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Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota, strongly associated with our overall health, has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans/E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan (locomotion), reduced stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased concentration of reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose-fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar, such as a Western diet, has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases. [ABSTRACT FROM AUTHOR]

This document is an editorial titled "Year in review: discussions in genetics of aging" published in the journal Frontiers in Genetics. It discusses a research topic that includes original articles, opinion articles, and a mini-review on genetics of aging. The articles cover various topics such as senescence, COVID-19, and aging clocks. The studies provide insights into aging biomarkers, the role of cellular senescence in diseases, and the effects of COVID-19 on epigenetic clocks. The editorial acknowledges the importance of these studies in advancing our understanding of age-related diseases. Additionally, the document discusses the SenNet Consortium's research project, funded by the National Institutes of Health (NIH), which aims to map senescent cells throughout the human lifespan to better understand their impact on physiological health. The project seeks to provide valuable insights into the biology of aging and potentially identify new therapeutic targets. The article highlights the importance of this research for advancing our understanding of aging and promoting healthier aging strategies. [Extracted from the article]

Aging is linked to a time-associated decline in both cellular function and repair capacity leading to malfunction on an organismal level, increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD+) as cosubstrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4'-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies. [ABSTRACT FROM AUTHOR]

Reactive cysteines often serve as functional sites on proteins and play important regulatory roles in various biological processes. A chemoproteomic method named "isoTOP‐ABPP" has enabled global profiling of cysteine reactivity in native systems and greatly increased our understanding on reactive cysteinome. This elegant method and its derived chemoproteomic technologies are now widely applied in profiling of reactive cysteinome and the associated post‐translational modifications, discovery of covalent ligands for undruggable targets as well as mechanistic investigation of various biological processes. In this review, we will briefly go over the history of isoTOP‐ABPP, summarize recent developments and applications of chemoproteomic technology in reactive cysteinome profiling, and discuss future directions in this field. [ABSTRACT FROM AUTHOR]

High-throughput imaging techniques have become widespread in many fields of biology. These powerful platforms generate large quantities of data that can be difficult to process and visualize efficiently using existing tools. We developed easyXpress to process and review C. elegans high-throughput microscopy data in the R environment. The package provides a logical workflow for the reading, analysis, and visualization of data generated using CellProfiler's WormToolbox. We equipped easyXpress with powerful functions to customize the filtering of noise in data, specifically by identifying and removing objects that deviate from expected animal measurements. This flexibility in data filtering allows users to optimize their analysis pipeline to match their needs. In addition, easyXpress includes tools for generating detailed visualizations, allowing the user to interactively compare summary statistics across wells and plates with ease. Researchers studying C. elegans benefit from this streamlined and extensible package as it is complementary to CellProfiler and leverages the R environment to rapidly process and analyze large high-throughput imaging datasets. [ABSTRACT FROM AUTHOR]

Sphingolipid metabolism is important to balance the abundance of bioactive lipid molecules involved in cell signaling, neuronal function, and survival. Specifically, the sphingolipid sphingosine mediates cell death signaling, whereas its phosphorylated form, sphingosine-1-phosphate (S1P), mediates cell survival signaling. The enzyme sphingosine kinase produces S1P, and the activity of sphingosine kinase impacts the ability of cells to survive under stress and challenges. To examine the influence of sphingolipid metabolism, particularly enzymes regulating sphingosine and S1P, in mediating aging, neuronal function and stress response, we examined life history traits, locomotor capacities and heat stress responses of young and old animals using the model organism Caenorhabditis elegans. We found that C. elegans sphk-1 mutants, which lack sphingosine kinase, had shorter lifespans, reduced brood sizes, and smaller body sizes compared to wild type animals. By analyzing a panel of young and old animals with genetic mutations in the sphingolipid signaling pathway, we showed that aged sphk-1 mutants exhibited a greater decline in neuromuscular function and locomotor behavior. In addition, aged animals lacking sphk-1 were more susceptible to death induced by acute and prolonged heat exposure. On the other hand, older animals with loss of function mutations in ceramide synthase (hyl-1), which converts sphingosine to ceramide, showed improved neuromuscular function and stress response with age. This phenotype was dependent on sphk-1. Together, our data show that loss of sphingosine kinase contributes to poor animal health span, suggesting that sphingolipid signalingmay be important for healthy neuronal function and animal stress response during aging. [ABSTRACT FROM AUTHOR]

Human genome-wide association studies (GWAS) and linkage studies have identified 695 genes associated with Alzheimer's disease (AD), the vast majority of which are associated with late-onset AD. Although orthologs of these AD genes have been studied in several model species, orthologs in the nematode, Caenorhabditis elegans, remain incompletely identified, with orthologs to only 17 AD-related genes identified in the C. elegans database, WormBase. Therefore, we performed a comprehensive search for additional C. Elegans orthologs of AD genes using well-established programs, including OrthoList, which utilizes four ontology prediction programs. We also validated 680 of the AD genes as a unique gene from the AlzGene database, including 431 genes (63%) that are predicted to have orthologs in C. Elegans. Another 178 human AD genes (26%) were associated with one or more other neurological diseases, including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and schizophrenia. Of these, there were 105 genes (59%) with orthologs in C. elegans. Interestingly, three AD genes (ACE, TNF and MTHFR) were associated with all four of the other neurological diseases. The human AD genes were enriched in three major ontology pathway groups, including lipoprotein metabolism, hemostasis and extracellular matrix organizations, as well as in pathways that are amyloid related (NOTCH signaling) and associated with neural (neurotransmitter clearance) and immune (advanced glycation end-product receptor signaling and TRAF6-NF-kappaB) systems. Thus, the results from this study provide a potentially useful system for assessing comorbidities that may be associated with late-onset AD and other neurological conditions. The technical advantages and limitations of the ortholog searches are further discussed. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.01.025 Byline: Srivatsan Padmanabhan (1), Arnab Mukhopadhyay (1), Sri Devi Narasimhan (1), Gregory Tesz (2), Michael P. Czech (2), Heidi A. Tissenbaum (1)(2) Keywords: SIGNALING; HUMDISEASE; CELLBIO Abstract: The C. elegans insulin/IGF-1 signaling (IIS) cascade plays a central role in regulating life span, dauer, metabolism, and stress. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine-specific protein kinases. An RNAi screen for serine/threonine protein phosphatases that counterbalance the effect of the kinases in the IIS pathway identified pptr-1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr-1 affects IIS pathway-associated phenotypes including life span, dauer, stress resistance, and fat storage. We show that PPTR-1 functions by regulating worm AKT-1 phosphorylation at Thr 350. With striking conservation, mammalian B56[beta] regulates Akt phosphorylation at Thr 308 in 3T3-L1 adipocytes. In C. elegans, this ultimately leads to changes in subcellular localization and transcriptional activity of the forkhead transcription factor DAF-16. This study reveals a conserved role for the B56 regulatory subunit in regulating insulin signaling through AKT dephosphorylation, thereby having widespread implications in cancer and diabetes research. Author Affiliation: (1) Program in Gene Function and Expression, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA (2) Program in Molecular Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA Article History: Received 8 October 2008; Revised 18 December 2008; Accepted 16 January 2009 Article Note: (miscellaneous) Published online: February 26, 2009

Quantitation of lipid storage, unsaturation, and oxidation in live C. elegans has been a long-standing obstacle. The combination of hyperspectral stimulated Raman scattering imaging and multivariate analysis in the fingerprint vibration region represents a platform that allows the quantitative mapping of fat distribution, degree of fat unsaturation, lipid oxidation, and cholesterol storage in vivo in the whole worm. Our results reveal for the first time that lysosome-related organelles in intestinal cells are sites for storage of cholesterol in C. elegans. [ABSTRACT FROM AUTHOR]

The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance. [ABSTRACT FROM AUTHOR]

The authors discuss aspects of model systems in cognitive aging and dementia. They hope to strengthen patient-centered care and medical research through personal accounts from patients affected with Alzheimer's disease (AD). The authors believe that a solid communication base between patients and healthcare providers can directly input and integrate medical science and medical care.

A quantitative trait locus (QTL) in the nematode C. elegans, "lsq4," was recently implicated by mapping longevity genes. QTLs for lifespan and three stress-resistance traits coincided within a span of <300 kbp, later narrowed to <200 kbp. A single gene in this interval is now shown to modulate all lsq4-associated traits. Full-genome analysis of transcript levels indicates that lsq4 contains a dimorphic gene governing the expression of many sperm-specific genes, suggesting an effect on spermatogenesis. Quantitative analysis of allele-specific transcripts encoded within the lsq4 interval revealed significant, 2- to 15-fold expression differences for 10 of 33 genes. Fourteen "dual-candidate" genes, implicated by both position and expression, were tested for RNA-interference effects on QTL-linked traits. In a strain carrying the shorter-lived allele, knockdown of rec-8 (encoding a meiotic cohesin) reduced its transcripts 4-fold, to a level similar to the longer-lived strain, while extending lifespan 25-26%, whether begun before fertilization or at maturity. The short-lived lsq4 allele also conferred sensitivity to oxidative and thermal stresses, and lower male frequency (reflecting X-chromosome non-disjunction), traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at <0.3% of its genome, derived no lifespan or stress-survival benefit from rec-8 knockdown. We consider two possible explanations: high rec-8 expression may include increased "leaky" expression in mitotic cells, leading to deleterious destabilization of somatic genomes; or REC-8 may act entirely in germ-line meiotic cells to reduce aberrations such as non-disjunction, thereby blunting a stress-resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741) by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival is widespread, exemplifying antagonistic pleiotropy (opposing effects on lifespan vs. reproduction), and/or balancing selection wherein genomic disruption increases genetic variation under harsh conditions. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.04.038 Byline: Bart Deplancke (1), Arnab Mukhopadhyay (1), Wanyuan Ao (2), Ahmed M. Elewa (1), Christian A. Grove (1), Natalia J. Martinez (1), Reynaldo Sequerra (3), Lynn Doucette-Stamm (3), John S. Reece-Hoyes (4), Ian A. Hope (4), Heidi A. Tissenbaum (1), Susan E. Mango (2), Albertha J.M. Walhout (1) Abstract: 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 equal to]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. Author Affiliation: (1) Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA (2) Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA (3) Agencourt Bioscience Corporation, Beverly MA 01915, USA (4) Institute of Integrative and Comparative Biology, Faculty of Biological Sciences, School of Biology, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom Article History: Received 8 November 2005; Revised 27 February 2006; Accepted 12 April 2006 Article Note: (miscellaneous) Published: June 15, 2006

