A naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging.

To ameliorate or even prevent signatures of aging in ultimately humans, we here report the identification of a previously undescribed polyacetylene contained in the root of carrots (Daucus carota), hereafter named isofalcarintriol, which we reveal as potent promoter of longevity in the nematode C. elegans. We assign the absolute configuration of the compound as (3 S,8 R,9 R,E)-heptadeca-10-en-4,6-diyne-3,8,9-triol, and develop a modular asymmetric synthesis route for all E-isofalcarintriol stereoisomers. At the molecular level, isofalcarintriol affects cellular respiration in mammalian cells, C. elegans, and mice, and interacts with the α-subunit of the mitochondrial ATP synthase to promote mitochondrial biogenesis. Phenotypically, this also results in decreased mammalian cancer cell growth, as well as improved motility and stress resistance in C. elegans, paralleled by reduced protein accumulation in nematodal models of neurodegeneration. In addition, isofalcarintriol supplementation to both wild-type C57BL/6NRj mice on high-fat diet, and aged mice on chow diet results in improved glucose metabolism, increased exercise endurance, and attenuated parameters of frailty at an advanced age. Given these diverse effects on health parameters in both nematodes and mice, isofalcarintriol might become a promising mitohormesis-inducing compound to delay, ameliorate, or prevent aging-associated diseases in humans.

From Coffee Waste to Active Ingredient for Cosmetic Applications.

Coffee silverskin (CS) is the thin epidermis covering and protecting the coffee bean and it represents the main by-product of the coffee roasting process. CS has recently gained attention due to its high content in bioactive molecules and the growing interest in valuable reutilization of waste products. Drawing inspiration from its biological function, here its potential in cosmetic applications was investigated. CS was recovered from one of the largest coffee roasters located in Switzerland and processed through supercritical CO2 extraction, thereby generating coffee silverskin extract. Chemical profiling of this extract revealed the presence of potent molecules, among which cafestol and kahweol fatty acid esters, as well as acylglycerols, ß-sitosterol and caffeine. The CS extract was then dissolved in organic shea butter, yielding the cosmetic active ingredient SLVR'Coffee™. In vitro gene expression studies performed on keratinocytes showed an upregulation of genes involved in oxidative stress responses and skin-barrier functionality upon treatment with the coffee silverskin extract. In vivo, our active protected the skin against Sodium Lauryl Sulfate (SLS)-induced irritation and accelerated its recovery. Furthermore, this active extract improved measured as well as perceived skin hydration in female volunteers, making it an innovative, bioinspired ingredient that comforts the skin and benefits the environment.

Ingestion of single guide RNAs induces gene overexpression and extends lifespan in Caenorhabditis elegans via CRISPR activation.

Inhibition of gene expression in Caenorhabditis elegans, a versatile model organism for studying the genetics of development and aging, is achievable by feeding nematodes with bacteria expressing specific dsRNAs. Overexpression of hypoxia-inducible factor 1 (hif-1) or heat-shock factor 1 (hsf-1) by conventional transgenesis has previously been shown to promote nematodal longevity. However, it is unclear whether other methods of gene overexpression are feasible, particularly with the advent of CRISPR-based techniques. Here, we show that feeding C. elegans engineered to stably express a Cas9-derived synthetic transcription factor with bacteria expressing promoter-specific single guide RNAs (sgRNAs) also allows activation of gene expression. We demonstrate that CRISPR activation via ingested sgRNAs specific for the respective promoter regions of hif-1 or hsf-1 increases gene expression and extends lifespan of C. elegans. Furthermore, and as an in silico resource for future studies aiming to use CRISPR activation in C. elegans, we provide predicted promoter-specific sgRNA target sequences for >13,000 C. elegans genes with experimentally defined transcription start sites. We anticipate that the approach and components described herein will help to facilitate genome-wide gene overexpression studies, for example, to identify modulators of aging or other phenotypes of interest, by enabling induction of transcription by feeding of sgRNA-expressing bacteria to nematodes.

Evolutionarily conserved transcription factors as regulators of longevity and targets for geroprotection.

