Gene expression hallmarks of cellular ageing

Biogerontology - Tập 19 - Trang 547-566 - 2018
Stephen Frenk1, Jonathan Houseley2
1Department of Genetics, University of North Carolina, Chapel Hill, USA
2Epigenetics Programme, Babraham Institute, Cambridge, UK

Tóm tắt

Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age-linked changes in basal gene expression across eukaryotes from yeast to human and identify six gene expression hallmarks of cellular ageing: downregulation of genes encoding mitochondrial proteins; downregulation of the protein synthesis machinery; dysregulation of immune system genes; reduced growth factor signalling; constitutive responses to stress and DNA damage; dysregulation of gene expression and mRNA processing. These encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses. We discuss how the existence of conserved transcriptomic hallmarks relates to genome-wide epigenetic differences underlying ageing clocks, and how the changing transcriptome results in proteomic alterations where data is available and to variations in cell physiology characteristic of ageing. Identification of gene expression events that occur during ageing across distant organisms should be informative as to conserved underlying mechanisms of ageing, and provide additional biomarkers to assess the effects of diet and other environmental factors on the rate of ageing.

Tài liệu tham khảo

Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY (2007) Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev 21:3244–3257. https://doi.org/10.1101/gad.1588507

Avrahami D et al (2015) Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved beta cell function. Cell Metab 22:619–632. https://doi.org/10.1016/j.cmet.2015.07.025

Bahar R et al (2006) Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441:1011–1014. https://doi.org/10.1038/nature04844

Bektas A et al (2014) Age-associated changes in basal NF-kappaB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase. Aging 6:957–974. https://doi.org/10.18632/aging.100705

Berchtold NC et al (2008) Gene expression changes in the course of normal brain aging are sexually dimorphic. PNAS 105:15605–15610. https://doi.org/10.1073/pnas.0806883105

Bryois J et al (2017) Time-dependent genetic effects on gene expression implicate aging processes. Genome Res 27:545–552. https://doi.org/10.1101/gr.207688.116

Buchwalter A, Hetzer MW (2017) Nucleolar expansion and elevated protein translation in premature aging. Nat Commun 8:328. https://doi.org/10.1038/s41467-017-00322-z

Butler JS, Dent SY (2012) Chromatin ‘resetting’ during transcription elongation: a central role for methylated H3K36. Nat Struct Mol Biol 19:863–864. https://doi.org/10.1038/nsmb.2370

Cannon L et al (2017) Expression patterns of cardiac aging in Drosophila. Aging Cell 16:82–92. https://doi.org/10.1111/acel.12559

Carlson KA et al (2015) Genome-wide gene expression in relation to age in large laboratory cohorts of Drosophila melanogaster. Genet Res Int 2015:835624. https://doi.org/10.1155/2015/835624

Chien Y et al (2011) Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–2136. https://doi.org/10.1101/gad.17276711

Choi KM, Hong SJ, van Deursen JM, Kim S, Kim KH, Lee CK (2017) Caloric restriction and rapamycin differentially alter energy metabolism in yeast. J Gerontol Ser A Biol Sci Med Sci. https://doi.org/10.1093/gerona/glx024

Contrepois K et al (2017) Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat Commun 8:14995. https://doi.org/10.1038/ncomms14995

Cruickshanks HA et al (2013) Senescent cells harbour features of the cancer epigenome. Nat Cell Biol 15:1495–1506. https://doi.org/10.1038/ncb2879

Cruz C, Della Rosa M, Krueger C, Gao Q, Field L, Houseley J (2017) Tri-methylation of histone H3 lysine 4 facilitates gene expression in ageing cells. bioRxiv, Preprint. https://doi.org/10.1101/238048

Curran SP, Ruvkun G (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 3:e56. https://doi.org/10.1371/journal.pgen.0030056

De Cecco M et al (2013a) Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12:247–256. https://doi.org/10.1111/acel.12047

De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA (2013b) Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging 5:867–883. https://doi.org/10.18632/aging.100621

