title: Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import.
abstract: The common non-steroidal anti-inflammatory drug ibuprofen has been associated with a reduced risk of some age-related pathologies. However, a general pro-longevity role for ibuprofen and its mechanistic basis remains unclear. Here we show that ibuprofen increased the lifespan of Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, indicative of conserved eukaryotic longevity effects. Studies in yeast indicate that ibuprofen destabilizes the Tat2p permease and inhibits tryptophan uptake. Loss of Tat2p increased replicative lifespan (RLS), but ibuprofen did not increase RLS when Tat2p was stabilized or in an already long-lived strain background impaired for aromatic amino acid uptake. Concomitant with lifespan extension, ibuprofen moderately reduced cell size at birth, leading to a delay in the G1 phase of the cell cycle. Similar changes in cell cycle progression were evident in a large dataset of replicatively long-lived yeast deletion strains. These results point to fundamental cell cycle signatures linked with longevity, implicate aromatic amino acid import in aging and identify a largely safe drug that extends lifespan across different kingdoms of life.
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Chong
authors.initials: C
authors.lastname: He
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Tsuchiyama
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Quynh T
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Institute of Biology of Komi Science Center of Ural Branch of RAS, Syktyvkar, Russia; Syktyvkar State University, Syktyvkar, Russia.
authors.forename: Ekaterina N
authors.initials: EN
authors.lastname: Plyusnina
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Terrill
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sahibzada
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Bhumil
authors.initials: B
authors.lastname: Patel
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Alena R
authors.initials: AR
authors.lastname: Faulkner
authors.affiliation: Institute of Biology of Komi Science Center of Ural Branch of RAS, Syktyvkar, Russia; Syktyvkar State University, Syktyvkar, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Shaposhnikov
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Ruilin
authors.initials: R
authors.lastname: Tian
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tsuchiya
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: Institute of Biology of Komi Science Center of Ural Branch of RAS, Syktyvkar, Russia; Syktyvkar State University, Syktyvkar, Russia; Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Moskalev
authors.affiliation: Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Polymenis
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000502:physiology; D004331:Drosophila melanogaster / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects*; D055550:Protein Stability; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D000894:Anti-Inflammatory Agents, Non-Steroidal; D029701:Saccharomyces cerevisiae Proteins; C429825:TAT2 protein, S cerevisiae; D014364:Tryptophan; D007052:Ibuprofen