlieb RA (2000) FEBS Lett "Mitochondria: execution central."

Gottlieb RA

[FEBS Lett, 2000]

Mitochondria play an essential function in eukaryotic life and death. They also play a central role in apoptosis regulation, reflected by the convergence of Bcl-2 family members on the mitochondrial outer membrane, and the presence of 'death factors' in the intermembrane space. Mitochondrial structure and function must be taken into consideration when evaluating mechanisms for cytochrome c release. The core machinery for caspase activation is conserved from Caenorhabditis elegans to man, and we consider parallels in the role of mitochondria in this process.

Mitchell DL et al. (1990) BioEssays "The regulation of DNA repair during development."

Hartman PS, Mitchell DL

[BioEssays, 1990]

DNA repair is important in such phenomena as carcinogenesis and aging. While much is known about DNA repair in single-cell systems such as bacteria, yeast, and cultured mammalian cells, it is necessary to examine DNA repair in a develomental context in order to completely understand its processes in complex metazoa such as man. We present data to support the notion that proliferating cells from organ systems, tumors, and embryos have a greater DNA repair capacity than terminally differentiated, nonproliferating cells. Differential expression of repair genes and accessibility of chromatin to repair enzymes are considered as determinants in the developmental regulation of DNA repair.

Casamassimi A et al. (2007) Biochimie "Mediator complexes and eukaryotic transcription regulation: an overview."

Casamassimi A, Napoli C

[Biochimie, 2007]

Mediator is an essential component of the RNA polymerase II-mediated transcription machinery. This component plays a key role both in the stimulation of basal transcription and in the regulation of eukaryotic mRNA synthesis. The Saccharomyces cerevisiae Mediator complex was the first to be studied and consists of at least 20 different subunits with multiple activities. Afterwards, its subunit composition was determined and related functions of C. elegans, Drosophila and mammalian complexes show a striking evolutionary conservation both of the structure and function from yeast to man. Recently, yeast studies strongly suggest additional roles for Mediator in coordinating transcription initiation with downstream transcriptional events in the coding region of genes; consequently, new models of recruitment-coupled regulation have been indicated. Further studies on transcription machinery should expand our knowledge of the pathways in which variant components of Mediator, or variant proteins interacting directly or in complexes, represent risk factors for complex inheritable disease.

Artal-Sanz M et al. (2008) IUBMB Life "Mechanisms of aging and energy metabolism in Caenorhabditis elegans."

Artal-Sanz M, Tavernarakis N

[IUBMB Life, 2008]

Aging studies on diverse species ranging from yeast to man have culminated in the delineation of several signaling pathways that influence the process of senescent decline and aging. While understanding these interlinked signal-transduction cascades is becoming even more detailed and comprehensive, the cellular and biochemical processes they impinge upon to modulate the rate of senescent decline and aging have lagged considerably behind. This fundamental question is one of the most important challenges of modern aging research and has been the focus of recent research efforts. Emerging findings provide insight into the facets of cellular metabolism which can be fine-tuned by upstream signaling events to ultimately promote longevity. Here, we survey the mechanisms regulating aging in the simple nematode worm Caenorhabditis elegans, aiming to highlight recent discoveries that shed light into the interface between aging signaling pathways and cellular energy metabolism. Our objective is to review the current understanding of the processes involved and discuss mechanisms that are likely conserved in higher organisms. (c) 2008 IUBMB IUBMB Life, 60(5): 315-322, 2008.

Dwyer DS (2018) Mol Neuropsychiatry "Crossing the Worm-Brain Barrier by UsingCaenorhabditis elegansto Explore Fundamentals of Human Psychiatric Illness."

Dwyer DS

[Mol Neuropsychiatry, 2018]

Endophenotypes and Research Domain Criteria (RDoC) represent recent efforts to deconvolute psychiatric illnesses into fundamental symptom clusters or biological markers more closely linked to genetic influences. By taking this one step farther, these biomarkers can be reduced to protophenotypes - endophenotypes conserved during evolution - with counterparts in lower organisms including<i>Caenorhabditis elegans</i>and<i>Drosophila</i>. Striking conservation in<i>C. elegans</i>of genes that increase the risk for mental illness bolsters the relevance of this model system for psychiatric research. Here, I review the characterization of several protophenotypes that are relevant for asociality, avolition/anhedonia, prepulse inhibition, and anorexia. Interestingly, the analogous behavioral defects in<i>C. elegans</i>are also corrected by psychotropic drugs used to treat the corresponding symptoms in man and/or are mediated by the same neurotransmitters. Overall, there is much we can learn about the complex human brain by studying simpler nervous systems directing evolutionarily conserved behaviors. The potential for generating important new insights from model organisms appears limitless when we begin to recognize the vestiges of evolution in ourselves.

Paschinger K et al. (2019) Front Mol Biosci "N-glycomic Complexity in Anatomical Simplicity: Caenorhabditis elegans as a Non-model Nematode?"

Yan S, Paschinger K, Wilson IBH

[Front Mol Biosci, 2019]

<i>Caenorhabditis elegans</i> is a genetically well-studied model nematode or &quot;worm&quot;; however, its N-glycomic complexity is actually baffling and still not completely unraveled. Some features of its N-glycans are, to date, unique and include bisecting galactose and up to five fucose residues associated with the asparagine-linked Man_2-3GlcNAc₂ core; the substitutions include galactosylation of fucose, fucosylation of galactose and methylation of mannose or fucose residues as well as phosphorylcholine on antennal (non-reducing) <i>N-</i>acetylglucosamine. Only some of these modifications are shared with various other nematodes, while others have yet to be detected in any other species. Thus, <i>C. elegans</i> can be used as a model for some aspects of N-glycan function, but its glycome is far from identical to those of other organisms and is actually far from simple. Possibly the challenges of its native environment, which differ from those of parasitic or necromenic species, led to an anatomically simple worm possessing a complex glycome.

Schumacher B et al. (2006) Future Oncol "Translational regulation of p53 as a potential tumor therapy target."

Schumacher B, Gartner A

[Future Oncol, 2006]

The tumor suppressor p53 is a central player in apoptosis induction in response to oncogenic stimuli and DNA damage. As activation of p53 has been suggested as a prime strategy for future tumor therapy, inhibition of negative regulators of p53 activity would be a similarly desirable strategy. The small worm Caenorhabditis elegans is a model organism in which many conserved biological pathways, including the core apoptotic machinery, were elucidated. The discovery of a worm p53 homolog cep-1/p53 (which stands for C. elegans p53) that specifically induces apoptosis upon DNA damage through a pathway that is conserved from worm to man opened the way for the use of C. elegans genetics to uncover regulatory mechanisms - and hence novel therapeutic targets - of p53-mediated apoptosis. The authors have recently reported a novel mechanism of C. elegans cep-1/p53 regulation through germ line defective-1-mediated translational repression. This review discusses the potential of the worm system to screen for apoptosis-inducing cancer drugs and to identify novel p53 regulators whose human counterparts might become potential tumor therapy targets.