Dephoure N, Hwang S, O’Sullivan C, Dodgson SE, Gygi SP, Amon A, Torres EM (2014) Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 3:e03023. https://doi.org/10.7554/eLife.03023

Digital Ageing Atlas. http://ageing-map.org/

Doroszuk A, Jonker MJ, Pul N, Breit TM, Zwaan BJ (2012) Transcriptome analysis of a long-lived natural Drosophila variant: a prominent role of stress- and reproduction-genes in lifespan extension. BMC Genomics 13:167. https://doi.org/10.1186/1471-2164-13-167

Duronio RJ, Xiong Y (2013) Signaling pathways that control cell proliferation. Cold Spring Harb Perspect Biol 5:a008904. https://doi.org/10.1101/cshperspect.a008904

Etges WJ, Trotter MV, de Oliveira CC, Rajpurohit S, Gibbs AG, Tuljapurkar S (2015) Deciphering life history transcriptomes in different environments. Mol Ecol 24:151–179. https://doi.org/10.1111/mec.13017

Farr JN et al (2015) Effects of age and estrogen on skeletal gene expression in humans as assessed by RNA sequencing. PLoS ONE 10:e0138347. https://doi.org/10.1371/journal.pone.0138347

Fehrmann S, Paoletti C, Goulev Y, Ungureanu A, Aguilaniu H, Charvin G (2013) Aging yeast cells undergo a sharp entry into senescence unrelated to the loss of mitochondrial membrane potential. Cell Rep 5:1589–1599. https://doi.org/10.1016/j.celrep.2013.11.013

Fok WC et al (2014a) Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver. Aging Cell 13:311–319. https://doi.org/10.1111/acel.12175

Fok WC et al (2014b) Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS ONE 9:e83988. https://doi.org/10.1371/journal.pone.0083988

Frenk S, Pizza G, Walker RV, Houseley J (2017) Aging yeast gain a competitive advantage on non-optimal carbon sources. Aging Cell 16:602–604. https://doi.org/10.1111/acel.12582

Gill S, Le HD, Melkani GC, Panda S (2015) Time-restricted feeding attenuates age-related cardiac decline in Drosophila. Science 347:1265–1269. https://doi.org/10.1126/science.1256682

Hamatani T et al (2004) Age-associated alteration of gene expression patterns in mouse oocytes. Hum Mol Genet 13:2263–2278. https://doi.org/10.1093/hmg/ddh241

Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6:95–110. https://doi.org/10.1111/j.1474-9726.2006.00267.x

Harries LW et al (2011) Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell 10:868–878. https://doi.org/10.1111/j.1474-9726.2011.00726.x

Hartl FU (2017) Protein Misfolding Diseases Annual review of biochemistry 86:21–26. https://doi.org/10.1146/annurev-biochem-061516-044518

Haustead DJ et al (2016) Transcriptome analysis of human ageing in male skin shows mid-life period of variability and central role of NF-kappaB Sci Rep 6:26846. https://doi.org/10.1038/srep26846

Heintz C et al (2017) Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541:102–106. https://doi.org/10.1038/nature20789

Holly AC, Melzer D, Pilling LC, Fellows AC, Tanaka T, Ferrucci L, Harries LW (2013a) Changes in splicing factor expression are associated with advancing age in man. Mech Ageing Dev 134:356–366. https://doi.org/10.1016/j.mad.2013.05.006

Holly AC et al (2013b) Towards a gene expression biomarker set for human biological age. Aging Cell 12:324–326. https://doi.org/10.1111/acel.12044

Horvath S et al (2014) Obesity accelerates epigenetic aging of human liver. PNAS 111:15538–15543. https://doi.org/10.1073/pnas.1412759111

Horvath S et al (2016) Huntington’s disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels. Aging 8:1485–1512. https://doi.org/10.18632/aging.101005

Hu Z et al (2014) Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes Dev 28:396–408. https://doi.org/10.1101/gad.233221.113

Human Ageing Geomic Resource. http://genomics.senescence.info/gene_expression/index.php