Aging is the single largest risk factor for many debilitating conditions, including heart diseases, stroke, cancer, diabetes, and neurodegenerative disorders. Although far from understood in its full complexity, it is scientifically well established that aging is influenced by genetic and environmental factors and can be modulated by various interventions. One of aging's early hallmarks is aberrations in transcriptional networks, controlling for example metabolic homeostasis or the response to stress. Evidence in different model organisms abounds that a number of evolutionarily conserved transcription factors, which control such networks, can affect life span and health span across species. These transcription factors thus potentially represent conserved regulators of longevity and are emerging as important targets in the challenging quest to develop treatments to mitigate age-related diseases, and possibly even to slow aging itself. This review provides an overview of evolutionarily conserved transcription factors that impact longevity or age-related diseases in at least one multicellular model organism (nematodes, flies, or mice) and/or are tentatively linked to human aging. Discussed is the general evidence for transcriptional regulation of aging and disease, followed by a more detailed look at selected transcription factor families, the common metabolic pathways involved, and the targeting of transcription factors as a strategy for geroprotective interventions.

Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan.

Aging is impacted by interventions across species, often converging on metabolic pathways. Transcription factors regulate longevity yet approaches for their pharmacological modulation to exert geroprotection remain sparse. We show that increased expression of the transcription factor Grainyhead 1 (GRH-1) promotes lifespan and pathogen resistance in Caenorhabditis elegans. A compound screen identifies FDA-approved drugs able to activate human GRHL1 and promote nematodal GRH-1-dependent longevity. GRHL1 activity is regulated by post-translational lysine methylation and the phosphoinositide (PI) 3-kinase C2A. Consistently, nematodal longevity following impairment of the PI 3-kinase or insulin/IGF-1 receptor requires grh-1. In BXD mice, Grhl1 expression is positively correlated with lifespan and insulin sensitivity. In humans, GRHL1 expression positively correlates with insulin receptor signaling and also with lifespan. Fasting blood glucose levels, including in individuals with type 2 diabetes, are negatively correlated with GRHL1 expression. Thereby, GRH-1/GRHL1 is identified as a pharmacologically malleable transcription factor impacting insulin signaling and lifespan.

Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A.

Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms. Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference (RNAi) screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematodal lifespan in a ROS-dependent manner. We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.

Correction to: DamID profiling of dynamic Polycomb-binding sites in Drosophila imaginal disc development and tumorigenesis.

Unfortunately, the original version of this article contained a typographical error in one of the author names. The name of the author Alexey Pindyurin was incorrectly spelt as Alexey Pinduyrin. The correct spelling is included here and has been updated in the original article.

DamID profiling of dynamic Polycomb-binding sites in Drosophila imaginal disc development and tumorigenesis.

BACKGROUND: Tracking dynamic protein-chromatin interactions in vivo is key to unravel transcriptional and epigenetic transitions in development and disease. However, limited availability and heterogeneous tissue composition of in vivo source material impose challenges on many experimental approaches. RESULTS: Here we adapt cell-type-specific DamID-seq profiling for use in Drosophila imaginal discs and make FLP/FRT-based induction accessible to GAL driver-mediated targeting of specific cell lineages. In a proof-of-principle approach, we utilize ubiquitous DamID expression to describe dynamic transitions of Polycomb-binding sites during wing imaginal disc development and in a scrib tumorigenesis model. We identify Atf3 and Ets21C as novel Polycomb target genes involved in scrib tumorigenesis and suggest that target gene regulation by Atf3 and AP-1 transcription factors, as well as modulation of insulator function, plays crucial roles in dynamic Polycomb-binding at target sites. We establish these findings by DamID-seq analysis of wing imaginal disc samples derived from 10 larvae. CONCLUSIONS: Our study opens avenues for robust profiling of small cell population in imaginal discs in vivo and provides insights into epigenetic changes underlying transcriptional responses to tumorigenic transformation.

Impairing L-Threonine Catabolism Promotes Healthspan through Methylglyoxal-Mediated Proteohormesis.

Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC 2.3.1.29). Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins. While high concentrations of MGO consistently exert toxicity in nematodes, we unexpectedly find that low-dose MGO promotes lifespan, resembling key mediators of gcat impairment. These were executed by the ubiquitin-proteasome system, namely PBS-3 and RPN-6.1 subunits, regulated by the stress-responsive transcriptional regulators SKN-1/NRF2 and HSF-1. Taken together, GCAT acts as an evolutionary conserved aging-related gene by orchestrating an unexpected nonlinear impact of proteotoxic MGO on longevity.