Author(s): Heidi A. Tissenbaum; Leonard Guarente (corresponding author) In Caenorhabditis elegans , mutations that reduce the activity of an insulin-like receptor ( daf-2 ) [1] or a phosphatidylinositol-3-OH kinase (age-1 [...]

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, Sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-i/β-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the β-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of β-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRTl overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between β-catenin and SIRT1 in the modulation of mutant polyQ cytoxirity. Taken together, these results suggest that integration of β-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity. [ABSTRACT FROM AUTHOR]

As a tool for measuring the aging process, life span has been invaluable in dissecting the genes that modulate longevity. Studies over the past few decades have identified several hundred genes that can modify life span in model organisms such as yeast, worms, and flies. Yet, despite this vast amount of research, we still do not fully understand how the genes that affect life span influence how an organism ages. How does modulation of the genes that affect life span contribute to the aging process? Does life-span extension result in extension of healthy aging? Here, we will focus primarily on the insulin/IGF-1 signaling pathway in Caenorhabditis elegans because members of this pathway have been shown to be associated with extended life span across phylogeny, from worms to humans. I discuss how this connects to the aging process, age-associated disease, and the potential to increase healthy aging in addition to lengthening life span. [ABSTRACT FROM PUBLISHER]

The nuo-6 and isp-1 genes of C. elegans encode, respectively, subunits of complex I and III of the mitochondrial respiratory chain. Partial loss-of-function mutations in these genes decrease electron transport and greatly increase the longevity of C. elegans by a mechanism that is distinct from that induced by reducing their level of expression by RNAi. Electron transport is a major source of the superoxide anion (O·-), which in turn generates several types of toxic reactive oxygen species (ROS), and aging is accompanied by increased oxidative stress, which is an imbalance between the generation and detoxification of ROS. These observations have suggested that the longevity of such mitochondrial mutants might result from a reduction in ROS generation, which would be consistent with the mitochondrial oxidative stress theory of aging. It is difficult to measure ROS directly in living animals, and this has held back progress in determining their function in aging. Here we have adapted a technique of flow cytometry to directly measure ROS levels in isolated mitochondria to show that the generation of superoxide is elevated in the nuo-6 and isp-1 mitochondrial mutants, although overall ROS levels are not, and oxidative stress is low. Furthermore, we show that this elevation is necessary and sufficient to increase longevity, as it is abolished by the antioxidants NAC and vitamin C, and phenocopied by mild treatment with the prooxidant paraquat. Furthermore, the absence of effect of NAC and the additivity of the effect of paraquat on a variety of long- and short-lived mutants suggest that the pathway triggered by mitochondrial superoxide is distinct from previously studied mechanisms, including insulin signaling, dietary restriction, ubiquinone deficiency, the hypoxic response, and hormesis. These findings are not consistent with the mitochondrial oxidative stress theory of aging. Instead they show that increased superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging. We propose that superoxide is generated as a protective signal in response to molecular damage sustained during wild-type aging as well. This model provides a new explanation for the well-documented correlation between ROS and the aged phenotype as a gradual increase of molecular damage during aging would trigger a gradually stronger ROS response. [ABSTRACT FROM AUTHOR]

Reports that conformational diversity in a yeast prion dictates its seeding specificity. Details of how prions composed of the same polypeptide can evoke different phenotypes, even when propagated in genetically identical hosts; Thoughts on the molecular basis of the strain diversity and the relationship between strains and barriers limiting transmission between species; Results; Conclusions.

Presents research which showed that null mutations in daf-16 suppress the effects of mutations in DAF-2 or AGE-1 and that lack of daf-16 bypasses the need for the insulin receptor-like signaling pathway in the nematode Caenorhabditis elegans. Mammalian insulin signaling; Dauer stage in normal and mutant animals; Role of DAF-2/AGE-1 signaling; Role of DAF-2 pathway; Human orthologs; Application of research to diabetes. INSET: Methods..

Presents research which showed that a pyridine derivative Y-27632 selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. Abnormal smooth-muscle contractility; Regulation of smooth-muscle contraction; Role of small GTPase Rho and Rho-associated kinase; Y-27632 target a Rho-associated protein kinase, p160ROCK7; Role of p160ROCK-mediated Ca2+ sensitization in pathophysiology of hypertension. INSET: Methods..

The article presents abstracts on medical topics which includes labeling of polysialic acids, cell division cycle (CDC) and charge-charge interactions.

A letter to the editor is presented in response to a article the retention of select p53 functions which account for embryonic lethality.