title: Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.
abstract: For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.
authors.affiliation: Insilico Medicine, Inc., Johns Hopkins University, ETC, B301, MD 21218, USA.|Federal Clinical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Aliper
authors.affiliation: Vision Genomics LLC, Washington DC 20011, USA.|Epigenetics Laboratory, Dept. of Anatomy, Howard University, Washington DC 20059, USA.
authors.forename: Antonei Benjamin
authors.initials: AB
authors.lastname: Csoka
authors.affiliation: Insilico Medicine, Inc., Johns Hopkins University, ETC, B301, MD 21218, USA.|Pathway Pharmaceuticals, Limited, Wan Chai, Hong Kong.
authors.forename: Anton
authors.initials: A
authors.lastname: Buzdin
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, 02-106 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Jetka
authors.affiliation: Insilico Medicine, Inc., Johns Hopkins University, ETC, B301, MD 21218, USA.|Pirogov Russian National Research Medical University, Moscow 117997, Russia.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141700, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Roumiantsev
authors.affiliation: Insilico Medicine, Inc., Johns Hopkins University, ETC, B301, MD 21218, USA.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141700, Russia.|George Mason University, Fairfax, VA 22030, USA.
authors.forename: Alexy
authors.initials: A
authors.lastname: Moskalev
authors.affiliation: Insilico Medicine, Inc., Johns Hopkins University, ETC, B301, MD 21218, USA.|Federal Clinical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141700, Russia.|The Biotechnology Research Foundation, BGRF, London W1J 5NE, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Zhavoronkov
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D030541:Databases, Genetic; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D010641:Phenotype; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*