Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway

In many species, reducing nutrient intake without causing malnutrition extends lifespan 1, 2, 3. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species 1, 2, 3, 4. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth [5]. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction

Reply to Piper et al.: Drosophila dietary restriction—Does it hold water?

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Thermodynamic properties and moisture sorption isotherms of two pharmaceutical compounds

[EN] This investigation examines and compares the water sorption isotherms and the thermodynamic properties of two pharmaceutical preparations (Hypril and Azix) intended to be manufactured with the same process plant and equipment. The moisture equilibrium isotherms were determined at 50, 60 and 70 °C using a gravimetric technique. Five isotherm models were explored for their fitting to the experimental data. Azix showed sigmoid type II isotherms while Hypril showed type III isotherms according to the BET classification. All investigated models fitted well the water sorption isotherms of Hypril. By contrast, only GAB and Adam and Shove equations gave appropriate fit to the experimental data of Azix. For both formulations, the isosteric heat and the differential entropy decreased sharply with the increase of equilibrium moisture content to minimum values and thereafter remain constant. In the case of Azix, the integral enthalpy decreased with equilibrium moisture content while the integral entropy increased until reaching a constant value. Contrariwise, Hypril showed decreasing of the integral enthalpy and entropy with the equilibrium moisture content.Zammouri, A.; Ben Zid, M.; Kechaou, N.; Boudhrioua Mihoubi, N. (2018). Thermodynamic properties and moisture sorption isotherms of two pharmaceutical compounds. En IDS 2018. 21st International Drying Symposium Proceedings. Editorial Universitat Politècnica de València. 449-456. https://doi.org/10.4995/IDS2018.2018.7702OCS44945

4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila

Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5′UTRs, which were important for their enhanced mRNA translation. The translational repressor 4E-BP, the eukaryotic translation initiation factor 4E binding protein, was upregulated upon DR and mediated DR dependent changes in mitochondrial activity and lifespan extension. Inhibition of individual mitochondrial subunits from Complex I and IV diminished the lifespan extension obtained upon DR, reflecting the importance of enhanced mitochondrial function during DR. Our results imply that translational regulation of nuclear-encoded mitochondrial gene expression by 4E-BP plays an important role in lifespan extension upon DR

Prevalence of Mood Disorders and Associated Factors at the Time of the COVID-19 Pandemic: Potocol for a Community Survey in La Manouba Governorate, Tunisia

Aims: The present survey aims to assess the overall mood disorder prevalence and identify associated socio-demographic and clinical factors in a Tunisian community sample, with special attention to the COVID-19 pandemic. Background: Mood disorders are one of the leading causes of all non-fatal burdens of disease, with depression being at the top of the list. The COVID-19 pandemic may have increased the prevalence of mood disorders, especially in Low and Middle-income countries (LMICs) and in vulnerable populations. Objective: 1/ Assess point and lifetime prevalence of depressive and bipolar disorders as well as subthreshold bipolarity in a representative population sample of La Manouba governorate and assess treatment patterns for these disorders; 2/Study socio-demographic and clinical correlates of mood disorders 3/ Assess the association between mood disorders and quality of life 4/ Study the impact of the COVID-pandemic on the prevalence of mood disorders 5/ Assess coping mechanisms to the COVID-pandemic and whether these mechanisms moderate the appearance of mood disorders or symptoms since the beginning of the pandemic Methods: This is a household cross-sectional observational survey to be conducted in La Manouba Governorate in a sample of 4540 randomly selected individuals aged ≥ 15 years. Data collection will be carried out by trained interviewers with clinical experience, through face-to-face interviews and the use of the computer assisted personal interviewing approach (CAPI). The following assessment tools are administered: Results: Structured clinical Interview for DSM IV-TR (Mood disorder section and Screening questions on Anxiety), Mood Disorder Questionnaire (MDQ), Suicide Behaviors Questionnaire-Revised (SBQ), 12-item Short Form Survey (SF-12), the Brief-COPE, and a questionnaire about a headache. In addition, socio-demographic and clinical data will be collected. Conclusion: This will be one of the very few household surveys in a general population sample to assess mental health problems and COVID-19-related variables since the beginning of the pandemic. Through this research, we aim to obtain an epidemiological profile of mood disorders in Tunisia and an estimation of the impact of the COVID-19 pandemic on their prevalence. Results should contribute to improving mental health care in Tunisia

Water- and nutrient-dependent effects of dietary restriction on Drosophila lifespan

Dietary restriction (DR) is a widely conserved intervention leading to lifespan extension. Despite considerable effort, the mechanisms underlying DR remain poorly understood. In particular, it remains unclear whether DR prolongs life through conserved mechanisms in different species. Here, we show that, in the most common experimental conditions, lifespan extension by DR is abolished by providing Drosophila with ad libitum water, without altering food intake, indicating that DR, as conventionally studied in flies, is fundamentally different from the phenomenon studied in mammals. We characterize an alternative dietary paradigm that elicits robust lifespan extension irrespective of water availability, and thus likely represents a more relevant model for mammalian DR. Our results support the view that protein:carbohydrate ratio is the main dietary determinant of fly lifespan. These findings have broad implications for the study of lifespan and nutrition

