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 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 transcriptome based aging clock near the theoretical limit of accuracy

2020 ◽  
Author(s):  
David H. Meyer ◽  
Björn Schumacher
Keyword(s):  
Aging Process ◽  
Biological Age ◽  
Therapeutic Interventions ◽  
Epigenetic Alterations ◽  
Theoretical Limit ◽  
C Elegans ◽  
Age Dependent ◽  
Affect Gene Expression ◽  
Age Prediction

Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this transcriptome clock can also be applied to human age prediction with high accuracy. This transcriptome aging clock could therefore find wide application in genetic, environmental and therapeutic interventions in the aging process.

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.

scholarly journals Extensive intraspecies cryptic variation in an ancient embryonic gene regulatory network

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Yamila N Torres Cleuren ◽  
Chee Kiang Ewe ◽  
Kyle C Chipman ◽  
Emily R Mears ◽  
Cricket G Wood ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Recombinant Inbred Lines ◽  
Single Species ◽  
C Elegans ◽  
Cryptic Variation ◽  
Absolute Requirement ◽  
Natural Isolates ◽  
Gene Regulatory ◽  
Metazoan Phylogeny

Innovations in metazoan development arise from evolutionary modification of gene regulatory networks (GRNs). We report widespread cryptic variation in the requirement for two key regulatory inputs, SKN-1/Nrf2 and MOM-2/Wnt, into the C. elegans endoderm GRN. While some natural isolates show a nearly absolute requirement for these two regulators, in others, most embryos differentiate endoderm in their absence. GWAS and analysis of recombinant inbred lines reveal multiple genetic regions underlying this broad phenotypic variation. We observe a reciprocal trend, in which genomic variants, or knockdown of endoderm regulatory genes, that result in a high SKN-1 requirement often show low MOM-2/Wnt requirement and vice-versa, suggesting that cryptic variation in the endoderm GRN may be tuned by opposing requirements for these two key regulatory inputs. These findings reveal that while the downstream components in the endoderm GRN are common across metazoan phylogeny, initiating regulatory inputs are remarkably plastic even within a single species.

scholarly journals Biological age in UK Biobank: biomarker composition and prediction of mortality, coronary heart disease and hospital admissions

2019 ◽  
Author(s):  
Mei Sum Chan ◽  
Matthew Arnold ◽  
Alison Offer ◽  
Imen Hammami ◽  
Marion Mafham ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Risk Factor ◽  
Heart Disease ◽  
Principal Components ◽  
Hospital Admissions ◽  
Principal Component ◽  
Age Effects ◽  
Biological Age ◽  
Chronological Age ◽  
Uk Biobank

AbstractBackgroundAge is the strongest risk factor for most chronic diseases, and yet individuals may age at different rates biologically. A biological age formed from biomarkers may be a stronger risk factor than chronological age and understanding what factors contribute to it could provide insight into new opportunities for disease prevention.Methods and findingsAmong 480,019 UK Biobank participants aged 40-70 recruited in 2006-2010 and followed up for 6-12 years via linked death registry and secondary care records, a subpopulation of 141,254 (29.4%) non-smoking adults in good health and with no medication use or disease history at baseline were identified. Independent components of 72 biomarkers measured at baseline were characterised by principal component analysis. The Klemera Doubal method (KDM), which derived a weighted sum of biomarker principal components based on the strengths of their linear associations with chronological age, was used to derive sex-specific biological ages in this healthy subpopulation. The proportions of the overall biological and chronological age effects on mortality, coronary heart disease and age-related non-fatal hospital admissions (based on a hospital frailty index) that were explained by biological age were assessed using log-likelihoods of proportional hazards models.Reduced lung function, reduced kidney function, slower reaction time, lower insulin-like-growth factor 1, lower hand grip strength and higher blood pressure were key contributors to biological age (explaining the highest percentages of its variance) in both men and women, while lower albumin, higher sex hormone-binding globulin and lower muscle mass in men, and higher liver enzymes, blood lipids and HbA1c in women were also important. Across both sexes, a 51-principal component biological age explained 66%, 80% and 63% of the age effects on mortality, coronary heart disease and hospital admissions, respectively. Restricting the biological age to the 12-13 key biomarkers corresponding to the 10 most importantly contributing principal components resulted in little change in these proportions for women, but a reduction to 53%, 63% and 50%, respectively, for men.ConclusionsThis study identified that markers of impaired function in a range of organs account for a substantial proportion of the apparent effect of age on disease and hospital admissions. It supports a broader, multi-system approach to research and prevention of diseases of ageing.

