Human Ageing Genomic Resources: Integrated databases and tools for the biology and genetics of ageing

Tăcutu, Robi; Craig, Thomas; Budovsky, Arie; Wuttke, Daniel; Lehmann, Gilad; Taranukha, Dmitri; Costa, Joana S.; Fraifeld, Vadim E.; Magalhães, João Pedro de

doi:10.1093/nar/gks1155

Cited by 502 publications

(584 citation statements)

References 29 publications

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“…Based on previous publications 44,45 , a list of genes being linked to senescence was curated. Of those, only the ones were kept having a fold-change > 1.5 or < -1.5 between 24-months old WT and 3-months old WT VAT macrophages, together with a corresponding p-value < 0.05 in dataset II.…”

Section: Bioinformaticsmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

369

352

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Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

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Section: Bioinformaticsmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

369

352

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“…For extant taxa, the majority of values for both body mass and endocranial volume were taken from supplementary files of Isler et al (2008). For non-primate euarchontans, we reference Stephan et al (1981), Pirlot and Kamiya (1982) and Tacutu et al (2013). For fossil taxa, we cite body mass and endocranial volumes reported in Radinsky (1979), Martin (1990), Godfrey and Jungers (2002), Bush et al (2004), Simons et al (2007), Silcox et al (2009aSilcox et al ( ,b, 2010, Catlett et al (2010), Kay et al (2012), Kirk et al (2014), Gonzales et al (2015), Ramdarshan and Orliac (2015), and Harrington et al (in press).…”

Section: Data Collection Protocolsmentioning

confidence: 99%

Internal carotid arterial canal size and scaling in Euarchonta: Re-assessing implications for arterial patency and phylogenetic relationships in early fossil primates

Boyer

Kirk

Silcox

et al. 2016

Journal of Human Evolution

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a b s t r a c tPrimate species typically differ from other mammals in having bony canals that enclose the branches of the internal carotid artery (ICA) as they pass through the middle ear. The presence and relative size of these canals varies among major primate clades. As a result, differences in the anatomy of the canals for the promontorial and stapedial branches of the ICA have been cited as evidence of either haplorhine or strepsirrhine affinities among otherwise enigmatic early fossil euprimates. Here we use micro X-ray computed tomography to compile the largest quantitative dataset on ICA canal sizes. The data suggest greater variation of the ICA canals within some groups than has been previously appreciated. For example, Lepilemur and Avahi differ from most other lemuriforms in having a larger promontorial canal than stapedial canal. Furthermore, various lemurids are intraspecifically variable in relative canal size, with the promontorial canal being larger than the stapedial canal in some individuals but not others. In species where the promontorial artery supplies the brain with blood, the size of the promontorial canal is significantly correlated with endocranial volume (ECV). Among species with alternate routes of encephalic blood supply, the promontorial canal is highly reduced relative to ECV, and correlated with both ECV and cranium size. Ancestral state reconstructions incorporating data from fossils suggest that the last common ancestor of living primates had promontorial and stapedial canals that were similar to each other in size and large relative to ECV. We conclude that the plesiomorphic condition for crown primates is to have a patent promontorial artery supplying the brain and a patent stapedial artery for various nonencephalic structures. This inferred ancestral condition is exhibited by treeshrews and most early fossil euprimates, while extant primates exhibit reduction in one canal or another. The only early fossils deviating from this plesiomorphic condition are Adapis parisiensis with a reduced promontorial canal, and Rooneyia and Mahgarita with reduced stapedial canals.

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“…DrugAge incorporates data from all these resources and improves on them by providing a more extensive and systematic repertoire of lifespan‐extending drugs, compounds and substances. Indeed, we followed the high standards for manual curation, user‐friendly interface and performance of HAGR (Tacutu et al ., 2013). Besides, DrugAge integrates drug–gene interactions and cross‐links to aging‐related genes, allowing a deeper examination of lifespan‐extending drugs.…”

Section: Discussionmentioning

confidence: 99%

The DrugAge database of aging-related drugs

et al. 2017

Self Cite

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SummaryAging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics.senescence.info/drugs/), a curated database of lifespan‐extending drugs and compounds. At the time of writing, DrugAge contains 1316 entries featuring 418 different compounds from studies across 27 model organisms, including worms, flies, yeast and mice. Data were manually curated from 324 publications. Using drug–gene interaction data, we also performed a functional enrichment analysis of targets of lifespan‐extending drugs. Enriched terms include various functional categories related to glutathione and antioxidant activity, ion transport and metabolic processes. In addition, we found a modest but significant overlap between targets of lifespan‐extending drugs and known aging‐related genes, suggesting that some but not most aging‐related pathways have been targeted pharmacologically in longevity studies. DrugAge is freely available online for the scientific community and will be an important resource for biogerontologists.

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Human Ageing Genomic Resources: Integrated databases and tools for the biology and genetics of ageing

Cited by 502 publications

References 29 publications

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Internal carotid arterial canal size and scaling in Euarchonta: Re-assessing implications for arterial patency and phylogenetic relationships in early fossil primates

The DrugAge database of aging-related drugs

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