Genomic Ancestry of North Africans Supports Back-to-Africa Migrations

North African populations are distinct from sub-Saharan Africans based on cultural, linguistic, and phenotypic attributes; however, the time and the extent of genetic divergence between populations north and south of the Sahara remain poorly understood. Here, we interrogate the multilayered history of North Africa by characterizing the effect of hypothesized migrations from the Near East, Europe, and sub-Saharan Africa on current genetic diversity. We present dense, genome-wide SNP genotyping array data (730,000 sites) from seven North African populations, spanning from Egypt to Morocco, and one Spanish population. We identify a gradient of likely autochthonous Maghrebi ancestry that increases from east to west across northern Africa; this ancestry is likely derived from “back-to-Africa” gene flow more than 12,000 years ago (ya), prior to the Holocene. The indigenous North African ancestry is more frequent in populations with historical Berber ethnicity. In most North African populations we also see substantial shared ancestry with the Near East, and to a lesser extent sub-Saharan Africa and Europe. To estimate the time of migration from sub-Saharan populations into North Africa, we implement a maximum likelihood dating method based on the distribution of migrant tracts. In order to first identify migrant tracts, we assign local ancestry to haplotypes using a novel, principal component-based analysis of three ancestral populations. We estimate that a migration of western African origin into Morocco began about 40 generations ago (approximately 1,200 ya); a migration of individuals with Nilotic ancestry into Egypt occurred about 25 generations ago (approximately 750 ya). Our genomic data reveal an extraordinarily complex history of migrations, involving at least five ancestral populations, into North Africa

Early holocenic and historic mtDNA african signatures in the iberian peninsula: The andalusian region as a paradigm

Determining the timing, identity and direction of migrations in the Mediterranean Basin, the role of "migratory routes" in and among regions of Africa, Europe and Asia, and the effects of sex-specific behaviors of population movements have important implications for our understanding of the present human genetic diversity. A crucial component of the Mediterranean world is its westernmost region. Clear features of transcontinental ancient contacts between North African and Iberian populations surrounding the maritime region of Gibraltar Strait have been identified from archeological data. The attempt to discern origin and dates of migration between close geographically related regions has been a challenge in the field of uniparental-based population genetics. Mitochondrial DNA (mtDNA) studies have been focused on surveying the H1, H3 and V lineages when trying to ascertain north-south migrations, and U6 and L in the opposite direction, assuming that those lineages are good proxies for the ancestry of each side of the Mediterranean. To this end, in the present work we have screened entire mtDNA sequences belonging to U6, M1 and L haplogroups in Andalusians--from Huelva and Granada provinces--and Moroccan Berbers. We present here pioneer data and interpretations on the role of NW Africa and the Iberian Peninsula regarding the time of origin, number of founders and expansion directions of these specific markers. The estimated entrance of the North African U6 lineages into Iberia at 10 ky correlates well with other L African clades, indicating that U6 and some L lineages moved together from Africa to Iberia in the Early Holocene. Still, founder analysis highlights that the high sharing of lineages between North Africa and Iberia results from a complex process continued through time, impairing simplistic interpretations. In particular, our work supports the existence of an ancient, frequently denied, bridge connecting the Maghreb and Andalusia.Financial support was provided by the Spanish Ministry of Competitiveness through Research Project CGL2010-15191/BOS granted to RC and International Mobility Program Acciones Integradas Hispano-Portuguesas (PRI-AIBPT-2011-1004) granted to RC (Spain) and LP (Portugal) (http://www.mineco.gob.es/portal/site/mineco/idi). The E.C. Sixth Framework Programme under Contract n° ERAS-CT-2003-980409 (EUROCORES project of the European Science Foundation) also provided financial support to JMD for North African population research. CLH has a predoctoral fellowship granted by Complutense University. PS is supported by FCT Investigator Programme (IF/01641/2013). IPATIMUP (https://www.ipatimup.pt/) integrates the Instituto the Investigação em Saúde (i3S) Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology. IPATIMUP is funded by FEDER funds through the Operational Programme for Competitiveness Factors - COMPETE and National Funds through the FCT - under the project PEst-C/SAU/LA0003/2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Pparγ2 Is a Key Driver of Longevity in the Mouse

Aging involves a progressive physiological remodeling that is controlled by both genetic and environmental factors. Many of these factors impact also on white adipose tissue (WAT), which has been shown to be a determinant of lifespan. Interrogating a transcriptional network for predicted causal regulatory interactions in a collection of mouse WAT from F2 crosses with a seed set of 60 known longevity genes, we identified a novel transcriptional subnetwork of 742 genes which represent thus-far-unknown longevity genes. Within this subnetwork, one gene was Pparg (Nr1c3), an adipose-enriched nuclear receptor previously not associated with longevity. In silico, both the PPAR signaling pathway and the transcriptional signature of Pparγ agonist rosiglitazone overlapped with the longevity subnetwork, while in vivo, lowered expression of Pparg reduced lifespan in both the lipodystrophic Pparg1/2-hypomorphic and the Pparg2-deficient mice. These results establish Pparγ2 as one of the determinants of longevity and suggest that lifespan may be rather determined by a purposeful genetic program than a random process

Resveratrol Inhibits Protein Translation in Hepatic Cells

Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2α. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling