title: Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.
abstract: Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Price
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alvin J Y
authors.initials: AJ
authors.lastname: Ling
authors.affiliation: Department of Medical Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Javid J
authors.initials: JJ
authors.lastname: Moslehi
authors.affiliation: Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Magdalene K
authors.initials: MK
authors.lastname: Montgomery
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Rajman
authors.affiliation: Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: White
authors.affiliation: Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: João S
authors.initials: JS
authors.lastname: Teodoro
authors.affiliation: Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christiane D
authors.initials: CD
authors.lastname: Wrann
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Basil P
authors.initials: BP
authors.lastname: Hubbard
authors.affiliation: Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Evi M
authors.initials: EM
authors.lastname: Mercken
authors.affiliation: Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Palmeira
authors.affiliation: Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Anabela P
authors.initials: AP
authors.lastname: Rolo
authors.affiliation: Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Paul F. Glenn Laboratory for the Science of Aging, Cambridge, MA 02139, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.affiliation: Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia. Electronic address: david_sinclair@hms.harvard.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000473:pathology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D009243:NAD; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1