Publications
127 results found
Liao C-Y, Anderson SS, Chicoine NH, et al., 2017, Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins, Cell Discovery, Vol: 3, ISSN: 2056-5968
The mechanistic target of rapamycin (mTOR) signaling pathway plays a central role in aging and a number of different disease states. Rapamycin, which suppresses activity of the mTOR complex 1 (mTORC1), shows preclinical (and sometimes clinical) efficacy in a number of disease models. Among these are Lmna−/− mice, which serve as a mouse model for dystrophy-associated laminopathies. To confirm that elevated mTORC1 signaling is responsible for the pathology manifested in Lmna−/− mice and to decipher downstream genetic mechanisms underlying the benefits of rapamycin, we tested in Lmna−/− mice whether survival could be extended and disease pathology suppressed either by reduced levels of S6K1 or enhanced levels of 4E-BP1, two canonical mTORC1 substrates. Global heterozygosity for S6K1 ubiquitously extended lifespan of Lmna−/− mice (Lmna−/− S6K1+/− mice). This life extension is due to improving muscle, but not heart or adipose, function, consistent with the observation that genetic ablation of S6K1 specifically in muscle tissue also extended survival of Lmna−/− mice. In contrast, whole-body overexpression of 4E-BP1 shortened the survival of Lmna−/− mice, likely by accelerating lipolysis. Thus, rapamycin-mediated lifespan extension in Lmna−/− mice is in part due to the improvement of skeletal muscle function and can be phenocopied by reduced S6K1 activity, but not 4E-BP1 activation.
Hine C, Kim H-J, Zhu Y, et al., 2017, Hypothalamic-pituitary axis regulates hydrogen sulfide production, Cell Metabolism, Vol: 25, Pages: 1320-+, ISSN: 1550-4131
Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.
Selman C, Withers DJ, 2017, Physiology: an atypical switch for metabolism and ageing, NATURE, Vol: 542, Pages: 299-300, ISSN: 0028-0836
Van de Pette M, Abbas A, Feytout A, et al., 2017, Visualizing changes in Cdkn1c expression links early life adversity to imprint mis-regulation in adults, Cell Reports, Vol: 31, Pages: 1090-1099, ISSN: 2211-1247
Imprinted genes are regulated according to parental origin and can influence embryonic growth and metabolism and confer disease susceptibility.Here we designed sensitive allele-specific reporters to non-invasively monitor imprinted Cdkn1cexpression in mice and showed that expression was modulated by environmental factors encounteredin utero.Acute exposure to chromatin modifyingdrugs resulted in de-repression of paternally inherited (silent) Cdkn1calleles in embryos that was temporary and resolved after birth.In contrast, deprivation of maternal dietary proteinin uteroprovoked permanent de-repression of imprinted Cdkn1cexpression that was sustained into adulthood and occurred through a folate-dependent mechanism of DNA methylation loss.Given the function of imprinted genes in regulating behavior and metabolic processes in adults, these results establish imprinting deregulation as a credible mechanism linking early life adversity to later-life outcomes.Furthermore,Cdkn1c-luciferasemice offer non-invasivetools to identify factors that disrupt epigenetic processes and strategies to limit their long-term impact.
Yavari A, Stocker CJ, Ghaffari S, et al., 2016, Chronic activation of γ2 AMPK induces obesity and reduces β cell function, Cell Metabolism, Vol: 23, Pages: 821-836, ISSN: 1932-7420
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.
Selman C, Sinclair A, Pedroni S, et al., 2016, Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice, Oncotarget, Vol: 7, Pages: 29937-29943, ISSN: 1949-2553
The mechanistic target of rapamycin (mTOR) signalling pathway plays a highly conserved role in aging; mice lacking ribosomal protein S6 kinase 1 (S6K1-/-) have extended lifespan and healthspan relative to wild type (WT) controls. Exactly how reduced mTOR signalling induces such effects is unclear, although preservation of stem cell function may be important. We show, using gene expression analyses, that there was a reduction in expression of cell cycle genes in young (12 week) and aged (80 week) S6K1-/- BM-derived c-Kit+ cells when compared to age-matched WT mice, suggesting that these cells are more quiescent in S6K1-/- mice. In addition, we investigated hematopoietic stem cell (HSC) frequency and function in young and aged S6K1-/- and WT mice. Young, but not aged, S6K1-/- mice had more LSK (lineage-, c-Kit+, Sca-1+) cells (% of bone marrow (BM)), including the most primitive long-term repopulating HSC (LT-HSC) relative to WT controls. Donor-derived engraftment of LT-HSCs in recipient mice was unaffected by genotype in young mice, but was enhanced in transplants using LT-HSCs derived from aged S6K1-/- mice. Our results are the first to provide evidence that age-associated HSC functional decline is ameliorated in a long-lived mTOR mutant mouse.