Iadevaia V, Liu R, Proud CG (2014) mTORC1 signaling controls multiple steps in ribosome biogenesis. Semin Cell Dev Biol 36:113–120. https://doi.org/10.1016/j.semcdb.2014.08.004

Janssens GE, Veenhoff LM (2016) The natural variation in lifespans of single yeast cells is related to variation in cell size, ribosomal protein, and division time. PLoS ONE 11:e0167394. https://doi.org/10.1371/journal.pone.0167394

Janssens GE et al (2015) Protein biogenesis machinery is a driver of replicative aging in yeast. eLife 4:e08527. https://doi.org/10.7554/eLife.08527

Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345. https://doi.org/10.1038/nature11861

Josefson R, Andersson R, Nystrom T (2017) How and why do toxic conformers of aberrant proteins accumulate during ageing? Essays Biochem 61:317–324. https://doi.org/10.1042/EBC20160085

Jurk D et al (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 2:4172. https://doi.org/10.1038/ncomms5172

Kaeberlein M et al (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310:1193–1196. https://doi.org/10.1126/science.1115535

Kamei Y, Tamada Y, Nakayama Y, Fukusaki E, Mukai Y (2014) Changes in transcription and metabolism during the early stage of replicative cellular senescence in budding yeast. J Biol Chem 289:32081–32093. https://doi.org/10.1074/jbc.M114.600528

Kannan S, Dawany N, Kurupati R, Showe LC, Ertl HC (2016) Age-related changes in the transcriptome of antibody-secreting cells Oncotarget 7:13340–13353. https://doi.org/10.18632/oncotarget.7958

Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ (2010) mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. PNAS 107:11823–11828. https://doi.org/10.1073/pnas.1005188107

Karunadharma PP et al (2015) Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell 14:547–557. https://doi.org/10.1111/acel.12317

Kaya A, Lobanov AV, Gladyshev VN (2015) Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae. Aging Cell 14:366–371. https://doi.org/10.1111/acel.12290

Khoo ML, Carlin SM, Lutherborrow MA, Jayaswal V, Ma DD, Moore JJ (2014) Gene profiling reveals association between altered Wnt signaling and loss of T-cell potential with age in human hematopoietic stem cells. Aging Cell 13:744–754. https://doi.org/10.1111/acel.12229

Kim YM et al (2013) Implications of time-series gene expression profiles of replicative senescence. Aging Cell 12:622–634. https://doi.org/10.1111/acel.12087

Kim DK, Kim TH, Lee SJ (2016a) Mechanisms of aging-related proteinopathies in Caenorhabditis elegans. Exp Mol Med 48:e263. https://doi.org/10.1038/emm.2016.109

Kirkwood TB (1977) Evolution of ageing. Nature 270:301–304

Kural KC, Tandon N, Skoblov M, Kel-Margoulis OV, Baranova AV (2016) Pathways of aging: comparative analysis of gene signatures in replicative senescence and stress induced premature senescence. BMC Genomics 17:1030. https://doi.org/10.1186/s12864-016-3352-4

Labbadia J, Morimoto RI (2015a) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435–464. https://doi.org/10.1146/annurev-biochem-060614-033955

Lackner DH, Hayashi MT, Cesare AJ, Karlseder J (2014) A genomics approach identifies senescence-specific gene expression regulation. Aging Cell 13:946–950. https://doi.org/10.1111/acel.12234

Lahteenvuo J, Rosenzweig A (2012) Effects of aging on angiogenesis. Circ Res 110:1252–1264. https://doi.org/10.1161/CIRCRESAHA.111.246116

Lamming DW (2016) Inhibition of the mechanistic target of rapamycin (mTOR)-rapamycin and beyond. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a025924

Landis GN et al (2004) Similar gene expression patterns characterize aging and oxidative stress in Drosophila melanogaster. PNAS 101:7663–7668. https://doi.org/10.1073/pnas.0307605101

Landis G, Shen J, Tower J (2012) Gene expression changes in response to aging compared to heat stress, oxidative stress and ionizing radiation in Drosophila melanogaster. Aging 4:768–789. https://doi.org/10.18632/aging.100499

