title: Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality.
abstract: Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, United States.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Rangaraju
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, United States.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Solis
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: Ryan C
authors.identifier: http://orcid.org/0000-0002-0450-8181
authors.initials: RC
authors.lastname: Thompson
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, United States.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Gomez-Amaro
authors.affiliation: Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Leo
authors.initials: L
authors.lastname: Kurian
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, United States.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Encalada
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, United States.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Niculescu
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Salomon
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States.|Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, United States.|Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Petrascheck
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008136:Longevity / Q000187:drug effects*; D008803:Mianserin / Q000008:administration & dosage; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D014158:Transcription, Genetic
chemical_list: D012702:Serotonin Antagonists; D008803:Mianserin
keywords: C. elegans; aging; chemical physiology; computational biology; human; lifespan; mouse; neuroscience; systems biology