title: Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity.
abstract: Mammalian lifespan differs by >100 fold, but the mechanisms associated with such longevity differences are not understood. Here, we conducted a study on primary skin fibroblasts isolated from 16 species of mammals and maintained under identical cell culture conditions. We developed a pipeline for obtaining species-specific ortholog sequences, profiled gene expression by RNA-seq and small molecules by metabolite profiling, and identified genes and metabolites correlating with species longevity. Cells from longer lived species up-regulated genes involved in DNA repair and glucose metabolism, down-regulated proteolysis and protein transport, and showed high levels of amino acids but low levels of lysophosphatidylcholine and lysophosphatidylethanolamine. The amino acid patterns were recapitulated by further analyses of primate and bird fibroblasts. The study suggests that fibroblast profiling captures differences in longevity across mammals at the level of global gene expression and metabolite levels and reveals pathways that define these differences.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Siming
authors.initials: S
authors.lastname: Ma
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Akhil
authors.initials: A
authors.lastname: Upneja
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, United States.|Geriatrics Center, University of Michigan Medical School, Ann Arbor, United States.|Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, United States.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Galecki
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, United States.|Geriatrics Center, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Yi-Miau
authors.initials: YM
authors.lastname: Tsai
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Sasha
authors.initials: S
authors.lastname: Raskind
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Quanwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, United States.
authors.forename: Zhengdong D
authors.initials: ZD
authors.lastname: Zhang
authors.affiliation: Department of Biology, University of Rochester, Rochester, United States.
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
authors.affiliation: Department of Biology, University of Rochester, Rochester, United States.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: Broad Institute, Cambridge, United States.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, United States.|Geriatrics Center, University of Michigan Medical School, Ann Arbor, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
authors.forename: Vadim N
authors.identifier: 0000-0002-0372-7016
authors.initials: VN
authors.lastname: Gladyshev
mesh_terms: D000818:Animals; D001717:Birds; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004260:DNA Repair; D004734:Energy Metabolism; D005347:Fibroblasts / Q000502:physiology; D020869:Gene Expression Profiling; D008136:Longevity; D008322:Mammals; D055432:Metabolomics
keywords: aging; cell biology; evolutionary biology; gene expression; genomics; human; lifespan; metabolite profiling; mouse; rat; rhesus macaque