Gil J, Withers DJ, 2016, Ageing: out with the old, Nature, Vol: 530, Pages: 164-165, ISSN: 0028-0836
The selective elimination of cells that have adopted an irreversible, senescent state has now been shown to extend the lifespan of mice and to ameliorate some age-related disease processes.
Herranz N, Gallage S, Mellone M, et al., 2015, Erratum: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype., Nat Cell Biol, Vol: 17
Ilse S Pienaar, Sarah E Gartside, Puneet Sharma, et al., 2015, Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson’s disease, Molecular Neurodegeneration, Vol: 10, ISSN: 1750-1326
Background: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, includingpostural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) ofa highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, theunderlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hamperingoptimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre+ transgenic rats were sham-lesioned orrendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomalsystem inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD),to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of thehuman PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including apartial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients.Results: In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in thelactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO),dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait,sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordingsrevealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fosexpression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased byCNO administration, consistent with upregulated neuronal activation in this defined neuronal population.Conclusions: Overall, these findings provide evidence that functional modulation of PPN cholinergic neuronsalleviates parkinson
Herranz N, Gallage S, Mellone M, et al., 2015, mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype, Nature Cell Biology, Vol: 17, Pages: 1205-1217, ISSN: 1476-4679
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
Smith MA, Katsouri L, Irvine EE, et al., 2015, Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice, Cell Reports, Vol: 11, Pages: 335-343, ISSN: 2211-1247
Page MM, Sinclair A, Robb EL, et al., 2014, Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress, AGING CELL, Vol: 13, Pages: 962-964, ISSN: 1474-9718
- Author Web Link
- Open Access Link
- Cite
- Citations: 4
Jove M, Naudi A, Ramirez-Nunez O, et al., 2014, Caloric restriction reveals a metabolomic and lipidomic signature in liver of male mice, AGING CELL, Vol: 13, Pages: 828-837, ISSN: 1474-9726
- Author Web Link
- Cite
- Citations: 56
Deas E, Piipari K, Machhada A, et al., 2014, PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice, OPEN BIOLOGY, Vol: 4, ISSN: 2046-2441
- Author Web Link
- Cite
- Citations: 34
Yousseif A, Emmanuel J, Karra E, et al., 2014, Differential Effects of Laparoscopic Sleeve Gastrectomy and Laparoscopic Gastric Bypass on Appetite, Circulating Acyl-ghrelin, Peptide YY3-36 and Active GLP-1 Levels in Non-diabetic Humans, OBESITY SURGERY, Vol: 24, Pages: 241-252, ISSN: 0960-8923
- Author Web Link
- Cite
- Citations: 180
Chandarana K, Gelegen C, Irvine EE, et al., 2013, Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance, MOLECULAR METABOLISM, Vol: 2, Pages: 142-152, ISSN: 2212-8778
- Author Web Link
- Cite
- Citations: 44
Karra E, Daly OG, Choudhury A, et al., 2013, A link between FTO, ghrelin and impaired brain food-cue responsivity, Journal of Clinical Investigation
Page MM, Withers DJ, Selman C, 2013, Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage, AGE, Vol: 35, Pages: 647-658, ISSN: 0161-9152
- Author Web Link
- Cite
- Citations: 4
Foukas LC, Bilanges B, Bettedi L, et al., 2013, Long-term p110 PI3K inactivation exerts a beneficial effect on metabolism, EMBO MOLECULAR MEDICINE, Vol: 5, Pages: 563-571, ISSN: 1757-4676
- Author Web Link
- Cite
- Citations: 77
Scott WR, Gelegen C, Chandarana K, et al., 2013, Differential Pre-mRNA Splicing Regulates Nnat Isoforms in the Hypothalamus after Gastric Bypass Surgery in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203