Leadsham JE et al (2013) Loss of cytochrome c oxidase promotes RAS-dependent ROS production from the ER resident NADPH oxidase, Yno1p, in yeast. Cell Metab 18:279–286. https://doi.org/10.1016/j.cmet.2013.07.005

Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294–297. https://doi.org/10.1038/77046

Lee JS et al (2012) Meta-analysis of gene expression in the mouse liver reveals biomarkers associated with inflammation increased early during aging. Mech Ageing Dev 133:467–478. https://doi.org/10.1016/j.mad.2012.05.006

Lee BP et al (2016) Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans. Aging Cell 15:903–913. https://doi.org/10.1111/acel.12499

Lesur I, Campbell JL (2004) The transcriptome of prematurely aging yeast cells is similar to that of telomerase-deficient cells. Mol Biol Cell 15:1297–1312. https://doi.org/10.1091/mbc.E03-10-0742

Li W, Prazak L, Chatterjee N, Gruninger S, Krug L, Theodorou D, Dubnau J (2013) Activation of transposable elements during aging and neuronal decline in Drosophila. Nat Neurosci 16:529–531. https://doi.org/10.1038/nn.3368

Lin SS, Manchester JK, Gordon JI (2001) Enhanced gluconeogenesis and increased energy storage as hallmarks of aging in Saccharomyces cerevisiae. J Biol Chem 276:36000–36007. https://doi.org/10.1074/jbc.M103509200

Lourenco dos Santos S, Baraibar MA, Lundberg S, Eeg-Olofsson O, Larsson L, Friguet B (2015) Oxidative proteome alterations during skeletal muscle ageing. Redox Biol 5:267–274. https://doi.org/10.1016/j.redox.2015.05.006

Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891. https://doi.org/10.1038/nature02661

Ma X, Zhan G, Sleumer MC, Chen S, Liu W, Zhang MQ, Liu X (2016) Analysis of C. elegans muscle transcriptome using trans-splicing-based RNA tagging (SRT). Nucleic Acids Res 44:e156. https://doi.org/10.1093/nar/gkw734

Maierhofer A, Flunkert J, Oshima J, Martin GM, Haaf T, Horvath S (2017) Accelerated epigenetic aging in Werner syndrome. Aging 9:1143–1152. https://doi.org/10.18632/aging.101217

Mair W, Piper MD, Partridge L (2005) Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol 3:e223. https://doi.org/10.1371/journal.pbio.0030223

Marthandan S et al (2016) Conserved genes and pathways in primary human fibroblast strains undergoing replicative and radiation induced senescence. Biol Res 49:34. https://doi.org/10.1186/s40659-016-0095-2

Martinez-Jimenez CP et al (2017) Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355:1433–1436. https://doi.org/10.1126/science.aah4115

Martin-Montalvo A et al (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192. https://doi.org/10.1038/ncomms3192

McCarroll SA et al (2004) Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet 36:197–204. https://doi.org/10.1038/ng1291

Mirza N, Pollock K, Hoelzinger DB, Dominguez AL, Lustgarten J (2011) Comparative kinetic analyses of gene profiles of naive CD4+ and CD8+ T cells from young and old animals reveal novel age-related alterations. Aging Cell 10:853–867. https://doi.org/10.1111/j.1474-9726.2011.00730.x

Miwa S et al (2014) Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nat Commun 5:3837. https://doi.org/10.1038/ncomms4837

Mylonakis E, Aballay A (2005) Worms and flies as genetically tractable animal models to study host–pathogen interactions. Infect Immun 73:3833–3841. https://doi.org/10.1128/IAI.73.7.3833-3841.2005

Nishtala K et al (2013) Proteomic analyses of age related changes in A.BY/SnJ mouse hearts. Proteome Sci 11:29. https://doi.org/10.1186/1477-5956-11-29

O’Hagan HM, Mohammad HP, Baylin SB (2008) Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet 4:e1000155. https://doi.org/10.1371/journal.pgen.1000155

