Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity
Siming Ma,
Akhil Upneja,
Andrzej Galecki,
Yi-Miau Tsai,
Charles F Burant,
Sasha Raskind,
Quanwei Zhang,
Zhengdong D Zhang,
Andrei Seluanov,
Vera Gorbunova,
Clary B Clish,
Richard A Miller,
Vadim N Gladyshev
Affiliations
Siming Ma
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
Akhil Upneja
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
Andrzej Galecki
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
Yi-Miau Tsai
Department of Pathology, University of Michigan Medical School, Ann Arbor, United States; Geriatrics Center, University of Michigan Medical School, Ann Arbor, United States
Charles F Burant
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
Sasha Raskind
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States
Quanwei Zhang
Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
Zhengdong D Zhang
Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
Andrei Seluanov
Department of Biology, University of Rochester, Rochester, United States
Vera Gorbunova
Department of Biology, University of Rochester, Rochester, United States
Clary B Clish
Broad Institute, Cambridge, United States
Richard A Miller
Department of Pathology, University of Michigan Medical School, Ann Arbor, United States; Geriatrics Center, University of Michigan Medical School, Ann Arbor, United States
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.