scholarly journals Biological Age Prediction From Wearable Device Movement Data Identifies Nutritional and Pharmacological Interventions for Healthy Aging

2021 ◽  
Vol 2 ◽  
Author(s):  
Rebecca L. McIntyre ◽  
Mizanur Rahman ◽  
Siva A. Vanapalli ◽  
Riekelt H. Houtkooper ◽  
Georges E. Janssens
Keyword(s):  
Healthy Aging ◽  
Machine Learning Algorithms ◽  
Biological Age ◽  
Wearable Device ◽  
Biological Aging ◽  
Accelerometer Data ◽  
Pharmacological Interventions ◽  
C Elegans ◽  
Movement Data ◽  
Age Related

Intervening in aging processes is hypothesized to extend healthy years of life and treat age-related disease, thereby providing great benefit to society. However, the ability to measure the biological aging process in individuals, which is necessary to test for efficacy of these interventions, remains largely inaccessible to the general public. Here we used NHANES physical activity accelerometer data from a wearable device and machine-learning algorithms to derive biological age predictions for individuals based on their movement patterns. We found that accelerated biological aging from our “MoveAge” predictor is associated with higher all-cause mortality. We further searched for nutritional or pharmacological compounds that associate with decelerated aging according to our model. A number of nutritional components peak in their association to decelerated aging later in life, including fiber, magnesium, and vitamin E. We additionally identified one FDA-approved drug associated with decelerated biological aging: the alpha-blocker doxazosin. We show that doxazosin extends healthspan and lifespan in C. elegans. Our work demonstrates how a biological aging score based on relative mobility can be accessible to the wider public and can potentially be used to identify and determine efficacy of geroprotective interventions.

Corrigendum to: IQ motif containing D (IQCD), a new acrosomal protein involved in the acrosome reaction and fertilisation

2019 ◽  
Vol 31 (5) ◽  
pp. 1033
Author(s):  
Peng Zhang ◽  
Wanjun Jiang ◽  
Na Luo ◽  
Wenbing Zhu ◽  
Liqing Fan
Keyword(s):  
Acrosome Reaction ◽  
Development Stage ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Dependent Manner ◽  
Iq Motif ◽  
C Elegans ◽  
Fertilisation Rate ◽  
Age Dependent ◽  
Mammalian Spermatozoa

The acrosome is single, large, dense-core secretory granule overlying the nucleus of most mammalian spermatozoa. Its exocytosis, the acrosome reaction, is a crucial event during fertilisation. In this study we identified a new acrosome-associated gene, namely IQ motif containing D (IQCD), expressed nearly in multiple tissues with highest expression levels in the testis. In mouse testis, Iqcd transcript accumulated from Postnatal Day (PND) 1 to adulthood. However, expression of IQCD protein at the testicular development stage started primarily from PND 18 and increased in an age-dependent manner until plateauing in adulthood. IQCD was primarily accumulated in the acrosome area of round and elongating spermatids within seminiferous tubules of the testes during the late stage of spermiogenesis; this immunolocalisation pattern is similar in mice and humans. IQCD levels in spermatozoa were significantly lower in IVF patients with total fertilisation failure or a low fertilisation rate than in healthy men. Anti-IQCD antibody significantly inhibited the acrosome reaction and slightly reduced protein tyrosine phosphorylation levels in human spermatozoa, but specifically blocked murine IVF. IQCD interacted with mammalian homolog of C. elegans uncoordinated gene 13 (Munc13) in spermatozoa and may participate in acrosome exocytosis. In conclusion, this study identified a new acrosomal protein, namely IQCD, which is involved in fertilisation and the acrosome reaction.

scholarly journals DAF-16 and SMK-1 Contribute to Innate Immunity During Adulthood in Caenorhabditis elegans

2020 ◽  
Vol 10 (5) ◽  
pp. 1521-1539 ◽  
Author(s):  
Daniel R. McHugh ◽  
Elena Koumis ◽  
Paul Jacob ◽  
Jennifer Goldfarb ◽  
Michelle Schlaubitz-Garcia ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Caenorhabditis Elegans ◽  
Host Defense ◽  
Insulin Signaling ◽  
Bacterial Pathogens ◽  
C Elegans ◽  
Link Type ◽  
Age Dependent ◽  
Over Time