Ori A et al (2015) Integrated transcriptome and proteome analyses reveal organ-specific proteome deterioration in old rats. Cell Syst 1:224–237. https://doi.org/10.1016/j.cels.2015.08.012

O’Sullivan RJ, Kubicek S, Schreiber SL, Karlseder J (2010) Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struct Mol Biol 17:1218–1225. https://doi.org/10.1038/nsmb.1897

Peters MJ et al (2015) The transcriptional landscape of age in human peripheral blood. Nat Commun 6:8570. https://doi.org/10.1038/ncomms9570

Philipp O, Hamann A, Servos J, Werner A, Koch I, Osiewacz HD (2013) A genome-wide longitudinal transcriptome analysis of the aging model Podospora anserina. PLoS ONE 8:e83109. https://doi.org/10.1371/journal.pone.0083109

Plank M, Wuttke D, van Dam S, Clarke SA, de Magalhaes JP (2012) A meta-analysis of caloric restriction gene expression profiles to infer common signatures and regulatory mechanisms. Mol BioSyst 8:1339–1349. https://doi.org/10.1039/c2mb05255e

Pu M et al (2015) Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev 29:718–731. https://doi.org/10.1101/gad.254144.114

Purcell M, Kruger A, Tainsky MA (2014) Gene expression profiling of replicative and induced senescence. Cell Cycle 13:3927–3937. https://doi.org/10.4161/15384101.2014.973327

Quach A et al (2017) Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 9:419–446. https://doi.org/10.18632/aging.101168

Rangaraju S et al (2015) Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality. eLife 4:e8833. https://doi.org/10.7554/eLife.08833

Rao SG, Jackson JG (2016) SASP: tumor suppressor or promoter? Yes! Trends Cancer 2:676–687. https://doi.org/10.1016/j.trecan.2016.10.001

Rea SL, Ventura N, Johnson TE (2007) Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol 5:e259. https://doi.org/10.1371/journal.pbio.0050259

Reis-Rodrigues P et al (2012) Proteomic analysis of age-dependent changes in protein solubility identifies genes that modulate lifespan. Aging Cell 11:120–127. https://doi.org/10.1111/j.1474-9726.2011.00765.x

Remondini D et al (2010) Complex patterns of gene expression in human T cells during in vivo aging. Mol BioSyst 6:1983–1992. https://doi.org/10.1039/c004635c

Rodriguez SA, Grochova D, McKenna T, Borate B, Trivedi NS, Erdos MR, Eriksson M (2016) Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging. Aging Cell 15:267–278. https://doi.org/10.1111/acel.12433

Roforth MM et al (2015) Global transcriptional profiling using RNA sequencing and DNA methylation patterns in highly enriched mesenchymal cells from young versus elderly women. Bone 76:49–57. https://doi.org/10.1016/j.bone.2015.03.017

Ryan NA, Zwetsloot KA, Westerkamp LM, Hickner RC, Pofahl WE, Gavin TP (2006) Lower skeletal muscle capillarization and VEGF expression in aged vs. young men. J Appl Physiol (1985) 100:178–185. https://doi.org/10.1152/japplphysiol.00827.2005

Sarup P, Sorensen P, Loeschcke V (2014) The long-term effects of a life-prolonging heat treatment on the Drosophila melanogaster transcriptome suggest that heat shock proteins extend lifespan. Exp Gerontol 50:34–39. https://doi.org/10.1016/j.exger.2013.11.017

Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312:1059–1063. https://doi.org/10.1126/science.1127168

Schumacher B et al (2008) Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet 4:e1000161. https://doi.org/10.1371/journal.pgen.1000161

Seim I, Ma S, Gladyshev VN (2016) Gene expression signatures of human cell and tissue longevity. NPJ Aging Mech Dis 2:16014. https://doi.org/10.1038/npjamd.2016.14

Sen P et al (2015) H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev 29:1362–1376. https://doi.org/10.1101/gad.263707.115

Shumaker DK et al (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. PNAS 103:8703–8708. https://doi.org/10.1073/pnas.0602569103

