Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality
Sunitha Rangaraju,
Gregory M Solis,
Ryan C Thompson,
Rafael L Gomez-Amaro,
Leo Kurian,
Sandra E Encalada,
Alexander B Niculescu III,
Daniel R Salomon,
Michael Petrascheck
Affiliations
Sunitha Rangaraju
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
Gregory M Solis
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
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States
Rafael L Gomez-Amaro
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
Leo Kurian
Center for Molecular Medicine, University of Cologne, Cologne, Germany
Sandra E Encalada
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
Alexander B Niculescu III
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, United States
Daniel R Salomon
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, United States
Michael Petrascheck
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
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.