Aging is accompanied by a progressive decline in immune function termed “immunosenescence”. Deficient surveillance coupled with the impaired function of immune cells compromises host defense in older animals. The dynamic activity of regulatory modules that control immunity appears to underlie age-dependent modifications to the immune system. In the roundworm Caenorhabditis elegans levels of PMK-1 p38 MAP kinase diminish over time, reducing the expression of immune effectors that clear bacterial pathogens. Along with the PMK-1 pathway, innate immunity in C. elegans is regulated by the insulin signaling pathway. Here we asked whether DAF-16, a Forkhead box (FOXO) transcription factor whose activity is inhibited by insulin signaling, plays a role in host defense later in life. While in younger C. elegansDAF-16 is inactive unless stimulated by environmental insults, we found that even in the absence of acute stress the transcriptional activity of DAF-16 increases in an age-dependent manner. Beginning in the reproductive phase of adulthood, DAF-16 upregulates a subset of its transcriptional targets, including genes required to kill ingested microbes. Accordingly, DAF-16 has little to no role in larval immunity, but functions specifically during adulthood to confer resistance to bacterial pathogens. We found that DAF-16-mediated immunity in adults requires SMK-1, a regulatory subunit of the PP4 protein phosphatase complex. Our data suggest that as the function of one branch of the innate immune system of C. elegans (PMK-1) declines over time, DAF-16-mediated immunity ramps up to become the predominant means of protecting adults from infection, thus reconfiguring immunity later in life.

Genetic Determinants of Hemolysis in Sickle Cell Anemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2104-2104
Author(s):  
Jacqueline N Milton ◽  
Helen Rooks ◽  
Emma Drasar ◽  
Elizabeth L McCabe ◽  
Clinton T. Baldwin ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Principal Component ◽  
Regulatory Elements ◽  
Intravascular Hemolysis ◽  
Plasma Hemoglobin ◽  
Hypersensitive Sites ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Abstract Abstract 2104 The phenotype of sickle cell disease is caused by sickle vasoocclusion and hemolytic anemia. Hemolysis in sickle cell anemia has been associated with complications that were presumed to result in part from vascular nitric oxide depletion due to scavenging by free plasma hemoglobin. Though plasma hemoglobin is a specific marker of intravascular hemolysis and red cell survival studies are the most definitive method of establishing the extent of hemolysis, these tests are rarely done and not available in large cohorts. However, the intensity of hemolysis can be estimated by the reticulocyte count, lactate dehydrogenase (LDH), aspartate aminotransaminase (AST) and bilirubin levels, all of which are commonly measured in cohort studies, although none of which is specific for hemolysis. We previously reported the results of a genome-wide association study (GWAS) of hemolysis where we used as a phenotype a new measure of the rate of intravascular hemolysis appropriate for cohort studies and GWAS. Using a principal component analysis of the commonly measured markers of hemolysis we derived a hemolytic score and found that the top SNPs associated with this score included a variant located in the first intron of NPRL3 (rs7203560; chr16p13.3, p=6.04×10−07) This result was replicated in two additional cohorts of 549 and 296 patients. We also established that while rs7203560 was associated with the ∝3.7 thalassemia gene deletion, when adjusted for HbF and ∝ thalassemia the association of NPRL3 with the hemolytic score remained significant (p=0.00375) and this association was also significant when examining only cases without ∝ thalassemia (p=0.02463). To further validate these results we studied 213 additional adult sickle cell anemia patients from King's College Hospital, London, UK. The mean age of these patients was 33 years. None had been treated with hydroxyurea and lab parameters obtained 3 months after, if transfused. Patients had similar clinical characteristics. The hemolytic score was calculated by using principal component analysis of the same markers of hemolysis. The SNPs associated with the hemolytic score in the primary study were genotyped in this cohort using TaqMan SNP genotyping assays according to standard Applied Biosystems protocol and their association with the derived hemolytic score studies using the same additive genetic model. The SNP rs7203560 replicated the association with hemolytic score (p= 0.03674) in this cohort. To examine the linkage disequilibrium (LD) structure of the region, we looked for conserved sequences in the α- globin cluster in multiple divergent species using the Basic Local Alignment Sequencing Tool (BLAST) to identify the approximate locations of the hypersensitive sites that are the major α-globin gene regulatory elements. On examination of the LD structure of SNPs in these regions with rs7203560, we found that rs7203560 was in LD with several SNPs located in and near the hypersensitive sites including rs2238368 (D'=1), rs2541612 (D'=0.89) and rs3331107 (D'=0.61). We hypothesize that rs7203560 is a marker for one or more variants in the major α-globin gene regulatory elements that down-regulate α-globin gene expression and cause a mild α thalassemia-like effect. In sickle cell anemia, perhaps by independently down-regulating expression of the α-globin genes, variants of the major ∝-globin gene regulatory loci reduce HbS concentration, lessen the polymerization potential of deoxy sickle hemoglobin and therefore retard hemolysis. Disclosures: No relevant conflicts of interest to declare.

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