Stauch KL, Purnell PR, Villeneuve LM, Fox HS (2015) Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism. Proteomics 15:1574–1586. https://doi.org/10.1002/pmic.201400277

Stubbs TM et al (2017) Multi-tissue DNA methylation age predictor in mouse. Genome Biol 18:68. https://doi.org/10.1186/s13059-017-1203-5

Thompson MJ, vonHoldt B, Horvath S, Pellegrini M (2017) An epigenetic aging clock for dogs and wolves. Aging 9:1055–1068. https://doi.org/10.18632/aging.101211

Tiku V et al (2016) Small nucleoli are a cellular hallmark of longevity. Nat Commun 8:16083. https://doi.org/10.1038/ncomms16083

Tsakiri EN, Sykiotis GP, Papassideri IS, Gorgoulis VG, Bohmann D, Trougakos IP (2013) Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress. FASEB J 27:2407–2420. https://doi.org/10.1096/fj.12-221408

Tsang CK, Liu H, Zheng XF (2010) mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. Cell Cycle 9:953–957. https://doi.org/10.4161/cc.9.5.10876

van den Akker EB et al (2014) Meta-analysis on blood transcriptomic studies identifies consistently coexpressed protein-protein interaction modules as robust markers of human aging. Aging Cell 13:216–225. https://doi.org/10.1111/acel.12160

Vavken P, Saad FA, Murray MM (2010) Age dependence of expression of growth factor receptors in porcine ACL fibroblasts. J Orthop Res 28:1107–1112. https://doi.org/10.1002/jor.21111

Venema J, Tollervey D (1999) Ribosome synthesis in Saccharomyces cerevisiae. Annu Rev Genet 33:261–311. https://doi.org/10.1146/annurev.genet.33.1.261

Vermeij WP et al (2016) Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature 537:427–431. https://doi.org/10.1038/nature19329

Voutetakis K, Chatziioannou A, Gonos ES, Trougakos IP (2015) Comparative meta-analysis of transcriptomics data during cellular senescence and in vivo tissue ageing. Oxid Med Cell Longev 2015:732914. https://doi.org/10.1155/2015/732914

Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22:1041–1050. https://doi.org/10.1111/j.1432-2277.2009.00927.x

Whitaker R, Gil MP, Ding F, Tatar M, Helfand SL, Neretti N (2014) Dietary switch reveals fast coordinated gene expression changes in Drosophila melanogaster. Aging 6:355–368. https://doi.org/10.18632/aging.100662

White RR, Milholland B, MacRae SL, Lin M, Zheng D, Vijg J (2015) Comprehensive transcriptional landscape of aging mouse liver. BMC Genomics 16:899. https://doi.org/10.1186/s12864-015-2061-8

Wiley CD et al (2017) Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16:1043–1050. https://doi.org/10.1111/acel.12632

Wilson CH et al (2015) Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice. Cell Death Dis 6:e1615. https://doi.org/10.1038/cddis.2014.567

Yu C et al (2011) RNA sequencing reveals differential expression of mitochondrial and oxidation reduction genes in the long-lived naked mole-rat when compared to mice. PLoS ONE 6:e26729. https://doi.org/10.1371/journal.pone.0026729

Zahn JM et al (2006) Transcriptional profiling of aging in human muscle reveals a common aging signature. PLoS Genet 2:e115. https://doi.org/10.1371/journal.pgen.0020115.eor

Zahn JM et al (2007) AGEMAP: a gene expression database for aging in mice. PLoS Genet 3:e201. https://doi.org/10.1371/journal.pgen.0030201

Zhang W et al (2015) Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160–1163. https://doi.org/10.1126/science.aaa1356

Zid BM et al (2009) 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 139:149–160. https://doi.org/10.1016/j.cell.2009.07.034

Zou S, Meadows S, Sharp L, Jan LY, Jan YN (2000) Genome-wide study of aging and oxidative stress response in Drosophila melanogaster. PNAS 97:13726–13731. https://doi.org/10.1073/pnas.260496697