scholarly journals LEVERAGING DRUG-DRUG INTERACTIONS FOR PHARMACOLOGICAL EXTENSION OF HEALTHY LIFESPAN

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S616-S616
Author(s):  
Jan Gruber
Keyword(s):  
Drug Interactions ◽  
Regulatory Network ◽  
Pharmacological Interventions ◽  
Distinct Entity ◽  
Promising Alternative ◽  
C Elegans ◽  
Ageing Processes ◽  
Age Dependent ◽  
Gene Regulatory ◽  
Traditional Approaches

Abstract Traditional approaches aimed at delaying or preventing age-dependent diseases view each disease as a distinct entity, resulting from separate pathophysiological chains of events. However, it is becoming increasing clear that even in adult animals there remains significant plasticity in terms of ageing trajectories and lifespan, suggesting that targeting ageing processes directly may be a promising alternative strategy. However, to date effects of even the most efficacious pharmacological interventions are smaller than those of ageing mutations, even when targeting the same ageing pathways. Interestingly, it has been shown that simultaneously targeting multiple ageing pathways can result in lifespan benefits that are synergistic (more than additive). We have recently shown that dramatic lifespan and healthspan extension can also be archived by leveraging interactions between drugs targeting distinct subsets of the gene-regulatory network controlling ageing of C. elegans. These interventions were highly efficacious, even when animals were treated only as adults.

scholarly journals A developmental gene regulatory network for invasive differentiation of theC. elegansanchor cell

2019 ◽  
Author(s):  
Taylor N. Medwig-Kinney ◽  
Jayson J. Smith ◽  
Nicholas J. Palmisano ◽  
Sujata Tank ◽  
Wan Zhang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Network ◽  
Cell Fate ◽  
Regulatory Network ◽  
Cell Biology ◽  
Type I ◽  
Cell Specification ◽  
C Elegans ◽  
Gene Regulatory ◽  
Anchor Cell

ABSTRACTCellular invasion is a key part of development, immunity, and disease. Using thein vivomodel ofC. elegansanchor cell invasion, we characterize the gene regulatory network that promotes invasive differentiation. The anchor cell is initially specified in a stochastic cell fate decision mediated by Notch signaling. Previous research has identified four conserved transcription factors,fos-1a(Fos),egl-43(EVI1/MEL),hlh-2(E/Daughterless) andnhr-67(NR2E1/TLX), that mediate anchor cell specification and/or invasive differentiation. Connections between these transcription factors and the underlying cell biology that they regulate is poorly understood. Here, using genome editing and RNA interference, we examine transcription factor interactions prior to and after anchor cell specification. During invasion we identify thategl-43,hlh-2, andnhr-67function together in a type I coherent feed-forward loop with positive feedback. Conversely, prior to specification, these transcription factors function independent of one another to regulate LIN-12 (Notch) activity. Together, these results demonstrate that, although the same transcription factors can function in fate specification and differentiated cell behavior, a gene regulatory network can be rapidly re-wired to reinforce a post-mitotic, pro-invasive state.SUMMARY STATEMENTBasement membrane invasion by theC. elegansanchor cell is coordinated by a dynamic gene regulatory network encompassing cell cycle dependent and independent sub-circuits.

scholarly journals Universal transcriptomic signature of age reveals temporal scaling ofCaenorhabditis elegansaging trajectories

2017 ◽  
Author(s):  
Andrei E. Tarkhov ◽  
Ramani Alla ◽  
Srinivas Ayyadevara ◽  
Mikhail Pyatnitskiy ◽  
Leonid I. Menshikov ◽  
...  
Keyword(s):  
Principal Component ◽  
Biological Age ◽  
Adult Lifespan ◽  
C Elegans ◽  
Stochastic Function ◽  
Age Dependent ◽  
Transcriptomic Signature ◽  
Median Lifespan ◽  
Gene Regulatory ◽  
Single Number

We collected 60 age-dependent transcriptomes forC. elegansstrains including four exceptionally long-lived mutants (mean adult lifespan extended up to 9.4-fold) and three examples of RNAi treatments that increased lifespan by 19 – 35%. Principal Component Analysis (PCA) reveals aging as a transcriptomic drift along a single direction, consistent across the vastly diverse biological conditions and coinciding with the first principal component, a hallmark of the criticality of the underlying gene regulatory network. We, therefore, expected that the organism’s aging state could be characterized by a single number closely related to vitality deficit or biological age. The “aging trajectory”, i.e. the dependence of the biological age on chronological age, is then a universal stochastic function modulated by the network stiffness; a macroscopic parameter reflecting the network topology and associated with the rate of aging. To corroborate this view, we used publicly available datasets to define a transcriptomic biomarker of age and observed that the rescaling of age by lifespan simultaneously brings together aging trajectories of transcription and survival curves. In accordance with the theoretical prediction, the limiting mortality value at the plateau agrees closely with the mortality rate doubling exponent estimated at the cross-over age near the average lifespan. Finally, we used the transcriptomic signature of age to identify possible life-extending drug compounds and successfully tested a handful of the top ranking molecules inC. eleganssurvival assays and achieved up to a +30% extension of mean and median lifespan.

scholarly journals The conserved molting/circadian rhythm regulator NHR-23/NR1F1 serves as an essential co-regulator of C. elegans spermatogenesis

Development ◽  
2020 ◽  
Vol 147 (22) ◽  
pp. dev193862
Author(s):  
James Matthew Ragle ◽  
Abigail L. Aita ◽  
Kayleigh N. Morrison ◽  
Raquel Martinez-Mendez ◽  
Hannah N. Saeger ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Nuclear Hormone Receptor ◽  
Model Systems ◽  
Residual Body ◽  
Major Sperm Protein ◽  
Sperm Protein ◽  
C Elegans ◽  
Gene Regulatory ◽  
Established Role

ABSTRACTIn sexually reproducing metazoans, spermatogenesis is the process by which uncommitted germ cells give rise to haploid sperm. Work in model systems has revealed mechanisms controlling commitment to the sperm fate, but how this fate is subsequently executed remains less clear. While studying the well-established role of the conserved nuclear hormone receptor transcription factor, NHR-23/NR1F1, in regulating C. elegans molting, we discovered that NHR-23/NR1F1 is also constitutively expressed in developing primary spermatocytes and is a critical regulator of spermatogenesis. In this novel role, NHR-23/NR1F1 functions downstream of the canonical sex-determination pathway. Degron-mediated depletion of NHR-23/NR1F1 within hermaphrodite or male germlines causes sterility due to an absence of functional sperm, as depleted animals produce arrested primary spermatocytes rather than haploid sperm. These spermatocytes arrest in prometaphase I and fail to either progress to anaphase or attempt spermatid-residual body partitioning. They make sperm-specific membranous organelles but fail to assemble their major sperm protein into fibrous bodies. NHR-23/NR1F1 appears to function independently of the known SPE-44 gene regulatory network, revealing the existence of an NHR-23/NR1F1-mediated module that regulates the spermatogenesis program.

scholarly journals A developmental gene regulatory network for C. elegans anchor cell invasion

Development ◽  
2019 ◽  
Vol 147 (1) ◽  
pp. dev185850 ◽  
Author(s):  
Taylor N. Medwig-Kinney ◽  
Jayson J. Smith ◽  
Nicholas J. Palmisano ◽  
Sujata Tank ◽  
Wan Zhang ◽  
...  
Keyword(s):  
Gene Regulatory Network ◽  
Cell Invasion ◽  
Regulatory Network ◽  
Developmental Gene ◽  
C Elegans ◽  
Gene Regulatory ◽  
Anchor Cell

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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