- Author Web Link
- Cite
- Citations: 12
Neuhaus B, Niessen CM, Mesaros A, et al., 2012, Experimental analysis of risk factors for ulcerative dermatitis in mice, EXPERIMENTAL DERMATOLOGY, Vol: 21, Pages: 712-713, ISSN: 0906-6705
- Author Web Link
- Cite
- Citations: 13
Gelegen C, Chandarana K, Choudhury AI, et al., 2012, Regulation of hindbrain <i>Pyy</i> expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 303, Pages: E659-E668, ISSN: 0193-1849
- Author Web Link
- Cite
- Citations: 15
Page MM, Withers DJ, Selman C, 2012, An evaluation of cellular stress resistance in long-lived insulin receptor substrate-1 (Irs1) null mice, FREE RADICAL BIOLOGY AND MEDICINE, Vol: 53, Pages: S75-S75, ISSN: 0891-5849
Wijeyesekera A, Selman C, Barton RH, et al., 2012, Metabotyping of Long-Lived Mice using H-1 NMR Spectroscopy, Journal of Proteome Research, Vol: 11, Pages: 2224-2235, ISSN: 1535-3893
Significant advances in understanding aging have been achieved through studying model organisms with extended healthy lifespans. Employing 1H NMR spectroscopy, we characterized the plasma metabolic phenotype (metabotype) of three long-lived murine models: 30% dietary restricted (DR), insulin receptor substrate 1 null (Irs1–/–), and Ames dwarf (Prop1df/df). A panel of metabolic differences were generated for each model relative to their controls, and subsequently, the three long-lived models were compared to one another. Concentrations of mobile very low density lipoproteins, trimethylamine, and choline were significantly decreased in the plasma of all three models. Metabolites including glucose, choline, glycerophosphocholine, and various lipids were significantly reduced, while acetoacetate, d-3-hydroxybutyrate and trimethylamine-N-oxide levels were increased in DR compared to ad libitum fed controls. Plasma lipids and glycerophosphocholine were also decreased in Irs1–/– mice compared to controls, as were methionine and citrate. In contrast, high density lipoproteins and glycerophosphocholine were increased in Ames dwarf mice, as were methionine and citrate. Pairwise comparisons indicated that differences existed between the metabotypes of the different long-lived mice models. Irs1–/– mice, for example, had elevated glucose, acetate, acetone, and creatine but lower methionine relative to DR mice and Ames dwarfs. Our study identified several potential candidate biomarkers directionally altered across all three models that may be predictive of longevity but also identified differences in the metabolic signatures. This comparative approach suggests that the metabolic networks underlying lifespan extension may not be exactly the same for each model of longevity and is consistent with multifactorial control of the aging process.
Costello DA, Claret M, Al-Qassab H, et al., 2012, Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity, PLOS ONE, Vol: 7, ISSN: 1932-6203
- Author Web Link
- Cite
- Citations: 56
Page MM, Withers DJ, Selman C, 2011, Contribution of ROS-Metabolism in Tissue Homogenates and Dermal Fibroblasts of Long-Lived Insulin Receptor Substrate 1 (Irs1) Knockout Mice, 18th Annual Meeting of the Society-for-Free-Radical-Biology-and-Medicine (SFRBM), Publisher: ELSEVIER SCIENCE INC, Pages: S78-S79, ISSN: 0891-5849
Irvine EE, Drinkwater L, Radwanska K, et al., 2011, Insulin receptor substrate 2 is a negative regulator of memory formation, LEARNING & MEMORY, Vol: 18, Pages: 375-383, ISSN: 1072-0502
- Author Web Link
- Cite
- Citations: 46
Claret M, Smith MA, Knauf C, et al., 2011, Deletion of <i>Lkb1</i> in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice, DIABETES, Vol: 60, Pages: 735-745, ISSN: 0012-1797
- Author Web Link
- Cite
- Citations: 44
Chandarana K, Gelegen C, Karra E, et al., 2011, Diet and Gastrointestinal Bypass-Induced Weight Loss The Roles of Ghrelin and Peptide YY, DIABETES, Vol: 60, Pages: 810-818, ISSN: 0012-1797
- Author Web Link
- Cite
- Citations: 100
Woods A, Heslegrave AJ, Muckett PJ, et al., 2011, LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice, BIOCHEMICAL JOURNAL, Vol: 434, Pages: 49-60, ISSN: 0264-6021
- Author Web Link
- Cite
- Citations: 62
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.